Cyclic amine compounds

• US 20090042967A1
• Filed: 08/06/2008
• Published: 02/12/2009
• Est. Priority Date: 08/07/2007
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Hasuoka, Atsushi
• Granted Patent: US 7,834,051 B2
• Time in Patent Office: Days
• US Class Current: 514/409
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/273 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 209/54 Spiro-condensed

Abstract

The present invention relates to pharmaceutical agents which are agents for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis; the pharmaceutical agents frailty suppressants, muscle strength enhancers, muscle increasing agents, cachexia suppressants, body weight decrease suppressants, agents for the prophylaxis or treatment of prostate hypertrophy, amyotrophy or muscle loss caused by a disease or an agent for reducing the prostate weight.

The present invention also relates to methods for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis in a mammal, which comprises administering an effective amount of the pharmaceutical agents of the present invention or a prodrug thereof; use of the pharmaceutical agents of the present invention or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis; and the like.

Claims

1. A compound represented by the formula (I)

2. The compound of claim 1, wherein Ring A is a pyrrolidine ring optionally further having substituent(s) or a piperidine ring optionally further having substituent(s) (the pyrrolidine ring and piperidine ring optionally form a spiro bond with C_3-6 cycloalkane).

3. The compound of claim 1, wherein

R¹ is a hydrogen atom, a halogen atom or a lower alkyl group optionally having substituent(s);

R² is a halogen atom, a lower alkyl group optionally having substituent(s) or a lower alkoxy group optionally having substituent(s);

R³ is a cyano group;

R⁴ is a hydrogen atom or a halogen atom;

R⁵ is a hydrogen atom;

R⁶ is a hydrogen atom;

R⁷ is a lower alkyl group optionally having substituent(s) or an aralkyl group optionally having substituent(s);

R⁸ is a hydrogen atom, a lower alkyl group optionally having substituent(s) or a C_3-6 cycloalkyl group optionally having substituent(s);

R⁹ is a hydroxy group; and

Ring A is a pyrrolidine ring which optionally has 1 or 2 substituents selected from a halogen atom, a lower alkyl group optionally having a hydroxy group, a lower alkenyl group and an aralkyl group, or a pyrrolidine ring forming a spiro bond with C_3-6 cycloalkane.

4. The compound of claim 1, wherein the formula (I) is the formula (I′

)

5. The compound of claim 4, wherein R¹ is a hydrogen atom, a halogen atom or a lower alkyl group;

R² is a halogen atom, a lower alkyl group optionally having halogen atom(s) or a lower alkoxy group optionally having halogen atom(s);

R⁷ is a lower alkyl group optionally having substituent(s) selected from a hydroxy group, a lower alkoxy group and a C_3-6 cycloalkyl group, or an aralkyl group optionally having substituent(s) selected from a halogen atom and a cyano group;

R⁸ is a hydrogen atom, a lower alkyl group or a C_3-6 cycloalkyl group; and

R¹⁰ and R¹¹ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group, or a lower alkyl group substituted by a hydroxyl group (in this case, R¹⁰ and R¹¹ optionally form cyclopropane together with the adjacent carbon atom).

16. A prodrug of the compound of claim 1.

17. A pharmaceutical agent comprising the compound of claim 1 or a prodrug thereof.

18. The pharmaceutical agent of claim 17, which is an androgen receptor modulator.

19. The pharmaceutical agent of claim 17, which is an androgen receptor agonist.

20. The pharmaceutical agent of claim 17, which is a tissue-selective androgen receptor modulator.

21. The pharmaceutical agent of claim 17, which is an agent for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis.

22. The pharmaceutical agent of claim 17, which is a frailty suppressant, a muscle strength enhancer, a muscle increasing agent, a cachexia suppressant, a body weight decrease suppressant, an agent for the prophylaxis or treatment of prostate hypertrophy, amyotrophy or muscle loss caused by a disease or an agent for reducing the prostate weight.

23. A method for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis in a mammal, which comprises administering an effective amount of the compound of claim 1 or a prodrug thereof.

24. Use of the compound of claim 1 or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypogonadism, male climacteric disorder, frailty, cachexia or osteoporosis.

6. 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, or a salt thereof.

7. 2-Chloro-4-[(4S,5S)-4-hydroxy-5-methyl-2-oxopyrrolidin-1-yl]benzonitrile, or a salt thereof.

8. 4-[(4R,5S)-5-ethyl-3,3-difluoro-4-hydroxy-2-oxopyrrolidin-1-yl]-2-methoxybenzonitrile, or a salt thereof.

9. 2-Chloro-4-[(2S,3S,4S)-2-ethyl-3-hydroxy-4-methyl-5-oxopyrrolidin-1-yl]benzonitrile, or a salt thereof.

10. 2-Chloro-4-[(4R,5S)-5-ethyl-3,3-difluoro-4-hydroxy-2-oxopyrrolidin-1-yl]benzonitrile, or a salt thereof.

11. 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile.

12. 2-Chloro-4-[(4S,5S)-4-hydroxy-5-methyl-2-oxopyrrolidin-1-yl]benzonitrile.

13. 4-[(4R,5S)-5-ethyl-3,3-difluoro-4-hydroxy-2-oxopyrrolidin-1-yl]-2-methoxybenzonitrile.

14. 2-Chloro-4-[(2S,3S,4S)-2-ethyl-3-hydroxy-4-methyl-5-oxopyrrolidin-1-yl]benzonitrile.

15. 2-Chloro-4-[(4R,5S)-5-ethyl-3,3-difluoro-4-hydroxy-2-oxopyrrolidin-1-yl]benzonitrile.