Piperidine derivative

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

 

The technical field to which the invention relates

This invention relates to a piperidine derivative having pharmacological activity, and/or its salt. In addition, this invention relates to a drug or pharmaceutical composition containing a derivative of piperidine and/or its salt described above, as the active ingredient.

The level of technology

Benign prostatic hyperplasia (national Department of standardization) is a disease that occurs mainly in men over the age of 50 years or more and is accompanied by urinary disorders, and the degree of its prevalence increases with age. The number of patients with the national Department of standardization in Japan has steadily increased in recent years with the growth of the aging population. National Department of standardization significantly affects the quality of life of older men because of urinary disorders and is a serious problem in the health plan's economy, as it is the most commonly diagnosed and being treated with disease in the field of urology.

It was found that two factors, namely the immediate urethral compression due to hypertrophy of the prostate (mechanical obstruction) and the rise of intraurethral pressure due to increased contraction of smooth muscles of the prostate through the sympathetic nerve (functional impassable is here), at the same time included in urinary disorders accompanying national Department of standardization. Drug therapy can be applied to both of these mechanisms, in the case of mechanical obstruction mainly used inhibitors of 5α-reductase in the case of functional obstruction mainly used α1-sympatholytic funds (α1-blockers). Inhibitors of 5α-reductase cause regression of the prostate because of their antiandrogenna effect based on inhibition of the conversion of testosterone to 5α-dihydrotestosterone (DHT), which is a more potent androgen, produced by 5α-reductase. Regresses only the epithelium of the prostate, however, requires a long period of time (from several weeks to several months), so that the efficiency of medicines has become obvious. On the other hand, since α1-blockers have shown its effectiveness as medicines very quickly after the introduction and are exceptional security, α1-blockers are currently the primary treatment for national Department of standardization. However, in the long-term clinical studies it was found that the inhibitor of 5α-reductase significantly slowed the transition to invasive therapy compared with single use of α1-blocker and others (“The New England Journal of Medicine, 2003, Vol. 349, p 2387-2398), therefore, the use of inhibitors of 5α-reductase has recently been reviewed again.

It was believed that DHT in the prostate is obtained under the action of 5α-reductase of testosterone produced by the testes and is endocrinologically in the prostate. Recently, however, it was reported that about half of DHT and its predecessor, the testosterone in the prostate synthesized from dehydroepiandrosterone (DHEA) is a steroid produced from the adrenal gland, in the cells of the prostate (“Frontier in Neuroendocrinology”, 2001, Vol. 22, p. 185-212). This type of system production of sex hormone in the cells of the target organs of sex hormones called intracrinology.

For inhibitors of 5α-reductase is difficult to inhibit the local synthesis of testosterone (intracrine the synthesis of testosterone in the prostate. For example, it was reported that the concentration of DHT in the prostate of patients with BHP was decreased after administration of finasteride, an inhibitor of 5α-reductase, approximately 20% of the concentration before the introduction, while the concentration of testosterone, a precursor in the prostate was reversibly increased 4 times (“The Journal of Urology”, 1999, Vol. 161, p. 332-337). This means that although the inhibitor of 5α-reductase has the effect to reduce the concentration of DHT in the prostate, it has no effect on the decrease in concentration of testosterone in the prostate and in return increases the concentration. Since testosterone has AK is ewnetu binding androgen receptor, approximately half of that of DHT, this local increase in concentration of testosterone in the prostate, as it should be partly responsible for the lack of drug efficacy of finasteride for BPH.

Antiandrogenna therapy with the use of surgical castration and agonists of gonadotropin-releasing hormone is also used against prostate cancer. It is reported that antiandrogenna therapy affect the insufficient effect of reducing the concentrations of testosterone in the prostate. For example, in patients with prostate cancer who receive antiandrogenna therapy, the concentration of testosterone in the blood decreased to 10% of the concentration before the introduction, while the concentration of DHT in the prostate remained approximately 50% (“The Journal of Clinical Endocrinology and Metabolism”, 1995, Vol. 80, p. 1066-1071). This suggests that the concentration of testosterone in the prostate also not sufficiently reduced. In addition, androgenic receptors localized in the nuclei of cells also prostate cancer, recurrent after antiandrogenna therapy (hormone-resistant prostate cancer), and there was no significant difference between the concentration of testosterone in the tissues of recurrent prostate cancer and concentration in normal prostate (“Clinical Cancer Research, 2004, Vol. 10, p. 440-448). These publications suggest that the effect of reducing the concentrations of the dough is Theron in the prostate in the existing therapeutic methods is absolutely insufficient for the treatment of recurrent prostate cancer and that the suppression mechanism of the synthesis of testosterone in the prostate, that is intracrine synthesis of testosterone in the prostate, may represent a new target for therapy of prostate cancer.

Taking into account the above known data as inhibitors intracrine synthesis of testosterone in the prostate have an effect on the decrease in concentration of testosterone in the prostate and have no effect on the decrease in concentration of testosterone in the blood, expect that these inhibitors will be a very attractive tool for the treatment of national Department of standardization and/or treatment for prostate cancer, (1) which can reduce not only the concentration of testosterone, but also the concentration of DHT in the prostate, and (2) which can be devoid of harmful effects due to suppression of testosterone concentrations obtained from the testicles, into the blood.

17β-hydroxysteroid dehydrogenase (17βHSD) is important for the biosynthesis of testosterone. There are several subtypes of 17βHSD. 17βHSD type 5 is widely represented in the prostate of a man and, as it was published, increases the manifestation of prostate cancer recurrent prostate cancer (“Steroids”, 2004, Vol. 69, p. 795-801; and “Cancer Research”, 2006, Vol. 66, p. 2815-2825). On the other hand, almost all the testosterone in the blood is performed with 17βHSD type 3 in the testes and expression of 17βHSD type 3 rarely observed in other tissues, including the prostate (“Nature Genetics, 1994, Vol. 7, p. 34-39). Thus I believe that 17βHSD type 5 is responsible for intra who rinny the synthesis of testosterone in the prostate and selective inhibitors of 17βHSD type 5 are assumed for the selective suppression intracrine synthesis of testosterone in the prostate. In addition, because the contribution of 17βHSD type 5 is also noted in estrogenzawisimy tissues such as the mammary gland, and the like, are selective inhibitors are expected to be effective for estrogenzawisimy diseases such as breast cancer, and the like (“Endocrine Reviews”, 2003, Vol. 24, p. 152-182). In addition, published that AKR1C3 (another name for 17βHSD type 5), which is a subtype aldoketoreductase (AKR), metabolizes polycyclic aromatic hydrocarbons (RAS) with the formation of reactive oxygen compounds (ROS) (“The Journal of Biological Chemistry, 2002, Vol. 277, No. 27, p. 24799-24808), and that single nucleotide polymorphism (SNP) AKR1C3 gene associated with oxidative stress correlates with risk of lung cancer (“Carcinogenesis”, 2004, Vol. 25, No. 11, p. 2177-2181). That is, it is assumed that the activity of AKR1C3 in the lungs increases the risk of lung cancer by generating ROS from PAH and it is expected that selective inhibitors of 17βHSD type 5 will be effective for the treatment of lung cancer.

As inhibitors 17βHSD type 5 known steroid derivatives (patent document 1) and NSAID (non-steroidal anti-inflammatory drugs), such as flutamida acid, indomethacin and the like (non-patent document 1), derivatives of cinnamic acid (non-patent document 2), and the like. Although the mechanism of action is different about svodnoe of indazole, represents a compound of formula (A), as it is known now for the national Department of standardization (patent document 2).

[Chem. 1]

According to patent document 3 N-substituted benzimidazolone derivative comprising a compound of formula (I)have inhibitory activity against c-Kit oncogene and is applicable for the treatment of prostate cancer or the like. However, there is no description indolines group and also there is no description inhibitory effect against 17βHSD type 5.

[Chem. 2]

According to patent document 4 derivatives of benzimidazole, comprising a compound of formula (C), have a regulating action on tyrosinekinase and applicable for the treatment of prostate cancer or the like. However, not described indlela group and also there is no description inhibitory effect against 17βHSD type 5.

[Chem. 3]

According to patent document 5 indole derivatives, comprising the compound of formula (D)have the histamine H4 antagonist effect and applicable to the treatment of inflammation. However, not described in non-core (piperideine)alkananda structure and also there is no description inhibitory effect against 17βHSD type 5 and efficacy against BPH, prostate cancer, and the like.

[Chem. 4]

According to the patent document 6 derivatives of indole, comprising the compound of formula (E), have a regulating action on the cannabinoid receptor and applicable to the treatment of cerebrovascular disorders and the like. However, there is no description inhibitory effect against 17βHSD

type 5 and efficacy against BPH, prostate cancer, and the like.

[Chem. 5]

[Patent document 1] the Prospect of international publication No. WO99/046279

[Patent document 2] the Prospect of international publication No. WO2004/064735

[Patent document 3] the Prospect of international publication No. WO2005/021531

[Patent document 4] the Prospect of international publication No. WO2007/056155

[Patent document 5] the Prospect of international publication No. WO2002/072548

[Patent document 6] JP-A-2005-162657

[Non-patent document 1] Cancer Research, 2004, Vol. 64, p. 1802-1810

[Non-patent document 2] Molecular and Cellular Endocrinology, 2006, Vol. 248, p. 233-235

DISCLOSURE of INVENTIONS

The PROBLEM WHICH the INVENTION PROPOSES TO SOLVE

The objective of the invention is to provide a connection that is applicable as a drug with selective inhibitory activity against 17βHSD type 5, in particular as a means for the treatment of benign prostate hyperplasia and/or prostate cancer.

WAYS TO SOLVE

In the result of the intensive studies on compounds having a selective inhibitory activity against 17βHSD type 5, the authors of the present invention found that {1-[(indol-2-yl)carbonyl]piperidyl}alkanol-derived has the potential selective inhibitory activity against 17βHSD type 5 and may be a means for the treatment and/or means for preventing the disease associated with 17βHSD type 5, such as benign prostatic hyperplasia and prostate cancer without the associated harmful effects due to the lowering of testosterone level. These research results were the basis of the present invention.

That is, this invention relates to the compound of formula (I) or salts thereof and to pharmaceutical compositions containing the compound of formula (I) or its salt and a filler.

[Chem. 6]

in the formula (I), R1, R2and R3that are the same or different, represent H or lower alkyl;

R4, R5, R6, R7and R8that are the same or different, represent H, lower alkyl, halogen, halogen-lower alkyl, nitro, -S-cycloalkyl, which may be substituted, -X-aryl which may be substituted, X is a heterocyclic group which may be substituted, -X-COOR0, -X,-CONR10R11, -X,-CN, -X,-OR0, -X-SR0, -XS(O)-lower alkyl, -X-S(O)2-lower alkyl, -X-NR10R11, -X-NR0C(O)R10, -X-NR0C(O)OR10, -X-NR0C(O)NR10R11, -X-NR0S(O)2R10, -X-O-halogen-lower alkyl, -X-O-X-cycloalkyl, which may be substituted, -X-O-X-aryl which may be substituted, -X-O-X-heterocyclic group which may be substituted, or-X-O-lower alkylene-OR0; or

R6and R7combined with education About the lowest alkylen-O-;

R0that is the same or different, represents H or lower alkyl;

R10and R11that are the same or different, represent H, lower alkyl, halogen-lower alkyl, -X-cycloalkyl, -X-aryl, or-S-heterocyclic group; or

R10and R11together with the N to which they are attached, form a saturated heterocyclic group which may be substituted; and

X, which is the same or different, represents a bond or a lower alkylene.

In this description of the characters mentioned above are used to, unless otherwise stated, represent the same value.

In addition, this invention relates to a pharmaceutical composition for the treatment and/or prevention of a disease associated with 17βHSD type 5, and the composition contains a compound of the formula (I) or its salt, and they are the NGOs means for the prevention and/or treatment for diseases associated with 17βHSD type 5, containing the compound of formula (I) or its salt.

In addition, this invention relates to the use of compounds of formula (I) or salts thereof for the manufacture of pharmaceutical compositions for the treatment and/or prevention of a disease associated with 17βHSD type 5.

In addition, this invention relates to a method of treatment and/or prevention of a disease associated with 17βHSD type 5, and the method comprises the administration to the patient an effective amount of the compounds of formula (I) or its salt.

In addition, this invention relates to an inhibitor of 17βHSD type 5 containing the compound of formula (I) or its salt.

In addition, this invention relates to a method for preparing a pharmaceutical composition for the prevention or treatment of a disease associated with 17βHSD type 5, and the method involves mixing the compounds of formula (I) or its salt and a pharmaceutically acceptable carrier, solvent or excipient.

In addition, this invention relates to packaging for sale, including pharmaceutical composition comprising a compound of formula (I) or its salt; and a statement, according to which the compound of formula (I) or its salt can be used or should be used for the treatment and/or prevention of a disease associated with 17βHSD type 5.

The EFFECT of the INVENTION

The compound of formula (I) selectively inhibits 17βHSD type 5. In accordance with this, the compound of formula (I) can be used as a tool for prevention and/or treatment of a disease associated with 17βHSD type 5. For example, it can be used as a tool for preventing and/or treating diseases associated with androgen, as the synthesis of androgen suppressed by inhibition of 17βHSD type 5.

The BEST WAY of carrying out the INVENTION

Later in this document, the invention will be described in more detail.

In the definition of “alkyl” and “alkylene” refers to linear or branched hydrocarbon chain, if, in particular, expressly agreed.

“Lower alkyl” means alkyl containing 1-6 carbon atoms (below in the present description are marked as “C1-6”), and its examples include methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, second-boutelou, tert-boutelou, n-pentelow, n-hexoloy group and the like. In another embodiment, it is a1-4alkyl. In still another embodiment, it represents a methyl, ethyl, n-propyl, isopropyl or tert-butyl.

“Lower alkylene” means1-6alkylen, and its examples include methylene, ethylene, trimethylene, tetramethylene, pentane Elenovo, hexamethylene, propylene, metilbutilovy, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group, and the like. In another embodiment, it is a1-5alkylen. In still another embodiment, it represents a methylene, ethylene, trimethylene, tetramethylene or pentamethylene.

“Halogen” means F, Cl, Br or I.

“Halogen-lower alkyl” denotes lower alkyl, substituted by one or more Halogens. In another embodiment, it represents a lower alkyl substituted by 1-5 halogen atoms. In still another embodiment, it represents trifluoromethyl.

“Cycloalkyl” is a3-10the saturated cyclic hydrocarbon group, which may be a bridge. Examples include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptanol, cyclooctanol, bicyclo[2.2.1]heptylene, adamantly group and the like. In another embodiment, it is a3-8cycloalkyl. In still another embodiment, it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

“Aryl” represents a C6-14from monocyclic to tricyclic aromatic hydrocarbon cyclic group which contains a cyclic g is the SCP, condensed with C5-8cycloalkenes on his plot with a double bond. Its examples include phenyl, naftalina, tetrahydronaphthalene, indenolol, fluorenyl group and the like. In another embodiment, it represents phenyl or naphthyl. In still another embodiment, it represents phenyl.

“Heterocyclic group” means a cyclic group selected from i) a 3-8-membered monocyclic, and in another embodiment from a 5-7-membered monocyclic heterocycle containing 1-4 heteroatoms selected from O, S and N, and ii) bicyclic to tetracyclic heterocycle containing 1-5 heteroatoms selected from O, S and N, which is formed by cyclic condensation of the monocyclic heterocycle with one or two cycles, selected from the group consisting of monocyclic heterocycle, benzene ring, With5-8cycloalkane and C5-8cycloalkene. Ring atom, S or N may be oxidized to form oxide or dioxide. In addition, it can be connected by a bridge or can form spirits.

Examples of “heterocyclic” groups include aziridinyl, azetidin, pyrrolidinyl, piperidyl, azepane, piperazinil, homopiperazine, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, morpholinyl, thiomorpholine, pyrrolyl, indolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, hinely, chinadoll, honokalani, benzofuranyl, benzothiophene, benzoxazole, benzthiazole, carbazolyl, indolyl, tetrahydroquinoline, tetrahydroisoquinoline, hinokitiol, dibenzofurans, and the like.

In another embodiment, it represents a monocyclic or bicyclic 5-to 10-membered heterocyclic group.

In still another embodiment, it is pyrrolidinyl, piperidyl, azepane, piperazinil, homopiperazine, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, homomorpholine, thiomorpholine, indolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isooxazolyl, thiadiazolyl, benzimidazolyl, tetrahydroquinoline, tetrahydroisoquinoline or dibenzofurans.

“Saturated heterocyclic group” refers to, among the above-mentioned “heterocyclic” group, a group in which all collabrasuite the bonds represent a single bond.

Examples of the “saturated heterocyclic” groups include pyrrolidinyl, piperidyl, azepane piperazinil, homopiperazine, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, homomorpholine, thiomorpholine and the like.

The expression “which may be substituted” in this description refers to unsubstituted or substituted by 1-5 substituents. In addition, if there are multiple substituents, then the substituents may be the same or different.

The substituents for the “cycloalkyl, which may be substituted”, “aryl which may be substituted”, or “heterocyclic group which may be substituted”, in R4, R5, R6, R7and R8include, for example, lower alkyl, halogen, halogen-lower alkyl, nitro, -X,-CN, -X,-OR0, -X-SR0, -X,-S(O)-lower alkyl, -X-S(O)2-lower alkyl, -X-NR10R11, -X-NR0C(O)R10, -X-NR0C(O)OR10, -X-NR0C(O)NR10R11, -X-NR0S(O)2R10, -X-O-halogen-lower alkyl or-h-O-a lower alkylene-OR0. In another embodiment, examples include groups selected from lower alkyl, halogen, halogen-lower alkyl, -CN, OR0. In yet another embodiment, examples include groups selected from methyl, ethyl, F, Cl, trifloromethyl and methoxy.

Although cycloalkyl, phenyl, cyclohexyl, and the like are described as the monovalent group in the description for convenience, they can be a polyvalent group, divalent or higher valency according to their structures. This invention covers these structures. Certain embodiments of divalent groups correspond to the groups that have the suffixes above ring groups, turned into dial in accordance with the nomenclature of organic chemistry. For example, dimalanta group, the corresponding phenyl group which is a monovalent group is a phenylene.

“Selective inhibitor of 17βHSD type 5” denotes inhibitor, in which inhibitory activity against 17βHSD type 3 occurs 3 times or more, preferably 10-fold or more and more preferably 100-fold or more value for inhibitory activity against human 17βHSD type 5 (AKK1C3) based on the value of the IC50.

Variant implementation of the compounds of formula (I) of the present invention will be described below.

(1) Compound of formula (Ia)

[Him]

(2) the Compound in which R1means N.

(3) the Compound in which R1means lower alkyl.

(4) the Compound in which R1means methyl.

(5) the Compound in which R2means N.

(6) the Compound in which R2means lower alkyl.

(7) the Connection to the or R 2means methyl.

(8) the Compound in which R3means N.

(9) a Compound in which R3means lower alkyl.

(10) the Compound in which R4means H, lower alkyl, halogen or-O-lower alkyl.

(11) a Compound in which R4means N.

(12) a Compound in which R4means lower alkyl.

(13) the Compound in which R4means halogen.

(14) the Compound in which R4means-O-lower alkyl.

(15) the Compound in which R5means H, lower alkyl, halogen or-O-lower alkyl.

(16) the Compound in which R5means N.

(17) the Compound in which R5means lower alkyl.

(18) the Compound in which R5means halogen.

(19) the Compound in which R5means-O-lower alkyl.

(20) the Compound in which R6means H, lower alkyl, halogen, halogen-lower alkyl, nitro, cycloalkyl, HE or-O-lower alkyl.

(21) the Compound in which R6means lower alkyl, halogen or-O-lower alkyl.

(22) the Compound in which R6means N.

(23) the Compound in which R6means lower alkyl.

(24) the Compound in which R6means halogen.

(25) the Compound in which R6means halogen-lower alkyl.

(26) the Compound in which R6means nitro.

(27) the Compound in which R means cycloalkyl.

(28) the Compound in which R6means IT.

(29) the Compound in which R6means-O-lower alkyl.

(30) the Compound in which R7means H, lower alkyl, halogen or-O-lower alkyl.

(31) the Compound in which R7means N.

(32) the Compound in which R7means lower alkyl.

(33) the Compound in which R7means halogen.

(34) the Compound in which R7means-O-lower alkyl.

(35) the Compound in which R8means H, lower alkyl, halogen or-O-lower alkyl.

(36) the Compound in which R8means N.

(37) the Compound in which R8means lower alkyl.

(38) the Compound in which R8means halogen.

(39) the Compound in which R8means-O-lower alkyl.

(40) the Compound, which is a combination of any two or more of the groups described in the above paragraphs(1)-(39).

Specific examples of the compounds of the above paragraph (40) include the following compounds.

(41) the Compound described in (1), in which R1and R3mean N.

(42) the Compound described in (41), where R4, R5, R7and R8that are the same or different represent H, lower alkyl, halogen or-O-lower alkyl, R6means H, lower alkyl, halogen, halogen-lower alkyl, who and Jethro, cycloalkyl, HE or-O-lower alkyl.

(43) the Compound described in (1), in which R1and R2mean lower alkyl, and R3means N.

(44) the Compound described in (43), where R4, R5, R7and R8that are the same or different represent H, lower alkyl, halogen or-O-lower alkyl.

(45) the Compound described in (43) or (44), where R6means H, lower alkyl, halogen, halogen-lower alkyl, nitro, cycloalkyl, HE or-O-lower alkyl.

(46) the Compound described in (43)-(45), where R6means lower alkyl, halogen or-O-lower alkyl.

Another variant implementation of the compounds of formula (I) of the present invention will be described below.

(47) the Compound described in (1), where R1, R2, R3and R4which are identical or different, denote H or lower alkyl, R5means H, lower alkyl, halogen or-O-lower alkyl, R6means H, lower alkyl, halogen, HE, -O-lower alkyl, -O-lower alkylester, -O -, halogen-lower alkyl, nitro, amino, amino-C(O)-lower alkyl or pyrrolyl, R7means H, halogen, or-O-lower alkyl, or R6and R7combined to form-O-lower alkylene-O-, and R8means H or halogen.

(48) the Compound described in (47), in which R1means lower alkyl.

(49) the Compound described in (48), to which m R 1means methyl.

(50) the Compound described in (47), in which R2means lower alkyl.

(51) the Compound described in (50), in which R2means methyl.

(52) the Compound described in (47), in which R3means N.

(53) the Compound described in (47), in which R4means N.

(54) the Compound described in (47), in which R5means H, Cl or methyl.

(55) the Compound described in (47), in which R6denotes H, Cl, methyl, methoxy or nitro.

(56) the Compound described in (47), in which R7means N.

(57) the Compound described in (47), in which R8means H or Cl.

(58) the Compound, which is a combination of two or more groups described in the above(48)-(57).

Specific compounds covered by this invention include the following compounds.

2-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}ethanol

1-[1-(1H-indol-2-ylcarbonyl)piperidine-4-yl]propan-2-ol,

1-[1-(1H-indol-2-ylcarbonyl)piperidine-4-yl]-2-methylpropan-2-ol,

2-methyl-1-{1-[(4-methyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol,

2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol,

1-{1-[(3,5-dimethyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(5-tert-butyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(4-fluoro-1H-indol-2-yl)carbonyl]piperidin the-4-yl}-2-methylpropan-2-ol,

1-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(4-chloro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(5-bromo-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(7-chloro-5-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

2-{[4-(2-hydroxy-2-methylpropyl " piperidine-1-yl]carbonyl}-1H-indol-5-ol,

1-{1-[(4-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

1-{1-[(6-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,

2-methyl-1-(1-{[(5-(triptoreline)-1H-indol-2-yl]carbonyl}piperidine-4-yl)propan-2-ol, and

2-methyl-1-{1-[(5-nitro-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol.

The compound of formula (I) in some cases, it may be in the form of the tautomers or geometrical isomers, depending on the kind of substituents. In the present description, the compound of formula (I) can be represented in only one form of isomers, but the invention includes other isomers, as well as selected forms or mixtures thereof.

In addition, the compound of formula (I) may have asymmetric carbon atoms or axial asymmetry in some cases and, accordingly, it may be in the form of optical isome the RC. The invention also includes isolates or mixture of optical isomers of compounds of formula (I).

In addition, the invention includes pharmaceutically acceptable prodrug compounds of formula (I). Pharmaceutically acceptable prodrug is a compound containing a group which can be converted into the amino group, hydroxyl group, carboxyl group or the like by solvolysis or under physiological condition. Examples of the group forming a prodrug, include groups described in Prog. Med., 5, 2157-2161 (1985)

or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, “Drug Design”, pp. 163-198.

In addition, the salt of the compounds of formula (I) is a pharmaceutically acceptable salt of the compounds of formula (I) can form acid additive salt or a salt with a base depending on the type of substituents. In particular, examples include acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic who Isleta, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditawarkannya acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, para-toluensulfonate acid, aspartic acid and glutamic acid, salts with inorganic bases, such as salts of sodium, potassium, magnesium, calcium and aluminum, or with organic bases, such as salts with methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and derivatives of amino acids, such as salts acetylleucine, ammonium, and the like.

In addition, this invention also includes various hydrates or solvate and polymorph crystalline substances the compounds of formula (I) and their salts. In addition, this invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

WAYS to GET

The compound of formula (I) and its salt can be obtained through the use of properties based on the types of its basic skeleton or deputies, and by applying various known synthetic methods. Currently, in some cases, based on the methods of obtaining effective is the replacement of functional groups suitable protective group (a group which can easily be turned into fun is inuu group) at the stage of the original product to intermediate depending on the type of functional groups in the process of obtaining. Examples of such functional groups include amino group, hydroxyl group, carboxyl group and the like, and examples of such protective groups include protective groups are described, for example, in “Protective Groups in Organic Synthesis, the third edition, 1999)” edited by Greene and Wuts, and the like, which may be appropriately selected and used depending on the reaction conditions. In these methods, the desired compound can be obtained by introducing protective groups and performing the reaction and then removing the protective group, if desired.

In addition, the prodrug of the compounds of formula (I) can be obtained in the same way as in the case of protective groups, performing the reaction after introducing a specific group at a stage from the original products to intermediate products or the use of the compounds of formula (I). The reaction can be carried out by methods known to experts in this field, such as esterification, amidation, dehydration, and the like.

Hereinafter in this description will be presented visual methods for obtaining the compounds of formula (I). Each of the methods of obtaining can also be done with reference to the links attached to the present description. In addition, methods of obtaining this invention is not limited to examples shown below.

[Chem. 8]

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

The reaction can be performed using the compound (II) and the compound (III) in equivalent amounts or their abundant in the presence of a condensing agent in condition from cooling to heating, preferably from -20°C to 60°C, usually stirring for 0.1 hour to 5 days, in a solvent which is inert to the reaction.

In this case, the choice of solvent is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform; ethers, such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, water or a mixture.

Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diphenylphosphoryl, phosphorus oxychloride and the like, but is not limited to them. In some cases, reactions may be useful, for example, to use an additive (for example, 1-hydroxybenzotriazole or the like). In some cases it may be useful for uniform reaction about what editorially in the presence of an organic base, such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, or inorganic bases such as potassium carbonate, sodium carbonate or potassium hydroxide.

In addition, can also be used a method in which a compound of carboxylic acid (II) is converted into its reactive derivative and then subjected to the interaction with the compound (III). Examples of the reactive derivative of carboxylic acid include gelegenheid obtained by the interaction with a halogenation agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydride obtained by the interaction with isobutylparaben, or the like, and the active ester obtained by the condensation of 1-hydroxybenzotriazole or the like. The reaction between the reactive derivative and the compound (III) can be carried out under conditions of from cooling to heating, preferably from -20°C to 60°C, in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons or ethers.

In addition, different substituents on the groups R1-R8in the compound of formula (I) can be easily transformed into other functional groups by the use of the compounds of formula (I) as the original product and the use of the reactions described in the trail of the common examples reactions are evident for specialists in this field, or modified methods. For example, such reactions can be carried out by any combination of methods, which can traditionally be used by specialists in this field, for example methods O-alkylation, N-alkylation, recovery, hydrolysis, amidation, and the like. Their examples will be described below.

The compound of formula (I)containing an amino group, can be obtained by reduction of the nitro group, for example, with reference to the method described in “The fourth edition of Courses in Experimental Chemistry (Vol. 26)” edited by the Chemical Society of Japan, Maruzen, 1992.

The compound of formula (I)containing aminogroup, can be obtained by acylation of the amino group, for example, with reference to the methods described in “The fourth edition of Courses in Experimental Chemistry (Vol. 22)” edited by the Chemical Society of Japan, Maruzen, 1992, and “The fifth edition of Courses in Experimental Chemistry (Vol. 16)” edited by the Chemical Society of Japan, Maruzen, 2005; or “Compendium of Synthetic Organic Methods”, Vols. 1-3.

The compound of formula (I)containing o-dihydroxyphenyl group, can be obtained by cleavage of the 1,3-dioxolane ring, for example, with reference to the method described in “Journal of Medicinal Chemisrty”. 2001, 44, 1794-1801.

The compound of formula (I)containing phenyl group, substituted pyrrolidino group, can be obtained by reaction with the formation of the pyrrole ring, for example, with reference to the method described is in “Tetrahedron Letters”, 1993, 34, 1929-1930.

(Initial connection)

The original compound (II) can be obtained by reaction of the Fischer synthesis of indole, for example, reference to a method described in “The Fischer Indole Synthesis”, edited by Robinson, 1982. The original compound (III)containing a tertiary alcohol can be obtained by the interaction of the carboxylic acid derivative (such as an ester) with a Grignard reagent, for example, with reference to the method described in “Synthesis”, 1983, 12, 1030-1031.

[Pharmacological test]

Excellent selective inhibitory activity against human 17βHSD type 5 compounds of the present invention was confirmed by the test methods described in sections 1-3 below. This test can be performed by reference to the details of the test procedures described in the publication Maniatis, T. et al., Molecular Cloning - A Laboratoty Manual Cold Spring Harbor Laboratory, NY (1982), and the like. In addition, genes encoding human 17βHSD type 5 and type 3 described in sections 1 and 2 below, and the human 17βHSD type 5 and type 3 can be obtained by the method described in Molecular Endocrinology, 1997, 11(13), 1971-1984.

1. The selection of the gene encoding human 17βHSD type 5, and purification of the enzyme

cDNA full length, encoding human 17βHSD type 5, used in the pharmacological test of the present invention, was obtained by PCR method using cDNA produced from the cell line, obtained the lung cancer is man, A cells as a matrix. The nucleotide sequence of the obtained cDNA was analyzed by the method of dimethoxyderivative and selected clone, compatible with the known sequence of human 17βHSD type 5 (number NM_003739 access in GenBank).Escherichia coliBL21 transformed with a plasmid containing the cDNA, and cultured in an enlarged scale. Proteins were purified using GSTrapFF column (produced by Amersham) and PreScissionProtease (produced by Amersham). Method of purification was performed according to instructions attached to GSTrapFF column.

2. The selection of the gene encoding human 17βHSD type 3, and purification of the enzyme

cDNA full length, encoding human 17βHSD type 3 used in the pharmacological test of the present invention, was obtained by PCR method using cDNA derived from human testes, as a matrix. The nucleotide sequence of the obtained cDNA was analyzed by the method of dimethoxyderivative and selected clone, compatible with the known sequence of human 17βHSD type 3 (number WS access in GenBank). Then cell line derived from the kidney of the fetus human 293 cells, transformed with a plasmid containing the cDNA, and the cells were collected after 24 hours. The collected cells were then broken in a phosphate buffer solution containing 5% glycerol (500 μl of 100 mm phosphate tablet in the morning the aqueous solution (pH 7.4, 200 mm)containing 5% glycerol) and centrifuged (16000 rpm, 5 min, 4°C)and the supernatant was used as source of enzyme.

3. Measurement of enzymatic activities of human 17βHSD type 5 and type 3

The enzyme activity was measured, referring to the publication Trevor M. Penning, et al., Biochem. J., 351, 67-77, (2000). In particular, using 100 mm potassium phosphate buffer (pH 6,0), (1) the enzyme purified in the above section 1 at a final concentration of 10 μg/ml, (2) Androstenedione at a final concentration of 300 nm, (3) NADPH at a final concentration of 200 nm and (4) the test compound was mixed for interaction at room temperature for 2 hours and then measured the amount of testosterone, using kits are used (registered trademark) testosterone reagents R050-201 (produced by PerkinElmer). The measurements were performed in accordance with the enclosed instructions. The degree of decrease in the formation of testosterone in the presence of the compounds were obtained as a relative value relative to the amount of testosterone in the absence of the enzyme at 0% and the amount of testosterone obtained in the absence of a connection 100%. Then the expected value IC50the method of logistic regression.

In addition, as a model of thein vitroclose to the living organism, the activity of the above enzymes can be esmerinemontreal cells, which expresses human 17βHSD type 5 or the like.

In addition, LNCaP cells expressing human 17βHSD type 5, was created from cell lines derived from prostate cancer human LNCaP cells, and evaluated the activity for inhibiting growth of cells under the action of the compounds of this invention.

4. The creation of LNCaP cells expressing human 17βHSD type 5

LNCaP cells are cell lines derived from prostate cancer human, transformed with a plasmid containing clone selected in the above section 1, and then received cell line showing stable expression.

5. Measurement of the ability of cell growth using LNCaP cells expressing human 17βHSD type 5

9000 cells/well of the transformed cells obtained in section 4 above, were sown in 96-well plate and cultured in the continuation of the night. Then there was added Androstenedione in combination with the test compound at a final concentration of 10 nm, followed by culturing for 7 days. After cultivation counted the number of cells using CellTiter-Glo (registered trademark) in fluorescent analysis of the viability of the cells (Promega). CellTiter-Glo (registered trademark) in fluorescent analysis of the viability of the cells is a reagent to the second measures the number of cells by monitoring the level of intracellular ATP(ATP) on the intensity of luminescence by luciferase. The experimental manipulation was performed according to the attached instructions. Activity inhibition of cell growth in the presence of test compounds was calculated as a relative value relative to the number of cells in the absence of a system of Androstenedione in proliferation at 0% and the number of cells in the presence of Androstenedione and in the absence of the test compound with the cell proliferation at 100%. Then the expected value IC50the method of logistic regression.

Table 1 shows the values of the IC50for inhibitory activity against human 17βHSD type 5 and type 3 illustrative compounds included in the compound of the present invention, and the value of the IC50inhibitory activity of cell growth using LNCaP cells expressing human 17βHSD type 5. The abbreviation “Ex” denotes the number of the example.

Table 1
ExType 5 IC50(nm)Type 3 IC50(nm)LNCaP-17β5 IC50(nm)
14,5>100008,9
9130 >1000010
1515>1000018
17390>1000020
2015>1000029
2221>1000060
24150>1000024
25230>1000012
3026>1000031

As shown above test results, the compounds of formula (I) almost do not possess inhibitory activity against human 17βHSD type 3 and have inhibitory activity selective to human 17βHSD type 5.

In accordance with this, the compound of formula (I) can be used as a means for preventing and/or treating diseases associated with 17βHS type 5. For example, it can be used as a means for preventing and/or treating diseases associated with androgen, as the synthesis of androgen suppressed by inhibition of 17βHSD type 5.

Examples of diseases associated with androgen, include prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, baldness, alopecia, early puberty, adrenal hypertrophy, polycystic ovary cancer, breast cancer, endometriosis, leiomyoma or the like. Their examples also include diseases associated with oxygen stress, such as lung cancer.

In addition, since 17βHSD type 5, as it is responsible for intracrine synthesis of androgen in the prostate, selective inhibitors of 17βHSD type 5 are assumed for the selective suppression intracrine synthesis of androgen in the prostate. Therefore, the compound of formula (I) can be used as a means for preventing and/or treating diseases associated with androgen, in particular in the prostate, namely prostate cancer and benign prostate hyperplasia.

In addition, as shown above test results, since the compounds of formula (I) have a very weak inhibitory activity against human 17βHSD type 3, they are assumed to selection is of the suppression of intracrine synthesis in the prostate due to their selective inhibitory effects against 17βHSD type 5 without affecting the biosynthesis of testosterone, produced from human 17βHSD type 3 in the testicles. In other words, since the compounds of formula (I) did not affect the concentration of testosterone in the blood, they can be used as a means for the treatment and/or prevention of benign prostate hyperplasia and prostate cancer without harmful effects such as sexual dysfunction due to a decrease in the concentration of testosterone in the blood, and the like.

In addition, as shown above test results, since the compounds of formula (I) exhibit inhibitory activity against cell growth in LNCaP cells expressing human 17βHSD type 5, they suppress intracrine testosterone synthesis selectively in cancer of the prostate due to their selective inhibitory properties against 17βHSD type 5, thus can be used for the treatment and/or prevention of prostate cancer without harmful effects.

Also useful is the package for sale, which contains the aforementioned pharmaceutical composition and instructions describing the above-mentioned effects.

Preparation containing one or two or more kinds of the compounds of formula (I) or its salt as an active ingredient, can be prepared in accordance with generally applicable method using a pharmaceutical carrier, excipient Il the like, what is usually used in this field.

The introduction can be made in any form for oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral administration via injections such as intraarticular injection, intravenous injection, intramuscular injection or the like, and by suppositories, eye drops, eye ointments, liquid preparations for insertion through the skin, ointments, subcutaneous plaques, transmucosal liquid preparations, transmucosal plaques, inhalations and the like.

As solid compositions for oral administration according to this invention used tablets, powders, granules or the like. In such solid compositions are mixed with one or two or more types of active ingredients, at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and/or aluminometasilicate magnesium. According to the conventional method, the composition may contain inert additives such as sizing, namely magnesium stearate, a disintegrator such as natrocarbonatite, stabilizer, and means imparting solubility. If necessary, tablets or pills mo the ut to be coated with sugar or with a film of gastric or intersolubility materials.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like and contain commonly used inert diluent such as purified water or ethanol. In addition to the inert diluent liquid composition may contain an adjuvant such as a tool, which gives the solubility, moisturizer and suspendisse agent, sweetener, corrigent, flavor and antiseptic.

Injections for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions or emulsions. The aqueous solvent includes, for example, distilled water for injection or saline. Examples of non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (Japanese Pharmacopoeia) and the like. Such a composition may further contain a tonic, antiseptic, moisturizer, emulsifier, dispersant, stabilizer, or tool, which gives the solubility. They are sterilized, for example, by filtration through filter traps bacteria, infused sterilizing agent or irradiation. In addition, it is also possible to use a preparation of sterile solid compositions or dissolution and the and suspendirovanie it in sterile water or a sterile solvent for injection before use.

Drugs for external use include ointments, plasters, creams, gel formulations containing drug, poultices, sprays, lotions, eye drops, eye ointments, and the like. Included commonly used basis of ointments, lotions, aqueous or nonaqueous liquids, suspensions, emulsions and the like. Examples of bases ointments or lotions include polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylenesorbitan castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, servicesecurity and the like.

As transmucosally drugs such as drugs for inhalation and transnasal preparations, used in solid, liquid or semi-solid form and can be prepared in accordance with the traditionally known method. For example, they may be added a known excipient, and means for bringing the pH, antiseptic, surfactant, lubricant, stabilizer, thickener, respectively, or the like. For their introduction can be used the appropriate device for the inhalation or purging. For example, the connection may be entered by itself or in the form of a powder mixture, prepared as a drug or in the form of a solution or suspension in combination the pharmaceutically acceptable carrier with a generally known device or sprayer, such as a device for inhalation dosed introduction. Device for inhalation of a dry powder or the like can be used for single or multiple injections, and can be applied dry powder or capsule containing the powder. In the alternative case, it may be in the form, such as an aerosol for spraying under pressure, which uses the corresponding substance propellant, such as a suitable gas, such as chlorphenesin, hydrofluroalkane or carbon dioxide, and the like.

By oral administration, the daily dose usually takes a value from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg and preferably from 0.1 to 10 mg/kg of body weight, administered in one single dose or 2-4 divided doses. In the case of intravenous administration, the daily dose appropriate value is from about 0.0001 to 10 mg/kg of body weight, once a day, or two or more times per day. In addition, transmucosally tool is administered at a dose of from about 0.001 to 100 mg/kg of body weight, once a day, or two, or more times per day. The dose accordingly choose in response to a specific case, taking into account the symptoms, age, gender, and the like.

The compounds of formula (I) can be used in combination with various means for the treatment or prevention of diseases, for the which the above-mentioned compounds of formula (I), considered to be effective. The combined composition may be introduced simultaneously, or separately and continuously, or with the desired time intervals. Formulations intended for joint injection may be a mixture or can be prepared separately.

EXAMPLES

Methods of obtaining for compounds of formula (I)as an active ingredient of the present invention will be described below as examples. In addition, methods of obtaining new compounds, along with the compounds used as starting materials compounds of the formula (I)will be described as examples of receipt. Methods of obtaining for compounds of formula (I) is not limited ways to get in the specific examples below, and can be performed by a combination of these methods of obtaining or known ways to get.

The following examples are described in order to further explain the invention, and this invention is not limited to the subsequent examples. Although the invention is fully explained with examples, it should be understood that the specialists in this area will take into account, which of course can be made a variety of changes and modifications. Accordingly, such changes and modifications are included in this invention unless they depart from the field of infusion is his invention.

The following abbreviations used in the examples of the preparation, the examples and tables below.

Ex: example, REx: the number of sample receipt, No: number of connections, mp/TPL: melting point, data:physicochemical data (FAB+: FAB-MS (M+H)+, FAB: FAB-MS (M-H)-, ESI+: ESI-MS (M+H)+, ESI-: ESI-MS (M-H)-API+: API-ES-MS (M+H)+, EI: EI-MS (M)+CI: CI-MS (M+H)+, NMR-DMSOd6/NMR-d6: δ (ppm) peak(s) in1H NMR in DMSO-d6), Str: structural formula, Syn (REx): number examples of the preparation, in which the compounds obtained using the same method, Syn (Ex): the number of examples in which the compounds obtained using the same method, DME: dimethoxyethane, DMF/DMF: dimethylformamide, DMSO/DMSO: dimethyl sulfoxide, THF/THF: tetrahydrofuran, 4M HCl/EtOAc: 4 mol/l hydrochloric acid-ethyl acetate, MeCN: acetonitrile, Meon: methanol, tBuOH: tert-butyl alcohol, RT: retention time (min) HPLC/HPLC.

Example obtain 1

3 g of sodium bicarbonate were added to a solution of 5 g ethylpiperidine-4-racette in 50 ml of dioxane and 50 ml of water at 0°C and the contents were added dropwise to 4.6 ml of benzylchloride, followed by stirring at room temperature for 3 days. The reaction liquid was concentrated to half volume under reduced pressure followed by extraction with ethyl is the Etat. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the 8.9 g of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate as a colorless oily substance.

Example of getting 2

To a solution of 8.9 g of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate in 100 ml of THF was added at 0°With 46 ml of 1.4 M methylmagnesium in toluene-THF, followed by stirring at room temperature for 3 hours. To the reaction liquid was added a 1 M aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 8.5 g benzyl 4-(2-hydroxy-2-methylpropyl " piperidine-1-carboxylate as a colorless oily substance.

Example of getting 3

To a solution of 8.5 g of benzyl 4-(2-hydroxy-2-methylpropyl " piperidine-1-carboxylate in 120 ml of methanol was added 500 mg of 10% palladium-carbon, followed by stirring in an atmosphere of hydrogen at room temperature for 1 day. The insoluble product was removed by filtration through celite and the filtrate was concentrated under PON the leaders introduce pressure to obtain 5.6 g of 2-methyl-1-(piperidine-4-yl)-2-propanol in the form of a white substance.

Example 4

To a solution of 250 mg of ethyl 7-chloro-5-fluoro-1H-indole-2-carboxylate in 2 ml of methanol was added 5 ml of 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 3 hours. The reaction liquid was brought in acidified condition by adding a 1 M aqueous solution of hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 210 mg of 7-chloro-5-fluoro-1H-indole-2-carboxylic acid as white matter.

Example of getting 5

To a solution of 250 mg of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate in 5 ml of THF was added 1.2 ml of 1.4 M methylmagnesium in toluene-THF, followed by stirring at room temperature for 2 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] to obtain 236 mg of tert-butyl 4-(2-hydroxypropyl)piperidine-1-carboxylate as a colorless oily substance.

Table 2
RexSyn(Rex)The structural formulaData
11FAB+: 306
22CI+: 292
33EI: 157
44FAB-: 212
55FAB+: 244

Example 1

To a solution of 370 mg of 5-Clorinda-2-carboxylic acid and 300 mg of 2-methyl-1-(piperidine-4-yl)-2-propanol in 8 ml DMF was added 360 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 250 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. To the reaction liquid was added 0.5 M aqueous chlorotoluron the acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then was led from diisopropyl ether to obtain 268 mg of 1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol as a white crystal.

Example 24

To a solution of 1800 mg 5-methylindol-2-carboxylic acids and 1500 mg of 2-methyl-1-(piperidine-4-yl)-2-propanol in 25 ml DMF was added 2100 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 1500 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. To the reaction liquid was added 0.5 M aqueous hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then was led from a mixture of ethyl acetate/diisopropyl ether to obtain 2140 mg of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol in the form of bulgaristanli.

Example 25

To a solution of 478 mg 5-methoxyindol-2-carboxylic acid and 432 mg of 2-methyl-1-(piperidine-4-yl)-2-propanol in 8 ml DMF was added 575 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 169 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. To the reaction liquid was added a 0.2 M aqueous hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M aqueous solution of sodium hydroxide and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0 to 24:1] and then was led from a mixture of ethyl acetate/diisopropyl ether to obtain 683 mg of 1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol as a white crystal.

Example 26

To a solution of 150 mg 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylic acid in 3 ml of dichloromethane was added 1.5 ml of 1 M solution of bartered in dichloromethane at 0°C, followed by stirring at room temperature for 8 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of lorida sodium, was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained white solids in 3 ml of DMF was added 140 mg of 2-methyl-1-(piperidine-4-yl)-2-propanol, 150 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 105 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. To the reaction liquid was added 0.5 M aqueous hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then subjected to hardening, using ethylacetate, to obtain 42 mg of 2-{[4-(2-hydroxy-2-methylpropyl " piperidine-1-yl]carbonyl}-1H-indole-5,6-diol as a white solid.

Example 27

To a solution of 838 mg of 2-methyl-1-{1-[(5-nitro-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol in 15 ml of methanol was added 80 mg of 10% palladium-carbon, followed by stirring in an atmosphere of hydrogen at room temperature for 1 day. The insoluble product was removed by filtration through celite and the filtrate was concentrated under reduced pressure. Estato which was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then subjected to hardening by using hexane-ethyl acetate to obtain 576 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol in the form of a light brown solid.

Example 28

To a solution of 105 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol in 2 ml of dioxane and 2 ml of THF was added 32 μl of acetic anhydride, followed by stirring at room temperature for 2 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then subjected to hardening, using ethylacetate, to obtain 110 mg of N-(2-{[4-(2-hydroxy-2-methylpropyl " piperidine-1-yl]carbonyl}-1H-indol-5-yl)ndimethylacetamide in the form of a white solid.

Example 29

To a solution of 127 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol in 3 ml of methanol was added to 90 µl of 2.5-dimethoxytetrahydrofuran and 1 ml of acetic acid, followed by stirring at 60°C for 1 day. To the reaction liquid was added 1 M hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. About who headed the remainder of the purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then subjected to hardening, using ethylacetate, receiving 30 mg of 2-methyl-1-(1-{[5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}piperidine-4-yl)propan-2-ol as a white solid.

Example 30

To a solution of 233 mg of tert-butyl 4-(2-hydroxypropyl)piperidine-1-carboxylate in 4 ml of ethyl acetate was added 3 ml of 4 M HCL/EtOAc, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure to obtain hydrochloride of 4-(2-hydroxypropyl)piperidine. To a solution of the hydrochloride of 4-(2-hydroxypropyl)piperidine and 155 mg of indole-2-carboxylic acid in 5 ml of DMF was added 0.15 ml of triethylamine, 190 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 130 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. To the reaction liquid was added 0.5 M aqueous hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel [chloroform:methanol=1:0-10:1] and then subjected to hardening, using diisopropyl ether, to obtain 49 mg of 1-[1-(1H-indol-2-ylcarbonyl)piperidine-4-yl]propan-2-ol in the form of a white t is ejogo substances.

Example 31

To a solution of 500 mg of indole-2-carboxylic acid and 530 mg ethylpiperidine-3-racette in 8 ml DMF was added 610 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide and 430 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 2 hours. To the reaction liquid was added 0.5 M aqueous hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 519 mg of ethyl [1-(1H-indol-2-ylcarbonyl)piperidine-3-yl]acetate. To a solution of 392 mg of the obtained ethyl [1-(1H-indol-2-ylcarbonyl)piperidine-3-yl]acetate in 7 ml of THF was added 30 mg of lithium borohydride, followed by stirring at room temperature for 1 day. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel [hexane:ethyl acetate=1:0-2:1] and then was led from diisopropyl ether to obtain 92 mg of 2-[1-(1H-indol-2-ylcarbonyl)piperidine-3-yl]etano is in the form of a white solid.

Example 32

To a solution of 4.1 mg of 4-piperidinemethanol, 5.3 mg of 5-fluoro-1H-indole-2-carboxylic acid and 4.0 mg of 1-hydroxybenzotriazole in 0.6 ml DMF was added 100 mg of PS-carbodiimide (Argonaut Technologies) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-carbonate (Argonaut Technologies) and 50 mg of PS-isocyanate (Argonaut Technologies) at room temperature, followed by stirring for 2 hours, and the insoluble product was filtered. The filtrate was concentrated under reduced pressure to get to 8.8 mg of 2-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}ethanol.

Conditions of HPLC performed to determine RT, shown below.

Column: Wakosil-II 5C18AR (registered trademark) (particle size: 5 μm, inner diameter: 2.0 mm length: 30 mm).

Table 3
Time (min)And the solution (%)In solution (%)
0-490→010→100
4-4,50100

Mobile phase: a solution of 5 mm aqueous solution triperoxonane acid In the solution, methanol

Flow rate: 1.2 ml/mi is

Wavelength definition: 254 nm

The temperature of the column: 35,0°C

The volume of injection: 5 ál

Connection examples up to example 48, shown in the following tables, obtained in a manner analogous to the methods of the above examples. The methods of production and patterns of the corresponding compounds of examples are shown in tables 4, 5, 8, and 9, and the physicochemical data are shown in tables 6, 7, and 10.

In addition, the structures of other compounds of this invention are shown in table 11. These compounds can be easily obtained according to the above methods of preparation, methods described in the examples and methods obvious to a person skilled in this field, or their modifications.

14
Table 4
Etc.Syn (Ex)The structural formulaEtc.Syn (Ex)The structural formula
112 1
3141
5161
7181
91101
111121
1311
151161

Table 5
Etc.Syn (Ex)The structural formulaEtc.Syn (Ex)The structural formula
171181
191201
211221
2312424
25252626
27272828
29293030
3131

Table 6
ExampleData
1NMR d6(400 MHz): 1,09-to 1.21 (8H, m)of 1.33 (2H, d, J=5.6 Hz), 1,75-1,89 (3H, m), 3,03 (2H, m), 4,12 (1H, s), 4,34 (2H, m), of 6.71 (1H, m), 7,17 (1H, m), 7,41 (1H, m), the 7.65 (1H, m), 11,74 (1H, s); FAB+: 335; TPL: 178-180°C
2FAB+: 335
3FAB+: 319
4FAB+: 319
5FAB+: 379
6FAB+: 353
7FAB+: 369
8FAB+: 369
9NMR d6(400 MHz): 1,11-to 1.21 (8H, m)of 1.34 (2H, d, J=5.6 Hz), 1,76-of 1.88 (3H, m), 3,03 (2H, m), 4,12 (1H, s), 4,37 (2H, m), 6,72 (1H, m), 7,03 (1H, m), 7,17 (1H, m), 7,40 (1H, m), to 7.59 (1H, m), 11,51 (1H, s); FAB+: 301; TPL: 153-163°C
10FAB+: 331
11FAB+: 331
12FAB+: 385
13FAB+: 407
14FAB+: 287
15NMR d6(400 MHz): 1,08-to 1.21 (8H, m)of 1.33 (2H, d, J=5,2 Hz), 1,72-to 1.87 (3H, m, 2,82-3,17 (2H, m), 4,11 (1H, s), 4,36 (2H, d, J=13,2 Hz), 6,53 (1H, m), 6,70 (1H, m), 6.87 in (1H, m), 7,20 (1H, m), 8,76 (1H, s), 11,20 (1H, s); FAB+: 317; TPL: 212-219°C
16FAB+: 345
17NMR d6(400 MHz): 1,05-1,18 (8H, m)of 1.33 (2H, d, J=5,2 Hz), 1,71-of 1.84 (3H, m), of 2.21 (3H, s), of 2.38 (3H, s), of 2.97 (2H, m), Android 4.04 (2H, m), 4,10 (1H, s), 6,97 (1H, m), 7,20 (1H, m), 7,30 (1H, m), br11.01 (1H, s); FAB+: 329; TPL: 166-168°C
18FAB+: 315
19FAB+: 357
20NMR d6(400 MHz): 1,11-of 1.23 (8H, m)of 1.33 (2H, d, J=5,2 Hz), 1.77 in-1,90 (3H, m), 2.77-to of 3.28 (2H, m), 4,12 (1H, s), 4,34 (2H, m), 7,03 (1H, m), 7,56 (1H, m), 8,07 (1H, m)8,64 (1H, m), to 12.28 (1H, s); FAB+: 346;
TPL: 223-225°C

Table 7
ExampleData
21EI: 272
22NMR d6(400 MHz): 1,11-1,19 (2H, m), 1,38 was 1.43 (2H, m), of 1.73 to 1.76 (3H, m), a 2.36 (3H, s), 2,98 (2H, s), 3.45 points-to 3.49 (2H, m), 4,37-of 4.44 (3H, m), 6,63 (1H, m), 7,00 (1H, m), 7,29 (1H, m), of 7.36 (1H, s), 11,38 (1H, s); EI: 286; TPL: 163-165°C
23FAB+: 273
24 NMR d6(400 MHz): 1,08-to 1.21 (8H, m)of 1.33 (2H, d, J=5.6 Hz), 1,75-of 1.88 (3H, m), a 2.36 (3H, s), a 3.01 (2H, m), 4,11 (1H, s), 4,37 (2H, m), 6,62 (1H, m), of 6.99 (1H, m), 7,29 (1H, m), of 7.36 (1H, m), 11,37 (1H, s); FAB+: 315; TPL: 149-150°C
25NMR d6(400 MHz): 1,11-to 1.21 (8H, m)of 1.33 (2H, d, J=5,2 Hz), 1,75-of 1.88 (3H, m), 3,01 (2H, m in), 3.75 (3H, s), 4,11 (1H, s), 4,36 (2H, m), 6,63 (1H, m), PC 6.82 (1H, m), 7,06 (1H, m), 7,29 (1H, m), 11,36 (1H, s); FAB+: 331; TPL: 149-151°C
26FAB+: 333
27FAB+: 316
28FAB+: 358
29FAB+: 366
30NMR d6(400 MHz): 1,02-of 1.24 (6H, m)of 1.34 (1H, m), 1,69 of-1.83 (3H, m), 2,81-3,18 (2H, m), and 3.72 (1H, m), 4,36 (1H, d, J=4,8 Hz), 4,42 (2H, m), 6.73 x (1H, m), 7,03 (1H, m), 7,17 (1H, m), 7,40 (1H, m), to 7.59 (1H, m), to 11.52 (1H, s); FAB+: 287; TPL: 163-167°C
31FAB+: 273

td align="center"> 32
Table 8
Etc.Syn (Ex)The structural formulaEtc.Syn (Ex)The structural formula
323332
34323532
36323732
38323932
40324132

Table 9
Etc. Syn (Ex)The structural formulaEtc.Syn (Ex)The structural formula
42324332
44324532
46324732
4832

Table 10
ExampleData
32RT: 2,16 ESI+: 291
33RT: 2,47ESI+: 307
34RT: 1,94ESI+: 303
35RT: 2,73ESI+: 379
36RT: 1,21ESI+: 289
37RT: 2,56ESI+: 301
38RT: 2,01ESI+: 318
39RT: 2,18ESI+: 291
40RT: 2,45ESI+: 307
41RT: to 2.06ESI+: 303
42RT: to 2.29ESI+: 309
43RT: 2,27ESI+: 309
44RT: 1,69ESI+: 317
45RT: 1,80ESI+: 333
46 RT: 1,74ESI+: 333
47RT: 1,30ESI+: 348
48RT: 2,48ESI+: 409

Table 11
No.The structural formulaNo.The structural formula
12
34
56
78
910
1112
1314
15

INDUSTRIAL APPLICABILITY

Because of this connection, which is an active ingredient of a medicinal product of this invention has a selective inhibitory effect against 17βHDS type 5 and on the basis of this excellent pharmacological activity, pharmaceutical composition of the present invention can be used as a means for the treatment and/or prevention of diseases associated with 17βHDS type 5, especially prostate cancer, benign prostate hyperplasia, acne, seborrhea, hirsutism, baldness, alopecia, early puberty, adrenal hypertrophy, polycystic ovary cancer, breast cancer, lung cancer, endometriosis, leiomyoma, or the like.

1. The compound of formula (I) or the pharmacist who Cesky acceptable salt: [Jim]

where R1, R2and R3that are the same or different, represent H or lower alkyl;
R4, R5, R6, R7and R8that are the same or different, represent H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or
R6and R7combined with education About the lowest alkylen-O-;
R0that is the same or different, represents H
or lower alkyl;
R10and R11that are the same or different, represent H, lower alkyl; and
X, which is the same or different, represents a bond or a lower alkylene.

2. The compound of formula (Ia) or its pharmaceutically acceptable salt: [Jim]

where all symbols have the same meanings as in claim 1.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, where R1and R3represent N.

4. The compound according to claim 3 or its pharmaceutically acceptable salt, where R4, R5, R7and R8that are the same or different, represent H, lower alkyl, halogen, or-O-lower alkyl, and R6represents H, lower alkyl, halogen, nitro, HE or-O-n is SSI alkyl.

5. The compound according to claim 2 or its pharmaceutically acceptable salt, where R1and R2represent lower alkyl, and R3represents N.

6. The compound according to claim 5 or its pharmaceutically acceptable salt, where R4, R5, R7and R8that are the same or different, represent H, lower alkyl, halogen, or-O-lower alkyl.

7. The compound according to claim 5 or 6, or its pharmaceutically acceptable salt, where R6represents H, lower alkyl, halogen, nitro, or-O-lower alkyl.

8. The connection according to claim 7 or its pharmaceutically acceptable salt, where R6represents lower alkyl, halogen, or-O-lower alkyl.

9. The compound according to claim 5, which is selected from the group including
1-[1-(1H-indol-2-ylcarbonyl)piperidine-4-yl]-2-methylpropan-2-ol,
2-methyl-1-{1-[(4-methyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol,
2-methyl-1-{1-[5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol,
1-{1-[(5-tert-butyl-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(4-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(4-chloro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(5-bromo-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methyl shall ropan-2-ol,
1-{1-[(7-chloro-5-fluoro-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
2-{[4-(2-hydroxy-2-methylpropyl " piperidine-1-yl]carbonyl}-1H-indol-5-ol,
1-{1-[(4-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
1-{1-[(6-methoxy-1H-indol-2-yl)carbonyl]piperidine-4-yl}-2-methylpropan-2-ol,
2-methyl-1-(1-{[5-(triptoreline)-1H-indol-2-yl]carbonyl}piperidine-4-yl)propan-2-ol, and
2-methyl-1-{1-[(5-nitro-1H-indol-2-yl)carbonyl]piperidine-4-yl}propan-2-ol, or its pharmaceutically acceptable salt.

10. The pharmaceutical composition exhibiting inhibitory activity against 17β-hydroxysteroid-dehydrogenase (17βHSD type 5 containing the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, solvent or excipient.

11. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of pharmaceutical compositions showing inhibitory activity against 17β-hydroxysteroid-dehydrogenase (17βHSD type 5.

12. The use of compounds according to claim 1 or its pharmaceutically acceptable salt as a means of inhibiting the activity of 17β-hydroxysteroid-dehydrogenase (17βHSD type 5.

13. Method of inhibiting 17β-hydroxysteroid-dehydrogenase (17βHSD type 5, comprising an introduction to patient effective the th number of compounds according to claim 1 or its pharmaceutically acceptable salt.

14. Inhibitor 17βHSD type 5 containing the compound according to claim 1 or its pharmaceutically acceptable salt.

15. Method of preparation of pharmaceutical compositions showing inhibitory activity against 17β-hydroxysteroid-dehydrogenase (17βHSD type 5, comprising mixing the compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, solvent or excipient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of noscapine of the general formula (1) or its racemates, optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing anticarcinogenic activity, and to a pharmaceutical composition as tablets, capsules or injection formulations placed into pharmaceutically acceptable package, ant to methods for their synthesis, and to a method for inhibition of proliferation by their using. In compounds of the formula (1) R1 represents a substitute of amino-group chosen from alkyl; R2 represents a substitute of cyclic system chosen from possibly substituted alkyl wherein substitutes are chosen from possibly substituted amino-group or azaheterocycle comprising possibly oxygen (O), sulfur (S) or nitrogen (N) atoms as an additional heteroatom, and added to alkyl group by nitrogen atom, possibly substituted aryl possibly substituted and possibly condensed heteroaryl comprising at least one heteroatom chosen from nitrogen, sulfur and oxygen atoms, possibly substituted sulfamoyl. Except for, invention relates to 3-(9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 3-(9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, 5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-9-carbaldehyde (or -9-carbonitrile, or -9-sulfonyl chloride, or -9-carboxylic acid) and 3-(9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo-[4,5-g]-isoquinoline-5-yl)-6,7-dimethoxy-3H-isobenzofuran-1-one, and method for their synthesis. Also, invention relates to combinatory and focused libraries.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 5 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of formula I or their pharmaceutically acceptable salts showing activity with respect to HIV reverse transcriptase, as well as to a based pharmaceutical composition (I). In formula I R1 means phenyl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, phenyl or heteroaryl optionally substituted by one-three substitutes independently specified in groups (a)-(r), R2 means -CN, -CH=CHCN or halogen; R3 means hydrogen, halogen, amino group, halogen(C1-C6)alkyl, -CN or methyl; R4 means hydrogen, Br or amino group; R5a and R5b independently mean hydrogen, C1-C6alkyl, C1-C6alkoxy group or halogen; R6a and R6b either independently mean hydrogen, or together mean ethylene; X means NH or O. The groups (a)-(r) are such as presented in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing activity with respect to HIV reverse transcriptase.

17 cl, 42 ex, 6 dwg, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to crystalline forms A, B and F of racemic ilaprazole (2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl]thionyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole). The invention also relates to a pharmaceutical composition based on crystalline ilaprazole and use of crystalline ilaprazole.

EFFECT: obtaining novel crystalline forms of ilaprazole which can be used to inhibit gastric acid secretion.

14 cl, 57 dwg, 39 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to new heterocyclic compounds of formula I wherein: n and m may have values 0, 1, 2 and 3; the sign (#) in what follows means the potential presence of a chiral centre; R represents optionally substituted C5-C10aryl or 5-6-member hetaryl containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur optionally condensed with a benzene ring with the substitutes specified in C1-C8alkyl, C1-C8alkoxy, halogen, OH, CF3, NO2, CF3O, COOH, an unsubstituted amino group or mono-C1-6alkyl- or di(C1-6alkyl)substituted amino-group, C1-8alkylsulphanyl, C1-8alkoxycarbonyl; A1 and A2 independently represent optionally substituted 5-6 member saturated, or aromatic azaheterocycle containing 1 to 2 nitrogen atoms in the cycle and optionally condensed with the benzene ring; or to their pharmaceutically acceptable salts or alkyl esters in the form of isolated optical isomers, or their mixtures. Also, the invention refers to a pharmaceutical composition on the basis of the compound of formula I, to a drug on the basis of the compound of formula I, as well as to a method for preparing the compound of formula I.

EFFECT: there are prepared new non-peptide heterocyclic low-molecular peptidomimetics of a secretory amyloid peptide precursor sAAP showing an ability to have an effective effect on the processes of formation, storage and restoration of the memory lost in health and none.

10 cl, 4 dwg, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of ilaprazole hydrate (2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl]sulphinyl]-5-(1H-pyrrol-1-yl) 1H-benzimidazole). The invention also relates to a pharmaceutical composition for inhibiting gastric acid secretion, as well as a method of treating inflammatory gastrointestinal disorders.

EFFECT: novel crystalline form of ilaprazole hydrate is obtained.

7 cl, 21 dwg, 19 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) p equals 1 or 2; R1 is methyl, ethyl, propyl, isobutyl, 2-fluoroethyl or cyclobutyl; m equals 0; each R2 is absent; n equals 0; each R3 is absent; R4 is a hydrogen atom; R5 is a hydrogen atom; R6 is -C(O)O-R6a; R6a is a C1-C6alkyl group which can have 1-3 substitutes selected from a group of substitutes α, where the group of substitutes α is a group consisting of a halogen atom, a hydroxyl group, a C1-C6alkoxy group, a C3-C7cycloalkyl group, an amino group, a mono- or di(C1-C6alkyl)amino group, a phenyl group, and a furyl group; and R7 is a hydrogen atom.

EFFECT: compounds have the property of reducing the blood glucose level and can be used to treat and/or prevent type 1 sugar diabetes, type 2 sugar diabetes or diabetes-associated diseases caused by low glucose tolerance, as well as to prevent obesity caused by low glucose tolerance.

11 cl, 2 tbl, 119 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered 5-substituted quinazolinone compounds having general structural formulas (II), (III) and (IV) or their pharmaceutically acceptable salts and stereomers. The radicals and symbols in the structural formulas presented below are designated as shown in the patent claim.

EFFECT: there are disclosed the methods for using and the pharmaceutical compositions of quinazolinone compounds.

16 cl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

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