WO2011055838A1 - Composé pour inhibition de la biosynthèse de la testostérone - Google Patents

Composé pour inhibition de la biosynthèse de la testostérone Download PDF

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Publication number
WO2011055838A1
WO2011055838A1 PCT/JP2010/069879 JP2010069879W WO2011055838A1 WO 2011055838 A1 WO2011055838 A1 WO 2011055838A1 JP 2010069879 W JP2010069879 W JP 2010069879W WO 2011055838 A1 WO2011055838 A1 WO 2011055838A1
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group
testosterone
salt
solvate
alkynyl
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PCT/JP2010/069879
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English (en)
Japanese (ja)
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幸一郎 原田
秀樹 久保
潤 安部
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住友化学株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a compound for inhibiting the biosynthesis of testosterone and the compound.
  • Male hormone-dependent diseases for example diseases whose onset or progression is promoted by the activity of male hormones are well known.
  • these diseases include prostate cancer, benign prostatic hypertrophy, acne, seborrhea, hirsutism, androgenic alopecia, sexual prematurity, adrenal hypertrophy, and polycystic ovary syndrome.
  • Androgenic activity can be reduced by inhibiting androgenic biosynthesis using inhibitors of enzymes that catalyze one or more steps of its biosynthesis.
  • inhibitors of enzymes such as 17 ⁇ -hydroxylase / C17-20 lyase (CYP-17) and type 3 17 ⁇ -hydroxysteroid dehydrogenase inhibit biosynthesis of testosterone, a type of male hormone. Yes.
  • the present invention provides compounds, pharmaceutical compositions, and the like used to treat or prevent diseases and disorders associated with testosterone biosynthesis. That is, the present invention includes the following ⁇ 1> to ⁇ 10>.
  • Formula (I) for inhibiting biosynthesis of testosterone (In the formula, R 1 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group, and these groups each may have one or more substituents.
  • R 2 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group
  • A represents a divalent aromatic group or a heteroaromatic group
  • the aromatic group or heteroaromatic group represents one or more
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group
  • Y 1 , Y 2 and Y 3 are the same or different and each represents an oxygen atom or a sulfur atom.
  • a salt thereof or a solvate thereof Or a salt thereof or a solvate thereof.
  • R 1 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group, and these groups each may have one or more substituents.
  • R 2 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group
  • A represents a divalent aromatic group or a heteroaromatic group
  • the aromatic group or heteroaromatic group represents one or more
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group
  • Y 1 , Y 2 and Y 3 are the same or different and each represents an oxygen atom or a sulfur atom.
  • a salt thereof or a solvate thereof Or a salt thereof or a solvate thereof.
  • R 1 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group, and these groups each may have one or more substituents.
  • R 2 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group
  • A represents a divalent aromatic group or a heteroaromatic group
  • the aromatic group or heteroaromatic group represents one or more
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group
  • Y 1 , Y 2 and Y 3 are the same or different and each represents an oxygen atom or a sulfur atom.
  • a salt or solvate thereof except the following compound or salt or solvate thereof: 5- [3,5-dimethoxy-4- (phosphonooxy) benzylidene] -2-thioxo-3- (3,4,5-trimethoxyphenyl) -1,3-thiazolidine-2,4-di
  • R 1 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group, and these groups each may have one or more substituents.
  • R 2 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group
  • A represents a divalent aromatic group or a heteroaromatic group
  • the aromatic group or heteroaromatic group represents one or more
  • R 3 and R 4 each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group or a heteroaryl group
  • Y 1 , Y 2 and Y 3 are the same or different and each represents an oxygen atom or a sulfur atom.
  • a salt thereof or a solvate thereof is administered to a patient in need of the treatment or prevention.
  • ⁇ 9> A method for treating or preventing a disease that can be treated or prevented by inhibiting testosterone biosynthesis, wherein a therapeutically effective amount of 5- [3,5-dichloro-4- (phosphonooxy) Benzylidene] -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidine-2,4-dione to a patient in need of the treatment or prevention.
  • the method according to item 8 or 9, wherein the disease that can be treated or prevented by suppressing biosynthesis of testosterone is an androgen-dependent disease.
  • the present invention can treat or prevent diseases and disorders associated with testosterone biosynthesis.
  • alkyl group is a linear or branched saturated hydrocarbon group.
  • Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t- Examples thereof include alkyl groups having 1 to 6 carbon atoms such as a butyl group, an isopentyl group, and an n-pentyl group.
  • An “alkenyl group” is a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon double bonds. Preferred alkenyl groups include those having 2 to 6 carbon atoms such as vinyl groups.
  • alkenyl group is mentioned.
  • the “alkynyl group” is a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon triple bonds. Preferred alkenyl groups include alkynyl having 2 to 6 carbon atoms such as ethynyl group. Groups.
  • the “cycloalkyl group” is a cyclic saturated hydrocarbon group, and preferred cycloalkyl groups are linear or branched such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group. Examples thereof include cycloalkyl groups having 3 to 7 carbon atoms.
  • the “aralkyl group” is an alkyl group in which at least one of the hydrogen atoms contained in the alkyl group is substituted with an aryl group.
  • Preferred aralkyl groups include aralkyl groups having 7 to 20 carbon atoms such as benzyl and phenethyl. It is done.
  • the “aryl group” is an aromatic group composed of a carbon atom and a hydrogen atom, and preferable aryl groups include aryl groups having 6 to 10 carbon atoms such as a phenyl group, a biphenyl group, and a naphthyl group.
  • heteroaryl group is a monocyclic or polycyclic aromatic group containing at least one selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • Preferred heteroaryl groups include thienyl group, furyl Group, pyrrolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group and the like.
  • the “divalent aromatic group” is a divalent group formed by removing one hydrogen atom of each of two ring carbon atoms from an arene composed of a carbon atom and a hydrogen atom.
  • divalent aromatic group examples include arenes having 6 to 10 carbon atoms such as benzene, biphenyl and naphthalene.
  • the “divalent heteroaromatic group” is a monocyclic or polycyclic heteroarene containing at least one selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and one each of two ring carbon atoms.
  • the heteroarene constituting the divalent heteroaromatic group which is a divalent group generated by removing the hydrogen atom of thiophene, furan, pyrrole, pyrazoline, isothiazoline, isoxazoline, pyridine, pyrazine , Pyrimidine, pyridazine and the like.
  • the “haloalkyl group” is an alkyl group in which at least one of the hydrogen atoms contained in the alkyl group is substituted with a halogen atom.
  • Preferred haloalkyl groups include a trifluoromethyl group and a 2,2,2-trifluoroethyl group. Etc.
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • the “alkoxy group” is a group represented by —ORa, and Ra represents the alkyl group.
  • the “haloalkoxy group” is a group represented by —ORb, and Rb represents the haloalkyl group.
  • the “alkylthio group” is a group represented by —SRa, and Ra represents the alkyl group.
  • alkylamino group is a group represented by —NHRa or —N (Ra) Ra ′, and Ra and Ra ′ independently represent the alkyl group.
  • the “alkoxycarbonyl group” is a group represented by —COORa, and Ra represents the alkyl group.
  • alkylcarbamoyl group is a group represented by —CONHRa or —CON (Ra) Ra ′, and Ra and Ra ′ independently represent the alkyl group.
  • the “acyl group” is a group represented by —C (O) Ra, and Ra represents the alkyl group.
  • the “acyloxy group” is a group represented by —OC (O) Ra, and Ra represents the alkyl group.
  • the “acylamino group” is a group represented by —NHC (O) Ra or —N (Ra) C (O) Ra ′, and Ra and Ra ′ independently represent the alkyl group.
  • alkylcarbamoyloxy group is a group represented by —OC (O) NHRa or —OC (O) N (Ra) Ra ′, and Ra and Ra ′ independently represent the alkyl group.
  • the “alkylsulfonyl group” is a group represented by —SO 2 Ra, and Ra represents the alkyl group.
  • the “alkylsulfonylamino group” is a group represented by —NHSO 2 Ra, and Ra represents the alkyl group.
  • alkylsulfamoyl group is a group represented by —SO 2 NHRa or —SO 2 N (Ra) Ra ′, and Ra and Ra ′ independently represent the alkyl group.
  • “May have a substituent” or “has a substituent” means that at least one of the hydrogen atoms contained in the target group may be substituted with any of the aforementioned substituents. Alternatively, it is substituted with any one of the above substituents.
  • Effective amount means the amount of a drug or agent that elicits a biological or medical response of a tissue system, animal or human, eg, as sought by a researcher or clinician. A biological or medical response can be considered a prophylactic or therapeutic response.
  • a “therapeutically effective amount” is an improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or progression of a disease or disorder compared to a counterpart who has not received such an amount.
  • the term means any amount that results in a delay in speed.
  • the term also includes within its scope amounts effective to promote normal physiological function.
  • a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof can be administered as the active ingredient.
  • the active ingredient can also be provided as a pharmaceutical composition.
  • the present invention further comprises a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a salt or solvate thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients in the formulation and not injurious to the recipient of the pharmaceutical composition.
  • R 1 in formula (I) is preferably an aryl group having one or more substituents, a heteroaryl group having one or more substituents, or a cycloalkyl group optionally having one or more substituents.
  • the substituent of the aryl group, heteroaryl group or cycloalkyl group includes an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, an alkylamino group, and an acylamino group.
  • One or more groups selected from the group consisting of famoyl groups are preferred.
  • the phenyl group having one or more substituents or the cycloalkyl group optionally having one or more substituents is more preferable, and a 4-methoxyphenyl group is more preferable.
  • A is preferably a phenylene group which may have one or more substituents other than the phosphate group. More preferably, it is a phenylene group having one or more groups selected from the group consisting of a halogen atom, an alkyl group and a haloalkyl group.
  • R 2 , R 3 and R 4 are preferably hydrogen atoms.
  • compound (I) 5- [3,5-dichloro-4- (phosphonooxy) benzylidene] -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidine-2,4-dione is preferable.
  • the salt of compound (I) is pharmaceutically acceptable and includes acid addition salts.
  • acetate, benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, edetate, cansylate, carbonate, clavulanate Citrate, dihydrochloride, edicylate, estrate, esylate, fumarate, glutceptate, gluconate, glutamate, glycolylarsanylate, hexyl resorcinate hydrabamine, hydrobromide , Hydrochloride, hydroxynaphthoate, iodate, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, Methyl sulfate, monopotassium malate, mucinate, napsylate, nitrate, N-methylglucamine, oxalate, pamoic acid (embonate) salt,
  • the “solvate” of compound (I) or a salt thereof means a complex of compound (I) or a salt thereof and a solvent.
  • the solvent include water, methanol, ethanol, acetic acid and the like. More preferred are water, ethanol and acetic acid, and further preferred is water.
  • Compound (I) or a salt thereof or a solvate thereof may exhibit two or more polymorphs as its crystal structure. Polymorphs can generally occur depending on conditions such as the solvent, temperature, pressure, etc. at which crystals are precipitated. Polymorphs can be distinguished by physical characteristics such as X-ray diffraction patterns, solubility and melting point. Next, a method for producing compound (I) or a salt thereof or a solvate thereof will be described.
  • a rhodanine derivative which is an intermediate necessary for the production of compound (I) or a salt thereof or a solvate thereof can be produced, for example, by the reaction described in the following formula.
  • Such a reaction is performed by, for example, coupling an amine compound and a bis (carboxymethyl) trithiocarbonate derivative in the presence of a base such as sodium carbonate to obtain a thioglycolic acid derivative,
  • the cyclization reaction can be carried out under acidic conditions such as in an aqueous sulfuric acid solution.
  • an amine compound and a trithiocarbonate bis (carboxymethyl) derivative are reacted in the presence of a condensing agent such as carbonyldiimidazole (CDI) to obtain an amide derivative, and then the amide derivative is cyclized under heating conditions. It can also be carried out by a reaction.
  • a condensing agent such as carbonyldiimidazole (CDI)
  • CDI carbonyldiimidazole
  • the former condition is preferred if R 1 is an aryl group, if R 1 is an alkyl group the latter conditions are preferred.
  • An oxazolidinone derivative which is an intermediate necessary for the production of compound (I) or a salt thereof or a solvate thereof can be produced, for example, by a reaction described in the following formula.
  • Such a reaction is performed, for example, by reacting an isocyanate with ethyl glycolate to obtain a urethane derivative, as exemplified in Method A, and then cyclizing the urethane derivative in the presence of a base such as sodium methoxide. Performed by reacting (Method A). Further, for example, a urethane derivative is obtained by reacting an amine compound with ethyl glycolate in the presence of a condensing agent such as carbonyldiimidazole (CDI), and cyclized in the presence of a base in the same manner as in the above method A. (Method B).
  • a condensing agent such as carbonyldiimidazole (CDI)
  • the benzylidene rhodanine derivative and the benzylidene oxazolidinone derivative which are intermediates necessary for the production of the compound (I) or a salt thereof or a solvate thereof, are, for example, a Knaevener gel of a rhodanine derivative or an oxazolidinone derivative represented by the following formula and an aldehyde or a ketone. It can be produced by a (Kneovenagel) reaction. Such a reaction is usually carried out in the presence of a base.
  • the base examples include inorganic bases such as sodium acetate, ammonium acetate, sodium hydroxide, potassium carbonate, and sodium bicarbonate; pyrrolidine, pyridine, triethylamine, 1,8-diazabicyclo [5,4,0] -7-undecene ( DBU) and organic bases such as ⁇ -alanine.
  • This reaction is usually carried out in the presence of a solvent.
  • the solvent include alcohol solvents such as methanol, ethanol and 2-methoxy-1-propanol; polar solvents such as acetonitrile, dimethylacetamide, dimethylformamide and acetic acid; Etc. are preferred.
  • the reaction temperature is preferably 80 to 120 ° C.
  • Compound (I) or a salt thereof or a solvate thereof can be produced, for example, by the reaction described in the following formula.
  • Such a reaction can be synthesized, for example, by converting a hydroxyl group of an alcohol derivative into a phosphate ester.
  • Examples of the phosphorylating agent used in the phosphorylation reaction include phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide; phosphoric anhydrides such as pyrophosphoric acid and polyphosphoric acid; phosphoric acid, p-nitrophenyl phosphate, Phosphoric monoesters such as 2- (N, N-dimethylamino) -4-nitrophenyl phosphate; 2-chloro-2-oxo-P V- 1,3,2-benzodioxophosphole, 2-methylthio Cyclic phosphorylating agents such as 2-oxo-P V -4H-1,3,2-benzodioxaphospholine; bis (4-nitrophenyl) formolochloridate, bis ( ⁇ , ⁇ , ⁇ -trichloroethyl) ) Forholochloridate, and chloridate phosphate prepared by dibenzyl phosphite / carbon tetrachloride; can be used.
  • this reaction is usually carried out in the presence of a catalyst.
  • the catalyst include pyridine, 4-methylaminopyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7-.
  • organic bases such as undecene (DBU); inorganic bases such as sodium hydrogen carbonate and potassium carbonate.
  • the reaction temperature is preferably -80 to 50 ° C, more preferably -20 to 10 ° C.
  • the compounds (I) thus obtained are exemplified in Table 1. Next, the use of compound (I) or a salt thereof or a solvate thereof for suppressing the biosynthesis of testosterone will be described.
  • Compound (I) or a salt thereof or a solvate thereof can be used as an active ingredient of a pharmaceutical composition for diseases that can be treated or prevented by inhibiting biosynthesis of testosterone.
  • the present invention is useful for the treatment or prevention of male hormone-dependent diseases, and includes the use of Compound (I) or a salt thereof or a solvate thereof in this treatment or prevention.
  • the present invention is useful for the treatment or prevention of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenetic alopecia or polycystic ovary syndrome, and the compound ( Including the use of I) or a salt thereof or a solvate thereof.
  • the present invention provides a method for treating or preventing an androgen-dependent disease comprising the compound (I) or a salt thereof or a solvate thereof and at least one antiandrogenic drug (ie, androgen). And agents that reduce the activity of synthetic or androgenic activity) simultaneously or sequentially.
  • the present invention provides a method for treating or preventing benign prostatic hyperplasia comprising the compound (I) or a salt thereof or a solvate thereof and at least one agent useful in the treatment or prevention of benign prostatic hypertrophy. Are used simultaneously or sequentially in combination.
  • the present invention provides a method of treating or preventing hair loss, which comprises compound (I) or a salt thereof or a solvate thereof and an agent useful in the treatment or prevention of at least one alopecia (eg, And a combination of a potassium channel agonist such as minoxidil and KC-516, and an anti-hair removal agent such as 5 ⁇ -reductase inhibitor such as finasteride and dutasteride, simultaneously or sequentially in combination.
  • the present invention provides a method for treating or preventing a proliferative disease, the method comprising compound (I) or a salt thereof or a solvate thereof and at least one useful in the treatment or prevention of a proliferative disease.
  • medical agent simultaneously or sequentially is included.
  • a method for treating or preventing cancer is provided.
  • Compound (I) or a salt thereof or a solvate thereof, and a chemotherapeutic agent, biological agent, surgical treatment And at least one treatment method selected from the group consisting of radiotherapy and simultaneous or sequential combination are used.
  • Non-limiting examples of cancer ie, tumor
  • lung cancer eg, lung adenocarcinoma
  • pancreatic cancer eg, exocrine pancreatic cancer
  • colon cancer eg, colon adenocarcinoma and colon adenoma
  • Renal cancer myeloid leukemia (eg, acute myeloid leukemia), follicular thyroid cancer, myelodysplastic syndrome (MDS), bladder cancer, epidermis cancer, melanoma, breast cancer and prostate cancer. It is not limited.
  • Methods of treating a proliferative disease (cancer) include effective amounts of at least one compound (I) or a salt or solvate thereof, and an effective amount of at least one chemotherapeutic agent, biological
  • chemotherapeutic agent a chemotherapeutic agent, biological
  • Abnormal growth of cells means, for example, cell growth independent of normal regulatory mechanisms (eg, contact inhibition or apoptosis), and includes the following abnormal cell growth: (1) expresses activated ras oncogene Tumor cells (tumors); (2) tumor cells in which ras protein is activated as a result of a tumorigenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases.
  • abnormal cell growth (1) expresses activated ras oncogene Tumor cells (tumors); (2) tumor cells in which ras protein is activated as a result of a tumorigenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases.
  • a method for treating or preventing tumor growth in a patient in need of treatment for tumor growth comprising (1) an effective amount of at least one compound ( I) or a salt thereof or a solvate thereof, and (2) an effective amount of at least one antineoplastic agent / microtubule agent, biological agent, and / or surgery (eg, prostatectomy) and / or radiation
  • an effective amount of at least one antineoplastic agent / microtubule agent, biological agent, and / or surgery eg, prostatectomy
  • tumors examples include epithelial cancer (eg, prostate cancer), lung cancer (eg, lung adenocarcinoma), pancreatic cancer (eg, exocrine pancreatic cancer), breast cancer, kidney cancer, colon cancer (eg, colon adenocarcinoma) And colon adenoma), ovarian cancer, and bladder cancer.
  • Other cancers that can be treated include melanoma, myeloid leukemia (eg, acute myeloid leukemia), sarcoma, follicular thyroid cancer, and myelodysplastic syndrome.
  • Types of sex hormone dependent diseases include, for example, prostate cancer, benign prostatic hyperplasia, prostate intraepithelial neoplasia, acne, seborrhea, hirsutism, androgenetic alopecia, sexual prematurity, adrenal hyperplasia and Examples include polycystic ovary syndrome, breast cancer, endometriosis and leiomyoma. Certain useful concomitant / related agents are described below. Classes of compounds that can be used as chemotherapeutic agents (anti-neoplastic agents) include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs) ), As well as composites.
  • Non-limiting examples of compounds within these classes include the following: Alkylating agents (including nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes): uracil mustard, chlormethine, cyclophosphamide [Cytoxan®], ifosfamide, melphalan, chlorambucil, piperobroman, tri Ethylene melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • Alkylating agents including nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes
  • Antimetabolites including folate antagonists, pyrimidine analogs, purine analogs and adenosine deamylase inhibitors: methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and Gemcitabine.
  • Natural products and their derivatives including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins: vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, Paclitaxel [Paclitaxel is commercially available as Taxol® and is described in more detail in the subsection entitled “Microtubule Agents” below], mitramycin, deoxycoformycin, mitomycin C, L- Asparaginase, interferon- ⁇ and interferon- ⁇ , etoposide, and teniposide.
  • Hormonal drugs and steroids include synthetic analogs: 17 ⁇ -ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, tamoxifen, methylprednisolone, methyl Testosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin and zoladex.
  • Synthetic products including inorganic complexes such as platinum coordination complexes: cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitozantrone, levamisole, navelbine, CPT-11, anastrazole, letrazole, capecitabine, ralodifine , Droxifene and hexamethylmelamine.
  • biological agents useful in the methods of the invention include, for example, interferon- ⁇ , interferon- ⁇ , and gene therapy.
  • Microtubule agents are compounds that interfere with cell mitosis by affecting microtubule formation and / or microtubule action, ie, compounds that have an anti-mitotic effect.
  • Such an agent can be, for example, a microtubule stabilizer or an agent that blocks microtubule formation.
  • microtubule agents useful in the present invention include: alocolchicine (Allocholicine, NSC 406042), halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (eg, , NSC 33410), Dolastatin 10 (NSC 376128), Maytansine (NSC 153858), Rhizoxin (NSC 332598), Paclitaxel [Taxol®, NSC 125973], Paclitaxel derivatives (eg NSC 608832), Thiocolchicine (NSC 361792) ), Tritylcysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothi Ron, discodermolide, estramustine, nocodazole and MAP4.
  • alocolchicine Allocholicine, NSC 406042
  • halichondrin B NSC 609395
  • Paclitaxel is a compound with paclitaxel-like activity. That is, paclitaxel, a paclitaxel derivative, and a paclitaxel analog are mentioned. Paclitaxel and its derivatives are commercially available, and more specifically, the term “paclitaxel” as used herein refers to a drug marketed as Taxol®.
  • inhibitors of 5 ⁇ -reductase type 1 and / or inhibitors of 5 ⁇ -reductase type 2 eg, finasteride, SKF105,657, LY191,704, LY320,236 and dutasteride
  • AR antagonists eg, Flutamide, nilutamide, and bicalutamide
  • LHRH agonists eg, leuprolide and zoladex
  • LHRH antagonists eg, abarelix and cetrorelix
  • inhibitors of 17 ⁇ -hydroxylase / C17-20 lyase eg, YM116, CB7630 and lyarozole
  • Inhibitors of isoenzymes for example, EM-1404).
  • agents useful in the treatment or prevention of benign prostatic hyperplasia include alpha-1 adrenergic antagonists such as tamsulosin, terazosin, prazosin, urapidil and naphthopidyl.
  • alpha-1 adrenergic antagonists such as tamsulosin, terazosin, prazosin, urapidil and naphthopidyl.
  • the pharmaceutically acceptable carrier for preparing the present pharmaceutical composition from Compound (I) or a salt thereof or a solvate thereof is usually a solid or a liquid.
  • solid preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. These powders and tablets are usually composed of 5-95% of compound (I) or a salt thereof or a solvate thereof.
  • Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions are described in, for example, A.
  • liquid preparations include solutions, suspensions, and emulsions.
  • examples include the addition of water or water-propylene glycol solutions for parenteral injection or sweeteners and opacifiers for oral solutions, suspensions and emulsions.
  • Liquid formulations also include solutions for intranasal administration. Aerosol formulations suitable for inhalation include, for example, solids in solution and powder form. The solutions and solids in powder form are usually administered in combination with a pharmaceutically acceptable carrier such as an inert compressed gas (eg, nitrogen). Also included are solid dosage forms that are converted, shortly before use, to liquid formulations for oral or parenteral administration.
  • a pharmaceutically acceptable carrier such as an inert compressed gas (eg, nitrogen).
  • solid dosage forms that are converted, shortly before use, to liquid formulations for oral or parenteral administration.
  • liquid preparations examples include solutions, suspensions and emulsions.
  • the compounds of the present invention can also be delivered transdermally.
  • Transdermal compositions include, for example, creams, lotions, aerosols and / or emulsion forms, and for this purpose, as usual in the art, in matrix-type transdermal patches or reservoir-type It can be contained in a skin patch.
  • the compounds of the present invention can also be delivered subcutaneously.
  • the preferred dosage form of the compound of the present invention is oral.
  • the pharmaceutical composition is preferably in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.
  • the amount of active compound in a unit dose of the preparation is preferably in the range of 1-100 mg, more preferably 1-50 mg, even more preferably 1-25 mg, according to its particular application.
  • the actual dosage will vary depending on the requirements of the patient and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular situation is within the skill of the art.
  • the total daily dosage is administered in multiple doses as needed.
  • the therapeutically effective amount of Compound (I) or a salt or solvate thereof can depend on a number of factors. For example, the species, age and weight of the recipient, the exact condition requiring treatment and its severity, the nature of the formulation and the route of administration are all factors to consider. The therapeutically effective amount should ultimately be left to the judgment of the attending physician.
  • a typical recommended daily dosage regimen for oral administration is preferably 2 to 4 divided doses, preferably 1 to about 500 mg per day, more preferably 1 to about 200 mg per day. It becomes a range.
  • the chemotherapeutic agent and / or radiation therapy is compound (I) according to the dosage and dosing schedule listed in the product information sheet of the approved drug in the Physicians Desk Reference (PDR) and therapeutic protocols well known in the art. Alternatively, it can be administered in combination with a salt or solvate thereof.
  • Table 11 illustrates the dosage ranges and dosage regimens of chemotherapeutic agents useful in the methods of the invention.
  • the administration of the chemotherapeutic agent and / or radiation therapy can be varied depending on the disease to be treated and the known effects of the drug and / or radiation therapy on the disease.
  • the above therapeutic protocols eg, dosage and number of administrations
  • Anti-androgenic agents, anti-benign prostatic hypertrophy agents, potassium channel agonists and biological agents are well known in the art as to dosages and schedules listed in the product information sheet of approved drugs in the Physicians Desk Reference (PDR)
  • PDR Physicians Desk Reference
  • the therapeutic protocol it can be administered in combination with compound (I) or a salt thereof or a solvate thereof.
  • the administration of the factor can be varied depending on the disease to be treated and the known effects of the factor on the disease.
  • the therapeutic protocol eg, dosage and number of doses
  • kits comprising Compound (I) or a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • a kit comprising an amount of Compound (I) or a salt or solvate thereof and an amount of at least one additional agent listed above.
  • the kit may include each of the above components in one or more containers in the kit.
  • Example 1-1 Preparation of 4-methoxyphenylcarbamoyloxyacetic acid ethyl ester 3.12 g (35.8 mmol) of ethyl glycolate and N, N-dimethylformamide (hereinafter referred to as DMF) were charged into a reactor. Cooled to 5 ° C. Under a nitrogen atmosphere, 5 mL of a DMF solution of 4.85 g (0.91 molar equivalent) of 4-methoxyphenyl isocyanate was added dropwise and stirred at 80 ° C. for 3 hours.
  • DMF N, N-dimethylformamide
  • Example 1-2 Preparation of 3- (4-methoxyphenyl) -1,3-oxazolidine-2,4-dione 2.48 g of 4-methoxyphenylcarbamoyloxyacetic acid ethyl ester obtained in Example 1-1 (9 .77 mmol), sodium methoxide 20 mg (0.037 molar equivalent), and toluene 20 mL were charged into a reactor, and the mixture was stirred at 100 ° C.
  • Example 1-3 Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -1,3-oxazolidine-2,4-dione 3 obtained in Example 1-2 -(4-Methoxyphenyl) -1,3-oxazolidine-2,4-dione 0.20 g (0.96 mmol), 3-bromo-4-hydroxybenzaldehyde 0.20 g (1.0 molar equivalent), sodium acetate 0 .16 g (2.0 molar equivalents) and 5 mL of acetic acid were charged into the reactor and refluxed for 16 hours under a nitrogen atmosphere.
  • Example 2-2 Preparation of potassium benzylthiosulfonylthiocarboxyoxyacetate 189 g (3.37 mol) of potassium hydroxide and 200 mL of water were charged into a reactor, cooled in an ice bath, and then 116 g (1.53 mol) of glycolic acid. 131 g (1.12 molar equivalent) of carbon disulfide was added.
  • Example 2-3 Preparation of 4-methoxyphenylthiocarbamoyloxyacetic acid 15.5 g (55.1 mmol) of benzylthiosulfonylthiocarboxyoxyacetic acid potassium salt obtained in Example 2-2 and 60 mL of water were charged into a reactor. The solution was completely dissolved by stirring. To this was added 6.8 g (1.0 molar equivalent) of 4-methoxyphenylamine, and the mixture was stirred at room temperature for 6 hours and left overnight.
  • the obtained reaction mixture was washed with water and washed with benzyl methyl ether, and then 5 mL of concentrated hydrochloric acid was added to the aqueous layer under ice-cooling to adjust to pH 3.
  • the precipitated crystals were extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was washed with hexane to obtain 11.3 g of the title compound as a white powder (yield 85%).
  • Example 2-4 Preparation of 3- (4-methoxyphenyl) -2-thioxo-1,3-oxalidin-4-one 5.0 g of 4-methoxyphenylthiocarbamoyloxyacetic acid obtained in Example 2-3 (20.7 mmol), 2.6 g (1.2 molar equivalents) of acetic anhydride and 10 mL of acetic acid were charged into the reactor, and heated under reflux for about 2 hours in a nitrogen atmosphere.
  • Example 2-5 Preparation of 5- (3,5-dichloro-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-oxazolidine-4-one
  • Example 1-3 instead of 3- (4-methoxyphenyl) -1,3-oxazolidine-2,4-dione, 3- (4-methoxyphenyl) -2-thioxo-1,3 obtained in Example 2-4 -Oxalidin-4-one (1.5 g, 6.7 mmol) was used instead of 3-bromo-4-hydroxybenzaldehyde, 1.3 g of 3,5-dichloro-4-hydroxybenzaldehyde obtained in Example 2-1.
  • Example 2-6 5- [3,5-dichloro-4- (phosphonooxy) benzylidene] -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidine-2,4-dione dibenzyl ester Preparation of 5- (3,5-dibromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl-2-thiooxo-1,3-oxazolidine-4-one obtained in Example 2-5 (1.00 g) 2.44 mmol) and 20 mL of
  • Example 3-1 Preparation of 5- (3,5-dichloro-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -1,3-thiazolidine-2,4-dione
  • Example 1-3 164 mg of the title compound was synthesized in the same manner as in Example 1-3 except that 183 mg (1.0 molar equivalent) of 3,5-dichloro-4-hydroxybenzaldehyde was used instead of 3-bromo
  • Example 2-6 instead of 5- (3,5-dichloro-4-hydroxy-benzylidene) -3- (4-methoxyphenyl) -2-thiooxo-1,3-oxazolidine-4-one Example except that 5- (3,5-dichloro-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -1,3-thiazolidine-2,4-dione obtained in Example 3-1 was used. The title compound was synthesized in the same manner as 2-6 and Example 2-7.
  • Example 2-3 the title compound was synthesized in the same manner as in Example 2-3 to Example 2-7, except that cyclohexylamine was used instead of 4-methoxyphenylamine.
  • 1 H-NMR (270 MHz, DMSO-d 6 ): ⁇ 1.12-1.32 (m, 2H), 1.62-1.80 (m, 7H), 2.08-2.16 (m, 1H) ), 6.87 (s, 1H), 7.98 (s, 2H)
  • Example 5 3- (4-cyclohexyl) -5- [3-chloro-5-fluoro-4- (phosphonooxy) benzylidene] -2-thioxo-1,3-oxazolidine-2,4-dione [compound number ( 5)]
  • cyclohexylamine was used instead of 4-methoxyphenylamine
  • 3-chloro was used instead of 3,5-dichloro-4-hydroxybenz
  • the present invention can treat or prevent diseases and disorders associated with testosterone biosynthesis.

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Abstract

L'invention porte sur l'utilisation et l'emploi analogue d'un composé représenté par la formule (I), un sel de celui-ci ou un solvate de celui-ci, dans le but d'inhiber la biosynthèse de la testostérone.
PCT/JP2010/069879 2009-11-04 2010-11-02 Composé pour inhibition de la biosynthèse de la testostérone WO2011055838A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0383998A (ja) * 1989-08-15 1991-04-09 Merrell Dow Pharmaceut Inc Ｃ１７‐２０リアーゼ阻害剤として有用な４‐置換１７β‐（シクロプロピルアミノ）アンドロスト‐５‐エン‐３β‐オール及び関連化合物類
JP2008546709A (ja) * 2005-06-17 2008-12-25 アムゲン インコーポレイティッド ベンズアミド誘導体およびそれに関連する使用
JP2009084269A (ja) * 2007-09-05 2009-04-23 Sumitomo Chemical Co Ltd クマリン化合物及びその用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0383998A (ja) * 1989-08-15 1991-04-09 Merrell Dow Pharmaceut Inc Ｃ１７‐２０リアーゼ阻害剤として有用な４‐置換１７β‐（シクロプロピルアミノ）アンドロスト‐５‐エン‐３β‐オール及び関連化合物類
JP2008546709A (ja) * 2005-06-17 2008-12-25 アムゲン インコーポレイティッド ベンズアミド誘導体およびそれに関連する使用
JP2009084269A (ja) * 2007-09-05 2009-04-23 Sumitomo Chemical Co Ltd クマリン化合物及びその用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WIEBKE ARLT: "Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta-Hydroxysteroid Dehydrogenase", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 276, no. 20, 2001, pages 16767 - 16771 *

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