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WO2012079154A1 - Selective estrogen receptor modulators - Google Patents

Selective estrogen receptor modulators Download PDF

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Publication number
WO2012079154A1
WO2012079154A1 PCT/CA2011/001368 CA2011001368W WO2012079154A1 WO 2012079154 A1 WO2012079154 A1 WO 2012079154A1 CA 2011001368 W CA2011001368 W CA 2011001368W WO 2012079154 A1 WO2012079154 A1 WO 2012079154A1
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Prior art keywords
hydrogen
estrogen receptor
branched
straight
compound
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PCT/CA2011/001368
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French (fr)
Inventor
Amitabh Jha
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Dalhousie University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • E2 The steroid hormone 17P-estradiol (E2) plays an important role in the development and growth of the mammary gland during puberty, pregnancy, and lactation, as well as cell proliferation under both physiological and pathophysiological states. E2 exerts its biological responses by binding to two estrogen receptor (ER) subtypes, ERa and ER .
  • ER estrogen receptor
  • the first ER identified and the first to determine breast tumor ER status was named ERa, and the more recently isolated receptor named ERp.
  • Both ERa (595 amino acids) and ERp (530 amino acids) are members of the nuclear receptor superfamily. Although they are encoded by separate genes on different chromosomes, they have similar modular protein structures with considerable homology. Both receptors bind 17P-estradiol (E2) with the same affinity, but they can activate certain promoters differentially and on some promoters, ERp can behave as a negative modulator of ERa activity. In women, estrogen-dependent breast cancer and uterine cancer are two common cancers that appear to involve both ERa and ERp. Anti-estrogen compounds, such as tamoxifen, have commonly been used as chemotherapy to treat breast cancer patients.
  • Tamoxifen a dual antagonist and agonist of estrogen receptors, is beneficial in treating estrogen-dependent breast cancer.
  • treatment with tamoxifen is less than ideal because tamoxifen's agonist behavior enhances its unwanted estrogenic side effects.
  • men suffering from prostatic cancer can also benefit from anti-estrogen compounds.
  • Prostatic cancer is often endocrine-sensitive; androgen stimulation fosters tumor growth, while androgen suppression retards tumor growth.
  • the administration of estrogen is helpful in the treatment and control of prostatic cancer because estrogen administration lowers the level of gonadotropin and, consequently, androgen levels.
  • Selective estrogen receptor modulating compounds also find utility in the treatment of a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
  • the approved selective estrogen receptor modulators consist of two main chemical classes: the triphenylethylene derivatives and benzothiophene derivatives.
  • Selective estrogen receptor modulators approved by the Food and Drug Administration (FDA) and used in the treatment of breast cancer are tamoxifen and toremifene.
  • FDA Food and Drug Administration
  • Another selective estrogen receptor modulator, raloxifene is currently approved by the FDA for osteoporosis.
  • Tamoxifen has been associated with endometrial cancer due to its estrogenic activity within the uterus while raloxifene lacks estrogenic activity within the uterus. Nevertheless, tamoxifen is associated with serious side effects, such as negative vasomotor symptoms, and an increased risk of cataracts. In addition, tamoxifen has been associated with endometrial cancer and venous blood clots (Jordan 1998;
  • R2 and R3 are each independently hydrogen, OH, oxo, C 1 -8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Ql or Q2;
  • X is a branched or straight C I - 12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q I)2-, -C(Q2)2-, -CHQ1-, CHQ2-, -CO-, -CS- , -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, - SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-;
  • each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q3;
  • each Q3 is halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C 1 -C4 alkyl optionally substituted with 1-3 of halo, oxo, -CN, -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, -NH2, or -COOH; and
  • G and Gl are each independently a branched or straight CI -12 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1-, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, - NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-.
  • Rl is hydrogen, halo, -CN, -N02, -OH, -NH2, -C(0)0H, -C(0)H, -C(0)NH2 or a straight or branched Cl-8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Cl-4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-.
  • Rl is hydrogen, halo, -CN, -N02, -OH, -NH2, alkoxy, or -C(0)OH.
  • Rl is hydrogen, OH, methoxy, or NH2.
  • Rl is OH.
  • Rl is hydrogen.
  • Rl is methoxy.
  • R2 and R3 are each independently hydrogen, OH, oxo, or a straight or branched Cl-8 aliphatic, optionally substituted with 1-3 of Ql or Q2.
  • R2 and R3 are each independently hydrogen or a straight or branched Cl-8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Cl-4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-, wherein the aliphatic is optionally substituted with up to 3 of Ql, or Q2.
  • R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of Ql or Q2.
  • R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -N02, -OQ2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3.
  • R2 and R3 are each independently hydrogen or a straight or branched C 1-8 alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N02, -OQ2, -N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3.
  • R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen, Cl-4 alkyl, cycloalkyl, heterocycloalkyl or phenyl.
  • R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen or Cl- 4 alkyl.
  • R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with OH, or NH2.
  • R2 is hydrogen or a straight or branched C I -8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from Q3.
  • R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C1-C4 alkyl optionally substituted with 1-3 of halo, -CN, -N02, -CF3, -OCF3, -OH or -COOH.
  • R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or CI -C4 alkyl.
  • R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
  • R2 is an ethylene group which is substituted with -N(Q2)2, wherein Q2 is hydrogen or Cl-4 alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or Cl-C4 alkyl.
  • R2 is chosen from
  • R3 is hydrogen, OH, oxo, or a straight or branched Cl-5 alkyl group, which is optionally substituted with OH. In one embodiment, R3 is chosen from hydrogen, OH,
  • X is a branched or straight Cl-12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1-, -CHQ2-, -CO-, -CONQ2-, -C02-, -NQ2-, -0-, -S-, -S02- or -S02NQ2-.
  • X is a branched or straight C l-12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-.
  • X is a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, CI -4 alkyl, cycloaikyl or heterocycloalkyi.
  • X is a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or CI -4 alkyl.
  • X is -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or Cl-4 alkyl. In a further embodiment, X is -CH2-.
  • G and G 1 are each independently a branched or straight Cl- 12 aliphatic chain, or a heterocycloalkyi, wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1 -, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -0C0-, -NQ2-, - NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-.
  • G and Gl are each independently a branched or straight Cl -12 aliphatic chain, or a heterocycloalkyi, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-.
  • G and Gl are each independently a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, Cl-4 alkyl, cycloaikyl or heterocycloalkyi.
  • G and G l are each independently a branched or straight CI -5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or CI -4 alkyl.
  • G and G l are each independently CI -12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -0-, -N-, -S-, -S(0)-, -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or, wherein Q2 is hydrogen or CI -4 alkyl.
  • G and Gl are each independently -0-.
  • the invention is directed to a pharmaceutical composition which comprises 1 ) a compound of Formula 1 , optionally as a pharmaceutically acceptable salt or solvate or prodrug thereof and 2) a pharmaceutically acceptable carrier, excipient. or diluent.
  • a third aspect of the invention is a method for inhibiting the growth of a cancer cell or tumor, the method comprising administering to a subject in need thereof, a therapeutically effective amount of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof or pharmaceutical composition thereof.
  • the invention provides a method for treating a disease, disorder, or syndrome, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a method for treating a tumor, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate or prodrug thereof.
  • the tumor is directly or indirectly effected by hormonal and/or estrogen-related activity, including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyelocytic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.
  • hormonal and/or estrogen-related activity including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central
  • the compounds of Formula 1 may be used to treat a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
  • hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
  • FIG. 1 depicts a bar chart representing human ER binding affinity tested using ActiveMotif s NR Peptide ERa Colorimetric ELISA kit.
  • Estradiol (E2) 25 uM
  • Positive Agonist
  • Tamoxifen (TEM) 25 ⁇
  • Negative Antagonist
  • Control treated with 25 ⁇ tamoxifen.
  • Four compounds (lg (8), 2h (19), 3h (29), and 4h (149)) with potent cytotoxicity against MCF7 cells were assayed at 25 ⁇ and 2.5 ⁇ concentration. Numbers in parenthesis refer to the corresponding compound number as provided in Table 1.
  • the words "preferred” and “preferably” refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.
  • compositional percentages are by weight of the total composition, unless otherwise specified.
  • the word "include,” and its variants is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology.
  • the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.
  • Disclosure of values and ranges of values for specific parameters are not exclusive of other values and ranges of values useful herein. It is envisioned that two or more specific exemplified values for a given parameter may define endpoints for a range of values that may be claimed for the parameter. For example, if Parameter X is exemplified herein to have value A and also exemplified to have value Z, it is envisioned that parameter X may have a range of values from about A to about Z.
  • a substituent "R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
  • Acyl means a -C(0)R radical where R is alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, trifluoromethylcarbonyl, or 2- methoxyethylcarbonyl, and the like.
  • Acylamino means a -NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R' is acyl, as defined herein.
  • Acyloxy means an -OR radical where R is acyl, as defined herein, e.g. cyanomethylcarbonyloxy, and the like.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound of the compound into the system of the animal, for example, a human in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkenyl means a means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but-3-enyl, and l-pent-3-enyl, and the like.
  • Alkoxy means an -OR group where R is alkyl group as defined herein.
  • Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
  • Alkoxycarbonyl means a -C(0)R group where R is alkoxy, as defined herein.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or entyl (including all isomeric forms), and the like.
  • Alkylamino means an -NHR group where R is alkyl, as defined herein.
  • Alkylaminoalkyl means an alkyl group substituted with one or two alkylamino groups, as defined herein.
  • Alkylaminoalkyloxy means an -OR group where R is alkylaminoalkyl, as defined herein.
  • Alkylcarbonyl means a -C(0)R group where R is alkyl, as defined herein.
  • Alkylsufonyl means an -S(0)2R group where R is alkyl, as defined herein.
  • Alkylsulfonylalkyl means an alkyl group, as defined herein, substituted with at least one, preferably one or two, alkylsulfonyl groups, as defined herein.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
  • Amino means -NH2.
  • aminoalkyl means an alkyl group substituted with at least one, specifically one, two or three, amino groups.
  • aminoalkyloxy means an -OR group where R is aminoalkyl, as defined herein.
  • Aminocarbonyl means a -C(0)NH2 group.
  • Alkylaminocarbonyl means a -C(0)NHR group where R is alkyl as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.
  • Arylalkyl means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
  • Arylalkyloxy means an -OR group where R is arylakyl, as defined herein.
  • Cancer refers to cellular-proliferative disease states, tumors, primary malignant tumors, and other hyperproliferative cellular diseases or conditions, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Breast: ductal carcinoma in situ, infiltrating ductal carcinoma, medullary carcinoma, infiltrating lobular carcinoma, tubular carcinoma, mucinous carcinoma,
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and
  • Cyanoalkyl means an alkyl group, as defined herein, substituted with one or two cyano groups.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohex-3-enyl, or (lr,3r,5R,7R)-tricyclo[3.3.1.13,7]decan-2-yl, and the like.
  • Cycloalkylalkyl means an alkyl group substituted with at least one, specifically one or two, cycloalkyl group(s) as defined herein.
  • Dialkylainino means a -NRR' radical where R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, ⁇ , ⁇ -methylpropylamino or ⁇ , ⁇ -methylethylamino, and the like.
  • Dialkylaminoalkyl means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
  • Dialkylaminoalkyloxy means an -OR group where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy, and the like.
  • Dialkylaminocarbonyl means a -C(0)NRR' group where R and R' are alkyl as defined herein.
  • Halogen or "halo” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkoxy means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
  • Haloalkyl mean an alkyl group substituted with one or more halogens, specifically 1, 2, 3, 4, 5, or 6 halo atoms, e.g., trifiuoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the like.
  • the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1 ,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthaIazin-3-yl, phthalaziii-4-yl, pteridinyl, purinyl
  • Heteroarylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting.
  • Ry is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2- oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidin
  • Heterocycloalkylalkyl means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, and 3-(N-azetidinyl)propyl, and the like.
  • Heterocycloalkyloxy means an -OR group where R is heterocycloalkyl, as defined herein.
  • Hydroxyalkyl means an alkyl group, as defined herein, substituted with at least one, preferably 1 , 2, 3, or 4, hydroxy groups.
  • Phenylalkyl means an alkyl group, as defined herein, substituted with one or two phenyl groups.
  • Phenylalkyloxy means an -OR group where R is phenylalkyl, as defined herein.
  • Optionally substituted aryl means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
  • aryl is pentafluorophenyl.
  • alkyl and alkenyl either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted arylalkyl means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
  • Optionally substituted cycloalkyl means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently acyl, acyloxy, acylamino, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, or cyano.
  • alkyl and alkenyl are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalk l sul fonyl .
  • Optionally substituted cycloalkylalkyl means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
  • Optionally substituted heteroaryl means a heteroaryl group optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
  • heteroaryl the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted heteroarylalkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
  • Optionally substituted heterocycloalkyl means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, haloalkyl, alkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or phenylalkyl.
  • heterocycloalkyl the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted heterocycloalkyl alkyl means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein.
  • Optionally substituted phenyl means a phenyl group optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, or aminoalkoxy, or aryl is pentafluorophenyl.
  • the alkyl and alkenyl are independently optionally substituted with one, two, three, four, or five halo.
  • Optionally substituted phenylalkyl means an alkyl group, as defined herein, substituted with one or two optionally substituted phenyl groups, as defined herein.
  • Optionally substituted phenylsulfonyl means an -S(0)2R group where R is optionally substituted phenyl, as defined herein.
  • Oxo means an oxygen which is attached via a double bond.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • Patient and “Subject” are used interchangeably herein and for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in a more specific embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Specific salts arc the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • Preventing or "prevention” of a disease, disorder, or syndrome includes inhibiting the disease from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
  • Treatment as a prophylactic measure is also included.
  • Treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs and the like, surgery; radiation therapy; and gene therapy.
  • Co-administration or “combined administration” or the like as utilized herein are meant to include modes of administration of the selected active, therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • Co-administration can also include delivery of the active ingredients in a "fixed combination,” e.g. a compound of Formulae 1 , la-ln, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a chemotherapeutic agent, which are both administered to a patient simultaneously in the form of a single entity or dosage.
  • a fixed combination means that the active ingredients, e.g.
  • a Compound of Formula 1, l -ln, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a second active agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, such that the administration provides therapeutically effective levels of the combination of active agents in the body of the patient.
  • selective inhibitor compound refers to a compound that selectively inhibits a specific function/activity of one or more target proteins.
  • selectively inhibits refers to the ability of a selective inhibitor compound to inhibit a specific function/activity of a target protein (e.g., the phosphotransferase activity of a kinase) with greater potency than the activity of a non-target protein.
  • selectively inhibiting refers to inhibiting a target protein activity with a selective inhibitor that has a IC 50 that is at least 10, 50, 100, 250, 500, 1000 or more times lower than for that of a non-target protein activity.
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a compound that alters an activity of a molecule.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
  • an inhibitor completely prevents one or more activities of a molecule.
  • a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of an estrogen receptor activity, cell death of a target cancer cell, in an assay that measures such response.
  • IC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • the present invention relates to compounds useful as estrogen receptor modulators.
  • Compounds of the present invention are described by the following chemical Formula 1 :
  • R 2 and R 3 are each independently hydrogen, Ci 8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Qi or Q 2 ;
  • Ci_ ] 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,) 2 -, -C(Q 2 ) 2 -, -CHQ r , -CHQ 2 -, -CO-, -CS-, -CONQ 2 -, -C0 2 -, -OCO-, -NQ 2 -, -NQ 2 C0 2 -, -0-, -NQ 2 CONQ 2 -, -OCONQ 2 -, -NQ 2 CO-, -S-, -SO-, -S0 2 -, -S0 2 NQ 2 -, -NQ 2 S0 2 -, or -NQ 2 S0 2 NQ 2 -;
  • each Q 2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q 3 ;
  • each Q is halo, oxo, CN, N0 2 , CF 3 , OCF 3 , OH, -COOH or C,-C 4 alkyl optionally substituted with 1 -3 of halo, oxo, -CN, -N0 2 , -CF 3 , -OCF 3 , -OH, -SH, -S(0) 3 H, -NH 2 , or -COOH; and
  • are each independently a branched or straight C 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qj) 2 -, -C(Q 2 )2-, -CHQ r , -CHQ 2 -, -CO-, -CS-,
  • G and G are each independently a branched or straight C].
  • are each independently a branched or straight C._ 5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C0 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or alkyl.
  • G and G are each independently -0-, -N-, S-, -S(0)-, -CH 2 -, -CH 2 CH 2 -, -CO-, -CONH-, -C0 2 -, -NQ 2 - or, wherein Q 2 is hydrogen or Cj. 4 alkyl.
  • G and Gj are each independently -0-.
  • R is hydrogen, halo, -CN, -N0 2 , -OH, -NH 2 , -C(0)OH, -C(0)H, alkoxy, -C(0)NH 2 or a straight or branched Ci s aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(C aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-.
  • R is hydrogen, halo, alkoxy, -CN, -N0 2 , -OH, -NH 2 or -C(0)OH.
  • Ri is hydrogen, OH, methoxy, or NH 2 .
  • is OH.
  • Ri is hydrogen.
  • Rj is methoxy.
  • R 2 and R 3 are each independently hydrogen or a straight or branched Ci. 8 aliphatic, optionally substituted with 1-3 of Oj or Q 2 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched Ci. 8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Ci.
  • R 2 and R 3 are each independently hydrogen or a straight or branched C h alky I group, which is optionally substituted with up to 3 of Qj or Q 2 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched C,_ 8 alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -N0 2 , -OQ 2 , -N(Q 2 ) 2 , -C(0)OQ 2 , -C(0)-Q 2 , -C(0)N(Q 2 ) 2 , cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q 3 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched C[_ 8 alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N0 2 , -OQ 2 , -N(Q 2 ) 2 , cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Qj.
  • R 2 and R 3 are each independently hydrogen or a straight or branched C 1 8 alkyl group, which is optionally substituted with up to 3 of -OQ 2 , -N(Q 2 ) 2 , wherein Q 2 is hydrogen, C alkyl, cycloalkyl, heterocycloalkyl or phenyl.
  • R 2 and R 3 are each independently hydrogen or a straight or branched Ci_ 8 alkyl group, which is optionally substituted with up to 3 of OQ 2 , -N(Q 2 ) 2 , wherein Q 2 is hydrogen or Ci alkyl.
  • R 2 and R 3 are each independently hydrogen or a straight or branched C
  • R 3 is OH.
  • R 2 is hydrogen or a straight or branched C
  • R 2 is hydrogen or a straight or branched C !
  • S alkyl group which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including I -3 substituents independently selected from halo, oxo, CN, N0 2 , CF 3 , OCF 3 , OH, -COOH or C r C 4 alkyl optionally substituted with 1-3 of halo, -CN, -N0 2 , -CF 3 , -OCF 3 , -OH or - COOH.
  • R 2 is hydrogen or a straight or branched Ci_ 8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N0 2 , -CF 3 , -OCF 3 , -OH, -COOH or Ci-C 4 alkyl.
  • R 2 is hydrogen or a straight or branched C
  • R 2 is an ethylene group which is substituted with -N(Q 2 ) 2 , wherein Q 2 is hydrogen or C alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N0 2 , -CF 3 , -OCF 3 , -OH, -COOH or C r C 4 alkyl.
  • R 2 is chosen from:
  • R 3 is hydrogen, OH, or a straight or branched Ci_ 5 alkyl group, which is optionally substituted with oxo, or OH. In one embodiment, R 3 is chosen from hydrogen, OH,
  • X is a branched or straight Q. ⁇ aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi) 2 ⁇ , -C(Q 2 ) 2 -, -CHQ , -CHQ 2 -, -CO-, -CONQ 2 -, -CO 2 -, -NQ 2 -, -0-, -S-, -SO 2 - or -S0 2 NQ 2 -.
  • X is a branched or straight C M aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ 2 -, -C0 2 -, -NQ 2 - or -0-.
  • X is a branched or straight C
  • X is a branched or straight C ⁇ aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, - C0 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or C l 4 alkyl.
  • X is -CH 2 -, -CH 2 CH 2 -, -CO-, -CONH-, -CO 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or C]_ 4 alkyl.
  • X is -CH 2 -.
  • G and Gi are each independently a branched or straight C,_ 12 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CiQ ⁇ -, -C(Q 2 ) 2 -, -CHQ r , -CHQ 2 -, -CO-, -CS-, -CONQ 2 -, -C0 2 -, -OCO-, -NQ 2 -, -NQ 2 C0 2 -, -0-, -NQ 2 CONQ 2 -, -OCONQ 2 -, -NQ 2 CO-, -S-, -SO-, -S0 2 -, -SO,NQ 2 -, -NQ 2 S0 2 -, or -NQ 2 S0 2 NQ 2 -.
  • G and Gj are each independently a branched or straight C,_ [ 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ 2 -, -C0 2 -, -NQ 2 - or -0-.
  • G and Gj are each independently a branched or straight Ci_ 5 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ 2 -, -C0 2 -, -NQv or -0-, wherein Q 2 is hydrogen, C alkyl, cycloalkyi or heterocycloalkyl.
  • G and Gi are each independently a branched or straight C 1 .5 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C0 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or CM alkyl.
  • G and Gi are each independently a heterocycloalkyl or -0-.
  • G and Gi are each independently -0-, -N-, S-, -S(O)-, -CH 2 -, -CH 2 CH 2 -, -CO-, -CONH-, -CO 2 -, -NQ 2 - or, wherein Q 2 is hydrogen or CM alkyl.
  • G and G[ are each independently -0-.
  • R' H, OH or C I S alkoxy;
  • the compounds of Formula 1 and la in can also be provided as pharmaceutically acceptable salts, wherein a pharmaceutically acceptable salt can include a pharmaceutically acceptable acid addition salt of the compound.
  • the pharmaceutically acceptable acid addition salt can include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropiomc acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Specific base addition salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabaraine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, or intramuscular
  • buccal e.g., intranasal, rectal or transdermal administration routes.
  • intranasal e.g., transdermal administration routes.
  • the term "subject” is used to mean an animal, preferably a mammal, including a human or non-human. Subjects may also include laboratory animals, including mice, rats, guinea-pigs, rabbits and the like which are commonly used for scientific experimental studies, for veterinary use, for example, companion animals, and livestock.
  • the terms patient and subject may be used interchangeably.
  • compositions described herein which include a compound provided herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • aqueous oral dispersions liquids, gels, syrups, elixirs, slurries, suspensions and the like
  • solid oral dosage forms including but not limited to, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, drag
  • the invention provides pharmaceutical compositions comprising a selective estrogen receptor modulator compound of Formula 1, la-ln or
  • compositions comprising pharmaceutically acceptable salts, solvates or prodrugs thereof according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms Preble for simple administration of precise dosages.
  • compositions can be added to a conventional pharmaceutical carrier or excipient, among other inert substances useful in the delivery of the therapeutic active compound or compounds of the present invention.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, macrocrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules
  • a bulk blend composition e.g., tablets, effervescent tablets, and capsules
  • the particles of the compound provided herein are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, e.g., one or a combination of methods: ( I ) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachraan et al., The Theory and Practice of Industrial Pharmacy (1986).
  • Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • the pharmaceutical solid dosage forms described herein can include a compound provided herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a film coating is provided around the formulation of the compound provided herein.
  • some or all of the particles of the compound provided herein are coated.
  • some or all of the particles of the compound provided herein are microencapsulated.
  • the particles of the compound provided herein are not microencapsulated and are uncoated.
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • disintegrants are often used in the formulation, especially when the dosage forms are compressed with a binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac- Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrroli
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g.
  • binder levels of 20-70% can be used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • stearic acid calcium hydroxide, talc, corn
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and nitrocellulose (e.g., having a density of about 0.45 g/cm 5 , e.g. Avicel, powdered cellulose), and talc.
  • exemplary wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ⁇ ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E, TPGS and the like.
  • quaternary ammonium compounds e.g., Polyquat 10 ⁇
  • sodium oleate sodium lauryl sulfate
  • magnesium stearate sodium docusate
  • triacetin vitamin E, TPGS and the like.
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic®. (BASF), and the like.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suitable suspending agents for use in the solid dosage forms described herein can include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone 25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such
  • Optional excipients such as antioxidants, for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol tocopherol
  • one or more layers of the pharmaceutical formulation are plasticized.
  • a plasticizer can be used, being generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01 % to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above.
  • compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents.
  • the compressed tablets will include a film surrounding the final compressed tablet.
  • the film coating can provide a delayed release of the compound disclosed herein from the formulation.
  • the film coating aids in patient compliance (e.g., Opadry® coatings or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight.
  • the compressed tablets include one or more excipients.
  • solid dosage forms may include capsules.
  • a capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule.
  • the formulations non-aqueous suspensions and solutions
  • the formulations are placed in a soft gelatin capsule.
  • the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC.
  • the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating.
  • the therapeutic dose is split into multiple (e.g., two, three, or four) capsules.
  • the entire dose of the formulation is delivered in a capsule form.
  • particles, spheres, or pellets of the compound disclosed herein and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 20 minutes, within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
  • dosage forms may include microencapsulated formulations.
  • one or more other compatible materials are present in the microencapsulation material.
  • exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti- foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
  • Materials useful for the microencapsulation described herein include materials compatible with compounds disclosed herein, which sufficiently isolate the compound disclosed herein from other non-compatible exeipients. Materials compatible with compounds disclosed herein are those that delay the release of the compounds disclosed herein in vivo.
  • Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds disclosed herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry A
  • HPC
  • CMC carboxymethylcelluloses
  • CMC carboxymethylcelluloses
  • polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RDI00, Eudragit® EI00, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.
  • CMC carboxymethylcelluloses
  • sepifilms such as mixtures
  • certain plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material.
  • the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF).
  • the microencapsulation material is Klucel.
  • the microencapsulation material is methocel.
  • Microencapsulated compounds disclosed herein may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • spray drying processes spinning disk-solvent processes
  • hot melt processes hot melt processes
  • spray chilling methods fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath.
  • several chemical techniques e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used.
  • other methods such as roller compaction, ex
  • the particles of compounds disclosed herein are microencapsulated prior to being formulated into one of the above forms.
  • some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).
  • the solid dosage formulations of the compounds disclosed herein are plasticized (coated) with one or more layers.
  • a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition.
  • Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
  • a powder including the formulations with a compound disclosed herein may be formulated to include one or more pharmaceutical excipients and flavors.
  • a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi- dosage packaging units.
  • Effervescent powders are also prepared in accordance with the present disclosure.
  • Effervescent salts have been used to disperse medicines in water for oral administration.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid.
  • the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence.”
  • effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
  • the formulations described herein which include a compound disclosed herein, are solid dispersions.
  • Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Pub. Appl 2004/0013734, each of which is specifically incorporated by reference.
  • the formulations described herein are solid solutions.
  • Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which can be further formulated or directly added to a capsule or compressed into a tablet.
  • Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4, 151,273, 5,281 ,420, and 6,083,518, each of which is specifically incorporated by reference.
  • the pharmaceutical solid oral dosage forms which include a compound disclosed herein, can be further formulated to provide a controlled release of the compound disclosed herein.
  • Controlled release refers to the release of the compound disclosed herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • immediate release compositions controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
  • Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
  • the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract.
  • the enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • delayed release refers to the delivery of the active agent so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations.
  • the method for delay of release is by providing a delayed release coating. Any coating or plurality of coatings, should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract.
  • the polymers for use in the present invention are anionic carboxylic polymers.
  • the polymers and compatible mixtures thereof, and some of their properties include, but are not limited to: shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH>7; Acrylic polymers.
  • shellac also called purified lac
  • acrylic polymers The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers.
  • the Eudragit series E, L, S, RL, RS and NE are available as solubilized in organic solvent, aqueous dispersion, or dry powders.
  • the Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
  • the Eudragit series E dissolve in the stomach.
  • the Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine; Cellulose Derivatives.
  • suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution.
  • Aquateric dissolves in pH > 6.
  • Aquateric FMC
  • FMC Cellulose acetate phthalate
  • Other components in Aquateric can include pluronics. Tweens, and acetylated monoglycerides.
  • Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)).
  • HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable.
  • the performance can vary based on the degree and type of substitution.
  • suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
  • AS-LG LF
  • MF AS-MG
  • HF AS-HG
  • PVAP Poly Vinyl Acetate Phthalate
  • PVAP dissolves in pH > 5, and it is much less permeable to water vapor and gastric fluids.
  • the coating can contain a plasticizer and possibly other coating excipients such as colorants, talc, magnesium stearate, among others, which are well known in the art.
  • Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec ⁇ 2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
  • anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • coating techniques such as spray or pan coating are employed to apply coatings.
  • the coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.
  • Further optional excipients may include colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., camuba wax or PEG) may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
  • the formulations described herein which include a compound or its pharmaceutically acceptable salt, solvate or prodrug thereof disclosed herein, are delivered using a pulsatile dosage form.
  • a pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites.
  • Pulsatile dosage forms including the formulations described herein, which include a compound disclosed herein, may be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Pat. Nos.
  • the controlled release dosage form is pulsatile release solid oral dosage form including at least two groups of particles, (i.e. multiparticulate) each containing the formulation described herein.
  • the first group of particles provides a substantially immediate dose of the compound disclosed herein upon ingestion by a mammal.
  • the first group of particles can be either uncoated or include a coating and/or sealant.
  • the second group of particles includes coated particles, which includes from about 2% to about 75%, preferably from about 2.5% to about 70%, and more preferably from about 40% to about 70%, by weight of the total dose of the compound disclosed herein in said formulation, in admixture with one or more binders.
  • the coating includes a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of from about 1 hour to about 12 hours following ingestion before release of the second dose.
  • Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH sensitive coatings (enteric coatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S 100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, Eudragit® NE 40D®) either alone or blended with a cellulose derivative, e.g., ethylcellulose, or non-enteric coatings having variable thickness to provide differential release of the formulation that includes a compound disclosed herein.
  • enteric coatings such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S
  • Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 754-757 (2002).
  • the liquid dosage forms may include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent.
  • the aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 Ed., chapter 905), for at least 4 hours.
  • the homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than I minute.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds.
  • an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
  • Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel® , or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PHI05, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-
  • the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP;
  • hydroxypropylcellulose and hydroxypropyl cellulose ethers e.g., HPC, HPC-SL, and HPC- L
  • hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers e.g.
  • HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(l,l,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional
  • the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g.
  • HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(l ,1 ,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®).
  • Pluronics F68®, F88®, and F108® which are block copolymers of ethylene oxide and propylene oxide
  • wetting agents suitable for the aqueous suspensions and dispersions useful for the liquid dosage forms herein include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin,
  • suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.
  • suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon® S- 630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.
  • sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint
  • the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005% to about 0.5% the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01 % to about 1.0% the volume of the aqueous dispersion.
  • the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances,
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of at least one suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with the rest being at least one suitable pharmaceutical excipient.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).
  • the composition to be administered will, in any event, contain a therapeutically effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the present invention relates to a method of treating cancer in a mammalian subject (e.g., a human patient).
  • a mammalian subject e.g., a human patient
  • methods are provided for inhibiting tumor or cancerous cell growth.
  • Methods encompassed in the present invention comprises administering a dose of one or more of the compounds of Formulae 1 and la- I n such that the compound of Formulae 1 and la-ln, pharmaceutically acceptable salts, solvates or prodrugs thereof will contact the tumor or cancerous cells in vivo.
  • Therapeutically effective doses of any one or more of the compounds of Formulae 1 and 1 a- 1 n are administered to the patient in need of such therapy.
  • the present invention provides a method for treating a tumor, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formulae 1 , 1 a- 1 n, or a pharmaceutically acceptable salt or solvate or prodrug thereof.
  • the methods may be used to treat any cancer or tumor which may be either directly or indirectly effected by hormonal and/or estrogen-related activity, including but not limited to solid tumors associated with breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyeloc tic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia among others.
  • solid tumors associated with breast, pancreatic, lung, colon, prostate, ovarian cancers as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, test
  • compositions for example a pharmaceutical composition containing a therapeutically effective amount of at least one selective estrogen receptor modulator of Formula 1 or Formulas 1 a-ln, or pharmaceutically acceptable salts, solvate or prodrugs thereof, including any of the above-mentioned compounds of Table 1 , can be used to treat or inhibit the growth of an estrogen-receptor positive cancer or tumor, preferably, estrogen-receptor positive breast cancer.
  • a compound of Formulae 1, la- ln, or their pharmaceutically acceptable salts, solvates or prodrugs thereof may be used to treat a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet of the subject, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a subject in need thereof, at dosage levels in the range of about 0.1 to about 1 ,500 mg per day, for example, or from about 1 mg to about 1 ,250 mg, or from about 1 mg to about 1 ,000 mg, or from about 1 mg to about 750 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 1 ,500 mg, or from about 25 mg to about 1 ,500 mg, or from about 50 mg to about 1 ,500 mg, or from about 100 mg to about 1 ,500 mg, or from about 150 mg to about 1 ,500 mg, or from about 200 mg to about 1 ,500 mg, or from about 250 mg to about 1 ,500 mg, or from about 300 mg to about 1,500 mg, or from about 400 mg to about 1 ,500 mg, or from
  • an exemplary daily dosage amount of a compound, or their pharmaceutically acceptable salt, solvate or prodrug thereof of the present invention includes: 50 mg per day, 100, per day mg, 150 per day mg, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 450 mg per day, 500 mg per day, 750 mg per day, 1 ,000 mg per day, 1 ,250 mg per day, or 1 ,500 mg per day.
  • the daily dosage amount can include: from about 0.01 mg/kg/day to about 100 mg/kg/per day, or from about 0.01 mg/kg/day to about 75 mg/kg/per day, from about 0.01 mg/kg/day to about 50 mg/kg/per day, from about 0.01 mg/kg day to about 25 mg/kg/per day, from about 0.01 mg/kg/day to about 20 mg/kg/per day, from about 0.01 mg/kg/day to about 10 mg/kg/per day, from about 0.01 mg/kg/day to about 5 mg/kg/per day.
  • the specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the Compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the term "daily dosage amount” refers to the amount of the compounds of Formula 1 , la-l n, or their pharmaceutically acceptable salts, solvates or prodrugs thereof, per day that is administered or prescribed to a patient. This amount can be administered in multiple unit doses or in a single unit dose, in a single time during the day or at multiple times during the day.
  • unit dose may be taken to indicate a discrete amount of the therapeutic composition which comprises a predetermined amount of the active compound.
  • the amount of the compound of Formula 1 , or Formulas la- ln, or pharmaceutically acceptable salts, solvates or prodrugs thereof is generally equal to the dosage of the compound of the present invention which may be administered once per day, or may be administered several times a day (e.g. the unit dose is a fraction of the desired daily dose).
  • the unit dose may also be taken to indicate the total daily dosage amount, which may be administered once per day or may be administered as a convenient fraction of such a dose (e.g. the unit dose is the total daily dosage amount which may be given in fractional increments, such as, for example, one-half or one-third the dosage).
  • administration of the compounds of the present invention for treatment of various cancer states may comprise administration of a compound of Formulae 1, la- In, pharmaceutically acceptable salts, solvates or prodrugs thereof, their pharmaceutically acceptable salts, solvates or prodrugs thereof, in combination with other adjunct cancer therapies, such as chemotherapy, radiotherapy, gene therapy, hormone therapy and other cancer therapies known in the art.
  • Combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6 th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A physician, veterinarian or clinician of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such anti-cancer or chemotherapeutic agents include: anti-neoplastic agents.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms. Both types of antineoplastic agents may be employed in combination with the compounds of the present invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; nonreceptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • anti-microtubule agents such as diterpenoids and vinca alkaloids
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • diterpenoids include, but arc not limited to, paclitaxel and its analog docetaxel.
  • vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-neoplastic agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin, carboplatin, and oxaliplatin.
  • Alkylating agents are non-phase anti-neoplastic specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Antibiotic chemotherapeutic agents are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but arc not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Topoisomerase II inhibitors include, but are not limited to,
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cyclophosphamide, cytarabine, mercaptopurine and thioguanine.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)- 10, 1 1 -ethylenedioxy-20-camptothecin.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children;
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors
  • progestins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma
  • estrogens, androgens, and anti- androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy
  • other anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene useful in the treatment of hormone dependent breast carcinoma
  • the selective estrogen receptor modulator compound of the present invention is combined with a biological or a small molecule anti-breast cancer agent and administered as a combination treatment.
  • the compound of the present invention is co-administered with a biological anti-cancer agent, for example, a biological response modifier, for example, an interferon (e.g.
  • an interferon alpha, interferon beta, and interferon gamma an interleukin (for example, interleukin-2, -1 1 (IL-2, IL-1 1), a colony-stimulating factor (for example, G-CSF (filgrastim) and GM-CSF (sargramostim)), a monoclonal antibody (for example, Rituxan® (rituximab), Herceptin® (trastuzumab), Omnitarg® (pertuzumab), Avastin® (bevacizumab)), a vaccine, gene therapy, and nonspecific immunomodulating agents.
  • an interleukin for example, interleukin-2, -1 1 (IL-2, IL-1 1
  • a colony-stimulating factor for example, G-CSF (filgrastim) and GM-CSF (sargramostim)
  • a monoclonal antibody for example, Rituxan® (rituximab), Herceptin® (t
  • the compound of the present invention is co-administered with an inhibitor of: Epidermal Growth Factor Receptor, Her2, Her3, PI3 kinase, mammalian target of rapamycin (mTOR) intracellular pathway signalling (for example, everolimus), and other growth factor receptors.
  • mTOR mammalian target of rapamycin
  • a combination therapy comprising a compound of Table
  • 1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in a combination therapy with Herceptin (at a dosage amount of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks, or an initial dose of 8 mg kg over 90 minutes IV infusion, then 6 mg/kg over 30-90 minutes IV infusion every three weeks for 52 weeks, or an initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions, or an initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks).
  • Herceptin at a dosage amount of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks, or an initial dose of 8 mg kg over 90 minutes IV infusion, then 6 mg/kg over 30-90 minutes IV infusion every three weeks for 52 weeks, or an initial dose of 4 mg/kg as
  • a combination therapy comprising a compound of Table 1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in combination with docetaxel (at a daily dosage amount of 10 mg - 1 00mg).
  • a combination therapy comprising a compound of Table 1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in combination with docetaxel (at a daily dosage amount of 10 mg - 1500mg) and Herceptin (at a dose described above for Herceptin).
  • the additional anti-cancer or chemotherapeutic agents described above are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific additional anti-cancer or chemotherapeutic agent employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,500 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the additional anti-cancer or chemotherapeutic agent being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the additional anti-cancer or chemotherapeutic agent can be administered in a fixed dose with a compound of Formulae 1 , 1 a- 1 n, pharmaceutically acceptable salts, solvates or prodrugs thereof or may be administered as a separate dose, to be taken either with the compound of Formulae 1, la- In, pharmaceutically acceptable salts, solvates or prodrugs thereof simultaneously or at a different time, either before or after administration of the compound of Formulae 1 , 1 a- 1 n, pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml).
  • the solvent was evaporated under reduced pressure from the combined organic layer and the residue was purified by column chromatography over silica gel ( 10-15 % ethyl acetate in hexanes, v/v as eluent) to obtain 4- (2-bromoethoxy)benzaldehyde as a white solid, m.pt. 55-56 "C, 68 % yield (lit. m.pt. 55-58 °C; Nagarapu et al. J. Helerocycl. Chem., 2009, 46, 195-200).
  • reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml).
  • the solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 % methanol in dichloromethane, v/v as eluent) to afford the four aldehyde products as colorless oils in 62-63 % yield.
  • the structures of the products were unambiguously established from the analysis of their spectral data (IR, ⁇ NMR, l3 C NMR and mass spectra).
  • reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml).
  • the solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 % methanol in dichloromethane, v/v as eluent) to afford the six pure 4-dialkylaminoethoxybenzaldehydes as colorless oils in 49-92 % yields.
  • the structures of these products were unambiguously established from the analysis of their spectral data (IR, ⁇ NMR, l3 C NMR and mass spectra).
  • [4- ⁇ 2-(Diisopropylamino)ethoxy)phenyl]methanol The title compound was obtained as a colorless oil in 83%.
  • [4- ⁇ 2-(Piperidin-l-yl)ethoxy ⁇ phenyl]methanol The title compound was obtained as a colorless oil in 95% yield by following the general procedure outlined above.
  • [4- ⁇ 2-(4-Methylpiperidin-l-yl)ethoxy)phenyl]methanol The title compound was obtained as a colorless oil in 88 % yield.
  • [4- ⁇ 2-(Azepan-l-yl)ethoxy ⁇ phenyl]methanoI The title compound was obtained as a colorless oil in 82 % yield.
  • Example 2 General procedure for the synthesis of 2-((l-(4-(2- (dialkylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)ethanols (Compounds 11, 12, 14-19): To a solution of appropriate l-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalene-2-ol (1-10; 1.32 mmol), anhydrous K 2 C0 3 (5.3 mmol) in dimethylformamide was refluxed for 2 h.
  • reaction mixture was allowed cool down to the room temperature and catalytic amount of potassium iodide, followed by bromoethanol (5.3 mmol) was added and the reaction mixture was once again stirred and heated at 130°C for 20 h.
  • inorganic salts were filtered off, solvent was removed under reduced pressure.
  • the residue was taken in ethyl acetate and washed with 2N NaOH and water.
  • the organic layer was dried over anhydrous Na 2 S0 4 and the solvent was removed under reduced pressure and the resulting residue was purified by column chromatoghaphy over silica gel using methanol-dichloromethane (6-8%) as eluent to afford pure products as a light brown viscous oil
  • reaction was generally complete in 13-16 h. After the completion of reaction, the reaction mixture was suction filtered and the solvent was removed in-vacuo. The residue was taken in ethylacetate and washed with 2N NaOH and water. The organic layer was dried over anhydrous Na 2 S0 4 and the solvent was removed under reduced pressure and the resulting residue was purified by column chromatoghaphy over silica gel using methanol-dichloromethane (6-8%) as eluent to afford pure products as a light brown viscous oil 56-76% yield. The structures of the products were unambiguously established from the analysis of their spectral data (IR, ⁇ , "c NMR and mass spectra).
  • reaction After completion of the reaction, inorganic salts were filtered off, solvent was removed under reduced pressure and the crude reaction mixture was purified on silica gel using 2-6 % of methanol in dichloromethane. The reaction provided the products as brown colored solid or oil with yields ranging in 50-70%.
  • reaction mixture was extracted with ethyl acetae, dried over anhydrous sodium sulphate and concentrated.
  • the crude reaction mixture was purified on silica gel using 5-8% methanol in dichloromethane. The reaction provided the products in yields ranging in 50- 60%.
  • reaction mixture was quenched with aq. NH 4 C1 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, concentrated and purified on silica gel using 5-10 % methanol in dichloromethane.
  • reaction provides 55-70 % of yield.
  • the ethyl acetate layer was dried over anhydrous sodium sulfate.
  • the organic solvent was evaporated under reduced pressure to give the product as a light brown solid.
  • the crude product was purified on silica gel by using 8-15% of ethyl acetate in hexanes as eluent to get the product as white solid with 70%.
  • Prodrugs can be prepared by techniques known to one skilled in the art.
  • the methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • the compounds of the present invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the exemplified assay below involves the reduction of tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), in the presence of phenazinemesosulfate (PMS), to produce formazan.
  • MTS phenazinemesosulfate
  • the absorbance of formazan can be measured directly at 490 nm in a spectrophotometer.
  • the reduction of MTS is catalyzed by cellular dehydrogenases and can be used as a direct measure of cell viability when compared to control cells (Barltrop, J. A. et al.
  • the MTS assay was used to measure the viability of MCF-7, MDA-231 B,
  • MCF10A, and LNCaP cells in the presence of estrogen inhibitor compounds of the present invention as recited in Table 1, to determine their effect on cell viability by measuring the IC50 for each compound from Table 1 tested.
  • Cells were treated with the analogues and compounds at varying concentrations for a period of 4 days prior to performing the MTS assay. After 4 days, the MTS/PMS mixture was added directly to the cell culture medium. Formazan levels were measured at 490 nm and were compared to levels found in control cells not treated with the estrogen analogues and compounds to determine the effect of each compound on cell viability.
  • E denotes estrogen receptor.
  • Examples of activities (IC 50 ) of the compounds of Formulae 1, and la-ln on causing cell death in various cancer cell lines are shown above in Table 8.
  • Anti-cancer activity using the compounds and controls were measured using an IC 50 cell viability assay. Anti-cancer activity is illustrated with "+++++” if activity was measured to be less than 1 ⁇ , "++++” if activity was measured to be from 1 ⁇ to 10 ⁇ , “+++” if activity was measured to be from 1 1 ⁇ to 25 ⁇ , , "++” if activity was measured to be from 26 ⁇ to 50 ⁇ , "+” if activity was measured to be from 50 ⁇ to 100 ⁇ , "Inactive” if activity was measured to be greater than 100 ⁇ , and "-” if no data was available.
  • exemplary compounds from Table 1 tested appear to be antagonists and display better binding than tamoxifen at 25 ⁇ as shown in Figure 1.
  • a selective estrogen receptor modulator compound of Formula 1 is A selective estrogen receptor modulator compound of Formula 1
  • R 2 and R 3 are each independently hydrogen, OH, oxo, C]_ 8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q 2 ;
  • X is a branched or straight C 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,) 2 -, -C(Q 2 ) 2 -, -CHQ , -CHQ , -CO-, -CS-, -CONQ 2 -, -C0 2 -, - OCO-, -NQ , -NQ 2 C0 2 -, -0-, -NQ 2 CONQ 2 -, -OCONQ 2 -, -NQ 2 C0-, -S-, -SO-, -S0 2 -, -S0 2 NQ 2 -, -NQ 2 S0 2 -, or -NQ 2 S0 2 NQ 2 -;
  • each Q 2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q 3 ;
  • each Q 3 is halo, oxo, CN, N0 2 , CF 3 , OCF 3 , OH, -COOH or C,-C 4 alkyl optionally substituted with 1-3 of halo, oxo, -CN, -N0 2 , -CF 3 , -OCF 3 , -OH, -SH, -S(0) 3 H, -NH 2 , or -COOH; and
  • G and Gj are each independently a branched or straight C M2 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q,) 2 -, -C(Q 2 ) 2 -, -CHQr, -CHQ , -CO-, -CS-, -CONQ 2 -, -C0 2 -, -OCO-, -NQ 2 -, -NQ 2 C0 2 -, -0-, -NQjCONQj-, -OCONQ,-, -NQ 2 CO-, -S-, -SO-, -S0 2 -, -S0 2 NQ 2 -, -NQ 2 S0 2 -, or -NQ 2 S0 2 NQ 2 -.
  • R is hydrogen, OH, halo, -CN, -N(3 ⁇ 4, -OH, -NH 2 , -C(0)OH, -C(0)H, -C(0)NH 2 , alkoxy, or a straight or branched C,_ 8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(C,. 4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-.
  • R is hydrogen, OH, halo, methoxy, -CN, -N0 2 , -OH, -NH 2 or -C(0)OH.
  • R is hydrogen, OH or NH 2 .
  • R is OH.
  • is hydrogen.
  • Ri is methoxy.
  • R and R 3 are each independently hydrogen, OH, oxo, or a straight or branched Ci_ 8 aliphatic, optionally substituted with 1-3 of Qj or Q 2 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched Ci.g alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -NO,, -OQ,, -N(Q 2 ) 2 , -C(0)OQ 2 , -C(0)-Q 2 , -C(0)N(Q 2 ) 2 , cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1 -3 substituents independently selected from Q 3 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched C,n alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N0 2 , -OQ 2 , -N(Q 2 ) 2 , cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q 3 .
  • R 2 and R 3 are each independently hydrogen or a straight or branched Cj_ 8 alkyl group, which is optionally substituted with up to 3 of -OQ 2 , -N(Q 2 ) 2 , wherein Q 2 is hydrogen, Q-4 alkyl, cycloalkyl, helerocycloalkyl or phenyl.
  • R 2 and R 3 are each independently hydrogen or a straight or branched Ci_ 8 alkyl group, which is optionally substituted with up to 3 of -OQ , -N(Q 2 ) 2 , wherein Q 2 is hydrogen or C
  • R 2 and R 3 are each independently hydrogen, OH, oxo, or a straight or branched C l s alkyl group, which is optionally substituted with OH, or NH 2 .
  • the selective estrogen receptor modulator compound of embodiment 1 wherein R 2 is hydrogen or a straight or branched C
  • the selective estrogen receptor modulator compound of embodiment 1 wherein R 2 is hydrogen or a straight or branched C,_ s alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1 -3 substituents independently selected from halo, oxo, CN, N0 2 , CF 3 , OCF 3 , OH, -COOH or C C 4 alkyl optionally substituted with 1-3 of halo, - CN, -NO,, -CF 3 , -OCF3, -OH or -COOH.
  • R 2 is hydrogen or a straight or branched C 1 x alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N0 2 , -CF 3 , -OCF3, -OH, -COOH or C,-C 4 alkyl.
  • R 2 is hydrogen or a straight or branched C
  • R 2 is an ethylene group which is substituted with -N(Q 2 ) 2 , wherein Q 2 is hydrogen or Ci_t alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -NO2, -CF 3 , -OCF 3 , -OH, -COOH or C,-C 4 alkyl.
  • X is a branched or straight C,_
  • X is a branched or straight C
  • X is a branched or straight Ci_ 5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C0 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or Ciching 4 alkyl.
  • X is -CH r , -CH 2 CH r , -CO-, -CONH-, -C0 2 -, -NQ 2 - or -0-, wherein Q 2 is hydrogen or C l . 4 alkyl.
  • a method for inhibiting the growth of a cancer cell or tumor comprising administering to a subject in need thereof, a therapeutically effective amount of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof or pharmaceutical composition thereof.
  • a method for treating a disease, disorder, or syndrome comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • a method for treating a tumor comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, said tumor directly or indirectly effected by hormonal and/or estrogen-related activity, including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyelocytic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.
  • a method for treating a hormonal disorder in a patient in need thereof comprising, administering to said patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, wherein said hormonal disorder includes one or more of: osteoporosis, menopausal symptoms, acne, dysmenorrhea and dysfunctional uterine bleeding, hirsutism, hot flashes and cardiovascular disease.
  • a pharmaceutical composition comprising a therapeutically effective amount of a selective estrogen receptor modulator compound, wherein said selective estrogen receptor modulator compound is recited in Table 1.

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Abstract

The invention provides compounds of Formula (I) : wherein R1 is hydrogen, OH, halo, -CN, -NO2, -N=0, -NHOQ2, -OQ2, -SOQ2, -SO2Q2, -SON(Q2)2, - SO2N(Q2)2, -N(Q2)2, -C(O)OQ2, -C(O)Q2, -C(O)N(Q2)2, -C(=NQ2)NQ2, -NQ2C(=NQ2)NQ2, - C(O)N(Q2)(OQ2), -N(Q2)C(O)-Q2, -N(Q2)C(O)N(Q2)2, -N(Q2)C(O)O-Q2, -N(Q2)SO2Q2, -N(Q2)SOQ2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl ring optionally including 1-3 substituents independently selected Q3; R2 and R3 are each independently hydrogen, OH, oxo, aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Q1 or Q2; X is a branched or straight C1-12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, CHQ1, CHQ2-, -CO-, -CS-, -CONQ2, -CO2-, -OCO-, -NQ2-, -NQ2CO2-, - O-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -SO2-, -SO2NQ2-, -NQ2SO2-, or -NQ2SO2NQ2-; G and G1 are each independently a branched or straight C1-2 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, CHQ1, CHQ2-, -CO-, - CS-, -CONQ2, -CO2-, -OCO-, -NQ2-, -NQ2CO2-, -O-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, - SO2-, -SO2NQ2-, -NQ2SO2-, or -NQ2SO2NQ2-, and pharmaceutically acceptable salts, solvates or prodaigs thereof, as well as methods of treating estrogen receptor mediated diseases and disorders using the compounds of Formula (I).

Description

SELECTIVE ESTROGEN RECEPTOR MODULATORS
CROSS REFERENCE TO PRIOR APPLICATIONS
[0001 ] This Application claims the benefit of U.S. Provisional Application No.
61/422,914 filed on December 14, 2010, which is herein incorporated by reference in its entirety.
BACKGROUND
[0002] The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
[0003] The steroid hormone 17P-estradiol (E2) plays an important role in the development and growth of the mammary gland during puberty, pregnancy, and lactation, as well as cell proliferation under both physiological and pathophysiological states. E2 exerts its biological responses by binding to two estrogen receptor (ER) subtypes, ERa and ER . The discovery in the mid 1990's that there are two subtypes of ER, with different expression profiles in normal and malignant tissues, encouraged research into to the possibility that ER+ breast tumors display heterogeneous behaviors with respect to estrogen than originally supposed. The first ER identified and the first to determine breast tumor ER status was named ERa, and the more recently isolated receptor named ERp.
[0004] Both ERa (595 amino acids) and ERp (530 amino acids) are members of the nuclear receptor superfamily. Although they are encoded by separate genes on different chromosomes, they have similar modular protein structures with considerable homology. Both receptors bind 17P-estradiol (E2) with the same affinity, but they can activate certain promoters differentially and on some promoters, ERp can behave as a negative modulator of ERa activity. In women, estrogen-dependent breast cancer and uterine cancer are two common cancers that appear to involve both ERa and ERp. Anti-estrogen compounds, such as tamoxifen, have commonly been used as chemotherapy to treat breast cancer patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is beneficial in treating estrogen-dependent breast cancer. However, treatment with tamoxifen is less than ideal because tamoxifen's agonist behavior enhances its unwanted estrogenic side effects. In addition to post-menopausal women, men suffering from prostatic cancer can also benefit from anti-estrogen compounds. Prostatic cancer is often endocrine-sensitive; androgen stimulation fosters tumor growth, while androgen suppression retards tumor growth. The administration of estrogen is helpful in the treatment and control of prostatic cancer because estrogen administration lowers the level of gonadotropin and, consequently, androgen levels. Selective estrogen receptor modulating compounds also find utility in the treatment of a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease. [0005] Currently, the approved selective estrogen receptor modulators consist of two main chemical classes: the triphenylethylene derivatives and benzothiophene derivatives. Selective estrogen receptor modulators approved by the Food and Drug Administration (FDA) and used in the treatment of breast cancer, are tamoxifen and toremifene. Another selective estrogen receptor modulator, raloxifene is currently approved by the FDA for osteoporosis. Tamoxifen has been associated with endometrial cancer due to its estrogenic activity within the uterus while raloxifene lacks estrogenic activity within the uterus. Nevertheless, tamoxifen is associated with serious side effects, such as negative vasomotor symptoms, and an increased risk of cataracts. In addition, tamoxifen has been associated with endometrial cancer and venous blood clots (Jordan 1998;
MacGregor and Jordan 1998). Other negative side effects may include tumor resistance to tamoxifen (MacGregor and Jordan 1998).
[0006] What is needed are selective estrogen receptor modulating compounds that offer enhanced ERct selective antagonist activity concomitant with reduced estrogenic side effects.
SUMMARY
[0007] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and the references incorporated by reference, the express disclosure of this specification shall control.
[0008] In a first asp invention provides a compound of Formula 1
Figure imgf000003_0001
Formula 1
[0009] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
[0010] Rl is hydrogen, OH, halo, -CN, -N02, -N=0, -NHOQ2, -OQ2, -SOQ2, -
S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(0Q2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, - N(Q2)S02Q2, -N(Q2)S0Q2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl ring optionally including 1-3 substituents independently selected from Q3;
[0011 ] R2 and R3 are each independently hydrogen, OH, oxo, C 1 -8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Ql or Q2; [0012] X is a branched or straight C I - 12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q I)2-, -C(Q2)2-, -CHQ1-, CHQ2-, -CO-, -CS- , -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, - SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-;
[0013] each Ql is independently halo, oxo, -CN, -N02, -N=0, -NHOQ2, =NQ2,
=NOQ2, -OQ2, -SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02-Q2 -N(Q2)SO-Q2 or aliphatic optionally including 1-3 substituents independently selected from Q2 or Q3.
[0014] each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q3;
[0015] each Q3 is halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C 1 -C4 alkyl optionally substituted with 1-3 of halo, oxo, -CN, -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, -NH2, or -COOH; and
[0016] G and Gl are each independently a branched or straight CI -12 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1-, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, - NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-.
[0017] The variable Rl :
[0018] In one aspect, Rl is hydrogen, OH, halo, -CN, -N02, -N=0, -NHOH, -OH, -
N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl optionally including 1-3 substituents independently selected from Q3. In another embodiment, Rl is hydrogen, halo, -CN, -N02, -OH, -NH2, -C(0)0H, -C(0)H, -C(0)NH2 or a straight or branched Cl-8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Cl-4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-. In another embodiment, Rl is hydrogen, halo, -CN, -N02, -OH, -NH2, alkoxy, or -C(0)OH. In a further embodiment, Rl is hydrogen, OH, methoxy, or NH2. In still a further embodiment, Rl is OH. In another embodiment, Rl is hydrogen. In another embodiment, Rl is methoxy.
[0019] The variable R2 and R3 :
[0020] In one embodiment, R2 and R3 are each independently hydrogen, OH, oxo, or a straight or branched Cl-8 aliphatic, optionally substituted with 1-3 of Ql or Q2. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched Cl-8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Cl-4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-, wherein the aliphatic is optionally substituted with up to 3 of Ql, or Q2. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of Ql or Q2.
[0021 ] In one aspect, R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -N02, -OQ2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched C 1-8 alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N02, -OQ2, -N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3. In another aspect, R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen, Cl-4 alkyl, cycloalkyl, heterocycloalkyl or phenyl. In another aspect, R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen or Cl- 4 alkyl. In a further aspect, R2 and R3 are each independently hydrogen or a straight or branched CI -8 alkyl group, which is optionally substituted with OH, or NH2.
[0022] In one aspect, R2 is hydrogen or a straight or branched C I -8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from Q3. In another embodiment, R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C1-C4 alkyl optionally substituted with 1-3 of halo, -CN, -N02, -CF3, -OCF3, -OH or -COOH. In another embodiment, R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or CI -C4 alkyl. In a further embodiment, R2 is hydrogen or a straight or branched Cl-8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from methyl, ethyl, propyl, isopropyl or tert-butyl. In another embodiment, R2 is an ethylene group which is substituted with -N(Q2)2, wherein Q2 is hydrogen or Cl-4 alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or Cl-C4 alkyl.
[0023] In one embodiment, R2 is chosen from
Figure imgf000006_0001
[0024] In one embodiment, R3 is hydrogen, OH, oxo, or a straight or branched Cl-5 alkyl group, which is optionally substituted with OH. In one embodiment, R3 is chosen from hydrogen, OH,
O OH OH
[0025] The variable X:
[0026] In one embodiment, X is a branched or straight Cl-12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1-, -CHQ2-, -CO-, -CONQ2-, -C02-, -NQ2-, -0-, -S-, -S02- or -S02NQ2-. In another embodiment, X is a branched or straight C l-12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-. In another embodiment, X is a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, CI -4 alkyl, cycloaikyl or heterocycloalkyi. In another embodiment, X is a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or CI -4 alkyl. In one embodiment, X is -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or Cl-4 alkyl. In a further embodiment, X is -CH2-.
[0027] The vari able G and G I :
[0028] G and G 1 are each independently a branched or straight Cl- 12 aliphatic chain, or a heterocycloalkyi, wherein up to two carbon units are optionally and independently replaced by -C(Q1)2-, -C(Q2)2-, -CHQ1 -, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -0C0-, -NQ2-, - NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-.
[0029] In another embodiment, G and Gl are each independently a branched or straight Cl -12 aliphatic chain, or a heterocycloalkyi, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-. In another embodiment, G and Gl are each independently a branched or straight Cl-5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, Cl-4 alkyl, cycloaikyl or heterocycloalkyi. In another embodiment, G and G l are each independently a branched or straight CI -5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or CI -4 alkyl. In one embodiment, G and G l are each independently CI -12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -0-, -N-, -S-, -S(0)-, -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or, wherein Q2 is hydrogen or CI -4 alkyl. In a further embodiment, G and Gl are each independently -0-.
[0030] In a second aspect, the invention is directed to a pharmaceutical composition which comprises 1 ) a compound of Formula 1 , optionally as a pharmaceutically acceptable salt or solvate or prodrug thereof and 2) a pharmaceutically acceptable carrier, excipient. or diluent.
[0031 ] In a third aspect of the invention is a method for inhibiting the growth of a cancer cell or tumor, the method comprising administering to a subject in need thereof, a therapeutically effective amount of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof or pharmaceutical composition thereof.
[0032] In a fourth aspect, the invention provides a method for treating a disease, disorder, or syndrome, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
[0033] In a fifth aspect, the present invention provides a method for treating a tumor, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate or prodrug thereof. In this aspect the tumor is directly or indirectly effected by hormonal and/or estrogen-related activity, including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyelocytic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.
[0034] In a sixth aspect, the compounds of Formula 1 may be used to treat a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
[0035] Further areas of applicability will become apparent from the description provided herein. It should be understood that the description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.
DRAWINGS
[0036] The drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure in any way.
[0037] FIG. 1 depicts a bar chart representing human ER binding affinity tested using ActiveMotif s NR Peptide ERa Colorimetric ELISA kit. Estradiol (E2) (25 uM): Positive (Agonist) Control treated with 25 μΜ estradiol; Tamoxifen (TEM) (25 μΜ): Negative (Antagonist) Control treated with 25 μΜ tamoxifen. Four compounds (lg (8), 2h (19), 3h (29), and 4h (149)) with potent cytotoxicity against MCF7 cells were assayed at 25 μΜ and 2.5 μΜ concentration. Numbers in parenthesis refer to the corresponding compound number as provided in Table 1.
DETAILED DESCRIPTION
[0038] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.
[0039] The following description of technology is merely exemplary in nature of the subject matter, manufacture and use of one or more inventions, and is not intended to limit the scope, application, or uses of any specific invention claimed in this application or in such other applications as may be filed claiming priority to this application, or patents issuing therefrom. The following definitions and non-limiting guidelines must be considered in reviewing the description of the technology set forth herein.
[0040] The headings (such as "Introduction" and "Summary") and sub-headings used herein are intended only for general organization of topics within the present technology, and are not intended to limit the disclosure of the present technology or any aspect thereof. In particular, subject matter disclosed in the "Introduction" may include novel technology and may not constitute a recitation of prior art. Subject matter disclosed in the "Summary" is not an exhaustive or complete disclosure of the entire scope of the technology or any embodiments thereof. Classification or discussion of a material within a section of this specification as having a particular utility is made for convenience, and no inference should be drawn that the material must necessarily or solely function in accordance with its classification herein when it is used in any given composition.
[0041 ] The citation of references herein does not constitute an admission that those references are prior art or have any relevance to the patentability of the technology disclosed herein. Any discussion of the content of references cited in the Introduction is intended merely to provide a general summary of assertions made by the authors of the references, and does not constitute an admission as to the accuracy of the content of such references. All references cited in the
"Description" section of this specification are hereby incorporated by reference in their entirety.
[0042] The description and specific examples, while indicating embodiments of the technology, are intended for purposes of illustration only and are not intended to limit the scope of the technology. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features, or other embodiments incorporating different combinations of the stated features. Specific examples are provided for illustrative purposes of how to make and use the compositions and methods of this technology and, unless explicitly stated otherwise, are not intended to be a representation that given embodiments of this technology have, or have not, been made or tested.
[0043] As used herein, the words "preferred" and "preferably" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.
[0044] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word "include," and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.
[0045] Disclosure of values and ranges of values for specific parameters (such as temperatures, molecular weights, weight percentages, etc.) are not exclusive of other values and ranges of values useful herein. It is envisioned that two or more specific exemplified values for a given parameter may define endpoints for a range of values that may be claimed for the parameter. For example, if Parameter X is exemplified herein to have value A and also exemplified to have value Z, it is envisioned that parameter X may have a range of values from about A to about Z. Similarly, it is envisioned that disclosure of two or more ranges of values for a parameter (whether such ranges are nested, overlapping or distinct) subsume all possible combination of ranges for the value that might be claimed using endpoints of the disclosed ranges. For example, if parameter X is exemplified herein to have values in the range of 1 - 10, or 2 - 9, or 3 - 8, it is also envisioned that Parameter X may have other ranges of values including 1 - 9, 1 - 8, 1 - 3, 1 - 2, 2 - 10, 2 - 8, 2 - 3, 3 - 10, and 3 - 9.
[0046] Although the open-ended term "comprising," as a synonym of terms such as including, containing, or having, is use herein to describe and claim the present invention, the invention, or embodiments thereof, may alternatively be described using more limiting terms such as "consisting of or "consisting essentially of the recited ingredients.
DEFINITIONS
[0047] The symbol "-" means a single bond, "=" means a double bond, "≡" means a triple bond, " " means a single or double bond. The symbol ">ΛΛΛ;" refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted removed from its parent Formula , the "--^" symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural Formula .
[0048] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual Formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH2CH2-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.
Figure imgf000010_0001
[0049] If a group "R" is depicted as "floating" on a ring system, as for example in the Formula :
Figure imgf000010_0002
[0050] then, unless otherwise defined, a substituent "R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
[0051 ] If a group "R" is depicted as floating on a fused or bridged ring system, as for example in the Formula e:
Figure imgf000010_0003
[0052] then, unless otherwise defined, a substituent "R" may reside on any atom of the fused or bridged ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the Formula above), implied hydrogen (for example as in the Formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the Formula above, "Z" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
[0053] When a group "R" is depicted as existing on a ring system containing saturated carbons, as for example in the Formula : [0054] where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. In another example, two R's on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring structure with the depicted ring as for example in the Formula :
Figure imgf000011_0001
[0055] "Acyl" means a -C(0)R radical where R is alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g., acetyl, trifluoromethylcarbonyl, or 2- methoxyethylcarbonyl, and the like.
[0056] "Acylamino" means a -NRR' radical where R is hydrogen, hydroxy, alkyl, or alkoxy and R' is acyl, as defined herein.
[0057] "Acyloxy" means an -OR radical where R is acyl, as defined herein, e.g. cyanomethylcarbonyloxy, and the like.
[0058] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound of the compound into the system of the animal, for example, a human in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0059] "Alkenyl" means a means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but-3-enyl, and l-pent-3-enyl, and the like.
[0060] "Alkoxy" means an -OR group where R is alkyl group as defined herein.
Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.
[0061] "Alkoxyalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like.
[0062] "Alkoxycarbonyl" means a -C(0)R group where R is alkoxy, as defined herein.
[0063] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or entyl (including all isomeric forms), and the like.
[0064] "Alkylamino" means an -NHR group where R is alkyl, as defined herein.
[0065] "Alkylaminoalkyl" means an alkyl group substituted with one or two alkylamino groups, as defined herein.
[0066] "Alkylaminoalkyloxy" means an -OR group where R is alkylaminoalkyl, as defined herein.
[0067] "Alkylcarbonyl" means a -C(0)R group where R is alkyl, as defined herein.
[0068] "Alkylsufonyl" means an -S(0)2R group where R is alkyl, as defined herein.
[0069] "Alkylsulfonylalkyl" means an alkyl group, as defined herein, substituted with at least one, preferably one or two, alkylsulfonyl groups, as defined herein.
[0070] "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one triple bond, e.g., ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
[0071] "Amino" means -NH2.
[0072] "Aminoalkyl" means an alkyl group substituted with at least one, specifically one, two or three, amino groups.
[0073] "Aminoalkyloxy" means an -OR group where R is aminoalkyl, as defined herein.
[0074] "Aminocarbonyl" means a -C(0)NH2 group.
[0075] "Alkylaminocarbonyl" means a -C(0)NHR group where R is alkyl as defined herein.
[0076] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like.
[0077] "Arylalkyl" means an alkyl radical, as defined herein, substituted with one or two aryl groups, as defined herein, e.g., benzyl and phenethyl, and the like.
[0078] "Arylalkyloxy" means an -OR group where R is arylakyl, as defined herein.
[0079] "Cancer" refers to cellular-proliferative disease states, tumors, primary malignant tumors, and other hyperproliferative cellular diseases or conditions, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Breast: ductal carcinoma in situ, infiltrating ductal carcinoma, medullary carcinoma, infiltrating lobular carcinoma, tubular carcinoma, mucinous carcinoma, inflammatory breast cancer;
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver, hepatoma (hepatocellular carcinoma), cholangiocarciiioma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa- thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancer cell", "cancerous cell", "tumor" or" tumor cell" as provided herein, includes a cell or group of cells afflicted by, or synonymous with, any one of the above-identified cancer conditions.
[0080] "Cyanoalkyl" means an alkyl group, as defined herein, substituted with one or two cyano groups.
[0081] "Cycloalkyl" means a monocyclic or fused or bridged bicyclic or tricyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. More specifically, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohex-3-enyl, or (lr,3r,5R,7R)-tricyclo[3.3.1.13,7]decan-2-yl, and the like.
[0082] "Cycloalkylalkyl" means an alkyl group substituted with at least one, specifically one or two, cycloalkyl group(s) as defined herein.
[0083] "Dialkylainino" means a -NRR' radical where R and R' are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, Ν,Ν-methylpropylamino or Ν,Ν-methylethylamino, and the like.
[0084] "Dialkylaminoalkyl" means an alkyl group substituted with one or two dialkylamino groups, as defined herein.
[0085] "Dialkylaminoalkyloxy" means an -OR group where R is dialkylaminoalkyl, as defined herein. Representative examples include 2-(N,N-diethylamino)-ethyloxy, and the like.
[0086] "Dialkylaminocarbonyl" means a -C(0)NRR' group where R and R' are alkyl as defined herein.
[0087] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
[0088] "Haloalkoxy" means an -OR' group where R' is haloalkyl as defined herein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.
[0089] "Haloalkyl" mean an alkyl group substituted with one or more halogens, specifically 1, 2, 3, 4, 5, or 6 halo atoms, e.g., trifiuoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the like.
[0090] "Heteroaryl" means a monocyclic or fused or bridged bicyclic monovalent radical of 5 to 14 ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms where each heteroatom is independently N, O, S, -S(0)n- (n is 0, 1 , or 2), -NH-, -N=, or N-oxide, with the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising the bicyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic radical may be replaced by a -C(O)-, - C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1 ,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthaIazin-3-yl, phthalaziii-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin- 6-yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, 2,3-dihydrobenzofuranyl,
benzo[d][l,3]dioxolyl, 2,3-dihydrobenzo|b]ll,4Jdioxinyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, or N-oxide or a protected derivative thereof. The term "5- or 6-membered heteroaryl" describes a subset of the term "heteroaryl."
[0091] "Heteroarylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two heteroaryl group(s), as defined herein.
[0092] "Heterocycloalkyl" means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused or bridged, bicyclic or tricyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms where each heteroatom is independently N, O, S, S(0)n (n is 0, 1 , or 2), -N=, or -NH-, the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2- oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, (3aR,6aS)-5-methyloctahydrocyclopenta[cJpyrrolyl, and (3aS,6aR)-5-methyl-l ,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl, and the derivatives thereof and N-oxide or a protected derivative thereof.
[0093] "Heterocycloalkylalkyl" means an alkyl radical, as defined herein, substituted with one or two heterocycloalkyl groups, as defined herein, e.g., morpholinylmethyl, N-pyrrolidinylethyl, and 3-(N-azetidinyl)propyl, and the like.
[0094] "Heterocycloalkyloxy" means an -OR group where R is heterocycloalkyl, as defined herein.
[0095] "Hydroxyalkyl" means an alkyl group, as defined herein, substituted with at least one, preferably 1 , 2, 3, or 4, hydroxy groups.
[0096] "Phenylalkyl" means an alkyl group, as defined herein, substituted with one or two phenyl groups.
[0097] "Phenylalkyloxy" means an -OR group where R is phenylalkyl, as defined herein.
[0098] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, unless stated otherwise. A list of exemplary optional substitutions is presented below in the definition of "substituted."
[0099] "Optionally substituted aryl" means an aryl group, as defined herein, optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
dialkylaminosulfonyl, alkylsulfonylamino, or aminoalkoxy; or aryl is pentafluorophenyl. Within the optional substituents on "aryl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[00100] "Optionally substituted arylalkyl" means an alkyl group, as defined herein, substituted with optionally substituted aryl, as defined herein.
[00101 ] "Optionally substituted cycloalkyl" means a cycloalkyl group, as defined herein, substituted with one, two, or three groups independently acyl, acyloxy, acylamino, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, carboxy, or cyano. Within the above optional substituents on "cycloalkyl", the alkyl and alkenyl,, either alone or as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e.g. haloalkyl, haloalkoxy, haloalkenyloxy, or haloalk l sul fonyl .
[00102] "Optionally substituted cycloalkylalkyl" means an alkyl group substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined herein.
[00103] "Optionally substituted heteroaryl" means a heteroaryl group optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, or dialkylaminoalkoxy. Within the optional substituents on "heteroaryl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo. [00104] "Optionally substituted heteroarylalkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heteroaryl group(s), as defined herein.
[00105] "Optionally substituted heterocycloalkyl" means a heterocycloalkyl group, as defined herein, optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, haloalkyl, alkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or phenylalkyl. Within the optional substituents on "heterocycloalkyl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[00106] "Optionally substituted heterocycloalkyl alkyl" means an alkyl group, as defined herein, substituted with at least one, specifically one or two, optionally substituted heterocycloalkyl group(s) as defined herein.
[00107] "Optionally substituted phenyl" means a phenyl group optionally substituted with one, two, or three substituents independently acyl, acylamino, acyloxy, alkyl, haloalkyl, alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, or aminoalkoxy, or aryl is pentafluorophenyl. Within the optional substituents on "phenyl", the alkyl and alkenyl, either alone or as part of another group (including, for example, the alkyl in alkoxycarbonyl), are independently optionally substituted with one, two, three, four, or five halo.
[00108] "Optionally substituted phenylalkyl" means an alkyl group, as defined herein, substituted with one or two optionally substituted phenyl groups, as defined herein.
[00109] "Optionally substituted phenylsulfonyl" means an -S(0)2R group where R is optionally substituted phenyl, as defined herein.
[00110] "Oxo" means an oxygen which is attached via a double bond.
[00111] "Yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.
[00112] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
[00113] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
[00114] "Patient" and "Subject" are used interchangeably herein and for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a specific embodiment the patient is a mammal, and in a more specific embodiment the patient is human.
[00115] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.
[00116] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like.
[00117] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Specific salts arc the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[00118] "Therapeutically effective amount" is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
[00119] "Preventing" or "prevention" of a disease, disorder, or syndrome includes inhibiting the disease from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
[00120] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art. Treatment as a prophylactic measure is also included. Treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs and the like, surgery; radiation therapy; and gene therapy.
[00121 ] "Co-administration" or "combined administration" or the like as utilized herein are meant to include modes of administration of the selected active, therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Co-administration can also include delivery of the active ingredients in a "fixed combination," e.g. a compound of Formulae 1 , la-ln, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a chemotherapeutic agent, which are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a Compound of Formula 1, l -ln, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a second active agent, for example, a chemotherapeutic agent as exemplified below, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, such that the administration provides therapeutically effective levels of the combination of active agents in the body of the patient.
[00122] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
[00123] As used herein, the term "selective inhibitor compound" refers to a compound that selectively inhibits a specific function/activity of one or more target proteins.
[00124] As used herein, the term "selectively inhibits" refers to the ability of a selective inhibitor compound to inhibit a specific function/activity of a target protein (e.g., the phosphotransferase activity of a kinase) with greater potency than the activity of a non-target protein. In certain embodiments, selectively inhibiting refers to inhibiting a target protein activity with a selective inhibitor that has a IC50 that is at least 10, 50, 100, 250, 500, 1000 or more times lower than for that of a non-target protein activity.
[00125] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
[00126] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. [00127] As used herein, the term "modulator" refers to a compound that alters an activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.
[00128] As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity.
[00129] As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of an estrogen receptor activity, cell death of a target cancer cell, in an assay that measures such response.
[00130] As used herein, IC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
[00131 ] The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
COMPOUNDS
[00132] The present invention relates to compounds useful as estrogen receptor modulators. Compounds of the present invention are described by the following chemical Formula 1 :
Figure imgf000021_0001
Formula 1
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
R, is hydrogen, halo, OH, -CN, -N02, -N=0, -NHOQ2, -OQ2, -SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ,C(=NQ2)NQ2-, - C(0)N(Q2)(0Q2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02Q2, -N(Q2)S0Q2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl ring optionally including 1 -3 substituents independently selected from Q3;
R2 and R3 are each independently hydrogen, Ci 8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Qi or Q2;
X is a branched or straight Ci_] 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQr, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-;
each Qi is independently halo, oxo, -CN, -N02, -N=0, -NHOQ2, =NQ2, =NOQ2, -OQ2, -SOQ2, - S02Q2, -SON(Q2)2, -S02N(Q2) , -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(0Q2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, - N(Q2)S02-Q2 -N(Q2)SO-Q2 or aliphatic optionally including 1-3 substituents independently selected from Q2 or Q3.
each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q3;
each Q, is halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C,-C4 alkyl optionally substituted with 1 -3 of halo, oxo, -CN, -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, -NH2, or -COOH; and
G and G| are each independently a branched or straight C 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qj)2-, -C(Q2)2-, -CHQr, -CHQ2-, -CO-, -CS-,
-CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ , -NQ2CO-, -S-, -
SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-. In some embodiments,
G and G , are each independently a branched or straight C].|2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-. In another embodiment, G and G, are each independently a branched or straight C].5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ , -C02-, -NQ2- or - 0-, wherein Q2 is hydrogen, C1.4 alkyl, cycloalkyl or heterocycloalkyl. In another embodiment, G and G| are each independently a branched or straight C._5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or alkyl. In one embodiment, G and G, are each independently -0-, -N-, S-, -S(0)-, -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or, wherein Q2 is hydrogen or Cj.4 alkyl. In a further embodiment, G and Gj are each independently -0-.
[00133] The variable R,:
[00134] In one embodiment, Rj is hydrogen, halo, -CN, -N02, -N=0, -NHOH, -OH, -
N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl optionally including 1-3 substituents independently selected from Q3. In another embodiment, R, is hydrogen, halo, -CN, -N02, -OH, -NH2, -C(0)OH, -C(0)H, alkoxy, -C(0)NH2 or a straight or branched Ci s aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(C aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-. In another embodiment, R, is hydrogen, halo, alkoxy, -CN, -N02, -OH, -NH2 or -C(0)OH. In a further embodiment, Ri is hydrogen, OH, methoxy, or NH2. In still a further embodiment, R| is OH. In another embodiment, Ri is hydrogen. In another embodiment, Rj is methoxy.
[00135] The variable R2 and R3:
[00136] In one embodiment, R2 and R3 are each independently hydrogen or a straight or branched Ci.8 aliphatic, optionally substituted with 1-3 of Oj or Q2. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched Ci.8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(Ci.4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-, wherein the aliphatic is optionally substituted with up to 3 of Qh or Q2 In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched Chalky I group, which is optionally substituted with up to 3 of Qj or Q2.
[00137] In one embodiment, R2 and R3 are each independently hydrogen or a straight or branched C,_8 alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -N02, -OQ2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched C[_8 alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N02, -OQ2, -N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Qj. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched C1 8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen, C alkyl, cycloalkyl, heterocycloalkyl or phenyl. In another embodiment, R2 and R3 are each independently hydrogen or a straight or branched Ci_8 alkyl group, which is optionally substituted with up to 3 of OQ2, -N(Q2)2, wherein Q2 is hydrogen or Ci alkyl. In a further embodiment, R2 and R3 are each independently hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with OH, or NH2. In one embodiment, R3 is OH.
[00138] In one embodiment, R2 is hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from Q3. In another embodiment, R2 is hydrogen or a straight or branched C! S alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including I -3 substituents independently selected from halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or CrC4 alkyl optionally substituted with 1-3 of halo, -CN, -N02, -CF3, -OCF3, -OH or - COOH. In another embodiment, R2 is hydrogen or a straight or branched Ci_8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or Ci-C4 alkyl. In a further embodiment, R2 is hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from methyl, ethyl, propyl, isopropyl or /ert-butyl. In another embodiment, R2 is an ethylene group which is substituted with -N(Q2)2, wherein Q2 is hydrogen or C alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or CrC4 alkyl.
[00139] In one embodiment, R2 is chosen from:
Figure imgf000024_0001
[00140] In one embodiment, R3 is hydrogen, OH, or a straight or branched Ci_5 alkyl group, which is optionally substituted with oxo, or OH. In one embodiment, R3 is chosen from hydrogen, OH,
Figure imgf000024_0002
[00141] The variable X:
[00142] In one embodiment, X is a branched or straight Q.^ aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2~, -C(Q2)2-, -CHQ , -CHQ2-, -CO-, -CONQ2-, -CO2-, -NQ2-, -0-, -S-, -SO2- or -S02NQ2-. In another embodiment, X is a branched or straight CM aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-. In another embodiment, X is a branched or straight C|_5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, CH alkyl, cycloalkyl or heterocycloalkyl. In another embodiment, X is a branched or straight C^ aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, - C02-, -NQ2- or -0-, wherein Q2 is hydrogen or Cl 4 alkyl. In one embodiment, X is -CH2-, -CH2CH2-, -CO-, -CONH-, -CO2-, -NQ2- or -0-, wherein Q2 is hydrogen or C]_4 alkyl. In a further embodiment, X is -CH2-.
[00143] The variable G and G , :
[00144] In some embodiments, G and Gi are each independently a branched or straight C,_12 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CiQ^-, -C(Q2)2-, -CHQr, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -SO,NQ2-, -NQ2S02-, or -NQ2S02NQ2-. In another embodiment, G and Gj are each independently a branched or straight C,_ [2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-. In another embodiment, G and Gj are each independently a branched or straight Ci_5 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQv or -0-, wherein Q2 is hydrogen, C alkyl, cycloalkyi or heterocycloalkyl. In another embodiment, G and Gi are each independently a branched or straight C1.5 aliphatic chain, or a heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or CM alkyl. In one embodiment, G and Gi are each independently a heterocycloalkyl or -0-. In one embodiment, G and Gi are each independently -0-, -N-, S-, -S(O)-, -CH2-, -CH2CH2-, -CO-, -CONH-, -CO2-, -NQ2- or, wherein Q2 is hydrogen or CM alkyl. In a further embodiment, G and G[ are each independently -0-.
[00145] In some embodiments, compounds of the present invention are described by the following chemical Formula la:
Figure imgf000025_0001
Formula la
Ra
wherein Rb is
Figure imgf000025_0002
[00146] In some embodiments, compounds of the present invention are described by the following chemical Formula lb:
Figure imgf000025_0003
Formula l b
Figure imgf000025_0004
[00147] In some embodiments, compounds of the present invention are described by the following chemical Formula lc:
Figure imgf000026_0001
Formula lc
Figure imgf000026_0002
[00148] In some embodiments, compounds of the present invention are described by
Figure imgf000026_0003
[00149] In some embodiments, compounds of the present invention are described by
Figure imgf000026_0004
wherein ^ is
Figure imgf000027_0001
[00150] In some embodiments, compounds of the present invention are described by
Figure imgf000027_0002
[00151 ] In some embodiments, compounds of the present invention are described by the following chemical Formula lg:
Figure imgf000027_0003
[00152] In some embodiments, compounds of the present invention are described by the following chemical Formula Ih:
Figure imgf000028_0001
[00153] In some embodiments, compounds of the present invention are described by the following chemical Formula li:
Figure imgf000028_0002
[00154] In some embodiments, compounds of the present invention are described by the following chemical Formula lj:
Figure imgf000028_0003
Figure imgf000029_0001
wherein R' = H, OH or CI S alkoxy; X can be -C=0, -0-, -NCH,, or -S-;and Y can be -CH2-> - CHCH3, -C(CHj)2, -(CH2)2-, or -(CH2)3-.
[00155] In some embodiments, compounds of the present invention are described by the following chemical Formula lk:
Figure imgf000029_0002
[00156] In some embodiments, compounds of the present invention arc described by
Figure imgf000029_0003
[00157] In some embodiments, compounds of the present invention are described by the following chemical Formula lm:
Figure imgf000030_0001
Formula lm
Raa
wherein Rbb is
N VN ,__/ ~~NvZ/N
Figure imgf000030_0002
J
[00158] In some embodiments, compounds of the present invention are described by the following chemical Formula lm:
Figure imgf000030_0003
Formula 1 m
Raa.N
vherein Rbb
Figure imgf000030_0004
[00159] In some embodiments, compounds of the present invention are described by the following chemical Formula I n:
Figure imgf000030_0005
Figure imgf000031_0001
Representative Compounds
[00160] Representative compounds of Formulas 1, and 1 a- 1 n are depicted below. The examples are merely illustrative and do not limit the scope of the invention in any way. Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).
Specifically, names in Table I were generated using ChemDraw Ultra, Version 1 1 .0(3) or 12.0 (CambridgeSoft).
Table 1
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Compd Structure Name
No.
169. l-(l-(4-(2-(azepan-l-
O yl)ethoxy)benzyl)naphthalen-2- yl)piperidin-4-ol
170. 1 -(l-(4-(2-(4-methylpiperazin- 1- yl)ethoxy)benzyl)naphthalen-2- kA. r"V0H yl)piperidin-4-ol
[00161] In various embodiments, the compounds of Formula 1 and la in can also be provided as pharmaceutically acceptable salts, wherein a pharmaceutically acceptable salt can include a pharmaceutically acceptable acid addition salt of the compound. In some embodiments, the pharmaceutically acceptable acid addition salt can include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropiomc acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like. In one embodiment, the pharmaceutically acceptable salt of the compounds of Formula 1 or la-ln are hydrochloric acid (.HQ) salts.
[00162] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Specific base addition salts include ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabaraine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
DOSAGE FORMS
[00163] The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. Subjects may also include laboratory animals, including mice, rats, guinea-pigs, rabbits and the like which are commonly used for scientific experimental studies, for veterinary use, for example, companion animals, and livestock. The terms patient and subject may be used interchangeably.
[00164] Moreover, the pharmaceutical compositions described herein, which include a compound provided herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
[00165] In some embodiments, the invention provides pharmaceutical compositions comprising a selective estrogen receptor modulator compound of Formula 1, la-ln or
pharmaceutically acceptable salts, solvates or prodrugs thereof according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other specific embodiments, administration is by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms uitable for simple administration of precise dosages.
[00166] In some embodiments, pharmaceutical compositions can be added to a conventional pharmaceutical carrier or excipient, among other inert substances useful in the delivery of the therapeutic active compound or compounds of the present invention.
[00167] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
[00168] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00169] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[00 70] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[00171 ] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, macrocrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[00172] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[00173] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
[001 4] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations of the present invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
[00175] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound provided herein, with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of the compound provided herein, are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.
[00176] Conventional pharmacological techniques include, e.g., one or a combination of methods: ( I ) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachraan et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
[00177] The pharmaceutical solid dosage forms described herein can include a compound provided herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20Ih Edition (2000), a film coating is provided around the formulation of the compound provided herein. In one embodiment, some or all of the particles of the compound provided herein are coated. In another embodiment, some or all of the particles of the compound provided herein are microencapsulated. In still another embodiment, the particles of the compound provided herein are not microencapsulated and are uncoated.
[00178] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
[00179] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
[00180] In order to release the compound disclosed herein from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with a binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac- Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
[00181 ] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and mierocrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Pol plasdone® XL- 10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.
[00182] In some embodiments, binder levels of 20-70% can be used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations.
[00183] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. [00184] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
[00185] The term "non water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and nitrocellulose (e.g., having a density of about 0.45 g/cm5, e.g. Avicel, powdered cellulose), and talc.
[00186] In some embodiments, exemplary wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10φ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E, TPGS and the like.
[00187] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic®. (BASF), and the like.
[00188] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[00189] Suitable suspending agents for use in the solid dosage forms described herein can include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone 25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.
[00190] Optional excipients, such as antioxidants, for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[00191 ] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms of the present invention. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
[00192] In various embodiments, one or more layers of the pharmaceutical formulation are plasticized. In one example, a plasticizer can be used, being generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01 % to about 50% by weight (w/w) of the coating composition. Plasticizers include, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
[00193] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of the compound disclosed herein from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry® coatings or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets include one or more excipients.
[00194] In still further embodiments, solid dosage forms may include capsules. A capsule may be prepared, for example, by placing the bulk blend of the formulation of the compound described above, inside of a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating. In some embodiments, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in a capsule form.
[00195] In various embodiments, particles, spheres, or pellets of the compound disclosed herein and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 20 minutes, within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.
[00196] In another aspect, dosage forms may include microencapsulated formulations.
In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti- foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.
[00197] Materials useful for the microencapsulation described herein include materials compatible with compounds disclosed herein, which sufficiently isolate the compound disclosed herein from other non-compatible exeipients. Materials compatible with compounds disclosed herein are those that delay the release of the compounds disclosed herein in vivo.
[00198] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds disclosed herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natro ol®, carboxymethylcelluloses and salts of
carboxymethylcelluloses (CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RDI00, Eudragit® EI00, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.
[00199] In still other embodiments, certain plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.
[00200] Microencapsulated compounds disclosed herein may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating may also be used.
[00201] In one embodiment, the particles of compounds disclosed herein are microencapsulated prior to being formulated into one of the above forms. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).
[00202] In other embodiments, the solid dosage formulations of the compounds disclosed herein are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
[00203] In other embodiments, a powder including the formulations with a compound disclosed herein may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi- dosage packaging units.
[00204] In still other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the present invention are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.
[00205] In other embodiments, the formulations described herein, which include a compound disclosed herein, are solid dispersions. Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Pub. Appl 2004/0013734, each of which is specifically incorporated by reference. In still other embodiments, the formulations described herein are solid solutions. Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which can be further formulated or directly added to a capsule or compressed into a tablet. Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 4, 151,273, 5,281 ,420, and 6,083,518, each of which is specifically incorporated by reference.
[00206] The pharmaceutical solid oral dosage forms, which include a compound disclosed herein, can be further formulated to provide a controlled release of the compound disclosed herein. Controlled release refers to the release of the compound disclosed herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
[00207] In some embodiments, the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
[00208] The term "delayed release" as used herein refers to the delivery of the active agent so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. In some embodiments the method for delay of release is by providing a delayed release coating. Any coating or plurality of coatings, should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. In some embodiments the polymers for use in the present invention are anionic carboxylic polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to: shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH>7; Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine; Cellulose Derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH > 6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles<l μιτι. Other components in Aquateric can include pluronics. Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example. HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH > 5, and it is much less permeable to water vapor and gastric fluids.
[00209] In some embodiments, the coating can contain a plasticizer and possibly other coating excipients such as colorants, talc, magnesium stearate, among others, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec Λ2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached. [00210] . Further optional excipients may include colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., camuba wax or PEG) may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
[00211 ] In other embodiments, the formulations described herein, which include a compound or its pharmaceutically acceptable salt, solvate or prodrug thereof disclosed herein, are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Pulsatile dosage forms including the formulations described herein, which include a compound disclosed herein, may be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Pat. Nos.
5,01 1,692, 5,017,381 , 5,229,135, and 5,840,329, each of which is specifically incorporated by reference. In one embodiment, the controlled release dosage form is pulsatile release solid oral dosage form including at least two groups of particles, (i.e. multiparticulate) each containing the formulation described herein. The first group of particles provides a substantially immediate dose of the compound disclosed herein upon ingestion by a mammal. The first group of particles can be either uncoated or include a coating and/or sealant. The second group of particles includes coated particles, which includes from about 2% to about 75%, preferably from about 2.5% to about 70%, and more preferably from about 40% to about 70%, by weight of the total dose of the compound disclosed herein in said formulation, in admixture with one or more binders. The coating includes a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of from about 1 hour to about 12 hours following ingestion before release of the second dose. Suitable coatings include one or more differentially degradable coatings such as, by way of example only, pH sensitive coatings (enteric coatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S 100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, Eudragit® NE 40D®) either alone or blended with a cellulose derivative, e.g., ethylcellulose, or non-enteric coatings having variable thickness to provide differential release of the formulation that includes a compound disclosed herein.
[00212] Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono- , di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed„ Vol. 1, pp. 209-214 (1990); Singh et al„ Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721 , 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is specifically incorporated by reference.
[00213] Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to the particles of compound disclosed herein, the liquid dosage forms may include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent.
[00214] The aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 Ed., chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than I minute. In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.
[00215] Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel® , or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PHI05, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.
[00216] In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP;
commercially known as Plasdone®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC- L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(l,l,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N J.)). In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(l ,1 ,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®).
[00217] In some illustrative examples, wetting agents suitable for the aqueous suspensions and dispersions useful for the liquid dosage forms herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like
[00218] In some embodiments, suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.
[00219] In some embodiments, suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon® S- 630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.
[00220] Examples of sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005% to about 0.5% the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01 % to about 1.0% the volume of the aqueous dispersion.
[00221] In addition to the additives listed above, the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
[00222] It is to be appreciated that there is overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in formulations described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[00223] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[00224] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[00225] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
[00226] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[00227] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of at least one suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with the rest being at least one suitable pharmaceutical excipient. [00228] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
METHODS OF USE
[00229] The present invention relates to a method of treating cancer in a mammalian subject (e.g., a human patient). In this aspect of the invention, methods are provided for inhibiting tumor or cancerous cell growth. Methods encompassed in the present invention comprises administering a dose of one or more of the compounds of Formulae 1 and la- I n such that the compound of Formulae 1 and la-ln, pharmaceutically acceptable salts, solvates or prodrugs thereof will contact the tumor or cancerous cells in vivo. Therapeutically effective doses of any one or more of the compounds of Formulae 1 and 1 a- 1 n are administered to the patient in need of such therapy.
[00230] In some embodiments, the present invention provides a method for treating a tumor, the method comprising: administering to a patient a therapeutically effective amount of a compound of Formulae 1 , 1 a- 1 n, or a pharmaceutically acceptable salt or solvate or prodrug thereof. In this aspect, the methods may be used to treat any cancer or tumor which may be either directly or indirectly effected by hormonal and/or estrogen-related activity, including but not limited to solid tumors associated with breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyeloc tic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia among others. The methods for treating a cancer or tumor by administering to a subject in need thereof a composition, for example a pharmaceutical composition containing a therapeutically effective amount of at least one selective estrogen receptor modulator of Formula 1 or Formulas 1 a-ln, or pharmaceutically acceptable salts, solvate or prodrugs thereof, including any of the above-mentioned compounds of Table 1 , can be used to treat or inhibit the growth of an estrogen-receptor positive cancer or tumor, preferably, estrogen-receptor positive breast cancer.
[00231] In another embodiment, a compound of Formulae 1, la- ln, or their pharmaceutically acceptable salts, solvates or prodrugs thereof, may be used to treat a variety of hormonal disorders such as treatment of osteoporosis, relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of hirsutism, treatment of hot flashes and prevention of cardiovascular disease.
[00232] The compounds of the invention, or their pharmaceutically acceptable salts or solvates or prodrugs thereof, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet of the subject, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a subject in need thereof, at dosage levels in the range of about 0.1 to about 1 ,500 mg per day, for example, or from about 1 mg to about 1 ,250 mg, or from about 1 mg to about 1 ,000 mg, or from about 1 mg to about 750 mg, or from about 1 mg to about 500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 1 ,500 mg, or from about 25 mg to about 1 ,500 mg, or from about 50 mg to about 1 ,500 mg, or from about 100 mg to about 1 ,500 mg, or from about 150 mg to about 1 ,500 mg, or from about 200 mg to about 1 ,500 mg, or from about 250 mg to about 1 ,500 mg, or from about 300 mg to about 1,500 mg, or from about 400 mg to about 1 ,500 mg, or from about 500 mg to about 1 ,500 mg, or from about 750 mg to about 1 ,500 mg. For a normal human adult having a body weight of about 70 kilograms, a daily dosage amount in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. In some embodiments, an exemplary daily dosage amount of a compound, or their pharmaceutically acceptable salt, solvate or prodrug thereof of the present invention includes: 50 mg per day, 100, per day mg, 150 per day mg, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 450 mg per day, 500 mg per day, 750 mg per day, 1 ,000 mg per day, 1 ,250 mg per day, or 1 ,500 mg per day. In some embodiments, the daily dosage amount can include: from about 0.01 mg/kg/day to about 100 mg/kg/per day, or from about 0.01 mg/kg/day to about 75 mg/kg/per day, from about 0.01 mg/kg/day to about 50 mg/kg/per day, from about 0.01 mg/kg day to about 25 mg/kg/per day, from about 0.01 mg/kg/day to about 20 mg/kg/per day, from about 0.01 mg/kg/day to about 10 mg/kg/per day, from about 0.01 mg/kg/day to about 5 mg/kg/per day. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the Compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art. The term "daily dosage amount" refers to the amount of the compounds of Formula 1 , la-l n, or their pharmaceutically acceptable salts, solvates or prodrugs thereof, per day that is administered or prescribed to a patient. This amount can be administered in multiple unit doses or in a single unit dose, in a single time during the day or at multiple times during the day. The term "unit dose" as used herein may be taken to indicate a discrete amount of the therapeutic composition which comprises a predetermined amount of the active compound. The amount of the compound of Formula 1 , or Formulas la- ln, or pharmaceutically acceptable salts, solvates or prodrugs thereof is generally equal to the dosage of the compound of the present invention which may be administered once per day, or may be administered several times a day (e.g. the unit dose is a fraction of the desired daily dose). The unit dose may also be taken to indicate the total daily dosage amount, which may be administered once per day or may be administered as a convenient fraction of such a dose (e.g. the unit dose is the total daily dosage amount which may be given in fractional increments, such as, for example, one-half or one-third the dosage).
[00233] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
[00234] In addition, administration of the compounds of the present invention for treatment of various cancer states may comprise administration of a compound of Formulae 1, la- In, pharmaceutically acceptable salts, solvates or prodrugs thereof, their pharmaceutically acceptable salts, solvates or prodrugs thereof, in combination with other adjunct cancer therapies, such as chemotherapy, radiotherapy, gene therapy, hormone therapy and other cancer therapies known in the art. Combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A physician, veterinarian or clinician of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
[00235] Such anti-cancer or chemotherapeutic agents include: anti-neoplastic agents.
Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms. Both types of antineoplastic agents may be employed in combination with the compounds of the present invention.
[00236] Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; nonreceptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. [00237] Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids. Examples of diterpenoids include, but arc not limited to, paclitaxel and its analog docetaxel. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
[00238] Platinum coordination complexes are non-phase specific anti-neoplastic agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin, carboplatin, and oxaliplatin.
[00239] Alkylating agents are non-phase anti-neoplastic specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
[00240] Antibiotic chemotherapeutic agents are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but arc not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
[00241] Topoisomerase II inhibitors include, but are not limited to,
epipodophyllotoxins. Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
[00242] Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cyclophosphamide, cytarabine, mercaptopurine and thioguanine.
[00243] Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)- 10, 1 1 -ethylenedioxy-20-camptothecin.
[00244] Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children;
aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti- androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; other anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene useful in the treatment of hormone dependent breast carcinoma; and gonadotropin- releasing hormone (GnRH) and analogues thereof which stimulate the release of luteinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagonists such as goserelin acetate and luprolide.
[00245] In one embodiment, the selective estrogen receptor modulator compound of the present invention is combined with a biological or a small molecule anti-breast cancer agent and administered as a combination treatment. In some embodiments, the compound of the present invention is co-administered with a biological anti-cancer agent, for example, a biological response modifier, for example, an interferon (e.g. an interferon alpha, interferon beta, and interferon gamma), an interleukin (for example, interleukin-2, -1 1 (IL-2, IL-1 1), a colony-stimulating factor (for example, G-CSF (filgrastim) and GM-CSF (sargramostim)), a monoclonal antibody (for example, Rituxan® (rituximab), Herceptin® (trastuzumab), Omnitarg® (pertuzumab), Avastin® (bevacizumab)), a vaccine, gene therapy, and nonspecific immunomodulating agents. In one embodiment, the compound of the present invention is co-administered with an inhibitor of: Epidermal Growth Factor Receptor, Her2, Her3, PI3 kinase, mammalian target of rapamycin (mTOR) intracellular pathway signalling (for example, everolimus), and other growth factor receptors.
[00246] In one embodiment, a combination therapy comprising a compound of Table
1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in a combination therapy with Herceptin (at a dosage amount of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 52 weeks, or an initial dose of 8 mg kg over 90 minutes IV infusion, then 6 mg/kg over 30-90 minutes IV infusion every three weeks for 52 weeks, or an initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions, or an initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks). In another embodiment, a combination therapy comprising a compound of Table 1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in combination with docetaxel (at a daily dosage amount of 10 mg - 1 00mg). In another embodiment, a combination therapy comprising a compound of Table 1 (at a daily dosage amount of 50 mg - 1500mg) is co-administered in combination with docetaxel (at a daily dosage amount of 10 mg - 1500mg) and Herceptin (at a dose described above for Herceptin).
[00247] The additional anti-cancer or chemotherapeutic agents described above are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific additional anti-cancer or chemotherapeutic agent employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,500 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the additional anti-cancer or chemotherapeutic agent being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art. The additional anti-cancer or chemotherapeutic agent can be administered in a fixed dose with a compound of Formulae 1 , 1 a- 1 n, pharmaceutically acceptable salts, solvates or prodrugs thereof or may be administered as a separate dose, to be taken either with the compound of Formulae 1, la- In, pharmaceutically acceptable salts, solvates or prodrugs thereof simultaneously or at a different time, either before or after administration of the compound of Formulae 1 , 1 a- 1 n, pharmaceutically acceptable salts, solvates or prodrugs thereof.
EXAMPLES
[00248] Example 1. Synthesis of β-Napthol Compounds
[00249] Melting points were determined on a MEL-TEMP II apparatus. The IR spectra were recorded on a Nicolet AVATAR 300 FT-IR instrument by making KBr discs for solid samples and thin films for oils. The Ή NMR and C NMR spectra were recorded on a Bruker AC- 300 Avance spectrometer or Bruker ARX-300 spectrometer at 300 and at 75.5 MHz, respectively. The chemical shift values are on δ scale and the coupling constants (J) are in Hz. The HRMS were recorded in positive ion mode on an ion spec Fourier transform mass spectrometer. CEM Discover S- class microwave reactor was used for the synthesis of compounds. All chemicals used were purchased either from Aldrich Chemical Co. or Fluka Chemicals Co., Canada and used without further purification. Analytical TLCs were performed on pre-coated Merck silica gel 60F254 plates; the spots were detected under UV light. Silica gel ( 100-200 mesh) was used for column chromatography. After column chromatography, fraction containing products were evaporated under reduced pressure and dried 12 h under high vacuum to give the product otherwise specified. Some reactions were conducted under an atmosphere of nitrogen when anhydrous solvents were used.
[00250] 4-(2-Bromoethoxy)benzaldehyde
Figure imgf000076_0001
Scheme-1
[00251] In a dried single-neck round bottom flask, 4-hydroxyIbenzaldehyde (4 mmol), potassium carbonate (20 mmol) and dry acetone (100 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of 1 ,2-dibromoethane (20 mmol) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 25 % ethyl acetate/hexane as the solvent system. The reaction was completed in 12 h. At this point, reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml). The solvent was evaporated under reduced pressure from the combined organic layer and the residue was purified by column chromatography over silica gel ( 10-15 % ethyl acetate in hexanes, v/v as eluent) to obtain 4- (2-bromoethoxy)benzaldehyde as a white solid, m.pt. 55-56 "C, 68 % yield (lit. m.pt. 55-58 °C; Nagarapu et al. J. Helerocycl. Chem., 2009, 46, 195-200).
[00252] General procedure A for the synthesis of 4- dial
Figure imgf000076_0002
Scheme-2
[00253] In a dried single-neck round bottom flask, appropriate amine (21 mmol), potassium carbonate (65 mmol) and dry acetone (80 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of 4-(2-bromoethoxy)benzaldehyde (21 mmol) dissolved in dry acetone (50 ml) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 10 % methanol/dichloromethane as the solvent system. The reaction was generally completed in 10-13 h. At this point, the reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 % methanol in dichloromethane, v/v as eluent) to afford the four aldehyde products as colorless oils in 62-63 % yield. The structures of the products were unambiguously established from the analysis of their spectral data (IR, Ή NMR, l3C NMR and mass spectra).
[00254] General procedure B for the synthesis of 4- dialkylaminoethoxybenzaldehydes.
Figure imgf000077_0001
Scheme 3
In a dried single-neck round bottom flask, 4-hydroxylbenzaldehyde (40 mmol), potassium carbonate (122 mmol) and dry acetone (160 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of the appropriate dialkylaminoethyl chloride hydrochloride (45 mmol) dissolved in dry acetone (50 ml) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 10 % methanol/dichloromethane as the solvent system. The reaction was generally complete in 10-13 h. At this point, reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 % methanol in dichloromethane, v/v as eluent) to afford the six pure 4-dialkylaminoethoxybenzaldehydes as colorless oils in 49-92 % yields. The structures of these products were unambiguously established from the analysis of their spectral data (IR, Ή NMR, l3C NMR and mass spectra).
[00255] 4-{2-(Dimethylamino)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 49 % yield by following the general procedure B. UV (EtOH) mm: 219 and 276 nm. IR (nujol): 2945, 2822, 2727, 1685, 1597, 1510, 1466, 131 1,1258, 1216 1 160, 1030 and 834 cm '. Ή NMR (300 MHz, CDCI3): δ 2.37 (6H, s, 2 x NC¾), 2.81(2H, t, J = 5.1Hz, -NCH2), 4. 1 1 (2H, t, J = 5.4 Hz, OCH2), 6.99 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.81 (2H, d, J = 7.8 Hz, 2 x Ar-H), 9.85 (1H, s, CHO). 13C NMR (75.5 MHz, CDC13): δ 45.68 (2 x NC¾), 57.90 (NCH2), 66.08 (OCH2), 1 14.82 (C-2 & C-6), 130.04(C-1), 13 1.92 (C-3 & C-5), 163.72 (C-4), 190.75 (C=0). HRMS m/z calculated for C„H,5N02 [M+H]+ 194.1 176, observed [M+Hf 194. 1 168.
[00256] 4-{2-(DiethyIamino)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 92 % yield by following the general procedure B. UV (EtOH) λ^^: 224, 273 and 319 nm. IR (nujol): 2966, 2872, 2826, 1693, 1604, 1509, 1466, 1361 , 1260, 1 185 1 158, 1016 and 832 cm ' . Ή NMR (300 MHz, CDC13): δ 1.06 (6H, t, = 7.2 Hz, 2 x CH3), 2.64 (4H, q, J = 7.2 Hz, 2 x NCH2), 2.89 (2H, t, J = 6.0 Hz, -NCH,), 4.1 1 (2H, t, J = 6.3 Hz, OCH2), 7.01 (2H, d, J = 8.7 Hz, 2 x Ar-H), 7.83 (2H, d, J = 8.7 Hz, 2 x Ar-H), 9.87 (1 H, s, CHO). UC NMR (75.5 MHz, CDC13): δ 1 1.85 (2 x CH3), 47.89 (2 x NCH2), 51.57 (NCH2), 67.12 (OCH2), 1 14.83 (C-2 & C-6), 129.92 (C-1 ), 131.93 (C-3 & C-5), 163.96 (C-4), 190.74 (C=0). HRMS m/z calculated for Cl 3H19N02 [M+H]+ 222.1416, observed [M+H]+ 222.141 1.
[00257] 4-{2-(Diisopropylamino)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 91 % yield by following the general procedure B. UV (EtOH) max: 219 and 283 nm. IR (nujol): 2967, 2873, 2804, 1694, 1604, 1510, 1473, 1385,1249, 1 164, 1 109, 1022 and 832 cm' 1. Ή NMR (300 MHz, CDC13): δ 1.06 (12H, d, J = 6.6 Hz, 4 x CH3), 2.88 (2H, t, J = 7.2Hz, -NCH2), 3.04-3.08 (2H, m, 2 x CH), 4.01 (2H, t, J = 7.2 Hz, OCH2), 7.00 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.83 (2H, d, J = 8.4 Hz, 2 x Ar-H), 9.87 (CHO). "C NMR (75.5 MHz, CDC13): δ 20.80 (4 x CH3), 44.19 (2 x CH), 49.73 (NCH2), 69.51 (OCH2), 1 14.81 (C-2 & C-6), 129.81 (C-1 ) 131.95 (C-3 & C-5), 164.08 (C-4), 190.72 (C=0). HRMS m/z calculated for d5H23N02 [M+H]+ 249.1729, observed [M+H]+ 249.171 1.
[00258] 4-{2-(Pyrrolidin-l-yl)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 83 % yield by following the general procedure B. UV (EtOH) λπ13χ: 217 and 274 nm. IR (nujol): 2962, 2785, 1691 , 1602, 1510, 1312, 1259, 1216, 1 160, 1033 and 833 cm 1 Ή NMR (300 MHz, CDC13): δ 1.82 (4H, brs, 2 x CH2), 2.65 (4H, brs, 2 x NCH2), 2.94 (2H, t, J = 5.7, -NCH2), 4.1 1 (2H, t, J = 5.7 Hz, OCH2), 7.01 (2H, d, J = 8.4Hz, 2 x Ar-H), 7.83 (2H, d, J = 8.4Hz, 2 x Ar-H), 9.87 ( 1H, s, CHO). 13C NMR (75.5 MHz, CDCI3): δ 23.50 (2 x CH2), 54.72 (2 x NCH2), 57.76 (NCH2), 67.42 (OCH2), 1 14.85 (C-2 & C-6), 130.04 (C-1), 131.92 (C-3 & C-5), 163.84 (C-4), 190.70 (C=0). HRMS m z calculated for CBH,7N02 [M+Hf 220.1332, observed [M+H]+ 220.1331.
[00259] 4-{2-(Piperidin-l-yl)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 91 % yield by following the general procedure B. UV (EtOH) Xn,ax: 218 and 274 nm. IR (nujol): 2934, 2852, 2788, 1693, 1602, 1577, 1509, 131 1 , 1258, 1215, 1 159, 1034 and 833 cm 1. Ή NMR (300 MHz, CDC13): δ 1.45-1.46 (2H, m, CH2), 1.58-1.63 (4H, m, 2 x CH2), 2.50-2.53 (4H, m, 2 x NCH2), 2.80 (2H, t, J = 6.0 Hz, NCH2), 4.19 (2H, t, J - 6.0 Hz, OCH2), 7.02 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.83 (2H, d, J = 8.4 Hz, 2 x Ar-H), 9.87 (CHO). UC NMR (75.5 MHz, CDClj): δ 24.10 (CH2), 25.89 (2 x CH2), 55.07 (2 x NCH2), 57.65 (NCH2), 66.44 (OCH2), 1 14.87 (C- 2 & C-6), 129.96 (C-1 ), 131.92 (C-3 & C-5), 163.89 (C-4), 190.72 (C=0). HRMS m/z calculated for C14Hi9N02 [M+Hf 234.1489, observed IM+HJ+ 234. 1486.
[00260] 4-(2-Morpholinoethoxy)benzaldehyde: The title compound was obtained as a colorless oil in 89 % yield by following the general procedure B. UV (EtOH) mnx: 219 and 274 nm. IR (nujol): 2960, 2855, 2809, 1687, 1600, 1578, 1510, 1453, 1255, 1215, 1 160, 1036 and 835 cm '. Ή NMR (300 MHz, CDClj): δ 2.68 (4H, brs, 2 x NCH2), 2.92 (2H, t, J = 4.8 Hz, NCH2), 3.79 (4H, brs, 2 x OCH2), 4.26 (2H, t, J = 5.1 Hz, OC¾), 7.03 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.86 (2H, d, J = 8.4 Hz, 2 x Ar-H), 9.90 (CHO). I3C NMR Data (75.5 MHz, CDClj): δ 53.97 (2 x NCH2), 57.3 1 (NCH2), 65.92 (OCH2), 66.75 (2 x OCH2), 1 14.85 (C-2 & C-6), 130.20 (C- l ),132.27 (C-3 & C-5), 163.53 (C-4), 190.70 (C=0). HRMS m/z calculated for CjHnNOj [M+H]+ 236.1281 , observed [M+Hf 236.1283.
[00261] 4-{2-(4-Methylpiperidin-l-yl)ethoxy}benzaldehyde: The title compound was obtained as a colorless oil in 62% yield by following the general procedure A.UV(EtOH) max: 217 and 273 nm. IR (nujol): 2923, 2947, 2719, 2745, 1695, 1602, 1509, 1260, 1 160, 1025 and 832 cm" 1. Ή NMR (CDClj, 300 MHz): δ 0.94 (3H, d, J = 6.0 Hz, CH3), 1.30-1 .37 (3H, m, CH2 & CH ), 1.62-1.66 (2H, m, CH2), 2.09-2.16 (2H, m, NCH2), 2.83 (2H, t, J = 5.7 Hz, NCH2), 2.96-3.00 (2H, m, NCH2), 4.20 (2H, t, J = 5.7 Hz, OCH2), 7.01 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.83 (2H, d, J = 8.7 Hz, 2 x Ar-H), 9.87 (CHO). 13C NMR (75.5 MHz, CDC13): δ 21.79 (C¾), 30.45 (CH), 34.32 (2 x CH2), 54.49 (2 x NCH2), 57.24 (NCH2), 66.42 (OCH2), 1 14.87 (C-2 & C-6), 130.29 (C-1 ), 131.92 (C-3 & C- 5), 1 3.82 (C-4), 190.70 (C=0). HRMS m/z calculated for d5H21N02 [M+H]+ 248.1645, observed [M+H]+ 248.1646.
[00262] 4-(2-(Azepan-l-yl)ethoxy)benzaldehyde: The title compound was obtained as a colorless oil in 63 % yield by following the general procedure A. UV (EtOH) λ^: 217 and 276 nm. IR (nujol): 2924, 2851, 1694, 1600, 1509, 131 2, 1258, 1 159, 1022 and 832 cm"1. 'H NMR (300 MHz, CDC13): δ 1.64-1.71 (8H, m, 4 x CH2), 2.86 (4H, brs, 2 x NCH2), 3.05 (2H, t, J = 5.7 Hz, NCH2), 4.21 (2H, t, / = 6.0 Hz, OCH2), 7.03 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.85 (2H, d, J = 8.4 Hz, 2 x Ar-H), 9.89 (CHO). 1JC NMR (75.5 MHz, CDCI3): δ 27.02 (2 x CH2),27.87 (2 x CH2), 55.82 (2 x NCH,), 57.95 (NCH2), 66.89 (OCH2), 1 14.86 (C-2 & C-6), 129.90 (C-1), 131.92 (C-3 & C-5), 163.96 (C-4), 190.72 (C=0). HRMS m/z calculated for C15H21N0 [M+Hf 248.1645, observed [ +H]+ 248.1649.
[00263] 4-(2-(4-Methylpiperazin-l-yl)ethoxy)benzaldehyde: The title compound was obtained as a brown colored oil in 61% yield by following the general procedure A. UV (EtOH) λ™,,: 217 and 276 nm. IR (nujol): 2924, 2851 , 1694, 1600, 1509, 1312, 1258, 1 159, 1022 and 832 cm" 1. Ή NMR (300 MHz, CDClj): δ 2.24 (3H, s), 2.56-2.66 (4H, m), 2.80 (2H, t, J = 5.7 Hz), 4.13 (2H, t, J = 5.7 Hz), 7.0 (2H, d, J = 8.7 Hz),7.80 (2H, d, J = 8.7 Hz), 9.81 ( 1 H, s). [00264] General procedure for the synthesis of 4-dialkylaminoethoxybenzyl alcohols:
Figure imgf000080_0001
[00265] In a round bottom flask, a solution of appropriate 4- dialkylaminoethoxybenzaldehyde (4.5 mmol) in methanol (25 ml) was taken and sodium borohydride (3.1 mmol) was added in small lots at room temperature. The reaction was monitored by TLC using 10% methanol/dichloromethane as the solvent system. The reaction was completed in 3-5 h. After completion of reaction, the methanol was removed under reduced pressure. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with water (3 x 50 ml) and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and dried under high vacuum to afford the desired benzyl alcohols as colorless oils in 76-95 % yields. The structures of these products were unambiguously established from the analysis of their spectral data (IR, Ή NMR, 1 'C NMR and mass spectra).
[00266] [4-{2-(Dimethylaniino)ethoxy}pheny]]methanol: The title compound was obtained as a colorless oil in 76 % yield. UV (EtOH) ™ίχ: 224, 269 nm. IR (nujol): 3244, 2947, 2864, 2828, 161 1, 15 12, 1465, 1299, 1243, 1 173, 1032, 1009 and 819 cm"1. Ή NMR(300 MHz, CDC1,): δ 2.36 (6H, s, 2 x NCH3), 2.77 (2H, t, J = 5.4 Hz, -NCH2), 4.06 (2H, t, J = 5.4 Hz, OCH2), 4.61 (2H, s, CH2OH), 6.89 (2H, d, J - 8.4Hz, 2 x Ar-H), 7.29 (2H, d, J = 8. 1 Hz, 2 x Ar-H). I3C NMR (75.5 MHz, CDCI3): δ 45.70 (2 x NCH3), 58.10 (NCH2), 64.99 (CH2OH), 65.78 (OCH2), 1 14.59 (C-2 & C-6), 128.77 (C-3 & C-5), 133.56(C-1), 158.24 (C-4). HRMS rn/z calculated for C| ,Hl 7N02 [M+Hf 196.1332, observed [M+H]+ 196.1329.
[00267] [4-{2-(Diethylamino)ethoxy}phenyl]methanol: The title compound was obtained as a colorless oil in 92 % yield. UV Data (EtOH) 217 and 276 nm. IR (nujol): 3369, 2969, 2873, 2825, 161 1, 1512, 1460, 1376, 1299, 1245, 1 173, 1037, 1009 and 825 cm" 1. 'H NMR (300 MHz, CDClj): δ 1.06 (6H, t, 7 = 7.2 Hz, 2 x CH3), 2.63 (4H, q, J = 7.2 Hz, 2 x NCH2), 2.84 (2H, t, J = 6.3 Hz, -NCH2), 4.00 (2H, t, J = 6.3 Hz, OCH2), 4.57 (2H, s, CH2OH), 6.86 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.26 (2H, d, J = 8.4 Hz, 2 x Ar-H). , 3C NMR (75.5 MHz, CDC13): δ 1 1.95 (2 x CH3), 47.67 (2 x NCH2), 51 .62 (NCH2), 64.60 (CH2OH), 66.40 (OCH2), 1 14.48 (C-2 & C-6), 128.45 (C-3 & C-5), 133.06 (C-1 ), 158.29 (C-4). HRMS rn/z calculated for C,3H2lN02 [M+H]+ 224.1645, observed [M+H]+ 224.1650. [00268] [4-{2-(Diisopropylamino)ethoxy)phenyl]methanol: The title compound was obtained as a colorless oil in 83%. UV (EtOH) λ™χ: 224 and 274 nm. IR (nujol): 3361 , 2969, 2874, 2828, 161 1, 1512, 1460, 1376, 1299, 1240, 1 173, 1044, 1009 and 825 cm 1. 'H NMR (300 MHz, CDC13) δ 1.10 (12H, d, J = 6.3 Hz, 4 x CH3), 1.95 ( 1 H , brs, OH ), 2.86 (2H, t, 7 = 7.2, - NCH2), 3.08-3.12 (2H, m, 2 x CH), 3.95 (2H, t, J = 6.9 Hz, OCH2), 4.62 (2H, d, 7 = 5.4 Hz, CH2OH), 6.91 (2H, d, 7 = 8.4 Hz, 2 x Ar-H), 7.30 (2H, d, 7 = 8.4 Hz, 2 x Ar-H). 13C NMR (75.5 MHz, CDCI3): δ 20.68 (4 x CH,), 44.50 (2 x CH), 49.92 (NCH2), 64.97 (CH2OH), 69.06 (OCH2), 1 15.00 (C-2 & C-6), 128.02 (C-3 & C-5), 133.12 (C- 1 ), 158.52 (C-4). HRMS m/z calculated for C15H25N02 [M+Hf 252.1958, observed [M+H]+ 252.1957.
[00269] [4-{2-(PyrroIidin-l-yl)ethoxy}phenyl]rnethanol: The title compound was obtained as a colorless oil in 81% yield. UV (EtOH) 224 and 267 nm. ¾ NMR (300 MHz, CDCI3) δ 1.81 (4H, brs, 2 x CH2), 2.64 (4H, brs, 2 x NCH2), 2.89 (2H, t, 7 = 6.0 Hz, NCH2), 4.06 (2H, t, 7 = 6.0 Hz, OCH2), 4.59 (2H, s, CH2OH), 6.87 (2H, d, = 8.1 Hz, Ar-H), 7.28 (2H, d, 7 = 8.1 Hz, Ar-H). 13C NMR (75.5 MHz, CDCl,): δ 23.44 (2 x CH2), 54.66 (2 x NCH2), 54.98 (NCH2), 64.72 (CH2OH), 66.85 (OCH2), 1 14.57 (C-2 & C-6), 128.47 (C-3 & C-5), 133.65 (C-1 ), 158.25 (C-4). HRMS m/z calculated for C13Hl 9N02 [M+H]+ 222.1489, observed [M+H]+ 222.1490.
[00270] [4-{2-(Piperidin-l-yl)ethoxy}phenyl]methanol: The title compound was obtained as a colorless oil in 95% yield by following the general procedure outlined above. UV (EtOH) 225 and 274 nm. IR (nujol): 3367, 2934, 2854, 2806, 161 1 , 1503, 1467, 1 01 , 1 244, 1 173, 1037 and 825 cm' 1. Ή NMR (300 MHz, CDC13): δ 1.51 (2H, brs, CH2), 1.69 (4H, brs, 2 x CH2), 2.63 (4H, brs, 2 x NCH2), 2.87 (2H, t, 7 = 5.4 Hz, NCH2), 4. 16 (2H, t, 7 = 5.4 Hz, OCH2), 4.65 (2H, s, CH2OH) 6.90 (2H, d, 7 = 7.8 Hz, 2 x Ar-H), 7.31 (2H, d, 7 = 7.5 Hz, 2 x Ar-H). 13C NMR (75.5 MHz, CDClj): δ 23.83 (CH2), 25.41 (2 x CH2), 54.89 (2 x NCH2), 57.66 (NCH2), 64.88 (CH2OH), 65.54 (OCH2), 1 14.81 (C-2 & C-6), 128.59 (C-3 & C-5), 133.56 (C-1), 158.17 (C-4). HRMS m/z calculated for Ci4H2 lN02 [M+H]+ 236.1645, observed [M+H]+ 236.1646.
[00271] {4-(2-Morpholinoethoxy)phenyl}methanol: The title compound was obtained as a colorless oil in 88%. UV (EtOH) mail: 225 and 273 nm. IR (nujol): 3383, 2932, 2854, 2860, 161 1 , 1507, 1455, 1299, 1241 , 1 173, 1053, 1009 and 817 cm'1. ¾ NMR (300 MHz, CDC13): δ 2.62-2.63 (4H, m, 2 x NCH2), 2.83 (2H, t, 7 = 5.4 Hz, NC¾), 3.74-3.77 (4H, m, 2 x OCH2), 4.13 (2H, t, 7 = 5.4 Hz, OCH2), 4.61 (2H, s, CH2OH), 6.90 (2H, d, 7 = 8.1 Hz, 2 x Ar-H), 7.30 (2H, d, 7 = 8.1 Hz, 2 x Ar-H). "C NMR (75.5 MHz, CDCI3): δ 53.99 (2 x NCH2), 57.57 (NCH2), 64.93 (CH2OH), 65.63 (OCH2), 66.78 (2 x OCH2), 1 14.64 (C-2 & C-6), 128.59 (C-3 & C-5), 133.61 (C-1), 158.16 (C-4). HRMS m/z calculated for Cl 3H19N03 [M+H]+ 238.1438, observed [M+H]+ 238.1440.
[00272] [4-{2-(4-Methylpiperidin-l-yl)ethoxy)phenyl]methanol: The title compound was obtained as a colorless oil in 88 % yield. UV (EtOH) 225 and 272 nm. IR (nujol): 3361 , 2932, 2868, 161 1 , 151 1, 1455, 1321 , 1298, 1244, 1 172, 1053, 1009 and 821 cm' 1. Ή NMR(300 MHz, CDCI3): δ 0.95 (3H, d, 7 = 5.4 Hz, CH3), 1.28- 1.36 (3H, m, CH2 & CH), 1 .63-1.67 (2H, m, CH2), 2.08-2.16 (2H, m, NCH2), 2.79 (2H, t, J = 6.0 Hz, NCH2), 2.96-3.00 (2H, m, NCH2), 4.10 (2H, t, J = 5.7 Hz, OCH2), 4.62 (2H, s, CH2OH), 6.89 (2H, d, J = 7.8 Hz, 2 x Ar-H), 7.30 (2H, d, J = 7.5 Hz, 2 x Ar-H). ,3C NMR (75.5 MHz, CDCI3): 6 21.81 (CH,), 30.51 (CH), 34.10 (2 x CH2), 54.46 (2 x NCH2), 57.48 (NCH2), 64.88 (CH2OH), 66.00 (OCH2), 114.65 (C-2 & C-6), 128.55 (C-3 & C-5), 133.56 (C-l), 158.36 (C-4). HRMS m/z calculated for C15H23N02 [M+H]+ 250.1802, observed LM+HJ+ 250.1802.
[00273] [4-{2-(Azepan-l-yl)ethoxy}phenyl]methanoI: The title compound was obtained as a colorless oil in 82 % yield. UV Data (EtOH) λ-,ω: 225 and 267 nm. IR (nujol): 3361, 2932, 2868, 161 1 , 151 1 , 1455, 1321 , 1298, 1244, 1 172, 1053, 1009 and 821 cm 1. 'H NMR (300 MHz, CDCI3): δ 1.64-1.73 (8H, m, 4 x CH2), 2.01 (1H, brs, OH), 2.88 (4H, brs, 2 x NCH2), 3.03 (2H, t, ./ = 5.7 Hz, NCH2), 4.14 (2H, t, = 6.0 Hz, OCH2), 4.63 (2H, s, CH2OH) 6.91 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.31 (2H, d, J = 8.4 Hz, 2 x Ar-H). "C NMR (75.5 MHz, CDCI3): δ 27.03 (2 x CH2), 27.18 (2 x CH2), 55.76 (2 x NCH2), 56.29 (NCH2), 64.92 (CH2OH), 65.99 (OCH2), 1 14.64 (C-2 & C- 6), 128.62 (C-3 & C-5), 133.48 (C-l), 158.24 (C-4). HRMS m/z calculated for C15H23N02 [M+H]+ 250.1802, observed [M+Hf 250.1800.
[00274] Example 1: General procedure for the synthesis of l-(4-(2-
Figure imgf000082_0001
Scheme 5
[00275] In a dry 250 mL round bottom flask 2-naphthol ( 1.2 equiv.) was dissolved in
1 ,4-dioxane solvent. Appropriate 4-(dialkylaminoethoxy)benzyI alcohol (1 equiv.) in 1,4-dioxane solution was added to the 2-naphthol solution, followed by dropwise addition of borontrifluoride etherate (4 equiv.). The reaction mixture turned brown in color and stirring was continued at room temparature until 4-(dialkylaminoethoxy)benzyl alcohol was completely consumed. Generally, the reaction takes two days to complete and the excess of borontrifluoride was quenched with aq.NaHC03 solution. Dioxane was removed under reduced pressure. The reaction mixture was extracted with dichlromethane. The organic layer was dried over anhydrous sodium sulphate. The crude reaction
mixture was purified on silica gel using 6-10 % of methanol in dichlorometahne. The reaction gave the desired product in the yield ranging in 30-65%.
[00276] l-[4-{2-(Dimethylamino)ethoxy}benz l]naphthalen-2-ol (1): Off white solid, 45% Yield, m.p. 122-125 "C. UV (EtOH) max: 229, 280 and 334 nm. IR (Or): 3370, 3060, 2938, 2825, 1593, 1507, 1465, 1369, 1244, 1 176, 1078, 1045 and 806 cm"1. Ή NMR (300 MHz, CDClj) δ 2.43 (6H, s, 2 x NCH3), 2.83 (2H, t, J = 5.4 Hz, -NCH2), 4.01 (2H, t, J = 5.4 Hz, OCH2), 4.37 (2H, s, ArCHiAr), 6.66 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.08 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.18 (1H, d, J = 9.0 Hz, Ar-H), 7.30 ( 1H, t, J = 6.9 Hz, Ar-H), 7.42 (1H, t, J = 7.8 Hz, Ar-H), 7.66 ( 1H, d, J = 8.7 Hz, Ar-H), 7.77 (1H, d, J = 8.1 Hz, Ar-H), 7.88 ( 1H, d, J = 8.7 Hz, Ar-H). 13C NMR (75.5 MHz, CDClj): δ 29.77 (ArCHjAr), 45.22 (2 x NCH3), 57.89 (NCH2), 64.81 (OCH2), 1 14.42 (Ar), 1 18.26 (Ar), 1 18.72 (Ar), 122.64 (Ar), 123.29 (Ar), 126.31 (Ar), 128.08 (Ar), 128.46 (Ar), 129.04 (Ar), 129.22 (Ar), 133.39 (Ar), 133.78 (Ar), 152.16 (Ar), 156.50 (Ar). HRMS m/z calculated for C21H23N02 [M+H]+ 322.1802, observed [M+HJ+ 322.1790.
[00277] l-[4-{2-(Diethylamino)ethoxy}benzyl]naphthalen-2-ol (2): Off white solid,
65% yield, m.p. 105- 107 aC. UV (EtOH) Xraax: 229, 279 and 334 nm. IR (KBr): 341 1 , 3059, 2973, 2935, 2857, 1582, 1507, 1443, 1354, 1241 , 1 176, 1036, 994 and 804 cm 1. Ή NMR (300 MHz, CDClj), Figure-9: 5 1.18 (6H, t, J = 7.2 Hz, 2 x CH3), 2.76 (4H, q, J = 7.2 Hz, 2 x NCH2), 2.93 (2H, t, J = 6.0 Hz, -NCH2), 4.02 (2H, t, J = 6.0 Hz, OCH2), 4.37 (2H, s, ArCH2Ar), 6.68 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.09 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.17 (1 H, d, J = 8.7 Hz, Ar-H), 7.32 (1H, t, J = 7.8 Hz, Ar-H), 7.43 (1 H, t, J = 6.9 Hz, Ar-H), 7.65 (2H, d, J = 9.0 Hz, Ar-H), 7.76 ( 1 H, d, J = 8.1 Hz, Ar-H), 7.89 (1H, d, J = 8.4 Hz, Ar-H). , C NMR (75.5 MHz, CDC1,), Figure-10: δ 10.70 (2 x CH3), 29.82 (ArCH2Ar), 47.32 (2 x NCH2), 51.57 (NCH2), 65.39 (OCH2), 1 14.41 (Ar), 1 18.33 (Ar), 1 18.86 (Ar), 122.72 (Ar), 123.32 (Ar), 126.34 (Ar), 128.10 (Ar), 128.47 (Ar), 129.14 (Ar), 129.21 (Ar), 133.10 (Ar), 133.78 (Ar), 151.97 (Ar), 156.67 (Ar). HRMS tn/z calculated for C23H27N02 [M+H]+ 350.21 15, observed [M+H]+ 350.2101.
[00278] l-[4-(2-(Dipropylamino)ethoxy}benzyl]naphthalen-2-o] (3): Brown viscous oil, 63% Yield. Ή NMR (300 MHz, CDClj) δ 0.90 (6H, t, J = 7.2 Hz), 1.47-1 .65 (4H, m), 2.56 (4H, t, J = 7.5 Hz), 2.91 (2H, t, J = 6.3 Hz), 4.01 (2H, t, J = 6.3 Hz), 4.40 (2H, s), 6.72 (2H, d, J = 8.1 Hz), 7.08-7.19 (3H, m), 7.31 (1H, t, J = 7.5 Hz), 7.43 (1 H, t, J = 7.5 Hz), 7.70 ( 1H, d, J = 8.1 Hz), 7.80 ( 1 H, d, J = 8.1 Hz), 7.91 ( 1 H, d, J = 8.4 Hz); 13C NMR (75.0 MHz, CDCI3): δ 1 1.9, 20.3, 30.1, 53.2, 57.1 , 66.8, 1 14.9, 1 18.4, 1 19.1 , 123.1 , 123.5, 126.6, 128.4, 128.6, 129.3, 129.6, 132.6, 134.0, 151 .8, 157.5.
[00279] l-[4-{2-(Diisopropylamino)ethoxy)benzyI]naphthalen-2-ol (4): Brown viscous oil, 68% Yield. UV (EtOH) ^ax: 229, 277 and 334 nm. IR (nujol): 3385, 3057, 2967, 1610, 1507, 1436, 1359, 1242, 1174, 1029, 991 and 810 cm" 1. Ή NMR (300 MHz, CD(¾) δ 1.10 (12H, d, J = 3.9 Hz, 4 x CH3), 2.88 (2H, brs, -NCH2), 3.12 (2H, brs, 2 x NCH), 3.92 (2H, brs, 0CH2), 4.40 (2H, s, ArCH2Ar), 6.79 (2H, d, J = 1.2 Hz, 2 x Ar-H), 7.14 (2H, d, J = 7.2 Hz, 2 x Ar-H), 7.20 ( 1 H, d, J = 8.7 Hz, Ar-H), 7.36 ( 1H, t, J = 6.6 Hz, Ar-H), 7.48 (1H, t, J = 6.3 Hz, Ar-H), 7.71 (1H, d, J = 8.4 Hz, Ar-H), 7.82 ( 1H, d, J = 7.5 Hz, Ar-H), 7.95 ( 1H, d, 7 = 8.1 Hz, Ar-H). 13C NMR (75.0 MHz, CDC13): δ 20.55 (4 x CH3), 29.85 (ArCH2Ar), 44.67 (2 x NCH), 50.14 (NCH2), 68.74 (OCH2), 1 14.57 (Ar), 1 1 8.18 (Ar), 1 1 8.73 (Ar), 1 23.03 (Ar), 123.37 (Ar), 1 26.53 (Ar), 128.30 (Ar), 128.53 (Ar), 129.19 (Ar), 129.40 (Ar), 132.23 (Ar), 133.72 (Ar), 151.49 (Ar), 157.16 (Ar). HRMS m/z calculated for C25H3|N02 [M+Hf 378.2428, observed [M+Hf 378.2417.
[00280] l-[4-{2-(Pyrrolidin-l-yl)ethoxy}benzyl]naphthalen-2-ol (4): Off white solid, 56% Yield, m.p. 1 17-1 19 °C. UV (EtOH) ™„: 229, 278 and 337 nm. 1R (KBr): 3436, 3054, 2930, 2874, 1626, 151 1 , 1438, 1357, 1242, 1 174, 1057, 1000 and 812 cm ' . Ή NMR (300 MHz, CDC¾), Figure-11: δ 1.87 (4H, brs, 2 x CH2), 2.84 (4H, brs, 2 x NCH2), 3.00 (2H, brs, NCH2), 4.06 (2H, t, J = 4.8 Hz, OCH2), 4.35 (2H, s, ArCH2Ar), 6.64 (2H, d, J = 7.5 Hz, 2 x Ar-H), 7.06 (2H, d, J = 7.8 Hz, 2 x Ar-H), 7.20-7.30 (2H, m, Ar-H), 7.40 (1H, t, J = 7.2 Hz, Ar-H), 7.64 (1H, d, J = 8.7 Hz, Ar-H), 7.75 ( 1H, d, J = 8.1 Hz, Ar-H), 7.86 (1H, d, J = 8.4 Hz, Ar-H). UC NMR Data (75.5 MHz, CDCI3), Figure-12: δ 23.28 (2 x CH2), 29.76 (ArCH2Ar), 54.47 (2 x NCH2), 54.75 (NCH2), 65.45 (OCH2), 1 14.42 (Ar), 1 18.24 (Ar), 1 1 8.67 (Ar), 122.63 (Ar), 1 23.28 (Ar), 126.30 (Ar), 128.08 (Ar), 128.46 (Ar), 129.05 (Ar), 129.23 (Ar), 133.44 (Ar), 133.77 (Ar), 152.17 (Ar), 156.40 (Ar). HRMS m/z calculated for CBH25N02 [M+Hf 348.1958, observed [M+H]+ 348.1952.
[00281 ] l-[4-{2-(Piperidin-l-yl)ethoxy)benzyl]naphthalen-2-ol (6): Off white solid,
52% Yield, m.p. 171-173 °C. UV (EtOH) ^: 227, 279 and 334 nm. IR (KBr): 3358, 3055, 2937, 2845, 1582, 1508, 1435, 1355, 1274, 1 174, 1039, 996 and 810 cm 1. Ή NMR (300 MHz, CDCI3) δ 1 .38- 1.78 (6H, m, 3 x CH2), 2.97 (2H, brs, NCH2), 3.44 (4H, brs, 2 x NCH2), 4.24 (2H, brs, OCH2), 4.30 (2H, s, ArCHjAr), 6.87 (2H, d, J = 7.8 Hz, 2 x Ar-H), 7.19 (2H, d, J = 8. 1 Hz, 2 x Ar-H), 7.27 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.40 ( 1H, t, J = 7.2 Hz, Ar-H), 7.71 (1H, d, J = 8.7 Hz, Ar-H), 7.79 (1 H, d, J = 8.1 Hz, Ar-H), 7.86 (1H, d, J = 8.4 Hz, Ar-H), 9.63 (IH, brs, OH). I3C NMR (75.5 MHz, CDCI3): δ 21.60 (CH2), 22.91 (2 x CH2), 29.47 (ArCH2Ar), 53.19 (2 x NCH2), 55.36 (NCH2), 62.54 (OC¾), 1 14.97 (Ar), 1 18.63 (Ar), 1 18.69 (Ar), 122.70 (Ar), 123.47 (Ar), 126.55 (Ar), 128.20 (Ar), 128.79 (Ar), 129.66 (Ar), 133.68 (Ar), 134.79 (Ar), 152.92 (Ar), 155.99 (Ar). HRMS m/z calculated for C24H27N02 [M+H]+ 362.21 15, observed [M+Hf 362.21 12.
[00282] l-{4-(2-Morpholinoethoxy)benzyl}naphthalen-2-ol (7): Off white solid, 70
% Yield, m.p. 129-132 °C. UV (EtOH) Xmax: 227, 277 and 336 nm. IR (KBr): 3378, 2935, 2866, 2813, 1610, 151 1 , 1438, 1358, 1297, 1240, 1059, 982 and 815 cm"1. 'H NMR (300 MHz, CDC13), Figure-13: δ 2.69 (4H, brs, 2 x NCH2), 2.86 (2H, t, J = 5.1 Hz, NCH2), 3.78 (4H, brs, 2 x OCH2), 4.07 (2H, t, J = 4.8 Hz, OCH2), 4.37 (2H, s, ArCH2Ar), 6.69 (2H, d, J = 8. 1 Hz, 2 x Ar-H), 7.08 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.19 ( 1H, d, J = 8.7 Hz, Ar-H), 7.82-7.34 (1H, m, Ar-H), 7.42 (1H, t, J = 7.2 Hz, Ar-H), 7.67 (1 H, d, J = 8.7 Hz, Ar-H), 7.78 ( 1H, d, J = 8.1 Hz, Ar-H), 7.88 ( 1 H, d, J = 8.4 Hz, Ar-H). 13C NMR (75.5 MHz, CDCI3), Figure-14: δ 29.76 (ArCH2Ar), 53.69 (2 x NCH2), 57.46 (NCHj), 64.73 (OCH2), 66.06 (2 x OCH2), 1 14.56 (Ar), 1 18.08 (Ar), 1 18.53 (Ar), 122.96 (Ar), 123.29 (Ar), 126.51 (Ar), 128.29 (Ar), 128.53 (Ar), 129.22 (Ar), 129.29 (Ar), 133.06 (Ar), 134.71 (Ar), 151.56 (Ar), 156.54 (Ar). HRMS m/z calculated for C23H25N03 [M+H]+ 364.1907, observed [M+H]+ 364.1904.
[00283] l-[4-{2-(4-Methylpiperidin-l-yl)ethox }benz l]naphthalen-2-ol (8): Off white solid, 65% Yield, m.p.154-156 °C. UV (EtOH) X-,ax: 229, 279 and 334 nm. IR (KBr): 3408, 3057, 2947, 2930, 2869, 2795, 1608, 1507, 1357, 1267, 1241, 1 177, 1060, 984 and 814 cm"1. Ή NMR (300 MHz, CDC1,), Figure-7: δ 0.85 (3H, d, J = 6.3 Hz, CH3), 1.03-1.16 (2H, m, CH2), 1.22- 1.32 (1 H, m, CH), 1.50-1.54 (2H, m, CH2), 1.90 1.97 (2H, m, NCH2), 2.61 (2H, t, J = 5.7 Hz, NCH2), 2.81-2.85 (2H, m, NCH2), 3.96 (2H, t, J = 6.0 Hz, OCH2), 4.28 (2H, s, ArCH2Ar), 6.76 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.1 1 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.21-7.27 (2H, m, 2 x Ar-H), 7.37 ( 1H, t, J = 7.2 Hz, Ar-H), 7.68 ( 1H, d, J = 9.0 Hz, Ar-H), 7.77 ( 1 H, d, J = 8.1 Hz, Ar-H), 7.85 ( 1H, d, J = 8.4 Hz, Ar-H). I3C NMR (75.5 MHz, CDClj), Figure-8: δ 22.28 (CH3), 29.48 (ArCH2Ar), 30.64(CH), 34.45 (2 x CH2), 54.24 (2 x NCH2), 57.49 (NCH2), 66.04 (OCH2), 1 14.66 (Ar), 1 18.65 (Ar), 1 18.81 (Ar), 122.66 (Ar), 123.51 (Ar), 126.53 (Ar), 128.1 1 (Ar), 128.75 (Ar), 129.51 (Ar), 133.69 (Ar), 133.74 (Ar), 152.93 (Ar), 156.94 (Ar). HRMS m/z calculated for C25H,,N02 [M+H|+ 376.2271 , observed [M+H]+ 376.2266.
[00284] l-[4-{2-(Azepan-l-yl)ethoxy}benzyl]naphthalen-2-ol (9): Off white solid,
70% Yield, m.p. 125-128 "C. UV (EtOH) max: 229, 276 and 336 nm. IR (KBr): 3415, 3060, 2926, 2851,1609, 1508, 1435, 1354, 1257, 1242, 1174, 1034, 994 and 804 cm"1. Ή NMR (300 MHz, CDClj): δ 1.62-1.71 (8H, m, 4 x CH2), 2.83-2.86 (4H, m, 2 x NCH2), 2.98 (2H, t, J = 5.4 Hz, NCH2), 4.04 (2H, t, J = 5.7 Hz, OCH2), 4.38 (2H, s, ArCH2Ar), 6.72 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.20 (1H, d, J = 8.7 Hz, Ar-H), 7.32 (1H, t, J = 8.1 Hz, Ar-H), 7.43 (1H, t, J = 7.2 Hz, Ar-H), 7.68 (1 H, d, J = 8.7 Hz, Ar-H), 7.78 (1H, d, J = 8.1 Hz, Ar-H), 7.90 (1H, d, J = 8.4 Hz, Ar-H). 13C NMR (75.5 MHz, CDClj): δ 26.84 (2 x CH2), 27.04 (2 x CH,), 29.81 (ArCH,Ar), 55.77 (2 x NCH2), 56.20 (NCH2), 65.68 (OCH2), 1 14.55 (Ar), 1 18.16 (Ar), 1 18.70 (Ar), 122.84 (Ar), 123.31 (Ar), 126.42 (Ar), 128.20 (Ar), 128.48 (Ar), 129.16 (Ar), 129.21 (Ar), 129.89 (Ar), 132.68 (Ar), 133.72 (Ar), 151.77 (Ar), 156.91 (Ar). HRMS m/z calculated for C25H2[,N02 [M+H]+ 376.2271, observed [M+H]+ 376. 2265.
Figure imgf000086_0001
Figure imgf000086_0002
Scheme 6: Synthetic Scheme for potential SERMs 11-60
[00285] Example 2: General procedure for the synthesis of 2-((l-(4-(2- (dialkylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)ethanols (Compounds 11, 12, 14-19): To a solution of appropriate l-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalene-2-ol (1-10; 1.32 mmol), anhydrous K2C03 (5.3 mmol) in dimethylformamide was refluxed for 2 h. The reaction mixture was allowed cool down to the room temperature and catalytic amount of potassium iodide, followed by bromoethanol (5.3 mmol) was added and the reaction mixture was once again stirred and heated at 130°C for 20 h. After completion of the reaction, inorganic salts were filtered off, solvent was removed under reduced pressure. The residue was taken in ethyl acetate and washed with 2N NaOH and water. The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure and the resulting residue was purified by column chromatoghaphy over silica gel using methanol-dichloromethane (6-8%) as eluent to afford pure products as a light brown viscous oil
56-76% yield. The structures of the products were unambiguously established from the analysis of their spectral data (IR, Ή, l3C NMR and mass spectra).
[00286] 2-(l-(4-(2-(Dimethylamino)ethoxy)benzyl)naphthalen-2-yIoxy)ethanol (11): The title compound 11 was obtained as light brown viscous oil in 56% yield by following the general procedure outlined above. UV Data (EtOH) λ^: 229, 280 and 334 nm. IR (nujol): 3370, 3060, 2938, 2825, 1593, 1509, 1465, 1369, 1244, 1 176, 1078 and 806 cm"1 . Ή NMR (CDC13, 300 MHz) δ 2.35 (6H, s, 2 x NCH3), 2.73 (2H, t, J = 5.4 Hz, NCH2), 3.90 (2H, t, J = 4.5 Hz, CH2OH), 4.02 (2H, t, J = 4.5 Hz, OCH2), 4.1 (2H, t, J = 4.5 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.81 (2H, d, J = 7.2 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.39 (2H, m, 2 x Ar-H), 7.46 (1H, I, J = 7.5 Hz, Ar-H), 7.81 (2H, t, J = 8.1 Hz, 2 x Ar-H), 7.99 (1H, d, J = 8.7 Hz, Ar-H). 13C NMR Data (75.0 MHz, CDC13): δ 29.94 (ArCHjAr), 45.72 (2 x NCH3), 58.18 (NCH2), 61.66 (CH2OH), 65.77 (OCH2), 70.91 (OCH2), 1 14.59 (Ar), 1 14.77 (Ar), 122.72 (Ar), 123.58 (Ar), 123.75 (Ar), 126.60 (Ar), 128.37 (Ar), 128.48 (Ar), 129.60 (Ar), 133.40 (Ar), 133.46 (Ar), 153.86 (Ar), 156.92 (C-4). HRMS m/z calculated for C23H37N03 [M+H]+ 366.2064, observed [M+H]+ 366.2057.
[00287] 2-(l-(4-(2-(Diethylamino)ethoxy)benzyl)naphthalen-2-yloxy)ethanoI (12):
The title compound was obtained as light brown viscous oil in 56% yield by following the general procedure outlined above. UV Data (EtOH) ,^: 227, 279 and 327 nm. IR (nujol): 3342, 3065, 2968, 2932, 2872, 1594, 1503, 1467, 1380, 1244, 1 157, 1079 and 805 cm"1. ]Η NMR (CDCI3, 300 MHz): δ 1.08 (6H, t, J -= 6.9 Hz, 2 x CHj), 2.66 (4H, q, J = 7.2 Hz, 2 x NCH2), 2.87 (2H, t, J = 6.3 Hz, -NCH2), 3.90 (2H, t, J = 4.5 Hz, CH2OH), 4.01 (2H, t, J = 5.7 Hz, OCH2), 4.19 (2H, t, J = 4.5 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.80 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.29-7.39 (2H, m, 2 x Ar-H), 7.47 ( 1H, t, J = 7.2 Hz, Ar-H), 7.81 (2H, t, = 8.1 Hz, 2 x Ar-H), 7.99 (1H, d, J = 8.7 Hz, Ar-H). "C NMR Data (CDCl.,,75.5 MHz): δ 1 1.67 (2 x CH3), 29.94 (ArCH2Ar), 47.75 (2 x NCH2), 51.70 (NCH2), 61.64 (CH2OH), 66.26 (OCH2), 70.90 (OCH2), 1 14.53 (Ar), 1 14.78 (Ar), 122.74 (Ar), 123.58 (Ar), 123.76 (Ar), 126.60 (Ar), 128.36 (Ar), 128.48 (Ar), 128.95 (Ar), 129.60 (Ar), 133.29 (Ar), 133.47 (Ar), 153.86 (Ar), 156.99 (C-4). HRMS m/z calculated for C25H31N03 [M+H]+ 394.2377, observed [M+H]+ 394.2374.
[00288] 2-(l-(4-(2-(Diisopropyl)ethoxy)benzyl)naphthalen-2-yloxy)ethanol (14): The title compound was obtained as light brown viscous oil in 63% yield by following the general procedure outlined above. UV Data (EtOH) λ-™: 229, 280 and 334 nm. IR (nujol): 3298, 3060, 2968, 2868, 1597, 1508, 1465, 1372, 1263, 1 176, 1071, 990 and 806 cm"1. Ή NMR (CDCI3, 300 MHz): δ 1.08 (12H, d, J = 5.7 Hz, 4 x CH3), 2.83 (2H, brs, NCH2), 3.09 (2H, brs, 2 x NCH), 3.91 (4H, t, J = 4.5 Hz, CH2OH & OCH2), 4.20 (2H, t, J = 4.5 Hz, OCH2), 4.45 (2H, s, ArCH2Ar), 6.80 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.10 (2H, d, / = 8.4 Hz, 2 x Ar-H), 7.28-7.37 (2H, m, 2 x Ar-H), 7.45 ( 1H, t, J = 7.5 Hz, Ar-H), 7.82 (2H, t, J = 7.5 Hz, 2 x Ar-H), 8.00 (1H, d, J = 8.4 Hz, Ar-H). 13C NMR Data (75.0 MHz, CDCI3): δ 20.63 (4 x CH3), 29.95 (ArCH2Ar), 44.58 (2 x NCH), 49.87 (NCH2), 61.71 (CH2OH), 68.74 (OCH2), 70.85 (OCH2), 1 14.48 (Ar), 1 14.74 (Ar), 122.76 (Ar), 123.35 (Ar), 123.76 (Ar), 126.61 (Ar), 128.25 (Ar), 128.37 (Ar), 129.18 (Ar), 129.61 (Ar), 133.13 (Ar), 133.48 (Ar), 153.82 (Ar), 157.04 (C-4). HRMS m/z calculated for C27¾5N03 [M+Hl+422.2690, observed [M+H]+ 422.2687.
[00289] 2-(l-(4-(2-(Pyrrolidin-l-yl)ethoxy)benz l)naphthalen-2-yloxy)ethanol
(15) . The title compound was obtained as light brown viscous oil in 58% yield by following the general procedure outlined above. UV Data (EtOH) λ„,»χ: 229, 280 and 334 nm. 1R (nujol): 3352, 3054, 2931, 2874, 2814, 1594, 1510, 1463, 1245, 1 176, 1077 and 806 cm"1. Ή NMR (CDC1„ 300 MHz) δ 1.81 (4H, s, 2 x CH2), 2.64 (4H, s, 2 x NCH2), 2.89 (2H, t, J = 6.0 Hz, NCH2), 3.90 (2H, t, J = 4.5 Hz, CH2OH), 4.06 (2H, t, J = 6.0 Hz, OCH2), 4.19 (2H, t, J = 4.5 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.81 (2H, d, J = 8.7 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.29-7.39 (2H, m, 2 x Ar-H), 7.46 (1H, t, .7 = 7.5 Hz, Ar-H), 7.81 (2H, t, J = 8.1 Hz, 2 x Ar-H), 7.99 (1 H, d, J = 8.7 Hz, Ar-H). "C NMR Data (75.0 MHz, CDC13): 5 23.46 (2 x CH2), 29.94 (ArCH2Ar), 54.63 (2 x NC¾), 55.02 (NCH2), 61.65 (CH2OH), 66.82 (OCH2), 70.92 (OCH2), 114.60 (Ar), 114.79 (Ar), 122.74 (Ar), 123.57 (Ar), 123.76 (Ar), 126.59 (Ar), 128.36 (Ar), 128.47 (Ar), 128.94 (Ar), 129.60 (Ar), 133.34 (Ar), 133.46 (Ar), 153.86 (Ar), 156.97 (C-4). HRMS m/z calculated for C25H29N03 [M+H]÷392.2220, observed [M+H]+ 392.2221.
[00290] 2-(l-(4-(2-(Piperidin-l-yl)ethoxy)benzyl)naphthalen-2-yloxy)ethanol
(16) : The title compound was obtained as light brown viscous oil in 76 % yield by following the general procedure outlined above. UV Data (EtOH) „a : 229, 280 and 332 nm. IR (nujol): 3358, 3058, 2935, 2855, 1594, 1510, 1454, 1394, 1262, 1244, 1176, 1078, 1046 and 805 cm 1. Ή NMR (CDCI3, 300 MHz): δ 1.45-1.46 (2H, m, CH2), 1.60-1.64 (4H, m, CH2), 2.52 (4H, brs, 2 x NCH2), 2.76 (2H, t, J = 6.0 Hz, 2 x NCH2), 3.91 (2H, t, J = 4.5 Hz, CH2OH), 4.06 (2H, t, J = 6.0 Hz, OCH2), 4.21 (2H, t, J = 3.9 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.79 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.09 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.29-7.39 (2H, m, 2 x Ar-H), 7.46 (1 H, t, J = 6.9 Hz, Ar-H), 7.81 (2H, t, J = 7.5 Hz, Ar-H), 7.98 (1H, d, J = 8.7 Hz, Ar-H). 13C NMR Data (75.5 MHz, DMSO): δ 24.07 (CH2), 25.74 (2 x CH2), 29.93 (ArCH2Ar), 54.93 (2 x NCH2), 57.85 (NCH2), 61.65 (CH2OH), 65.71 (OCH2), 70.89 (OCH2), 1 14.60 (Ar), 1 14.75 (Ar), 122.71 (Ar). 123.58 (Ar). 123.74 (Ar), 126.60 (Ar), 128.36 (Ar), 128.47 (Ar), 128.93 (Ar), 129.95 (Ar), 133.32 (Ar), 133.45 (Ar), 153.84 (Ar), 156.93 (C-4). HRMS m/z calculated for C2(,H3 lN03 [M+H1+406.2377, observed [M+H]+ 406.2374.
[00291 ] 2-(l-(4-(2-Morpholinoethoxy)benzyi)naphthalen-2-yloxy)ethanol (17): The title compound was obtained as light brown viscous oil in 69% yield by following the general procedure outlined above. UV Data (EtOH) raax: 229, 280 and 332 nm. IR (nujol): 3445, 2934, 2866, 1597, 1510, 1445, 1361 , 1241 , 1 176, 1 1 15, 1069. 910 and 807 cm"1. Ή NMR δ 2.38 (1H, s, CHjOH), 2.56 (4H, t, J = 4.5 Hz, 2 x NCH2), 2.76 (2H, t, J = 5.7 Hz, NCH2), 3.74 (4H, t, J = 4.5 Hz, 2 x OCH2), 3.90 (2H, t, J = 4.2 Hz, OCH2), 4.04 (2H, t, J = 5.4 Hz, OCH2), 4.19 (2H, t, J = 4.2 Hz, OCH2), 4.45 (2H, s, ArCH2Ar), 6.80 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.12 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.29-7.40 (2H, m, 2 x Ar-H), 7.47 (1 H, t, J = 7.2 Hz, Ar-H), 7.82 (2H, t, J = 8.7 Hz, 2 x Ar-H), 7.99 ( I H, d, J = 8.4 Hz, Ar-H). 13C NMR Data (75.5 MHz, CDC13): δ 29.94 (ArCH2Ar), 54.04 (2 x NCH2), 57.66 (NCH2), 61.63 (CH2OH), 65.70 (OCH2), 66.88 (2 x OCH2), 70.96 (OCH2), 1 14.63 (Ar), 1 14.83 (Ar), 122.70 (Ar), 123.61 (Ar), 123.76 (Ar), 126.62 (Ar), 128.41 (Ar), 128.52 (Ar), 129.01 (Ar), 129.22 (Ar), 133.46 (Ar), 133.51 (Ar), 153.89 (Ar), 156.89 (C-4). HRMS m/z calculated for C25H29NO4 LM+H]+ 408.2169, observed [M+H]+ 408.2158.
[00292] 2-(l-(4-(2-(4-Methylpiperidin-l-yl)ethoxy)ben2yl)naphthalen-2- y!oxy)ethanol (18): The title compound was obtained as light brown viscous oil in 66% yield by following the general procedure outlined above. UV Data (EtOH) λ-,8Χ: 229, 277 and 332 nm. IR (nujol): 3370, 2924, 2870, 1623, 1595, 1510, 1455, 1245, 1 176, 1081 and 805 cm 1. Ή NMR δ 0.94 (3H, d, J = 5.7 Hz, CH,), 1.28-1.34 (3H, m, CH & CH2), 1.61-1.65 (2H, m, CH2), 2.05-2.12 (3H, t, J = 10.5 Hz, NCH2 & OH), 2.77 (2H, t, J = 6.0 Hz, NCH2), 2.94-2.98 (2H, m, NCH2), 3.91 (2H, t, J = 4.5 Hz, CH2OH), 4.06 (2H, t, J = 6.0 Hz, OCH2), 4.20 (2H, t, J = 4.5 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.79 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.39 (2H, m, 2 x Ar-H), 7.46 ( 1H, t, J = 8.4 Hz, Ar-H), 7.82 (2H, t, J = 7.2 Hz, 2 x Ar-H), 7.99 (1 H, d, J = 8.4 Hz, Ar-H). I3C NMR Data (75.5 MHz, CDCI3): δ 21.83 (CH,), 29.94 (ArCH2Ar), 30.52 (CH), 34.13 (2 x CH2), 54.41 (2 x NCH2), 57.53 (NCH2), 61.68 (CH2OH), 65.87 (OCH2), 70.87 (OCH2), 1 14.61 (Ar), 1 14.72 (Ar), 122.71 (Ar), 123.58 (Ar), 123.74 (Ar), 126.61 (Ar), 128.37 (Ar), 128.48 (Ar), 128.92 (Ar), 129.60 (Ar), 129.90 (Ar), 133.29 (Ar), 133.46 (Ar), 153.82 (Ar), 156.97 (C-4). HRMS m/z calculated for C27H33N03 [M+H]+ 420.2533, observed [M+H]+ 420.2527.
[00293] 2-(l-(4-(2-(Azepan-l-yl)ethoxy)benzyl)naphthaIen-2-yloxy)ethanol (19): The title compound was obtained as light brown viscous oil in 58% yield by following the general procedure outlined above. UV Data (EtOH) -,^: 229, 280 and 334 nm. IR (nujol): 3371 , 2925, 2856, 1623, 1594, 1515, 1467, 1244, 1 172, 1079 and 805 cm"1. Ή NMR (CDC13, 300 MHz): δ 1.62- 1.66 (8H, m, 4 x CH2), 2.64 ( 1 H, brs, OH), 2.76-2.78 (4H, m, 2 x NCH2), 2.93 (2H, t, J = 5.7 Hz, NCH2), 3.91 (2H, t, J = 3.9 Hz, OCH2), 4.02 (2H, t, J = 6.3 Hz, OCH2), 4.19 (2H, t, J = 3.9 Hz, OCH2), 4.45 (2H, s, ArCH2Ar), 6.80 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.1 1 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.29-7.40 (2H, m, 2 x Ar-H), 7.47 ( 1H, t, J = 7.2 Hz, Ar-H), 7.82 (2H, t, J = 8.1 Hz, 2 x Ar-H), 8.00 ( 1H, d, J = 8.4 Hz, Ar-H). I3C NMR Data (75.5 MHz, CDC13): δ 27.07 (2 x CH2), 27.71 (2 x CH2), 29.95 (ArCH2Ar), 55.79 (2 x NCHa), 56.35 (NCH,), 61.66 (CH2OH), 66.28 (OCH,), 70.91 (OCH,), 1 14.60 (Ar), 1 14.78 (Ar), 122.74 (Ar), 123.58 (Ar), 123.77 (Ar), 126.60 (Ar), 128.36 (Ar), 128.49 (Ar), 128.95 (Ar), 129.21 (Ar), 133.26 (Ar), 133.47 (Ar), 153.86 (Ar), 157.05 (C-4). HRMS m/z calculated for C27H33NO3 [M+H]+ 420.2533, observed [M+H]+ 420.2532.
[00294] Example 3: General procedure for the synthesis of 2-((l-(4-(2-
(dialkylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)propanols (Compounds 21, 22, 24-29): To a solution of appropriate 1 -(4-(2-(dialkylamino)ethoxy)benzyl)naphthalene-2-ol (1-10, 1.38 mmol) and potassium carbonate (5.54 mmol) in dimethylformamide ( 15 ml), the reaction mixture was heated at 1 30°C for 2 h. Reaction mixture was then cooled to room temperature when 1-bromopropanol (5.54 mmol) was added and the reaction mixture was again heated to 130"C and while regularly monitoring the reaction progress by TLC using 10% methanol-dichloromethane as the solvent system. The reaction was generally complete in 13-16 h. After the completion of reaction, the reaction mixture was suction filtered and the solvent was removed in-vacuo. The residue was taken in ethylacetate and washed with 2N NaOH and water. The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure and the resulting residue was purified by column chromatoghaphy over silica gel using methanol-dichloromethane (6-8%) as eluent to afford pure products as a light brown viscous oil 56-76% yield. The structures of the products were unambiguously established from the analysis of their spectral data (IR, Ή, "c NMR and mass spectra).
[00295] 3-(l-(4-(2-(Dimethylamino)ethoxy)benzyl)naphthalen-2-yIoxy)propan-l- ol (21): The title compound was obtained as light brown viscous oil in 32% yield by following the general procedure outlined above. UV Data (EtOH) λ™,: 229, 281 and 336 nm. IR (nujol): 3361, 3056, 2936, 2871 , 2823, 1594, 1503, 1466, 1244, 1 176, 1077, 1046 and 806 cm 1. Ή NMR δ 2.04 (2H, pent., J = 6.0, CH2), 2.56 (6H, s, 2 x NCH3), 3.03 (2H, t. J = 5.1 Hz, NCH:), 3.78 (2H, t, J = 6.0 Hz, C¾OH), 4.14 (2H, t, J = 4.8 Hz, OCH2), 4.23 (2H, l, J = 6.0 Hz, OCH2), 4.41 (2H, s, ArCH2Ar), 6.78 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.36 (2H, m, 2 x Ar-H), 7.43 (1 H, t, J = 6.9 Hz, Ar-H), 7.77-7.81 (2H, m, 2 x Ar-H), 7.94 (1H, d, J = 8.4 Hz, Ar-H). "C NMR Data (75.5 MHz, CDCIj): δ 29.85 (ArCH2Ar), 32.46 (CH,), 44.80 (2 x NCH3), 57.40 (NCH2), 60.02 (CH2OH), 64.00 (OCH2), 66.77 (OCH2), 1 14.53 (Ar), 122.15 (Ar), 123.42 (Ar), 123.67 (Ar), 126.54 (Ar), 128.35 (Ar), 128.48 (Ar), 129.24 (Ar), 129.39 (Ar), 1 33.35 (Ar), 134.46 (Ar), 154.02 (Ar), 155.98 (C-4). HRMS m/z calculated for C24H33NO, [M+H]+ 380.2220, observed [M+H]+ 380.2212.
[00296] 3-(l-(4-(2-(Diethylamin )ethoxy)benzyl)naphthalen-2-yloxy)propan-l-ol (22): The title compound was obtained as light brown viscous oil in 61 % yield by following the general procedure outlined above. UV Data (EtOH) λ™χ: 229, 280 and 335 nm. IR (nujol): 3364, 3056, 2967, 2932, 2875, 1594, 1507, 1463, 1244, 1 175, 1078, 1045 and 807 cm"1. ]H NMR (CDCI3, 300 MHz): δ 1.10 (6H, t, / = 6.9 Hz, 2 x CH,), 2.04 (2H, pent., J = 6.0 Hz, CH2), 2.71 (4H, q, J = 7.2 Hz, 2 x NCH2), 2.91 (2H, t, J = 6.3 Hz, -NCH2), 3.79 (2H, t, J = 6.0 Hz, CH2OH), 4.04 (2H, t, J = 6.3 Hz, OCH2), 4.24 (2H, t, ./ = 5.7 Hz, OCH2), 4.42 (2H, s, ArCH Ar), 6.78 (2H, d, / = 8.1 Hz, 2 x Ar, 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H). 7.28-7.37 (2H, m, 2 x Ar-H), 7.44 ( 1H, t, J = 7.2 Hz, Ar-H), 7.80 (2H, t, J = 6.6 Hz, 2 x Ar-H), 7.95 ( 1H, d, J = 8.4 Hz, Ar-H). I3C NMR Data (CDCl.,, 75.5 MHz): δ 1 1.36 (2 x CH,), 29.86 (ArCH2Ar), 32.45 (CH2), 47.68 (2 x NCH2), 51.59 (NCH2), 60.03 (CH2OH), 65.90 (OCH2), 66.85 (OCH2), 1 14.39 (Ar), 1 14.64 (Ar), 122.33 (Ar), 123.39 (Ar), 123.78 (Ar), 126.47 (Ar). 128.28 (Ar), 128.43 (Ar), 129.09 (Ar), 129.44 (Ar), 133.42 (Ar), 1 54.06 (AT), 156.73 (C-4). HRMS m/z calculated for C26H33N03 [M+H]+ 408.2533, observed LM+HJ+ 408.2521.
[00297] 3-(l-(4-(2-(Diisoproply)ethoxy)benzyI)naphthalen-2-yloxy)propan-l-ol (24): The title compound was obtained as light brown viscous oil in 72% yield by following the general procedure outlined above. UV Data (EtOH) J : 233, 280 and 335 nm. IR (nujol): 3369, 2965, 2875, 1610, 1595, 1510, 1464, 1379, 1245, 1 175, 1078, 1055 and 807 cm"'. Ή NMR δ 1 .08 ( 12H, d, J = 4.8 Hz, 4 x CH3), 1.86 (IH, brs, OH), 2.05 (2H, pent., J = 6.0 Hz, CH2), 2.83 (2H, brs, NCH2), 3.09 (2H, brs, 2 x NCH), 3.81 -3.89 (4H, m, CH2OH & OCH2), 4.25 (2H, t, J = 6.0 Hz, OCH2), 4.44 (2H, s, ArCH2Ar), 6.80 (2H, d, ./ = 8.4 Hz, 2 x Ar-H), 7.1 1 (2H, d, J = 7.5 Hz, 2 x Ar-H), 7.33-7.38 (2H, ra, 2 x Ar-H), 7.45 (I H, t, J = 7.2 Hz, Ar-H), 7.81 (2H, t, J = 6.3 Hz, 2 x Ar-H), 7.97 ( 1H, d, J = 8.4 Hz, Ar-H). 13C NMR Data (75.5 MHz, CDClj): δ 20.69 (4 x CH3), 29.87 (ArCH2Ar), 32.44 (CH2), 44.60 (2 x NCH), 49.86 (NCH2), 60.15 (CH2OH), 66.91 (OC¾), 69.07 (OCH2), 1 14.34 (Ar), 1 14.67 (Ar), 122.41 (Ar), 123.41 (Ar), 123.83 (Ar), 126.48 (Ar), 128.27 (Ar), 128.43 (Ar), 129.07 (Ar), 129.47 (Ar), 133.12 (Ar), 133.46 (Ar), 154.06 (Ar), 156.95 (C-4). HRMS m/z. calculated for C28H37N03 [M+H]+ 436.2846, observed [M+H]+ 436.2833.
[00298] 3-(l-(4-(2-(Pyrrolidin-l-yl)ethoxy)benzyl)naphthalen-2-yloxy)propan-l- ol (25): The title compound was obtained as light brown viscous oil in 57% yield by following the general procedure. UV Data (EtOH) 229, 280 and 329 nm. IR (nujol): 3345, 3056, 2933, 2874, 2814, 1594, 1507, 1464, 1245, 1076, 1049 and 805 cm" 1. Ή NMR δ 1 .83 (4H, s, 2 x CH2), 2.03 (2H, pent., J = 6.0 Hz, CH2), 2.63 (4H, s, 2 x NCH,), 2.91 (2H, t, J = 5.7 Hz, NCH2), 3.78 (2H, t, / = 6.0 Hz, CH2OH), 4.08 (2H, t, J = 6.0 Hz, OCH2), 4.23 (2H, t, J = 6.0 Hz, OCH2), 4.42 (2H, s, ArCH2Ar), 6.79 (2H, d, J = 8.4 Hz. 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.37 (2H, m, 2 x Ar-H), 7.44 ( IH, t, J = 6.9 Hz, Ar-H), 7.80 (2H, t, J = 7.2 Hz, 2 x Ar-H), 7.95 (IH, d, J = 8.4 Hz, Ar-H). I3C NMR Data (75.5 MHz, CDCI3): δ 27.32 (2 x CH2), 33.76 (ArCH2Ar), 33.36 (CH2), 58.49 (2 x NCH2), 58.83 (NCH2), 63.83 (CH2OH), 70.44 (OCH2), 70.69 (OCH2), 1 18.35 (Ar), 1 18.52 (Ar), 126.21 (Ar), 127.26 (Ar), 127.67 (Ar), 130.35 (Ar), 132.15 (Ar), 132.32 (Ar), 132.97 (Ar), 133.32 (Ar), 137.34 (Ar), 157.95 (Ar), 160.63 (C-4). HRMS m/z calculated for C26H31N03 LM+HJ+ 406.2377, observed [M+H1+ 406.2369.
[00299] 3-(l-(4-(2-(Piperidin-l-yl)ethoxy)benzyl)naphthalen-2-yIoxy)propan-l-ol (26): The title compound was obtained as light brown viscous oil in 60% yield by following the general procedure outlined above. UV Data (EtOH) X^: 229, 280 and335 nm. IR (nujol): 3370. 3055, 2935, 2878, 1610, 1594, 1507, 1464, 1434, 1244, 1 176, 1078 and 807 cm"1. Ή NMR δ 1.46- 1.48 (2H, m, CH2), 1.64-1.68 (4H, in, CH2), 2.58 (4H, brs, 2 x NCH2), 2.81 (2H, t, J = 5.7 Hz, 2 x NCH2). 3.80 (2H, t, J = 5.7 Hz, CH2OH), 4.10 (2H, t, J = 5.7 Hz, OCH2), 4.24 (2H, t, J = 5.7 Hz, OCH2), 4.42 (2H, s, ArCH2Ar), 6.78 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.09 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.28-7.36 (2H, m, 2 x Ar-H), 7.44 (IH, t, J = 7.2 Hz, Ar-H), 7.80 (2H, t, J = 6.3 Hz, Ar-H), 7.95 ( IH, d, J = 8.7 Hz, Ar-H). 13C NMR Data (75.5 MHz, DMSO): δ 23.84 (CH2), 25.43 (2 x CH2), 29.86 (ArCH2Ar), 32.46 (CH2), 54.83 (2 x NCH2), 57.69 (NCH2), 60.04 (CH2OH), 65.41 (OCH2), 66.86 (OCH2), 1 14.46 (Ar), 1 14.63 (Ar), 122.31 (Ar), 123.39 (Ar), 123.78 (Ar), 126.48 (Ar), 128.28 (Ar), 128.43 (Ar), 129.95 (Ar), 133.43 (Ar), 133.46 (Ar), 154.05 (Ar), 156.66 (C-4). HRMS m z calculated for C27H33N03 [M+H]+ 420.2533, observed [M+H]+ 420.2524. [00300] 3-(l-(4-(2-Morpholinoethoxy)benzyl)naphthalen-2-yloxy)propan-l-ol
(27): The title compound was obtained as light brown viscous oil in 60% yield by following the general procedure outlined above. UV Data (EtOH) λ™*: 229, 280 and 332 nm. IR (nujol): 3406, 3055, 2933, 2871 , 1610, 1594, 1510, 1463, 1263, 1245, 1 176, 1078 and 807 cm"1. Ή NMR δ 1.91 ( 1H, brs, OH), 2.05 (2H, pent., J = 6.0 Hz, CH2), 2.59 (4H, brs, 2 x NCH2), 2.79 (2H, t, J = 5.1 Hz, NCH2), 3.73-3.82 (6H, t, J = 4.5 Hz, 2 x OCH2 & CH2OH), 4.07 (2H, t, 7 = 5.1 Hz, OCH2), 4.25 (2H, t, J = 6.0 Hz, OCH2), 4.43 (2H, s, ArCH2Ar), 6.79 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.1 1 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.37 (2H, m, 2 x Ar-H), 7.44 (1H, t, J = 7.2 Hz, Ar-H), 7.78-7.83 (2H, m, 2 x Ar- H), 7.95 ( 1H, d, J = 8.4 Hz, Ar-H). 13C NMR Data (75.5 MHz, CDC13): δ 29.86 (ArCH2Ar), 32.45 (CH2), 53.97 (2 x NCH2), 57.62 (NCH2), 60.12 (CH2OH), 65.55 (OCH2). 66.73 (2 x OCH2), 66.86 (OCH2), 1 14.48 (Ar), 1 14.61 (Ar), 122.28 (Ar), 123.42 (Ar), 123.77 (Ar), 126.49 (Ar), 128.31 (Ar), 128.45 (Ar), 129.10 (Ar), 129.45 (Ar), 133.42 (Ar), 133.51 (Ar), 154.04 (Ar), 156.71 (C-4). HRMS m/z calculated for C26H3|N04 [M+Hf 422.2326, observed [M+H]+ 422.2322.
[00301] 3-(l-(4-(2-(4-Methylpiperidin-l-yl)ethoxy)benzyl)naphthalen-2- yloxy)propan-l-ol (28): The title compound was obtained as light brown viscous oil in 62% yield by following the general procedure outlined above. UV Data (EtOH) ™,: 229, 280 and 334 nm. IR (nujol): 3363, 3057, 2924, 2873, 1595, 1510, 1464, 1371 , 1244, 1 176, 1078 and 807 cm 1. Ή NMR δ 0.95 (3H, d, ./ = 5.4 Hz, CH3), 1 .32-1.38 (3H, m, CH & CH2), 1.63- 1.66 (2H, m, CH2), 2.02-2.18 (5H, m, CH2, NCH2 & OH), 2.80 (2H, t, J = 5.7 Hz, NCH2), 2.98-3.02 (2H, m, NCH2), 3.80 (2H, t, J = 5.7 Hz, CH2OH), 4.09 (2H, t, J = 5.7 Hz, OCH2), 4.24 (2H, t, ./ = 6.0 Hz, OCH2), 4.42 (2H, s, ArCH2Ar), 6.78 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.4 Hz, 2 x Ar-H), 7.28-7.37 (2H, m, 2 x Ar-H), 7.44 (1H, t, J - 7.2 Hz, Ar-H), 7.80 (2H, t, J = 6.6 Hz, 2 x Ar-H), 7.95 (1H, d, J = 8.4 Hz, Ar-H). 13C NMR Data (75.5 MHz, CDC13): δ 21.75 (CH,), 29.94 (ArCH2Ar), 30.37 (CH), 32.46 (CH2), 33.82 (2 x CH2), 54.31 (2 x NCH2), 57.39 (NCH2), 60.02 (CH2OH), 65.59 (OCH2), 66.85 (OCH2), 1 14.46 (Ar), 1 14.63 (Ar), 122.32 (Ar), 123.39 (Ar), 123.78 (Ar), 126.48 (Ar), 128.28 (Ar), 128.44 (Ar), 129.08 (Ar), 129.44 (Ar), 133.42 (Ar), 154.05 (Ar), 156.73 (C-4). HRMS m/z calculated for C28H35N03 [Μ+ΗΓ 434.2690, observed [M+H]+ 434.2677.
[00302] 3-(l-(4-(2-(Azepan-l-yl)ethoxy)benzyl)naphthalen-2-yloxy)propan-l-ol (29): The title compound was obtained as light brown viscous oil in 65% yield by following the general procedure outlined above. UV Data (EtOH)
Figure imgf000092_0001
231 , 283 and 334 nm. IR (nujol): 3370, 2926, 2873, 1594, 1509, 1463, 1262, 1244, 1175, 1078 and 807 cm 1. Ή NMR (CDC1,, 300 MHz): δ 1.62-1.71 (8H, m, 4 x CH,), 1.98 ( 1H, brs, OH), 2.05 (2H, m, J = 6.0 Hz, CH2) 2.84-2.86 (4H, m, 2 x NCH2), 2.99 (2H, t, J = 5.7 Hz, NCH2), 3.80 (2H, t, J = 5.7 Hz, OCH2), 4.08 (2H, t, J = 5.7 Hz, OCH2), 4.25 (2H, t, J = 5.7 Hz, OCH2), 4.42 (2H, s, ArCH2Ar), 6.78 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.10 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.28-7.35 (2H, m, 2 x Ar-H), 7.44 (1H, t, J = 6.9 Hz, Ar-H), 7.80 (2H, t, J = 6.0 Hz, 2 x Ar-H), 7.95 (1H, d, J = 8.4 Hz, Ar-H). "C NMR Data (75.5 MHz, CDCI3): δ 27.00 (2 x CH2), 2706 (2 x CH2), 29.86 (ArCH2Ar), 32.44 (CH2), 55.70 (2 x NCH2), 56.34 (NCH2), 60.10 (CH2OH), 65.76 (OCH2), 66.87 (OCH2), 1 14.47 (Ar), 1 14.62 (Ar), 122.31 (Ar), 123.40 (Ar), 123.77 (Ar), 126.48 (Ar), 128.29 (Ar), 128.44 (Ar), 129.09 (Ar),l 29.44 (Ar), 133.43 (Ar), 133.47 (Ar), 154.05 (Ar), 156.69 (C-4). HRMS m/z calculated for C28H35N03 [M+Hf 434.2690, observed [M+H]+ 434.2684.
[00303] Example 4: General procedure for the synthesis of l-(4-(2-
(dialkylamino)ethoxy)benzyl)naphthalene-2-yl)oxy)propan-2-one (31-40): To a solution of appropriate l -(4-(2-(diaIkylamino)ethoxy)benzyl)naphthalene-2-ol (la-.j; 1 equiv.), anhydrous K2C03 (3 equiv.) in acetone was refiuxed for 3-4 h. The reaction mixture was allowed cool down to the room temperature and catalytic amount of potassium iodide, followed by chloroacetone ( 1. 1 equiv.) was added and the reaction mixture was once again refiuxed for 20 h. After completion of the reaction, inorganic salts were filtered off, solvent was removed under reduced pressure and the crude reaction mixture was purified on silica gel using 2-6 % of methanol in dichloromethane. The reaction provided the products as brown colored solid or oil with yields ranging in 50-70%.
[00304] l-(l-(4-(2-(Dimethylamino)ethoxy)benzyl)naphthalen-2-yloxy)propan-2- one hydrochloride (31): Dark brown colored solid, mp 58-60 "C; FTIR (Nujol): 736, 813, 907, 1060, 1235, 1376, 1464, 1620, 2800 cm'l ; Ή NMR (300 MHz, CDC13): δ 1.50 (3H, s), 1.88-2.01 (1H, m), 2.05-2.22 ( 1H, m), 2.94 (6H, s), 3.52 (2H, s), 3.65-3.78 (2H, m ), 4.43 (2H, s), 6.94,( 1 H, d, J = 7.5 Hz), 7.04 (2H, d, 7 = 9.0 Hz), 7.30 ( 1H, t, J = 7.2 Hz), 7.40 (1 H, d, J = 7.5 Hz), 7.44 (2H, t, J = 8.4 Hz), 7.60 ( 1H, d, J = 8.7 Hz), 7.71 ( 1H, d, J = 8.1 Hz), 7.84 (1 H, d, J = 8.4 Hz); l 3C NMR (75 MHz, CDC13): 5 22.7, 26.1 , 37.1 , 43.8, 56.7, 63.3, 1 15.1 , 1 19.3, 122.3, 123.1 , 126.4, 127.7, 127.9, 128.1 , 128.8, 129.6, 132.7, 135.8, 151 .9, 157.2, 190.0.
[00305] l-(l-(4-(2-(Diethylamino)ethoxy)benzyl)naphthalen-2-yloxy)propan-2- one hydrochloride (32): Yellow colored semi solid; FTIR (Nujol): 735, 807, 908, 1029, 1240, 1378, 1465, 1732, 2800 cm 1 ; Ή NMR (300 MHz, CDCI3+MeOD): δ 1.1 (6H, t, 7 = 7.2 Hz), 2.22 (3H, s), 2.72 (4H, t, J = 7.2 Hz), 2.92 (2H, t, ./ = 6.0 Hz), 4.03 (2H, t, ./ = 6.0 Hz), 4.50 (2H, s), 4.63 (2H, s), 6.8,(2H, d, J = 8.4 Hz), 7.12 (3H, d, J = 8.7 Hz), 7.36 ( 1 H, t, J = 7.8 Hz), 7.50 ( 1H, t, 7 = 8.1 Hz), 7.80 (2H, t, 7 = 8.4 Hz), 7.95 (1 H, d, 7 = 8.4 Hz); '¾ NMR (75 MHz, CDC,3): δ 25.8, 29.3, 47.7, 49.1 , 50.3, 52.0, 62.1 , 73.8, 1 13.7, 1 14.2, 122.2, 123.2, 125.3, 126.1 , 128.0, 128.9, 129.5, 133.0, 134.0, 152.6, 155.1 , 205.0; HRMS (m z): [M+H+] calcd for C26H3 lN03: 406.2382; found: 406.2380.
[00306] l-(l-(4-(2-(Dipropylamino)ethoxy)benzyl)naphthalen-2-yloxy)propan-2- one (33): Dark brown semi solid; FTIR (Nujol): 744, 1263, 1376, 1460, 1630, 2800 cm'l ; Ή NMR (300 MHz, CDC13): δ 0.90 (6H, t, J = 7.2 Hz), 1 .40-1.55 (4H, m), 2.18 ( 3H, s), 2.50 (4H, t, 7 = 7.2 Hz), 2.83 (2H, t, 7 = 6.3 Hz), 3.96 (2H, t, 7 = 6.3 Hz), 4.50 (2H, s), 4.62 (2H, s), 6.8,(2H, d, 7 = 8.4 Hz), 7. 1 1 (3H, d, 7 = 8.4 Hz), 7.30-7.50 (2H, m), 7.80 (2H, t, 7 = 8.4 Hz), 8.0 ( 1H, d, 7 = 8.4 Hz); IJC NMR (75 MHz, CDCI3): δ 1 1.3, 17.1, 26.7, 30.2, 52.1 , 55.2, 63.0, 74.7, 1 14.2, 1 14.8, 1 18.6, 122.9, 124.0, 126.5, 127.0, 128.7, 128.9, 129.7, 130.2, 133.7, 1 34.8, 155.7, 204.5; HRMS (m z): [M+H+] calcd for C28H35N03: 434.2695; found: 434.2688. [00307] l-(l-(4-(2-(Diisopropylamino)ethoxy)benzyl)naphthalen-2-yloxy)propan- 2-one (34): Brown colored solid, mp 47-50 "C; FTIR (Nujol): 744, 808, 1069, 1243, 1377, 1 65, 1732, 2800 crn l ; Ή NMR (300 MHz, CDC13): δ 1.03 (12H, t, / = 6.3 Hz), 2.25 (3H, s), 2.80 (2H, t, J = 7.5 Hz), 2.95-3.10 (2H, m), 3.84(2H, t, J = 7.5 Hz), 4.51 (2H, s), 4.64 (2H, s), 6.70,(2H, d, J = 8.4 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 9.0 Hz), 7.40 (lH, t, J = 7.8 Hz), 7.50 (1H, t, J = 7.8 Hz), 7.81 (1H, t, J = 9.0 Hz), 8.0 (1H, t, J = 8.4 Hz); 13C NMR (75 MHz, CDC13): δ 21.2, 26.7, 30.2, 44.6, 49.8, 69.9, 74.8, 114.3, 1 14.9, 123.4, 124.1, 124.3, 126.9, 128.7, 129.3, 130.0, 130.2, 133.0, 134.0, 153.4, 157.6, 205.7; HRMS (m/z): [M+H+] calcd for C28H35N03: 434.2695; found: 434.271 1.
[00308] l-((l-(4-(2-(Pyrrolidin-l-yl)ethoxy)benzyl)naphthalen-2-y])oxy)propan- 2-one (35): Brown colored solid, mp 52-54 °C; FTIR (Nujol): 722, 1 171 , 1240, 1377, 1460, 1780, 2724 cm 1 ; Ή NMR (300 MHz, CDC13): δ 2.50 (3H, s), 3.50-3.70 (4H, m), 4.25-4.50 (6H, m), 4.65- 4.80 (2H, m), 5.12 (2H, s), 5.29 (2H, s), 7.10 (2H, d, ./ = 8.1 Hz), 7.48-7.60 (2H, m), 7.71 (1H, t, J = 7.5 Hz), 7.80 (2H, t, J = 8.1 Hz), 8.16 (1H, t, J = 8.4 Hz), 8.30 (2H, d, J = 8.4 Hz); l 3C NMR (75 MHz, CDCl3+MeOD): 26.0, 28.0, 29.4, 59.4, 62.6, 64.7, 73.9, 1 13.7, 1 14.2, 1 15.3, 122.1 , 123.3, 126.2, 128.1, 128.2, 129.1, 130.2, 133.0, 134.5, 152.7, 154.5, 204.0; HRMS (m/z): [M+H+] calcd for C26H25,NO3:404.2226; found: 404.221 1.
[00309] l-(l-(4-(2-(Piperidin-l-yl)ethoxy)benzyl)naphthalen-2-yloxy)propan-2- one (36): Brown colored semi solid; FTIR (Nujol): 736, 806, 907, 1 107, 1242, 1460, 1732, 2722 cm 1 ; Ή NMR (300 MHz, CDCl3+MeOD): δ 2.25 (3H, s), 2.70 (2H, s), 2.83-2.92 (3H, m), 3.01-3.13(6H, m), 3.90-4.10 (3H, m), 4.50 (2H, s), 4.70 (2H, s), 6.74,(2H, d, J = 8.4 Hz), 7.0-7.20 (3H, m), 7.36 (1H, t, 7 = 7.5 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.80 (2H, t, J = 7.5 Hz), 7.95 (1H, d, J = 8.4 Hz); 13C NMR (75 MHz, CDClj+MeOD): δ 21.7, 22.6, 26.5, 30.1, 54.0, 56.3, 62.8, 74.7, 1 14.3, 1 15.0, 122.9, 123.9, 126.9, 128.6, 128.7, 129.6, 130.1 , 130.2, 133.6, 134.8, 153.3, 155.7, 204.8; HRMS (m/z): [M+H*] calcd for C27H„N03: 418.2382; found: 418.2375.
[00310] l-(l-(4-(2-Morpholinoethoxy)benzyl)naphthalen-2-yloxy)propan-2-one (37): Off white solid, mp 56-58 "C; FTIR (Nujol): 736, 807, 907, 1 100, 1243, 1377, 1463, 1732, 2750 cra l : Ή NMR (300 MHz, CDC13): δ 2.32 (3H, s), 3.10-3.25 (2H, m), 3.98-4.08 (2H, m), 4.10- 4.32(6H, m), 4.42-4.50 (2H, m), 4.60 (2H, s), 4.80 (2H, s), 6.90,(2H, d, J = 7.5 Hz), 7.2-7.3 (3H, m), 7.40-7.60 (2H, m), 7.82-7.87 (2H, m), 8.01 (1H, d, J = 8.0 Hz); L,C NMR (75 MHz, CDC13): δ 26.1 , 29.8, 46.0, 525.5, 56.4, 62.6, 63.5, 114.1, 1 14.7, 122.6, 123.7, 125.7, 126.6, 128.4, 128.5, 129.3, 129.9, 133.4, 135.0, 153.1, 155.4, 205.4; HRMS (m/z): [M+H+] calcd for C26HMN04: 420.2175; found: 420.2185.
[00311] l-((l-(4-(2-(4-Methylpiperidin-l-yI)ethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-one (38): Yellow colored solid, mp 52-54 °C; FTIR (Nujol):736, 806, 907, 1108, 1241 , 1377, 1460, 1732, 2723 cm-1; Ή NMR (300MHz, CDC13): δ 0.90 (3H, s), 1.40-1.70 (5H, m), 2.20 (3H, s), 2.43 (2H, t, J = 9.0 Hz), 3.0 (2H, t, J = 5.4 Hz), 3.10-3.20 (2H, m), 4.20 (2H, t,J = 5.4 Hz), 4.50 (2H, s), 4.61 (2H, s), 6.73 (2H, d, J - 8.4 Hz), 7.10 (3H, d, J = 8.1 Hz), 7.33 (2H, d, J = 7.5 Hz), 7.41 (2H, t, J = 7.5 Hz), 7.75 (2H, t, 7 = 9.6 Hz), 7.91 (1H, d, J = 8.7 Hz); l3C NMR (75 MHz, CDC13): δ 21.0, 26.3, 28.7, 29.9, 31.0, 53.7, 56.3, 62.8, 74.5, 1 14.2, 114.9, 1 15.0, 123.8, 126.7, 128.4,
128.5, 129.4, 129.9, 130.0, 133.4, 134.5, 153.2, 156.2, 204.5; HRMS (m/z): [M+H+l calcd for C28H33N03: 432.2539; found: 432.2519.
[00312] l-((l-(4-(2-(Azepan-l-yl)ethoxy)benzyI)naphthaIen-2-yl)oxy)propan-2- one (39): Yellow colored solid, mp 64-66 °C; FTIR (Nujol): 730, 1460, 1760, 2724 cm"1; Ή NMR (300MHz, CDC13): δ 2.25 (3H, s), 1.44-1.80 (8H, in), 3.20-3.45 (6H, m), 3.93-4.10 (2H, m), 4.25 (2H, s), 4.40 (2H, s); 13C NMR (75 MHz, CDC13): δ 20.3, 24.9, 25.9, 27.0, 59.6, 60.9, 63.4, 65.1 , 1 13.3,
1 13.6, 121 .2, 122.4, 125.3, 125.8, 126.9, 127.3, 128.3, 128.8, 133.5, 152.0, 154.3, 203.4; ; HRMS (m z): [M+H+] calcd for C28H33N03: 432.2539; found: 432.2513.
[00313] l-((l-(4-(2-(4-MethyIpiperazin-l-yl)ethoxy)benzyl)naphthaIen-2- yl)oxy)propan-2-one (40): Yellow colored solid, mp 86-88 "C; FTIR (Nujol): 756, 808, 906, 1106, 1242, 1377, 1464, 1732, 2723 cm"1 ; Ή NMR (300MHz, CDC13): 6 2.30 (3H, s), 2.80-3.13 (9H, m), 3.43-4.52 (2H, m), 3.96-4.09 (4H, m), 4.50 (2H, s), 4.64 (2H, s), 6.73 (2H, d, 7 = 8.1 Hz), 7.11 (3H, t, 7 = 7.8 Hz), 7.35 (1H, t, 7 = 7.5 Hz), 7.44 (1H, t, 7 = 8.1 Hz), 7.80 (2H, t, 7 = 8.7 Hz), 7.93 (1H, d, 7 = 8.4 Hz); "C NMR (75 MHz, CDC13): δ 30.2, 46.7, 48.3, 54.2, 62.0, 66.0, 74.8, 114.3, 1 15.0, 123.5, 124.1 , 126.9, 128.7, 129.5, 129.9. 132.0, 133.6, 134.0, 136.0, 154.0, 156.8, 203.0; HRMS (m/z): [M+H+] calcd for C27H,,N203: 433.2491 ; found: 433.2467.
[00314] Example 5: General procedure for the synthesis of l-(4-(2-
(dialkylamino)ethoxy)benzyl)naphthalene-2-yl)oxy)propan-2-oI (41-50): In a round bottom flask, appropriate l-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalene-2-yl)oxy)propan-2-one (31-40; 1 equiv.) was taken in to a methanol. To this solution, sodium borohydride (0.6 equiv.) was added in portions. The reaction mixture was stirred at room temperature until complete disappearance of the starting material. The reaction was quenched with aqueous NaHC03 solution and methanol was removed under reduced pressure. The reaction mixture was extracted with ethyl acetae, dried over anhydrous sodium sulphate and concentrated. The crude reaction mixture was purified on silica gel using 5-8% methanol in dichloromethane. The reaction provided the products in yields ranging in 50- 60%.
[00315] l-((l-(4-(2-(Dimethylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)propan- 2-ol (41): Dark brown colored solid, mp 58-60 "C; FTIR (Nujol): 739, 809, 1080, 1 178, 1263, 1464, 2923, 3381 cm"1; Ή NMR (300MHz, CDClj): δ 1.30 (3H, d, 7 = 6.3 Hz), 2.70 (6H, s), 3.30 (2H, 7 = 4.8 Hz), 3.91 (1H, t, 7 = 7.8 Hz), 4.12-4.20 (2H, m), 4.31 (2H, t, 7 = 4.8 Hz), 4.42 (2H, s), 6.80 (2H, d, 7 = 8.4 Hz), 7.10 (2H, d, 7 = 8.7 Hz), 7.28 (1H, t, 7 = 4.8 Hz), 7.40 (1H, d, 7 = 7.2 Hz), 7.50 (1H, t, 7 = 7.2 Hz), 7.80 (2H, t, 7 = 8.4 Hz), 7.93 (1H, d, 7 = 8.7 Hz); l3C NMR (75 MHz, CDC13): δ 23.7, 26.1, 37.1, 43.8, 56.7, 63.3, 72.6, 1 15.1 , 1 18.5, 1 19.3, 122.3, 123.1 , 126.4, 127.8, 128.1, 128.8, 129.7,
132.7, 135.8, 151.9, 157; ; HRMS (m/z): [M+H+] calcd for C24H2,N03: 380.2226; found: 380.2218. [00316] l-((l-(4-(2-(Diethylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)propan-2- ol (42): Yellow colored semi solid; FTIR (Nujol): 737, 907, 1078, 1177, 1262, 1377, 1460, 2723, 3383 cm 1; Ή NMR (300MHz, CDCl^+MeOD): δ 1.30 (3H, d, J = 6.3 Hz), 1.41 (6H, t, J = 7.2 Hz), 2.30 (IH, bs, -OH), 3.18-3.31 (4H, m), 3.37-3.50 (m, 2H), 3.84-3.96 (IH, m), 4.0-4.22 (2H, m), 4.41 (4H, s), 6.80 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.30 (IH, d, J = 8.7 Hz), 7.34 (IH, t, J = 7.5 Hz), 7.50 (IH, t, J = 8.1 Hz), 7.80 (2H, t, J =8.1 Hz), 7.92 (IH, d, J = 8.7 Hz); '¾ NMR (75 MHz, CDCl3+MeOD): δ 9.3, 20.1 , 30.6, 49.7, 52.4, 63.5, 67.2, 75.9, 1 15.7, 1 16.2, 123.6, 124.3, 124.6, 127.3, 129.3, 130.4, 130.8, 131.0, 134.4, 136.1, 155.3, 156.8;; HRMS (m/z): [M+H+] calcd for C26Hj3NO3:408.2539; found: 408.2535.
[00317] l-((l-(4-(2-(Dipropylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)propan- 2-ol (43): Brown colored semi solid; FTIR (Nujol): 721, 805, 880, 1050, 1087, 1 147, 1242, 1376, 1460, 2725, 3346 cm"1; Ή NMR (300 MHz, CDC¾): δ 0.90 (6H, t, J = 7.5 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.42-1.56 (4H, m), 2.50-2.55 (4H, m), 2.80 (2H, t, J = 6.6 Hz), 3.87-4.12 (5H, m), 4.40 (2H, s), 6.80 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.30 (IH, d, 7 = 9 Hz), 7.40 ( IH, t, J = 7.5 Hz), 7.50 (IH, t, J = 7.5 Hz), 7.82 (2H, t, J = 8.7 Hz), 8.0 (IH, d, J = 8.4 Hz); l3C NMR (75 MHz, CDCl,): δ 12.0, 19.2, 21.0, 30.4, 53.7, 57.5, 66.9, 67.4, 75.4, 1 15.1, 123.2, 124.1 , 126.8, 128.7, 128.8, 129.2, 130.1 , 133.5, 134.0, 154.3, 157.7.
[00318] l-((l-(4-(2-(Diisopropylamino)ethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-ol (44): Dark brown colored semi solid; FTIR (Nujol): 744, 808, 1079, 1176, 1263, 1377, 1463, 2750, 3341 cm 1; Ή NMR (300 MHz, CDC13): δ 1.20 (12H, d, J = 7.5 Hz), 1.23 (3H, d, J = 6.3 Hz), 3.06-3.14 (2H, m), 3.52 (2H, t, J = 7.2 Hz), 3.80-3.91 (2H, m), 4.02 ( IH, dd, J = 1 1.55, 5.7 Hz), 4.20 (2H, s), 4. 27 (2H, s), 6.62 (2H, d, J = 8.4 Hz), 7.0 (2H, d, J = 8.4 Hz), 7.20 (IH, t, J = 8.4 Hz), 7.30 (2H, t, J = 7.8 Hz), 7.62 (2H, t, J = 8.7 Hz), 7.80 (IH, d, J = 8.4 Hz); 1 C NMR (75 MHz, CDCB): δ 17.0, 18.2, 29.6, 46.0, 55.0, 63.3, 66.0, 74.7, 1 14.6, 114.7, 122.2, 123.2, 123.4, 126.2, 128.1 , 129.0, 129.4, 129.8, 133.2, 134.4, 153.8, 155.4; ; HRMS (m z): [M+H+] calcd found
C28H37NO3: 436.2852; found: 436.2831
[00319] l-((l-(4-(2-(PyrroIidin-l-yl)ethoxy)benzyl)naphthalen-2-yl)oxy)propan- 2-ol (45): Yellow colored semi solid; FTIR (Nujol): 740, 807, 918, 1080, 1243, 1463, 2927, 3388 cm" '; Ή NMR (300 MHz, CDCI3): δ 1.20-1.38 (7H, m), 3.23 (bs,-OH), 3.30-3.42 (6H, m), 3.92 (IH, dd, J = 15, 5.1 Hz), 4.02-4.12 (2H, m), 4.40 (2H, t, J = 5.4 Hz), 4.43 (2H, s), 6.82 (2H, dd, J = 22.8, 8.4 Hz), 7.04-7.20 (2H, m), 7.40 (IH, t, 7 = 6.9 Hz), 7.50 (IH, t, J = 7.2 Hz), 7.70 (I H, t, J = 8.7 Hz), 7.81 (2H, t, J = 6.6 Hz), 7.95 (IH, d, J = 8.4 Hz); l 3C NMR (75 MHz, CDC13): δ 19.0, 23.0, 29.8, 53.3, 53.9, 63.4, 66.2, 75.0, 1 14.8, 1 14.9, 1 18.6, 123.4, 123.5, 126.4, 128.3, 129.2, 130.0, 132.0, 133.4, 134.9, 154.0, 155.6; ; HRMS (m/z): LM+H+J calcd for C26H3lN03: 406.2382; found: 406.2368.
[00320] l-((l-(4-(2-(Piperidin-l-yl)ethoxy)benzyl)naphthaIen-2-yI)oxy)propan-2- ol (46): Yellow colored semi solid; FTIR (Nujol): 730, 1029, 1460, 2780, 3300 cm"1; Ή NMR (300 MHz, CDClj+MeOD): δ 1.30 (3H, d, J = 6.3 Hz), 1.54-2.05 (6H, m), 3.05-3.26 (3H, m), 3.3 (2H, t, J = 4.5 Hz), 3.86-3.95 (1H, m), 4.04-4.21 (2H, m), 4.43 (4H, s), 6.80 (2H, d, = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.30 ( 1H, t, J = 9 Hz), 7.40 (1H, d, J = 7.5 Hz), 7.44 (1H, t, J = 7.2 Hz), 7.77-7.87 (2H, m),
7.94 (I H, d, J = 8.7 Hz); "C NMR (75 MHz, CDCl3+MeOD): δ 20.0, 22.3, 23.8, 30.6, 54.9, 57.0, 63.4, 67.3, 76.0, 115.8, 1 16.2, 123.7, 124.5, 124.7, 127.3, 129.4, 130.4, 131.0, 134.5, 136.2, 155.4, 157.0; ; HRMS (m z): [M+H+] calcd for C27H33N03: 420.2539; found: 420.2536.
[00321] l-((l-(4-(2-Morpholinoethoxy)benzyl)naphthalen-2-yl)oxy)propan-2-ol (47): Pale yellow colored solid, mp 73-75 °C; FTIR (Nujol): 730, 1210, 1376, 1460, 3417 cm 1; Ή NMR (300 MHz, CDCI3): δ 1.30 (3H, d, J = 6.3 Hz), 2.50-2.63 (4H, m), 2.70-2.80 (2H, m), 3.74 (4H, t, J = 4.5 Hz), 3.88-3.97 (IH, m), 4.0-4.10 (3H, m), 4.12-4.22 (IH, m), 4.50 (2H, s), 6.80 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.7 Hz), 7.30 (IH, d, J = 9 Hz), 7.40 (IH, t, 7 = 7.2 Hz), 7.50 (IH, t, 7 = 7.5 Hz), 7.81 (2H, t, J = 9.3 Hz), 8.0 (I H, d, 7 = 8.4 Hz); l3C NMR (75 MHz, CDC13): δ 19.6, 30.2, 52.8, 56.5, 62.4, 64.2, 66.8, 75.2, 1 15.5, 1 16.1 , 123.3, 124.1 , 124.2, 127.1, 129.1, 129.2, 130.1 , 130.2, 133.8, 135.4, 154.7, 156.1; ; HRMS (m/z): [M+H+J calcd for C26H31N04: 422.2331; found: 422.2329.
[00322] l-((l-(4-(2-(4-Methylpiperidin-l-yl)ethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-ol hydrochloride (48): Yellow colored solid, mp 113-1 15 °C; FTIR (Nujol): 735, 907, 1030, 1377, 1460, 2854, 3400 cm"1; Ή NMR (300 MHz, CDC13): δ 0.96-1.05 (3H, m), 1.27- 1.43 (8H, m), 1.78-1.92 (4H, m), 2.75-2.85 (2H, m), 3.20-3.60 (3H, m), 3.90 (2H, s), 4.4 (2H, s), 6.68-6.86 (2H, m), 7.02-7.20 (3H, m), 7.21-7.56 (2H, m), 7.60-7.95 (3H, m); 13C NMR (75 MHz, CDC13): 6 18.6. 19.4, 27.1, 27.5, 29.2, 30.8, 60.5, 65.8, 67.6, 74.5, 1 14.2, 1 14.6, 122.0, 122.9, 123.1, 125.8, 127.9, 129.0, 129.5, 133.0, 135.0, 153.8, 154.5.
[00323] l-((l-(4-(2-(Azepan-l-yl)ethoxy)benzyl)naphthalen-2-yl)oxy)propan-2-ol hydrochloride (49): Pale yellow colored semi solid, FTIR (Nujol): 920, 1377, 1460, 2850, 3350 cm'1, Ή NMR (300 MHz, CDC13): δ 1.30 (3H, d, 7 = 6.6 Hz), 1.60-1.90 (8H, m), 3.04-3.25 (6H, m), 3.85-
3.95 (IH, m), 4.0-4.10 (2H, m), 4.22 (2H, t, 7 = 5.4 Hz), 4.42 (2H, s), 6.80 (2H, d, 7 = 8.4 Hz), 7.10 (2H, d, 7 = 8.4 Hz), 7.30 (IH, t, 4.8 Hz), 7.40 (IH, t, 7 = 6.9 Hz), 7.50 (IH, t, 7 = 8.4 Hz), 7.70 (IH, t, 7 = 8.7 Hz), 7.81 (lH, t, 7 = 8.1 Hz), 7.95 (IH, d, 7 = 8.4 Hz); l3C NMR (75 MHz, CDC13): δ 19.0, 25.8, 27.0, 30.2, 55.8, 56.7, 64.9, 66.7, 75.2, 1 15.0, 1 18.9, 122.8, 123.9, 126.8, 128.7, 129.3, 129.9, 130.2, 133.8, 134.4, 137.0, 154.1, 156.5; HRMS (m/z): [M+H+] calcd for C 8H35N03: 434.2695; found: 434.2687.
[00324] l-((l-(4-(2-(4-Methylpiperazin-l-yl)ethoxy)benzyI)naphthalen-2- yl)oxy)propan-2-o! hydrochloride (50): Yellow colored solid, mp 108-1 10 °C; FTIR (Nujol): 735, 791, 1038, 1241 , 1449, 1501, 2710, 3389 cm '; Ή NMR (300 MHz, CDC13): 5 1.25 (3H, d, 7 = 4.8 Hz), 2.52 (3H, s), 2.80-3.0 (I0H, m), 3.84-3.93 (IH, m), 4.02-4.12 (4H, m), 4.41 (2H, s), 6.75 (2H, d, 7 = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.23-7.30 ( IH, m), 7.35 (IH, t, J = 7.8 Hz), 7.5 (IH, t, J = 7.8 Hz), 7.8 (2H, t, J = 8.4 Hz), 7.95 (IH, d, J = 8.7 Hz); l3C NMR (75 MHz, CDC13): δ 19.1, 30.0, 51.4, 44.5, 51.4, 54.2, 56.7, 66.1, 66.5, 75.1, 1 14.9, 122.7, 123.6, 126.6, 128.5, 129.1, 129.8, 133.6, 133.9, 154.0, 156.8; HRMS (m/z): [M+H+] calcd for C27H 203; 435.2648; found: 435.2652. [00325] Example 6: General procedure for the synthesis of l-((l-(4-(2-
(dialkylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)-2-methylpropan-2-ol (51-60): In a dry single neck round bottom flask, appropriate l-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalene-2- yl)oxy)propan-2-one (31-40, 1 equiv.) was dissolved in dry THF. To this stirred solution methyl magnesium iodide in ether (0.6 M, 1.2 equiv.) was added slowly at 0 "C. The reaction turns to white in color, the stirring was continued for 30-45 minutes. Progress of the reaction was checked on TLC. Once the starting material completely consumed, reaction mixture was quenched with aq. NH4C1 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, concentrated and purified on silica gel using 5-10 % methanol in dichloromethane.
Generally, the reaction provides 55-70 % of yield.
[00326] l-((l-(4-(2-(Dimethylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)-2- methylpropan-2-ol hydrochloride (51): Black colored foam, mp 73-75 °C; FTIR (Nujol): 737, 814, 1047, 177, 1379, 1464, 151 1, 2925, 3288 cm"1; Ή NMR (300 MHz, CDC13): 5 1.55 (s, 6H), 1.42 (6H, s), 3.10-3.45 (2H, m), 3.90 (2H, s), 4.34 (2H, s), 4.55 (2H, s), 6.90 (1H, d, J = 7.5 Hz), 7.0 (2H, d, J =8.5 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.31 -7.42 (3H, m), 7.50 ( IH, d, J = 8.7 Hz), 7.76 ( IH, d, J = 9.3 Hz); l C NMR (75 MHz, CDC13): δ 18.6, 22.8, 26.5, 29.0, 30.3, 37.4, 72.8, 115.2, 1 19.4, 122.4, 123.2, 123.8, 126.5, 128.0, 128.3, 128.7, 128.9, 129.6, 132.9, 154.0, 154.5.
[00327] l-((l-(4-(2-(Diethylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)-2- methylpropan-2-ol hydrochloride (52): Yellow colored liquid; FTIR (Nujol): 737, 809, 1044, 1240, 1485, 1510, 3311 cm1; Ή NMR (300 MHz, CDC13): δ 1.33 (6H, s), 1.40 (6H X, J = 12 Hz), 3.20 (4H, q, ./ = 7.2 Hz), 3.30-3.55 (2H, m), 3.93 (2H, s), 4.40 (2H, s), 4.50 (2H, s), 6.80 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.30 (IH, d, J = 7.5 Hz), 7.40 (IH, d, J = 7.8 Hz), 7.50 (IH, m), 7.78-7.79 (2H, m), 7.93 (IH, d, J = 8.7 Hz); 1 C NMR (75 MHz, CDC13): δ 9.3, 26.3, 30.0, 48.1, 51.1, 53.4, 63.2, 70.3, 114.7, 114.9, 122.2, 123.5, 123.8, 126.6, 128.5, 129.2, 129.7, 130.1 , 133.5, 134.6, 154.0, 156.8.
[00328] l-((l-(4-(2-(Dipropylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)-2- methylpropan-2-ol hydrochloride (53): Brown colored solid, mp 50-52 °C; FTIR (Nujol): 736, 81 1, 1081 , 1 178, 1242, 1460, 1510, 2506, 2613, 3355 cm" 1; Ή NMR (300 MHz, CDCI3): δ 0.91 (6H t, J = 7.5 Hz), 1.40 (6H, s), 1.55-1.60 (4H, m), 2.60-2.77 (4H, m), 3.03 (2H, t, J = 5.7 Hz), 3.92 (2H, s), 4.12 (2H, t, J = 6 Hz), 4.50 (2H, s ), 6.80 (2H, d, J = 8.4 Hz), 7.02-7.12 (2H,m), 7.30 (IH, d, J = 7.2 Hz), 7.50 (2H, d, J = 8.1 Hz), 7.82 (2H, dd, J = 5.1, 8.25 Hz),7.90-8.0 (IH, m), '¾ NMR (75 MHz, CDClj): δ 1 1.7, 19.7, 26.4, 32.2, 52.8, 53.0, 56.7, 70.4, 72.18, 1 14.9, 122.6, 123.7, 123.8, 126.7, 128.6, 129.1, 129.9, 130.1, 133.8, 154.1, 156.9.
[00329] l-((l-(4-(2-(Diisopropylamino)ethoxy)benzyl)naphthalen-2-yl)oxy)-2- methylpropan-2-oI hydrochloride (54): Black colored semi solid, FTIR (Nujol): 735, 810, 1045, 1176, 1241, 1384, 1465, 1510, 2900, 3283 cm"1; Ή NMR (300 MHz, CDCI3): δ 1.10 (12H, d, 7 = 6.6 Hz), 1.40 (6H, s), 2.81 (2H, t, J = 7.5 Hz), 2.98-3.14 (2H, m) 3.90 (2H, t, J = 7.8 Hz), 3.94 (2H, s), 4.50 (2H, s); 6.80 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.30 (1H, d, J = 9 Hz), 7.40 (1H, t, J = 6.9 Hz), 7.50 (1H, t, J = 6.9 Hz), 7.83 (1H, t, J = 7.2 Hz), 8.0 (2H, d, J = 8.4 Hz); 13C NMR (75 MHz, CDC13): δ 17.4, 18.5, 26.2, 29.9, 55.1, 58.0, 63.5, 70.3, 1 14.9, 122.2, 123.4, 123.5, 124.9, 125.6, 126.5, 128.3, 129.1, 129.6, 133.4, 134.4, 154.0, 155.6.
[00330] 2-Methyl-l-((l-(4-(2-(pyrrolidin-l-yl)ethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-ol hydrochloride (55): Yellow colored foam, mp 53-55 "C; FTIR (Nujol): 736, 810, 1081, 1 179, 1237, 1378, 1465, 1509, 2850, 3354 cm '; Ή NMR (300 MHz, CDCI3): δ 1.32 (6H, s), 1.39-1.50 (2H, m), 2.18-2.33 (6H, m), 3.87-3.98 (2H, m), 4.22-4.38 (2H, m), 4.50 (2H, s), 4.70 (2H, s), 6.75 (2H, d, J = 8.7 Hz), 7.08-7.20 (3H, m), 7.23-7.38 (3H, m), 7.75-7.95 (2H, m); 13C NMR (75 MHz, CDC13): δ 21.6, 25.1, 25.8, 29.7, 59.8, 62.8, 65.3, 69.9, 114.4, 1 14.9, 1 18.6, 123.3, 123.5, 126.4, 128.3, 129.2, 130.0, 132.0, 133.3, 134.0, 153.9, 155.5.
[00331] 2-Methyl-l-((l-(4-(2-(piperidin-l-yl)ethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-ol hydrochloride (56): Yellow colored liquid; FTIR (Nujol): 735, 810, 1081, 1 179, 1238, 1465, 1510, 1594, 2870, 3380 cm'1; 'H NMR (300 MHz, CDCI3): δ 1.40 (6H, s), 1.50-2.10 (6H, s). 3.40-3.50 (2H, m), 3.65-3.89 (4H, m), 4.20-4.30 (2H, m ), 4.48 (2H, s), 4.52 (2H, s), 6.84 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.45 (2H, t, J = 6.9 Hz), 7.54 (1H, t, J = 8.1 Hz), 7.90 (2H, dd, J = 4.5, 8.4 Hz), 8.0 (IH, t, J = 8.4 Hz), l3C NMR (75 MHz, CDC13): δ 20.4, 20.7, 26.5, 30.2, 49.8, 62.4, 62.7, 70.4, 1 14.8, 115.0, 119.0, 122.2, 123.7, 126.8, 128.7, 129.5, 129.8, 133.6, 135.2, 154.1 , 155.4.
[00332] 2-Methy -((l-(4-(2-morpholinoethoxy)benzyl)naphthalen-2- yl)oxy)propan-2-ol hydrochloride (57): Grey colored solid, mp 58-60 °C; FTIR (Nujol): 736, 809, 1049, 1083, 1 179, 1243, 1464, 1510, 1594, 2870, 3049, 3372 cm 1; Ή NMR (300 MHz, CDCI3): δ 1.33 (6H, s), 2.60 (4H, t, J = 4.5 Hz), 2.77 (2H, t, J = 6.0 Hz), 3.73 (4H, t, J = 4.8 Hz), 3.93 (2H, s ), 4.05 (2H, t, J = 5.7 Hz), 4.50 (2H, s), 6.80 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.40 (1H, d, / = 7.2 Hz), 7.50 (1H, t, J = 7.2 Hz), 7.82 (2H, dd, J = 5.4, 6.6 Hz), 8.0 (1H, t, 7 = 8.7 Hz), C NMR (75 MHz, CDCI3): δ 26.4, 30.7, 54.3, 57.9, 66.4, 67.1, 70.4, 76.7, 1 14.8,
1 15.1 , 122.7. 123.7, 123.9, 126.7, 128.5, 128.6, 129.1 , 129.9, 133.6, 133.9, 154.2, 157.3.
[00333] 2-Methyl-l-((l-(4-(2-(4-methylpiperidin-l-yl)ethoxy)benzyl)naphthalen- 2-yl)oxy)propan-2-ol hydrochloride (58): Yellow colored solid, mp 76-78 °C; FTIR (Nujol): 736, 808, 1081, 1 178, 1241 , 1379, 1458, 1510, 2815, 3386 cm 1; Ή NMR (300 MHz, CDC13): δ 0.96 (3H, d, .7 = 6.0 Hz), 1.30 (6H, s), 1.70-2.10 (5H, m), 2.72-2.91 (2H, m), 3.30-3.41 (2H, m), 3.52-3.70 (2H, m ), 3.90 (2H, s), 4.45 (4H, s), 6.80 (2H, d, J = 8.4 Hz), 7.01-7.16 (3H, m), 7.32 (1H, d, J = 7.8 Hz), 7.41 (1H, t, J = 8.1 Hz), 7.62 (l H, t, y = 9.6 Hz), 7.70 (1H, dd, J = 4.2, 8.6 Hz), 7.90 (1H, d, / = 8.7 Hz); 13C NMR (75 MHz, CDCI3): δ 21.0, 26.5, 29.2, 30.3, 31.1, 41 .3, 54.0, 56.7, 62.9, 70.4, 1 14.8,
1 15.2, 119.0, 123.8, 126.8, 127.2, 128.3, 128.7, 129.5, 130.4, 133.8, 135.2, 154.2, 155.6.
[00334] l-((l-(4-(2-(Azepan-l-yl)ethoxy)benzyl)naphthalen-2-yl)oxy)-2- niethylpropan-2-ol hydrochloride (59): Yellow colored solid, mp 61.63 °C; FTIR (Nujol): 736, 81 1, 1081, 1179, 1235, 1380, 1466, 1510, 2868, 3036, 3347 cm" 1; Ή NMR (300 MHz, CDC13): δ 1.30 (6H, s), 1.36-1.70 (8H, m), 3.65-3.84 (6H, ra), 4.02 (2H, s), 4.10-4.24 (2H, m), 4.42 (2H, s), 6.80 (1H, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.4 Hz), 7.04-7.19 (3H, m), 7.30-7.47 (1H, m), 7.64 (1H, t, 7 = 9 Hz), 7.80 (1H, dd, J = 3.6, 8.4 Hz), 7.86-7.94 (1 H, m); "C NMR (75 MHz, CDC13): δ 22.7, 26.5, 27.9, 31.5, 41.3, 62.7, 65.8, 70.3, 71.1 , 1 15.2. 1 19.0, 123.8, 127.0, 127.3, 128.3, 128.8, 129.3, 129.6, 130.5, 134.0, 135.0, 154.6, 155.8.
[00335] 2-Methy]-l-((l-(4-(2-(4-methylpiperazin-l-yl)ethoxy)benzyl)naphthalen- 2-yl)oxy)propan-2-ol hydrochloride (60): Off white colored solid, mp °C; FTIR (Nujol): 739, 804, 1083, 1 179, 1263, 1377, 1456, 151 1, 2850, 3354 cm 1 ; Ή NMR (300 MHz, CDC13): δ 1.33 (6H, s), 2.40 (3H, s), 2.55-2.78 (8H, ra), 2.80 (2H, t, J = 5.7 Hz), 3.92 (2H, s), 4.04 (2H, s), 4.45 (2H, s), ; 13C NMR (75 MHz, CDC13): δ 26.3, 30.1 , 45.5, 54.8, 57.0, 66.2, 70.2, 1 14.7, 114.9, 122.5, 123.5, 123.7, 126.6, 128.4, 128.5, 129.0, 129.7, 133.5, 133.6, 154.0, 157.1.
[00336] Example 6: Synthesis of l-(6-hydroxy)-l-(4-(2-
(dimethylamino)ethoxy)benzyl)naphthalen-2-yl)piperidin-4-ols (151-160):
Figure imgf000100_0001
Figure imgf000100_0002
Scheme 7
[00337] Synthesis of 2-(benzyloxy)-6-bromonaphthalene (intermediate): In a dry single neck round bottom flask, sodium hydride (460 mg, 20 mmol, 2 equiv.) was added to 6-bromo- 2-naphthol (2.2 g, 10 mmol, 1 equiv.) in anhydrous ^.A'-dimethylformamide (15 mL) at 0 °C. Approximately 15-20 minutes later, benzyl bromide (1.2 mL, 10 mmol, 1 equiv.) was added drop- wise and the stirring was continued until the starting material was completely consumed. It takes generally 3-4 h for the reaction to go to completion. Saturated aqueous NaHC03 was added to the reaction mixture, and the solution was extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified on silca gel to provide the desired product with 95% of yield as white solid.
[00338] Synthesis of l-(6-(benzyloxy)naphthalen-2-yl)piperidin-4-ol
(intermediate): In a dry single neck round bottom flask equipped with septum, 2-(benzyloxy)-6- bromonaphthalene (9.6 mmol, 1 equiv.), copper iodide (3.84 mmol, 0.40 equiv.), L-proline (1.92 mmol, 0.2 equiv.), potassium carbonate (19.2, 2 equiv.) were taken and the contents were dried under vacuum followed by flushing with nitrogen. DMSO (30 niL) was added and reaction mixture was stirred at 1 10"C for 24h. After completion of the reaction, DMSO was removed by extraction with water and ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure to give the product as a light brown solid. The crude product was purified on silica gel by using 8-15% of ethyl acetate in hexanes as eluent to get the product as white solid with 70%.
[00339] Synthesis of l-(6-(benzyloxy)-l-(4-(2-
(dialkylamino)ethoxy)benzyl)naphthalen-2-yl)piperidin-4-ol (intermediates): Similar procedure was adopted, which was developed for the synthesis of l-(4-(2- (dialkylamino)ethoxy)benzyl)naphthalene-2-ol (Example 1, Compounds 1-10).
[00340] Debenzylation of l-(6-(benzyloxy)-l-(4-(2- (dimethylamino)ethoxy)benzyl)naphthaIen-2-yl)piperidin-4-ols to produce compounds 151-160: A mixture of l-(l -(4-(2-(dialkylamino)ethoxy)benzyl)-6-hydroxynaphthalen-2-yl)piperidin-4-ol (1.5 g), 10 % palladium-carbon (lg) in methanol (25 mL) was stirred for 4 h at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated which afforded l-(l-(4-(2-(dialkylamino)ethoxy)benzyl)-6-hydroxynaphfhalen-2- yl)piperidin-4-ols (151-160) as white solids with yields in the range 90-95% without the need of further purification.
[00341] l-(l-(4-(2-(Dimethylamino)ethoxy)benzyl)-fi-hydroxynaphthalen-2- yl)piperidin-4-ol (151): Pale pink colored solid, mp 93-95 "C; FTIR (Nujol): 740, 1034, 1377, 1462, 1643, 2800, 3419 cm"1; Ή NMR (300 MHz, CDC13): δ 1.74 (2H, q, 7 = 9 Hz), 1.98-2.10 (2H, m), 2.40 (6H, s), 2.75 (2H, t, J = 5.7 Hz), 2.93 (2H, t, J = 10.8), 3.56-3.62 (2H, m), 3.80-3.86 (1H, m), 4.0 (2H, t, J = 5.7 Hz), 4.32 (2H, s), 6.70 (2H, d, J = 7.8), 6.99-7.13 (2H, m), 7.20 (2H, d, J = 9.3 Hz), 7.50 (IH, d, J = 8.7 Hz), 7.60 (1H, d, J = 9 Hz); l C NMR (75 MHz, MeOD): δ 18.3, 30.5, 32.3, 58.1, 58.4, 63.7, 1 16.0, 1 19.0, 120.6, 121.2, 121.8, 126.8, 127.4, 129.7, 130.5, 135.3, 136.0, 137.6, 155.8, 157.3; HRMS (m/z): [M+H+] calcd for C2(,H32N203: 421.2491 ; found: 421.2484.
[00342] l-(l-(4-(2-(DiethyIamino)ethoxy)benzyl)-6-hydroxynaphthalen-2- yl)piperidin-4-ol (152): Off white solid, mp 75-78 "C; FTIR (Nujol): 732, 805, 990, 1060, 1 174, 1242, 1383, 1465, 1510, 1607, 2947, 3336 cm 1; Ή NMR (300 MHz, CDC13): δ 1.07 (6H, t, 7 = 6.9 Hz), 1.65-1.82 (2H, m), 1.98-2.10 (2H, m), 2.68 (4H, q, J = 6.9 Hz), 2.82-3.0 (4H, m), 3.52-3.68 (2H, m), 3.80-3.92 (1H, m), 3.98 (2H, t, ./ = 6.0 Hz), 4.32 (2H, s), 6.69 (2H, d, J = 4.0 Hz), 7.0-7.30 (5H, m), 7.50 (IH, d, J = 8.7 Hz), 7.77 (1H, d, J = 9.3 Hz); "C NMR (75 MHz, CDC13) 1 1.9, 30.3, 34.6, 48.1 , 52.3, 53.5, 67.0, 68.0, 1 12.1, 1 15.1 , 1 18.8, 120.6, 124.5, 125.1, 127.0, 127.6, 128.6, 129.4, 135.0, 136.5, 157.5, 159.0; HRMS (m/z): [M+H+] calcd for C28H36N203: 449.2804; found: 449.2809.
[00343] l-(l-(4-(2-(Dipropylamino)ethoxy)benzyl)-6-hydroxynaphthaIen-2- yl)piperidin-4-ol (153): Off white solid, mp 100-102 °C; FTIR (Nujol): 748, 81 1, 985, 1061 , 1 173, 1242, 1381, 1465, 1501, 1610, 2958, 3344 cm 1 ; Ή NMR (300 MHz, CDCl3+MeOD): δ 0.80 (6H, t, J = 9 Hz), 1.35-1.53 (4H, m), 1.58-1.73 (2H, m), 1.90-2.0 (2H, m,), 2.50 (4H, t, 7 = 8.0 Hz), 2.83 (4H, t, J = 6.7 Hz ), 3.72-3.78 (1H, m), 3.92 (2H, t, J = 6.0 Hz), 4.30 (2H, s), 6.66 (2H, d, J = 8.4 Hz), 7.0- 7.17 (5H, m), 7.43 (1H, d, J = 8.7 Hz), 7.70 ( 1H, d, J = 9.0 Hz); l3C NMR (75 MHz, D20): 1 1.1 , 17.9, 30.1, 31.8, 53.2, 54.4, 56.8, 58.5, 63.4, 1 16.0, 1 19.1, 120.6, 121.2, 127.3, 129.5, 129.8, 130.4, 134.4,
135.4, 137.2, 154.1 , 156.5; HRMS (m/z): [M+H+] calcd for C30H4oN203: 477.31 17; found: 477.3118.
[00344] l-(l-(4-(2-(Diisopropylamino)ethoxy)benzyl)-6-hydroxynaphthalen-2- yl)piperidin-4-ol (154): Pale pink colored solid, mp 94-96 °C; FTIR (Nujol): 743, 808, 1061. 1 173, 1263, 1464, 1609, 2800, 3200 cm 1; Ή NMR (300 MHz, CDCl3+MeOD): δ 0.91 (12H, d, 7 = 6.6 Hz), 1.43-1.60 (2H, m), 1.75-1.87 (2H, m), 2.6-2.74 (4H, m,), 2.92-3.41 (2H, m), 3.30-3.40 (2H, m), 3.50-3.63 (1H, m), 4.13 (2H, s), 6.53 (2H, d, J = 8.4 Hz), 6.89-7.01 (5H, m), 7.30 (1H, d, J = 8.7 Hz), 7.53 (1H, d, J = 9.3Hz); "C NMR (75 MHz, CDCl3+MeOD): δ 19.4, 29.5, 33.7, 44.9, 48.1 , 51.0,
67.1. 67.5, 1 12.1 , 1 14.2, 118.1, 1 18.7, 120.2, 124.1 , 126.5, 128.7, 129.0, 133.8, 146.5, 150.4, 156.3; HRMS (m/z): [M+H+] calcd for C30H4oN203: 477.31 17; found: 477.3104.
[00345] l-(l-(4-(2-(Pyrrolidin-l-yl)ethoxy)benzyI)-6-hydroxynaphthalen-2- yl)piperidin-4-o] (155): Brown colored solid, mp 92-94 °C; FTIR (Nujol): 723, 881 , 1051, 1 154, 1376, 1457, 2724, 3331 cm"1; Ή NMR (300 MHz, CDCl3+MeOD): δ 1.68-1.81 (6H, m), 1.90-2.20 (2H, m), 2.57-2.67 (4H, m), 2.78-2.90 (4H, m,), 3.42-3.60 (2H, m), 3.70-3.81 (1H, m), 4.0 (2H, t, J = 5.7 Hz ), 4.30(2H, s), 6.60 (2H, d, J = 7.2 Hz), 7.04 (3H, d, J = 8.4 Hz), 7.13(2H, d, J = 9.0 Hz), 7.43 (1 H, d, J = 8.7Hz), 7.7 (1H, d, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3+MeOD): 23.5, 30.0, 34.3,
48.1. 54.6, 55.1, 66.8, 67.7, 1 12.2, 1 14.8, 1 18.5, 119.1, 120.6, 124.4, 126.9, 128.9, 129.3, 130.4,
133.5, 147.0, 150.4, 157.0; HRMS (m/z): [M+H+] calcd for C28H34N20j: 447.2648; found: 447.2640.
[00346] l-(6-hydroxy-l-(4-(2-(Piperidin-l-yl)ethoxy)benzyl)naphthalen-2- yl)piperidin-4-ol (156): Off white solid, mp 1 18-120 °C; FTIR (Nujol): 759, 819, 990, 1060, 1 176, 1263, 1382, 1470, 1510, 1609, 2943, 3404 cm"1 ; Ή NMR (300 MHz, d6-DMSO): δ 1.22-1.68 (lOH, m), 1.80-1.95 (2H, m), 2.57-2.67 (3H, m), 2.70-2.82 (2H, m), 3.35-3.54(3H, m), 3.58-3.75 (1H, m ), 3.90 (2H, m), 4.20 (2H, m), 6.60 (2H, d, J = 7.5 Hz), 6.53-7.10 (5H, m), 7.33 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 9.0 Hz); l3C NMR (75 MHz, < -DMSO): δ 24.4, 26.0, 29.7, 34.6, 47.7, 54.8, 57.9, 66.6, 1 1 1.5, 115.0, 1 19.0, 120.2, 124.3, 126.7, 128.3, 129.6, 130.2, 134.2, 134.5, 147.0, 150.9, 157.1; HRMS (m z): [M+H+] calcd for CMH36N203: 461.2804; found: 461.2804.
[00347] l-(l-(4-(2-Morpholinoethoxy)benzyl)-6-hydroxynaphthalen-2- yl)piperidin-4-ol (157): Light brown colored solid, mp 79-82 "C; FTIR (Nujol): 777, 808, 988, 1062, 1 173, 1243, 1382, 1456, 1510, 1609, 2926, 3345 cm"';'H NMR (300 MHz, CDCl3+MeOD): δ 1.66- 1.81 (2H, m), 1.98-2.10 (2H, m), 2.52-2.62 (4H. m), 2.80 (2H, t, J = 5.4 Hz), 2.93 (2H, t, J = 9.9 Hz), 3.56-3.62 (2H, m), 3.73 (4H, t, J = 4.5 Hz ), 3.80-3.91 (1H, m), 4.03 (2H, x, J = 5.4 Hz), 4.33 (2H, s), 6.72 (2H, d, J = 8.4 Hz), 6.96-7.17 (3H, m), 7.21 (2H, d, J = 8.7 Hz), 7.5 (1H, d, J = 8.7 Hz), 7.70 (1H, d, J = 9.0 Hz); l3C NMR (75 MHz, CDCl3+MeOD): δ 29.9, 34.4, 48.0, 54.1 , 57.8, 66.0, 66.9, 67.7, 1 12.2, 1 14.8, 1 18.4, 1 19.1 , 120.5, 124.4, 126.9, 128.8, 129.3, 130.5, 133.6, 147.1 , 150.2, 157.0; HRMS (m/z): [M+H+J calcd for C28H34N204: 463.2597; found: 463.2597.
[00348] l-(l-(4-(2-(4-Methylpiperidin-l-yl)ethoxy)benzyl)-6-hydroxynaphthalen- 2-yl)piperidin-4-ol (158): Pale yellow colored solid, mp 91 -93 °C; FTIR (Nujol): 730, 877, 1049, 1 124, 1377, 1460, 2725, 3334 cm 1; Ή NMR (300 MHz, CDCl3+MeOD): δ 0.70 (3H, d, J = 4.0 Hz), 1.0- 1.24 (3H, m), 1.30- 1.60(4H, m), 1.71-2.0 (4H, m), 2.58 (2H, t, J = 5.7 Hz), 2.63-2.98 (4H, m), 3.30-3.41 (2H, m), 3.57-3.70( lH, m). 3.81 (2H, t, 7 = 5.7 Hz), 4.1 (2H, s), 6.50 (2H, d, J = 8.1 Hz), 6.74-6.91 (3H, m), 6.99 (2H, d, J = 9.0 Hz), 7.30 (1H, d, J = 8.7 Hz), 7.53 (1 H, d, J = 9.0 Hz); l 3C NMR (75 MHz, CDCl3+MeOD): δ 20.5, 24.8, 27.4, 28.4, 29.4, 31.0, 45.9, 53.8, 63.3, 66.9, 1 1 1 .0, 1 14.6, 1 17.8, 120.2, 120.7, 124.8, 125.6, 125.9, 128.4, 129.2, 133.8, 134.3, 154.2, 155.5; HRMS (m/z): [M+H+l calcd for C,BH38N203: 475.2961 ; found: 475.2944.
[00349] l-(l-(4-(2-(Azepan-l-yl)ethoxy)benzyl)-6-hydroxynaphthaIen-2- yl)piperidin-4-ol (159): Pale pink colored solid, mp 88-90 °C; FTIR (Nujol): 744, 1 154, 1263, 1376, 1460, 2724, 3300 cm 1 ; Ή NMR (300 MHz, CDCl3+MeOD): δ 1.50-1.80 ( 10H, m), 1.90-2.10 (2H, m), 2.72-3.0 (8H, m), 3.17 ( 1 H, bs), 3.50-3.60 (2H, m), 3.70-3.84 (1H, m), 4.03 (2H, s), 4.3 (2H, s), 6.70 (2H, d, J = 8.4 Hz), 7.0-7.12 (3H, m), 7.20 (2H, d, J = 9.0 Hz), 7.50 ( I H, d, J = 8.7 Hz), 7.72 ( 1H, d, J = 9.3 Hz); l3C NMR (75 MHz, CDCl3+MeOD): δ 26.1 , 27.0, 30.0, 34.0, 48.1 , 56.0, 56.1 , 65.3, 67.2, 1 12.1 , 1 14.3, 1 18.2, 1 18.8, 120.2,124.1, 126.6, 128.7, 129. 1 , 129.9, 133.9, 146.6, 150.4, 156.4; HRMS (m/z): [M+H+] calcd for C30H38N2O3: 475.2961 ; found: 475.2958.
[00350] l-(l-(4-(2-(4-Methylpiperazin-l-yl)ethoxy)benzyl)-6-hydroxynaphthalen- 2-yl)piperidin-4-ol (160): Off white, mp 83-85 °C; FTIR (Nujol): 751, 801 , 990, 1062, 1 167, 1239, 1382, 1460, 1509, 1609, 2937, 3387 cm"1 ; Ή NMR (300 MHz, CDC13): δ 1 .66- 1 .81 (2H, m), 1.98- 2.10 (2H, m), 2.30 (3H, s), 2.42-2.68 (7H, m), 2.72 (3H, t, J = 5.4 Hz), 2.88-3.0 (2H, m ), 3.50- 3.65(2H, m), 3.80-3.90 (1 H, m), 3.97 ( 2H, t, J = 5.4 Hz), 4.32 (2H, s), 6.70 (2H, d, J = 8.4 Hz), 6.92- 7. 15 (3H, m), 7.20 (2H, d, J = 9.0 Hz), 7.50 ( 1H, d, / = 8.7 Hz), 7.76 (1H, d, J = 9.3 Hz); 13C NMR (75 MHz, CDC13): 6 30.3, 34.7, 46.1 , 48.2, 53.5, 55.2, 57.5, 66.3, 68.1 , 1 12.3, 1 15.1, 1 19.0, 1 19.6, 120.2, 124.6, 127.1 , 129.0, 129.5, 133.4, 134.0, 147.3, 150.4, 157.4; HRMS (m/z): [M+H+] calcd for C29H37N303: 476.2913; found: 476.2893.
[00351 ] Prodrugs can be prepared by techniques known to one skilled in the art.
These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes. [00352] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some embodiments, the compounds of the present invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
[00353] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
[00354] Example 3. Cytotoxicity of Selective Estrogen Receptor Modulators of Table 1.
[00355] Conversion to hydrochloride salt: All compounds were converted to corresponding hydrochloride salts prior to cytotoxicity screening passing HC1 gas in solution using appropriate solvents (dichloromethane or ethanol) for 15 minutes. The removal of solvent under vacuum resulted in formation of solid products.
[00356] MTS assay to measure cell viability.
[00357] The exemplified assay below involves the reduction of tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), in the presence of phenazinemesosulfate (PMS), to produce formazan. The absorbance of formazan can be measured directly at 490 nm in a spectrophotometer. In metabolically active cells, the reduction of MTS is catalyzed by cellular dehydrogenases and can be used as a direct measure of cell viability when compared to control cells (Barltrop, J. A. et al. (1991) 5-(3-carboxymethoxyphenyl)-2- (4,5-dimethylthiazoly)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5- dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water soluble formazans as cell-viability indicators. Bioorg. Med. Chem. Lett. 1, 61 1-614.).
[00358] The MTS assay was used to measure the viability of MCF-7, MDA-231 B,
MCF10A, and LNCaP cells in the presence of estrogen inhibitor compounds of the present invention as recited in Table 1, to determine their effect on cell viability by measuring the IC50 for each compound from Table 1 tested. Cells were treated with the analogues and compounds at varying concentrations for a period of 4 days prior to performing the MTS assay. After 4 days, the MTS/PMS mixture was added directly to the cell culture medium. Formazan levels were measured at 490 nm and were compared to levels found in control cells not treated with the estrogen analogues and compounds to determine the effect of each compound on cell viability. E denotes estrogen receptor.
[00359] Results: Table 8. Relative Cytotoxicity (IC50) Against Cancer Cell Lines of Synthesized SERMs of Table 1.
Identifier/Compound MCF-7 MDA-231 MCF-10 LNCaP No. (Table 1) (ER +ve) (ER -ve) (Benign) (Prostrate)
Tamoxifen +++ - - -
Raloxifene +++ - - -
Hydroxy-tamoxifen ++++ - - -
1 ++++ - - -
2 ++++ - - -
4 ++++ -
5 ++++ - - -
6 ++++ - -
7 ++ - -
8 ++++ - - -
9 + - -
1 1 ++++ +++ - -
12 ++++ +++ - -
14 ++++ +++ - -
15 ++++ +++ - -
16 ++++ +++ - -
17 ++ ++ - -
18 ++++ +++
19 ++++ +++ -
21 ++++ - - -
22 ++++ - - -
24 ++++ - - -
25 ++++ - -
26 ++++ - - -
27 +++ - - -
28 ++++ - - -
29 ++++ ++++ - +++
31 ++++ ++++ ++++ ++++
32 ++++ ++++
33 ++++ ++++ - -
34 +++ -
35 Inactive -
36 ++ - - -
37 Inactive - - -
38 ++++ ++++ - -
39 ++ -
40 inactive - - -
41 ++ -
42 ++ - -
43 ++++ - - -
44 +++
45 ++ -
46 +++ - - -
47 + - - -
48 ++ - - -
49 ++++ - - -
50 ++ - - -
51 ++ -
52 +++ - - - Identifier/Compound MCF-7 MDA-231 MCF-10 LNCaP No. (Table 1) (ER +ve) (ER -ve) (Benign) (Prostrate)
53 ++ - -
54 +++ -
55 ++
56 Inactive - - -
57 ++ - -
58 ++++ -
59 ++ - - -
60 ++++ - - -
141 ++++
142 ++++
144 ++++ - - -
145 ++++
146 ++++ - - -
147 ++ - -
148 ++++ - - -
149 ++++ - -
151 + -
152 + -
153 ++ - - -
154 ++ - - -
155 ++
156 ++ -
157 ++ - - -
158 ++
1 9 ++ - - -
160 ++ -
[00360] Examples of activities (IC50) of the compounds of Formulae 1, and la-ln on causing cell death in various cancer cell lines are shown above in Table 8. Anti-cancer activity using the compounds and controls were measured using an IC50 cell viability assay. Anti-cancer activity is illustrated with "+++++" if activity was measured to be less than 1 μΜ, "++++" if activity was measured to be from 1 μΜ to 10 μΜ, "+++" if activity was measured to be from 1 1 μΜ to 25 μΜ, , "++" if activity was measured to be from 26 μΜ to 50 μΜ, "+" if activity was measured to be from 50 μΜ to 100 μΜ, "Inactive" if activity was measured to be greater than 100 μΜ, and "-" if no data was available. With regards to the ability of the compounds of Formula 1 and la-ln to bind to estrogen receptors, exemplary compounds from Table 1 tested appear to be antagonists and display better binding than tamoxifen at 25 μΜ as shown in Figure 1.
EMBODIMENTS
[00361 ] 1. A selective estrogen receptor modulator compound of Formula 1
Figure imgf000107_0001
Formula 1
wherein
R, is hydrogen, OH, halo, -CN, -N02, -N=0, -NHOQ2, -OQ2, -SOQ2, -SO,Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, - C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02Q2, -N(Q2)SOQ2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl ring optionally including 1-3 substituents independently selected from Q3;
R2 and R3 are each independently hydrogen, OH, oxo, C]_8 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q2;
X is a branched or straight C 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQ , -CHQ , -CO-, -CS-, -CONQ2-, -C02-, - OCO-, -NQ , -NQ2C02-, -0-, -NQ2CONQ2-, -OCONQ2-, -NQ2C0-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-;
each Qi is independently halo, oxo, -CN, -N02, -N=0, -NH0Q2, =NQ2, =NOQ2, -OQ2, - SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, - N(Q2)S02-Q2 -N(Q2)SO-Q2 or aliphatic optionally including 1-3 substituents independently selected from Q2 or Q3.
each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q3;
each Q3 is halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C,-C4 alkyl optionally substituted with 1-3 of halo, oxo, -CN, -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, -NH2, or -COOH; and
G and Gj are each independently a branched or straight CM2 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQr, -CHQ , -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2C02-, -0-, -NQjCONQj-, -OCONQ,-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2S02NQ2-.
[00362] The selective estrogen receptor modulator compound according to embodiment 1, wherein R, is hydrogen, halo, -CN, -N02, -N=0, -NHOH, -OH, -N(Q2)2, -C(0)OQ2, - G(0)Q2, -C(0)N(Q2) , aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyi, heterocyclic, and heteroaryl optionally including 1-3 substituents independently selected from Q3.
[00363] The selective estrogen receptor modulator compound according to embodiment 1 , wherein R, is hydrogen, OH, halo, -CN, -N(¾, -OH, -NH2, -C(0)OH, -C(0)H, -C(0)NH2, alkoxy, or a straight or branched C,_8 aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(C,.4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-.
[00364] The selective estrogen receptor modulator compound of embodiment 1, wherein R, is hydrogen, OH, halo, methoxy, -CN, -N02, -OH, -NH2 or -C(0)OH. In a further embodiment, R, is hydrogen, OH or NH2. In still a further embodiment, R, is OH. In another embodiment, R| is hydrogen. In still a further embodiment, Ri is methoxy.
[00365] The selective estrogen receptor modulator compound of embodiment 1 , wherein R and R3 are each independently hydrogen, OH, oxo, or a straight or branched Ci_8 aliphatic, optionally substituted with 1-3 of Qj or Q2.
[00366] The selective estrogen receptor modulator compound of embodiment 1, wherein R2 and R3 are each independently hydrogen or a straight or branched Ci.g alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -NO,, -OQ,, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1 -3 substituents independently selected from Q3.
[00367] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 and R3 are each independently hydrogen or a straight or branched C,n alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N02, -OQ2, -N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3.
[00368] The selective estrogen receptor modulator compound of embodiment 1, wherein R2 and R3 are each independently hydrogen or a straight or branched Cj_8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen, Q-4 alkyl, cycloalkyl, helerocycloalkyl or phenyl.
[00369] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 and R3 are each independently hydrogen or a straight or branched Ci_8 alkyl group, which is optionally substituted with up to 3 of -OQ , -N(Q2)2, wherein Q2 is hydrogen or C|.4 alkyl.
[00370] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 and R3 are each independently hydrogen, OH, oxo, or a straight or branched Cl s alkyl group, which is optionally substituted with OH, or NH2.
[00371 ] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 is hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from [00372] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 is hydrogen or a straight or branched C,_s alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1 -3 substituents independently selected from halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C C4 alkyl optionally substituted with 1-3 of halo, - CN, -NO,, -CF3, -OCF3, -OH or -COOH.
[00373] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 is hydrogen or a straight or branched C 1 x alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or C,-C4 alkyl.
[00374] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 is hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from methyl, ethyl, propyl, isopropyl or ίίτΓ-butyl.
[00375] The selective estrogen receptor modulator compound of embodiment 1, wherein R2 is an ethylene group which is substituted with -N(Q2)2, wherein Q2 is hydrogen or Ci_t alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -NO2, -CF3, -OCF3, -OH, -COOH or C,-C4 alkyl.
[00376] The selective estrogen receptor modulator compound of embodiment 1 , wherein R2 is selected from the group consisting of
Figure imgf000109_0001
[00377] The selective estrogen receptor modulator compound of embodiment 1, wherein R3 is hydrogen, OH, or a straight or branched C,_5 alkyl group, which is optionally substituted with OH or oxo.
[00378] The selective estrogen receptor modulator compound of embodiment 1 , wherein R3 is selected from the group consisting of hydrogen, OH,
Figure imgf000109_0002
[00379] The selective estrogen receptor modulator compound of embodiment 1, wherein X is a branched or straight C,_|2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2),-, -CHQr, -CHQ,-, -CO-, -CONQ2-, -CO,-, -NQ2-, - 0-, -S-, -SO2- or -S02NQ2-. [00380] The selective estrogen receptor modulator compound of embodiment 1 , wherein X is a branched or straight Ci_J2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ , -C<¾-, -NQ2- or -0-.
[00381] The selective estrogen receptor modulator compound of embodiment 1, wherein X is a branched or straight C|_5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -CO2-, -NQ2- or -0-, wherein Q2 is hydrogen, C]_4 alkyl, cycloalkyl or heterocycloalkyl.
[00382] The selective estrogen receptor modulator compound of embodiment 1, wherein X is a branched or straight Ci_5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or Ci„4 alkyl. In one embodiment, X is -CHr, -CH2CHr, -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or Cl.4 alkyl.
[00383] The selective estrogen receptor modulator compound of embodiment 22, wherein X is -CH -.
[00384] A method for inhibiting the growth of a cancer cell or tumor, said method comprising administering to a subject in need thereof, a therapeutically effective amount of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof or pharmaceutical composition thereof.
[00385] The method according to embodiment 24, wherein the cancer cell or tumor is a breast cancer cell or breast cell tumor.
[00386] A method for treating a disease, disorder, or syndrome, said method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
[00387] A method for treating a tumor, said method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, said tumor directly or indirectly effected by hormonal and/or estrogen-related activity, including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyelocytic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.
[00388] The method according to embodiment 27, wherein the tumor is a breast cell tumor.
[00389] A method for treating a hormonal disorder in a patient in need thereof comprising, administering to said patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, wherein said hormonal disorder includes one or more of: osteoporosis, menopausal symptoms, acne, dysmenorrhea and dysfunctional uterine bleeding, hirsutism, hot flashes and cardiovascular disease.
[00390] A compound according to embodiment 1, wherein said compound is recited in Table 1.
[00391 ] A pharmaceutical composition comprising a therapeutically effective amount of a selective estrogen receptor modulator compound, wherein said selective estrogen receptor modulator compound is recited in Table 1.
[00392] The embodiments and the examples described herein are exemplary and not intended to be limiting in describing the full scope of compositions and methods of the present invention. Equivalent changes, modifications and variations of some embodiments, materials, compositions and methods can be made within the scope of the present invention, with substantially similar results.

Claims

CLAIMS What is claimed is:
1. A selective estrogen receptor modulator compound of Formula 1
Figure imgf000112_0001
Formula 1
wherein
R[ is hydrogen, OH, halo, -CN, -N02, -N=0, -NHOQ2, -OQ2, -SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, - C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02Q2, -N(Q2)SOQ2. aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyi, heterocyclic, or heteroaryl ring, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyi, heterocyclic, and heteroaryl ring optionally including 1 -3 substituents independently selected from Q3;
R2 and R3 are each independently hydrogen, OH, oxo, Cj.g aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1-3 of Qi or Q2;
X is a branched or straight CM2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQ,-. -CHQ2-, -CO-, -CS-, -CONQ2-, -CO > - 0C0-, -NQ2-, -NQ2C02-, -0-, -NQ2C0NQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -S02-, -SO,NQ2-, -NQ2S02-. or -NQ2S02NQ2-;
each Q, is independently halo, oxo, -CN, -N0 , -N=0, -NHOQ2, =NQ2, =NOQ2, -OQ , - SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, - N(Q2)S02-Q2 -N(Q2)SO-Q3 or aliphatic optionally including 1 -3 substituents independently selected from Q2 or Q3.
each Qi is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyi, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q3;
each Q3 is halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C,-C4 alkyl optionally substituted with 1-3 of halo, oxo, -CN, -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, -NH2, or -COOH; and
G and G| are each independently a branched or straight C|.] 2 aliphatic chain, or heterocycloalkyl, wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQr, -CHQ2-, -CO-, -CS-, -CONQ2-, -C02-, -OCO-, -NQ2-, -NQ2CO,-, -0-, -NQ2CONQ2-, -OCONQ,-, -NQ2CO-, -S-, -SO-, -S02-, -S02NQ2-, -NQ2S02-, or -NQ2SO,NQ2-.
2. The selective estrogen receptor modulator compound according to claim 1 , wherein Rt is hydrogen, halo, -CN, -N02, -N=0, -NHOH, -OH, -N(Q2)2, -C(0)OQ2, -C(0)Q2, -C(0)N(Q2)2, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl, each aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, and heteroaryl optionally including 1-3 substituents independently selected from Q3.
3. The selective estrogen receptor modulator compound according to claim 1 , wherein Ri is hydrogen, halo, -CN, -N02, -OH, -NH2, -C(0)OH, -C(0)H, -C(0)NH2 or a straight or branched C|_g aliphatic, wherein up to 3 carbon units are optionally and independently replaced with -0-, -N(d. 4 aliphatic)-, -NH-, -C(0)0-, -C(O)-, -C(0)NH-.
4. The selective estrogen receptor modulator compound of claim 1 , wherein Ri is hydrogen, halo, methoxy, -CN, -NO,, -OH, -NH2 or -C(0)OH.
5. In a further embodiment, R| is hydrogen, OH, methoxy or NH2.
6. The selective estrogen receptor modulator compound of claim 1 , wherein R2 and R3 are each independently hydrogen, OH, oxo, or a straight or branched Cj_8 aliphatic, optionally substituted with 1-3 of Q[ or Q2.
7. The selective estrogen receptor modulator compound of claim 1, wherein R2 and R3 are each independently hydrogen or a straight or branched C1 8 alkyl group, which is optionally substituted with up to 3 of halo, oxo, -CN, -N02, -OQ2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3.
8. The selective estrogen receptor modulator compound of claim 1 , wherein R2 and R3 are each independently hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with up to 3 of halo, -CN, -N02, -OQ2, -N(Q2)2, cycloaliphatic or heterocyclic, each cycloaliphatic and heterocyclic optionally including 1-3 substituents independently selected from Q3.
9. The selective estrogen receptor modulator compound of claim 1, wherein R2 and R3 are each independently hydrogen or a straight or branched Ci_8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen, C alkyl, cycloalkyl, heterocycloalkyl or phenyl.
10. The selective estrogen receptor modulator compound of claim 1, wherein R2 and R3 are each independently hydrogen or a straight or branched C,_8 alkyl group, which is optionally substituted with up to 3 of -OQ2, -N(Q2)2, wherein Q2 is hydrogen or C alkyl.
1 1. The selective estrogen receptor modulator compound of claim 1 , wherein R2 and R3 are each independently hydrogen, OH, oxo, or a straight or branched C,_8 alkyl group, which is optionally substituted with OH, or NH2.
12. The selective estrogen receptor modulator compound of claim 1 , wherein R2 is hydrogen or a straight or branched C|_8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from Q3.
13. The selective estrogen receptor modulator compound of claim 1, wherein R2 is hydrogen or a straight or branched C|.8 alkyl group, which is optionally substituted with cycloaliphatic or heterocyclic, each optionally including 1-3 substituents independently selected from halo, oxo, CN, N02, CF3, OCF3, OH, -COOH or C,-C4alkyl optionally substituted with 1-3 of halo, -CN, -N02, -CF3, -OCF3, -OH or -COOH.
1 . The selective estrogen receptor modulator compound of claim 1 , wherein R2 is hydrogen or a straight or branched C|_s alkyl group, which is optionally substituted with heterocyclic, optionally including 1 -3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF5, -OH, -COOH or C,-C4 alkyl.
15. The selective estrogen receptor modulator compound of claim 1 , wherein R2 is hydrogen or a straight or branched Ci_8 alkyl group, which is optionally substituted with heterocyclic, optionally including 1-3 substituents independently selected from methyl, ethyl, propyl, isopropyl or i<?rr-butyl.
16. The selective estrogen receptor modulator compound of claim 1, wherein R2 is an ethylene group which is substituted with -N(Q2)2, wherein Q2 is hydrogen or CM alkyl, or heterocyclic, optionally including 1-3 substituents independently selected from halo, -CN, -N02, -CF3, -OCF3, -OH, -COOH or C,-C4 alkyl.
17. The selective estrogen receptor modulator compound of claim 1 , wherein R2 is selected from the group consisting of
Figure imgf000114_0001
18. The selective estrogen receptor modulator compound of claim 1, wherein R3 is hydrogen, OH, or a straight or branched C|_5 alkyl group, which is optionally substituted with OH or oxo.
19. The selective estrogen receptor modulator compound of claim 1 , wherein R3 is selected from the group consisting of hydrogen, OH,
Figure imgf000114_0002
20. The selective estrogen receptor modulator compound of claim 1, wherein X is a branched or straight C|.!2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q,)2-, -C(Q2)2-, -CHQ,-, -CHQ2-, -CO-, -CONQ2-, -C02-, -NQr, -0-, - S-, -S02- or -S02NQ2-.
21. The selective estrogen receptor modulator compound of claim 1 , wherein X is a branched or straight CM2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ or -0-.
22. The selective estrogen receptor modulator compound of claim 1 , wherein X is a branched or straight Ci_5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONQ2-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen, Cu4 alkyl, cycloalkyl or heterocycloalkyl.
23. The selective estrogen receptor modulator compound of claim 1 , wherein X is a branched or straight Ci_5 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or C,_4 alkyl. In one embodiment, X is -CH2-, -CH2CH2-, -CO-, -CONH-, -C02-, -NQ2- or -0-, wherein Q2 is hydrogen or C alkyl.
24. The selective estrogen receptor modulator compound of claim 23, wherein X is
-CH2-.
25. A method for inhibiting the growth of a cancer cell or tumor, said method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof or pharmaceutical composition thereof.
26. The method according to claim 25, wherein the cancer cell or tumor is a breast cancer cell or breast cell tumor.
27. A method for treating a disease, disorder, or syndrome, said method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
28. A method for treating a tumor, said method comprising: administering to a patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, said tumor directly or indirectly effected by hormonal and/or estrogen-related activity, including tumors associated with: breast, pancreatic, lung, colon, prostate, ovarian cancers, as well as brain, liver, spleen, kidney, lymph node, small intestine, blood cells, bone, stomach, endometrium, testicular, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer; as well as hematological cancers, such as leukemia, acute promyelocytic leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.
29. The method according to claim 28, wherein the tumor is a breast cell tumor.
30. A method for treating a hormonal disorder in a patient in need thereof comprising, administering to said patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, wherein said hormonal disorder includes one or more of: osteoporosis, menopausal symptoms, acne, dysmenorrhea and dysfunctional uterine bleeding, hirsutism, hot flashes and cardiovascular disease.
31. A compound according to claim 1, wherein said compound is recited in Table 1.
32. A pharmaceutical composition comprising a therapeutically effective amount of a selective estrogen receptor modulator compound, wherein said selective estrogen receptor modulator compound is recited in Table I .
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