Claims
- 1. A compound selected from the group consisting of the following formulae:
- 2. The compound of claim 1 selected from formula (I):
- 3. The compound of claim 2 wherein:
n, m and p are each independently 0 to 2; A1 is —O—(CH2)q— (where q is 0 to 1), —(CH2)q—O— (where q is 0 to 1), —N(R6)—(CH2)q— (where q is 0 to 1) or —(CH2)q—N(R6)— (where q is 0 to 1); R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); R2 is halo, haloalkyl, alkyl, nitro, —OR6, —C(O)OR6, —C(O)N(R6)R7, or —N(R6)R7; each R3 is independently hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and each R6 and R7 is independently hydrogen or alkyl.
- 4. The compound of claim 3 wherein:
n, m and p are each independently 0 to 2; A1 is —O—, —CH2—O—, or —N(R6)—; R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); or R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); or R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; each R3 is independently hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 5. The compound of claim 4 wherein:
n is 0 to 2; m is 0 to 1; p is 0 to 2; A1 is —O—, —CH2O— or —N(R6)—; R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); or R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); or R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; each R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 6. The compound of claim 5 wherein:
n is 0; m is 0 to 1; p is 0 to 2; A1 is —O—; R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 7. The compound of claim 5 wherein:
n is 0; m is 0 to 1; p is 0 to 2; A1 is —O— or —CH2O—; R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 8. The compound of claim 7 selected from the group consisting of the following compounds:
3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; (3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; 2-methoxycarbonyl-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine 2-carboxy-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine; and 2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine.
- 9. The compound of claim 5 wherein:
n is 0; m is 0 to 1; p is 0 to 2; A1 is —O—; R1 is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 10. The compound of claim 9, namely, 3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)carbonyl]pyrrolidine.
- 11. The compound of claim 5 wherein:
n is 1 or 2; m is 0 to 1; p is 0 to 2; A1 is —O—, —CH2—O— or —N(H)—; R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); or R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 12. The compound of claim 11 wherein:
A1 is —O—, —CH2O— or —N(H)—; and R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy).
- 13. The compound of claim 12 selected from the group consisting of the following compounds:
3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; (3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; 2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; 3-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; 3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; and 3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1H-azepine.
- 14. The compound of claim 11 wherein:
A1 is —O—; and R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy).
- 15. The compound of claim 14 selected from the group consisting of the following compounds:
3-[4-(imidazol-1-yl)phenoxy]-1-(3,4-dimethoxybenzyl)piperidine; and 3-[4-(imidazol-1-yl)phenoxy]-1-(4-methoxynaphth-1-yl)methylpiperidine.
- 16. The compound of claim 1 selected from formula (II):
- 17. The compound of claim 16 wherein:
n and p are each independently 0 to 2; A1 is —(CH2)q— (where q is 0 to 1), —(CH2)q—O— (where q is 0 to 1), —N(R6)—(CH2)q— (where q is 0 to 1) or —(CH2)q—N(R6)— (where q is 0 to 1); R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); R2 is halo, haloalkyl, alkyl, nitro, —OR6, —C(O)OR6, —C(O)N(R6)R7, or —N(R6)R7; each R3 is independently hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and each R6 and R7 is independently hydrogen or alkyl.
- 18. The compound of claim 17 wherein:
n and p are each independently 0 to 2; A1 is —O—, —CH2—O—, or —N(R6)—; R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; each R3 is independently hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 19. The compound of claim 18 wherein:
n is 0 to 2; p is 0 to 2; A1 is —O— or —CH2O—; R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, and alkoxy); R2 is halo, haloalkyl, alkyl, or —OR6; R3 is hydrogen or alkyl; each R4 is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R6 is hydrogen or alkyl.
- 20. The compound of claim 19 selected from the group consisting of the following compounds:
3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine; and 2-[((6-(imidazol-1-yl)pyridazin-3-yl)oxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine.
- 21. The compound of claim 1 selected from formula (III):
- 22. The compound of claim 21 wherein:
m is 0 to 4; A2 is —(CH2)q—O— (where q is 2 to 3); R1 is aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); each R2 is independently halo, haloalkyl, alkyl, —OR6, —C(O)OR6, —C(O)N(R6)R7, —N(R6)R7, or —N(R6)C(O)R7; R3 is independently hydrogen or alkyl; R5 is hydrogen, alkyl, aralkyl, —(CH2)m—C(O)—OR9 (where m is 1 to 4), —(CH2)m—C(O)—N(R9)R10 (where m is 1 to 4), or (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); each R6 and R7 is independently hydrogen or alkyl; each R9 is independently hydrogen or alkyl; and R10 is hydrogen, alkyl, aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is N-heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl).
- 23. The compound of claim 22 wherein:
m is 0; A2 is —CH2—CH2—O—; R1 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); R3 is hydrogen; R5 is hydrogen, —(CH2)m—C(O)—OR9 (where m is 1 to 4), —(CH2)m—C(O)—N(R9)R10 (where m is 1 to 4), or (1,3-benzodioxol-5-yl)alkyl; each R9 is independently hydrogen or alkyl; and R10 is hydrogen, alkyl, aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is N-heterocyclylalkyl (where the heterocyclyl radical is optionally substituted by by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl).
- 24. The compound of claim 23 wherein:
R1 is (1,3-benzodioxol-5-yl)methyl; R5 is hydrogen, —CH2—C(O)—OR9, —CH2—C(O)—N(R9)R10, or (1,3-benzodioxol-5-yl)methyl; each R9 is independently hydrogen or alkyl; and R10 is hydrogen, alkyl, aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is (1,3-benzodioxol-5-yl)methyl; and or R10 is piperidin-1-ylalkyl (wherein the piperidinyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl).
- 25. The compound of claim 24 wherein:
R5 is hydrogen or —CH2—C(O)—OR9; and R9 is hydrogen or alkyl.
- 26. The compound of claim 25 selected from the group consisting of the following compounds:
N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine; N-(carboxymethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine; and N-(ethoxycarbonylmethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.
- 27. The compound of claim 24 wherein R5 is (1,3-benzodioxol-5-yl)methyl, namely, N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N,N-di[(1,3-benzodioxol-5-yl)methyl]amine.
- 28. The compound of claim 24 wherein:
R5 is —CH2—C(O)—N(R9)R10; R9 is independently hydrogen or alkyl; and R10 is hydrogen, alkyl, aralkyl (where the aryl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R10 is (1,3-benzodioxol-5-yl)methyl; and or R10 is piperidin-1-ylalkyl (wherein the piperidinyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl).
- 29. The compound of claim 28 selected from the group consisting of the following compounds:
N-[(((3-(2-methylpiperidin-1-yl)propyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine; N-[((((1,3-benzodioxol-5-yl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine; N-[((((4-trifluoromethylphenyl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine; and N-[(((butyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.
- 30. A pharmaceutical composition useful in treating a condition in a mammal resulting from an abnormality in nitric oxide production, which composition comprises a pharmaceutically excipient excipient and a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- 31. A method of treating a condition in a mammal resulting from an abnormality in nitric oxide production which comprises administering to a mammal having a condition resulting from an abnormality in nitric oxide production a therapeutically effective amount of a compound selected from the group consisting of the following formulae:
- 32. The method according to claim 31 wherein said condition resulting from an abnormality in nitric oxide production is chosen from the group consisting of multiple sclerosis, stroke or cerebral ischemia, Alzheimer's disease, HIV dementia, Parkinson's disease, meningitis, dilated cardiomyopathy and congestive heart failure, atherosclerosis, restenosis or graft stenosis, septic shock and hypotension, hemorrhagic shock, asthma, acute respiratory distress syndrome, smoke or particulate-mediated lung injury, pathogen-mediated pneumonias, trauma of various etiologies, rheumatoid arthritis and osteoarthritis, glomerulonephritis, systemic lupus erythematosus, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, insulin dependent diabetes mellitus, diabetic neuropathy or nephropathy, acute and chronic organ transplant rejection, transplant vasculopathies, graft-versus-host disease, psoriasis and other inflammatory skin diseases, and cancer.
- 33. The method of claim 32 wherein the condition is multiple sclerosis.
- 34. The method of claim 32 wherein the condition is rheumatoid arthritis.
- 35. The method of claim 32 wherein the condition is dilated cardiomyopathy.
- 36. The method of claim 32 wherein the condition is congestive heart failure.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application Serial No. 60/377,274, filed Apr. 30, 2002, which is incorporated herein in full by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60377274 |
Apr 2002 |
US |