JP2012102017A - Indole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound for a pharmaceutical composition, useful for example as a therapeutic agent of diseases associated with 17βHSD type 5.SOLUTION: As a result of eager investigation of a compound useful as a therapeutic agent of diseases associated with 17βHSD type 5, it is found that an indole compound having a substituted carbamoyl group at 2-position has a strong inhibitory action on the 17βHSD type 5, and is able to be a therapeutic and/or preventive agent for diseases such as prostatic hypertrophy and prostate cancer associated with the 17βHSD type 5 without accompanied by side effects caused by testosterone reduction.

Description

  The present invention relates to an indole compound useful as an active ingredient of a pharmaceutical composition such as a pharmaceutical composition for treating prostatic hypertrophy or prostate cancer.

Benign prostatic hyperplasia (BPH) is a disease accompanied by dysuria that occurs mainly in elderly men over 50 years of age, and its incidence 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 a medically important disease because it significantly lowers the quality of life of elderly men due to its dysuria and is the most frequently diagnosed and treated in urological practice.
Two causes of dysuria associated with BPH are direct urethral compression (mechanical occlusion) due to enlarged prostate and increased urethral pressure (functional occlusion) due to excessive contraction of prostate smooth muscle via sympathetic nerves. 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 α1 blocker alone (The New England Journal of Medicine, 2003, 349, 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 and its precursor testosterone in the prostate are synthesized from the adrenal steroid dehydroepiandrosterone (DHEA) in prostate cells (Frontier in Neuroendocrinology). , 2001, 22, 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 in this prostate region (intracrine testosterone synthesis). 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 increased fourfold. There have been reports of an increase (The Journal of Urology, 1999, 161, 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 testosterone concentration in the prostate region is 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 received the above-described antiandrogen therapy, the blood testosterone concentration decreased to about 10% before the treatment, whereas the DHT concentration in the prostate remained about half (The Journal of Clinical Endocrinology and Metabolism, 1995, 80, 1066-1071). This suggests that the testosterone concentration in the prostate is not sufficiently reduced. Also in prostate cancer that relapsed after antiandrogen therapy (Hormone Refractory Prostate Cancer), the androgen receptor is localized in the nucleus, and there is a significant difference between testosterone levels in relapsed prostate cancer tissues and testosterone levels in normal prostate Was not seen (Clinical Cancer Research, 2004, 10, 440-448). These reports indicate that the existing treatments are completely inadequate in reducing prostate testosterone concentration in the treatment of relapsed prostate cancer. 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 blood testosterone concentration, (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 that can avoid side effects due to suppression of testosterone-derived blood testosterone concentration.

  In the biosynthesis of testosterone, 17β-hydroxysteroid dehydrogenase (17βHSD) is essential. Although 17βHSD has several subtypes, 17βHSD type 5 (17βHSD type 5) is highly expressed in human prostate, and increased expression in prostate cancer and relapsed prostate cancer has also been reported (Steroids, 2004). 69, 795-801; Cancer Research, 2006, 66, 2815-2825). On the other hand, almost all testosterone in the blood is produced in the testis by 17βHSD type 3 (17βHSD type 3), and 17βHSD type 3 is hardly expressed in other tissues including the prostate (Nature Genetics, 1994). , 7, 34-39). Therefore, 17βHSD type 5 is thought to be responsible for prostate intracrine testosterone synthesis, and it is expected that 17βHSD type 5 selective inhibitors will selectively suppress prostate intracrine testosterone synthesis. In addition, the contribution of 17βHSD type 5 has been pointed out in estrogen-dependent tissues such as the mammary gland and is expected to be effective in estrogen-dependent diseases such as breast cancer (Endocrine Reviews, 2003, 24, 152-182). In addition, AKR1C3 (also known as 17βHSD type 5), a subtype of aldo-keto reductase (AKR), metabolizes Polycyclic Aromatic Hydrocarbon (PAH) to produce reactive oxygen species (ROS) (The Journal of Biological Chemistry , 2002, 277 (27), 24799-24808), single nucleotide polymorphism (SNP) of AKR1C3 gene associated with oxidative stress correlates with lung cancer risk (Carcinogenesis, 2004, 25 (11), 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 17βHSD type 5 is expected to be effective against lung cancer.

  Examples of 17βHSD type 5 inhibitors include steroid derivatives (Patent Document 1), NSAIDs (Non-steroidal Anti-Inflammatory Drugs) such as flufenamic acid and indomethacin (Non-Patent Document 1), and cinnamic acid derivatives (Non-Patent Document 2). It has been reported.

International Publication WO99 / 046279 Pamphlet

Cancer Research, 2004, 64, 1802-1810 Molecular and Cellular Endocrinology, 2006, 248, 233-235

    An object of the present invention is to provide a compound useful as a therapeutic agent for a disease involving a pharmaceutical composition such as 17βHSD type 5.

（式中、
R¹は、OH、OR⁰又はハロゲン；
R²、R³、R⁴及びR⁵は、同一又は互いに異なって、H又はR⁰；或いは、R²とR³又はR⁴とR⁵が一体となってC_2-5アルキレンを形成してもよく；或いは、R¹とR²が一体となってオキソ；
R⁶及びR⁷は、同一又は互いに異なって、H又はR⁰、或いは、R⁶とR⁷が一体となってR⁰⁰；
R⁸、R⁹、R¹⁰、R¹¹、及びR¹²は、同一又は互いに異なって、H、R⁰、ハロゲン、ハロゲノ低級アルキル、OH、O-R⁰、SH、S-R⁰、SO-R⁰、SO₂-R⁰、O-ハロゲノ低級アルキル、O-シクロアルキル、O-へテロシクロアルキル、O-アリール、O-ヘテロアリール、O-R⁰⁰-OH、O-R⁰⁰-O-R⁰、O-R⁰⁰-シクロアルキル、O-R⁰⁰-ヘテロシクロアルキル、O-R⁰⁰-アリール、O-R⁰⁰-ヘテロアリール、O-R⁰⁰-(置換されていてもよいアミノ)、O-R⁰⁰-CO₂H、O-R⁰⁰-CO₂R⁰、O-R⁰⁰-CO-(置換されていてもよいアミノ)、CO₂H、CO₂R⁰、CO-(置換されていてもよいアミノ)、R⁰⁰-OH、R⁰⁰-O-R⁰、R⁰⁰-(置換されていてもよいアミノ)、R⁰⁰-CO-(置換されていてもよいアミノ)、R⁰⁰-シクロアルキル、R⁰⁰-へテロシクロアルキル、シクロアルキル、へテロシクロアルキル、アリール、ヘテロアリール、ニトロ、置換されていてもよいアミノ、NO₂、
ここに、R⁸、R⁹、R¹⁰、R¹¹、及びR¹²におけるシクロアルキル、へテロシクロアルキル、アリール、ヘテロアリールは、それぞれ、低級アルキル、OH、O-R⁰及びハロゲンから選択される基で置換されていてもよく；
あるいは、R⁹とR¹⁰、又は、R¹⁰とR¹¹が一体となって-O-R⁰⁰-O-；
R⁰は、同一又は互いに異なって、低級アルキル；
R⁰⁰は、同一又は互いに異なって、低級アルキレン；
Xは、N又はCH；
Yは、メチレン、O又は単結合を示し；
nは、１又は２をそれぞれ示す。）
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。 As a result of intensive studies on compounds useful as therapeutic agents for diseases involving 17βHSD type 5, the present inventors have found that indole compounds having a substituted carbamoyl group at the 2-position have potent 17βHSD type 5 inhibitory activity, and The present invention was completed by discovering that it can be 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.
That is, the present invention 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, and an excipient.

(Where
R ¹ is OH, OR ⁰ or halogen;
R ² , R ³ , R ⁴ and R ⁵ are the same or different from each other, and H or R ⁰ ; or R ² and R ³ or R ⁴ and R ⁵ together form C _2-5 alkylene. Or R ¹ and R ² together may be oxo;
R ⁶ and R ⁷ are the same or different from each other, and H or R ⁰ , or R ⁶ and R ⁷ together are R ⁰⁰ ;
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are the same or different from each other, and H, R ⁰ , halogen, halogeno lower alkyl, OH, OR ⁰ , SH, SR ⁰ , SO-R ⁰ , SO ₂ -R ⁰ , O-halogeno lower alkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, OR ⁰⁰ -OH, OR ⁰⁰ -OR ⁰ , OR ⁰⁰ -cycloalkyl, OR ⁰⁰ -heterocycloalkyl, OR ⁰⁰ -aryl, OR ⁰⁰ -heteroaryl, OR ^00- (optionally substituted amino), OR ⁰⁰ -CO ₂ H, OR ⁰⁰ -CO ₂ R ⁰ , OR ⁰⁰ -CO- (Optionally substituted amino), CO ₂ H, CO ₂ R ⁰ , CO- (optionally substituted amino), R ⁰⁰ -OH, R ⁰⁰ -OR ⁰ , R ^00- (substituted also an amino), R ⁰⁰ -CO- (amino optionally substituted), R ⁰⁰ - cycloalkyl, R ⁰⁰ - heterocycloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, nitro, substituted Or unprotected amino, NO _2,
Here, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl in R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are groups selected from lower alkyl, OH, OR ^0, and halogen, respectively. May be substituted;
Alternatively, R ⁹ and R ¹⁰ , or R ¹⁰ and R ¹¹ are combined to form -OR ⁰⁰ -O-;
R ⁰ is the same or different and is lower alkyl;
R ⁰⁰ is the same or different from each other, lower alkylene;
X is N or CH;
Y represents methylene, O or a single bond;
n represents 1 or 2, respectively. )
Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol indicates the same meaning.

The present invention also relates to a pharmaceutical composition for treating and / or preventing a disease involving 17βHSD type 5 comprising a compound of formula (I) or a salt thereof. This pharmaceutical composition includes a prophylactic or therapeutic agent for a disease involving 17βHSD type 5 comprising a compound of formula (I) or a salt thereof.
The present invention also relates to the use of a compound of formula (I) or a salt thereof for producing a pharmaceutical composition for treating and / or preventing a disease involving 17βHSD type 5. Furthermore, the present invention also relates to a compound of formula (I) or a salt thereof used for treating and / or preventing diseases involving 17βHSD type 5.
The present invention also relates to a method for treating and / or preventing a disease involving 17βHSD type 5, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject. The “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.

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 the prevention or treatment of a disease associated with 17βHSD type 5, which comprises 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 of producing a pharmaceutical composition.
The present invention also provides a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and a compound of formula (I) or a salt thereof for treating and / or preventing diseases involving 17βHSD type 5. It relates to a commercial package that contains a statement that it can or should be used.

  The compound of the formula (I) has 17βHSD type 5 inhibitory activity and can be used as an active ingredient of a pharmaceutical composition for prevention and / or treatment of a disease involving 17βHSD type 5. For example, it can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating diseases related to androgens.

Hereinafter, the present invention will be described in detail.
In the present specification, “alkyl” and “alkylene” mean a linear or branched hydrocarbon chain unless otherwise specified.
“Lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Another embodiment is C _1-4 alkyl, yet another embodiment is C _1-3 alkyl, and yet another embodiment is methyl.
“Lower alkylene” means linear or branched C _1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethyl. Ethylene, 1,1,2,2-tetramethylethylene and the like. In another embodiment, it is C _1-4 alkylene. In still another embodiment, methylene and ethylene are used. In still another embodiment, methylene is used.

“Halogen” means F, Cl, Br, I.
“Halogeno lower alkyl” is C _1-6 alkyl substituted with one or more halogens. In another embodiment, it is a lower alkyl substituted with 1 to 5 halogens, and in another embodiment, it is a C _1-3 alkyl substituted with 1 to 5 F, In an embodiment, it 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, adamantyl and the like. Another embodiment is C _3-8 cycloalkyl, yet another embodiment is C _3-6 cycloalkyl, and still another embodiment is cyclopropyl, 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, 1-tetrahydronaphthyl, 5-tetrahydronaphthyl, 1-indanyl, 4-indenyl, 1-fluorenyl and the like. In another embodiment, phenyl, naphthyl, tetrahydronaphthyl, and indanyl are used. In another embodiment, phenyl is used.

Examples of the “heterocycle” include the following embodiments.
(1) Monocyclic saturated heterocyclic ring (a) One containing 1 to 4 nitrogen atoms, for example, azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl and the like;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like;
(C) those containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl;
(D) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such as oxathiolanyl;
(E) those containing 1 to 2 oxygen atoms, such as oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl and the like;

(2) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, Triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like;
(C) those containing 1 to 2 sulfur atoms, such as thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl and the like;
(D) one containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, specifically, dihydrooxathiopyranyl and the like;
(E) those containing 1 to 2 oxygen atoms, such as furyl, pyranyl, oxepinyl, dioxolyl and the like;

(3) condensed polycyclic saturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, such as quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl ;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like;
(C) those containing 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as 2,6-dioxabicyclo [3.2.2] oct-7-yl;

(4) condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, tetrahydroindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzoimidazolyl, tetrahydolobenzoimidazolyl Quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, benzopyrazolyl, tetrahydrobenzopyrazolyl, pyrrolopyridyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxali Nyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, etc .;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, furopyrrolyl, thienopyrrolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzooxadiazolyl, benzoisothiazolyl, benzoisoxazolyl, etc .;
(C) those containing 1 to 3 sulfur atoms, such as benzothienyl, benzodithiopyranyl, dibenzo [b, d] thienyl, etc .;
(D) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, for example, benzooxathiopyranyl, phenoxazinyl and the like;
(E) those containing 1 to 3 oxygen atoms, such as benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, dibenzo [b, d] furanyl, methylenedioxyphenyl, Ethylenedioxyphenyl and the like;
Such.

The “nitrogen-containing heterocycle” means that (1) (a), (1) (b), (2) (a), (2) (b), (3 ) A material containing at least one nitrogen atom, such as (a), (3) (b), (4) (a) and (4) (b).
“Heteroaryl” is a heterocyclic group having aromaticity among (2) and (4) of the above “heterocycle”. In one embodiment, the bond is attached to a carbon atom constituting the ring. Means a group having For example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl etc. monocyclic heteroaryl, indolyl, isoindolyl, benzoimidyl , Indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothienyl, 3,4-dihydro-2H-1 Bicyclic heteroaryl such as 1,4-benzoxazinyl, tricyclic heteroaryl such as carbazolyl, dibenzo [b, d] furanyl, dibenzo [b, d] thienyl In another embodiment, it is pyridyl, pyrrolyl, pyrazolyl, thienyl, furyl, indolyl, 3,4-dihydro-2H-1,4-benzoxazinyl.
“Heterocycloalkyl” is a heterocyclic group in which the bond between ring atoms consists of only a single bond, as in (1) and (3) of the above “heterocycle”. The group which has a bond in the carbon atom which comprises is meant. For example, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, and in another embodiment, oxetanyl, tetrahydrofuryl, tetrahydropyranyl.

The “optionally substituted amino” means NH ₂ or an amino group substituted with one or two arbitrary groups, and “heteroaryl” having a bond on a nitrogen atom constituting the ring And “heterocycloalkyl”. Examples of the substituent in the “amino group substituted with one or two arbitrary groups” include R ⁰ , halogeno lower alkyl, R ⁰⁰ —OH, R ⁰⁰ —OR ⁰ , CO—R ⁰ , CO— Halogeno lower alkyl, CO-R ⁰⁰ -OH, CO-R ⁰⁰ -OR ⁰ , CO-cycloalkyl, CO-heterocycloalkyl, CO-aryl, CO-heteroaryl, SO ₂ -R ⁰ and SO _2- ( R ⁰ , halogeno lower alkyl or aryl optionally substituted with OR ⁰ ). Further, as an embodiment of “heteroaryl” and “heterocycloalkyl” having a bond at a nitrogen atom constituting the ring, 1-azepanyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-pyrazolidinyl, 1-piperazinyl , 4-thiomorpholinyl, 3-oxazolidinyl, morpholino, 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 2-isoindolyl, 1-tetrahydroindolyl, 1-indolinyl, 1-benzimidazolyl, 1,2,3,4-tetrahydro 1-quinolyl, 1,2,3,4-tetrahydro-2-isoquinolyl, and in another embodiment, 1-pyrrolidinyl, piperidino, morpholino.

One embodiment of “17βHSD type 5 inhibition” is “17βHSD type 5 selective inhibition”. “Selective inhibition of 17βHSD type 5” means that the inhibitory activity against 17βHSD type 5 is stronger than the inhibitory activity against 17βHSD type 3, and in one embodiment, the IC ₅₀ value is 3 times or more, preferably 10 times or more. More preferably, it means that there is a difference of 100 times or more.
In the present specification, “optionally substituted” means unsubstituted or substituted with 1 to 5 identical or different substituents. When there are a plurality of substituents, these substituents may be the same or different from each other.

Certain embodiments of the present invention are shown below.
(1) As ^one embodiment of R ¹ , OH, OC _1-3 alkyl, F or Cl is used. In another embodiment, OH or OC _1-3 alkyl is used. In another embodiment, OH is used. is there.
(2) As an aspect of R ² and R ³ , they are the same or different from each other, and are H or R ⁰ , as another aspect, H or C _1-3 alkyl, and as another aspect, C _1-3 alkyl, and in yet another embodiment, is methyl or ethyl. As another embodiment of R ² , an oxo group is formed together with R ¹ , and R ³ is methyl or ethyl. Still another embodiment of R ² and R ³ is C _2-5 alkylene as a whole.
(3) As an aspect of R ⁴ and R ⁵ , they are the same or different from each other, and are H or R ⁰ , as another aspect, H, methyl or ethyl, and as another aspect, H .
(4) The aspect of the R ⁶ and R ^7, R ⁶ and R ⁷ is C _1-4 alkylene together, In another embodiment, it is methylene, in a further embodiment be ethylene Yet another embodiment is trimethylene.
(5) As an aspect with R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , H, R ⁰ , halogen, OR ⁰ , O-cycloalkyl, O-heterocycloalkyl, OR ⁰⁰ -OH, OR ⁰⁰ -OR ⁰ , OR ⁰⁰ -cycloalkyl, OR ⁰⁰ -heterocycloalkyl, OR ⁰⁰ -aryl, OR ⁰⁰ -heteroaryl, OR ⁰⁰ -CO ₂ H, OR ⁰⁰ -CO- (optionally substituted amino ), CO ₂ H, CO ₂ R ⁰ , CO- (optionally substituted amino), R ⁰⁰ -OH, R ⁰⁰ -OR ⁰ , R ^00- (optionally substituted amino), R ^00- Heterocycloalkyl, aryl, nitro, optionally substituted amino.
Here, as an aspect of “optionally substituted amino”, (i) NH ₂ , (ii) 1 or 2 R ⁰ , halogeno lower alkyl, R ⁰⁰ -OH, R ⁰⁰ -OR ⁰ , CO-R ⁰ , CO-halogeno lower alkyl, CO-R ⁰⁰ -OH, CO-R ⁰⁰ -OR ⁰ , CO-cycloalkyl, CO-heterocycloalkyl, CO-aryl, CO-heteroaryl, SO _2- Amino substituted with a group selected from R ⁰ and SO ₂ — (R ⁰ , aryl optionally substituted with halogeno lower alkyl or OR ⁰ ), and (iii) 1-azepanyl, 1-azetidinyl, 1- Pyrrolidinyl, piperidino, 1-pyrazolidinyl, 1-piperazinyl, 4-thiomorpholinyl, 3-oxazolidinyl, morpholino, 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 2-isoindolyl, 1-tetrahydroindolyl, 1-indolinyl, 1-indolinyl Benzimidazolyl, 1,2,3,4-tetrahydro-1-quino Le, 1,2,3,4-tetrahydro a 2-isoquinolyl, and in another _{embodiment, (iv) NH 2, (} v) 1 or 2 C _1-3 alkyl, halogeno C _1-3 alkyl C _1-3 alkylene-OH, C _1-3 alkylene-OC _1-3 alkyl, CO-C _1-3 alkyl, CO-halogeno C _1-3 alkyl, CO-C _1-3 alkylene-OH, CO- C _1-3 alkylene-OC _1-3 alkyl, CO-cycloalkyl, CO-heterocycloalkyl, CO-aryl, CO-heteroaryl, SO ₂ -C _1-3 alkyl and SO _2- (C _1-3 Alkyl substituted with a group selected from alkyl, halogeno C _1-3 alkyl or aryl optionally substituted with OC _1-3 alkyl), and (vi) 1-pyrrolidinyl, piperidino, morpholino.
(6) One embodiment of X is N, and another embodiment is CH.
(7) One embodiment of Y is O, another embodiment is a single bond, and yet another embodiment is methylene.
(8) One embodiment of n is 1, and another embodiment is 2.

As an aspect with the compound of the formula (I) of this invention, it is a compound which consists of 1 or more combinations of the aspect of the group as described in said (1)-(8), Specifically, for example, the following combinations are Can be mentioned.
(9) A compound wherein X is CH, R ¹ is OH, OC _1-3 alkyl, F or Cl, and R ⁴ and R ⁵ are H, methyl or ethyl.
(10) The compound wherein X is CH, R ¹ is OH or Cl, and R ⁴ and R ⁵ are H, methyl or ethyl.
(11) A compound wherein X is CH, R ¹ is OH or Cl, and R ⁴ and R ⁵ are H.

(12) The compound according to any one of (9) to (11), wherein R ² and R ³ are H or R ⁰ .
(13) The compound according to any one of (9) to (11), wherein R ² and R ³ are combined to form C _2-5 alkylene.
(14) The compound according to any one of (9) to (11), wherein R ² and R ³ are R ⁰ .
(15) The compound according to any one of (9) to (14), wherein n is 2.
(16) The compound according to any one of (9) to (14), wherein Y is a single bond and n is 2.
(17) The compound according to (9) to (14), wherein Y is methylene or O, and n is 1.
(18) The compound according to any one of (9) to (17), wherein R ⁶ and R ⁷ are combined to form C _1-4 alkylene.
(19) The compound according to any one of (9) to (17), wherein R ⁶ and R ⁷ are methylene together.
(20) The compound according to any one of (9) to (17), wherein R ⁶ and R ⁷ are united with ethylene.
(21) The compound according to any one of (9) to (17), wherein R ⁶ and R ⁷ are trimethylene together.
(22) The compound according to any one of (9) to (21), wherein one or both of R ⁸ and R ¹² is H.

Examples of specific compounds included in the present invention include the following compounds.
2- [1- (1H-indol-2-ylcarbonyl) azetidin-3-yl] ethanol,
2-{[4- (2-chloro-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indole,
1- (1-{[5- (cyclopropylmethoxy) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methylpropan-2-ol,
2-[(2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) oxy] acetamide,
5-chloro-N- (5-hydroxy-5-methylhexyl) -N-methyl-1H-indole-2-carboxamide,
3-({1-[(5-chloro-1H-indol-2-yl) carbonyl] piperidin-4-yl} methyl) pentan-3-ol,
1-({1-[(5-chloro-1H-indol-2-yl) carbonyl] azetidin-3-yl} oxy) -2-methylpropan-2-ol,
2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -N, N-dimethyl-1H-indole-5-carboxamide,
1- (1-{[5- (methoxymethyl) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methylpropan-2-ol,
1- {1-[(6-fluoro-5-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(6-chloro-5-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
4- {1-[(5-chloro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylbutan-2-ol,
1- {1-[(4-bromo-5-methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- {1-[(5-isopropoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol,
1- (1-{[5- (cyclopentyloxy) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methylpropan-2-ol, and
1- (1-{[5- (2-methoxyethoxy) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methylpropan-2-ol.

Some of the compounds of formula (I) may exist as tautomers and geometric isomers 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. And mixtures thereof.
Some of the compounds of formula (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on these may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, this invention also includes the pharmaceutically acceptable prodrug of the compound shown by a formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, 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. Is 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, dibenzoyltartaric acid, ditoluoyltartaric 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 or amino acid derivatives such as acetylleucine and ammonium salts Etc.

  Furthermore, the present invention also includes 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 a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure 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 an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There are cases. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected depending on the reaction conditions. In such a method, a desired compound can be produced by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
Moreover, the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate, or reacts further using the obtained compound of the formula (I) in the same manner as the protecting group. Can be manufactured. The reaction can be carried out by applying a method known to 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.

本発明化合物（Ｉ）は、化合物（１）と化合物（２）との反応により得ることができる。
この反応では、化合物（１）と化合物（２）とを等量若しくは一方を過剰量用い、これらの混合物を、縮合剤の存在下、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃〜60℃において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、酢酸エチル、アセトニトリル又は水、及びこれらの混合物が挙げられる。縮合剤の例としては、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド、ジシクロヘキシルカルボジイミド、1,1'-カルボニルジイミダゾール、ジフェニルリン酸アジド、オキシ塩化リンが挙げられるが、これらに限定されるものではない。添加剤（例えば1-ヒドロキシベンゾトリアゾール）を用いることが反応に好ましい場合がある。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下で反応を行うことが、反応を円滑に進行させる上で有利な場合がある。
また、カルボン酸（１）を反応性誘導体へ変換した後にアミン（２）と反応させる方法も用いることができる。カルボン酸の反応性誘導体の例としては、オキシ塩化リン、塩化チオニル等のハロゲン化剤と反応して得られる酸ハロゲン化物、クロロギ酸イソブチル等と反応して得られる混合酸無水物、1-ヒドロキシベンゾトリアゾール等と縮合して得られる活性エステル等が挙げられる。これらの反応性誘導体と化合物（２）との反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類等の反応に不活性な溶媒中、冷却下〜加熱下、好ましくは、-20℃〜60℃で行うことができる。 (First manufacturing method)

The compound (I) of the present invention can be obtained by reacting the compound (1) with the compound (2).
In this reaction, the compound (1) and the compound (2) are used in an equal amount or in an excess amount, and these mixtures are preferably used in the presence of a condensing agent in a solvent inert to the reaction from cooling to heating. Is usually stirred at -20 ° C to 60 ° C for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, but aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, tetrahydrofuran , Ethers such as dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile or water, and mixtures thereof. Examples of condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, diphenyl phosphate azide, and phosphorus oxychloride. Is not to be done. It may be preferred for the reaction to use an additive (eg 1-hydroxybenzotriazole). Performing 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 can facilitate the reaction. May be advantageous.
Moreover, the method of making it react with amine (2) after converting carboxylic acid (1) 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, 1-hydroxy Examples include active esters obtained by condensation with benzotriazole and the like. The reaction of these reactive derivatives with the compound (2) 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.

R¹がOHである本発明化合物（Ｉ-a）は、対応するエステル化合物（３）より得ることができる。即ち、エステル化合物（３）を還元することによりR²及びR³がHである化合物が、エステル化合物（３）をGrignard反応に付すことによりR²及びR³が低級アルキルである化合物が製造できる。
この反応では、化合物（３）に対し還元剤又はGrignard試薬を等量若しくは過剰量用い、反応に不活性な溶媒中、冷却下から加熱下、好ましくは-20℃〜室温下において、通常0.1時間〜5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、及びこれらの混合物が挙げられる。還元剤の例としては、水素化ホウ素リチウム、水素化アルミニウムナトリウム、水素化アルミニウムリチウム、水素化リチウム トリ-tert-ブトキシアルミニウム、水素化ジイソブチルアルミニウムが挙げられるが、これらに限定されるものではない。またGrignard試薬の例としては、メチルマグネシウムブロミド、エチルマグネシウムブロミド、プロピルマグネシウムブロミド等が挙げられ、例えばSynthesis 1983, 12, 1030-1031に記載の方法が適用できる。 (Second manufacturing method)

The compound (Ia) of the present invention in which R ¹ is OH can be obtained from the corresponding ester compound (3). That is, a compound in which R ² and R ³ are H can be produced by reducing the ester compound (3), and a compound in which R ² and R ³ are lower alkyl can be produced by subjecting the ester compound (3) to a Grignard reaction. .
In this reaction, the reducing agent or Grignard reagent is used in an equivalent amount or excess amount relative to compound (3), and in a solvent inert to the reaction, from cooling to heating, preferably from -20 ° C to room temperature, usually 0.1 hour Stir for ~ 5 days. Examples of the solvent used here are not particularly limited, but include aromatic hydrocarbons, halogenated hydrocarbons, ethers, and mixtures thereof. Examples of the reducing agent include, but are not limited to, lithium borohydride, sodium aluminum hydride, lithium aluminum hydride, lithium tri-tert-butoxyaluminum hydride, and diisobutylaluminum hydride. Examples of Grignard reagents include methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide and the like. For example, the method described in Synthesis 1983, 12, 1030-1031 can be applied.

(Other manufacturing methods)
Various compounds of the present invention (I) can be produced as appropriate using the compounds of the present invention (I) as raw materials using amidation, oxidation, reduction, hydrolysis, alkylation, condensation reaction, substitution reaction, etc., which are usually performed by those skilled in the art. can do.
For example, a compound in which R ¹ is OH is treated with thionyl chloride or phosphorus oxychloride to treat a compound in which R ¹ is Cl with diethylaminosulfur trifluoride, bis (2-methoxyethyl) aminosulfur trifluoride, etc. Thus, a compound in which R ¹ is F can be obtained. A compound in which R ¹ is OR ⁰ can be produced by subjecting a compound in which R ¹ is OH to an O-alkylation reaction.

原料化合物（３）は、原料化合物（４）及び（１）の反応により製造できる。反応条件は前記第1製法に準じて行うことができる。 (Raw material synthesis)
The starting compound (1) can be produced by referring to the Fischer indole synthesis reaction, for example, the method described in “The Fischer Indole Synthesis (1982)” by Robinson.

The raw material compound (3) can be produced by the reaction of the raw material compounds (4) and (1). The reaction conditions can be performed according to the first production method.

また、XがCH、Yがメチレンである原料化合物（３-a）は、対応するオレフィン化合物（５）を、水素雰囲気下、パラジウム炭素等を触媒とする接触還元反応に付すことにより製造できる。

The starting compound (3-a) in which X is CH and Y is methylene can be produced by subjecting the corresponding olefin compound (5) to a catalytic reduction reaction using palladium carbon or the like as a catalyst in a hydrogen atmosphere.

（式中、P¹はアミノ基の保護基を示す。）
原料化合物（４）、（２a）及び（２b）は、それぞれ対応する原料化合物の脱保護により得ることができる。原料化合物（７b）は、化合物（６）の還元又はGrignard反応により得られる化合物（７a）のクロロ化により製造できる。

(In the formula, P ¹ represents an amino-protecting group.)
Raw material compounds (4), (2a) and (2b) can be obtained by deprotection of the corresponding raw material compounds. The starting compound (7b) can be produced by reduction of the compound (6) or chlorination of the compound (7a) obtained by Grignard reaction.

XがCH、Yがメチレンである原料化合物は、オレフィン化合物（８）の接触還元により得られる化合物（６a）を、前記と同様に処理することで種々の化合物が得られる。

The raw material compound in which X is CH and Y is methylene can be obtained by treating the compound (6a) obtained by catalytic reduction of the olefin compound (8) in the same manner as described above.

XがCH、YがOである化合物は、アルコール化合物（９）を、エポキシ化合物（１０）と反応させることで得ることができる。塩基又はルイス酸の存在下に反応を行うのが有利な場合がある。

A compound in which X is CH and Y is O can be obtained by reacting an alcohol compound (9) with an epoxy compound (10). It may be advantageous to carry out the reaction in the presence of a base or a Lewis acid.

The compounds of formula (I) are isolated and purified as free compounds, their salts, hydrates, solvates or polymorphic substances. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

Test Example The human 17βHSD type 5 inhibitory activity and 17βHSD type 3 inhibitory activity of the compounds of the present invention were confirmed by the test methods shown below. For detailed test procedures, Maniatis, T. et al., Molecular Cloning-A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1982) and the like can be referred to. Further, the genes encoding human 17βHSD type 5 and type 3 and 17βHSD type 5 and type 3 described in 1 and 2 below can also be obtained by the method described in Molecular Endocrinology 1997, 11 (13), 1971-1984. it can.

1. Isolation and enzyme purification of the gene encoding human 17βHSD type 5 The full-length cDNA encoding human 17βHSD type 5 used in the pharmacological tests of the present invention is obtained by PCR using the cDNA derived from A549 cells of the human lung cancer-derived cell line as a template. did. 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 a GSTrapFF column (Amersham) and PreScissionProtease (Amersham). The purification method followed the instructions attached to the GSTrapFF column.

2. Isolation and Enzyme Purification of Gene Encoding Human 17βHSD Type 3 Full-length cDNA encoding human 17βHSD type 3 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 a 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 them, and the cells were collected after 24 hours. Next, the collected cells are disrupted in a phosphate buffer containing 5% glycerol (500 μl of phosphate buffer containing 5% glycerol (pH 7.4, 200 mM) per 100 mm-dish) and centrifuged. After (16000 rpm, 5 min, 4 ° C.), the supernatant was used as an enzyme source.

3. Measurement of enzyme activity of human 17βHSD type 5 and type 3 The enzyme activity was measured with reference to Trevor M. Penning et al., Biochem. J., 2000, 351, 67-77. Specifically, using 100 mM potassium phosphate buffer (pH 6.0), (1) the enzyme purified in 1 above in an amount that the final concentration is 10 μg / ml, (2) the final concentration is 300 nM. The amount of androstenedione, (3) NADPH with a final concentration of 200 μM, and (4) the test substance were mixed and reacted at room temperature for 2 hours, and then the amount of testosterone produced was determined as DELFIA® Testosterone Reagents R050 -201 (Perkin Elmer) was used for measurement. 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 the logistic regression method.
Table 1 shows IC ₅₀ values of human 17βHSD type 5 inhibitory activity of some of the compounds of the present invention. Ex represents an example compound number described later.

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

4). Production of human 17βHSD type 5 expressing LNCaP cells Human prostate cancer-derived LNCaP cells were transformed with the plasmid containing the clone selected in 1 above to obtain a stable expression cell line

5. Measurement of cell growth ability using human 17βHSD type 5 expressing LNCaP cells The transformed cells obtained in 4 above were seeded at a density of 5000 cells / well in a 96-well plate and cultured overnight. Androstenedione was added to a concentration of 5 nM and cultured for 5 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 by 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 no test compound was added as 100%. IC ₅₀ values were then calculated by the logistic regression method.

As is clear from the above test results, it was confirmed that the compound of formula (I) has human 17βHSD type 5 inhibitory activity.
Therefore, the compound of the formula (I) can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating a disease involving 17βHSD type 5. For example, since inhibition of 17βHSD type 5 suppresses androgen synthesis and estrogen synthesis, it can be used as an active ingredient in a pharmaceutical composition for preventing and / or treating diseases involving androgens and estrogens.

  17βHSD type 5 related diseases, ie, androgen or estrogen related diseases include prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, baldness, alopecia, precociousness, adrenal hypertrophy And polycystic ovary syndrome, breast cancer, endometriosis, leiomyoma and the like. Another embodiment is prostate cancer, and another embodiment is prostatic hypertrophy. Yet another embodiment is a disease related to oxidative stress such as lung cancer. For example, since it is thought that 17βHSD type 5 is responsible for the intracrine androgen synthesis of the prostate, it is useful for the prevention and / or treatment of prostate cancer and prostatic hypertrophy, which are diseases involving androgen, particularly in the prostate.

  In addition, a compound having a weak human 17βHSD type 3 inhibitory activity which is an embodiment of the present invention does not affect testosterone biosynthesis derived from human 17βHSD type 3 in the testis, and has an inhibitory effect on the prostate due to a 17βHSD type 5 selective inhibitory action. It can be expected to selectively suppress testosterone synthesis. 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

A pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, etc. Can be prepared by a commonly used method.
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 a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, 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. Non-aqueous solvents include alcohols such as ethanol. 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.

  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 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 appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once a day or divided into multiple times. In addition, 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 agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The pharmaceutical preparation containing various therapeutic or prophylactic agents for the diseases for which the compound of the above formula (I) is considered to be effective and the compound of the formula (I), even if the coadministration preparation is formulated separately It may be a composition.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. The production methods of the raw material compounds are shown in Production Examples, and the production of known compounds is shown in Reference Examples. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below. The compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

In the examples and production examples, the following abbreviations may be used.
Ex: Example number, Pre: Production number, No: Compound number, mp: Melting point (° C.), Dat: Physicochemical data (FAB +: FAB-MS (M + H) ⁺ , FAB-: FAB-MS ( MH) ^- , ESI +: ESI-MS (M + H) ⁺ , ESI-: ESI-MS (MH) ^- , APCI +: APCI-MS (M + H) ⁺ , APCI / ESI +: APCI / ESI-MS (M + H) ⁺ , APCI / ESI-: APCI / ESI-MS (MH) ⁻ , EI: EI-MS (M) ⁺ , CI +: CI-MS (M + H) ⁺ , NMR: in DMSO-d ₆ ¹ H NMR peak δ (ppm), RT: HPLC retention time (min)), Str: Structural formula, Syn: Production example or example number prepared in the same manner, DMF: N, N-dimethyl Formamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, 4 M HCl / EtOAc: 4 mol / L hydrogen chloride in ethyl acetate, MeOH: methanol, EtOH: ethanol, Me: methyl, Et: ethyl, iPr: 2-propyl, cPr : Cyclopropyl, tBu: tert-butyl, cBu: cyclobutyl, cPen: cyclopentyl, Ac: acetyl, Bn: benzyl, Boc: tert-butoxy Carbonyl.
Condition column of HPLC performed to determine RT: Wakosil-II 5C18AR (registered trademark) (particle size: 5 μm inner diameter: 2.0 mm length: 30 mm); flow rate: 1.2 ml / min; detection wavelength: 254 nm; column Temperature: 35.0 ° C; Injection volume: 5 μl
Mobile phase A liquid: 5 mM trifluoroacetic acid aqueous solution; B liquid: methanol

Production Example 1
A solution of tert-butyl 3- (2-ethoxy-2-oxoethylidene) azetidine-1-carboxylate (237 mg) and trifluoroacetic acid (0.1 ml) in chloroform (4 ml) was stirred at room temperature for 1 hour. 4 ml HCl / EtOAc 2 ml was added to the mixture, and the mixture was stirred at the same temperature for 2 hours, and then the mixture was concentrated under reduced pressure. Add 180 mg of indole-2-carboxylic acid, 0.41 ml of triethylamine, 230 mg of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride, and 160 mg of 1-hydroxybenzotriazole at 0 ° C to a 5 ml solution of the residue in DMF. The mixture was stirred at room temperature for 2 hours. 0.5 M hydrochloric acid and ethyl acetate were added to the mixture and the phases were separated. The organic layer was washed with 1 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ethyl [1- (1H-indol-2-ylcarbonyl) azetidin-3-ylidene]. 96 mg of acetate was obtained as a colorless oil.
Production Example 2
To a solution of 2-fluoro-4-methylpyridine (2 g) in THF (30 ml), 1.6 M n-butyllithium in hexane (16 ml) was added dropwise at -78 ° C., and the mixture was stirred at the same temperature for 1 hour. After adding 2.5 ml of acetone to the mixture, the mixture was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the mixture, and the mixture was warmed to room temperature and separated. 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 1.45 g of 1- (2-fluoropyridin-4-yl) -2-methylpropan-2-ol was colorless oil Obtained as a thing.

Production Example 3
To a solution of 5.07 g of benzyl 4- (2-oxoethyl) piperidine-1-carboxylate in 100 ml of THF was added dropwise a 20 ml solution of 1.4 M methylmagnesium bromide in toluene / THF (75/25) at 0 ° C. After the mixture was stirred for 1 hour, a saturated aqueous ammonium chloride solution and ethyl acetate were added for liquid separation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and benzyl 4- (2-hydroxypropyl) piperidine-1-carboxylate. 5.38 g was obtained as a colorless oil.
Production Example 4
To a solution of 4.7 ml of DMSO in 40 ml of dichloromethane, 3 ml of oxalyl chloride was added dropwise at -60 ° C or lower. The mixture was stirred at the same temperature for 20 minutes, and then a solution of 4.63 g of benzyl 4- (2-hydroxypropyl) piperidine-1-carboxylate in 30 ml of dichloromethane was added dropwise to the mixture over 40 minutes. The mixture was further stirred at the same temperature for 10 minutes, and 9 ml of triethylamine was added dropwise to the mixture over 20 minutes. The temperature of the reaction solution was raised to −30 ° C. over 20 minutes, and then a saturated aqueous ammonium chloride solution was added to the mixture, followed by liquid separation. The aqueous layer was extracted with chloroform, and the organic layers were combined, 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 (hexane: ethyl acetate = 10: 1-1: 1) to obtain 1.82 g of benzyl 4- (2-oxopropyl) piperidine-1-carboxylate as a colorless oil.

Production Example 5
Ethyl 5-hydroxy-1H-indole-2-carboxylate 400 mg, tributylphosphine 0.72 ml, cyclopropylmethanol 0.31 ml and THF 10 ml in a mixture of 1,1'-azobis (N, N-dimethylformamide) 504 mg And stirred at room temperature for 3 hours. To the mixture, 0.72 ml of tributylphosphine, 0.31 ml of cyclopropylmethanol and 504 mg of 1,1′-azobis (N, N-dimethylformamide) were added, and the mixture was further stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-80: 20) to obtain 149 mg of ethyl 5- (cyclopropylmethoxy) -1H-indole-2-carboxylate as a white solid. .
Production Example 6
To a mixture of ethyl 5-hydroxy-1H-indole-2-carboxylate 400 mg, cyclopentylmethanol 390 mg, triphenylphosphine 1.02 g and THF 10 ml, add 1.77 ml of diethyl azodicarboxylate at 0 ° C and overnight at room temperature. Stir. At 0 ° C., 390 mg of cyclopentylmethanol, 1.02 g of triphenylphosphine and 1.77 ml of diethyl azodicarboxylate were added to the mixture, and the mixture was further stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-80: 20), and the eluate was concentrated. The residue was washed with hexane and collected by filtration to obtain 260 mg of ethyl 5- (cyclopentylmethoxy) -1H-indole-2-carboxylate as a white solid.

Production Example 7
To a mixture of 11.62 g of benzylmethyl carbamate and 50 ml of DMF, 55% sodium hydride was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 5-bromopentanoate was added, and the mixture was stirred at room temperature for 2 hours and at 70 ° C. for 2 hours. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-50: 50) to obtain 5.88 g of ethyl 5-{[(benzyloxy) carbonyl] (methyl) amino} pentanoate as a colorless oil. It was.
Production Example 8
To a mixture of 5.88 g of ethyl 5-{[(benzyloxy) carbonyl] (methyl) amino} pentanoate and 50 ml of THF, a solution of 3M methylmagnesium chloride in 16.7 ml of THF was added dropwise at 0 ° C. After the mixture was stirred at room temperature for 3 hours, water, 50 ml of 1 M hydrochloric acid, and ethyl acetate were added to the mixture and the phases were separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-0: 100) to obtain 2.91 g of a colorless oil.
To a mixture of 2.91 g of colorless oil and 20 ml of MeOH was added 481 mg of 54% water-containing 10% palladium on carbon, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure. The residue was dissolved in 50 ml of dioxane, 10 ml of 4 M HCl / dioxane solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. Toluene was added to the reaction solution, and the solvent was concentrated under reduced pressure to obtain 1.89 g of 2-methyl-6- (methylamino) -2-hexanol hydrochloride as a colorless oil.

Production Example 9
To a mixture of 4.43 g of tert-butyl 4- (2-ethoxy-2-oxoethylidene) azepane-1-carboxylate and 30 ml of MeOH, add 370 mg of 54% water-containing 10% palladium on carbon, and at room temperature under a hydrogen atmosphere overnight. Stir. The reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure to give 3.62 g of tert-butyl 4- (2-ethoxy-2-oxoethyl) azepan-1-carboxylate as a colorless oil.
Production Example 10
To a mixture of 1.75 g of tert-butyl 4- (2-hydroxy-2-methylpropyl) azepane-1-carboxylate and 20 ml of dioxane, 16.13 ml of 4 M HCl / dioxane solution was added dropwise and stirred at room temperature overnight. Toluene was added to the reaction solution, and the solvent was concentrated under reduced pressure. The residue was washed with ethyl acetate and collected by filtration to obtain 1.07 g of 4- (2-chloro-2-methylpropyl) azepan hydrochloride as a white solid.

Production Example 11
A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate 300 mg, 2,2-dimethyloxirane 0.78 ml, powdered potassium hydroxide 117 mg, and DMSO 1.5 ml was stirred at 30 ° C. for 24 hours, then the mixture Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 10-5: 5) to obtain 282 mg of tert-butyl 3- (2-hydroxy-2-methylpropoxy) azetidine-1-carboxylate. Obtained as a white solid.
Production Example 12
To a mixture of 2.00 g of benzyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylate and 10 ml of THF was added 5.24 ml of 3 M ethylmagnesium bromide in THF at 0 ° C. and stirred at room temperature for 3 hours. did. To the mixture was added 2.62 ml of 3 M ethylmagnesium bromide in THF, and the mixture was further stirred at room temperature for 1 hour. At 0 ° C., 23.6 ml of 1M hydrochloric acid and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-65: 35), and 1.21 g of benzyl 4- (2-ethyl-2-hydroxybutyl) piperidine-1-carboxylate was obtained as a yellow oil. Got as.

Production Example 13
To a mixture of 2.00 g of benzyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylate, 0.387 ml of tetraisopropyl orthotitanate and 30 ml of diethyl ether, 6.55 ml of a THF solution of 3 M ethylmagnesium bromide is slowly added dropwise. And stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C., 32.8 ml of 1 M hydrochloric acid and ethyl acetate were added, and a liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-50: 50), and 550 mg of benzyl 4-[(1-hydroxycyclopropyl) methyl] piperidine-1-carboxylate was obtained as a colorless oil Got as.
Production Example 14
1-tert-butyl 2-ethyl 5-hydroxy-1H-indole-1,2-dicarboxylate 100 mg, (3R) -tetrahydrofuran-3-ol 57.7 mg and (tributylphosphoranylidene) acetonitrile 158 mg toluene 1 The ml solution was stirred at 60 ° C. overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 10-3: 7) to give 1-tert-butyl 2-ethyl 5-[(3S) -tetrahydrofuran-3-yloxy] -1H- 112 mg of indole-1,2-dicarboxylate was obtained as a colorless oil.

Production Example 15
1-tert-butyl 2-ethyl 5-[(3S) -tetrahydrofuran-3-yloxy] -1H-indole-1,2-dicarboxylate 111 mg, EtOH 1 ml, and 1 M aqueous sodium hydroxide solution 1.5 ml The mixture was stirred at room temperature for 2 days. The mixture was concentrated, acidified with 1 M hydrochloric acid, and extracted with a mixed solvent of methanol-chloroform (1: 9). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 60 mg of a solid. The solid was dissolved in a mixture of dioxane and 4 M HCl / dioxane solution (1: 1) and left overnight at room temperature. After the mixture was concentrated and dried, the residue was pulverized with a mixed solvent of chloroform-hexane to give 45 mg of 5-[(3S) -tetrahydrofuran-3-yloxy] -1H-indole-2-carboxylic acid as a brown powder. Obtained.
Production Example 16
To a mixture of 1.00 g of 2- (ethoxycarbonyl) -1H-indole-5-carboxylic acid and 40 ml of THF, 16.2 ml of 1.06 M borane in THF was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. To the reaction solution, 30 ml of 1 M hydrochloric acid and ethyl acetate were added, and a liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (10% methanol / chloroform) = 100: 0-60: 40). The residue was washed with ethyl acetate and collected by filtration to give 500 mg of ethyl 5- (hydroxymethyl) -1H-indole-2-carboxylate as a white solid.

Production Example 17
To a mixture of 224 mg of 1- (1-{[5- (hydroxymethyl) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methyl-2-propanol and 30 ml of dichloromethane, 589 mg was added and stirred at room temperature overnight. The reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure to give 2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indole-5-carbaldehyde 179 mg Was obtained as a white solid.

Production Example 18
A mixture of ethyl 5-hydroxy-1H-indole-2-carboxylate 300 mg, cesium fluoride 444 mg, 2,2,2-trifluoroethyl trifluoromethanesulfonate 0.288 ml and DMF 3 ml was stirred at 50 ° C overnight. did. 50 ml of water was added to the mixture, and the precipitate was collected by filtration, washed with water, and dried to give a brown solid. The solid was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 10-4: 6) to give ethyl 5- (2,2,2-trifluoroethoxy) -1H-indole-2-carboxylate 228 mg Was obtained as a white solid.

Production Example 19
To a mixture of ethyl 6-fluoro-5-methoxy-1H-indole-2-carboxylate (1.34 g), MeOH (16 ml) and THF (8 ml) was added 1 M aqueous sodium hydroxide solution (8 ml), and the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture is allowed to cool and concentrated. To the residue is added 30 ml of water and 8 ml of 1 M hydrochloric acid, and the solid is collected by filtration, washed with water and EtOH, and washed with 6-fluoro-5-methoxy-1H-indole-2. -1.09 g of carboxylic acid was obtained as a beige solid.
Production Example 20
1-tert-butyl 2-ethyl 5-bromo-1H-indole-1,2-dicarboxylate 1.00 g, cyclopropylboronic acid 303 mg, tricyclohexylphosphine 152 mg, tripotassium phosphate 2.02 g, toluene 20 ml and To a mixture of 2 ml of water, 61 mg of palladium acetate was added, and the mixture was stirred at 100 ° C. for 3 hours under an argon atmosphere. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-70: 30) to give 1-tert-butyl 2-ethyl 5-cyclopropyl-1H-indole-1,2-dicarboxylate 816 mg was obtained as a yellow oil.

Production Example 21
To a mixture of 816 mg of 1-tert-butyl 2-ethyl 5-cyclopropyl-1H-indole-1,2-dicarboxylate and 20 ml of dichloromethane, 2.00 ml of trifluoroacetic acid was added and stirred at room temperature for 30 minutes. Toluene was added to the reaction solution, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-80: 20) to obtain 513 mg of ethyl 5-cyclopropyl-1H-indole-2-carboxylate as a yellow solid.
Production Example 22
1.24 g of potassium carbonate and 0.64 ml of bromocyclopentane were added to a solution of 616 mg of ethyl 5-hydroxy-1H-indole-2-carboxylate in 10 ml of DMF, and the mixture was stirred at 80 ° C. for 16 hours. Ethyl acetate and 0.5 M aqueous sodium hydroxide solution were added to the mixture for liquid separation. 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 (hexane: ethyl acetate = 10: 0-4: 1) to obtain 622 mg of ethyl 5- (cyclopentyloxy) -1H-indole-2-carboxylic acid as a beige solid. .

Production Example 23
2-methyl-1- {1-[(5-nitro-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-propanol 838 mg in methanol 15 ml solution, 10% palladium on carbon 80 mg And stirred at room temperature for 1 day under 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-2 There was obtained 576 mg of -yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol as a light brown solid.
Production Example 24
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. 0.2 M 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 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: 0-24: 1] and crystallized from a mixture of ethyl acetate / diisopropyl ether to give 1- {1-[(5-methoxy-1H-indole -2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 683 mg was obtained as white crystals.

Production Example 25
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 26
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 27
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 28
To a mixture of 2.07 g of ethyl 6-hydroxy-1H-indole-2-carboxylate, 3.3 g of di-tert-butyl dicarbonate, and 20.7 ml of dioxane, 2.1 ml of triethylamine was added at room temperature. The mixture was stirred at room temperature overnight, water and 1 M hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a pale yellow solid. The solid was triturated with 100 ml of hexane to give 2.83 g of 1-tert-butyl 2-ethyl 6-hydroxy-1H-indole-1,2-dicarboxylate as a white powder.

Production Example 29
1-tert-butyl 2-ethyl 6- (cyclopropylmethoxy) -1H-indole-1,2-dicarboxylate 143 mg, EtOH 2 ml, and 1 M aqueous sodium hydroxide solution 2 ml Stir. The mixture was concentrated and acidified with 1 M hydrochloric acid, saturated aqueous sodium sulfate solution was added, and the mixture was extracted with a mixed solvent of methanol / chloroform (1: 9). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was pulverized from chloroform / hexane, purified by silica gel column chromatography (chloroform: methanol = 1: 0-9: 1), pulverized from a mixed solvent of ethyl acetate / diisopropyl ether, and 6- (cyclo Propylmethoxy) -1H-indole-2-carboxylic acid (78.5 mg) was obtained as a white powder.
In the same manner as in the above production examples, the production example compounds shown in the table below were produced. The structure, physicochemical data, and production methods of the production example compounds are shown in the table below.

Example 1
To a solution of 94 mg of ethyl [1- (1H-indol-2-ylcarbonyl) azetidin-3-ylidene] acetate in 2 ml of THF was added 20 mg of lithium borohydride, and the mixture was stirred at room temperature for 1 day. Water and ethyl acetate were added to the mixture and the phases were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 2 ml of methanol, 10 mg of 50% water-containing 10% palladium on carbon was added, and the mixture was stirred in a hydrogen atmosphere for 1 day. 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 the resulting solid was washed with diisopropyl ether to give 2- [1- (1H-indol-2-ylcarbonyl). ) Azetidin-3-yl] ethanol 25 mg was obtained as a white powder.
Example 2
Ethyl 2- [1- (1H-indol-2-ylcarbonyl) piperidin-4-yl] -2-methylpropanate Add 250 mg of lithium borohydride to a solution of 250 mg in THF and stir at room temperature for 1 day did. Water and ethyl acetate were added to the mixture and the phases were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, 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), solidified with diisopropyl ether, and 2- [1- (1H-indol-2-ylcarbonyl) piperidine-4- Ir] -2-methylpropan-1-ol 32 mg was obtained as a white powder.

Example 3
100 mg of platinum oxide was added to a mixture of 1.45 g of 1- (2-fluoropyridin-4-yl) -2-methylpropan-2-ol, 14 ml of EtOH, and 14 ml of 1 M hydrochloric acid. The mixture was stirred at room temperature for 1 day under a hydrogen atmosphere of 3.1 atm, the insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. To a solution of the residue in 8 ml of DMF, 300 mg of 1H-indole-2-carboxylic acid, 0.3 ml of triethylamine, 360 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride, and 1-hydroxybenzo 250 mg of triazole was added. The mixture was stirred at room temperature for 1 day, and 0.5 M hydrochloric acid and ethyl acetate were added to the mixture for liquid separation. The organic layer was washed with 1 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 then solidified with diisopropyl ether to give 2-{[4- (2-chloro-2-methylpropyl) piperidine-1 74 mg of -yl] carbonyl} -1H-indole were obtained as a white powder.
Example 4
To a solution of 300 mg of benzyl 4- (2-oxopropyl) piperidine-1-carboxylate in 5 ml of MeOH, 30 mg of 10% palladium carbon containing 50% water was added. The mixture was stirred at room temperature for 1 day under a hydrogen atmosphere, and the insoluble material was filtered off using celite. After adding 1 M hydrochloric acid to the filtrate, the mixture was concentrated under reduced pressure. 1H-indole-2-carboxylic acid 190 mg, triethylamine 0.16 ml, N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride 230 mg, and 1-hydroxybenzotriazole 160 mg was added and stirred at room temperature for 1 day. About 0.5 M hydrochloric acid and ethyl acetate were added to the reaction mixture for liquid separation, and the organic layer was washed with about 0.5 M sodium hydroxide and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (chloroform: methanol = 1: 0-10: 1), solidified with diisopropyl ether, and 1- [1- (1H -Indol-2-ylcarbonyl) piperidin-4-yl] acetone 147 mg was obtained as a white powder.

Example 5
[(2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) oxy] ethyl acetate 481 mg, MeOH 20 ml 0.9 ml of 4 M lithium hydroxide aqueous solution was added and stirred at room temperature for 5 hours. Water and chloroform were added to the reaction liquid, and liquid separation operation was performed. To the aqueous layer, 1 M hydrochloric acid was added until the pH reached 1, followed by liquid separation with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate and [(2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) oxy] acetic acid (300 mg) was white. Obtained as a powder.
Example 6
1- {1-[(5-Methoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol 150 mg and dichloromethane 3 ml Under atmosphere, bis (2-methoxyethyl) aminosulfur trifluoride was added dropwise and stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution cooled with ice water, and water and ethyl acetate were added to carry out a liquid separation operation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (10% methanol / chloroform) = 100: 0-70: 30), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 70 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration to obtain 114 mg of 2-{[4- (2-fluoro-2-methylpropyl) piperidin-1-yl] carbonyl} -5-methoxy-1H-indole as a white powder. It was.

Example 7
To a solution of tert-butyl 3- (2-hydroxy-2-methylpropoxy) azetidine-1-carboxylate 282 mg in dioxane 1.4 ml was added 4 M HCl / dioxane solution at 0 ° C. The mixture was stirred at room temperature overnight, then concentrated and dried under reduced pressure overnight to obtain 198 mg of a colorless solid. N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride 176 mg, 1-hydroxybenzotriazole 124 mg, and DMF solution of solid 198 mg and 5-chloroindole-2-carboxylic acid 150 mg, and Triethylamine 0.15 ml was added and stirred at room temperature for 1 day. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 50: 50-100: 0) and powdered from a mixed solvent of chloroform and hexane to give 1-({1-[(5-chloro-1H- 112 mg of indol-2-yl) carbonyl] azetidin-3-yl} oxy) -2-methylpropan-2-ol were obtained as a white solid.
Example 8
To a mixture of 350 mg of ethyl 5- (hydroxymethyl) -1H-indole-2-carboxylate and 15 ml of MeOH, 4.79 ml of 1 M aqueous sodium hydroxide solution was added and stirred at 60 ° C. for 3 hours. To the reaction solution, 4.79 ml of 1 M hydrochloric acid was added, concentrated under reduced pressure, and dried to obtain 305 mg of a white solid.
To a solution of white solid 305 mg and 2-methyl-1-piperidin-4-yl-2-propanol 276 mg in DMF 25 ml, 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride 459 mg, 1-hydroxybenzo 324 mg of triazole and 1.11 ml of triethylamine were added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (10% methanol / chloroform) = 100: 0-30: 70), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 80 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration, and 1- (1-{[5- (hydroxymethyl) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methyl-2-propanol 330 mg was obtained as a white powder.

Example 9
Triethylamine 0.374 ml and 2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indole-5- in a mixture of 109 mg of dimethylamine hydrochloride and 5 ml of dichloromethane Carbaldehyde 88 mg was sequentially added, and the mixture was stirred at room temperature for 1 hour. Next, 170 mg of sodium triacetoxyborohydride was added to the mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution, water, and chloroform were added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform: (10% methanol / chloroform) = 100: 0-80: 20), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 70 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration and 1- [1-({5-[(dimethylamino) methyl] -1H-indol-2-yl} carbonyl) piperidin-4-yl] -2-methyl-2 -68 mg of propanol was obtained as a white powder.
Example 10
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol 150 mg, triethylamine 0.199 ml, dichloromethane 3 ml, and THF 3 ml To the mixed solution, 0.064 ml of 2,2-dimethylpropanoyl chloride was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water, chloroform, and a small amount of methanol were added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (25% methanol / chloroform) = 100: 0-80: 20), and the eluate was concentrated. The residue was suspended in ethyl acetate at 70 ° C., and a small amount of hexane was added dropwise. After cooling to room temperature, the solid was collected by filtration, and N- (2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) -2, 137 mg of 2-dimethylpropanamide was obtained as a white powder.

Example 11
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol 120 mg, triethylamine 0.159 ml, and THF 3 ml , 0.032 ml of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. Water and chloroform were added to the reaction solution to separate it. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (25% methanol / chloroform) = 100: 0-80: 20), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 70 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration, and N- (2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) methanesulfonamide 83 mg was obtained as a yellow powder.
Example 12
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol 120 mg, triethylamine 0.159 ml, and THF 3 ml , 0.086 ml of trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. Water and chloroform were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (25% methanol / chloroform) = 100: 0-80: 20), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 70 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration and 2,2,2-trifluoro-N- (2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H- 99 mg of indol-5-yl) acetamide were obtained as a white powder.

Example 13
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methyl-2-propanol 100 mg, propionic acid 0.028 ml, DMF 3 ml 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride 91 mg and 1-hydroxybenzotriazole 64 mg were added, and the mixture was stirred at room temperature for 8 hours. Water and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: (25% methanol / chloroform) = 100: 0-70: 30), and the eluate was concentrated. The residue was dissolved in ethyl acetate at 70 ° C., and hexane was slowly added dropwise until cloudy. After cooling to room temperature, the solid was collected by filtration and N- (2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) propanamide 44 mg was obtained as a white powder.
Example 14
Methyl 3- {1-[(5-chloro-1H-indol-2-yl) carbonyl] piperidin-4-yl} propanate 254 mg of THF in 4 ml of THF and 0.93 M of methylmagnesium bromide in 3.92 ml of 0 After adding in 2 portions at 0 ° C., the mixture was stirred at room temperature for 2 hours. After 4 ml of 1 M hydrochloric acid was added at 0 ° C., the mixture was partitioned by adding 15 ml of ethyl acetate and 15 ml of water. The organic layer was washed with 10 ml of 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: 0-96: 4), powdered from 6 ml of hexane-ethyl acetate (1: 2), and 4- {1-[(5-chloro -1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylbutan-2-ol 103 mg was obtained as a beige powder.

Example 15
To a solution of 178 mg 5-isopropoxy-1H-indole-2-carboxylic acid and 140 mg 2-methyl-3-piperidin-4-yl-2-propanol in 5 ml DMF, add 1-ethyl-3- (dimethylaminopropyl). ) Carbodiimide hydrochloride 187 mg, 1-hydroxybenzotriazole 55 mg, and triethylamine 0.034 ml were added, and the mixture was stirred at room temperature for 20 hours. Liquid separation operation was performed by adding 0.2 M hydrochloric acid and ethyl acetate to the mixed solution. The organic layer was washed with 0.2 M aqueous sodium hydroxide solution and 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: 0-96: 4), powdered from 8 ml of hexane-ethyl acetate (5: 3), and 1- {1-[(5-iso Propoxy-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 272 mg was obtained as a beige powder.
Example 16
1- {1-[(5-Amino-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-methylpropan-2-ol 150 mg of dichloromethane in 5 ml of dichloromethane, 0.19 ml of formaldehyde solution, And acetic acid were added, and the mixture was stirred at room temperature for 30 minutes. Then, 318 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution, water, ethyl acetate, and a small amount of MeOH were added to the mixture, and the mixture was separated. The residue was purified by silica gel column chromatography (chloroform: (25% methanol / chloroform) = 1: 0-7: 3), powdered with hexane / ethyl acetate, and 1- (1-{[5- 66 mg of (dimethylamino) -1H-indol-2-yl] carbonyl} piperidin-4-yl) -2-methylpropan-2-ol was obtained as a yellow solid.

Example 17
2-methyl-1- (piperidin-4-yl) -2-propanol 4.7 mg, 3-methyl-1H-indole-2-carboxylic acid 5.3 mg, triethylamine 0.0042 ml, and 1-hydroxybenzotriazole 4.0 mg DMF 0.5 To the ml solution, 100 mg of PS-carbodiimide (PS-Carbodiimide: Argonaute Technology) was added at room temperature and stirred overnight. MP-Carbonate (MP-Carbonate: Argonaute Technology) 50 mg and PS-isocyanate (PS-Isocyanate: Argonaute Technology) 50 mg were added to the reaction solution at room temperature, and the mixture was stirred for 2 hours. did. The filtrate was concentrated under reduced pressure to obtain 7.2 mg of 2-methyl-1- {1-[(3-methyl-1H-indol-2-yl) carbonyl] piperidin-4-yl} -2-propanol.
Example 18
Examples using [(2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) oxy] acetic acid and dimethylamine hydrochloride 2-[(2-{[4- (2-hydroxy-2-methylpropyl) piperidin-1-yl] carbonyl} -1H-indol-5-yl) oxy] -N, N-dimethyl Acetamide was prepared.
Example compounds shown in the table below were produced in the same manner as in the above Examples. The structures, physicochemical data and production methods of the example compounds are shown in the table below.

  Further, the following table shows other embodiments of the compound of the formula (I). These compounds can be easily produced by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.

  The compound of the formula (I) has 17βHSD type 5 inhibitory activity and can be used as an active ingredient of a pharmaceutical composition for prevention and / or treatment of a disease involving 17βHSD type 5. For example, it can be used as an active ingredient of a pharmaceutical composition for preventing and / or treating diseases related to androgens.

Claims (1)

A compound of formula (I) or a salt thereof.

(Where
R ¹ is OH, OR ⁰ or halogen;
R ² , R ³ , R ⁴ and R ⁵ are the same or different from each other, and H or R ⁰ ; or R ² and R ³ or R ⁴ and R ⁵ together form C _2-5 alkylene. Or R ¹ and R ² together may be oxo;
R ⁶ and R ⁷ are the same or different from each other, and H or R ⁰ , or R ⁶ and R ⁷ together are R ⁰⁰ ;
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are the same or different from each other, and H, R ⁰ , halogen, halogeno lower alkyl, OH, OR ⁰ , SH, SR ⁰ , SO-R ⁰ , SO ₂ -R ⁰ , O-halogeno lower alkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, OR ⁰⁰ -OH, OR ⁰⁰ -OR ⁰ , OR ⁰⁰ -cycloalkyl, OR ⁰⁰ -heterocycloalkyl, OR ⁰⁰ -aryl, OR ⁰⁰ -heteroaryl, OR ^00- (optionally substituted amino), OR ⁰⁰ -CO ₂ H, OR ⁰⁰ -CO ₂ R ⁰ , OR ⁰⁰ -CO- (Optionally substituted amino), CO ₂ H, CO ₂ R ⁰ , CO- (optionally substituted amino), R ⁰⁰ -OH, R ⁰⁰ -OR ⁰ , R ^00- (substituted also an amino), R ⁰⁰ -CO- (amino optionally substituted), R ⁰⁰ - cycloalkyl, R ⁰⁰ - heterocycloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, nitro, substituted Or unprotected amino, NO _2,
Here, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl in R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are groups selected from lower alkyl, OH, OR ^0, and halogen, respectively. May be substituted;
Alternatively, R ⁹ and R ¹⁰ , or R ¹⁰ and R ¹¹ are combined to form -OR ⁰⁰ -O-;
R ⁰ is the same or different and is lower alkyl;
R ⁰⁰ is the same or different from each other, lower alkylene;
X is N or CH;
Y represents methylene, O or a single bond;
n represents 1 or 2, respectively. )