JP5609150B2 - Piperidine derivatives - Google Patents

Description

  The present invention relates to a medicament or pharmaceutical composition comprising a piperidine compound and / or a 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 for relapsed prostate cancer are not enough to reduce the testosterone concentration in the prostate, and the inhibition of the intracranial testosterone synthesis mechanism, ie, the 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, p.2177-2181) has been reported. That is, it is suggested that the activity of AKR1C3 in the lung increases the risk of lung cancer through the production of ROS from PAH, and a selective inhibitor of 17βHSDtype5 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. In addition, although the mechanism of action is different, it is also known that an indazole derivative containing a compound of the formula (A) is effective for BPH (Patent Document 2).

Patent Document 3 shows that an N-substituted benzimidazole derivative containing a compound of the formula (B) has a c-Kit proto-oncogene inhibitory action and is useful for prostate cancer and the like. However, there is no disclosure of indolyl group, and there is no description of 17βHSDtype5 inhibitory action.

Patent Document 4 shows that a benzimidazole derivative containing a compound of the formula (C) has a tyrosine kinase regulating action and is useful for prostate cancer and the like. However, there is no disclosure of indolyl group, and there is no description of 17βHSDtype5 inhibitory action.

Patent Document 5 shows that an indole derivative containing a compound of formula (D) has a histamine H4 antagonistic action and is useful for inflammation. However, there is no disclosure of a non-basic (piperidyl) alkanol structure, and there is no description that it is effective for 17βHSD type 5 inhibitory activity, BPH, prostate cancer and the like.

Patent Document 6 shows that an indole derivative containing a compound of the formula (E) has a cannabinoid receptor modulating action and is useful for cerebrovascular disorders and the like. However, there is no description that it is effective for 17βHSD type 5 inhibitory action, BPH, prostate cancer and the like.

  In addition, N-sulfonylindole derivatives (Patent Document 7), benzoimidazolylbenzoic acid derivatives (Patent Document 8) and the like have been reported as compounds having 17βHSD type 5 inhibitory action other than the above. In addition, Patent Document 9 published after the priority date of the present application discloses an indol-2-ylcarbonylpiperidine derivative.

International Publication WO99 / 046279 Pamphlet International Publication WO 2004/064735 Pamphlet International Publication WO2005 / 021531 Pamphlet International Publication WO2007 / 056155 Pamphlet International Publication WO2002 / 072548 Pamphlet JP 2005-162657 A International Publication WO2007 / 100066 Pamphlet International Publication WO2009 / 014150 Pamphlet International Publication WO2009 / 028618 Pamphlet

“Cancer Research”, 2004, Vol. 64, p. 1802-1810 “Molecular and Cellular Endocrinology”, 2006, Vol. 248, p. 233-235

  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 {1-[(indol-2-yl) carbonyl] piperidyl} alkanol derivatives have potent 17βHSDtype5 selective inhibitory activity, and The present invention was completed by discovering that it can be used as a therapeutic and / or prophylactic agent for diseases associated with 17βHSD type 5 such as prostatic hypertrophy and prostate cancer without side effects due to testosterone reduction.

式（Ｉ）において、
Ｒ¹、Ｒ²、及びＲ³は、同一又は互いに異なって、Ｈ又は低級アルキル；
Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、及びＲ⁸は、同一又は互いに異なって、Ｈ、低級アルキル、ハロゲン、ハロゲノ低級アルキル、ニトロ、−Ｘ−置換されていてもよいシクロアルキル、−Ｘ−置換されていてもよいアリール、−Ｘ−置換されていてもよいヘテロ環基、
−Ｘ−ＣＯＯＲ⁰、−Ｘ−ＣＯＮＲ¹⁰Ｒ¹¹、−Ｘ−ＣＮ、−Ｘ−ＯＲ⁰、−Ｘ−ＳＲ⁰、−Ｘ−Ｓ（Ｏ）−低級アルキル、−Ｘ−Ｓ（Ｏ）₂−低級アルキル、−Ｘ−ＮＲ¹⁰Ｒ¹¹、−Ｘ−ＮＲ⁰Ｃ（Ｏ）Ｒ¹⁰、−Ｘ−ＮＲ⁰Ｃ（Ｏ）ＯＲ¹⁰、−Ｘ−ＮＲ⁰Ｃ（Ｏ）ＮＲ¹⁰Ｒ¹¹、−Ｘ−ＮＲ⁰Ｓ（Ｏ）₂Ｒ¹⁰、−Ｘ−Ｏ−ハロゲノ低級アルキル、−Ｘ−Ｏ−Ｘ−置換されていてもよいシクロアルキル、−Ｘ−Ｏ−Ｘ−置換されていてもよいアリール、−Ｘ−Ｏ−Ｘ−置換されていてもよいヘテロ環基、又は−Ｘ−Ｏ−低級アルキレン−ＯＲ⁰；
あるいはＲ⁶とＲ⁷が一体となって−Ｏ−低級アルキレン−Ｏ−；
Ｒ⁰は、同一又は互いに異なって、Ｈ又は低級アルキル；
Ｒ¹⁰及びＲ¹¹は、同一又は互いに異なって、Ｈ、低級アルキル、ハロゲノ低級アルキル、−Ｘ−シクロアルキル、−Ｘ−アリール、又は−Ｘ−ヘテロ環基；
あるいはＲ¹⁰及びＲ¹¹がそれらが結合するＮと共に置換されていてもよい飽和ヘテロ環基を形成；
Ｘは、同一又は互いに異なって、結合又は低級アルキレンである。
本明細書中において、上で定義された記号は特に断らない限り同じ意味で用いる。 That is, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and an excipient.

In formula (I):
R ¹ , R ² , and R ³ are the same or different from each other, and H or lower alkyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are the same or different from each other, and H, lower alkyl, halogen, halogeno lower alkyl, nitro, -X-optionally substituted cycloalkyl, -X -Optionally substituted aryl, -X-optionally substituted heterocyclic group,
^{-X-COOR 0, -X-CONR} 10 R 11, -X-CN, -X-OR 0, -X-SR 0, -X-S (O) - lower alkyl, -X-S (O) ₂ - lower ^{alkyl, -X-NR 10 R 11,} -X-NR 0 C (O) R 10, -X-NR 0 C (O) OR 10, -X-NR 0 C (O) NR 10 R 11, —X—NR ⁰ S (O) ₂ R ¹⁰ , —X—O-halogeno lower alkyl, —X—O—X—optionally substituted cycloalkyl, —X—O—X—substituted. Good aryl, —X—O—X—optionally substituted heterocyclic group, or —X—O—lower alkylene-OR ⁰ ;
Alternatively, R ⁶ and R ⁷ are combined to form —O-lower alkylene-O—;
R ⁰ is the same or different from each other, and H or lower alkyl;
R ¹⁰ and R ¹¹ are the same or different from each other and represent H, lower alkyl, halogeno lower alkyl, —X-cycloalkyl, —X-aryl, or —X-heterocyclic group;
Or R ¹⁰ and R ¹¹ form an optionally substituted saturated heterocyclic group with the N to which they are attached;
X is the same or different and is a bond or lower alkylene.
In the present specification, the symbols defined above are used in the same meaning unless otherwise specified.

  The present invention also relates to a pharmaceutical composition for treatment and / or prevention of a disease involving 17βHSDtype5 containing a compound of formula (I) or a salt thereof, ie, involvement of 17βHSDtype5 containing a compound of formula (I) or a salt thereof. The present invention relates to a preventive agent and / or a therapeutic agent for a disease.

  The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating and / or preventing diseases involving 17βHSDtype5.

  The present invention also relates to a method for treating and / or preventing a disease associated with 17βHSD type 5 comprising administering an effective amount of a compound of formula (I) or a salt thereof to a patient.

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

  The present invention also relates to a pharmaceutical composition for preventing or treating a disease associated with 17βHSDtype5, comprising the step of mixing a compound of formula (I) or a salt thereof and a pharmaceutically acceptable carrier, solvent, or excipient. It relates to a method for producing goods.

  The present invention also relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof used for the treatment and / or prevention of a disease involving 17βHSDtype5. It relates to a commercial package containing a statement that it should be obtained or used.

  The compound of formula (I) selectively inhibits 17βHSDtype5. Therefore, the compound of the formula (I) is a prophylactic and / or therapeutic agent for a disease associated with androgen and / or estrogen since inhibition of 17βHSD type5 suppresses androgen and / or estrogen synthesis due to inhibition of 17βHSD type5. Can be used as

Hereinafter, the present invention will be described in detail.
In the definition in the present specification, “alkyl” and “alkylene” mean a linear or branched hydrocarbon chain unless otherwise specified.

“Lower alkyl” means an alkyl having 1 to 6 carbon atoms (hereinafter referred to as C _1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. , N-pentyl, n-hexyl group and the like. Another embodiment is C _1-4 alkyl, and yet another embodiment is methyl, ethyl, n-propyl, isopropyl, tert-butyl.

“Lower alkylene” means C _1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2 , 2-tetramethylethylene group and the like. Another embodiment is C _1-5 alkylene, and yet another embodiment is methylene, ethylene, trimethylene, tetramethylene, pentamethylene.

  “Halogen” means F, Cl, Br, I.

  A “halogeno lower alkyl” is a lower alkyl substituted with one or more halogens. Another embodiment is lower alkyl substituted with 1 to 5 halogens, and yet another embodiment is trifluoromethyl.

“Cycloalkyl” is a C _3-10 saturated hydrocarbon ring group, which may have a bridge. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, adamantyl group and the like. Another embodiment is C _3-8 cycloalkyl, and yet another embodiment is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

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 or naphthyl, and yet another embodiment is phenyl.

A “heterocycle” group is i) a 3-8 membered, alternatively 5-7 membered monocyclic heterocycle containing 1-4 heteroatoms selected from O, S and N, and Ii) The monocyclic heterocycle is condensed with one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, a C _5-8 cycloalkane and a C _5-8 cycloalkene. Means a cyclic group selected from bi to tricyclic heterocycles containing 1 to 5 heteroatoms selected from O, S and N. The ring atom S or N may be oxidized to form an oxide or a dioxide, may have a bridge, or may form a spiro ring.
Examples of `` heterocyclic '' groups include aziridinyl, azetidyl, pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl, pyrrolyl, indolyl, imidazolyl, Pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, quinolyl, quinazolyl, quinoxalinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthazolyl, Indolinyl, tetrahydroquinolinyl, te La tetrahydroisoquinolinyl, quinuclidinyl, dibenzofuranyl, dibenzofuranyl group, and the like. Another embodiment is a 5- to 10-membered monocyclic to bicyclic heterocyclic group. Still another embodiment is pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl, indolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, Tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiadiazolyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dibenzofuranyl.

The “saturated heterocycle” group means a “heterocycle” group in which the bond constituting the ring consists of only a single bond.
Examples of “saturated heterocycle” groups include pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl groups and the like.

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

Substitution in “optionally substituted cycloalkyl”, “optionally substituted aryl” or “optionally substituted heterocyclic group” for R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ As the group, for example, lower alkyl, halogen, halogeno lower alkyl, nitro, -X-CN, -X-OR ⁰ , -X-SR ⁰ , -XS (O) -lower alkyl, -XS (O) ₂ - lower ^{alkyl, -X-NR 10 R 11,} -X-NR 0 C (O) R 10, -X-NR 0 C (O) OR 10, -X-NR 0 C (O) NR 10 R 11 ^{, -X-NR 0 S (O} ) 2 R 10, -X-O- halogeno-lower alkyl, or -X-O-lower alkylene -OR ⁰ and the like, lower alkyl in another embodiment, halogen, halogeno-lower alkyl , -CN, and groups selected include from -OR ^0, and yet another aspect Te methyl, ethyl, F, Cl, trifluoromethyl, and groups selected from methoxy and the like.

  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.

By "17BetaHSDtype5 selective inhibition" and "AKR1C3 selective inhibition", the inhibitory activity of 17βHSDtype3 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.

（２）Ｒ¹がＨである化合物。
（３）Ｒ¹が低級アルキルである化合物。
（４）Ｒ¹がメチルである化合物。
（５）Ｒ²がＨである化合物。
（６）Ｒ²が低級アルキルである化合物。
（７）Ｒ²がメチルである化合物。
（８）Ｒ³がＨである化合物。
（９）Ｒ³が低級アルキルである化合物。
（１０）Ｒ⁴がＨ、低級アルキル、ハロゲン、又は−Ｏ−低級アルキルである化合物。
（１１）Ｒ⁴がＨである化合物。
（１２）Ｒ⁴が低級アルキルである化合物。
（１３）Ｒ⁴がハロゲンである化合物。
（１４）Ｒ⁴が−Ｏ−低級アルキルである化合物。
（１５）Ｒ⁵がＨ、低級アルキル、ハロゲン、又は−Ｏ−低級アルキルである化合物。
（１６）Ｒ⁵がＨである化合物。
（１７）Ｒ⁵が低級アルキルである化合物。
（１８）Ｒ⁵がハロゲンである化合物。
（１９）Ｒ⁵が−Ｏ−低級アルキルである化合物。
（２０）Ｒ⁶がＨ、低級アルキル、ハロゲン、ハロゲノ低級アルキル、ニトロ、シクロアルキル、ＯＨ、又は−Ｏ−低級アルキルである化合物。
（２１）Ｒ⁶が低級アルキル、ハロゲン、又は−Ｏ−低級アルキルである化合物。
（２２）Ｒ⁶がＨである化合物。
（２３）Ｒ⁶が低級アルキルである化合物。
（２４）Ｒ⁶がハロゲンである化合物。
（２５）Ｒ⁶がハロゲノ低級アルキルである化合物。
（２６）Ｒ⁶がニトロである化合物。
（２７）Ｒ⁶がシクロアルキルである化合物。
（２８）Ｒ⁶がＯＨである化合物。
（２９）Ｒ⁶が−Ｏ−低級アルキルである化合物。
（３０）Ｒ⁷がＨ、低級アルキル、ハロゲン、又は−Ｏ−低級アルキルである化合物。
（３１）Ｒ⁷がＨである化合物。
（３２）Ｒ⁷が低級アルキルである化合物。
（３３）Ｒ⁷がハロゲンである化合物。
（３４）Ｒ⁷が−Ｏ−低級アルキルである化合物。
（３５）Ｒ⁸がＨ、低級アルキル、ハロゲン、又は−Ｏ−低級アルキルである化合物。
（３６）Ｒ⁸がＨである化合物。
（３７）Ｒ⁸が低級アルキルである化合物。
（３８）Ｒ⁸がハロゲンである化合物。
（３９）Ｒ⁸が−Ｏ−低級アルキルである化合物。
（４０）上記（１）乃至（３９）に記載の基のうち二以上の組み合わせである化合物。 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 (Ia).

(2) A compound in which R ¹ is H.
(3) The compound wherein R ¹ is lower alkyl.
(4) A compound in which R ¹ is methyl.
(5) A compound wherein R ² is H.
(6) The compound wherein R ² is lower alkyl.
(7) The compound wherein R ² is methyl.
(8) The compound wherein R ³ is H.
(9) The compound wherein R ³ is lower alkyl.
(10) The compound wherein R ⁴ is H, lower alkyl, halogen, or —O-lower alkyl.
(11) The compound wherein R ⁴ is H.
(12) The compound wherein R ⁴ is lower alkyl.
(13) The compound wherein R ⁴ is halogen.
(14) The compound wherein R ⁴ is —O-lower alkyl.
(15) The compound wherein R ⁵ is H, lower alkyl, halogen, or —O-lower alkyl.
(16) The compound wherein R ⁵ is H.
(17) The compound wherein R ⁵ is lower alkyl.
(18) The compound wherein R ⁵ is halogen.
(19) The compound wherein R ⁵ is —O-lower alkyl.
(20) The compound wherein R ⁶ is H, lower alkyl, halogen, halogeno lower alkyl, nitro, cycloalkyl, OH, or —O-lower alkyl.
(21) The compound wherein R ⁶ is lower alkyl, halogen, or —O-lower alkyl.
(22) The compound wherein R ⁶ is H.
(23) The compound wherein R ⁶ is lower alkyl.
(24) The compound wherein R ⁶ is halogen.
(25) The compound wherein R ⁶ is halogeno lower alkyl.
(26) The compound wherein R ⁶ is nitro.
(27) The compound wherein R ⁶ is cycloalkyl.
(28) The compound wherein R ⁶ is OH.
(29) The compound wherein R ⁶ is —O-lower alkyl.
(30) The compound wherein R ⁷ is H, lower alkyl, halogen, or —O-lower alkyl.
(31) The compound wherein R ⁷ is H.
(32) The compound wherein R ⁷ is lower alkyl.
(33) The compound wherein R ⁷ is halogen.
(34) The compound wherein R ⁷ is —O-lower alkyl.
(35) The compound wherein R ⁸ is H, lower alkyl, halogen, or —O-lower alkyl.
(36) The compound wherein R ⁸ is H.
(37) The compound wherein R ⁸ is lower alkyl.
(38) The compound wherein R ⁸ is halogen.
(39) The compound wherein R ⁸ is —O-lower alkyl.
(40) A compound which is a combination of two or more of the groups described in (1) to (39) above.

Specific examples of the compound (40) include the following compounds.
(41) The compound described in (1), wherein R ¹ and R ³ are H.
(42) R ⁴ , R ⁵ , R ⁷ and R ⁸ are the same or different and are H, lower alkyl, halogen, or —O-lower alkyl, and R ⁶ is H, lower alkyl, halogen, halogeno. The compound described in (41), which is lower alkyl, nitro, cycloalkyl, OH, or -O-lower alkyl.
(43) The compound described in (1), wherein R ¹ and R ² are lower alkyl, and R ³ is H.
(44) The compound described in (43), wherein R ⁴ , R ⁵ , R ⁷ , and R ⁸ are the same or different and are H, lower alkyl, halogen, or —O-lower alkyl.
(45) The compound described in (43) or (44), wherein R ⁶ is H, lower alkyl, halogen, halogeno lower alkyl, nitro, cycloalkyl, OH, or —O-lower alkyl.
(46) The compound described in (43) to (45), wherein R ⁶ is lower alkyl, halogen, or —O-lower alkyl.

Another embodiment of the compound of the formula (I) which is an active ingredient of the present invention is shown below.
(47) R ¹ , R ² , R ³ , and R ⁴ are the same or different from each other, H or lower alkyl, R ⁵ is H, lower alkyl, halogen, or —O-lower alkyl, R ⁶ is H, Lower alkyl, halogen, OH, -O-lower alkyl, -O-lower alkylene-phenyl, -O-halogeno lower alkyl, nitro, amino, -amino-C (O) -lower alkyl, or pyrrolyl, R ⁷ is H , Halogen, OH, or —O-lower alkyl, or R ⁶ and R ⁷ combined to form —O-lower alkylene-O—, and R ⁸ is H or halogen.
(48) The compound described in (47), wherein R ¹ is lower alkyl.
(49) The compound described in (48), wherein R ¹ is methyl.
(50) The compound described in (47), wherein R ² is lower alkyl.
(51) The compound described in (50), wherein R ² is methyl.
(52) The compound described in (47), wherein R ³ is H.
(53) The compound described in (47), wherein R ⁴ is H.
(54) The compound described in (47), wherein R ⁵ is H, Cl, or methyl.
(55) The compound described in (47), wherein R ⁶ is H, Cl, methyl, methoxy, or nitro.
(56) The compound described in (47), wherein R ⁷ is H.
(57) The compound described in (47), wherein R ⁸ is H or Cl.
(58) A compound which is a combination of two or more of the groups described in (48) to (57) above.

Specific compounds included in the present invention include the following compounds.
2- {1-[(5-methyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} ethanol,
1- [1- (1H-indol-2-ylcarbonyl) piperidin-4-yl] propan-2-ol,
1- [1- (1H-indol-2-ylcarbonyl) piperidin-4-yl] -2-methylpropan-2-ol,
2-methyl-1- {1-[(4-methyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} propan-2-ol,
2-methyl-1- {1-[(5-methyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} propan-2-ol,
1- {1-[(3,5-dimethyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-tert-butyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(4-fluoro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-fluoro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(4-chloro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-chloro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-bromo-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(7-chloro-5-fluoro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indole-5-ol,
1- {1-[(4-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(6-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
2-methyl-1- (1-{[5- (trifluoromethoxy) -1H-indol-2-yl] carbonyl} piperidin-4-yl) propan-2-ol, and
2-Methyl-1- {1-[(5-nitro-1H-indol-2-yl) carbonyl] piperidin-4-yl} propan-2-ol.

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.

  Furthermore, the present invention includes pharmaceutically acceptable prodrugs of the compound of formula (I). Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to amino groups, hydroxyl groups, carboxyls, etc. 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.

  The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

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

(Production method)
The compound of the formula (I) and salts thereof can be produced by applying various known synthesis methods utilizing 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 replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. 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 (Third Edition), by Greene and Wuts. 1999) ”and the like, and may be appropriately selected and used depending on the reaction conditions. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
In addition, the prodrug of the compound of formula (I) may be further reacted by introducing a specific group at the stage of the raw material or intermediate, or by using the obtained compound of formula (I), in the same manner as the protective group. Can be manufactured. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

  The compound of formula (I) can be obtained by reacting compound (II) with compound (III).

  In the reaction, an equal amount or an excess of compound (II) and compound (III) are used, and in the presence of a condensing agent, in a solvent inert to the reaction, from cooling to heating, preferably from −20 ° C. to 60 ° C. The reaction is usually carried out at 0.1 ° C. by stirring for 0.1 hour to 5 days.

  Examples of the solvent used here are not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, Examples thereof include ethers such as tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile or water, or a mixture thereof.

  Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a hydrochloride thereof, dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, diphenylphosphoric acid azide, and phosphorus oxychloride. It is not limited to these. It may be preferable for the reaction to use an additive (such as 1-hydroxybenzotriazole). The reaction 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 is advantageous for smoothly proceeding the reaction. There are cases.

  Moreover, the method of making it react with compound (III) after converting carboxylic acid compound (II) into a reactive derivative can also be used. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, etc., 1-hydroxy Examples include active esters obtained by condensation with benzotriazole and the like. The reaction of these reactive derivatives with compound (III) is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably −20 It can be carried out at a temperature between 60C and 60C.

The various substituents on the groups R ^{1 to} R ⁸ in the compound of the formula (I) are the reactions described in Reference Examples described below, reactions that are obvious to those skilled in the art, and compounds thereof. By using a modification method, it can be easily converted to another functional group. For example, steps that can be usually employed by those skilled in the art, such as O-alkylation, N-alkylation, reduction, hydrolysis, amidation, etc., can be performed in any combination. An example is shown below.

The compound of formula (I) having an amino group can be obtained by referring to the reduction reaction of a nitro group, for example, the method described in “Chemical Society of Japan, 4th edition, Experimental Chemistry Course (Vol. 26)”, Maruzen, 1992. Can be manufactured.
The compound of formula (I) having an amide group is an acylation reaction of an amino group, for example, edited by Chemical Society of Japan, 4th edition, Experimental Chemistry Course (Vol.22), Maruzen, 1992; "Lecture (Vol. 16)", Maruzen, 2005; or "Compendium of Organic Synthetic Methods", Vols. 1-3.
The compound of the formula (I) having an o-dihydroxyphenyl group can be produced with reference to a cleavage reaction of a 1,3-dioxolane ring, for example, a method described in Journal of Medicinal Chemistry 2001, 44, 1794-1801.
Compounds of formula (I) having a phenyl group substituted with a pyrrolyl group can be prepared with reference to a pyrrole ring formation reaction, for example the method described in Tetrahedron Letters 1993, 34, 1929-1930.

(Manufacture of raw material compounds)
The starting compound (II) can be produced by referring to Fischer's indole synthesis reaction, for example, the method described in “The Fischer Indole Synthesis (1982)” by Robinson. The raw material compound (III) having a tertiary alcohol can be produced by referring to a reaction between a carboxylic acid derivative such as an ester and a Grignard reagent, for example, a method described in Synthesis 1983, 12, 1030-1031.

  The excellent selective inhibitory activity of human 17βHSD type 5 of the compound of the present invention was confirmed by the test methods shown in the following 1 to 3. Detailed test procedures are described in Maniatis, T .; In addition, Molecular Cloning-A Laboratory Manual Cold Spring Harbor Laboratory, NY (1982) can be referred to. 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 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.

  Further, as an in vitro model closer to a living body, the enzyme activity can also be measured using cells expressing human 17βHSD type 5 or the like.

  In addition, 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 A human prostate cancer-derived cell line LNCaP cell was transformed with the plasmid containing the clone selected in step 1 to obtain a stable expression cell line.

Example 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 added and 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 (Perkin Elmer). .
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 a reference example number described later, and Inh represents a testosterone production inhibition rate when 3 mg / kg of a reference example compound described later is administered.

  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, the compound of the formula (I) showed cell growth inhibitory activity in human 17βHSDtype5-expressing LNCaP cells, and showed intratumoral testosterone production inhibitory activity in CWR22R-bearing mice.

  Therefore, the compound of the formula (I) can be used as a preventive and / or therapeutic agent for a disease involving 17βHSDtype5. For example, since inhibition of 17βHSDtype5 suppresses androgen and / or estrogen synthesis, it can be used as a prophylactic and / or therapeutic agent for androgen and / or estrogen-related diseases.

  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. Also included are diseases associated with oxidative stress such as lung cancer.

  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.

  Further, as apparent from the above test results, the compound of formula (I) has a very weak human 17βHSD type 3 inhibitory activity, and thus has a selective inhibitory effect on 17βHSD type 5 without affecting the testosterone biosynthesis derived from human 17β HSD type 3 in the testis. Thus, it can be expected to selectively suppress the intracrine testosterone synthesis in the prostate. That is, 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. Can be used for

  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, or 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.

  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 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.

  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.

In addition, the following abbreviations are used in Production Examples, Reference Examples, and Tables below.
Ex: Reference example number, REx: Production example number, No: Compound number, mp: Melting point, 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) ⁺ , CI: CI-MS (M + H) ⁺ , NMR-DMSOd6: δ (ppm) of peak in ¹ H NMR in DMSO-d ₆ ), Str: Structural formula, Syn (REx): Production example produced by the same method No., Syn (Ex): Reference Example No. produced in the same manner, DME: Dimethoxyethane, DMF: N, N-dimethylformamide, DMSO: Dimethyl sulfoxide, THF: Tetrahydrofuran, 4M HCl / EtOAc: 4 mol / l hydrogen chloride Ethyl acetate solution, MeCN: acetonitrile, MeOH: methanol, tBuOH: tert-butyl alcohol, RT: retention time in HPLC (min).

Production Example 1
To a solution of 5 g of ethyl piperidin-4-yl acetate in 50 ml of dioxane and 50 ml of water was added 3 g of sodium bicarbonate at 0 ° C., and then 4.6 ml of benzyl chloroformate was added dropwise and stirred at room temperature for 3 days. . The reaction mixture was concentrated to half volume under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.9 g of benzyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carbosylate as a colorless oil. Got as.

Production Example 2
Benzyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carbosylate To a solution of 8.9 g of THF in 100 ml of THF was added 46 ml of a 1.4 M methylmagnesium bromide in toluene-THF at 0 ° C., and then at room temperature for 3 hours. Stir. To the reaction solution was added 1 M aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give benzyl 4- (2-hydroxy-2-methylpropyl) piperidine. 8.5 g of -1-carboxylate was obtained as a colorless oil.

Production Example 3
To a solution of 8.5 g of benzyl 4- (2-hydroxy-2-methylpropyl) piperidine-1-carboxylate in 120 ml of methanol was added 500 mg of 10% palladium carbon, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. The insoluble material was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 5.6 g of 2-methyl-1- (piperidin-4-yl) -2-propanol as a white solid.

Production Example 4
To a solution of ethyl 7-chloro-5-fluoro-1H-indole-2-carboxylate (250 mg) in methanol (2 ml) was added 1 M aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 210 mg of 7-chloro-5-fluoro-1H-indole-2-carboxylic acid as a white solid.

Production Example 5
To a solution of tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate 250 mg in THF 5 ml was added 1.4 M methylmagnesium bromide toluene-THF solution 1.2 ml, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] to obtain 236 mg of tert-butyl 4- (2-hydroxypropyl) piperidine-1-carboxylate as a colorless oil. .
The structural formula, production method and physicochemical data of each production example compound are shown in the table.

Reference example 1
To a solution of 370 mg 5-chloroindole-2-carboxylic acid and 300 mg 2-methyl-1- (piperidin-4-yl) -2-propanol in 8 ml DMF, add 1-ethyl-3- (dimethylaminopropyl) carbodiimide. Hydrochloride 360 mg and 1-hydroxybenzotriazole 250 mg were added, and the mixture was stirred at room temperature for 1 day. To the reaction solution was added 0.5 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and crystallized from diisopropyl ether to give 1- {1-[(5-chloro-1H-indol-2-yl) Carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 268 mg was obtained as white crystals.

Reference Example 24
1-ethyl-3- (dimethylaminopropyl) carbodiimide was added to a solution of 1800 mg of 5-methylindole-2-carboxylic acid and 1500 mg of 2-methyl-1- (piperidin-4-yl) -2-propanol in 25 ml of DMF. Hydrochloride 2100 mg and 1-hydroxybenzotriazole 1500 mg were added, and the mixture was stirred at room temperature for 1 day. To the reaction solution was added 0.5 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and crystallized from a mixture of ethyl acetate / diisopropyl ether to give 2-methyl-1- {1-[(5-methyl -1H-Indol-2-yl) carbonyl] piperidin-4-yl} propan-2-ol 2140 mg was obtained as white crystals.

Reference Example 25
1-ethyl-3- (dimethylaminopropyl) carbodiimide was added to a solution of 478 mg of 5-methoxyindole-2-carboxylic acid and 432 mg of 2-methyl-1- (piperidin-4-yl) -2-propanol in 8 ml of DMF. Hydrochloride 575 mg and 1-hydroxybenzotriazole 169 mg were added, and the mixture was stirred at room temperature for 1 day. 0.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.2 M aqueous sodium hydroxide and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-24: 1], crystallized from a mixture of ethyl acetate / diisopropyl ether, and 1- {1-[(5-methoxy-1H-indole -2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 683 mg was obtained as white crystals.

Reference Example 26
5H- [1,3] Dioxolo [4,5-f] indole-6-carboxylic acid 150 mg in dichloromethane 3 ml is added at 0 ° C with 1 M boron tribromide dichloromethane 1.5 ml at room temperature. Stir for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. In a solution of the obtained white solid in DMF 3 ml, 2-methyl-1- (piperidin-4-yl) -2-propanol 140 mg, 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride 150 mg and 1-Hydroxybenzotriazole (105 mg) was added, and the mixture was stirred at room temperature for 1 day. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and solidified with ethyl acetate-hexane to give 2-{[4- (2-hydroxy-2-methylpropyl). ) Piperidin-1-yl] carbonyl} -1H-indole-5,6-diol 42 mg was obtained as a white solid.

Reference Example 27
2-Methyl-1- {1-[(5-nitro-1H-indol-2-yl) carbonyl] piperidin-4-yl} propan-2-ol 838 mg in a solution of 15 ml of methanol in 10% palladium on carbon 80 mg was added, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and solidified with hexane-ethyl acetate to give 1- {1-[(5-amino-1H-indole- 576 mg of 2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol was obtained as a light brown solid.

Reference Example 28
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 105 mg in dioxane 2 ml and THF 2 ml Acetic acid 32 μl was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1], solidified with ethyl acetate-hexane, and N- (2-{[4- (2-hydroxy-2 110 mg of -methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) acetamide were obtained as a white solid.

Reference Example 29
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 127 mg of methanol in 3 ml of 2,5-dimethoxy Tetrahydrofuran (90 μl) and acetic acid (1 ml) were added, and the mixture was stirred at 60 ° C. for 1 day. To the reaction solution was added 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and then solidified from ethyl acetate-hexane to give 2-methyl-1- (1-{[5- (1H- 30 mg of pyrrol-1-yl) -1H-indol-2-yl] carbonyl} piperidin-4-yl) propan-2-ol were obtained as a white solid.

Reference Example 30
To a solution of 233 mg of tert-butyl 4- (2-hydroxypropyl) piperidine-1-carboxylate in 4 ml of ethyl acetate was added 3 ml of 4 M HCl / EtOAc, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 4- (2-hydroxypropyl) piperidine hydrochloride. To this 4- (2-hydroxypropyl) piperidine hydrochloride and indole-2-carboxylic acid 155 mg in DMF 5 ml solution, triethylamine 0.15 ml, 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride 190 mg and 1 -130 mg of hydroxybenzotriazole was added and stirred at room temperature for 1 day. To the reaction solution was added 0.5 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform: methanol = 1: 0-10: 1] and solidified with diisopropyl ether to give 1- [1- (1H-indol-2-ylcarbonyl) piperidine- 49 mg of 4-yl] propan-2-ol was obtained as a white solid.

Reference Example 31
Add 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride 610 mg and 1-hydroxybenzotriazole 430 mg to a DMF 8 ml solution of indole-2-carboxylic acid 500 mg and piperidin-3-ylethyl acetate 530 mg. The mixture was further stirred at room temperature for 2 hours. 0.5 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [1- (1H-indol-2-ylcarbonyl) piperidin-3-yl] 519 mg of ethyl acetate was obtained. 30 mg of lithium borohydride was added to a solution of 392 mg of ethyl [1- (1H-indol-2-ylcarbonyl) piperidin-3-yl] acetate in 7 ml of THF, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane: ethyl acetate = 1: 0-2: 1] and crystallized from diisopropyl ether to give 2- [1- (1H-indol-2-ylcarbonyl) 92 mg of piperidin-3-yl] ethanol was obtained as a white solid.

Reference Example 32
To a solution of 4-piperidineethanol 4.1 mg, 5-fluoro-1H-indole-2-carboxylic acid 5.3 mg, and 1-hydroxybenzotriazole 4.0 mg in DMF 0.6 ml at room temperature, PS-carbodiimide (PS-Carbodiimide: Argonaute) (Technology) 100 mg was added and stirred overnight. To the reaction solution, 50 mg of MP-Carbonate (MP-Carbonate: Argonaute Technology) and 50 mg of PS-isocyanate (PS-Isocyanate: Argonaute Technology) were added at room temperature and stirred for 2 hours, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain 8.8 mg of 2- {1-[(5-fluoro-1H-indol-2-yl) carbonyl] piperidin-4-yl} ethanol.

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)

移動相：Ａsol ５ｍＭトリフルオロ酢酸水溶液、Ｂsol メタノール
流速：１．２ｍｌ／ｍｉｎ
検出波長：２５４ｎｍ
カラム温度：３５．０℃
注入量：５μｌ

Mobile phase: Asol 5 mM trifluoroacetic acid aqueous solution, Bsol Methanol flow rate: 1.2 ml / min
Detection wavelength: 254 nm
Column temperature: 35.0 ° C
Injection volume: 5 μl

  In the same manner as in the above Reference Example, compounds up to Reference Example 48 shown in the table below were produced. The production methods and structures of the respective Reference Example compounds are shown in Tables 5, 6, 9, and 10, and the physicochemical data are shown in Tables 7, 8, and 11, respectively.

Table 12 shows the structure of another compound of the present invention. These can be easily synthesized by using the methods described in the above production methods and reference examples, methods obvious to those skilled in the art, or variations thereof.

  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 thereon, the pharmaceutical composition of the present invention is suitable for diseases involving 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 (2)

N- (2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) acetamide or a salt thereof, and a pharmaceutically acceptable agent A pharmaceutical composition comprising a dosage form. 2. The pharmaceutical composition according to claim 1, which is a pharmaceutical composition for treating prostate cancer.