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WO2007025031A2 - Prodrogues de composes d'indanone et de tetralone - Google Patents

Prodrogues de composes d'indanone et de tetralone Download PDF

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Publication number
WO2007025031A2
WO2007025031A2 PCT/US2006/033057 US2006033057W WO2007025031A2 WO 2007025031 A2 WO2007025031 A2 WO 2007025031A2 US 2006033057 W US2006033057 W US 2006033057W WO 2007025031 A2 WO2007025031 A2 WO 2007025031A2
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WIPO (PCT)
Prior art keywords
compound according
subject
pharmaceutically acceptable
hydrogen
acceptable salt
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PCT/US2006/033057
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WO2007025031A3 (fr
Inventor
Qi Chao
Mimi K. Phillips
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Cephalon, Inc.
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Publication of WO2007025031A2 publication Critical patent/WO2007025031A2/fr
Publication of WO2007025031A3 publication Critical patent/WO2007025031A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the present invention relates generally to prodrugs of indanone and tetralone compounds and methods of using them to treat diseases.
  • Microtubule-binding agents represent a large class of anti-tumor drugs that have in common the binding to tubulin, an essential component of the cell's cytoskeleton.
  • the binding to tubulin results in the inhibition of chromosome segregation during mitosis, leading to a cell cycle arrest, followed by cell death. For this reason these drugs have been generally considered as "cell cycle" dependent.
  • the tubulin-binders can be divided into 2 main groups, based on their effect on microtubule polymerization equilibrium: 1) Microtubule stabilizing agents, promoting polymerization of microtubules and inducing microtubule bundling; and 2) Microtubule de-polymerizing agents, leading to microtubule "melting".
  • Several tubulin binding sites or pockets have been identified and include the taxol binding site, the vinca binding site, and the colchicine-binding site.
  • Indanocine is a tubulin-binding agent that blocks tublin polymerization through its binding at the colchicine-binding site
  • mdanocine and indanocine analogs are cytotoxic to tumor cell lines. These indanones differ from other tubulin-binding agents because they are able to induce apopotosis in stationary phase cancer cells at concentrations that do not kill normal non-proliferating cells.
  • Indanocine and related analogs unlike other hydrophobic anti-neoplastic agents such as the taxanes and vinca alkaloids, retain potent cytotoxicity against multidrug-resistant tumor cells, which contain elevated levels of p-glycoprotein and other transporters.
  • indanocine and related compounds such as indanorine, indano-amine, and indano-diamine
  • indanocine and related compounds are good cytostatic and cytotoxic agents, they possess low solubility in many solvents.
  • the present invention provides phosphate methylene ether prodrugs of indanone and tetralone compounds, pharmaceutical compositions containing such compounds, and methods of using them.
  • the invention provides phosphate methylene ether prodrugs of indanorine, indanocine, indano-amine, and indano-diamine.
  • Figure 1 Efficacy of Sodium 4-[(E)-(7-amino-5,6-dimethoxy-l-oxo-lH-inden- 2(3H)-ylidene)methyl]-2,6-dimethylphenoxymethyl Phosphate on Daudi Tumor growth in SCID mouse.
  • the present invention provides, inter alia, phosphate prodrugs of indanone and tetralone compounds, processes for preparing such compounds, pharmaceutical compositions containing such compounds, and methods for using such compounds, for example, in medical therapies.
  • Preferred compounds are cytotoxic to cancer cell lines, and, in particular, to multi-drug-resistant cancer cell lines, hi one particular embodiment, the present invention provides phosphate prodrugs of indanorine, indanocine, indano-amine, and indano-diamine.
  • prodrug refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently (though not necessarily) pharmacologically inactive until converted to the parent drug.
  • Preferred prodrugs of the present invention include compounds of the following formula:
  • Formula 1 or a pharmaceutically acceptable salt or ester form thereof, wherein R 1 is hydrogen or C 1 -C 6 alkyl; R 2 is hydrogen or C 1 -C 6 alkyl; W is NH or O;
  • R 3 and R 4 are, independently, hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, NO 2 , NH 2 , acyl, acyloxy, aryl, heteroaryl, acylphosphonate, or together form -O-(CH 2 ) a -O-;
  • R 8 ,R 9 , and R 10 are, independently, hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, NO, NO 2 , NH 2 , acyl, acyloxy, acylamino, carboxyacyl, or together form -O-(CH 2 ) b -O-;
  • R 11 is hydrogen or C 1 -C 6 alkyl
  • R 12 is hydrogen, C 1 -C 6 alkyl, aryl, or aralkyl
  • M is a metal ion
  • A is (CH 2 ) n ; a is 1, 2, or 3; b is 1, 2, or 3; and n is 1 or 2. More preferred prodrugs of the present invention include compounds of
  • Formula 2 or a pharmaceutically acceptable salt or ester form thereof, wherein R 1 is hydrogen or C 1 -C 6 alkyl; R 2 is hydrogen or C 1 -C 6 alkyl; W is NH or O;
  • R 7 is hydrogen or NH 2 ;
  • R 11 is hydrogen or C 1 -C 6 alkyl;
  • R 12 is hydrogen, C 1 -C 6 alkyl, aryl, or aralkyl; and
  • M is a metal ion.
  • prodrugs of the present invention include compounds of Formulas 3, 4, 5, and 6 or pharmaceutically acceptable salt or ester forms thereof:
  • Preferred compounds of Formulas 1 to 6 include those wherein: R 1 is hydrogen or Ci-C 6 alkyl; R 2 is hydrogen or C 1 -C 6 alkyl; Z is P(0)(0 " M + ) 2 , P(O)(OR 12 )(O-M + ), P(O)(OR 12 )( OR 12 ), or P(O)(O "
  • R 12 is hydrogen, C 1 -C 6 alkyl, aryl, or aralkyl; M + is Na + , K + , Li + , and M 2+ is Ca 2+ , OrMg 2+ or a pharmaceutically acceptable salt or ester form thereof.
  • R 12 is hydrogen,
  • R 1 and R 2 are, independently, hydrogen or C 1 -C 3 alkyl or R 1 and R 2 are both hydrogen.
  • R 12 is hydrogen or C 1 -C 6 alkyl.
  • M + is a metal ion such as Na + , K + , Li + , or an organic amine and M 2+ is a metal ion such as Ca 2+ , or Mg 2+ or an organic amine.
  • Preferred prodrugs of the present invention also include compounds of Formula 7, 8, 9, and 10:
  • Exemplary compounds of the present invention include, but are not limited to, sodium 4-[(E)-(7-amino-5,6-dimethoxy-l-oxo-lH-inden-2(3H)-ylidene)methyl]-2,6- dimethylphenoxymethyl phosphate, sodium 4-[(E)-(5,6-dimethoxy-l-oxo-lH-inden- 2(3H)-ylidene)methyl]-2,6-dimethylphenoxymethyl phosphate, sodium 4- ⁇ [(E)-(5,6- dimethoxy-l-oxo-lH-inden-2(3H)-ylidene)methyl]-2,6-dimethylphenylamino ⁇ methyl phosphate, sodium 4- ⁇ [(E)-(7-amino-5,6-dimethoxy-l-oxo-lH-inden-2(3H)- ylidene)methyl]-2,6-dimethylphenylamino ⁇ methyl phosphate or
  • alkyl and alkylene refer to substituted or unsubstituted aliphatic hydrocarbon chains, the difference being that alkyl groups are monovalent (i.e., terminal) in nature whereas alkylene groups are divalent and typically serve as linkers. Both include, but are not limited to, straight and branched chains containing from 1 to about 20 carbon atoms, preferably 1 to about 6 carbon atoms, unless explicitly specified otherwise.
  • alkyl methyl, ethyl, propyl, isopropyl, butyl, z-butyl and t-butyl are encompassed by the term "alkyl.”
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • cycloalkyl refers to a substituted or unsubstituted alicyclic hydrocarbon group having 3 to about 20 carbon atoms (unless explicitly specified otherwise), preferably 3 to about 6 carbon atoms. Also included within the definition of "cycloalkyl” are cycloalkyl radicals such as cyclopentylmethyl, cyclohexylethyl, and the like.
  • aryl refers to an unsaturated hydrocarbon radical of 5 to about 20 carbon atoms (unless explicitly specified otherwise), 6 to 14 carbon atoms being preferred, having one or more rings, at least one of which is aromatic.
  • the "aryl” group can have a single ring or multiple condensed rings.
  • aryl includes, but is not limited to phenyl, ⁇ - naphthyl, ⁇ -naphthyl, indanyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
  • aryl aryl groups that are optionally substituted.
  • the "aryl” groups are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, acyl, acyloxy, nitro, amino, hydroxy, halo, and dioxy-methylene bridges of the form -O(CH 2 ) C O-, where c is 1, 2, or 3.
  • arylalkyl refers to the group -Ra-Rb 5 where R 3 is a C 1-6 alkyl group as defined above, substituted by R b , an aryl group, as defined above.
  • Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl refers to an aryl or aralkyl group having one or more heteroatoms selected from the group consisting of O, N, S, and P heteroatoms.
  • Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (unless explicitly specified otherwise), with from about 4 about 10 being preferred.
  • heteroaryl groups are aromatic heterocyclic ring systems having about 4 to about 14 ring atoms and containing carbon atoms and one or more heteroatoms selected from the group consisting of O, N, S, and P heteroatoms.
  • heteroaryl groups are furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N- methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1 -methyl- 1,2,4-triazole, IH- tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzothiophene, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline.
  • Preferred heteroaryl groups include pyridyl, pyrid-4-methyl, furyl and imidazolyl.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, P, or S.
  • heteroaryl those aromatic groups that are optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, acyl, acyloxy, nitro, amino, hydroxy, halo, and dioxy-methylene bridges of the form - O(CH 2 ) C O-, where c is 1, 2, or 3.
  • alkoxy refers to the group R a -O- wherein R a is an alkyl group as defined above.
  • acyl refers to a radical of the formula RC(O)-, where R is C 1-6 alkyl, aryl, or cycloalkyl as defined herein. Suitable acyl radicals include formyl, acetyl, propionyl, and the like.
  • acyloxy refers to radicals of the formula RC(O)O-, where R is C 1-6 alkyl or cycloalkyl as defined herein. Suitable acyloxy radicals include CH 3 COO-, CH 3 CH 2 COO-, benzoyloxy, and the like.
  • halogen or “halo” refers to chlorine, bromine, fluorine, and iodine.
  • compositions, carriers, diluents and reagents are used interchangeably and represent that the materials are capable of administration to or upon a human without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like which would be to a degree that would prohibit administration of the compound.
  • “Pharmaceutically acceptable salts and esters” refers to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include, for example, salts that can be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include, for example, those formed with the alkali metals or alkaline earth metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include, for example, those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine, and the like.
  • Pharmaceutically acceptable salts can also include acid addition salts formed from the reaction of amine moieties in the parent compound with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid).
  • inorganic acids e.g. hydrochloric and hydrobromic acids
  • organic acids e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid.
  • Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds, e.g. C 1-6 alkyl esters.
  • a pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di- salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esterified.
  • Compounds named in this invention can be present in unsalified or unesterified form, or in salified and/or esterified form, and the naming of such compounds is intended to include both the original (unsalified and unesterified) compound and its pharmaceutically acceptable salts and esters.
  • certain compounds named in this invention can be present in more than one stereoisomeric form, and the naming of such compounds is intended to include all single stereoisomers and all mixtures (whether racemic or otherwise) of such stereoisomers.
  • Preferred pharmaceutically acceptable salts of the present invention include those wherein M is an organic amine.
  • Certain compounds named in this invention can be present in more than one stereoisomeric form, and the naming of such compounds is intended to include all single stereoisomers and all mixtures (whether racemic or otherwise) of such stereoisomers.
  • the compounds of this invention are meant to include all possible E and Z configurations.
  • protecting groups In some of the following synthetic schemes, it may be necessary to use protecting groups ("pg").
  • protecting group refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties can be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties can also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties can be protected by conversion to simple ester derivatives as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride labile silyl carbamates.
  • Ally! blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd 0 - catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • Exemplary blocking/protecting groups can be selected from:
  • Preferred compounds of the present invention can be administered to a subject for the purpose of inhibiting growth and/or inducing apoptosis in targeted cells; e.g., malignant and other hyperproliferative cells, infected cells and cells being treated for either condition which have acquired MDR. Accordingly, the present invention provides methods of treating cancer and other hyperproliferative diseases.
  • Preferred compounds of the present invention are microtubule-depolymerization agents with antiproliferative activity. Preferred compounds induce apoptotic cell death in a broad range of human tumor cell lines, including multidrug-resistant cells. Accordingly, the present invention provides methods for inducing apoptosis in tumor cells, including MDR tumor cells and stationary phase tumor cells; methods for inducing apoptosis in virus infected cells, including virus infected cells with MDR; methods for inhibiting the growth of malignant cells in a subject, including MDR cells and stationary phase malignant cells; and methods for inhibiting the growth of virus- infected cells in a subject; including virus-infected, MDR cells. These methods include the step of administering a compound of the present invention to a subject.
  • Preferred compounds of the invention are active in a variety of MDR cell types, including those whose resistance is primarily owing to overexpression of p- glycoprotein and of mdr. Such cells generally acquire collateral sensitivity to the compounds of the invention by virtue of preceding treatment with other pharmaceutical agents and acquisition of MDR.
  • Preferred compounds allow targeting of the large factor of non-cycling cells present in many solid tumors, as well as cancers in stationary phase cells (e.g., those in remission), while not posing great risk to the majority of normal tissues. Because the performance of the preferred compounds actually improves in MDR cells, the preferred compounds provide a means to continue or supplement chemotherapy of malignancies and infections while avoiding the obstacles presented by acquisition of MDR in targeted cells.
  • Compounds of the invention can be tested for activity using any generally accepted test for cell proliferation and/or viability.
  • Bi general, compounds can be tested by providing a sample of cells believed to be susceptible (along with suitable positive and negative control cell lines), contacting the cells with the test compound in a range of dilutions, and determining an effective dose.
  • the effective dose can be, for example, the concentration of compound required to kill about 50% of the test cells, which can be measured by standard techniques such as 51 Cr labeling.
  • one can measure the inhibition of proliferation, for example by measuring the reduction in 3 H- Thy uptake.
  • Compounds of the invention can also be tested in suitable in vivo models, for example by treating nude mice implanted with susceptible tumor cells, and recording the survival rates of treated and control animals.
  • subject or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as animals such as rabbits, rats, dogs, cats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • treating refers to any indication of success in amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neurological examination, and/or psychiatric evaluation.
  • treating includes, for example, the administration of the prodrugs of the present invention to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with cancer.
  • treatment can refer to the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.
  • Cancer refers to any of a number of diseases that are characterized by uncontrolled, abnormal proliferation of cells, as well as any of a number of characteristic structural and/or molecular features.
  • a "cancerous cell” is understood as a cell having specific structural properties, lacking differentiation and in many instances, being capable of invasion and metastasis, see DeVita, V. et al. (eds.), 2001, Cancer Principles and Practice of Oncology, 6th. Ed., Lippincott Williams & Wilkins, Philadelphia, PA).
  • cancer includes, but is not limited to, cancers of the female reproductive organs including, but not limited to, ovarian cancer, cervical cancer and uterine cancer; lung cancer; breast cancer; renal cell carcinoma; lymphomas including Hodgkin's lymphoma; and Non-Hodgkin's lymphoma; cancers of the genitourinary system including, but not limited to, kidney cancer, prostate cancer, bladder cancer, and urethral cancer; cancers of the head and neck; liver cancer; cancers of the gastrointestinal system including, but not limited to, stomach cancer, esophageal cancer, small bowel cancer or colon cancer; cancers of the biliary tree; pancreatic cancer; cancers of the male reproductive system including, but not limited to, testicular cancer; Gestational trophoblastic disease; cancers of the endocrine system including, but not limited to, thyroid cancer, parathyroid cancer, adrenal gland cancer, carcinoid tumors, insulinomas and PNET tumors; sarcomas, including but not limited
  • methods of the present invention include the treatment of leukemia, lung cancer, including non-small cell lung cancer, colon cancer, cancer of the central nervous system, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, or lymphoma by administering a compound of the present invention to a subj ect in need thereof.
  • the compounds of the present invention can be administered to a subject to inhibit tumor growth or cause tumor regression.
  • the tumors will be malignant tumors, e.g., malignant liposarcomas and epithelial tumors.
  • the tumors will be benign, such as adenomas. Accordingly, disease caused by benign tumors, e.g., acromegaly, are also treatable by the methods of the present invention
  • Tumor cells refers to an aggregate of abnormal cells and/or tissue which may be associated with (e.g., implicated in) diseased states that are characterized by uncontrolled cell proliferation.
  • the disease states may involve a variety of cell types, including, for example, endothelial, epithelial and myocardial cells. Included among the disease states are cancers.
  • the compounds of the invention can be administered alone for use in single agent therapy, concomitantly with another pharmaceutical agent for use in combination therapy, or following a course of treatment for use in MDR cells.
  • Concomitant administration means administration of the additional therapeutic agent at such time that both the additional therapeutic agent and the compounds of the present invention will have a therapeutic effect. Such concomitant administration may involve concurrent (i.e. at the same time), prior, or subsequent administration of the therapeutic agent in relation to administration of a compound of the present invention.
  • a person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs.
  • Therapeutic drugs useful for treating cancer in combination therapy with the methods of the present invention include, for example, chemotherapeutic agents, alone, or in combination with, radiation treatment, surgical treatment, or treatments using biological or immunomodulatory agents.
  • Chemotherapeutic drugs useful in treating cancer include alkylating agents, antimetabolites, natural products, hormones and antagonists (reviewed in B.A. Chabner and D.L. Longo Eds. Cancer Chemotherapy and Biotherapy, 3 rd Edition, 2001).
  • nitrogen mustards including but not limited to mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil
  • ethylenimines and methylmelamines including but not limited to, hexamethylmelamine and thiotepa
  • alkyl sulfonates including but not limited to, busulfan, carmustine, lomustine, semustine, and streptozocin
  • triazenes including but not limited to, dacarbazine and temozolamide, folic acid analogs, including but not limited to, methotrexate and trimetrexate
  • 5-fluoropyrimidines including but not limited to, fluorouracil, floxuridine, ftorafur, capecitabine, and eniluracil,cytidine analogs, including cytarabine
  • 5-azacytidine, gemcitabine purine analogs and related inhibitors, including but
  • faranesyl transferase inhibitors including, but not limited to Rl 15777 (tipifarnib, Zarnestra ® ), SCH66336 (lonafarnib, Sarasar ® ) and BMS-214662, including formulations of chemotherapy drugs including, but not limited to, liposomal formulations, including arsenic trioxide, including cancer differentiating agents including but not limited to all trans retinoic acid, including cancer treatments that use adoptive immunotherapy and including cancer treatments that use gene therapy. Methods of administering chemotherapeutic agents for treating cancer are known in the art.
  • Li employing a compound of the invention for treatment of disease, including cancer and hyperproliferative diseases, any pharmaceutically acceptable mode of administration can be used, including oral, buccal, topical, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, subcutaneous, or intravenous injection).
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, gels, emulsions, syrups, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable excipient.
  • Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, can be found in such standard references as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, EastonPA, 1985. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, and the like.
  • suitable liquid carriers especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols.
  • a compound of the invention can be administered in sustained or controlled release dosage forms (e.g., employing a slow release bioerodable delivery system), including depot injections, osmotic pumps (such as the Alzet implant made by Alza), pills, transdermal and transcutaneous (including electrotransport) patches, and the like, for prolonged administration at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages.
  • the compositions will typically include a conventional pharmaceutical carrier or excipient and a compound of the invention, m addition, these compositions can include other active agents, carriers, adjuvants, and the like.
  • Aqueous suspensions of the invention can contain a compound of the present invention in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients can include, for example, a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g.
  • a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia
  • dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (
  • polyoxyethylene stearate a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., heptadecaethylene oxycetanol
  • a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol e.g., polyoxyethylene sorbitol mono-oleate
  • the aqueous suspension can also contain, for example, one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolality.
  • OiI suspensions can be formulated by, for example, suspending a compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain, for example, a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Titer. 281:93-102, 1997.
  • the pharmaceutical formulations of the invention can also be in the form of oil-in- water emulsions.
  • the oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include, for example, naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
  • Formulations of a compound of the invention can also be administered to the respiratory tract as a nasal or pulmonary inhalation aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose, or with other pharmaceutically acceptable excipients.
  • the particles of the formulation may advantageously have diameters of less than about 50 microns, preferably less than about 10 microns (see, e.g., U.S. Pat. No. 5,364,838, which discloses a method of administration for insulin that can be adapted for the administration of a compound of the invention in the present invention).
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.
  • the compounds are sufficiently soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol.
  • Dispersions of the finely divided compounds can, for example, be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in suitable oil, such as arachis oil. These formulations can be sterilized by conventional, well known sterilization techniques.
  • the formulations can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally- acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.
  • concentration of compounds of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the percentage of a compound of the invention contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. However, percentages of active ingredient of about 0.01% to about 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • One approach for parenteral administration employs the implantation of a slow- release or sustained-release system, such that a constant level of dosage is maintained.
  • Various matrices e.g., polymers, hydrophilic gels, and the like
  • for controlling the sustained release, and for progressively diminishing the rate of release of active agents such as a compound of the invention are known in the art. See, e.g., U.S. Pat. No. 3,845,770 (describing elementary osmotic pumps); U.S. Pat. No. 3,995,651, U.S. Pat. No. 4,034,756 and U.S. Pat. No. 4,111,202 (describing miniature osmotic pumps); U.S. Pat. No. 4,320,759 and U.S. Pat. No. 4,449,983 (describing multichamber osmotic systems referred to as push-pull and push-melt osmotic pumps); and U.S. Pat. No.
  • Compounds of the present invention can be administered orally.
  • the amount of a compound of the present invention in the composition can vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art.
  • the final composition can comprise, about 0.1% to about 90%, preferably about 0.5% to about 50%, by weight of a compound of the invention, the remainder being pharmaceutically acceptable excipients
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, the disclosure of which is hereby incorporated by reference in its entirety.
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
  • Such carriers enable the pharmaceutical formulations to be formulated in unit dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for ingestion by the patient.
  • Formulations suitable for oral administration can, for example, consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.
  • compositions for oral use can be obtained, for example, through combination of the compounds of the present invention with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores.
  • suitable solid excipients include, for example, carbohydrate or protein fillers and include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen.
  • disintegrating or solubilizing agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • the compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug.
  • These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
  • Transdermal delivery systems can be formulated, for example, as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Encapsulating materials can be employed with the compounds of the present invention and the term "composition" can include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers.
  • the compounds of the present invention can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously; as biodegradable and injectable gel formulations; or, as microspheres for oral administration. Both transdermal and intradermal routes afford constant delivery for weeks or months. Cachets can also be used in the delivery of the compounds of the present invention.
  • the compounds of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compound into the target cells in vivo.
  • the preferred preparation can be a lyophilized powder which may contain, for example, any or all of the following: about 1 mM-50 mM histidine, about 0.1%-2% sucrose, about 2%-7% mannitol, at a pH range of about 4.5 to 5.5, that is combined with buffer prior to use.
  • a pharmaceutical composition of the invention can optionally contain, in addition to a compound of the present invention, at least one other therapeutic agent useful in the treatment of a disease or condition associated with a disease treatable by the present methods.
  • the pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
  • GMP Good Manufacturing Practice
  • the prodrugs of present invention will be active and therapeutic at dosage levels equivalent or, in some cases, lower than those utilized for their non-prodrug counterparts or for other existing tubulin-binding drugs.
  • the identification and application of clinically acceptable dosage ranges for the compounds of the invention within these parameters is well within the ordinary level of skill in the art.
  • effective administration of the compounds of this invention can be given at an oral dose of, for example, from about 0.1 mg/kg/day to about 1000 mg/kg/day. In a preferred embodiment, administration will be from about 50 mg/kg/day to about 250 mg/kg/day, e.g., at about 100 mg/kg/day.
  • compositions or compounds disclosed herein can be administered to the subject in a single bolus delivery, via continuous delivery (e.g., continuous transdermal, mucosal, or intravenous delivery) over an extended time period, or in a repeated administration protocol (e.g., by an hourly, daily or weekly, repeated administration protocol).
  • a repeated administration protocol e.g., by an hourly, daily or weekly, repeated administration protocol.
  • the pharmaceutical formulations of the present invention can be administered, for example, one or more times daily, 3 times per week, or weekly.
  • the actual dosage of biologically active agents will of course vary according to factors such as the extent of exposure and particular status of the subject (e.g., the subject's age, size, fitness, extent of symptoms, susceptibility factors, etc), time and route of administration, as well as other drugs or treatments being administered concurrently. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response.
  • therapeutically effective dose herein is meant a dose that produces effects for which it is administered.
  • a therapeutically effective dose is also one in which any toxic or detrimental side effects of the active agent is outweighed in clinical terms by therapeutically beneficial effects.
  • unit dosage forms of the compounds are prepared for standard administration regimens.
  • the composition can be subdivided readily into smaller doses at the physicians direction.
  • unit dosages can be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.
  • another pharmaceutical comprising at least one other therapeutic agent useful in the treatment of a disease or condition treatable by the present methods can be placed in the container as well and labeled for treatment of the indicated disease or condition.
  • a single pharmaceutical comprising a compound of the present invention and at least one other therapeutic agent useful in the treatment of a disease or condition treatable by the present methods can be placed in an appropriate container and labeled for treatment.
  • labeling can include, for example, instructions concerning the amount, frequency and method of administration.
  • such labeling can include, for example, instructions concerning the amount, frequency and method of administration of each pharmaceutical.
  • Example 5 Efficacy of exemplary indanocine prodrug (4-[(E)-(7-Amino-5,6- dimethoxy-l-oxo-lH-inden-2(3H)-ylidene)methyl]-2,6-dimethylphenoxymethyl Phosphate) and chlorambucil in a xenograft model of daudi cell line in SCID mice
  • mice A total of 23 male SCID mice, 6-8 weeks of age, were obtained from Charles River Laboratories, Inc., Wilmington, MA.
  • the model system included 9 mice (groups 1, & 2) for each of the test and control groups except 5 mice in group 3. Each mouse was uniquely identified by marking the assigned number on the cage card as well as by ear tagging.
  • SCID mice were housed in filter-top plastic cages, and were maintained on a 12-hour light/12-hour dark cycle. Room temperature was maintained at 70 0 F +/- 4°F. The relative humidity of the room was not monitored. Prior to being placed on study, the mice were allowed to acclimate to laboratory environment for a minimum of 5 days to ascertain their continued good health. Standard laboratory rodent chow and water were supplied ad libitum.
  • Daudi cells were processed, counted, suspended, and inoculated.
  • Daudi cell (Human Lymphoma) suspension was mixed well by inverting the conical tube a few times and pulling cells in a 1.0 ml syringe with a 25G1/2 needle attached to it.
  • the mice to be injected were anesthetized in a chamber with Isoflurane/ O 2 mixture. Once anesthetized, the mouse was laid on its side and the needle was slowly inserted under the skin into the cavity between skin and muscle.
  • Cells (lxl0 7 /0.2ml) were inoculated s.c. in the flank (hair shaved) of each male SCID mouse. The syringe's plunger was gradually pushed to deliver exactly 0.2ml of cell suspension, and then the needle was slowly withdrawn. This procedure was repeated for each mouse injected.
  • Tumors were allowed to grow to a size of 80-120mm 3 . Mice were randomized to a matched pair. Tumors were measured in the following manner:
  • Tumors were measured in a sequence starting with the control group.
  • Tumors were measured in three dimension (Vl, V2, V3) using calibrated digital calipers. Care was taken to ensure that the tumor was not squeezed.
  • Measurement data was recorded in tumor data worksheets. Information in the worksheets included: measurement day and date and calculation of tumor volume (TV) (mm 3 ) using the formula: 4/37ir 3 .
  • mice displaying tumors were randomized into groups and weighed. All tumors were measured and volumes calculated. This information was recorded in the Tumor Measurement Worksheet.
  • mice in group 1 were treated as controls, sesame oil was used as the vehicle for po (0.2 ml each) and saline was used as vehicle for ip (0.2 ml each). These mice were dosed 5 times a week 2 weeks total.
  • Group 2 was treated with Chlorambucil ip at 2 mg/kg/d, 5 days a week for 2 weeks.
  • Group 3 was given the exemplary indanocine prodrug at 100 mg/kg/d, ip, 5 days for 2 weeks.
  • the percent tumor volume of all groups was normalized based on the mean tumor volume of 100% for each group on Day 1.
  • Below and in figure 1 are the data of percent tumor volume vs. time. Data were presented as mean -1- SE of 9 tumors in group 1 and 2. For group 3, there were 5 animals on day 1 and 4, and 4 animals on day 9 and 11.
  • the exemplary indanocine prodrug (4-[(E)-(7-Amino-5,6-dimethoxy-l-oxo-lH- inden-2(3H)-ylidene)methyl]-2,6-dimethylphenoxymethyl phosphate) was found to be stable at 7.38 physiological pH at room temperature for three days. The purity of the prodrug remained at greater than about 99%.

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Abstract

La présente invention concerne notamment des prodrogues de phosphate des composés d'indanone et de tétralone, des procédés de préparation de tels composés, des composés pharmaceutiques contenant de tels composés et des procédés permettant d'utiliser de tels composés, par exemple, dans les thérapies médicales.
PCT/US2006/033057 2005-08-24 2006-08-24 Prodrogues de composes d'indanone et de tetralone WO2007025031A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012526148A (ja) * 2009-05-07 2012-10-25 リージェンツ オブ ザ ユニバーシティ オブ ミネソタ トリプトリド製品
US9150600B2 (en) 2009-05-07 2015-10-06 Regents Of The University Of Minnesota Triptolide prodrugs
JP2016034983A (ja) * 2008-05-20 2016-03-17 ニューロジェシックス， インコーポレイテッド カーボネートプロドラッグおよびそれを使用する方法
CN116283657A (zh) * 2023-02-22 2023-06-23 贵州大学 一种茚酮衍生物及其合成方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUA ET AL. CANCER RESEARCH 01 October 2001, pages 7248 - 7254 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016034983A (ja) * 2008-05-20 2016-03-17 ニューロジェシックス， インコーポレイテッド カーボネートプロドラッグおよびそれを使用する方法
JP2012526148A (ja) * 2009-05-07 2012-10-25 リージェンツ オブ ザ ユニバーシティ オブ ミネソタ トリプトリド製品
US9150600B2 (en) 2009-05-07 2015-10-06 Regents Of The University Of Minnesota Triptolide prodrugs
US9623035B2 (en) 2009-05-07 2017-04-18 Regents Of The University Of Minnesota Triptolide prodrugs
US10183033B2 (en) 2009-05-07 2019-01-22 Regents Of The University Of Minnesota Triptolide prodrugs
CN116283657A (zh) * 2023-02-22 2023-06-23 贵州大学 一种茚酮衍生物及其合成方法和应用

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