Heterocyclic compounds
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Abstract
Heterocyclic compounds and methods of making them and using them.
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Citations
40 Claims
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1. A compound of formula (I) wherein:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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2. A compound of claim 1 of the following formula wherein:
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3. A compound of claim 1, wherein R1 is Ra, RaRb—
- , Ra—
O—
Rb—
, or (Rc)(Rd)N—
Rb—
, where Ra is H, C1-10 alkyl, C2-5 alkenyl, C3-8 cycloalkyl, C2-5 heterocyclic radical, or phenyl;
where Rb is C1-6 alkylene, or C2-8 alkenylene; and
Rc and Rd are each independently H, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, or phenyl;
R2′
is methyl or H;
R3′
is methyl or H;
R5′
is methyl or H;
R6′
is methyl or H;
R7′
is methyl or H;
X1 is CR3;
R3 is F, Cl, Br, methyl, ethyl, or propyl;
X2 is NRe or O, provided that X2 is NRe where X1 is N;
Re is H or C1-6 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, C1-3 alkoxy, or C1-3 alkyl;
R5 is H, F, Cl, Br, I, (C═
O)Rj, OH, nitro, NRjRk, cyano, —
OCH2—
Ph, C1-4 alkoxy, or C1-4 alkyl;
R7 is H, F, Cl, Br, I, (C═
O)Rm, OH, nitro, NRlRm, cyano, C1-4 alkoxy, or C1-4 alkyl;
wherein each of Rj, Rk, Rl, and Rm is independently selected from H, C1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C1-6 alkoxy;
each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C1-3 alkyl, halo, hydroxy, amino, and C1-3 alkoxy;
n is 1;
provided at least one of R1, R2′
, R3, R4, R5, R6, and R7 is other than H when Z is O;
or a pharmaceutically acceptable salt, ester, or amide thereof.
- , Ra—
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4. A compound of claim 1, wherein
R1 is H, methyl, or ethyl; -
One of R2′
and R3′
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 NRe or O;
Re is H or C1-3 alkyl;
Z is ═
O or ═
S;
each of R4 and R6 is independently H, OH, C1-4 alkyl, C1-4 alkoxy, cyano, or amino;
R5 is H, F, Cl, Br, COOH, OH, amino, cyano, C1-4 alkoxy, or C1-4 alkyl; and
R7 is H, F, Cl, Br, C1-4 alkyl, C1-4 alkoxy, cyano, or amino;
provided at least one of R5 and R7 is not H.
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5. A compound of claim 1, wherein
R1 is H, methyl, or ethyl; -
R2′
and R3′
are independently methyl or H;
X1 is CR3 or N;
R3 is H, F, or Cl;
X2 is NRe or O, provided that X2 is NRe where X1 is N;
Re is H or C1-6 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 C1-4 alkyl;
provided at least one of R5 and R7 is not H.
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6. A compound of claim 1, wherein X2 is N.
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7. A compound of claim 1, wherein X2 is O.
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8. A compound of claim 1, wherein R1 is H, methyl or ethyl.
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9. A compound of claim 8, wherein R1 is methyl.
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10. A compound of claim 1, wherein R2′
- is H.
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11. A compound of claim 1, wherein R2′
- is methyl.
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12. A compound of claim 1, wherein R3 is H or Cl.
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13. A compound of claim 12, wherein R3 is Cl.
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14. A compound of claim 1, wherein R5 is F, Cl, Br, or methyl and R7 is F, Cl, or Br.
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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.
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16. A compound of claim 1, wherein each of R4 and R6 is independently H, methyl, or Cl.
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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.
- R5 is F, Cl, Br, or methyl; and
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18. A compound of claim 17, wherein each of R4 and R6 is independently H, methyl, or Cl.
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19. A compound of claim 1, wherein Z is ═
- S.
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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.
- (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
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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.
- (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
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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.
- (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
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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.
- (4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-1H-indol-2-yl)-methanone;
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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.
- (5,7-Dichloro-1H-indol-2-yl)-piperazin-1-yl-methanone;
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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.
- 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methyl ester;
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26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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27. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
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28. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.
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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.
- (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
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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.
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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.
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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.
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33. A method of claim 32 wherein said compound is a compound of claim 2.
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34. A method of claim 32, wherein said compound is a compound of claim 3.
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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.
- (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
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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.
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37. A method of claim 36, wherein said H4-mediated condition is an inflammatory disorder or an allergic disorder.
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38. A method of claim 37, wherein said inflammatory disorder is an inflammation-mediated condition selected from:
- acute inflammation, allergic inflammation, and chronic inflammation.
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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.
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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.
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2. A compound of claim 1 of the following formula wherein:
Specification
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Current AssigneeOrtho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
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Original AssigneeOrtho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
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InventorsCarruthers, 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.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/254.02
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CPC Class CodesA61K 31/496 Non-condensed piperazines c...A61P 1/04 for ulcers, gastritis or re...A61P 11/06 AntiasthmaticsA61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 25/28 for treating neurodegenerat...A61P 29/00 Non-central analgesic, anti...A61P 37/04 ImmunostimulantsA61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 Antiallergic agents antiast...A61P 43/00 Drugs for specific purposes...A61P 7/00 Drugs for disorders of the ...A61P 9/06 AntiarrhythmicsC07D 209/42 Carbon atoms having three b...C07D 401/12 linked by a chain containin...