Substituted Pyrrole Derivative

• US 20080176906A1
• Filed: 12/13/2005
• Published: 07/24/2008
• Est. Priority Date: 12/14/2004
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Matsunaga, Nobuyuki, Hitaka, Takenori
• Application Number:
  US11/793,113
• Publication Number:
  US 20080176906A1
• Time in Patent Office: Days
• US Class Current: 514/343
• 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 5/28 Antiandrogens
• CPC Class Codes: C07D 207/327 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/34 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 ring carbon atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The present invention provides a novel pyrrole derivative having excellent androgen receptor antagonism, which is represented by the formula:

wherein R¹ represents a hydrogen atom, a cyano group or a group represented by the formula COOR^A (wherein R^A represents an optional substituted C_1-6 alkyl group), R² and R⁴ are the same or different, and each represents a hydrogen atom, a C_1-6 alkyl group, a C_3-6 cycloalkyl group, a trifluoromethyl group, an amino-C_1-6 alkyl group, a mono- or di-substituted amino-C_1-6 alkyl group, an optionally halogenated C_1-6 alkyl group substituted with an optionally substituted hydroxyl group, a C_2-6 alkenyl group substituted with an optionally substituted hydroxyl group, a C_1-6 alkyl group substituted with an optionally substituted and optionally oxidized thiol group, an optionally substituted with and optionally oxidized thiol group, a cyano group, an acyl group, an optionally substituted oxazolyl group or a 1,3-dioxolan-2-yl group, R³ represents a group represented by the formula:

(wherein X represents a halogen atom, Y represents a carbon atom or a nitrogen atom, Alk represents an optionally substituted C_1-4 alkylene group, and R^B represents a hydrogen atom or an acyl group), and R⁵ represents a phenyl group which has a cyano group at a 4-position or a 3-position thereof, and may be further substituted, or a salt thereof. The present invention also provides an androgen receptor antagonist containing the pyrrole derivative, or a salt thereof.

Claims

1. A compound represented by the formula:

2. The compound according to claim 1, wherein R¹ is a cyano group.

3. The compound according to claim 1, wherein R² is a C_1-6 alkyl group, a C_3-6 cycloalkyl group, a trifluoromethyl group, an amino-C_1-6 alkyl group, a mono- or di-substituted amino-C_1-6 alkyl group, a C_1-6 alkyl group substituted with an optionally substituted hydroxyl group, a C_1-6 alkyl group substituted with an optionally substituted and optionally oxidized thiol group, an optionally substituted and optionally oxidized thiol group, a cyano group or an acyl group.

4. The compound according to claim 1, wherein R² is a C_1-6 alkyl group, a C_3-6 cycloalkyl group, a trifluoromethyl group, an amino-C_1-6 alkyl group, a mono- or di-substituted amino-C_1-6 alkyl group, a C_1-6 alkyl group substituted with an optionally substituted hydroxyl group, a C_1-6 alkyl group substituted with an optionally substituted and optionally oxidized thiol group, a cyano group or an acyl group.

5. The compound according to claim 3, wherein R² is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a mono- or di-substituted amino-methyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxyisopropyl group, a C_1-6 alkyloxymethyl group, a C_1-6 alkylthio group, a C_1-6 alkylsulfonyl group, a C_1-6 alkylthiomethyl group, a C_1-6 alkylsulfonylmethyl group, an acetyl group, a carbamoyl group or a mono- or di-substituted carbamoyl group.

6. The compound according to claim 3, wherein R² is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a mono- or di-substituted amino-methyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxyisopropyl group, a C_1-6 alkyloxymethyl group, a C_1-6 alkylthiomethyl group, a C_1-6 alkylsulfonylmethyl group, an acetyl group, a carbamoyl group or a mono- or di-substituted carbamoyl group.

7. The compound according to claim 1, wherein R³ is a group represented by the formula:

8. The compound according to claim 7, wherein X is a chlorine atom or a fluorine atom.

9. The compound according to claim 7, wherein R^B is a hydrogen atom, a succinoyl group or a dimethylaminomethylcarbonyl group.

10. The compound according to claim 7, wherein Alk is a methylene group.

11. The compound according to claim 1, wherein R⁴ is a C_1-6 alkyl group, a C_3-6 cycloalkyl group, a trifluoromethyl group, an amino-C_1-6 alkyl group, a mono- or di-substituted amino-C_1-6 alkyl group, a C_1-6 alkyl group substituted with an optionally substituted hydroxyl group, a C_1-6 alkyl group substituted with an optionally substituted and optionally oxidized thiol group, an optionally substituted and optionally oxidized thiol group, a cyano group or an acyl group.

12. The compound according to claim 1, wherein R⁴ is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a mono- or di-substituted amino-methyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxyisopropyl group, a C_1-6 alkyloxymethyl group, a C_1-6 alkylthio group, a C_1-6 alkylsulfonyl group, a C_1-6 alkylthiomethyl group, a C_1-6 alkylsulfonylmethyl group, an acetyl group, a carbamoyl group or a mono- or di-substituted carbamoyl group.

13. The compound according to claim 1, wherein R⁵ is a 4-cyanophenyl group, a 3-cyanophenyl group, or a 4-cyano-3-(trifluoromethyl)phenyl group.

14. The compound according to claim 1, wherein R¹ is a hydrogen atom, a cyano group or a C_1-6 alkoxycarbonyl group,

R² is (i) a hydrogen atom,

(ii) an optionally halogenated C_1-6 alkyl group,

(iii) a C_3-6 cycloalkyl group,

(iv) a trifluoromethyl group,

(v) a C_1-6 alkyl group substituted with an amino mono- or di-substituted with C_1-6 alkyl,

(vi) an optionally halogenated C_1-6 alkyl group substituted with a hydroxyl group optionally substituted with C_1-6 alkyl,

(vii) a C_2-6 alkenyl group substituted with a hydroxyl group,

(viii) a C_1-6 alkyl group substituted with an optionally oxidized thiol group optionally substituted with C_1-6 alkyl,

(ix) an optionally oxidized thiol group optionally substituted with C_1-6 alkyl,

(x) a cyano group,

(xi) a C_1-6 alkanoyl group,

(xii) an oxazolyl group, or

(xiii) a 1,3-dioxolan-2-yl group,

Alk is a C_1-4 alkylene group optionally substituted with an optionally halogenated C_1-6 alkyl,

R^B is (i) a hydrogen atom, (ii) a carbamoyl group, (iii) a carboxy-C_1-6 alkyl-carbonyl group or (iv) a mono- or di-C_1-6 alkylamino-C_1-6 alkyl-carbonyl group,

X is a halogen atom,

Y is a carbon atom or a nitrogen atom,

R⁴ is a C_1-6 alkyl group optionally substituted with a hydroxyl group, a trifluoromethyl group, or a cyano group,

R⁵ is a phenyl group which has a cyano group at a 4-position or a 3-position thereof, and may be substituted with an optionally halogenated C_1-6 alkyl.

15. The compound according to claim 1, wherein R¹ is a hydrogen atom, a cyano group or a methoxycarbonyl group, R² is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a trifluoromethyl group, a 1-hydroxyethyl group or an acetyl group, R³ is a 6-chloro-5-(hydroxymethyl)pyridin-3-ylmethyl group, a 6-chloro-5-(1-hydroxy-2,2,2-trifluoroethyl)pyridin-3-ylmethyl group, a 4-chloro-3-(1-hydroxy-2,2,2-trifluoroethyl)benzyl group, a 4-chloro-3-(acetoxymethyl)benzyl group or a 4-chloro-3-(hydroxymethyl)benzyl group, R⁴ is a cyano group, a methyl group or an ethyl group, and R⁵ is a 4-cyano-2-fluorophenyl group or a 4-cyanophenyl group.

16. The compound according to claim 1, wherein R¹ is a hydrogen atom, a cyano group or a methoxycarbonyl group, R² is a methyl group, an ethyl group, a propyl group, a cyclopropyl group or a trifluoromethyl group, R³ is a 6-chloro-5-(hydroxymethyl)pyridin-3-ylmethyl group, a 6-chloro-5-(1-hydroxy-2,2,2-trifluoroethyl)pyridin-3-ylmethyl group, a 4-chloro-3-(1-hydroxy-2,2,2-trifluoroethyl)benzyl group, a 4-chloro-3-(acetoxymethyl)benzyl group or a 4-chloro-3-(hydroxymethyl)benzyl group, R⁴ is a cyano group, a methyl group or an ethyl group, and R⁵ is a 4-cyano-2-fluorophenyl group or a 4-cyanophenyl group.

17. A prodrug of the compound according to claim 1.

19. A process for preparing the compound according to claim 1 or a salt thereof, which comprises the steps of:

subjecting a compound represented by the formula;

18. (i) 1-{[6-Chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile,

(ii) 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrole-3-carbonitrile,

(iii) 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-5-methyl-2-propyl-1H-pyrrole-3-carbonitrile,

(iv) 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2-cyclopropyl-5-methyl-1H-pyrrole-3-carbonitrile,

(v) 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(3-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile,

(vi) 1-[4-chloro-3-(hydroxymethyl)benzyl]-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile,

(vii) 2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl]methyl}benzyl N,N-dimethylglycinate,

(viii) 4-[(2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrol-1-yl]methyl}benzyl)oxy]-4-oxobutanoic acid,

(ix) 4-[(2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-5-methyl-2-propyl-1H-pyrrol-1-yl]methyl}pyridin-3-yl)methoxy]-4-oxobutanoic acid,

(x) 4-[(2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2-ethyl-5-methyl-1H-pyrrol-1-yl]methyl}pyridin-3-yl)methoxy]-4-oxobutanoic acid,

(xi) 4-[(2-chloro-5-{[3-cyano-4-(4-cyanophenyl)-2-cyclopropyl-5-methyl-1H-pyrrol-1-yl]methyl}pyridin-3-yl)methoxy]-4-oxobutanoic acid,

(xii) 1-{[6-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile,

(xiii) 4-(1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-2,5-dimethyl-1H-pyrrol-3-yl)benzonitrile,

(xiv) 4-(1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-5-cyclopropyl-2-methyl-1H-pyrrol-3-yl)benzonitrile, or

(xv) 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-3-(4-cyanophenyl)-5-methyl-1H-pyrrole-2-carbonitrile, or a salt thereof.

20. A medicament comprising a compound represented by the formula:

21. The medicament according to claim 20, which is an androgen receptor antagonist.

22. The medicament according to claim 20, wherein the androgen receptor is a normal androgen receptor and/or a mutated androgen receptor.

23. The medicament according to claim 20, which is an agent for preventing or treating hormone-sensitive cancer at an androgen dependent term and/or at an androgen independent term.

24. The medicament according to claim 20, which is an agent for preventing or treating prostate cancer.

25. A medicament which comprises a combination of a compound represented by the formula:

26. The medicament according to claim 25, wherein the anti-cancer drug is an LH-RH derivative.

27. A method for antagonizing an androgen receptor of a mammal which comprises administering an effective amount of a compound represented by the formula:

28. A method for preventing or treating hormone-sensitive cancer at an androgen dependent term and/or at an androgen independent term, which comprises administering an effective amount of a compound represented by the formula:

30. The method according to claim 28, wherein an effective amount of an anti-cancer drug is further administered.

31. The method according to claim 30, wherein the anti-cancer drug is an LH-RH derivative.

29. A method of preventing or treating prostate cancer, which comprises administering an effective amount of a compound represented by the formula:

37. The method according to claim 29, wherein an effective amount of an anti-cancer drug is further administered.

38. The method according to claim 37, wherein the anti-cancer drug is an LH-RH derivative.

32-36. -36. (canceled)