JP2010195774A - Benzimidazole derivative - Google Patents

Abstract

The present invention provides a novel and excellent method for the treatment and / or prevention of prostatic hypertrophy, prostate cancer and the like based on the selective inhibitory action of 17βHSDtype5.
An indole or benzimidazole derivative in which a phenyl group substituted with COOH is substituted with a nitrogen atom of an indole ring or a benzimidazole ring has potent 17βHSD type5 selective inhibitory activity and is free from side effects due to testosterone reduction. A therapeutic and / or prophylactic agent for diseases involving 17βHSD type 5 such as prostatic hypertrophy and prostate cancer.
[Selection figure] None

Description

  The present invention relates to a medicament or pharmaceutical composition comprising an indole compound and / or a benzimidazole compound and / or a pharmaceutically acceptable salt thereof as an active ingredient.

  Benign prostatic hyperplasia (BPH) is a disease accompanied by dysuria that occurs mainly in elderly men over 50 years of age, and the frequency of onset increases with age. The number of BPH patients in Japan has been increasing in recent years with the rapid aging of the population structure. BPH is an important medical and economical disease because it significantly lowers the quality of life of elderly men due to its dysuria and is diagnosed and treated most frequently in urological practice.

  The two causes of dysuria associated with BPH are direct urethral compression (mechanical occlusion) due to enlargement of the prostate and increased intraurethral pressure (functional occlusion) due to excessive contraction of prostate smooth muscle via the sympathetic nerve. Has been shown to be involved at the same time. Drug therapy can cope with both mechanisms, and 5α reductase inhibitors are mainly used for mechanical occlusion, and α1 sympathetic blockade (α1 blocker) is mainly used for functional occlusion. 5α reductase inhibitors regress the prostate by antiandrogenic action based on inhibition of the conversion of testosterone to 5α dehydrotestosterone (DHT), a more powerful androgen, by 5α reductase. However, it is only the prostate epithelium that regresses, and it takes a long time (several weeks to several months) to develop the drug effect. On the other hand, α1 blockers are effective as soon as they are administered and are excellent in safety. Therefore, α1 blockers are currently the first choice for BPH treatment. However, as a result of a long-term clinical trial, the 5α reductase inhibitor significantly delayed the transition to invasive treatment compared to the case of the α1 blocker alone (“The New England Journal of Medicine”, 2003). 349, pp. 2387-2398), in recent years, the usefulness of 5α reductase inhibitors is being recognized again.

  DHT in the prostate has been thought to be produced by 5α reductase from testosterone produced in the testis and endocrineally supplied to the prostate. Recently, however, it has been reported that about half of DHT in the prostate and its precursor testosterone are synthesized in the prostate cells from the adrenal steroid dehydroepiandrosterone (DHEA) ("Frontier in Neuroendocrinology ", 2001, Vol. 22, p. 185-212). Such a sex hormone production system in the cells of the sex hormone target organ is called intracrinology.

  With 5α reductase inhibitors, it is difficult to inhibit testosterone synthesis (intracrine testosterone synthesis) in the prostate region. For example, in BPH patients after administration of the 5α reductase inhibitor finasteride, the DHT concentration in the prostate decreased to about 20% before the administration, whereas the concentration of the prostatic testosterone in the prostate was quadrupled. There is a report that it has risen ("The Journal of Urology", 1999, 161, pp. 332-337). That is, the 5α reductase inhibitor has an effect of suppressing the DHT concentration in the prostate, but does not have an effect of suppressing the testosterone concentration in the prostate, and conversely increases the concentration. Since testosterone has an androgen receptor binding activity that is about half that of DHT, this increase in the testosterone concentration in the prostate region is also considered to contribute to the insufficient efficacy of finasteride on BPH.

  Anti-androgen therapy with surgical castration and gonadotropin-releasing hormone agonist is also used in prostate cancer. It has been reported that these antiandrogen therapies are insufficient in the testosterone concentration suppressing effect in the prostate gland. For example, in prostate cancer patients who have undergone the above-described antiandrogen therapy, the blood testosterone concentration decreased to about 10% before treatment, whereas the DHT concentration in the prostate remained about half (“The Journal of” Clinical Endocrinology and Metabolism ”, 1995, 80, p. 1066-1071). This suggests that the testosterone concentration in the prostate is not sufficiently reduced. Also in prostate cancer (Homone Refractory Prostate Cancer) that relapsed after antiandrogen therapy, androgen receptor is localized in the nucleus, and there is a significant difference between the testosterone concentration in relapsed prostate cancer tissue and the testosterone concentration in normal prostate ("Clinical Cancer Research", 2004, Vol. 10, pp. 440-448). These reports indicate that the existing treatments are completely inadequate in reducing prostate testosterone concentration in the treatment of relapsed prostate cancer, and the inhibition of intracranial testosterone synthesis, i.e., intracrine testosterone synthesis, is a new treatment for prostate cancer treatment. It strongly suggests that it can be a target.

  From the above known techniques, since the intracrine testosterone synthesis inhibitor of the prostate has an action to lower the testosterone concentration in the prostate and has no action to lower the testosterone concentration in the blood, (1) not only the testosterone concentration in the prostate but also DHT The concentration is also lowered, and (2) it is expected to be a very attractive BPH therapeutic agent and / or prostate cancer therapeutic agent capable of avoiding side effects due to suppression of testosterone-derived blood testosterone concentration.

  In the biosynthesis of testosterone, 17β-hydroxysteroid dehydrogenase (17βHSD) is essential. There are several subtypes of 17βHSD, but 17βHSD type 5 (17βHSDtype5) is highly expressed in human prostate, and increased expression in prostate cancer and relapsed prostate cancer has also been reported (“Steroids”, 2004). Year 69, p.795-801; “Cancer Research” 2006, 66, p.2815-2825). On the other hand, almost all testosterone in the blood is produced in the testis by 17βHSD type 3 (17βHSDtype3), and 17βHSDtype3 is hardly expressed in other tissues including the prostate (“Nature Genetics”, 1994, Volume 7, pages 34-39). Therefore, it is considered that 17βHSD type 5 is responsible for the synthesis of prostate intracrine testosterone, and it is expected that the 17 β HSD type 5 selective inhibitor selectively suppresses prostate intracrine testosterone synthesis. In addition, the contribution of 17βHSDtype5 has been pointed out in estrogen-dependent tissues such as the mammary gland, and an effect is also expected in estrogen-dependent diseases such as breast cancer (“Endocrine Reviews”, 2003, Vol. 24, p.152-182). ). In addition, AKR1C3 (an alternative name for 17βHSDtype5), which is a subtype of aldo-keto reductase (AKR), metabolizes Polycyclic Aromatic Hydrocarbon (PAH) to produce reactive oxygen species (ROS) (“The Journal of Chemical Bio”). 2002, 277, 27, p. 24799-24808), that the single nucleotide polymorphism (SNP) of the AKR1C3 gene associated with oxidative stress correlates with the risk of lung cancer ("Carcinogenesis", 2004, No. 25, No. 11, pp. 2177-2181) suggests that the activity of AKR1C3 in the lung increases the risk of lung cancer through the production of ROS from PAH, and 17βHSDtyp The selective inhibitor of e5 is expected to be effective against lung cancer.

  Examples of 17βHSDtype5 inhibitors include steroid derivatives (Patent Document 1), NSAIDs (Non-stereoidal Anti-Inflammatory Drugs) (Non-Patent Document 1), such as Fluffenamic acid, Indomethacin, and cinnamic acid derivatives (Non-Patent Document 2). ing. Although the mechanism of action is different, it is also known that a certain type of indazole derivative is effective for BPH (Patent Document 2).

  On the other hand, certain types of 3- (indol-1-yl) benzoic acid derivatives (Patent Document 3), 3- (1H-benzimidazol-1-yl) benzoic acid derivatives having heat shock protein (HSP90) inhibitory activity ( Patent Document 4), 3- (1H-benzimidazol-1-yl) benzoic acid derivatives (Patent Document 5) having telomerase inhibitory activity are known to be useful for prostate diseases such as prostate cancer. In addition, certain types of 3- (indol-1-yl) benzoic acid derivatives (Patent Document 6) and, for example, 3- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid It is known that certain types of 3- (1H-benzimidazol-1-yl) benzoic acid derivatives (Patent Documents 7 to 12) are effective for central nervous system disorders such as Alzheimer's disease and dementia. Furthermore, it is also known that another 3- (1H-benzimidazol-1-yl) benzoic acid derivative is effective for arteriosclerosis (Patent Document 13). Furthermore, it has antiviral activity (Patent Document 14), vascular endothelial growth factor (VEGF) receptor antagonistic activity (Patent Document 15), and platelet-derived growth factor (PDGF) inhibitory activity (Non-Patent Documents 3 to 5) 3- ( 1H-benzimidazol-1-yl) benzoic acid derivatives and 3- (indol-1-yl) benzoic acid derivatives (Patent Document 16) effective for pain and the like are known. However, there are no reports of compounds described in the present application effective for BPH, prostate cancer and the like.

International Publication WO99 / 046279 Pamphlet International Publication WO 2004/064735 Pamphlet International Publication WO2003 / 056770 Pamphlet US Patent Application Publication No. 2007/0105862 International Publication WO2001 / 007020 Pamphlet International Publication WO2006 / 041874 Pamphlet European Patent Application Publication No. 563001 European Patent Application No. 616807 US Pat. No. 5,554,630 International Publication WO96 / 033194 Pamphlet International Publication WO 98/017651 Pamphlet International Publication WO98 / 034923 Pamphlet JP-A-7-133224 International Publication WO97 / 033872 Pamphlet JP 2002-193947 A International Publication WO2008 / 006790 Pamphlet

“Cancer Research”, 2004, Vol. 64, p. 1802-1810 “Molecular and Cellular Endocrinology”, 2006, Vol. 248, p. 233-235 “The Journal of Medicinal Chemistry”, 1998, Vol. 41, No. 27, p. 5457-5465 “Bioorganic and Medicinal Chemistry”, 2004, Vol. 12, No. 15, p. 4009-4015 “Bioorganic and Medicinal Chemistry”, 2005, Vol. 13, No. 24, p. 6598-6608

  An object of the present invention is to provide a compound having a 17βHSD type 5 selective inhibitory activity, particularly a compound useful as a therapeutic agent for prostatic hypertrophy and / or prostate cancer.

  As a result of intensive studies on a compound having 17βHSDtype5 selective inhibitory activity, the present inventors have found that a compound in which a phenyl group having a carboxy group at the 3-position is substituted at the 1-position of an indole ring and / or a benzimidazole ring is a potent 17βHSDtype5. The present invention has been completed by discovering that it has a selective inhibitory activity and can be used as a therapeutic and / or prophylactic agent for diseases involving 17βHSD type 5 such as prostatic hypertrophy and prostate cancer without side effects due to testosterone reduction.

式（Ｉ）において、
Ａは、Ｃ−Ｒ¹⁰又はＮ；
Ｒ¹は、水素、低級アルキル、ハロゲノ低級アルキル、低級アルキル−Ｏ−で置換された低級アルキル、低級アルキル−Ｏ−、ハロゲノ低級アルキル−Ｏ−、低級アルキル−Ｏ−で置換された低級アルキル−Ｏ−、置換されていてもよいシクロアルキル−Ｌ−、置換されていてもよいアリール−Ｌ−、又は置換されていてもよいヘテロ環基−Ｌ−；
Ｌは、結合、低級アルキレン、低級アルケニレン、Ｏ、低級アルキレン−Ｏ、又はＯ−低級アルキレン；
Ｒ²、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹は、同一又は互いに異なって、水素、低級アルキル、ハロゲン、シアノ、低級アルケニル、ハロゲノ低級アルキル、低級アルキル−Ｏ−、シアノ低級アルキル−Ｏ−、ハロゲノ低級アルキル−Ｏ−、シクロアルキル、アリール、ヘテロアリール、アリール−Ｏ−、ヘテロアリール−Ｏ−、アリール−低級アルキレン−、ヘテロアリール−低級アルキレン−、アシル、アシル−Ｏ−、ヘテロアリール−低級アルキレン−Ｏ−、低級アルキルスルファニル、アミノ、ヒドロキシ、スルファニル、モノ低級アルキルアミノ、ジ低級アルキルアミノ、アシルアミノ、又はアリールアミノ；
Ｒ³は、水素、ハロゲン、シアノ、ニトロ、ハロゲノ低級アルキル、又は低級アルキル−Ｏ−；
Ｒ¹⁰は、水素、置換されていてもよいアリール、又はヒドロキシ若しくは低級アルキル−Ｏ−で置換されていてもよい低級アルキルを示す。
ただし、
ＡがＣ−Ｒ¹⁰である場合は、Ｒ¹は水素又は低級アルキルを示し；
ＡがＮ、Ｒ¹、Ｒ²、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹が水素である場合は、Ｒ³はハロゲン、シアノ、ハロゲノ低級アルキル、又は低級アルキル−Ｏ−を示し；
ＡがＮ、Ｒ¹がメチル、並びにＲ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、及びＲ⁹が水素である場合は、Ｒ⁸は［（２Ｅ）−３−（２−ナフタレニル）−１−オキソ−２−ブテン−１−イル］アミノ以外の基を示す。
記号の意味は、以下同様である。 That is, the present invention relates to a pharmaceutical composition for preventing or treating a disease related to 17βHSD type 5, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In formula (I):
A is C—R ¹⁰ or N;
R ¹ is hydrogen, lower alkyl, halogeno lower alkyl, lower alkyl substituted with lower alkyl-O—, lower alkyl-O—, halogeno lower alkyl-O—, or lower alkyl-substituted with lower alkyl-O—. O-, an optionally substituted cycloalkyl-L-, an optionally substituted aryl-L-, or an optionally substituted heterocyclic group -L-;
L is a bond, lower alkylene, lower alkenylene, O, lower alkylene-O, or O-lower alkylene;
R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different from each other, and are hydrogen, lower alkyl, halogen, cyano, lower alkenyl, halogeno lower alkyl, lower alkyl-O—. Cyano lower alkyl-O-, halogeno lower alkyl-O-, cycloalkyl, aryl, heteroaryl, aryl-O-, heteroaryl-O-, aryl-lower alkylene-, heteroaryl-lower alkylene-, acyl, acyl -O-, heteroaryl-lower alkylene-O-, lower alkylsulfanyl, amino, hydroxy, sulfanyl, mono-lower alkylamino, di-lower alkylamino, acylamino, or arylamino;
R ³ is hydrogen, halogen, cyano, nitro, halogeno lower alkyl, or lower alkyl-O—;
R ¹⁰ represents hydrogen, optionally substituted aryl, or lower alkyl optionally substituted with hydroxy or lower alkyl-O—.
However,
When A is C—R ¹⁰ , R ¹ represents hydrogen or lower alkyl;
When A is N, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, R ³ is halogen, cyano, halogeno lower alkyl, or lower alkyl- Indicates O-;
When A is N, R ¹ is methyl, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁹ are hydrogen, R ⁸ is [(2E) -3- (2 A group other than -naphthalenyl) -1-oxo-2-buten-1-yl] amino is shown.
The meanings of the symbols are the same below.

式（ＩＩ）において、
Ａは、Ｃ−Ｒ¹⁰又はＮ；
Ｒ¹は、水素、低級アルキル、ハロゲノ低級アルキル、低級アルキル−Ｏ−で置換された低級アルキル、低級アルキル−Ｏ−、ハロゲノ低級アルキル−Ｏ−、低級アルキル−Ｏ−で置換された低級アルキル−Ｏ−、置換されていてもよいシクロアルキル−Ｌ−、置換されていてもよいアリール−Ｌ−、又は置換されていてもよいヘテロ環基−Ｌ−；
Ｌは、結合、低級アルキレン、低級アルケニレン、Ｏ、低級アルキレン−Ｏ、又はＯ−低級アルキレン；
Ｒ²、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹は、同一又は互いに異なって、水素、低級アルキル、ハロゲン、シアノ、低級アルケニル、ハロゲノ低級アルキル、低級アルキル−Ｏ−、シアノ低級アルキル−Ｏ−、ハロゲノ低級アルキル−Ｏ−、シクロアルキル、アリール、ヘテロアリール、アリール−Ｏ−、ヘテロアリール−Ｏ−、アリール−低級アルキレン−、ヘテロアリール−低級アルキレン−、アシル、アシル−Ｏ−、ヘテロアリール−低級アルキレン−Ｏ−、低級アルキルスルファニル、アミノ、ヒドロキシ、スルファニル、モノ低級アルキルアミノ、ジ低級アルキルアミノ、アシルアミノ、又はアリールアミノ；
Ｒ_a ³は、水素、ハロゲン、シアノ、ハロゲノ低級アルキル、又は低級アルキル−Ｏ−；
Ｒ¹⁰は、水素、置換されていてもよいアリール、又はヒドロキシ若しくは低級アルキル−Ｏ−で置換されていてもよい低級アルキルを示す。
ただし、
ＡがＣ−Ｒ¹⁰である場合は、Ｒ¹は水素又は低級アルキルを示すが、Ｒ¹、Ｒ²、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹が水素、Ｒ⁴がクロロ、並びにＲ¹⁰がイソブチルである場合は、Ｒ_a ³は水素以外の基であり；
ＡがＮ、Ｒ¹、Ｒ²、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹が水素である場合は、Ｒ_a ³はハロゲン、シアノ、又は低級アルキル−Ｏ−を示し；
ＡがＮ、Ｒ¹がメチル、Ｒ²、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、及びＲ⁹が水素、並びにＲ⁸が［（２Ｅ）−３−（２−ナフタレニル）−１−オキソ−２−ブテン−１−イル］アミノである場合は、Ｒ_a ³は水素以外の基であり；
ＡがＮ、Ｒ¹、Ｒ²、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、及びＲ⁹が水素、並びにＲ⁴がｔｅｒｔ−ブチルである場合は、Ｒ_a ³は水素以外の基であり；
ＡがＮ、Ｒ¹が水素若しくはメチル、Ｒ²、Ｒ⁶、及びＲ⁷が水素、Ｒ⁴及びＲ⁸がヒドロキシ、並びにＲ⁵がカルボキシである場合は、Ｒ_a ³は水素以外の基を示す。
記号の意味は、以下同様である。 The present invention also relates to a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In formula (II):
A is C—R ¹⁰ or N;
R ¹ is hydrogen, lower alkyl, halogeno lower alkyl, lower alkyl substituted with lower alkyl-O—, lower alkyl-O—, halogeno lower alkyl-O—, or lower alkyl-substituted with lower alkyl-O—. O-, an optionally substituted cycloalkyl-L-, an optionally substituted aryl-L-, or an optionally substituted heterocyclic group -L-;
L is a bond, lower alkylene, lower alkenylene, O, lower alkylene-O, or O-lower alkylene;
R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different from each other, and are hydrogen, lower alkyl, halogen, cyano, lower alkenyl, halogeno lower alkyl, lower alkyl-O—. Cyano lower alkyl-O-, halogeno lower alkyl-O-, cycloalkyl, aryl, heteroaryl, aryl-O-, heteroaryl-O-, aryl-lower alkylene-, heteroaryl-lower alkylene-, acyl, acyl -O-, heteroaryl-lower alkylene-O-, lower alkylsulfanyl, amino, hydroxy, sulfanyl, mono-lower alkylamino, di-lower alkylamino, acylamino, or arylamino;
R _a ³ is hydrogen, halogen, cyano, halogeno lower alkyl, or lower alkyl-O—;
R ¹⁰ represents hydrogen, optionally substituted aryl, or lower alkyl optionally substituted with hydroxy or lower alkyl-O—.
However,
When A is C—R ¹⁰ , R ¹ represents hydrogen or lower alkyl, but R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, and R ⁴ is chloro. And when R ¹⁰ is isobutyl, R _a ³ is a group other than hydrogen;
When A is N, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, R _a ³ represents halogen, cyano, or lower alkyl-O—. Show;
A is N, R ¹ is methyl, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁹ are hydrogen, and R ⁸ is [(2E) -3- (2-naphthalenyl) -1-oxo. -2-buten-1-yl] amino, R _a ³ is a group other than hydrogen;
When A is N, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, and R ⁴ is tert-butyl, R _a ³ is a group other than hydrogen. ;
When A is N, R ¹ is hydrogen or methyl, R ² , R ⁶ , and R ⁷ are hydrogen, R ⁴ and R ⁸ are hydroxy, and R ⁵ is carboxy, R _a ³ is a group other than hydrogen. Show.
The meaning of the symbols is the same below.

  The present invention also relates to a prophylactic and / or therapeutic agent for diseases related to 17βHSD type 5, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating and / or preventing a disease associated with 17βHSDtype5.

  The present invention also relates to a method for treating and / or preventing a disease related to 17βHSD type 5, which comprises administering to a patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

  The present invention also relates to an inhibitor of 17βHSD type 5 containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

  The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a compound of formula (I), or a pharmaceutically acceptable salt thereof, Treat and / or treat cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, baldness, alopecia, premature gestation, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, endometriosis, lung cancer, or leiomyoma It relates to a commercial package that can be used to prevent or contain a statement that it should be used.

  The compound of formula (I) selectively inhibits 17βHSDtype5. Therefore, the compound of the formula (I) can prevent androgen and / or estrogen-related diseases because androgen and / or estrogen synthesis is suppressed by inhibiting 17βHSD type5, for example, inhibiting 17βHSDtype5. It can be used as a therapeutic agent. Diseases related to androgen and / or estrogen include prostate cancer, prostatic hypertrophy, acne, seborrhea, hirsutism, baldness, alopecia, precocious ripening, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, intrauterine Examples include membranous disease and leiomyoma. In addition, AKR1C3 (an alternative name for 17βHSDtype5), a subtype of aldo-keto reductase (AKR), metabolizes Polycyclic Aromatic Hydrocarbon (PAH) to produce reactive oxygen species (ROS), and AKR1C3 gene related to oxidative stress Since a single nucleotide polymorphism (SNP) of 1 correlates with the risk of lung cancer, a disease related to 17βHSDtype5 also includes lung cancer. Therefore, the compounds of formula (I) can be used as therapeutic and / or prophylactic agents for these diseases.

  In addition, since it is considered that 17βHSD type 5 is responsible for prostate intracrine androgen synthesis, it is expected that 17 βHSD type 5 selective inhibitor selectively inhibits prostate intracrine androgen synthesis. Therefore, the compound of the formula (I) can be used as a preventive and / or therapeutic agent for androgen-related diseases, particularly prostate cancer, prostatic hypertrophy, particularly in the prostate gland.

  In addition, since the compound of formula (I) does not affect blood testosterone concentration, treatment and / or prevention of prostatic hypertrophy and prostate cancer without side effects such as sexual dysfunction due to suppression of blood testosterone concentration. It can be a medicine.

Hereinafter, the present invention will be described in detail.
Hereinafter, the compound of formula (I) and / or formula (II), which is an active ingredient of the present invention, will be described in detail. Since the compound of the formula (II) is included in the compound of the formula (I) and is a preferred embodiment of the compound of the formula (I), the compound of the formula (I) will be mainly described below.

In the above or below description of the present specification, suitable examples of various definitions included in the scope of the present invention will be described in detail below.
The term “lower” means a group having 1 to 10 carbon atoms (hereinafter sometimes abbreviated as C _1-10 ) unless otherwise specified.

“Lower alkyl” is linear or branched alkyl having 1 to 10 carbon atoms, preferably C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl group and the like.
“Lower alkylene” means a divalent group formed by removing a hydrogen atom from “lower alkyl”.

“Lower alkenyl” means an unsaturated, linear or branched acyclic hydrocarbon containing 2 to 10 carbon atoms containing at least one double bond. Preferably the number of carbon atoms is 2-6. For example, vinyl, propenyl, butenyl, pentenyl, hexenyl and the like are included.
“Lower alkenylene” means a divalent group formed by removing a hydrogen atom from “lower alkenyl”.

  “Halogen” includes F, Cl, Br, and I, preferably F, Cl, or Br.

  A “halogeno lower alkyl” is a lower alkyl substituted with one or more halogens. In another embodiment, it means lower alkyl substituted with 1 to 10 halogens. For example, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2 3,3,3-pentafluoropropyl, fluoropropyl, fluorobutyl, fluorohexyl and the like.

  “Cycloalkyl” is a saturated hydrocarbon ring group having 3 to 10 carbon atoms, and may have a bridge. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl groups and the like.

The “aryl” is a C _6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a cyclic group condensed with a C _5-8 cycloalkene at its double bond site. For example, phenyl, naphthyl, tetrahydronaphthalenyl, indenyl, fluorenyl group and the like. Another embodiment is phenyl, naphthyl, and anthryl, and yet another embodiment is phenyl.

  A “heterocyclic” group is preferably a 3- to 6-membered heteroaromatic monocyclic group having 1 to 4 nitrogen atoms such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H— 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; 1 to 5 nitrogen atoms Fused heteroaromatic cyclic groups having, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (eg tetrazolo [1,5-b] pyridazinyl, etc.) , Quinoxalinyl, imidazopyridyl (eg Dazo [1,2-a] pyridyl, etc.); 3- to 6-membered heteroaromatic monocyclic groups having one oxygen atom, such as pyranyl, furyl, etc .; 3- to 6-membered members having 1 to 2 sulfur atoms Heteroaromatic monocyclic groups such as thienyl; 3- to 6-membered heteroaromatic monocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (for example 1,2, 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); condensed heteroaromatic cyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzofurazanyl, benz Oxazolyl, benzoxiadiazolyl, etc .; 3-6 membered heteroaromatic monocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, eg Thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) and the like; condensed heterocycles having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Aromatic cyclic groups such as benzothiazolyl, benzothiadiazolyl, imidazothiazolyl (eg imidazo [2,1-b] [1,3] thiazolyl etc.); condensed heteroaromatics having 1 to 2 oxygen atoms And cyclic groups such as benzofuranyl and dibenzo [b, d] furanyl; condensed heteroaromatic cyclic groups having 1 to 2 sulfur atoms such as benzothienyl and the like.

  Furthermore, the “heterocyclic” group also means a 3 to 10-membered saturated or unsaturated cyclic group containing 1 to 4 heteroatoms selected from O, N and S, preferably nitrogen. 3 to 7 membered saturated heteromonocyclic groups having 1 to 4 atoms, such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc .; 3 to 10 membered saturated or unsaturated bicyclic heterocycles having 1 to 4 nitrogen atoms Groups such as quinuclidinyl; 3- to 6-membered saturated heteromonocyclic groups having one oxygen atom, such as 1H-tetrahydropyranyl, tetrahydrofuranyl, etc .; 3 having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms 1 to 6 membered saturated or unsaturated heteromonocyclic group such as morpholinyl, oxazolinyl (eg 2-oxazolinyl etc.); 1 to 2 sulfur atoms and nitrogen atom Or 3 to 6-membered saturated or unsaturated heteromonocyclic group having three, for example, thiazolidinyl, etc .; and the like.

  “Heteroaryl” means an aromatic group among the groups included in the “heterocycle” group.

  “Cyano lower alkyl” is lower alkyl substituted with one or more cyano groups. In another embodiment, it means lower alkyl substituted with 1 to 3 cyano groups. For example, cyanomethyl, cyanoethyl, 2,3-dicyanopropyl and the like are included.

  Examples of the “acyl group” include carboxy; esterified carboxy; lower alkyl, aryl, aryl-lower alkylene, arylsulfonyl, sulfonyl substituted with a heterocyclic group, lower alkylsulfonyl, or substituted with a heterocyclic group. Substituted or unsubstituted arylsulfonyl; sulfonyl substituted with a heterocyclic group; lower alkylsulfonyl; cycloalkylcarbonyl; lower alkyl-CO-; HCO-; substituted or unsubstituted aryl-CO -; Carbonyl substituted by a heterocyclic group and the like are included.

  Esterified carboxy groups include substituted or unsubstituted lower alkyl-O—C (═O) — (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxycarbonyl , 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), substituted or unsubstituted aryl-O—C (═O) — (eg phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2- Naphthyloxycarbonyl, etc.), substituted or unsubstituted aryl-lower alkylene-O—C (═O) — (eg benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxy) Carbonyl, etc.), and the like.

  The carbamoyl group substituted with lower alkyl includes methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl and the like.

  The carbamoyl group substituted with aryl includes phenylcarbamoyl, naphthylcarbamoyl, lower alkyl-substituted phenylcarbamoyl (for example, tolylcarbamoyl, xylylcarbamoyl, etc.) and the like.

  Examples of the carbamoyl group substituted with aryl-lower alkylene include benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl and the like.

  Examples of the carbamoyl group substituted with arylsulfonyl include phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.

  Examples of the carbamoyl substituted with (sulfonyl substituted with a heterocyclic group) include pyridylsulfonylcarbamoyl and the like.

  Examples of the carbamoyl group substituted with lower alkylsulfonyl include methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.

  Substituted or unsubstituted arylsulfonyl groups include phenylsulfonyl, tolylsulfonyl, halophenylsulfonyl (eg, fluorophenylsulfonyl) and the like.

  Examples of the sulfonyl group substituted with a heterocyclic group include pyrrolidinylsulfonyl and the like.

  The lower alkylsulfonyl group includes methylsulfonyl, ethylsulfonyl and the like.

  Examples of the cycloalkylcarbonyl group include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and the like.

  Lower alkyl-CO- groups include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like.

  Substituted or unsubstituted aryl-CO— groups include benzoyl, naphthoyl, toluoyl, di (tert-butyl) benzoyl, halogeno lower alkyl-O-benzoyl (eg, trifluoromethoxybenzoyl, etc.), and the like.

  The heterocyclic group moiety in “carbonyl substituted with a heterocyclic group” means the above “heterocyclic” group. For example, pyridylcarbonyl and the like are included.

  “Mono-lower alkylamino” means an amino group substituted with one of the above “lower alkyl”. Examples include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, hexylamino and the like.

  The “di-lower alkylamino” means an amino group substituted by the same or different two “lower alkyl”. Examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylpropylamino, butylethylamino and the like.

  “Optionally substituted” means unsubstituted or substituted with 1 to 5 substituents. “Substituted” means having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

Examples of the substituent in the “optionally substituted cycloalkyl”, “optionally substituted aryl”, or “optionally substituted heterocyclic group” for R ¹ and R ¹⁰ include, for example, lower alkyl, halogen, Cyano, lower alkenyl, cycloalkyl, halogeno lower alkyl, lower alkyl-O-, cyano lower alkyl-O-, halogeno lower alkyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, aryl- Lower alkylene-, acyl, acyl-O-, heteroaryl-lower alkylene-O-, lower alkylsulfanyl, nitro, amino, hydroxy, sulfanyl, mono-lower alkylamino, di-lower alkylamino, acylamino, arylamino groups In another embodiment, lower alkyl, halogen, cyano Groups selected from lower alkenyl, halogeno-lower alkyl, lower alkyl-O—, cyano lower alkyl-O—, halogeno-lower alkyl-O—, and lower alkyl-CO—, and as yet another embodiment, lower alkyl, And groups selected from halogen, halogeno lower alkyl, lower alkyl-O—, and lower alkyl-CO—.

  In the present specification, “cycloalkyl”, “phenyl”, “cyclohexyl” and the like are described as monovalent groups for convenience, but may be divalent or higher polyvalent groups depending on the structure. The present invention includes these structures. Specific embodiments of the divalent group correspond to those obtained by converting the suffix of the ring group to diyl according to the organic compound nomenclature. For example, a divalent group corresponding to a phenyl group that is a monovalent group is phenylene. The divalent group corresponding to the benzothiazolyl group which is a monovalent group is benzothiazolediyl.

By "17BetaHSDtype5 selective" and "AKR1C3 selective", inhibitory activity of 17βHSDtype3 and AKR1C2 is, with respect to inhibitory activity of human 17βHSDtype5 (AKR1C3), 3 times or more in an IC ₅₀ value, preferably 10 times or more, more preferably Means that the numerical value is 100 times or more.

Certain embodiments of the compound of formula (I), which is an active ingredient of the present invention, are shown below.
(1) A compound of formula (II).
(2) The compound wherein A is C—R ¹⁰ .
(3) A compound in which A is N.
(4) compounds wherein R ¹ is hydrogen.
(5) The compound wherein R ¹ is lower alkyl.
(6) The compound wherein R ¹ is halogeno lower alkyl.
(7) The compound wherein R ¹ is lower alkyl substituted with lower alkyl-O—.
(8) A compound in which R ¹ is lower alkyl substituted with phenyl, and the phenyl may be substituted with a group selected from lower alkyl, halogen, halogeno lower alkyl, and lower alkyl-O—.
(9) R ¹ is lower alkyl substituted with phenyl-O—, and the phenyl may be substituted with a group selected from lower alkyl, halogen, halogeno lower alkyl, and lower alkyl-O—. Compound.
(10) The compound wherein R ¹ is lower alkyl-O— optionally substituted with phenyl.
(11) The compound wherein R ¹ is cycloalkyl.
(12) The compound wherein R ¹ is phenyl optionally substituted with a group selected from lower alkyl, halogen, and lower alkyl-O—.
(13) The compound wherein R ² is hydrogen.
(14) compounds wherein R ⁴ is hydrogen.
(15) The compound wherein R ⁵ is hydrogen.
(16) The compound wherein R ⁶ is hydrogen.
(17) The compound wherein R ⁷ is hydrogen.
(18) The compound wherein R ⁸ is hydrogen.
(19) The compound wherein R ⁹ is hydrogen.
(20) A compound in which R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are hydrogen or halogen.
(21) The compound wherein R ³ or R _a ³ is halogeno lower alkyl or cyano.
(22) The compound wherein R ³ or R _a ³ is halogeno lower alkyl.
(23) The compound wherein R ³ or R _a ³ is cyano.
(24) Compound R ³ or R _a ³ is trifluoromethyl.
(25) A compound which is a combination of two or more of the groups described in (1) to (24) above.

Specific examples of the compound (25) include the following compounds.
(26) A is C-R ^10, the compound of formula (II).
(27) The compound described in (26), wherein R ¹ is hydrogen, and R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are hydrogen or halogen.
(28) The compound described in (27), wherein R _a ³ is halogeno lower alkyl or cyano.
(29) A compound of formula (II) wherein A is N.
(30) The compound described in (29), wherein R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are hydrogen or halogen.
(31) The compound described in (30), wherein R _a ³ is halogeno lower alkyl or cyano.
(32) R _a ³ is trifluoromethyl, (31) compounds according.
(33) R ¹ is hydrogen; lower alkyl; halogeno lower alkyl; lower alkyl substituted with lower alkyl-O—, phenyl or phenyl-O—; substituted with lower alkyl, halogen, or lower alkyl-O— Phenyl, which represents cycloalkyl; wherein the phenyl moiety in the lower alkyl substituted with phenyl or phenyl-O- is substituted with lower alkyl, halogen, halogeno-lower alkyl, or lower alkyl-O- Or a compound according to any one of (29) to (32).
(34) The compound described in (32), wherein R ¹ is lower alkyl substituted with hydrogen, lower alkyl, halogeno lower alkyl, or lower alkyl-O—.
(35) The compound described in (32), wherein R ¹ is lower alkyl-O— optionally substituted with phenyl.
(36) The compound described in (32), wherein R ¹ is cycloalkyl.
(37) The compound described in (32), wherein R ¹ is phenyl optionally substituted with a group selected from lower alkyl, halogen, and lower alkyl-O—.
(38) R ¹ is lower alkyl substituted with phenyl or lower alkyl substituted with phenyl-O—, wherein the phenyl is selected from lower alkyl, halogen, halogeno-lower alkyl, and lower alkyl-O— The compound described in (32), which may be substituted with a group.

Specific compounds included in the present invention include the following compounds.
3- (5-cyano-1H-indol-1-yl) benzoic acid,
3- [3-phenyl-5- (trifluoromethyl) -1H-indol-1-yl] benzoic acid,
3- [3- (2-methoxyethyl) -5- (trifluoromethyl) -1H-indol-1-yl] benzoic acid,
3- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-methyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-propyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2,5-bis (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-phenoxymethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-methoxy-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-cyclopropyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-cyclohexyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-phenyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2- (3-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2-benzyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2- (3-fluorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2- (4-fluorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid,
3- [2- (4-chlorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid, and 3- [2- (benzyloxy) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid.

In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. Also includes mixtures.
In addition, the compound of formula (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  The compound of formula (I) can be converted into a salt by a conventional method. The salt of the compound of formula (I) is a pharmaceutically acceptable salt, such as an alkali metal salt (for example, sodium salt or potassium salt) or an alkaline earth metal salt (for example, calcium salt or magnesium salt). Metal salt, ammonium salt, organic base salt (eg trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt etc.), organic acid salt (eg acetate, malonate, tartrate, methanesulfonate, benzene) Sulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), inorganic acid salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acid salt (eg, arginine salt, aspartic acid) Salt, glutamate, etc.). Accordingly, the present invention includes all compounds of formula (I) or pharmaceutically acceptable salts thereof.

  The present invention also includes various hydrates and solvates of the compound of the formula (I) and pharmaceutically acceptable salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

  Furthermore, the present invention includes pharmacologically acceptable prodrugs of the compounds of formula (I). A pharmacologically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.

(General manufacturing method)
The compound of the formula (I), which is an active ingredient of the present invention, can be produced by applying various known synthetic methods utilizing the characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of protective groups thereof include, for example, “Protective Groups in Organic Synthesis (3rd edition, by TW Greene) and Utz (PGM Wuts). 1999) ”, which may be appropriately selected depending on the reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group.

(First manufacturing method)

The first production method is a method for obtaining a compound of the formula (Ia) by subjecting a compound of the formula (III) (wherein R _f represents lower alkyl) to a hydrolysis reaction.

  The hydrolysis reaction can be performed under acidic conditions or basic conditions, but is preferably performed under basic conditions. The base used is preferably an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or the like.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but alcohols such as methanol, ethanol, 2-propanol, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, or cyclopentyl methyl ether, water, or a mixed solvent thereof, and a mixed solvent of tetrahydrofuran and water is preferable.

The reaction temperature of this reaction varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
The reaction time of this reaction varies depending on the raw material compound, reagent, reaction temperature, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

(Second manufacturing method)
(Second production method-1)

In the second production method-1, formula (IV) (wherein R _f represents lower alkyl) and formula (V) (wherein R _b ¹ represents lower alkyl, halogeno lower alkyl, or lower alkyl-O—). substituted lower alkyl, optionally substituted cycloalkyl -L _a -, optionally substituted aryl -L _a -, or optionally substituted heterocyclic group optionally -L _a -; L _a is A compound of the formula (VI) (wherein R _b ¹ and R _f are as defined above) is reacted with a compound of a bond, lower alkylene, or lower alkenylene; X represents a leaving group. How to get.

(Second production method-2)
In the second production method-2, the obtained compound of the formula (VI) is subjected to a hydrolysis reaction to give a compound of the formula (Ib)

（式中、Ｒ_b ¹は上記定義の通りである。）の化合物を得る方法である。

In the formula, R _b ¹ is as defined above.

  The solvent used in the second production method-1 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene, or xylene; dichloromethane Halogenated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, or Ethers such as cyclopentyl methyl ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethyl Amides such as cetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; alcohols such as methanol, ethanol, 2-propanol; and mixtures thereof Preferred are ethers, particularly tetrahydrofuran.

  Examples of the leaving group X include a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group, and the like.

The reaction temperature of the second production method-1 varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C to 100 ° C, preferably 20 ° C to 100 ° C.
The reaction time of the second production method-1 varies depending on the raw material compounds, reagents, reaction temperature, and the like, but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

  The 2nd manufacturing method-2 can be performed on the conditions similar to the hydrolysis of a 1st manufacturing method.

  Further, the order of the second production method-1 and the second production method-2 is changed, and the compound of the formula (IV) is first subjected to hydrolysis, and subsequently reacted with the compound of the formula (V) to obtain the formula (Ib). This compound can also be obtained. In this case, each reaction condition is as described above.

(3rd manufacturing method)
(Third production method-1)

In the second production method-1, not the compound of formula (VI) but a compound of formula (VII) (wherein R _b ¹ and R _f are as defined above) may be isolated. The third production method-1 is a method in which a compound of formula (VII) is subjected to a hydrolysis reaction to obtain a compound of formula (VIII) (wherein R _b ¹ is as defined above).

(3rd manufacturing method-2)
The third production method-2 is a method for obtaining the compound of the formula (Ib) by heating the obtained compound of the formula (VIII) under acidic conditions.

  The 3rd manufacturing method-1 can be performed on the conditions similar to the hydrolysis of a 1st manufacturing method.

The solvent used in the third production method-2 is preferably an acidic solvent such as acetic acid, trifluoroacetic acid, and aqueous hydrochloric acid.
The reaction temperature of the third production method-2 varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.

(4th manufacturing method)
(Fourth Production Method-1)

In the fourth production method-1, the compound of formula (IV) is reacted with the compound of formula (IX) or the acid addition salt of (IX) to thereby give the formula (X) (wherein R _f is as defined above). Is a method of obtaining a compound.

(Fourth Production Method-2)
In the fourth production method-2, the obtained compound of the formula (X) is subjected to a hydrolysis reaction to give a compound of the formula (Ic)

の化合物を得る方法である。

This is a method for obtaining the compound.

  The solvent used in the fourth production method-1 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; dichloromethane, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, or cyclopentyl methyl Ethers such as ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetate Amides, or amides such as N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane; alcohols such as methanol, ethanol, 2-propanol; and mixtures thereof Preferred are alcohols, particularly ethanol.

Although the reaction temperature of the 4th manufacturing method-1 changes with a raw material compound, a reagent, etc., it is 0 degreeC thru | or 100 degreeC normally, It is 20 degreeC thru | or 100 degreeC suitably.
Although the reaction time of the 4th manufacturing method-1 changes with a raw material compound, a reagent, reaction temperature, etc., it is 5 minutes thru | or 24 hours normally, It is 10 minutes thru | or 12 hours suitably.

  The 4th manufacturing method-2 can be performed on the conditions similar to the hydrolysis of a 1st manufacturing method.

(Fifth manufacturing method)
(5th manufacturing method -1)

In the fifth production method-1, the compound of the formula (IV) (wherein R _f represents lower alkyl) and the compound of the formula (XI) is reacted, and the formula (XII) (wherein R _f is as defined above). This is a method for obtaining a compound.

(5th manufacturing method-2)

第５製法−２は、得られた式（ＸＩＩ）の化合物をハロゲン化反応に付し、式（ＸＩＩＩ）（式中、Ｒ_fは上記定義の通りである。）の化合物を得る方法である。

The fifth production method-2 is a method of subjecting the obtained compound of the formula (XII) to a halogenation reaction to obtain a compound of the formula (XIII) (wherein R _f is as defined above). .

(5th manufacturing method-3)

第５製法−３は、得られた式（ＸＩＩＩ）の化合物と式（ＸＩＶ）（式中、Ｒ_c ¹は低級アルキル、ハロゲノ低級アルキル、低級アルキル−Ｏ−で置換された低級アルキル、置換されていてもよいシクロアルキル、置換されていてもよいアリール、又は置換されていてもよいヘテロ環基；Ｍは金属を示す。）の化合物を反応させることにより、式（ＸＶ）（式中、Ｒ_c ¹及びＲ_fは上記定義の通りである。）の化合物を得る方法である。

The fifth production method-3 includes the compound of formula (XIII) and formula (XIV) (wherein R _c ¹ is lower alkyl, halogeno lower alkyl, lower alkyl substituted with lower alkyl-O—, substituted By reacting a compound of the formula (XV) (wherein R represents an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heterocyclic group; M represents a metal). _c ¹ and R _f are as defined above).

(5th manufacturing method-4)
In the fifth production method-4, the obtained compound of the formula (XV) is subjected to hydrolysis reaction to give a compound of the formula (Id)

の化合物を得る方法である。

This is a method for obtaining the compound.

  The fifth production method-1 can be performed under the same conditions as the second production method-1. The reaction is carried out in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide in order to facilitate the reaction. May be advantageous.

  Examples of the leaving group Y include a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group, and the like, and an imidazolyl group is preferable.

  The fifth production method-2 can be carried out by dissolving the obtained compound of the formula (XII) in phosphorus oxychloride and adding phosphorus pentachloride as necessary and heating.

The reaction temperature of the fifth production method-2 varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C to 120 ° C, preferably 20 ° C to 100 ° C.
The reaction time of the fifth production method-2 varies depending on the raw material compounds, reagents, reaction temperature, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 20 hours.

  The solvent used in the fifth production method-3 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether , Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, tert-butyl methyl ether or cyclopentyl methyl ether; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, or N-methyl- Amides such as 2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; alcohols such as methanol, ethanol and 2-propanol; and mixtures thereof Is, preferably alcohols, N, is N- dimethylformamide or dimethyl sulphoxide.

  Examples of the metal M include alkali metals such as lithium, sodium, and potassium, or alkaline earth metals such as magnesium and calcium.

Although the reaction temperature of the 5th manufacturing method-3 changes with raw material compounds, a reagent, etc., it is 0 degreeC thru | or 100 degreeC normally, It is 20 degreeC thru | or 100 degreeC suitably.
Although the reaction time of the 5th manufacturing method-3 changes with a raw material compound, a reagent, reaction temperature, etc., they are 5 minutes thru | or 24 hours normally, Preferably they are 10 minutes thru | or 20 hours.

  The fifth production method-4 can be carried out under the same conditions as the hydrolysis in the first production method.

  Further, the order of the fifth production method-3 and the fifth production method-4 is changed, and the compound of the formula (XIII) is first subjected to hydrolysis, and subsequently reacted with the compound of the formula (XIV) to obtain the formula (Id). This compound can also be obtained. In this case, each reaction condition is as described above.

  In addition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is subjected to usual alkylation, esterification, amidation, acylation, reduction (reduction of aryl and / or heteroaryl, dehalogenation, etc.). Other compounds of formula (I) can be obtained by applying methods known to those skilled in the art.

  The compound of the formula (I) having various functional groups can also be produced by applying a method obvious to those skilled in the art, a known production method, or a modification thereof. For example, a desired compound can be produced by subjecting the compound obtained by the above production method to a substituent modification reaction. A typical reaction is shown below.

(1) Alkylation Among the compounds of formula (I), a compound having a lower alkoxy group or a lower alkylamino group can be produced by subjecting a compound having a hydroxyl group or an amino group to an alkylation reaction. For example, edited by The Chemical Society of Japan, “Fourth edition Experimental Chemistry Course (Volume 20)”, Maruzen, 1992; “Fifth Edition Experimental Chemistry Course (Volume 14)”, Maruzen, 2005; or “Compendium of Organic Synthetic Methods ", Volume 1 to Volume 3 and the like.

(2) Reduction reaction Among the compounds of formula (I), a compound having a saturated cycloalkyl group or a saturated heterocyclic group can also be produced by an aryl and / or heteroaryl reduction reaction. For the reaction, for example, the reaction conditions described in the Chemical Society of Japan, “Fourth Edition, Experimental Chemistry Course (Vol. 26)”, Maruzen, 1992 may be appropriately selected and used. The reduction of halogen on the aryl and / or heteroaryl ring can be carried out using the reaction conditions described in Synthesis 1982, 10, 876-878.

(3) Amidation and esterification Among the compounds of formula (I), a compound having an amide group or a compound having an ester group reacts with a carboxylic acid or a reactive derivative thereof using a compound having an amino group or a hydroxyl group as a raw material. Can be manufactured. The reaction can be performed, for example, by the Chemical Society of Japan, “4th edition, Experimental Chemistry Course (Vol. 22)”, Maruzen, 1992; “5th edition, Experimental Chemistry Course (Vol. 16)”, Maruzen, 2005; of Organic Synthetic Methods ", Volumes 1 to 3 and the like.

(Production method of raw material compounds)
Among the raw material compounds in the first production method, the raw material compound (III) is produced according to a method of coupling an indole ring and a benzene ring, for example, the method described in Journal of the American Chemical Society 2001, 123, 7727-7729. Can do.

  In addition, in the production of the raw material compounds in the second production method to the fifth production method, the amino group of the raw material compound can be produced by a reduction reaction of a nitro group. Volume) ”, Maruzen, 1992, etc.

(Example)
The excellent selective inhibitory activity of human 17βHSD type 5 of the compound of the present invention was confirmed by the test method shown below. For details of the test procedure, see Maniatis, T .; Et al., Molecular Cloning-A Laboratory Manual Cold Spring Harbor Laboratory, NY (1982). The genes encoding human 17βHSD type 5 and type 3 described in 1 and 2 below and human 17βHSD type 5 and type 3 can also be obtained by the method described in Molecular Endocrinology 1997, 11 (13), 1971-1984.

Example 1. Isolation and Enzyme Purification of Gene Encoding Human 17βHSDtype5 Full-length cDNA encoding human 17βHSDtype5 used in the pharmacological test of the present invention was obtained by PCR using cDNA derived from A549 cell of human lung cancer-derived cell line as a template. The base sequence of the obtained cDNA was analyzed by the dideoxy terminator method, and a clone that matched the known human 17βHSD type 5 sequence (GenBank accession No. NM_003739) was selected. Escherichia coli BL21 was transformed with the plasmid containing these and cultured in large quantities, and the protein was purified using GSTrapFF column (Amersham) and PreScissionProtease (Amersham). The purification method followed the instructions attached to the GSTrapFF column.

Example 2 Isolation and Enzyme Purification of Gene Encoding Human 17βHSDtype3 Full-length cDNA encoding human 17βHSDtype3 used in the pharmacological test of the present invention was obtained by PCR using cDNA derived from human testis as a template. The base sequence of the obtained cDNA was analyzed by the dideoxy terminator method, and a clone that matched the known human 17βHSD type 3 sequence (GenBank accession No. BC034281) was selected. Thereafter, 293 cells of a human fetal kidney-derived cell line were transformed with a plasmid containing these, and the cells were collected after 24 hours. Next, the collected cells were disrupted in a phosphate buffer containing 5% glycerol (500 μl of 5% glycerol phosphate buffer (pH 7.4, 200 mM) per 100 mm-dish) and centrifuged (16000 rpm, After 5 min at 4 ° C., the supernatant was used as the enzyme source.

Example 3 FIG. Measurement of enzyme activity of human 17βHSD type 5 and type 3 The enzyme activity was measured by Trevor M. et al. Penning et al., Biochem. J. et al. , 351, 67-77, (2000). Specifically, using 100 mM potassium phosphate buffer (pH 6.0), (1) in the above amount of 1. to a final concentration of 10 μg / ml. (2) Androstenedione with a final concentration of 300 nM, (3) NADPH with a final concentration of 200 μM, and (4) Test substance to be mixed and reacted at room temperature for 2 hours, The amount of testosterone produced was measured using DELFIA (registered trademark) Testosterone Reagents R050-201 (manufactured by PerkinElmer). The measurement method followed the attached instructions. The amount of testosterone produced when no enzyme was added was 0%, the amount of testosterone produced when no compound was added was 100%, and the amount of testosterone produced when the compound was added was determined as a relative value. IC ₅₀ values were then calculated by a logistic regression method.

  Subsequently, human 17βHSDtype5-expressing LNCaP cells were prepared from LNCaP cells of a human prostate cancer-derived cell line, and the cell growth inhibitory activity of the compounds of the present invention was evaluated.

Example 4 Production of Human 17βHSDtype5-expressing LNCaP Cells The full-length cDNA encoding human 17βHSDtype5 used in the pharmacological test of the present invention was obtained by PCR using cDNA derived from A549 cells of a human lung cancer-derived cell line as a template. The base sequence of the obtained cDNA was analyzed by the dideoxy terminator method, and a clone that matched the known human 17βHSD type 5 sequence (GenBank accession No. NM_003739) was selected. Thereafter, LNCaP cells of a human prostate cancer-derived cell line were transformed with a plasmid containing these to obtain a stable expression cell line.

Embodiment 5 FIG. 3. Measurement of cell growth ability using human 17βHSDtype5-expressing LNCaP cells The transformed cells obtained in (1) were seeded in a 96-well plate at 9000 cells / well and cultured overnight, and then androstenedione was added to the final concentration of 10 nM together with the test compound and cultured for 7 days. . After culture, the number of cells was measured using CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega). CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay is a reagent for measuring the number of cells by monitoring the amount of intracellular ATP with the luminescence intensity by luciferase. The experimental procedure followed the attached instructions. The cell growth inhibitory activity when the test compound was added was determined as a relative value, with the number of cells without addition of androstenedione as 0% growth, the number of cells when androstenedione was added and when no test compound was added as 100%. IC ₅₀ values were then calculated by a logistic regression method.

The IC ₅₀ values of inhibitory activity of human 17βHSDtype5 and type3 of an active ingredient Reference Example compounds of the present invention, as well as IC ₅₀ values of cell growth inhibitory activity using human 17βHSDtype5 expressing LNCaP cells shown in Table 1. Ex represents a reference example number described later.

  Subsequently, a mouse transplanted with CWR22R (“Cancer Research”, 1996, Vol. 56, p. 3042-3046), a human prostate cancer-derived cell line, was prepared, and the intratumoral testosterone production inhibitory activity of the compound of the present invention was demonstrated. evaluated.

Example 6 Inhibition of intratumoral testosterone production in CWR22R cancer-bearing mice BD Matrigel (registered trademark) phenol red-free 356237 (manufactured by Becton Dickinson) was used as the matrigel described below.
CWR22R tumors were excised from CWR22R subcutaneous tumor-bearing nude mice. The excised tumor was subdivided into pieces of about 5 mm. The tumor pieces were washed twice with RPMI1640 medium containing 20% serum and then stirred for about 20 minutes in RPMI1640 medium containing 0.1% protease and 20% serum. The supernatant was collected and the cells were collected by centrifugation. This was repeated as necessary, and the collected cells were combined into a cell solution. After measuring the number of cells, the cell solution was adjusted to 2 × 10 ⁷ cells / mL. Further, the cell solution and Matrigel were mixed in an equal amount, and finally adjusted to 1 × 10 ⁷ cells / mL. A male nude mouse from which the testis had been removed was subcutaneously implanted in the back of the cell by injecting 0.1 mL of the cell matrigel mixed solution prepared by the above method into one place. When the tumor volume reached 100 mm ³ or more after transplantation, the following experiments were conducted after grouping based on the tumor volume.
The test substance was orally administered to CWR22R subcutaneous cancer-bearing mice. One hour later, ie one hour before dissection, androstenedione was administered into the tumor to give a 1 ng / 100 mm ³ tumor. The composition of the androstenedione administration solution was 0.000075% DMF / 0.00005% polysorbate 80 / 9.9999875% saline / 90% Matrigel. After dissection, the tumor was removed, and after measuring the tumor weight, it was stored frozen. For measurement of the background value, tumors of mice that were orally administered only with the test substance administration solvent were excised, and an androstenedione administration solution was added under ice-cooling and rapidly frozen.
0.2 M Na-K phosphate buffer (pH 7.4) was added to the cryopreserved tumor sample, and a tumor homogenate was prepared with a homogenizer (Polytron) under ice cooling. After adding 6 times volume of tert-butyl methyl ether to the tumor crush solution and centrifuging (3000 rpm, 5 min), transfer the supernatant to another test tube and keep it at 40 ° C in a heat block with nitrogen gas. The solvent was distilled off. A test tube was mixed with 10 mM Tris-Cl buffer (pH 7.4) containing 2% BSA to obtain an extract, and the testosterone concentration was measured using DELFIA (registered trademark) Testosterone Reagents R050-201 (manufactured by PerkinElmer). .
The inhibition rate was calculated by the following formula.
Inhibition rate (%) = 100 × (average testosterone concentration of test substance-administered solvent administration group−average testosterone concentration of test substance-administered group) / (average testosterone concentration of test substance-administered solvent group−background testosterone concentration)

  Table 2 shows the inhibition rate (%) of intratumoral testosterone production in CWR22R cancer-bearing mice of Reference Example compounds which are active ingredients of the present invention. Ex represents the reference example number described later, and Inh represents the testosterone production inhibition rate upon administration of 10 mg / kg of the reference example compound described later.

  As is apparent from the above test results, the compound of the formula (I) has little human 17βHSD type 3 inhibitory activity and has selective human 17β HSD type 5 inhibitory activity.

  Further, as is clear from the above test results, the compound of formula (I) has very weak human 17βHSD type 3 inhibitory activity, and therefore, selective inhibition of 17β HSD type 5 without affecting the testosterone biosynthesis derived from human 17β HSD type 3 in the testis. Since it can be expected to selectively suppress the intracrine testosterone synthesis of the prostate by the action, it can be used for the treatment and / or prevention of prostatic hypertrophy and prostate cancer without side effects.

  Further, as is clear from the above test results, the compound of formula (I) showed cell growth inhibitory activity in human 17βHSDtype5-expressing LNCaP cells, and showed tumor tumorosterone production-suppressing activity in CWR22R tumor-bearing mice. Therefore, 17βHSDtype5 selection was selected. It can be used for the treatment and / or prevention of prostate cancer without side effects, by selectively suppressing the synthesis of intracrine testosterone in prostate cancer by its inhibitory action.

  Further, a commercial package including the above-mentioned pharmaceutical composition and a description describing the above-described effects is also useful.

  Formulations containing one or more of the compounds of formula (I) or salts thereof as active ingredients are generally used methods using pharmaceutical carriers, excipients and the like that are usually used in the art Can be prepared.

  Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.

  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

  In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. In the case of intravenous administration, the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

The compound of the formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of the formula (I) is considered effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.
(Reference example)

  Hereafter, the manufacturing method of the compound of Formula (I) which is an active ingredient of this invention is described as a reference example. Moreover, the manufacturing method of a novel compound is described as a manufacture example among the compounds used as a raw material of the compound of a formula (I). In addition, the manufacturing method of the compound of Formula (I) is not limited only to the manufacturing method of the specific reference example shown below, It can manufacture also by the combination of these manufacturing methods, or a well-known manufacturing method.

In addition, the following abbreviations are used in Production Examples, Reference Examples, and Tables below.
Ex: Reference example number, REx: Production example number, Data: Physicochemical data (FAB +: FAB-MS (M + H) ⁺ , FAB-: FAB-MS (MH) ⁻ , ESI +: ESI-MS (M + ^{H) +, ESI-: ESI-} MS (MH) -, API +: API-ES-MS (M + H) +, EI: EI-MS (M) +, NMR-DMSOd6: 1 in DMSO-d ₆ Δ (ppm) of peak in 1 H NMR), Str: Structural formula, Syn (REx): Production example number produced by the same method, Syn (Ex): Reference example number produced by the same method, DME: Dimethoxyethane , DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, tBuOH: tert-butyl alcohol, n-BuLi: n-butyllithium, RT: HPLC retention time (Minutes).

Production Example 1
Cool a mixture of 5.03 g of 2-fluoro-4-methoxy-1-nitrobenzene and 100 ml of THF to -50 ° C, add 90 ml of 1M vinylmagnesium bromide-THF at -30 ° C or less, and add 2 at -50 ° C. Stir for hours. To the reaction solution, 100 ml of saturated aqueous ammonium chloride solution and 90 ml of 1M hydrochloric acid were added, and the mixture was warmed to room temperature and stirred for 15 minutes. The mixture was extracted twice with 100 ml of ethyl acetate, and the extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane = 1: 20 → 1: 9) to obtain 470 mg of 7-fluoro-5-methoxy-1H-indole as a brown oil.

Production Example 2
Add 3-ml-5- (trifluoromethyl) -1H-indole-2-carboxylate 1.35 g, methanol 10 ml, and THF 10 ml to a mixture of 1 M aqueous sodium hydroxide solution 6.0 ml at 50 ° C for 3 hours. Stir. 30 ml of water and 6 ml of 1M hydrochloric acid were added to the reaction solution, and the precipitated solid was collected by filtration and dried. The obtained solid was dissolved in 15 ml of N-methyl-2-pyrrolidinone, 100 mg of copper powder was added, and the mixture was stirred overnight at 160 ° C. The reaction solution was allowed to cool, 100 ml of ethyl acetate was added to remove insoluble matters, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane = 1: 4) to obtain 770 mg of 3-phenyl-5- (trifluoromethyl) -1H-indole as a brown oil.

Production Example 3
In a mixture of cuprous iodide 120 mg, trans-N, N'-dimethylcyclohexane-1,2-diamine 160 mg and dioxane 6 ml, ethyl 3-iodobenzoate 1.2 ml, 1H-indole-5-carbonitrile 850 mg and 1.65 g of potassium carbonate were added and stirred at 110 ° C. overnight. The reaction solution was allowed to cool, 50 ml of ethyl acetate was added to remove insoluble matters, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform), washed with ether-hexane (1: 5), and ethyl 3- (5-cyano-1H-indol-1-yl) benzoate 1.41 g Was obtained as a white solid.
The compounds of Production Examples 4 to 10 listed in Tables 3 and 4 were obtained in the same manner as in Production Example 3.

Production Example 11
A mixture of 1.0 g of 4-fluoro-3-nitrobenzonitrile, 1.09 g of ethyl 3-aminobenzoate, 1.25 g of potassium carbonate and 10 ml of DMF was stirred at 100 ° C. for 3 hours. 60 ml of water was added to the reaction solution, and the mixture was extracted with 120 ml of ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethanol to give 1.43 g of ethyl 3-[(4-cyano-2-nitrophenyl) amino] benzoate as a brown solid.
The compound of Production Example 12 listed in Table 4 was obtained in the same manner as in Production Example 11.

Production Example 13
Palladium acetate 85 mg, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl 350 mg and toluene 15 ml mixed with ethyl 3-bromobenzoate 1.8 ml, 2-nitroaniline 1.02 g and carbonic acid 4.81 g of cesium was added and stirred at 110 ° C. for 5 hours. The reaction solution was allowed to cool, 50 ml of ethyl acetate was added to remove insoluble matters, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 9) to obtain 2.10 g of ethyl 3-[(2-nitrophenyl) amino] benzoate as an amber oil.
The compounds of Production Examples 14 to 16 listed in Table 4 were obtained in the same manner as in Production Example 13.

Production Example 17
0.77 g of iron powder was added to a mixture of 1.42 g of ethyl 3-[(4-cyano-2-nitrophenyl) amino] benzoate and 10 ml of acetic acid, and the mixture was stirred at 80 ° C. for 2 hours. The insoluble material in the reaction solution was removed, and the solvent was evaporated under reduced pressure. To the residue was added 100 ml of saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with 50 ml of chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 1.35 g of ethyl 3-[(2-amino-4-cyanophenyl) amino] benzoate as a pale yellow solid.
The compounds of Production Examples 18 to 20, 76 and 77 shown in Tables 5 and 14 were obtained in the same manner as in Production Example 17.

Production Example 21
0.12 ml of acetyl chloride was added to a mixture of 400 mg of ethyl 3-[(2-amino-4-cyanophenyl) amino] benzoate and 5 ml of THF, and the mixture was stirred at room temperature for 2 hours and at 70 ° C. for 2 hours. The reaction mixture was allowed to cool, 30 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with 60 ml of ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 1) to obtain 360 mg of ethyl 3- (5-cyano-2-methyl-1H-benzimidazol-1-yl) benzoate. Obtained as a white solid.
The compounds of Production Examples 22 to 48 listed in Tables 5 to 9 were obtained in the same manner as in Production Example 21.

Production Example 49
Ethyl 3-[(2-amino-4-cyanophenyl) amino] benzoate 232 mg of (3-fluorophenyl) acetyl chloride was added to a solution of 315 mg of 315 mg of THF, 2.5 hours at room temperature, and 16 hours at 80 ° C. Stir. The reaction mixture was allowed to cool, 20 mL of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with 50 mL of ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 6) to give 3- [5-cyano-2- (3-fluorobenzyl) -1H-benzimidazole-1- 189 mg of ethyl yl] benzoate was obtained as a colorless oil.
Compounds of Production Examples 50 to 55 listed in Tables 10 and 11 were obtained in the same manner as in Production Example 49.

Production Example 56
To a mixed solution of ethyl 3-{[2-amino-4- (trifluoromethyl) phenyl] amino} benzoate (320 mg) and ethanol (4 ml) was added formamidine acetate (310 mg) and the mixture was stirred overnight with heating under reflux. The reaction mixture was allowed to cool, 30 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with 60 ml of ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and then washed with hexane, and 290 mg of ethyl 3- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate was pale yellow. Obtained as a solid.
The compound of Production Example 57 described in Table 11 was obtained in the same manner as in Production Example 56.

Production Example 58
Ethyl 3-{[2-amino-4- (trifluoromethyl) phenyl] amino} benzoate 0.25 mg of triethylamine 0.468 ml and 1,1-carbonylbis (1H-imidazole) 409 mg were added to a solution of 545 mg of acetonitrile in 10 ml. The mixture was stirred at 90 ° C. for 7 hours. After cooling to room temperature, the resulting precipitate was collected by filtration, and 499 mg of ethyl 3- [2-oxo-5- (trifluoromethyl) -2,3-dihydro-1H-benzimidazol-1-yl] benzoate was added. Obtained as a white solid.

Production Example 59
3- (2-Oxo-5- (trifluoromethyl) -2,3-dihydro-1H-benzimidazol-1-yl] ethyl benzoate 889 mg of phosphorus oxychloride in 10 ml solution of phosphorus pentachloride 793 mg In addition, the mixture was stirred at 100 ° C. for 15 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the resulting residue, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 985 mg of ethyl 3- [2-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate as a light mixture. Obtained as a yellow oil.

Production Example 60
3- [2-Chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl] ethyl benzoate 588 mg in methanol 5 ml solution, 28% sodium methoxide methanol solution 0.920 ml was added, And stirred for 16 hours. The precipitate produced in the reaction solution was collected by filtration to obtain 384 mg of methyl 3- [2-methoxy-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate as a white solid.

Production Example 61
3- [2-Chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl] ethyl benzoate (111 mg) in THF (3 ml) was added 1 M aqueous sodium hydroxide solution (0.330 ml) at room temperature. Stir for 15 hours. Under ice-cooling, 0.3M ml of 1 M aqueous hydrochloric acid solution was added to the reaction solution, and then ethyl acetate and saturated brine were added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 113 mg of 3- [2-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid as a white solid Got as.

Production Example 62
Platinum (IV) oxide in a mixture of ethyl 3- [2-pyridin-4-yl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate 1.15 g, concentrated hydrochloric acid 0.5 ml and ethanol 15 ml 0.15 g was added, and the mixture was stirred overnight at room temperature under a hydrogen gas atmosphere. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. To the residue were added 60 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-concentrated aqueous ammonia = 20: 1: 0.1 → 10: 1: 0.1) to give 3- [2-piperidin-4-yl-5- ( 1.05 g of ethyl (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate was obtained as a white amorphous solid.

Production Example 63
Add 0.12 ml of acetic anhydride to a mixture of 420 mg of ethyl 3- [2-piperidin-4-yl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate, 0.17 ml of triethylamine and 4 ml of THF Stir at room temperature for 5 hours. To the reaction solution was added 60 ml of ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol = 100: 1) to give 3- [2- (1-acetylpiperidin-4-yl) -5- (trifluoromethyl) -1H- 430 mg of ethyl benzoimidazol-1-yl] benzoate was obtained as a white amorphous solid.

Production Example 64
Ethyl 3- [2- (4-bromobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoate 272 mg was dissolved in ethanol 2.7 mL, and palladium-carbon 13.6 mg was added. Thereafter, the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate, water and saturated brine. This was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 6) to give 3- [2-benzyl-5- (trifluoromethyl) -1H-benzimidazole-1- Il] 229 mg of ethyl benzoate was obtained as a pale amber oil.

Production Example 65
3-{[2-amino-4- (trifluoromethyl) phenyl] amino} ethyl benzoate (300 mg), pyridine (0.11 ml) and THF (3 ml) were added with cyclohexanecarbonyl chloride (0.16 ml) at room temperature for 1 hour at 80 ° C. For 5 hours. The reaction solution was allowed to cool, 30 ml of water was added, and the precipitated solid was collected by filtration. The obtained solid was washed with hexane to obtain 360 mg of ethyl 3-({2-[(cyclohexylcarbonyl) amino] -4- (trifluoromethyl) phenyl} amino) benzoate as a pale yellow solid.
The compounds of Production Examples 66 to 70 listed in Tables 12 and 13 were obtained in the same manner as in Production Example 65.

Production Example 71
3-({2-[(cyclohexylcarbonyl) amino] -4- (trifluoromethyl) phenyl} amino) ethyl benzoate (340 mg), methanol (2.5 ml) and THF (2.5 ml) were mixed with 1 M aqueous sodium hydroxide solution (1.1 ml). The mixture was further stirred at 50 ° C. for 3 hours. To the reaction solution, 1.1 ml of 1 M hydrochloric acid and 30 ml of water were added, and the precipitated solid was collected by filtration. The obtained solid was washed with ethanol to obtain 210 mg of 3-({2-[(cyclohexylcarbonyl) amino] -4- (trifluoromethyl) phenyl} amino) benzoic acid as a white solid.
Compounds of Production Examples 72 to 74, 78 and 79 listed in Tables 13 and 14 were obtained in the same manner as in Production Example 71.

Production Example 75
3-{[2-Amino-4- (trifluoromethyl) phenyl] amino} ethyl benzoate 324 mg of ethanol and THF in a 5 ml solution, 1.50 ml of 1 M aqueous sodium hydroxide solution was added, and 2 hours at room temperature Stir. To the reaction solution was added 1 M aqueous sodium hydroxide solution (1.00 ml), and the mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated under reduced pressure, and 2.50 ml of 1 M aqueous hydrochloric acid and 10 ml of water were added to the resulting residue under ice cooling, and the resulting precipitate was collected by filtration to give 3-{[2-amino-4- ( Trifluoromethyl) phenyl] amino} benzoic acid 281 mg was obtained as a brown solid.
The structural formula, production method and physicochemical data of each production example compound are shown in the table.

  The following reference examples are intended to explain the present invention in more detail, and the present invention is not limited to the following reference examples. While the invention has been fully described by reference examples, it will be understood that various changes and modifications will be apparent to those skilled in the art. Therefore, unless such changes and modifications depart from the scope of the present invention, they are included in the present invention.

Reference example 1
To a mixture of 1.0 g of ethyl 3- (5-cyano-1H-indol-1-yl) benzoate, 10 ml of methanol and 20 ml of THF, 5.5 ml of 1 M aqueous sodium hydroxide solution was added and stirred at room temperature for 3 hours. 1 M hydrochloric acid (5.5 ml) and water (50 ml) were added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed with ethanol-ether (1: 2) to obtain 800 mg of 3- (5-cyano-1H-indol-1-yl) benzoic acid as a white solid.
The compounds of Reference Examples 2 to 46 listed in Tables 15 to 18 were obtained in the same manner as in Reference Example 1.

Reference Example 47
To a mixture of 3- [3- (2-hydroxyethyl) -5- (trifluoromethyl) -1H-indol-1-yl] benzoic acid 150 mg, methyl iodide 0.090 ml and THF 2 ml, Sodium hydride (55% liquid paraffin dispersion) (60 mg) was added, and the mixture was stirred under ice-cooling for 3 hours and at room temperature overnight. 20 ml of water and 10 ml of 5% aqueous potassium hydrogen sulfate solution were added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed with ether-hexane to give 110 mg of 3- [3- (2-methoxyethyl) -5- (trifluoromethyl) -1H-indol-1-yl] benzoic acid as a pale yellow solid Obtained.

Reference Example 48
A mixture of 190 mg of 3-({2-[(cyclohexylcarbonyl) amino] -4- (trifluoromethyl) phenyl} amino) benzoic acid and 4 ml of acetic acid was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 160 mg of 3- [2-cyclohexyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid as a white solid. .
The compounds of Reference Examples 49 to 53 described in Tables 18 and 19 were obtained in the same manner as in Reference Example 48.

Reference Example 54
To a solution of 3-{[2-amino-4- (trifluoromethyl) phenyl] amino} benzoic acid 275 mg in THF 5 ml, add 0.157 ml of trifluoroacetic anhydride under ice cooling, and stir at room temperature for 30 minutes did. The reaction mixture was concentrated under reduced pressure, 5 ml of acetic acid was added to the resulting residue, and the mixture was stirred at 90 ° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was crystallized from a mixture of hexane and ethyl acetate to give 3- [2,5-bis (trifluoromethyl) -1H-benzimidazole-1- Yl] benzoic acid 176 mg was obtained as a pale yellow solid.

Reference Example 55
To a suspension of sodium ethoxide 163 mg in DMF 3 ml, ice-cooled 3- [2-chloro-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid 163 mg DMF 2 ml The solution was added and stirred at room temperature for 1 hour. To the reaction solution, 163 mg of sodium ethoxide was added and stirred at room temperature for 2 hours. Under ice-cooling, 1 M hydrochloric acid (4.8 ml) was added to the reaction mixture, and ethyl acetate and water were added to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol = 24: 1), and the obtained solid was recrystallized from a mixture of hexane and ethyl acetate to give 3- [2-ethoxy-5 -(Trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid 202 mg was obtained as a white solid.
The compound of Reference Example 56 described in Table 19 was obtained in the same manner as in Reference Example 55.

Tables 20 to 22 show the physicochemical data of the compounds of Reference Examples 1 to 56.

Reference Example 57
Add 13 mg of ethyl 3- [2-amino-4- (trifluoromethyl) phenyl] aminobenzoate and 0.02 ml of THF in 0.3 ml of THF to 6 mg of isovaleryl chloride in THF and stir overnight at room temperature. did. Water and chloroform were added, the organic layer was separated, and the solvent was distilled off under reduced pressure. Acetic acid (0.5 ml) was added to the resulting residue, and the mixture was stirred overnight at 90 ° C., and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 0.2 ml of methanol, 0.2 ml of THF and 0.1 ml of 5 M aqueous sodium hydroxide solution, and stirred at 60 ° C. overnight. After cooling to room temperature, the mixture was neutralized with 1 M hydrochloric acid, the solvent was distilled off under reduced pressure, the residue was purified by preparative HPLC, and 3- [2-isobutyl-5- (trifluoromethyl) -1H- Benzimidazol-1-yl] benzoic acid 4.1 mg was obtained.

HPLC condition column used for purification: SunFire (registered trademark) (particle size: 5 μm, inner diameter: 19 mm, length: 100 mm)
Mobile phase: A Sol methanol, B Sol 0.1% formic acid aqueous solution

流速：２５ｍｌ／ｍｉｎ
カラム温度：２０℃
注入量：８００ μｌ

Flow rate: 25 ml / min
Column temperature: 20 ° C
Injection volume: 800 μl

Here, the conditions of HPLC performed for obtaining RT are shown below.
Column: Wakosil-II 5C18AR (registered trademark) (particle size: 5 μm, inner diameter: 2.0 mm, length: 30 mm)
Mobile phase: A Sol 5 mM trifluoroacetic acid aqueous solution, B Sol methanol

流速：１．２ｍｌ／ｍｉｎ
検出波長：２５４ｎｍ
カラム温度：３５．０℃
注入量：５μｌ
表２５に記載の参考例５８乃至６０の化合物を、参考例５７と同様の方法で得た。

Flow rate: 1.2 ml / min
Detection wavelength: 254 nm
Column temperature: 35.0 ° C
Injection volume: 5 μl
The compounds of Reference Examples 58 to 60 listed in Table 25 were obtained in the same manner as in Reference Example 57.

  Since the compound which is an active ingredient of the medicament of the present invention has a selective inhibitory action of 17βHSDtype5 and a good pharmacological action based on this, the pharmaceutical composition of the present invention is suitable for diseases related to 17βHSDtype5, particularly prostate cancer, prostate As a therapeutic and / or prophylactic agent for hypertrophy, acne, seborrhea, hirsutism, baldness, alopecia, premature gestation, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, lung cancer, endometriosis or leiomyoma, etc. Can be used.

Claims (19)

Formula (I)

[Where:
A is C—R ¹⁰ or N;
R ¹ is hydrogen, lower alkyl, halogeno lower alkyl, lower alkyl substituted with lower alkyl-O—, lower alkyl-O—, halogeno lower alkyl-O—, or lower alkyl-substituted with lower alkyl-O—. O-, an optionally substituted cycloalkyl-L-, an optionally substituted aryl-L-, or an optionally substituted heterocyclic group -L-;
L is a bond, lower alkylene, lower alkenylene, O, lower alkylene-O, or O-lower alkylene;
R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different from each other and represent hydrogen, lower alkyl, halogen, cyano, lower alkenyl, halogeno lower alkyl, lower alkyl-O—. Cyano lower alkyl-O-, halogeno lower alkyl-O-, cycloalkyl, aryl, heteroaryl, aryl-O-, heteroaryl-O-, aryl-lower alkylene-, heteroaryl-lower alkylene-, acyl, acyl -O-, heteroaryl-lower alkylene-O-, lower alkylsulfanyl, amino, hydroxy, sulfanyl, mono-lower alkylamino, di-lower alkylamino, acylamino, or arylamino;
R ³ is hydrogen, halogen, cyano, nitro, halogeno lower alkyl, or lower alkyl-O—;
R ¹⁰ represents hydrogen, optionally substituted aryl, or lower alkyl optionally substituted with hydroxy or lower alkyl-O—.
However,
When A is C—R ¹⁰ , R ¹ represents hydrogen or lower alkyl;
When A is N, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, R ³ is halogen, cyano, halogeno lower alkyl, or lower alkyl- Indicates O-;
When A is N, R ¹ is methyl, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁹ are hydrogen, R ⁸ is [(2E) -3- (2 -Naphthalenyl) -1-oxo-2-buten-1-yl] groups other than amino. ]
A pharmaceutical composition for preventing or treating a disease associated with 17βHSDtype5, comprising the compound or a salt thereof. Formula (II)

[Where:
A is C—R ¹⁰ or N;
R ¹ is hydrogen, lower alkyl, halogeno lower alkyl, lower alkyl substituted with lower alkyl-O—, lower alkyl-O—, halogeno lower alkyl-O—, or lower alkyl-substituted with lower alkyl-O—. O-, an optionally substituted cycloalkyl-L-, an optionally substituted aryl-L-, or an optionally substituted heterocyclic group -L-;
L is a bond, lower alkylene, lower alkenylene, O, lower alkylene-O, or O-lower alkylene;
R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different from each other, and are hydrogen, lower alkyl, halogen, cyano, lower alkenyl, halogeno lower alkyl, lower alkyl-O—. Cyano lower alkyl-O-, halogeno lower alkyl-O-, cycloalkyl, aryl, heteroaryl, aryl-O-, heteroaryl-O-, aryl-lower alkylene-, heteroaryl-lower alkylene-, acyl, acyl -O-, heteroaryl-lower alkylene-O-, lower alkylsulfanyl, amino, hydroxy, sulfanyl, mono-lower alkylamino, di-lower alkylamino, acylamino, or arylamino;
R _a ³ is hydrogen, halogen, cyano, halogeno lower alkyl, or lower alkyl-O—;
R ¹⁰ represents hydrogen, optionally substituted aryl, or lower alkyl optionally substituted with hydroxy or lower alkyl-O—.
However,
When A is C—R ¹⁰ , R ¹ represents hydrogen or lower alkyl, but R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, and R ⁴ is chloro. And when R ¹⁰ is isobutyl, R _a ³ is a group other than hydrogen;
When A is N, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, R _a ³ represents halogen, cyano, or lower alkyl-O—. Show;
A is N, R ¹ is methyl, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁹ are hydrogen, and R ⁸ is [(2E) -3- (2-naphthalenyl) -1-oxo. -2-buten-1-yl] amino, R _a ³ is a group other than hydrogen;
When A is N, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen, and R ⁴ is tert-butyl, R _a ³ is a group other than hydrogen. ;
When A is N, R ¹ is hydrogen or methyl, R ² , R ⁶ , and R ⁷ are hydrogen, R ⁴ and R ⁸ are hydroxy, and R ⁵ is carboxy, R _a ³ is a group other than hydrogen. Show. ]
Or a salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 2, wherein A is C—R ¹⁰ . The pharmaceutical composition according to claim 3, wherein R ¹ is hydrogen, and R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same or different and are hydrogen or halogen. The pharmaceutical composition according to claim 4, wherein R _a ³ is halogeno lower alkyl or cyano.   The pharmaceutical composition according to claim 2, wherein A is N. ^{R 2, R 4, R 5} , R 6, R 7, R 8, and R ⁹ are the same or different, is hydrogen or halogen, A pharmaceutical composition according to claim 6. R _a ³ is halogeno lower alkyl, or cyano A pharmaceutical composition according to claim 7. The pharmaceutical composition according to claim 8, wherein R _a ³ is trifluoromethyl. R ¹ is hydrogen; lower alkyl; halogeno lower alkyl; lower alkyl substituted with lower alkyl-O—, phenyl or phenyl-O—; phenyl optionally substituted with lower alkyl, halogen, or lower alkyl-O— In which: the phenyl moiety in the lower alkyl substituted with phenyl or phenyl-O— may be substituted with lower alkyl, halogen, halogeno lower alkyl, or lower alkyl-O—; ;
The pharmaceutical composition according to claim 6, wherein 10. The pharmaceutical composition according to claim 9, wherein R < ¹ > is lower alkyl substituted with hydrogen, lower alkyl, halogeno lower alkyl, or lower alkyl-O-. The pharmaceutical composition according to claim 9, wherein R ¹ is lower alkyl-O- which may be substituted with phenyl. The pharmaceutical composition according to claim 9, wherein R ¹ is cycloalkyl. 10. The pharmaceutical composition according to claim 9, wherein R < ¹ > is phenyl optionally substituted with a group selected from lower alkyl, halogen, and lower alkyl-O-. R ¹ is lower alkyl substituted with phenyl or lower alkyl substituted with phenyl-O—, wherein the phenyl is substituted with a group selected from lower alkyl, halogen, halogeno lower alkyl, and lower alkyl-O— The pharmaceutical composition according to claim 9, which may be used. 3- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-methyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-ethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-propyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2,5-bis (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-phenoxymethyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-methoxy-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-cyclopropyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-cyclohexyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-phenyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2- (3-methylphenyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2-benzyl-5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2- (3-fluorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2- (4-fluorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
3- [2- (4-chlorobenzyl) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid; and 3- [2- (benzyloxy) -5- (trifluoromethyl) -1H-benzimidazol-1-yl] benzoic acid;
Or a salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable excipient.   Prostate cancer, prostatic hypertrophy, acne, seborrhea, hirsutism, baldness, alopecia, precocious ripening, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, comprising the compound according to claim 1 or a salt thereof A preventive or therapeutic agent for endometriosis, lung cancer, or leiomyoma.   The inhibitor of 17 (beta) HSDtype5 containing the compound or its salt of Claim 1.   A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and the compound or salt according to claim 1, wherein prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, baldness, alopecia Commercial package containing a statement that can or should be used to treat and / or prevent sexual prematurity, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, endometriosis, lung cancer, or leiomyoma .