JP2011057644A - USE OF COMPOUND FOR INHIBITING 3-TYPE 17beta-HYDROXYSTEROID DEHYDROGENASE, AND MEDICINE THEREFOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound and a medicine composition which are used for the treatment or prophylaxis of the diseases and lesions in relation to 3-type 17β-hydroxysteroid dehydrogenase. <P>SOLUTION: This invention relates to the use of a compound expressed by formula (I), or a salt thereof, or a solvate thereof. In the formula, R<SP>1</SP>is an alkyl group or the like; R<SP>2</SP>is a hydroxyl group-bearing aryl group or a hydroxyl group-bearing heteroaryl group, and this aryl group or this heteroaryl group may have a substituent except a hydroxyl group; R<SP>3</SP>is a hydrogen atom, an alkyl group, an alkenyl group, an alkinyl group, or a haloalkyl group; and X and Y are each the same or different, an oxygen atom or a sulfur atom. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to the use of compounds for inhibiting type 3 17β-hydroxysteroid dehydrogenase and pharmaceutical compositions therefor.

  Male hormone-dependent diseases, for example diseases whose onset or progression is promoted by the activity of male hormones are well known. Examples of 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. Type 3 17β-hydroxysteroid dehydrogenase is the major enzyme that converts androstenedione to testosterone in the testis. Type 3 17β-hydroxysteroid dehydrogenase is described in US Pat.

JP 2002-506077 gazette

  There has been a need for compounds and pharmaceutical compositions used to treat or prevent diseases and disorders associated with Type 3 17β-hydroxysteroid dehydrogenase.

  Under such circumstances, the present inventors have studied compounds and pharmaceutical compositions used for treating or preventing diseases and disorders related to type 3 17β-hydroxysteroid dehydrogenase, and as a result, the present invention has been achieved. That is, the present invention provides the inventions described in <1> to <10> below.

（式中、Ｒ^１はアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アラルキル基、アリール基またはヘテロアリール基を表し、これらの基はいずれも置換基を有していてもよい。Ｒ^２は水酸基を有するアリール基または水酸基を有するヘテロアリール基を表し、該アリール基またはヘテロアリール基は水酸基以外の置換基を有していてもよい。Ｒ^３は水素原子、アルキル基、アルケニル基、アルキニル基またはハロアルキル基を表す。ＸおよびＹはそれぞれ同一または相異なって酸素原子または硫黄原子を表す。）
で示される化合物もしくはその塩またはその溶媒和物の使用；
＜２＞３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための式（Ｉ）

（式中、Ｒ^１は置換基を有するアリール基、置換基を有するヘテロアリール基または置換基を有してもよいシクロアルキル基を表す。Ｒ^２は水酸基以外の置換基を有していてもよい４−ヒドロキシフェニル基、または、水酸基以外の置換基を有していてもよい５−ヒドロキシ−ピリジン−２−イル基を表す。Ｒ^３は水素原子を表す。Ｘは酸素原子を表し、Ｙは酸素原子または硫黄原子を表す。）
で示される化合物もしくはその塩またはその溶媒和物の使用； <1> Formula (I) for inhibiting type 3 17β-hydroxysteroid dehydrogenase

(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 any of these groups may have a substituent. R ² Represents an aryl group having a hydroxyl group or a heteroaryl group having a hydroxyl group, and the aryl group or heteroaryl group may have a substituent other than the hydroxyl group, and R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group. And X and Y are the same or different and each represents an oxygen atom or a sulfur atom.)
Or a salt thereof or a solvate thereof;
<2> Formula (I) for inhibiting type 3 17β-hydroxysteroid dehydrogenase

(In the formula, R ¹ represents an aryl group having a substituent, a heteroaryl group having a substituent, or an optionally substituted cycloalkyl group. R ² may have a substituent other than a hydroxyl group. Represents a good 4-hydroxyphenyl group or a 5-hydroxy-pyridin-2-yl group which may have a substituent other than a hydroxyl group, R ³ represents a hydrogen atom, X represents an oxygen atom, Y Represents an oxygen atom or a sulfur atom.)
Or a salt thereof or a solvate thereof;

<3> Use of a compound selected from the following group or a salt thereof or a solvate thereof for inhibiting type 3 17β-hydroxysteroid dehydrogenase;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one;
[5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methylbenzamide;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one; and 5- (3-bromo-4-hydroxybenzylidene)- 3- (4-Methoxyphenyl) -1,3-thiazolidine-2,4-dione

（式中、Ｒ^１はアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アラルキル基、アリール基またはヘテロアリール基を表し、これらの基はいずれも置換基を有していてもよい。Ｒ^２は水酸基を有するアリール基または水酸基を有するヘテロアリール基を表し、該アリール基またはヘテロアリール基は水酸基以外の置換基を有していてもよい。
Ｒ^３は水素原子、アルキル基、アルケニル基、アルキニル基またはハロアルキル基を表す。ＸおよびＹはそれぞれ同一または相異なって酸素原子または硫黄原子を表す。）
で示される化合物もしくはその塩またはその溶媒和物の使用；
＜５＞３型１７β−ヒドロキシステロイドデヒドロゲナーゼを阻害することにより治療または予防可能となる疾患が、男性ホルモン依存性疾患であることを特徴とする＜４＞記載の使用； <4> Formula (I) as an active ingredient of a pharmaceutical composition for diseases that can be treated or prevented by inhibiting type 3 17β-hydroxysteroid dehydrogenase

(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 any of these groups may have a substituent. R ² Represents an aryl group having a hydroxyl group or a heteroaryl group having a hydroxyl group, and the aryl group or heteroaryl group may have a substituent other than a hydroxyl group.
R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. X and Y are the same or different and each represents an oxygen atom or a sulfur atom. )
Or a salt thereof or a solvate thereof;
<5> Use according to <4>, wherein the disease that can be treated or prevented by inhibiting type 3 17β-hydroxysteroid dehydrogenase is a male hormone-dependent disease;

<6> A compound selected from the following group or a salt thereof or a solvate thereof.
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one;
[5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methylbenzamide;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-Bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -1,3-thiazolidine-2,4-dione

  The present invention can treat or prevent diseases and disorders associated with type 3 17β-hydroxysteroid dehydrogenase.

  Hereinafter, the present invention will be described in detail.

  The terms used in the present specification shall be as defined below.

  The “alkyl group” is a linear or branched saturated hydrocarbon group. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t- C1-C6 alkyl groups, such as a butyl group, an isopentyl group, n-pentyl group, are mentioned.

  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. An 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. A C3-C6 cycloalkyl group is mentioned.

  The “aralkyl group” is an alkyl group in which at least one of hydrogen atoms contained in the alkyl group is substituted with an aryl group, and 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.

  The “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 “haloalkyl group” is an alkyl group in which at least one of hydrogen atoms contained in the alkyl group is substituted with a halogen atom, and preferred haloalkyl groups include a trifluoromethyl group, a 2-fluoroethyl group, and the like.

  Examples of the halogen atom 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.

  The “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.

  The “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.

  The “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 “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. Mean any amount that causes a delay in speed. The term also includes within its scope amounts effective to promote normal physiological function. For use in therapy, 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.

  Accordingly, 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. I will provide a. 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.

  Next, the compound represented by formula (I) (hereinafter sometimes referred to as compound (I)) or a salt thereof or a solvate thereof will be described.

R ¹ in formula (I) is preferably an aryl group having a substituent, a heteroaryl group having a substituent, or an optionally substituted cycloalkyl group.

  Here, 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. Group, cyano group, nitro group, acyl group, formyl group, carboxy group, alkoxycarbonyl group, carbamoyl group, alkylcarbamoyl group, hydroxyl group, acyloxy group, alkylcarbamoyloxy group, alkylsulfonyl group, sulfonate group, sulfamoyl group and alkylsulfuric group At least one group selected from the group consisting of famoyl groups is preferred.

  A phenyl group having the above substituent, a pyridyl group having the above substituent, or a 5- to 7-membered cycloalkyl group is more preferable.

R ² is preferably a 4-hydroxyphenyl group which may have a substituent other than a hydroxyl group, and a 5-hydroxy-pyridin-2-yl group which may have a substituent other than a hydroxyl group. More preferably, a 4-hydroxyphenyl group in which the 3-position hydrogen atom is substituted with a group selected from the group consisting of a halogen atom and an alkyl group, or the 4- or 6-position hydrogen atom is a halogen atom and an alkyl group. A 5-hydroxy-pyridin-2-yl group substituted with a group selected from the group consisting of groups.

R ³ is preferably a hydrogen atom.

Compound (I) is preferably a compound selected from the following group.
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one;
[5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methylbenzamide;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one; and 5- (3-bromo-4-hydroxybenzylidene)- 3- (4-Methoxyphenyl) -1,3-thiazolidine-2,4-dione

  The salt of compound (I) is pharmaceutically acceptable and includes acid addition salts. Specifically, 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, Mytate, Pantothenate, Phosphate / Diphosphate, Polygalacturonate, Salicylate, Stearate, Basic Acetate, Succinate, Sulfate, Tannate, Tartrate, Theocrate, Examples include tosylate, triethiozide, and valerate.

  The “solvate” of compound (I) or a salt thereof means a complex of compound (I) or a salt thereof and a solvent. Examples of 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. In general, polymorphs can be generated depending on conditions such as a solvent, temperature, pressure and the like during precipitation of crystals. 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 a amine compound and a trithiocarbonate bis (carboxymethyl) derivative in the presence of a base such as sodium carbonate to obtain a thioglycolic acid derivative, and then converting the thioglycolic acid derivative into, for example, The cyclization reaction can be carried out under acidic conditions such as in an aqueous sulfuric acid solution. In addition, for example, 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. The former condition is preferred if R ¹ is an aryl group, if R ¹ is an alkyl group the latter conditions are preferred.

Compound (I) or a salt thereof or a solvate thereof can be produced, for example, by a Kneovenagel reaction of a rhodanine derivative represented by the following formula and an aldehyde or a ketone. Such a reaction is usually carried out in the presence of a base. Examples of the base 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 β-alanine. This reaction is usually carried out in the presence of a solvent. Examples of 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.

  The compounds (I) thus obtained are exemplified in Tables 1 to 3.

  Next, the use of compound (I) or a salt thereof or a solvate thereof for inhibiting type 3 17β-hydroxysteroid dehydrogenase will be described.

  Compound (I) or a salt thereof or a solvate thereof is an inhibitor of a type 3 17β-hydroxysteroid dehydrogenase, which is effective for treating or preventing a pharmaceutical composition for diseases that can be treated or prevented by inhibiting the type 3 17β-hydroxysteroid dehydrogenase. Can be used as an ingredient.

  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 5α-reductase inhibitor such as finasteride and dutasteride, simultaneously or sequentially.

  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. The aspect which uses combining a chemical | medical agent simultaneously or sequentially is included. As such proliferative disease, specifically, a method for treating or preventing cancer (tumor) 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) that can be treated or prevented include 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) according to the present invention 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 To treat (inhibit) the abnormal growth of cells, including transformed cells, in patients in need of such treatment by administering drugs, surgery (prostatectomy) and / or radiation simultaneously or sequentially The method is mentioned. 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.

  In an embodiment of the invention, 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 By administering the treatment simultaneously or sequentially. Examples of tumors that can be treated 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.

  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 marketed as Taxol® and is described in more detail in the subsection entitled “Microtubule Agents” below], mitramycin, deoxycoformycin, mitomycin C, L- Asparaginase, interferon-α and interferon-β, etoposide, and teniposide.

  Hormonal drugs and steroids (including synthetic analogs): 17α-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.

  Non-limiting examples of biological agents useful in the methods of the invention include, for example, interferon-α, interferon-β, 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.

  Non-limiting examples of microtubule agents useful in the present invention include: arocolchicine (Allocolchicine, NSC 406042), halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (eg, NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), lysoxin (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, epothilone, discodermolide, estramustine, nocodazole and MAP4.

  Particularly preferred drugs are compounds 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®.

  Other drugs include, for example, inhibitors of 5α-reductase type 1 and / or inhibitors of 5α-reductase type 2 (eg, finasteride, SKF105,657, LY191,704, LY320,236, dutasteride, flutamide, nilutamide, bicalutamide) LHRH agonists (eg, leuprolide and zoladex), LHRH antagonists (eg, abarelix and cetrorelix), inhibitors of 17α-hydroxylase / C17-20 lyase (eg, YM116, CB7630 and riarosol), 17β-hydroxysteroid dehydrogenase Inhibitors of type 5 and / or other 17β-hydroxysteroid dehydrogenase / 17β-oxidoreductase isoenzymes (eg, EM-1404).

  Examples of agents useful in the treatment or prevention of benign prostatic hyperplasia include alpha-1 adrenergic antagonists such as tamsulosin, terazosin, prazosin, urapidil and naphthopidyl.

  Next, a pharmaceutical composition containing compound (I) or a salt thereof or a solvate thereof will be described.

  The pharmaceutical composition usually comprises compound (I) or a salt thereof or a solvate thereof and at least one pharmaceutically acceptable carrier. Further, inhibitors of 5α-reductase type 1, inhibitors of 5α-reductase type 2, inhibitors of androgen receptor, LHRH agonists, LHRH antagonists, inhibitors of 17α-hydroxylase / C17-20 lyase, inhibitors of 17β-hydroxysteroid dehydrogenase type 5 17β-hydroxysteroid dehydrogenase / 17β-oxidoreductase isoenzyme inhibitor, α-1 adrenergic antagonist, potassium channel agonist, 5α-reductase inhibitor, chemotherapeutic agent and biological agent, at least one selected from the group consisting of It may contain drugs. Specific examples of these drugs include those described above.

  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. Examples of solid preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. This powder and tablet 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. Gennaro, Remington's Pharmaceutical Sciences, 18 (1990), Mack Publishing Co., Easton, Pennsylvania.

  Examples of 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. Examples of such liquid preparations 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 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 1 to about 500 mg per day, more preferably 1 to about 200 mg per day, in two to four divided doses. It becomes a range.

  Chemotherapeutic agents and / or radiation therapy are administered according to the dosages and dosing schedules listed in the product information sheet for that approved drug in the Physicians Desk Reference (PDR) and therapeutic protocols well known in the art, according to compound (I) Alternatively, it can be administered in combination with a salt or solvate thereof. Table 4 illustrates dosage ranges and dosage regimens of chemotherapeutic agents useful in the methods of the invention. To those skilled in the art, 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. Also, according to the knowledge of one of ordinary skill in the art, the above therapeutic protocols (eg, dosage and number of doses) can be observed for the administered chemotherapeutic agent (ie, antineoplastic agent or radiation) for the patient. Can be varied to take into account the effects of the disease and the observed response of the disease to the administered drug.

  Anti-androgenic agents, anti-benign prostatic hypertrophy agents, potassium channel agonists and biological agents are well known in the art as to dosages and dosing schedules listed in the product information sheet of approved drugs in the Physicians Desk Reference (PDR) According to the therapeutic protocol, it can be administered in combination with compound (I) or a salt thereof or a solvate thereof. For those skilled in the art, 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. Also, according to the knowledge of those skilled in the art, the therapeutic protocol (eg, dosage and number of doses) should be considered in view of the observed effects of the administered factor on the patient and the treatment administered. It can be changed to take into account the observed response of the disease to the drug.

  Another aspect of the present invention is a kit comprising Compound (I) or a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

  Yet another aspect of the invention is 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.

  The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

Example 1-1 Preparation of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one 5.3 g (42.2 mmol) of p-anisidine and 5.3 wt% aqueous sodium carbonate solution 100 mL was charged into the reactor, 10.0 g (1.0 molar equivalent) of trithiocarbonate (biscarboxymethyl) was added, and the mixture was heated to 65 ° C. and stirred for about 14 hours. After cooling, the precipitated crystals were separated by filtration, adjusted to weak acidity (pH 4) by adding 10 wt% aqueous hydrochloric acid to the filtrate, and then stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water, dried under reduced pressure, charged into another reactor, added with 100 mL of 30 wt% sulfuric acid aqueous solution, and stirred at 50 ° C. for 1 hour. After cooling, it was collected by filtration, washed with water, and dried under reduced pressure to give 2.38 g of the title compound as a pale yellow powder (yield 23%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.84 (s, 3H), 4.17 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.9Hz, 2H)

Example 1-2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (1)] 2.28 g (9.53 mmol) of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one obtained in Example 1-1, 1.92 g of 3-bromo-4-hydroxybenzaldehyde (1.0 molar equivalent), 1.6 g (2.0 molar equivalents) of sodium acetate and 50 mL of acetic acid were charged into the reactor and heated under reflux in a nitrogen atmosphere for 3 hours, and then 1.47 g (2. (0 molar equivalent) was added, and the mixture was further refluxed for 3 hours. After cooling, the precipitated crystals were filtered, washed with water, and then repulped with 100 mL of ethanol to obtain 3.49 g of the title compound as a yellow powder (yield 85%).
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.81 (s, 3H), 7.07 (d, J = 9.2 Hz, 2H), 7.13 (d, J = 8.6 Hz, 1H) ), 7.29 (d, J = 8.9 Hz, 2H), 7.51 (dd, J = 2.2, 8.4 Hz, 1H), 7.72 (s, 1H), 7.87 (d , J = 2.2 Hz, 1H), 11.31 (s, 1H)

Example 2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (2)] Example 1 The title compound was obtained in the same manner as in Examples 1-1 and 1-2 except that 4-chloroaniline was used in place of p-anisidine.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 7.15 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.54 (dd, J = 1.9, 8.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H) , 11.34 (s, 1H)

Example 3: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (3)] In 1-1, the title compound was obtained in the same manner as in Examples 1-1 and 1-2 except that 4-cyanoaniline was used instead of p-anisidine.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 7.14 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 2.2, 8.4 Hz, 1H), 7.70 (D, J = 8.9 Hz, 2H), 7.78 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.9 Hz, 2H)

Example 4-1: Preparation of 4- (4-oxo-2-thioxo-1,3-thiazolidin-3-yl) benzoic acid In Example 1-1, 4-aminobenzoic acid was used instead of p-anisidine. The title compound was obtained in the same manner as in Example 1-1 except that was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 4.99 (s, 2H), 7.42 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H) )

Example 4-2: Preparation of N-methyl-4- (4-oxo-2-thiooxo-1,3-thiazolidin-3-yl) -benzamide 4- (4-oxo- obtained in Example 4-1 2-thioxo-1,3-thiazolidin-3-yl) benzoic acid 1.00 g (3.55 mmol), methylamine hydrochloride 0.27 g (1.1 molar equivalent), 1-hydroxybenzotriazole 0.53 g (1 .1 molar equivalents), 0.89 g (1.3 molar equivalents) of 1-ethyl-3- (3′-dimethylaminopropyl) -carbodiimide hydrochloride and 60 mL of N, N-dimethylformamide were charged to the reactor and a nitrogen atmosphere The mixture was stirred at room temperature for 24 hours. Ethyl acetate and water were added for liquid separation, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. By drying under reduced pressure, 0.21 g of the title compound was obtained as a yellow powder (yield 24%).
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.80 (d, J = 4.3 Hz, 3H), 4.40 (s, 2H), 7.37 (d, J = 8.6 Hz, 2H) ), 7.93 (d, J = 8.6 Hz, 2H), 8.54 (d, J = 4.3 Hz, 1H)

Example 4-3: 4- [5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methyl-benzamide [Compound No. ( 4)] In Example 1-2, instead of 3- (4-methoxyphenyl) -2-thiooxo-1,3-thiazolidin-4-one, N-methyl- obtained in Example 4-2 The title compound was obtained in the same manner as in Example 1-2 except that 4- (4-oxo-2-thiooxo-1,3-thiazolidin-3-yl) benzamide was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.81 (d, J = 4.2 Hz, 3H), 6.89 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H) ) 7.49-7.56 (m, 3H), 7.76 (s, 1H), 7.90-7.97 (m, 3H), 8.57 (d, J = 4.5 Hz, 1H)

Example 5: 5- (3-Bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (5)] In Example 1-1, the title compound was obtained in the same manner as in Examples 1-1 and 1-2 except that 5-amino-2-methoxypyridine was used instead of p-anisidine.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.92 (s, 3H), 7.01 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H) ), 7.79 (dd, J = 3.2, 8.1 Hz, 2H), 7.80 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 8.23 (d , J = 2.4Hz, 1H)

Example 6: 5- (3-Bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (6)] In Example 1-1, the title compound was obtained in the same manner as in Examples 1-1 and 1-2 except that 5-amino-2-methylpyridine was used in place of p-anisidine.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.56 (s, 3H), 7.15 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H) ), 7.55 (dd, J = 2.2, 8.6 Hz, 1H), 7.79 (dd, J = 3.2, 8.1 Hz, 1H), 7.80 (s, 1H), 7 .92 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H)

Example 7: Preparation of 3- (4-methoxyphenyl) -5- (3-methyl-4-hydroxybenzylidene) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (7)] In 1-2, the title compound was obtained in the same manner as in Example 1-2 except that 4-hydroxy-3-methylbenzaldehyde was used instead of 3-bromo-4-hydroxybenzaldehyde.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.19 (s, 3H), 3.82 (s, 3H), 6.98 (d, J = 8.1 Hz, 1H), 7.08 ( d, J = 8.9 Hz, 2H), 7.38-7.42 (m, 2H), 7.69 (s, 1H), 10.44 (s, 1H)

Example 8: 5- (6-Bromo-5-hydroxypyridin-2-ylmethylene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (8)] Preparation of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one 0.24 g (1.0 mmol), 6-bromo-5-hydroxypyridine-carbaldehyde 0.20 g (1. 0 molar equivalents), 75 mg (1.0 molar equivalents) of glycine, 53 mg (0.5 molar equivalents) of sodium carbonate and 7.5 mL of water were charged to the reactor and heated at 70 ° C. for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 0.29 g of the title compound as a pale yellow powder (yield 69%).
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.83 (s, 3H), 7.08 (d, J = 9.2 Hz, 2H), 7.30 (d, J = 9.2 Hz, 2H) ), 7.40 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 11.77 (br.s, 1H) )

Example 9: 5- (3,5-dichloro-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (9 )]] In Example 1-1, 6-methoxypyridin-3-ylamine was used instead of p-anisidine, and in Example 1-2, instead of 3-bromo-4-hydroxybenzaldehyde, 3 The title compound was obtained in the same manner as in Examples 1-1 and 1-2 except that, 5-dichloro-4-hydroxybenzaldehyde was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.91 (s, 3H), 7.01 (d, J = 8.9 Hz, 1H), 7.69 (s, 2H), 7.76- 7.81 (m, 2H), 8.22 (d, J = 2.7 Hz, 1H), 11.96 (br.s, 1H)

Example 10: 5- (3,5-difluoro-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (10 )]] In Example 1-1, 6-methoxypyridin-3-ylamine was used instead of p-anisidine, and in Example 1-2, instead of 3-bromo-4-hydroxybenzaldehyde, 3 , 5-difluoro-4-hydroxybenzaldehyde The title compound was obtained in the same manner as in Examples 1-1 and 1-2, except that it was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.91 (s, 3H), 7.00 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 9.8 Hz, 2H) ), 7.77 (s, 1H), 7.78 (dd, J = 2.7, 8.9 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H)

Example 11-1: Preparation of 3-bromo-4-hydroxyacetophenone 200 ml of methanol, 27.6 g (62.9 mmol) of N-methylpyrrolidin-2-one / hydrotribromide complex and 30% by weight of hydrogen peroxide solution 21. 4 ml (2.0 molar equivalents) was charged to the reactor and a solution of 17.0 g (2.0 molar equivalents) of 4-hydroxyacetophenone in 150 ml of methanol was added at room temperature. After stirring at room temperature for 1 hour, a sodium bisulfite solution was added, and the mixture was further stirred for 10 minutes. The precipitated white crystals were separated by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give 8.8 g of the title compound as an orange solid (yield). Rate 33%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ2.55 (s, 3H), 6.01 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 2.2, 8.6 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H)

Example 11-2: 5- [1- (3-Bromo-4-hydroxyphenyl) -ethylidene] -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (11)] In Example 1-2, Example 1 was used except that 3-bromo-4-hydroxyacetophenone obtained in Example 11-1 was used instead of 3-bromo-4-hydroxybenzaldehyde. The title compound was obtained in the same manner as -2.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.67 (s, 3H), 3.82 (s, 3H), 7.07 (d, J = 8.9 Hz, 2H), 7.17 ( d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.9 Hz, 2H), 7.39 (dd, J = 1.6 Hz, 1H), 7.70 (d, J = 2) .2Hz, 1H)

Example 12-1: Preparation of 1- (3-bromo-4-methoxyphenyl) -2,2,2-trifluoroethanone 2,2,2-trifluoro-1- (4-methoxyphenyl) ethanone13. 8 g (67.6 mmol), carbon tetrachloride 130 mL, mercury (II) oxide 1.76 g (0.12 molar equivalent) and concentrated sulfuric acid 6.5 mL were charged into a reactor and cooled to 5 ° C., after which bromine 11.1 g (1.03 molar equivalent) was added and heated at 65 ° C. for 8 hours. After standing overnight at room temperature, the reaction mixture was poured into ice water, extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, the organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: hexane / Purification by ethyl acetate = 3/1) gave 17.3 g of the title compound as an orange oil (yield 90%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 4.03 (s, 3H), 7.00 (d, J = 8.9 Hz, 1H), 8.05 (dd, J = 1.1, 7.8 Hz) , 1H), 8.29 (d, J = 1.1 Hz, 1H)

Example 12-2: Preparation of 1- (3-bromo-4-hydroxyphenyl) -2,2,2-trifluoroethanone 1- (3-Bromo-4-methoxyphenyl) obtained in Example 12-1 -2,2,2-trifluoroethanone 7.52 g (26.6 mmol) and N, N-dimethylformamide 75 mL were charged to the reactor, and 4.0 g (3.6 molar equivalents) of lithium chloride was added at room temperature. After stirring for 2 hours, the mixture was stirred for 1 hour under reflux. The reaction mixture was returned to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 100 mL of methanol. A 1N hydrogen chloride-methanol solution was added dropwise to adjust the pH to 3, and then the residue obtained by concentrating the solution under reduced pressure was purified by silica gel column chromatography (eluent: hexane / tetrahydrofuran = 3/1). Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) gave 4.68 g of the title compound as a pale yellow oil (yield 65%).
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 7.16 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 8.11 (s, 1H )

Example 12-3: 5- [1- (3-Bromo-4-hydroxyphenyl) -2,2,2-trifluoroethylidene] -3- (4-methoxyphenyl) -2-thioxo-1,3- Preparation of thiazolidin-4-one [Compound No. (12)] In Example 1-2, 1- (3-bromo-4-) obtained in Example 12-2 was used instead of 3-bromo-4-hydroxybenzaldehyde. The title compound was obtained in the same manner as in Example 1-2 except that (hydroxyphenyl) -2,2,2-trifluoroethanone was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.77 (s, 3H), 6.93 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H) ), 7.20 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H)

Example 13: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3-methyl-2-thioxo-1,3-thiazolidin-4-one [Compound No. (13)] In Example 1-2 The title compound was obtained in the same manner as in Example 1-2, except that 3-methylrhodanine was used instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.39 (s, 3H), 7.12 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 2.4, 8) .6 Hz, 1H), 7.73 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 11.31 (s, 1H)

Example 14: Preparation of 3-allyl-5- (3-bromo-4-hydroxybenzylidene) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (14)] In Example 1-2 The title compound was obtained in the same manner as in Example 1-2 except that 3-allylrhodanine was used instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 4.64 (d, J = 5.1 Hz, 2H), 5.09-5.20 (m, 2H), 5.77-5.92 (m , 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 2.3, 8.5 Hz, 1H), 7.75 (s, 1H), 7.87. (D, J = 2.2 Hz, 1H), 11.35 (s, 1H)

Example 15-1 Preparation of 3-propargyl-2-thioxo-1,3-thiazolidin-4-one 4.06 g (17.2 mmol) bis (carboxylmethyl) trithiocarbonate, N, N′-carbonyldiimidazole 5 .88 g (2.0 molar equivalents) and 250 mL of tetrahydrofuran were charged into the reactor, and stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Next, a solution of 1.00 g (1.0 molar equivalent) of propargylamine in 10 mL of tetrahydrofuran was added, and the mixture was stirred for 4 hours under reflux. The reaction mixture was returned to room temperature, 250 mL of 2M aqueous hydrochloric acid was added dropwise, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1). Purification gave 0.48 g of the title compound as a black brown oil (yield 15%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 2.04 (s, 1H), 4.06 (s, 2H), 4.73 (s, 2H)

Example 15-2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3-propargyl-2-thioxo-1,3-thiazolidin-4-one [Compound No. (15)] Example 1-2 In the above, instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3-propargyl-2-thioxo-1,3-thiazolidine-obtained in Example 15-1 was used. The title compound was obtained in the same manner as Example 1-2 except that 4-one was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.26 (t, J = 2.4 Hz, 1H), 4.76 (d, J = 2.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 2.2, 8.6 Hz, 1H), 7.78 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H) , 11.36 (br.s, 1H)

Example 16-1: Preparation of 3- (2-methoxyethyl) -2-thioxo-1,3-thiazolidin-4-one In Example 15-1, 2-methoxyethylamine is used in place of propargylamine. The title compound was obtained in the same manner as Example 15-1 except for the above.
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.33 (s, 3H), 3.64 (t, J = 5.6 Hz, 2H), 3.99 (s, 2H), 4.21 (t, J = 5.6Hz, 2H)

Example 16-2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxyethyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (16)] In Example 1-2, instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3- (2-methoxyethyl)-obtained in Example 16-1 was used. The title compound was obtained in the same manner as in Example 1-2 except that 2-thioxo-1,3-thiazolidin-4-one was used.
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.37 (s, 3H), 3.72 (t, J = 5.8 Hz, 2H), 4.36 (t, J = 5.8 Hz, 2H), 5.98 (s, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 2.2, 8.6 Hz, 1H), 7.59 (s, 1H) ), 7.63 (d, J = 2.2 Hz, 1H)

Example 17-1: Preparation of 3-cyclohexyl-2-thioxothiazolidin-4-one In Example 15-1, except that cyclohexylamine was used instead of propargylamine, the same procedure as in Example 15-1 was performed. To give the title compound.
¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.15-2.33 (m, 10H), 3.82 (s, 2H), 4.81-4.90 (m, 1H)

Example 17-2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (17)] -2, in place of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3-cyclohexyl-2-thioxothiazolidine-4-one obtained in Example 17-1. The title compound was obtained in the same manner as in Example 1-2 except that ON was used.
¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.24-1.92 (m, 10H), 4.96-5.05 (m, 1H), 5.91 (s, 1H), 7.11 ( d, J = 8.6 Hz, 1H), 7.37 (dd, J = 2.2, 8.4 Hz, 1H), 7.59 (s, 1H), 7.61 (d, J = 2.4 Hz) , 1H)

Example 18-1: Preparation of 3- (tetrahydropyran-4-yl) -2-thioxo-1,3-thiazolidin-4-one In Example 15-1, instead of propargylamine, 4-aminotetrahydropyran The title compound was obtained in the same manner as Example 15-1 except that was used.
¹ H-NMR (270 MHz, CDCl ₃ ): δ 1.52-1.59 (m, 2H), 2.60-2.80 (m, 2H), 3.41-3.65 (m, 2H), 3.98 (s, 2H), 4.08 (dd, J = 4.86, 11.3 Hz, 2H), 5.08-5.17 (m, 1H)

Example 18-2: 5- (3-bromo-4-hydroxybenzylidene) -3- (4-tetrahydropyranyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (18)] Production In Example 1-2, instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3- (tetrahydropyran-4-one) obtained in Example 18-1 was used. Yl) -2-thioxo-1,3-thiazolidin-4-one, except that the title compound was obtained in the same manner as in Example 1-2.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 1.60 (d, J = 12.0 Hz, 2H), 2.60 (dd, J = 8.1, 16.5 Hz, 2H), 3.40 (D, J = 12.0 Hz, 2H), 3.98 (dd, J = 4.2, 11.2 Hz, 2H), 5.20-5.10 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 2.2, 8.4 Hz, 1H), 7.67 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H) ), 11.32 (s, 1H)

Example 19-1: Preparation of 3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one 6.50 g (24.8 mmol) of triphenylphosphine and 200 mL of tetrahydrofuran were charged into a reactor. Under a nitrogen atmosphere, a solution of diethyl azadicarboxylate 10.80 g (1.0 molar equivalent) in 40% by weight in toluene and 5.14 g (1.5 molar equivalent) of 4-methoxybenzyl alcohol were successively added dropwise at −65 ° C. or lower. Later, 3.3 g (1.0 molar equivalent) of rhodanine was added. After stirring at -65 ° C for a while, the mixture was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, toluene is added, insolubles are filtered off, the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1). This afforded 0.73 g of the title compound as a yellow oil (yield 11.6%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.78 (s, 3H), 3.96 (s, 2H), 5.12 (s, 2H), 6.83 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H)

Example 19-2: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one [Compound No. (19)] Instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one in Example 1-2, 3- (4-methoxybenzyl)-obtained in Example 19-1 The title compound was obtained in the same manner as in Example 1-2 except that 2-thioxo-1,3-thiazolidin-4-one was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.72 (s, 3H), 5.16 (s, 2H), 6.88 (d, J = 8.6 Hz, 2H), 7.12 ( d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.49 (dd, J = 1.6, 8.4 Hz, 1H), 7.76 (s). , 1H), 7.86 (d, J = 1.6 Hz, 1H), 11.35 (s, 1H)

Example 20: Preparation of 5- [1- (3-bromo-4-hydroxyphenyl) ethylidene] -3-methyl-2-thioxo-1,3-thiazolidin-4-one [Compound No. (20)] In 1-2, instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3-methylrhodanine was used, and instead of 3-bromo-4-hydroxybenzaldehyde, The title compound was obtained in the same manner as in Example 1-2 except that 3-bromo-4-hydroxyacetophenone was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 2.68 (s, 3H), 3.35 (s, 3H), 7.04 (d, J = 8.6 Hz, 1H), 7.36 ( dd, J = 2.0, 8.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 10.97 (br.s, 1H)

Example 21: Preparation of 3-allyl-5- [1- (3-bromo-4-hydroxyphenyl) ethylidene] -2-thioxo-1,3-thiazolidin-4-one [Compound No. (21)] In 1-2, instead of 3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one, 3-allylrhodanine was used, and instead of 3-bromo-4-hydroxybenzaldehyde, The title compound was obtained in the same manner as in Example 1-2 except that 3-bromo-4-hydroxyacetophenone was used.
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ2.71 (s, 3H), 4.71 (d, J = 5.6 Hz, 2H), 5.20-5.27 (m, 2H), 5.78-5.93 (m, 1H), 5.99 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 2.3, 8 .5 Hz, 1 H), 7.52 (d, J = 2.2 Hz, 1 H)

Example 22-1: Preparation of 1,3-bis (4-methoxyphenyl) thiourea 3.69 g (30.0 mmol) of 4-methoxyphenylamine and 75 mL of toluene were charged into a reactor, and 4-methoxyphenyl isocyanate was obtained at 38 ° C. 25 mL of a toluene solution of 4.96 g (1.0 molar equivalent), 0.18 g (0.059 molar equivalent) of triethylamine and 15 mL of toluene were sequentially added dropwise, heated to 100 ° C., and stirred for 4 hours. Crystals precipitated after cooling were collected by filtration, washed with toluene, and dried. In addition, hexane was added to the residue after concentration of the filtrate, and the precipitated crystals were collected by filtration and dried, and combined with the crystals obtained earlier to obtain 7.28 g of the crude title compound as a pale yellow powder (yield). 84%).
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ 3.73 (s, 3H), 6.88 (d, J = 8.9 Hz, 4H), 7.30 (d, J = 8.6 Hz, 4H) )

Example 22-2: Preparation of 3- (4-methoxyphenyl) -2- (4-methoxyphenylimino) -1,3-thiazolidin-4-one 1,3-bis ( 4-Methoxyphenyl) thiourea (3.00 g, 10.1 mmol), chloroacetic acid (1.03 g, 1.05 molar equivalent), and acetic acid (15 mL) were charged into the reactor under a nitrogen atmosphere, and heated at reflux for 6 hours. After cooling, ethanol, ethyl acetate and water were added for liquid separation, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1). Recrystallization from acetone-water gave 1.73 g of the title compound as pale yellow crystals (yield 45%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.78 (s, 3H), 3.82 (s, 3H), 3.95 (s, 2H), 6.86 (s, 4H), 7.02 (D, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H)

Example 22-3: Preparation of 3- (4-methoxyphenyl) thiazolidine-2,4-dione 3- (4-methoxyphenyl) -2- (4-methoxyphenylimino)-obtained in Example 22-2 A reactor was charged with 0.700 g (1.82 mmol) of 1,3-thiazolidine-4-one, 10 mL of ethanol, and 10 mL of 35 wt% hydrochloric acid, heated to 85 ° C. under a nitrogen atmosphere, and stirred for 9 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with ethanol and water, and dried under reduced pressure to obtain 0.29 g of the title compound as white crystals (yield 68%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.83 (s, 3H), 4.10 (s, 2H), 7.00 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 9.2Hz, 2H)

Example 22-4: Preparation of 5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -1,3-thiazolidine-2,4-dione [Compound No. (22)] 3- (4-Methoxyphenyl) -1,3-thiazolidine-2,4-dione 0.20 g (0.85 mmol) obtained in 22-3, 0.173 g (1.05 g) of 3-bromo-4-hydroxybenzaldehyde Molar equivalents), 0.138 g (2.0 molar equivalents) of ammonium acetate and 35 mL of acetic acid were charged into the reactor and heated to reflux for 2 hours under a nitrogen atmosphere. After cooling, the precipitated crystals were collected by filtration, washed with water and ethanol, and then dried under reduced pressure to obtain 0.25 g of the title compound as pale yellow crystals (yield 69%).
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.80 (s, 3H), 7.06 (d, J = 9.2 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.9 Hz, 2H), 7.51 (dd, J = 2.0, 8.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7 .87 (s, 1H), 11.20 (s, 1H)

Test Example 1: Measurement of enzyme activity A human type 17 β-hydroxysteroid dehydrogenase was transiently expressed in HeLa cells, androstenedione was added, and the concentration of testosterone produced by conversion was measured by a method. HeLa cells in which human 3 type 17β-hydroxysteroid dehydrogenase suspended in D-MEM medium containing 10% FCS was transiently expressed were added to 96-well plates at 1 × 10 ⁴ cells (100 μL) per well, and 20-20 It was allowed to stand in a CO ₂ incubator for 24 hours. After standing, the medium was extracted with a pipette, and 80 μL of FCS-free medium was newly added. 10 μL of a compound diluted with 1% DMSO-containing FCS-free medium was added, and the mixture was allowed to stand in a CO ₂ incubator for 30 minutes. Thereto was added 10 μL of 500 nM androstenedione diluted with an FCS-free medium, and the mixture was allowed to stand in a CO ₂ incubator for 20 minutes. Thereafter, the concentration of testosterone in the medium was measured using a kit (DELFIA Testosterone Reagents, catalog number R050-201) manufactured by PerkinElmer, Inc. according to the instructions attached to the kit. The measurement used Tecan Ultra. Measurement wavelength is excitation 340 nm, fluorescence is 612 nm. The Lag time is 400 μsec. Integration time is 400μsec. 10% each of 1% DMSO-containing FCS-free medium and 500 nM androstenedione was added to cells left for 20 to 24 hours as 0% inhibition, and 1% DMSO-containing FCS-free medium and FCS-free medium each 10 μL The inhibition rate at each concentration (1 nM, 10 nM, 100 nM, 1 μM) was determined for each compound with the addition as 100% inhibition, and the IC ₅₀ value was calculated. The results are listed in Table 5.

  The present invention can treat or prevent diseases and disorders associated with type 3 17β-hydroxysteroid dehydrogenase.

Claims (6)

Formula (I) for inhibiting type 3 17β-hydroxysteroid dehydrogenase

(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 any of these groups may have a substituent. R ² Represents an aryl group having a hydroxyl group or a heteroaryl group having a hydroxyl group, and the aryl group or heteroaryl group may have a substituent other than the hydroxyl group, and R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group. And X and Y are the same or different and each represents an oxygen atom or a sulfur atom.)
Or a salt thereof or a solvate thereof. Formula (I) for inhibiting type 3 17β-hydroxysteroid dehydrogenase

(In the formula, R ¹ represents an aryl group having a substituent, a heteroaryl group having a substituent, or an optionally substituted cycloalkyl group. R ² may have a substituent other than a hydroxyl group. Represents a good 4-hydroxyphenyl group or a 5-hydroxy-pyridin-2-yl group which may have a substituent other than a hydroxyl group, R ³ represents a hydrogen atom, X represents an oxygen atom, Y Represents an oxygen atom or a sulfur atom.)
Or a salt thereof or a solvate thereof. Use of a compound selected from the following group or a salt thereof or a solvate thereof for inhibiting type 3 17β-hydroxysteroid dehydrogenase.
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one;
[5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methylbenzamide;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one; and 5- (3-bromo-4-hydroxybenzylidene)- 3- (4-Methoxyphenyl) -1,3-thiazolidine-2,4-dione Formula (I) as an active ingredient of a pharmaceutical composition for diseases that can be treated or prevented by inhibiting type 3 17β-hydroxysteroid dehydrogenase

(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 any of these groups may have a substituent. R ² Represents an aryl group having a hydroxyl group or a heteroaryl group having a hydroxyl group, and the aryl group or heteroaryl group may have a substituent other than a hydroxyl group.
R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. X and Y are the same or different and each represents an oxygen atom or a sulfur atom. )
Or a salt thereof or a solvate thereof. The use according to claim 4, wherein the disease that can be treated or prevented by inhibiting type 3 17β-hydroxysteroid dehydrogenase is a male hormone-dependent disease. A compound selected from the following group, a salt thereof, or a solvate thereof.
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxyphenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-chlorophenyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-cyanophenyl) -2-thioxo-1,3-thiazolidin-4-one;
[5- (3-Bromo-4-hydroxybenzylidene) -4-oxo-2-thioxo-1,3-thiazolidin-3-yl] -N-methylbenzamide;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methoxypyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (2-methylpyridin-5-yl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (cyclohexyl) -2-thioxo-1,3-thiazolidin-4-one;
5- (3-bromo-4-hydroxybenzylidene) -3- (4-methoxybenzyl) -2-thioxo-1,3-thiazolidin-4-one; and 5- (3-bromo-4-hydroxybenzylidene)- 3- (4-Methoxyphenyl) -1,3-thiazolidine-2,4-dione