Heterocyclic compounds

• US 20030207893A1
• Filed: 03/08/2002
• Published: 11/06/2003
• Est. Priority Date: 03/09/2001
• Status: Active Grant

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Carruthers, Nicholas I., Edwards, James P., Grice, Cheryl A., Dvorak, Curt A., Chai, Wenying, Thurmond, Robin L., Kwok, Annette K., Lovenberg, Timothy W., Karlsson, Lars, Shah, Chandravadan R., Pio, Barbara, Xiao, Wei, Jablonowski, Jill A., Wei, Jianmei, Khatuya, Haripada, Sun, Siquan, Ly, Kiev S., Kreisberg, Jennifer D.
• Granted Patent: US 6,803,362 B2
• Time in Patent Office: Days
• US Class Current: 514/254.02
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 209/42 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 401/12 linked by a chain containing hetero atoms as chain links

Abstract

Heterocyclic compounds and methods of making them and using them.

Claims

1. A compound of formula (I) wherein:

2. A compound of claim 1 of the following formula wherein:

3. A compound of claim 1, wherein R₁ is R_a, R_aR_b—

, R_a—

O—

R_b—

, or (R_c)(R_d)N—

R_b—

, where R_a is H, C_1-10 alkyl, C_2-5 alkenyl, C_3-8 cycloalkyl, C_2-5 heterocyclic radical, or phenyl;

where R_b is C_1-6 alkylene, or C_2-8 alkenylene; and

R_c and R_d are each independently H, C_1-8 alkyl, C_2-8 alkenyl, C_3-8 cycloalkyl, or phenyl;

R_2′

is methyl or H;

R_3′

is methyl or H;

R_5′

is methyl or H;

R_6′

is methyl or H;

R_7′

is methyl or H;

X₁ is CR₃;

R₃ is F, Cl, Br, methyl, ethyl, or propyl;

X₂ is NR_e or O, provided that X₂ is NR_e where X₁ is N;

R_e is H or C_1-6 alkyl;

X₃ is N;

Z is ═

O or ═

S;

each of R₄ and R₆ is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C_1-3 alkoxy, or C_1-3 alkyl;

R₅ is H, F, Cl, Br, I, (C═

O)R_j, OH, nitro, NR_jR_k, cyano, —

OCH₂—

Ph, C_1-4 alkoxy, or C_1-4 alkyl;

R₇ is H, F, Cl, Br, I, (C═

O)R_m, OH, nitro, NR_lR_m, cyano, C_1-4 alkoxy, or C_1-4 alkyl;

wherein each of R_j, R_k, R_l, and R_m is independently selected from H, C_1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C_1-6 alkoxy;

each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C_1-3 alkyl, halo, hydroxy, amino, and C_1-3 alkoxy;

n is 1;

provided at least one of R₁, R_2′

, R₃, R₄, R₅, R₆, and R₇ is other than H when Z is O;

or a pharmaceutically acceptable salt, ester, or amide thereof.

4. A compound of claim 1, wherein

R₁ is H, methyl, or ethyl;

One of R_2′

and R_3′

is methyl, and the other is H, where R₁ is H;

R₂ is otherwise H;

X₁ is CR₃;

R₃ is H, F, Cl, or Br;

X₂ is NR_e or O;

R_e is H or C_1-3 alkyl;

Z is ═

O or ═

S;

each of R₄ and R₆ is independently H, OH, C_1-4 alkyl, C_1-4 alkoxy, cyano, or amino;

R₅ is H, F, Cl, Br, COOH, OH, amino, cyano, C_1-4 alkoxy, or C_1-4 alkyl; and

R₇ is H, F, Cl, Br, C_1-4 alkyl, C_1-4 alkoxy, cyano, or amino;

provided at least one of R₅ and R₇ is not H.

5. A compound of claim 1, wherein

R₁ is H, methyl, or ethyl;

R_2′

and R_3′

are independently methyl or H;

X₁ is CR₃ or N;

R₃ is H, F, or Cl;

X₂ is NR_e or O, provided that X₂ is NR_e where X₁ is N;

R_e is H or C_1-6 alkyl;

Z is ═

O or ═

S;

each of R₄ and R₆ is H;

R₅ is H, F, Cl, Br, methyl, ethyl, or propyl; and

R₇ is H, F, Cl, Br, or C_1-4 alkyl;

provided at least one of R₅ and R₇ is not H.

6. A compound of claim 1, wherein X₂ is N.

7. A compound of claim 1, wherein X₂ is O.

8. A compound of claim 1, wherein R₁ is H, methyl or ethyl.

9. A compound of claim 8, wherein R₁ is methyl.

10. A compound of claim 1, wherein R_2′

is H.

11. A compound of claim 1, wherein R_2′

is methyl.

12. A compound of claim 1, wherein R₃ is H or Cl.

13. A compound of claim 12, wherein R₃ is Cl.

14. A compound of claim 1, wherein R₅ is F, Cl, Br, or methyl and R₇ is F, Cl, or Br.

15. A compound of claim 1, wherein each of R₅ and R₇ is independently selected from H, F, Cl, Br, and methyl, provided at least one of R₅ and R₇ is not H.

16. A compound of claim 1, wherein each of R₄ and R₆ is independently H, methyl, or Cl.

17. A compound of claim 1, wherein R₃ is H or Cl;

R₅ is F, Cl, Br, or methyl; and

R₇ is H, F, Cl, or Br.

18. A compound of claim 17, wherein each of R₄ and R₆ is independently H, methyl, or Cl.

19. A compound of claim 1, wherein Z is ═

S.

20. A compound of claim 1 selected from:

(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

21. A compound of claim 1 selected from:

(6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;

(7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione.

22. A compound of claim 20 selected from:

(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Difluoro-1H-indol -2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

23. A compound of claim 1, selected from:

(4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-1H-indol-2-yl)-methanone;

(7-Amino-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Amino-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(7-Amino-5-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Amino-7-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Fluoro-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(7-Fluoro-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(6-Bromo-5-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-6-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(6-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(4-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(6-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(4-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

24. A compound of claim 1, selected from:

(5,7-Dichloro-1H-indol-2-yl)-piperazin-1-yl-methanone;

(5,7-Difluoro-1H-indol-2-yl)-piperazin-1-yl-methanone;

(5,7-Difluoro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;

(5,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(4,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.

25. A compound of claim 1, selected from:

1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methyl ester;

4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methyl ester;

4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid amide;

1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid amide;

4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methylamide;

1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methylamide;

4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid dimethylamide;

1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid dimethylamide;

(5-Chloro-1H-indol-2-yl)-(3-hydroxymethyl-4-methyl-piperazin-1-yl)-methanone;

(5-Chloro-1H-indol-2-yl)-(3-methoxymethyl-4-methyl-piperazin-1-yl)-methanone;

(5-Chloro-1H-indol-2-yl)-(2-methoxymethyl-4-methyl-piperazin-1-yl)-methanone;

(5-Chloro-1H-indol-2-yl)-(4-methyl-3-methylaminomethyl-piperazin-1-yl)-methanone;

(5-Chloro-1H-indol-2-yl)-(4-methyl-2-methylaminomethyl-piperazin-1-yl)-methanone;

(5-Chloro-1H-indol-2-yl)-(3-dimethylaminomethyl-4-methyl-piperazin-1-yl)-methanone; and

(5-Chloro-1H-indol-2-yl)-(2-dimethylaminomethyl-4-methyl-piperazin-1-yl)-methanone.

26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition of claim 23, comprising a compound selected from (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;

(7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione.

30. A packaged drug comprising (a) a pharmaceutical composition comprising a compound of claim 1, 2, or 3 and a pharmaceutically acceptable carrier, and (b) instructions for the administration of said composition for the treatment or prevention of an H₄-mediated disease or condition.

31. A method for treating an H₄-mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1.

32. A method for treating an H₄-mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective H₄-inhibiting amount of a composition comprising a compound of claim 1.

33. A method of claim 32 wherein said compound is a compound of claim 2.

34. A method of claim 32, wherein said compound is a compound of claim 3.

35. A method of claim 32, wherein said compound is selected from:

(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;

(7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;

(5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and

(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione.

36. A method of claim 32, wherein said H₄-mediated condition is selected from:

inflammatory disorders, asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn'"'"'s disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders.

37. A method of claim 36, wherein said H₄-mediated condition is an inflammatory disorder or an allergic disorder.

38. A method of claim 37, wherein said inflammatory disorder is an inflammation-mediated condition selected from:

acute inflammation, allergic inflammation, and chronic inflammation.

39. A method for treating asthma in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1, 21, or 22.

40. A method for treating an allergic disorder in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of claim 1, 21, or 22.