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WO2013013240A2 - Composés macrocycliques et compositions associées et procédés d'utilisation - Google Patents

Composés macrocycliques et compositions associées et procédés d'utilisation Download PDF

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Publication number
WO2013013240A2
WO2013013240A2 PCT/US2012/047863 US2012047863W WO2013013240A2 WO 2013013240 A2 WO2013013240 A2 WO 2013013240A2 US 2012047863 W US2012047863 W US 2012047863W WO 2013013240 A2 WO2013013240 A2 WO 2013013240A2
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Prior art keywords
compound
mmol
etoac
hexane
stirred
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PCT/US2012/047863
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English (en)
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WO2013013240A3 (fr
Inventor
Lijun Sun
James Barsoum
Ronald WESTER
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Theracrine, Inc.
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Publication of WO2013013240A2 publication Critical patent/WO2013013240A2/fr
Publication of WO2013013240A3 publication Critical patent/WO2013013240A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00

Definitions

  • Migrastatin is a 14-membered ring macrolide natural product that was first isolated from a cultured broth of Steptomyces sp. MK929-43F1.
  • Migrastatin and related compounds have been shown to inhibit migration and anchorage-independent growth of human tumor cells. Specifically, migration of tumor cells is part of the process of metastasis, which is a leading cause of death in cancer patients. Therefore, Migrastatin, derivatives thereof, and related compounds could be useful as therapeutic agents in the treatment of cancer. Summary of the invention
  • macrocyclic compounds of formula (I) Described herein are macrocyclic compounds of formula (I), compositions comprising a compound of formula (I), and methods of using these compounds and compositions.
  • the compounds can inhibit cell migration, and be useful, for example, in the treatment of cancer.
  • the invention features a compound having formula (I), shown below.
  • n and m are each independently 0, 1, 2, 3 or 4;
  • X 1 is -0-, -NR. 7 -, -CR 9a R 9b -, -C(0)-NR 7 -, -NR 7 -C(0)-, -NR 8 -S(0) 2 - or -S(0) 2 -NR 8 -;
  • X 2 is -NR 8 -,-CR 9a R 9b -, -S-, -0-, -S(O)-, -S(0) 2 -, -C(0)-NR 8 -, -NR 8 -C(0)-, -NR 8 -S(0) 2 - or -S(0) 2 -NR -;
  • R 1 is halo, C 1-6 alkyl or C 1-6 alkoxy;
  • R a and R are each independently hydrogen or C 1-6 alkyl;
  • each R 4a and R 4b are independently hydrogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • each R 5a and R 5b are independently hydrogen, halo, amino, amido, C 1-6 alkyl or C 1-6 alkoxy;
  • each R 6a and R 6b are independently hydrogen, halo, amino, amido, C 1-6 alkyl or C 1-6 alkoxy;
  • R is hydrogen, C 1-6 alkyl, acyl, aryl or aralkyl
  • R is hydrogen, Ci_ 6 alkyl, acyl, aryl or aralkyl
  • R 9a and R 9b are each independently hydrogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, halo, amino, amido, aryl or heteroaryl,
  • the invention features a composition comprising a compound of formula
  • the invention features a method of treating a subject, e.g., a method of treating cancer, comprising administering to the subject a compound of formula (I) or a composition comprising a compound of formula (I).
  • the invention features a kit comprising a compound of formula (I) or a composition comprising a compound of formula (I).
  • Figure 1 represents the efficacy of THC-010 and Sutent in an intracranial glioma rat model.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1 -C 12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
  • arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group.
  • arylalkyl or “aralkyl” include benzyl, 2-phenylethyl, and 3- phenylpropyl.
  • heteroarylalkyl refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by a heteroaryl group.
  • Heteroaralkyl includes groups in which more than one hydrogen atom is replaced by a heteroaryl group. Examples or “heteroarylalkyl” or “heteroaralkyl” include methyl-3-pyridyl and methyl-2-pyridyl.
  • alkylene refers to a divalent alkyl, e.g., -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.
  • alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds.
  • alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.
  • One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
  • alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
  • One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
  • alkylamino and dialkylamino refer to -NH(alkyl) and -NH(alkyl) 2 radicals respectively.
  • aralkylamino refers to a -NH(aralkyl) radical.
  • alkylaminoalkyl refers to a (alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a (alkyl) 2 N-alkyl- radical
  • alkoxy refers to an -O-alkyl radical.
  • mercapto refers to an SH radical.
  • thioalkoxy refers to an -S-alkyl radical.
  • thioaryloxy refers to an -S- aryl radical.
  • aryl refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents).
  • aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • cycloalkyl as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents).
  • the cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
  • cycloalkylenyl refers to a divalent cycloalkyl.
  • heterocyclyl or “heterocyclic group” refer to 3- to 14-membered non- aromatic ring structures (e.g., 3- to 10-membered rings, more preferably 3- to 7-membered rings), whose ring structures include one to four heteroatoms independently selected from O, N and S.
  • the heterocyclyl or heterocyclic groups can contain fused or spiro rings.
  • Heterocycles can also be polycycles, with each group having, e.g., 5-7 ring members.
  • the term “heterocyclyl” or “heterocyclic group” includes saturated and partially saturated heterocyclyl structures.
  • heteroaryl refers to a 5-14 membered (i.e., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic) aromatic ring system having 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatoms if bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring heteroatoms independently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any substitutable ring atom can be substituted (e.g., by one or more substituents).
  • Heterocyclyl and heteroaryl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrol
  • the heterocyclic or heteroaryl ring can be substituted at one or more positions with such substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate,
  • cycloalkenyl refers to partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons.
  • the unsaturated carbon may optionally be the point of attachment of the cycloalkenyl substituent. Any substitutable ring atom can be substituted (e.g., by one or more substituents).
  • the cycloalkenyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkenyl moieties include, but are not limited to, cyclohexenyl, cyclohexadienyl, or norbornenyl.
  • heterocycloalkenyl refers to a partially saturated, nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S (e.g., 1-3, 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively).
  • the unsaturated carbon or the heteroatom may optionally be the point of attachment of the heterocycloalkenyl substituent.
  • heterocycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocycloalkenyl include but are not limited to
  • heteroaryl refers to an alkyl group substituted with a heteroaryl group.
  • the ring heteroatoms of the compounds provided herein may be in the form of N-O, S(O), or S(0) 2 .
  • oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
  • acyl refers to an alkylcarbonyl, alkoxycarbonyl,
  • cycloalkylcarbonyl arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted (e.g., by one or more substituents).
  • substituted refers to a group “substituted” on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any substitutable atom of that group. Any substitutable atom can be substituted. Unless otherwise specified, such substituents include, without limitation, alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cll, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g.,
  • perfluoroalkyl such as CF 3
  • aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF 3 ), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl amino, S0 3 H, sulfate, phosphate, methylenedioxy (-O-CH 2 -O- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C S), imino (alkyl, aryl, aralkyl), S(0) n alkyl (where n is 0-2), S(0) n aryl (where n is 0-2), S(0) n heteroaryl (where n
  • n and m are each independently 0, 1, 2, 3 or 4;
  • X 1 is -0-, -NR. 7 -, -CR 9a R 9b -, -C(0)-NR 7 -, -NR 7 -C(0)-, -NR 8 -S(0) 2 - or -S(0) 2 -NR 8 -;
  • X 2 is -NR 8 -,-CR 9a R 9b -, -S-, -0-, -S(O)-, -S(0) 2 -, -C(0)-NR 8 -, -NR 8 -C(0)-, -NR 8 -S(0) 2 or -S(0) 2 -NR 8 -;
  • R 1 is halo, Ci- 6 alkyl or Ci- 6 alkoxy
  • R 2a and R 2b are each independently hydrogen or Ci_ 6 alkyl
  • each R 4a and R 4b are independently hydrogen, hydroxyl, Ci- 6 alkyl or Ci- 6 alkoxy;
  • each R 5a and R 5b are independently hydrogen, halo, amino, amido, Ci_ 6 alkyl or Ci_ 6 alkoxy:
  • each R a and R are independently hydrogen, halo, amino, amido, Ci_ 6 alkyl or Ci_ 6 alkoxy:
  • R is hydrogen, C 1-6 alkyl, acyl, aryl or aralkyl
  • R is hydrogen, C 1-6 alkyl, acyl, aryl or aralkyl
  • R 9a and R 9b are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, amino, amido, aryl or heteroaryl,
  • R 1 is C 1-6 alkyl (e.g., methyl).
  • one of R 2a and R 2b is hydrogen and the other is C 1-6 alkyl (e.g., methyl). In some embodiments, both R 2a and R 2b are C 1-6 alkyl (e.g., methyl).
  • one or R 4a and R 4b is hydrogen and the other is Ci_ 6 alkoxy (e.g., methoxy).
  • X 1 is -0-. In some embodiments, X 1 is -NR7 -. In some embodiments, X 1 is -C(0)-NR7 -. In some embodiments, X 1 is -NR7 -C(O)-. In some embodiments, X 1 is -S(0) 2 -NR7 -. In some embodiments, R 7 is hydrogen. In some embodiments,
  • R 7 is Ci_ 6 alkyl (e.g., methyl). In some embodiments, R 7 is acyl.
  • X 1 is -CR 9a R 9b -.
  • R 9a and R 9b are both hydrogen.
  • one of R 9a and R 9b is hydrogen and the other is amido (e.g., - C(O)-NHMe).
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • m is 0. In some embodiments m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • n is 1 and m is 3. In some embodiments, n is 2 and m is 2. In some embodiments, n is 3 and m is 1. In some embodiments, n is 4 and m is 0.
  • X 2 is -CR 9a R 9b -.
  • R 9a and R 9b are both halo (e.g., fluoro).
  • R 9a and R 9b are both hydrogen.
  • one of R 9a and R 9b is amino and the other is hydrogen.
  • X 2 is -0-. In some embodiments, X 2 is -S-. In some
  • X 2 is -S(O)-. In some embodiments, X 2 is -S(0) 2 -. In some embodiments, X 2 is
  • X 2" i ⁇ s -NR 8 -S(0) 2 -.
  • X 2 is -S(0) 2 - NR 8 -.
  • X 2 is -NR 8 -.
  • R 8 is hydrogen.
  • R 8 is Ci_ 6 alkyl (e.g., methyl).
  • R 8 is acyl.
  • the compound of formula (I) is a compound of formula (la):
  • the compound of formula (I) is selected from the following:
  • the compound of formula (I) is selected from the following:
  • the compound of formula (I) is:
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • Certain compounds disclosed herein may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • the invention includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically pure compounds.
  • the composition can contain, e.g., more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a single enantiomer.
  • enantiomeric excess or "% enantiomeric excess” of a composition can be calculated using the equation shown below.
  • a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.
  • composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
  • enantiomerically pure compounds are known in the art. If, for instance, a particular enantiomer of a compound disclosed herein is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl
  • diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared by using synthetic intermediates that are
  • the compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, deuterated compounds and compounds incorporating 13 C are intended to be encompassed within the scope of the invention.
  • Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming
  • “pharmaceutically acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds disclosed herein. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like See, for example,
  • the compounds disclosed herein may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds disclosed herein. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • the compounds described herein can be synthesized by conventional methods. As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those skilled in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein may be known in the art and include, for example, those described in R. Larock,
  • the compounds described herein can be separated from a reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization.
  • Techniques useful for the separation of isomers, e.g., stereoisomers are within skill of the art and are described in Eliel E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of
  • Described herein are methods of treating a subject having disorder associated with metastasis and/or increased angiogenic activity, such as cancer. For example, included herein are methods of inhibiting metastasis and/or the growth of tumor cells by administering to a subject a compound or composition described herein.
  • the term "subject” is intended to include human and non-human animals.
  • exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject.
  • non-human animals of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
  • Methods of treating cancer include administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof.
  • a method for the treatment of cancer is can include administering a therapeutically effective amount of a compound described herein, or a pharmaceutical composition comprising an compound described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result.
  • Exemplary cancers include glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer
  • a compound described herein can be used to treat ovarian cancer, for example, metastatic ovarian cancer.
  • the compounds of the present invention inhibit metastasis of tumor cells and/or inhibiting the growth of tumor cells.
  • the compounds are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer, to name a few.
  • the compounds are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas.
  • the compounds are active against solid tumors.
  • the present invention provides a method for the treatment for solid tumors.
  • the present invention provides a method for treating and/or preventing metastasis and/or proliferation of tumor cells in a subject comprising administering to a subject (including, but not limited to, a human or animal) in need thereof a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the method is used to treat and/or prevent metastasis and/or proliferation of prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma, to name a few.
  • the method is for treating and/or preventing ovarian and/or colon cancer.
  • the method is for treating and/or preventing metastatic ovarian and/or colon cancer.
  • the present invention provides methods for decreasing migration of tumor cells. In a further aspect, the present invention provides methods for decreasing anchorage-independent growth of tumor cells.
  • the present invention provides methods for inhibiting
  • angiogenesis means the generation of new blood vessels into a tissue or organ.
  • Angiogenesis is prominent in solid tumor formation and metastasis. Angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes.
  • Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas. Prevention of angiogenesis could halt the growth of these tumors and the resultant damage to the animal due to the presence of the tumor.
  • Angiogenesis has been associated with blood-born tumors such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.
  • Angiogenesis can be important in two stages of tumor metastasis.
  • the first stage where angiogenesis stimulation is important is in the vascularization of the tumor which allows tumor cells to enter the blood stream and to circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastasis site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site.
  • the invention provides a method for preventing unwanted angiogenesis in a subject (including, but not limited to, a human or animal) comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the invention in an amount effective to inhibit angiogenesis.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with metastasis and/or angiogenesis.
  • the expression "effective amount” as used herein refers to a sufficient amount of agent to inhibit the growth of tumor cells, or refers to a sufficient amount to reduce the effects of cancer.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular anticancer agent, its mode of administration, and the like.
  • the compounds of the formulae described herein can, for example, be administered to a subject by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, e.g., between 0.001-lmg/kg, 1-lOOmg/kg, or 0.01-5mg/kg, every 4 to 120 hours, e.g., about every 6, 8, 12, 24, 48, or 72 hours, or according to the requirements of the particular compound.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect (e.g., reduction of feeding in a subject).
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day, for example, the compounds can be administered about 1 to about 4 (e.g., 1, 2, 3, or 4) hours prior to meal time.
  • the compounds can be administered as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional compound including for example, a steroid or an analgesic; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compositions delineated herein include the compounds of the formulae delineated herein, as well as additional therapeutic compounds if present, in amounts effective for achieving a modulation of disease or disease symptoms, including kinase mediated disorders or symptoms thereof.
  • the compositions are made by methods including the steps of combining one or more compounds delineated herein with one or more carriers and, optionally, one or more additional therapeutic compounds delineated herein.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase which can be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional compound should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • combinations of a plurality of compounds described herein are also envisioned.
  • the additional compounds may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those compounds may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. Dosages:
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound disclosed herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventncular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some embodiments, the dose will be 1-20, or 5-10 mg per kilogram of body weight, administed twice daily.
  • a compound described herein can be provided in a kit.
  • the kit includes (a) a composition that includes a compound described herein, and, optionally (b) informational material.
  • the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compound described herein for the methods described herein.
  • the informational material of the kits is not limited in its form.
  • the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth.
  • the informational material relates to use of the compound described herein to treat a disorder described herein.
  • the informational material can include instructions to administer the compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein).
  • Preferred doses, dosage forms, or modes of administration are parenteral, e.g., intravenous, intramuscular, subcutaneous, intraparenteral, bucosal, sublingual, intraoccular, and topical.
  • the informational material can include instructions to administer the compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.
  • the material can include instructions to administer the compound described herein to such a subject.
  • the informational material of the kits is not limited in its form.
  • the informational material e.g., instructions
  • the informational material is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet.
  • the informational material can also be provided in other formats, such as computer readable material, video recording, or audio recording.
  • the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about an compound described herein and/or its use in the methods described herein.
  • the informational material can also be provided in any combination of formats.
  • the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, and/or a second compound for treating a condition or disorder described herein.
  • the other ingredients can be included in the kit, but in different compositions or containers than the compound described herein.
  • the kit can include instructions for admixing the compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients.
  • the compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that the compound described herein be substantially pure and/or sterile.
  • the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred.
  • a suitable solvent e.g., sterile water or buffer, can optionally be provided in the kit.
  • the kit can include one or more containers for the composition containing the compound described herein.
  • the kit contains separate containers, dividers or compartments for the composition and informational material.
  • the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet.
  • the separate elements of the kit are contained within a single, undivided container.
  • the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
  • the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein.
  • the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein.
  • the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
  • the kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device.
  • a device suitable for administration of the composition e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device.
  • the device is an implantable delivery device.
  • THC-10 (110 mg, 408mmol), HCHO (12mg, 0.408mmol), NaBH(OAc) 3 (173mg, 0.817mmol), DCM (2mL), were stirred at room temperature for 16h. The volatiles from the reaction were removed under reduced pressure to obtain the crude residue which was purified by silica gel column chromatography (MeOH/CHCl 3 1 : 19) to afford THC-011 (34.2 mg, 76.5%) as a pale yellow liquid.
  • THC-027) (3Z, 5R, 6S, 7S, 8E)-7-methoxy-3, 5-dimethylazacyclotetradeca-3, 8-dien-6-ol (THC-027): To a stirred solution of compound 56 (130 mg, 0.341 mmol) in THF (2 mL) at 0°C, TBAF (1.0M in THF, 133 mg, 0.51 mmol) was added slowly and stirred at RT for 16 h. The reaction mixture was concentrated under vacuum and the crude material was purified by silica gel column chromatography (MeOH/CH 2 Cl 2 3:47) to afford THC-027 (23 mg, 25.5%).
  • Pent-4-en-l-yl ((4R, 5S, 6S, Z)-5-((tert-butyldimethylsilyl) oxy)-6-methoxy-2, 4-dimethylocta-2, 7-dien-l-yl) carbamate (63):
  • THC-115A The diastereomers of THC-115 (73.1 g) were separated by normal-phase preparative high performance liquid chromatography (Chiralpak IA, 250 x 20 mm, 5 ⁇ ; using (A) n-hexane - (B) ethanol (A:B : 98:2) as a mobile phase; Flow rate: 15 mL/min) to obtain THC-115A (28 mg) and THC-115B (19 mg). Analytical data for THC-115A:
  • THC- 65B (lS,2R,3Z,7R,12E,14S)-7-amino-14-methoxy-2,4-dimethylcyclotetradeca-3,12-dienol (THC- 65B): To a stirred solution of THC-115B (14 mg, 0.036 mmol) in CH 2 C1 2 (1 niL), cooled to 0°C, Et 2 0-HCl (1 niL) was added. The reaction mixture warmed to RT and stirred for 16 h, while TLC examination revealed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to afford THC-65B (9.1 mg, 80%) as amorphous white solid.
  • Example 2 Use of fascin inhibitor THC-010 for treatment of glioma in an orthotopic glioma model.
  • Fascin is highly expressed in glioma cells where it plays a major role in migration and invasion of this cancer type.
  • Glioma can be modeled in orthotopic tumor models in mice or rats, with rats being the preferred host due to the greater ease of injection of cancer cells into the brain.
  • either rat glioma cells such as 9L cells are introduced into immune-competent rats or human glioma cells such as U-87 MG, U251, SNB19 or LN-229, are inoculated into immune- deficient rats such as nude rats.
  • nerve models have utilized glioma tumor-initiating cells or glioma stem cells taken from human glioma patients.
  • the glioma cancer cells are injected into the brain by stereotactic injection.
  • rat 9L glioma cells are injected into the brains of normal Fisher 344 rats by stereotactic intracranial injection.
  • the 9L tumors can be grown subcutaneously in the flanks of mice and hen tumor chunks can be implanted into the brain in a surgical procedure.
  • the glioma cells grow as a tumor mass in the brain parenchyma and invade into distant sites within the brain.
  • Drugs and controls can be administered at the time of cancer cell injection or various numbers of days thereafter. Drugs can be administered by intracranial injection, perhaps in polymer formulation or, preferentially by oral administration of drugs that cross the blood-brain barrier.
  • THC-10 exhibited low to moderate systemic clearance.
  • the value of 18.6 mL/min/kg for CL in the rat is 33.8 % of hepatic blood flow (55 mL/min/kg in rat).
  • THC-10 exhibited rapid absorption as maximum plasma concentrations were observed from the first time point (0.25 hr) to the 3 rd time point (1 h) with a mean Tmax at 0.5 hr.
  • THC-10 in the brain tissue were roughly equivalent to the plasma levels.
  • tumor size can be monitored by imaging or measured at sacrifice and dissection of the brain to determine the effect of drug treatment on tumor size and invasion within the brain. Animal behavior, body weight and survival also would be evaluated.
  • angiogenesis inhibitors such as antibody inhibitors of VEGF or small molecule inhibitors of VEGFR can induce increased tumor invasion and metastasis (Paez-Ribes et al. Cancer Cell 15:220, 2009; Ebos et al. Cancer Cell 15:232, 2009).
  • One promising therapeutic use of a fascin inhibitor is in combination with an angiogenesis inhibitor or treatment soon after treatment with an angiogenesis inhibitor to block invasion and metastasis. This may be particularly beneficial in the treatment of glioma, a setting in which the angiogenesis inhibitor bevacizumab is widely used.
  • Clinical findings suggest that glioma patients treated with the bevacizumab display greater cancer invasion to distant parts of the brain.
  • Combination treatment with a fascin inhibitor could increase the duration of clinical benefit of treatment with angiogenesis inhibitors.
  • This drug combination could be modeled in the orthotopic glioma model.
  • a small molecule angiogenesis inhibitor such as sunitinib (Sutent) could be used.
  • Table 4 A study design is shown in Table 4.
  • rat 9L glioma cells were implanted intracranially into the brains of immune-competent rats in a surgical procedure. After recovery from anesthesia, rat received their corresponding drugs by mouth. They then received the same treatments daily by mouth until the last animal died on day 24. In this case, the compounds were formulated in 0.5% methylcellulose (MC). The control group received 0.5% MC without any compounds. Dosing was done orally once per day starting at the time at which the tumor chunks were surgically implanted. Table 4. Rat glioma model study design

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Abstract

La présente invention concerne des composés et des compositions, qui peuvent être utilisés, par exemple, pour traiter un cancer.
PCT/US2012/047863 2011-07-21 2012-07-23 Composés macrocycliques et compositions associées et procédés d'utilisation WO2013013240A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020046991A1 (fr) 2018-08-27 2020-03-05 Spinogenix, Inc. Composés de liaison à la fascine pour la spinogenèse

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US20070037852A1 (en) * 2003-03-28 2007-02-15 Danishefsky Samuel J Migrastatin analogs and uses thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020046991A1 (fr) 2018-08-27 2020-03-05 Spinogenix, Inc. Composés de liaison à la fascine pour la spinogenèse
EP3843846A4 (fr) * 2018-08-27 2022-09-07 Spinogenix, Inc. Composés de liaison à la fascine pour la spinogenèse

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