The present invention relates to bisarylimidazolyl derivatives and pharmaceutical compositions comprising said compounds inhibiting fatty acid amide hydrolase and useful for the treatment of pain, particularly neuropathic pain, psychomotor disorder, hypertension, cardiovascular disease, eating disorder, nausea, AIDS-related complex, glaucoma, inflammation, psoriasis or multiple sclerosis, and other conditions the treatment of which can be effected by inhibiting fatty acid amide hydrolase.

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Patent
   RE39634
Priority
Apr 27 2001
Filed
Jul 01 2004
Issued
May 15 2007
Expiry
Apr 23 2022
Inventors
Sit, Sing-…
Assg.orig
Bristol-My…
Assg.curr
Bristol-My…
Entity
Large
Referenced by
0
References
1
Maint.:
all paid
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20. A method of treating neuropathic pain by the administration of a pharmaceutical composition comprising ##STR00125##
or a pharmaceutically acceptable salt or solvate thereof.
19. A method of treating chronic pain, acute pain and neuropathic pain by the administration of a pharmaceutical composition comprising ##STR00124##
or a pharmaceutically acceptable salt or solvate thereof.
0. 31. A method of treating chronic pain, acute pain or neuropathic pain in a mammal in need thereof by the administration of an effective amount of a pharmaceutical composition comprising a compound according to claims 21, 22 or 23-30.
0. 27. A compound of formula (I) ##STR00132##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each H;
R3 is c1-c3alkyl;
A is c7-10alkylene;
D is HYC(O)O;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy.
0. 29. A compound of formula (I) ##STR00134##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H;
R3 is c1-c3alkyl;
A is c7-10alkylene;
D is HYC(O)ON═C(G′);
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxyl and c1-3alkoxy; and
G′ is H, c1-5alkyl or c1-5haloalkyl.
0. 28. A compound of formula (I) ##STR00133##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each H;
R3 is c1-c3alkyl;
A is c1-5alkylene;
D is HYC(O)O;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxyl and c1-3alkoxy; and
wherein A—D is interrupted with —Z-phenyl-;
wherein Z is O or S and is attached to A.
0. 24. A compound of formula (I) ##STR00129##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene;
D is HYC(O)ON═C(G′);
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy; and
G′ is H, c1-5alkyl or c1-5haloalkyl.
0. 23. A compound of formula (I) ##STR00128##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
D is X(O)O;
X is c and is attached to A; and
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy.
0. 30. A compound of formula (I) ##STR00135##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each H;
R3 is c1-c3alkyl;
A is c1-5alkylene;
D is HYC(O)ON═C(G′);
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is interrupted with —Z-phenyl-;
wherein Z is O or S and is attached to A.
0. 22. A compound of formula (I) ##STR00127##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are substituted with cyano;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12alkylene.
0. 21. A compound of formula (I) ##STR00126##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are substituted with fluoro;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12alkylene.
17. [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester; [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester; or
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester or a pharmaceutically acceptable salt or solvate thereof.
0. 25. A compound of formula (I) ##STR00130##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is —C1-2alkylene-phenyl, said —C1-2alkylene-phenyl is optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12alkylene.
0. 26. A compound of formula (I) ##STR00131##
or a pharmaceutically acceptable salt or solvate thereof wherein
R1 and R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12alkylene.
16. [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester; [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester; or
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester or a pharmaceutically acceptable salt or solvate thereof.
15. [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid cyclohexyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid methyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester; [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid methyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid ethyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid o-tolyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid isopropyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid ethyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Isopropyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester; or
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-1-phenyl-hexyl]-carbamic acid 2-fluoro-phenyl ester or a pharmaceutically acceptable salt or solvate thereof.
14. [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[6-(2-Ethyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid tert-butyl ester;
6-(2-Ethyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid sec-butyl ester; [6-(2-Ethyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid sec-butyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid benzyl ester;
2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid methyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester; [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid methyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid ethyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid o-tolyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid ethyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime; 3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-fluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2,6-difluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid ethyl ester;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Isopropyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester; or
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-1-phenyl-hexyl]-carbamic acid 2-fluoro-phenyl ester or a pharmaceutically acceptable salt or solvate thereof.
0. 1. compounds of formula (I) ##STR00111##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3 alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 2. compounds of formula (I) ##STR00112##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is HYC(O)O;
X is c and is attached to A;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 3. compounds of formula (I) ##STR00113##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H; c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 4. compounds of formula (I) ##STR00114##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is c3-7cycloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 5. compounds of formula (I) ##STR00115##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is —C1-2alkylene-phenyl said —C1-2alkylene-phenyl is optionally substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 6. compounds of formula (I) ##STR00116##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are optionally substituted with the same or different substitutents selected from the group consisting of halo, CN, —C(O)O—C1-3-alkyl, c1-3alkyl and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 7. compounds of formula (I) ##STR00117##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are substituted with halo, —C(O)O—C1-3-alkyl, c1-3alkyl or c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 8. compound of formula (I) ##STR00118##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are substituted with fluoro;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 9. compounds of formula (I) ##STR00119##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each independently H, c1-3alkyl or halo;
R3 is c1-c3alkyl or c3-7cycloalkyl;
A is c1-12alkylene or l;
l is -phenyl-O—C1-4alkylene wherein said c1-4alkylene is attached to D;
provided that if A is l, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C1-3 alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is c and is attached to A;
Y is N and is attached to A;
G is phenyl or —C1-2alkylene-phenyl, said phenyl or phenyl of said —C1-2alkylene-phenyl are substituted with cyano;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 10. compounds of formula (I) ##STR00120##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each H;
R3 is c1-c3alkyl;
A is c7-10alkylene;
D is HYC(O)O;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy; and
G′ is H, c1-5alkyl or c1-5haloalkyl.
0. 11. compounds of formula (I) ##STR00121##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each H;
R3 is c1-c3alkyl;
A is c1-5alkylene;
D is HYC(O)O;
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 12. compounds of formula (I) ##STR00122##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each H;
R3 is c1-c3alkyl;
A is c7-10alkylene;
D is HYC(O)ON═C(G′);
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy; and
G′ is H, c1-5alkyl or c1-5haloalkyl.
0. 13. compounds of formula (I) ##STR00123##
and pharmaceutically acceptable salts and solvates thereof wherein
R1 are R2 are each H;
R3 is c1-c3alkyl;
A is c1-5alkylene;
D is HYC(O)ON═C(G′);
Y is N and is attached to A;
G is H, c1-5alkyl, c1-5haloalkyl, c3-7cycloalkyl, phenyl, —C1-2alkylene-phenyl, c-pyridyl or N-pyridyl, said phenyl or —C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, —C(O)O—C1-3-alkyl, c1-3alkyl, hydroxy and c1-3alkoxy;
G′ is H, c1-5alkyl or c1-5haloalkyl; and
wherein A—D is interrupted with J—J′, —Z-phenyl- or —Z—C1-3alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is c1-4alkyl or phenyl;
provided that
if A—D is interrupted with —Z-phenyl-, then A is c1-5alkylene;
if A—D is not interrupted with —Z-phenyl-, then A is c5-12 alkylene.
0. 18. A method of treating chronic pain, acute pain or neuropathic pain in a mammal in need thereof by the administration of an effective amount of a pharmaceutical composition comprising a compound according to claims 1, 2, 3 or 4.
2-Propanone, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino)carbonyl]oxime: 2-Propanone,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. 1H NMR (DMSO): δ1.11 (m, 4H), 1.30 (m, 2H), 1.50 (m, 2H), 1.92 (d, J=9.25 mHz, 6H), 2.74 (s, 3H), 2.96 (m, 2H), 3.94 (t, 2H), 7.29 (t, 1H), 7.39 (m, 2H), 7.41 (m, 3H), 7.49 (m, 2H), 7.61 (m, 2H). Mass Spec: 433.31 (MH+).

EXAMPLE 7

##STR00024##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid cyclohexyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.64 min (85%). Mass spec: 460.21 (MH+).

EXAMPLE 8

##STR00025##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid methyl ester: Prepared as described for the example above. Analytical HPLC 1.33 min. (80%). Mass spec: 392.12 (MH+).

EXAMPLE 9

##STR00026##

6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.50 min (83%). Mass Spec: 454.15 (MH+).

EXAMPLE 10

##STR00027##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.52 min (97%). Mass Spec: 472.09 (MH+).

EXAMPLE 11

##STR00028##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.54 min (96%). Mass Spec. 490.06 (MH+).

EXAMPLE 12

##STR00029##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical 1.61 min (95%). Mass Spec: 488.02 (MH+).

EXAMPLE 13

##STR00030##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.51 min (96%). Mass Spec: 484.11 (MH+).

EXAMPLE 14

##STR00031##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester: (Scheme 1 (D)) Prepared as described for the example above. H Analytical HPLC 1.54 min (92%). Mass Spec: 468.11 (MH+).

EXAMPLE 15

##STR00032##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.46 min (94%). Mass Spec: 479.08 (MH+).

EXAMPLE 16

##STR00033##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,6-dimethoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.43 min (94%). Mass Spec: 514.10 (MH+).

EXAMPLE 17

##STR00034##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.48 min (99%). Mass Spec: 484.12 (MH+).

EXAMPLE 18

##STR00035##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid methyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.41 min (98%). Mass Spec: 406.32 (MH+).

EXAMPLE 19

##STR00036##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.49 min (95%). Mass Spec: 420.35 (MH+).

EXAMPLE 20

##STR00037##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.58 min (99%). Mass Spec: 468.32 (MH+).

EXAMPLE 21

##STR00038##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.60 min (98%). Mass Spec: 486.30 (MH+).

EXAMPLE 22

##STR00039##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.58 min (96%). Mass Spec: 486.31 (MH+).

EXAMPLE 23

##STR00040##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.61 min (90%). Mass Spec: 504.31 (MH+).

EXAMPLE 24

##STR00041##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.68 min (90%). Mass Spec: 502.29 (MH+).

EXAMPLE 25

##STR00042##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.59 min (90%). Mass Spec: 498.33 (MH+).

EXAMPLE 26

##STR00043##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.63 min (90%). Mass Spec: 482.33 (MH+).

EXAMPLE 27

##STR00044##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.53 min (90%). Mass Spec: 493.31 (MH+).

EXAMPLE 28

##STR00045##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,6-dimethoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.53 min (96%). Mass Spec: 528.37 (MH+).

EXAMPLE 29

##STR00046##

[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.57 min (90%). Mass Spec: 498.33 (MH+).

EXAMPLE 30

##STR00047##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid ethyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.36 min (98%). Mass Spec: 392.35 (MH+).

EXAMPLE 31

##STR00048##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.48 min (97%). Mass Spec: 440.36 (MH+).

EXAMPLE 32

##STR00049##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.51 min (97%). Mass Spec: 458.33 (MH+).

EXAMPLE 33

##STR00050##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.52 min (95%). Mass Spec: 476.32 (MH+).

EXAMPLE 34

##STR00051##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.48 min (98%). Mass Spec: 458.33 (MH+).

EXAMPLE 35

##STR00052##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.62 min (98%). Mass Spec: 474.29 (MH+).

EXAMPLE 36

##STR00053##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.49 min (99%). Mass Spec: 470.35 (MH+).

EXAMPLE 37

##STR00054##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid o-tolyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.56 min (95%). Mass Spec: 454.36 (MH+).

EXAMPLE 38

##STR00055##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.44 min (99%). Mass Spec: 465.32 (MH+).

EXAMPLE 39

##STR00056##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,6-dimethoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.44 min (99%). Mass Spec: 500.38 (MH+).

EXAMPLE 40

##STR00057##

[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-methoxy-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.46 min (97%). Mass Spec: 470.34 (MH+).

EXAMPLE 41

##STR00058##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.55 min (84%). Mass Spec: 490.32 (MH+).

EXAMPLE 42

##STR00059##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid isopropyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.47 min (83%). Mass Spec: 420.17 (MH+).

EXAMPLE 43

##STR00060##

{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.50 min (95%). Mass Spec: 508.29 (MH+).

EXAMPLE 44

##STR00061##

{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.50 min (85%). Mass Spec: 526.31 (MH+).

EXAMPLE 45

##STR00062##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid ethyl ester: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.40 min (82%). Mass Spec: 406.15 (MH+).

EXAMPLE 46

##STR00063##

Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.48 min (89%). Mass Spec: 481.26 (MH+).

EXAMPLE 47

##STR00064##

4-Fluorobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: 4-Fluorobenzaldehyde,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.58 min (87%). Mass Spec: 499.32 (MH+).

EXAMPLE 48

##STR00065##

2-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: 2-Nitrobenzaldehye, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.56 min (95%). Mass Spec: 526.3 (MH+).

EXAMPLE 49

##STR00066##

3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: 3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.57 min (83%). Mass Spec: 526.32 (MH+).

EXAMPLE 50

##STR00067##

4-Nitrobenzaldehyde, O-{6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: 4-Nitrobenzaldehyde, O-{6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.58 min (94%). Mass Spec: 526.29 (MH+).

EXAMPLE 51

##STR00068##

3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime: 3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylaminocarbonyl]oxime: (Scheme 1 (D)) Prepared as described for the example above. Analytical HPLC 1.24 min (94%). Mass Spec: 482.26 (MH+). ##STR00069##

The following Intermediates 14-20 may be used to synthesize Examples 52-74.

Intermediate 14

##STR00070##

1-(5-Bromo-pentyl)-2-methyl-4,5-diphenyl-1H-imidazole: (Scheme 2 (E)) To a solution of 2-Methyl-4,5-diphenyl-1H-imidazole (2.0 g, 8.5 mmol) and 1,5-dibromopentane (3.01 g, 12.7 mmol) in DMF (100 mL) was added NaH (60% in mineral oil, 0.50 g, 12.7 mmol). The resulting mixture was stirred at rt for 1 hour, quenched by addition of water, extracted by CH2Cl2, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow oil (2.2 g, 5.7 mmol, 67% yield): 1H NMR (DMSO): δ1.20 (m, 2H), 1.47 (m, 2H), 1.64 (m, 2H), 2.41 (s, 3H), 3.45 (t, 2H), 3.72 (t, 2H), 7.16 (m, 3H), 7.31 (m, 4H), 7.55 (t, 3H). Mass Spec: 384.57 (MH+).

Intermediate 15

##STR00071##

1-(6-Bromo-hexyl)-2-methyl-4,5-diphenyl-1H-imidazole: (Scheme 2 (E)) Prepared as described for the example above. 1H NMR (DMSO): δ1.2 (m, 4H), 1.5 (m, 2H), 1.75 (m, 2H), 2.5 (s, 3H), 3.4 (t, 2H), 3.69 (t, 2H), 7.14 (m, 3H), 7.36 (m, 4H), 7.516 (m, 3H). Mass Spec: 399.14 (MH+).

Intermediate 16

##STR00072##

1-(3-Bromo-propyl)-2-methyl-4,5-diphenyl-1H-imidazole: (Scheme 2 (E)) Prepared as described for the example above. 1H NMR (DMSO): δ1.99 (m, 2H), 2.43 (s, 3H), 3.39 (t, 2H), 3.88 (t, 2H), 7.17 (m, 3H), 7.35 (m, 4H), 7.53 (m, 3H), Mass Spec: 356.59 (MH+).

Intermediate 17

##STR00073##

4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-benzoic acid ethyl ester: (Scheme 2 (H)) To a solution of 1-(3-Bromo-propyl)-2-methyl-4,5-diphenyl-1H-imidazole (0.80 g, 2.2 mmol) and ethyl 4-hydroxybenzoate (1.20 g, 7.2 mmol) in DMF (30 mL) was added K2CO3 (0.40 g, 2.9 mmol). The resulting mixture was stirred at 55° C. for 1 hour, quenched by addition of water, extracted by EtOAc, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow gum (0.92 g, 2.0 mmol, 94% yield): 1H NMR (DMSO): δ1.32 (t, 3H), 1.85 (m, 2H), 2.402 (s, 3H), 3.87 (m, 4H), 4.28 (q, 2H), 6.89 (d, J=8.82 Hz, 2H), 7.143 (m, 3H), 7.36 (m, 4H), 7.46 (m, 3H), 7.82 (d, J=8.85 mHz, 2H). Mass spec: 441.28 (MH+).

Intermediate 18

##STR00074##

4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-benzoic acid ethyl ester: (Scheme 2 (H)) Prepared as described for the example above. 1H NMR (DMSO): δ1.31 (t, 3H), 2.5 (s, 3H), 4.07 (m, 2H), 4.15 (m, 2H), 4.26 (q, 2H), 6.91 (d, J=8.88 mHz, 2H), 7.16 (m, 3H), 7.33 (d, J=7.56 mHz, 2H), 7.41 (m, 2H), 7.53 (m, 3H), 7.85 (d, J=8.85 mHz, 2H).

Intermediate 19

##STR00075##

4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-benzoic acid: (Scheme 2 (I)) To a solution of 4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-benzoic acid ethyl ester (0.80 g, 1.8 mmol) in EtOH (20 mL) was added NaOH (10 N, 4.0 mL, 40.0 mmol). The resulting mixture was stirred at rt for 3 hours, diluted with water, acidified to pH˜1 using 1N HCl, extracted by CH2Cl2, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: MeOH/CH2Cl2). This compound was obtained as a white dry foam in HCl salt form (0.80 g, 1.8 mmol, 99% yield): 1H NMR (DMSO): δ1.93 (m, 2H), 2.67 (s, 3H), 3.97 (t, 2H), 4.13 (t, 2H), 6.85 (d, J=8.82 mHz, 2H), 7.33 (s, 5H), 7.43 (m, 2H), 7.55 (m, 3H), 7.86 (d, J=8.82 mHz, 2H), 12.64 (b, 1H).

Intermediate 20

##STR00076##

4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxyl-benzoic acid: (Scheme 2 (I)) Prepared as described for the example above. 1H NMR (DMSO): δ2.82 (s, 3H), 4.19 (m, 2H), 4.39 (m, 2H), 6.93 (d, J=8.85 mHz, 2H), 7.359 (m, 5H), 7.54 (m, 2H), 7.61 (m, 3H), 7.86 (d, J=8.76 mHz, 2H), 12.685 (b, 1H).

EXAMPLE 52

##STR00077##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester: (Scheme 2 (J)) To a suspension of 4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-benzoic acid (0.10 g, 0.23 mmol) in a mixture of Et3N (0.09 g, 0.88 mmol) and toluene (2 mL) was added azide (0.1 g, 0.35 mmol). The resultant mixture was stirred at r.t. for 10 min. and then at 108° C. under N2 for 45 min. After the mixture was cooled to r.t., 3,4-difluorophenol (0.10 g, 1.0 mmol) was added. The reaction mixture was stirred at r.t. for 10 min and then at 80° C. for 1 h. The mixture was diluted with EtOAc, washed with H2O. After filtration and concentration in vacuo, the residue was purified by preparative HPLC (YMC 30×100 mm (5 uM packing), 10% MeOH/90% water/01% TFA as mobile phase A, 90% MeOH/10% water/0.1% TFA as mobile phase B). This compound was obtained as a white solid (0.082 g, 0.13 mmol, 55% yield): 1H NMR (DMSO): δ2.83 (s, 3H), 4.06 (t, 2H), 4.39 (t, 2H), 6.82 (d, J=7.05 mHz, 2H), 7.29 (m, 2H), 7.32 (m, 2H), 7.45 (m, 4H), 7.52 (m, 4H), 7.61 (m, 3H). Mass Spec: 526.22 (MH+).

EXAMPLE 53

##STR00078##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. 1H NMR (DMSO): δ2.83 (s, 3H), 4.07 (t, 2H), 4.39 (t, 2H), 6.83 (d, J=10.3 mHz, 2H), 7.24 (d, J=10.3 mHz, 2H), 7.30 (m, 2H), 7.36 (m, 5H), 7.46 (d, J=12.6 mHz, 2H), 7.59 (m, 2H), 7.61 (m, 3H). Mass Spec: 524.18 (MH+).

EXAMPLE 54

##STR00079##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid methyl ester: (Scheme 2 (J)) Prepared as described for the example above. 1H NMR (DMSO): δ2.82 (s, 3H), 3.62 (s, 3H), 4.05 (t, 2H), 4.38 (t, 2H), 6.77 (d, J=7 mHZ, 2H), 7.28 (m, 1H), 7.31 (m, 3H), 7.36 (m, 3H), 7.53 (m, 2H), 7.61 (m, 3H), 9.45 (b, 1H). Mass Spec: 428.24 (MH+).

EXAMPLE 55

##STR00080##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.66 min (95%). Mass Spec: 540.25 (MH+).

EXAMPLE 56

##STR00081##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.52 min (98%). Mass Spec: 534.35 (MH+).

EXAMPLE 57

##STR00082##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.62 min (81%). Mass Spec: 538.22 (MH+).

EXAMPLE 58

##STR00083##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.49 min (95%). Mass Spec: 534.43 (MH+).

EXAMPLE 59

##STR00084##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.71 min (90%). Mass Spec: 538.23 (MH+).

EXAMPLE 60

##STR00085##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.58 min (84%). Mass Spec: 490.25 (MH+).

EXAMPLE 61

##STR00086##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.49 min (92%). Mass Spec: 508.23 (MH+).

EXAMPLE 62

##STR00087##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-fluoro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.53 min (92%). Mass Spec: 508.23 (MH+).

EXAMPLE 63

##STR00088##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol1-yl)-propoxy]-phenyl}-carbamic acid phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.53 min (95%). Mass Spec: 504.39 (MH+).

EXAMPLE 64

##STR00089##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.50 min (94%). Mass Spec: 520.24 (MH+).

EXAMPLE 65

##STR00090##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid o-tolyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.54 min (92%). Mass Spec: 504.25 (MH+).

EXAMPLE 66

##STR00091##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.52 min (95%). Mass Spec: 522.32 (MH+).

EXAMPLE 67

##STR00092##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.46 min (97%). Mass Spec: 520.25 (MH+).

EXAMPLE 68

##STR00093##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.61 min (97%). Mass Spec: 524.18 (MH+).

EXAMPLE 69

##STR00094##

{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2,6-difluoro-phenyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.58 min (90%). Mass Spec: 540.25 (MH+). Notebook number:

EXAMPLE 70

##STR00095##

{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid ethyl ester: (Scheme 2 (J)) Prepared as described for the example above. Analytical HPLC 1.45 min (72%). Mass Spec: 442.25 (MH+). ##STR00096##

The following Intermediates 21-24 may be used to synthesize Examples 75-77.

Intermediate 21

##STR00097##

2-Methyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester: (Scheme 3 (O)) Sodium bis (trimethylsilyl)amide (1M in THF) (3.0 ml, 3.0 mmole) was added dropwise to a solution of starting material 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (1 g, 2.5 mmole) in anhydrous THF (10 ml) at −78° C. under Nitrogen. After addition, the reaction was let stirred 2 minutes, then Iodomethane (0.06 ml, 0.96 mmole) was added slowly at −78° under Nitrogen. The reaction mixture was let stirred at −78° C. for 1 hr, then warming up to room temperature and let stirred for 18 hrs. The next day, analysis by TLC indicated consumption of starting material. The reaction was quenched with aqueous Ammonium Chloride (10 ml). The aqueous layer was extracted with Ethyl Acetate (3×25 ml). The organic layers obtained were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo. Purification by flash column chromatography using Hexane/Ethyl Acetate (4:1) gave rise to product (150 mg, 45%). 1H NMR (CDCl3): δ1.09 (d, J=6.95 mHz, 6H), 1.15 (t, 3H), 1.51 (m, 2H), 2.32 (m, 1H), 2.50 (s, 3H), 3.70 (t, 2H), 4.11 (q, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.45 (m, 5H), 13C NMR (CDCl3): δ13.7, 14.3, 17.1, 26.4, 26.6, 30.3, 33.4, 39.4, 43.8, 60.2, 125.9, 126.5, 128.0, 128.4, 128.5, 129.0, 131.1, 131.8, 134.8, 136.3, 144.0, 176.6. Anal. Calcd. for C26H32N2O20.25 H2O: C, 76.34; H, 8.01; N, 6.85. Found: C, 76.38; H, 8.13; N, 6.83. Mass Spec: 405.29 (MH+).

Intermediate 22

##STR00098##

2-Ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester: (Scheme 3 (O)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (390 mg, 1 mmole), Sodium bis(trimethylsilyl)amide (1M in THF) (1.2 ml, 1.2 mmole), Iodoethane (0.4 ml, 779.8 mg, 5 mmole), anhydrous THF (10 ml). Product was obtained (100 mg, 24%). 1H NMR (CDCl3): δ0.88 (t, 3H), 1.23 (m, 4H), 1.33 (t, 3H), 1.54 (m, 4H), 1.68 (b, 1H), 2.04 (s, 1H), 2.17 (m, 1H), 2.49 (s, 3H), 3.709 (t, 2H), 4.15 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H), 7.46 (m, 4H). 13C NMR (CDCl3): δ12.0, 13.9, 14.6, 25.7, 26.6, 27.0, 30.5, 31.9, 44.0, 47.3, 60.2, 126.1, 126.7, 128.2, 128.7, 129.2, 131.3. Anal. Calcd. for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C, 77.34; N, 8.01; N, 6.56. Mass Spec: 419.32 (MH+).

Intermediate 23

##STR00099##

2-Isopropy-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester: (Scheme 3 (O)) Sodium bis (trimethylsilyl)amide (1M in THF) (1.2 ml, 1.2 mmole) was added dropwise to a solution 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (390 mg, 1 mmole) in anhydrous THF (10 ml) at −78° C. under Nitrogen. The reaction solution was let stirred warming up to room temperature during a period of 3 hrs. The reaction solution was cooled to −78° C., and 2-Iodopropane (499.97 ul, 849.95 mg, 5 mmole) was added in dropwise. The reaction was let stirred at room temperature for 1 hr, then at 50° C. for 1 hr. Analysis by TLC indicated consumption of starting material. The reaction was worked-up using the procedures as described above. Crude material was purified by flash column chromatography using Hexane/Ethyl Acetate (4:1) to give product (80 mg, 18.5%). 1H NMR CDCl3): δ0.89 (t, 6H), 1.14 (m, 4H), 1.249 (t, 3H), 1.49 (m, 3H), 1.81 (m, 2H), 1.989 (m, 1H), 2.49 (s, 3H), 3.70 (t, 2H), 4.1 (m, 2H), 7.15 (m, 1H), 7.31 (t, 2H), 7.40 (m, 2H), 7.445 (m, 5H). 13C NMR (CDCl3): δ13.7, 14.4, 20.2, 20.4, 26.5, 27.2, 29.3, 30.3, 30.7, 43.8, 52.6, 59.9, 125.9, 126.5, 128.0, 128.3, 128.5, 129.0, 131.0, 131.8, 134.8, 136.3, 144.0, 175.6. Anal. Calcd. for C28H36N2O2.0.21 H2O: C, 77.07, H, 8.41; N, 6.42. Found: C, 77.08; H, 8.84; N, 6.22. Mass Spec: 433.2 (MH+).

Intermediate 24

##STR00100##

2-Methyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid: (Scheme 3 (P)) A solution of starting material 2-Methyl-7-(2-methyl-4,5-diphenyl-imidazol-2-yl)-heptanoic acid ethyl ester (130 mg, 0.32 mmole) in Methanol (5 ml) and Sodium Hydroxide (64 mg, 1.61 mmole) was let stirred under reflux for 18 hrs. The next day, the reaction was let cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and acidified with Hydrochloric Acid (3N). The aqueous layer was extracted with Dichloromethane (3×10 ml). The organic layers were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo to afford product as a white solid (120 mg, 99%). Mass Spec: 377 (MH+).

Intermediate 25

##STR00101##

2-Ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid: (Scheme 3 (P)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 2-Ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (100 mg, 0.24 mmole), Sodium hydroxide (2N, 0.5 mL, 1.0 mmole), Methanol (5 mL). Product was obtained as white solid (90 mg, 96%). Mass Spec: 391.25 (MH+).

Intermediate 26

##STR00102##

2-Ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid: (Scheme 3 (P)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 2-Isopropyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (80 mg, 0.18 mmole), Sodium hydroxide (2N, 0.5 mL, 1.0 mmole), Methanol (5 mL). Product was obtained as white solid (46 mg, 64%). Mass Spec: 405.37 (MH+).

EXAMPLE 71

##STR00103##

[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 3 (Q)) Diphenylphosphoryl Azide (0.083 ml, 0.38 mmole) was added to a suspension of starting material 2-methyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid (120 mg, 0.32 mmole) and Triethylamine (0.14 ml, 1.005 mmole) in Toluene (5 ml) at room temperature. The reaction mixture was let stirred at room temperature for 10 minutes under Nitrogen, then at 108° C. for 90 minutes. The reaction was let cooled to room temperature, to which 2-Fluorophenol (0.03 ml, 0.038 g, 0.338 mmole) was added. The reaction mixture was let stirred at room temperature for 30 minutes, then at 100° C. for 18 hrs. The next day, analysis by TLC (Dichloromethane/Ethyl Acetate 3:1) indicated consumption of starting material. The reaction was let cooled to room temperature, where the solvent was removed by rotorvap. The crude material was purified by flash column chromatography using Dichloromethane/Ethyl Acetate (6:1 to 3:1). Product was obtained (110 mg, 71%). 1H NMR (CDCl3): δ1.21 (d, J=8.75 mHz, 6H), 1.35 (m, 2H), 1.51 (m, 2H), 2.50 (s, 3H), 3.71 (m, 3H), 4.93 (b, 1H), 7.18 (m, 6H), 7.32 (m, 2H), 7.46 (m, 6H). 13C NMR (CDCl3): 813.7, 21.1, 25.2, 30.3, 36.7, 43.7, 47.5, 116.5, 116.650, 124.132, 124.325, 125.943, 126.520, 128.027, 128.347, 128.509, 129.018, 131.101, 131.796, 134.8, 136.4, 138.6, 144.1, 153.0, 153.7, 155.6. Anal. Calcd. for C30H32FN3O20.42 H2O: C, 73.06; H, 6.71; N, 8.52. Found: C, 73.24; H, 6.82; N, 8.29. Mass Spec: 486.27 (MH+).

EXAMPLE 72

##STR00104##

[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 3 (Q)) This compound was prepared using the procedures as described above. The following scales and reagents were used: Starting material 2-ethyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid (90 mg, 0.23 mmole). Diphenylphosphoryl Azide (0.060 ml, 0.276 mmole), Triethylamine (0.14 ml, 1.005 mmole), and 2-Fluorophenol (30 ul, 0.338 mmole). After purification by flash column chromatography, product was obtained (90 mg, 18%). 1H NMR (CDCl3): δ0.96 (t, 3H), 1.24 (m, 5H), 1.51 (m, 2H), 1.54 (m, 3H), 2.50 (s, 3H), 3.72 (t, 2H), 4.77 (d, J=9.28 mHz, 1H), 7.16 (m, 7H), 7.342 (m, 2H), 7.45 (m, 5H). 13C NMR (CDCl3): δ10.2, 13.7, 25.1, 26.3, 28.2, 30.3, 34.7, 43.7, 53.076, 116.466, 116.650, 124.108, 124.276, 125.937, 126.527, 128.015, 128.348, 128.483, 129.001, 131.1, 131.8, 134.8, 136.3, 144.1, 153.5. Anal. Calcd. for C31H34FN3O2: C, 74.52; H, 6.86; N, 8.41. Found: C, 74.43; H, 6.98; N, 8.32. Mass Spec: 500.34 (MH+).

EXAMPLE 73

##STR00105##

[1-Isopropyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 3 (Q)) This compound was obtained using the procedures as described above. The following scales and reagents were used: Starting material 2-isopropyl-7-(2-methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid (45.8 mg, 0.113 mmole), Diphenylphosphoryl Azide (0.029 ml, 0.135 mmole), Triethylamine (0.049 ml, 0.351 mmole), and 2-Fluorophenol (0.012 ml, 0.135 mmole). After purification by flash column chromatography, product was obtained (27.5 mg, 47%). 1H NMR (CDCl3): δ0.95 (m, 6H), 1.27 (m, 5H), 1.53 (m, 2H), 1.73 (m, 2H), 2.50 (s, 3H), 3.56 (m, 1H), 3.73 (t, 2H), 4.75 (d, J=10 mHz, 1H), 7.19 (m, 7H), 7.33 (m, 2H), 7.45 (m, 5H). 13C NMR (CDCl3): δ13.7, 17.5, 19.3, 25.5, 26.3, 30.3, 32.2, 32.3, 43.7, 56.7, 116.5, 116.6, 124.1, 124.3, 124.3, 125.9, 126.4, 126.5, 128.0, 128.3, 128.5, 128.8, 131.1, 131.8, 134.8, 136.4, 144.1, 153.7, Anal. Calcd. for C32H36FN3O2.0.59 H2O: C, 73.31; H, 7.15; N, 8.01. Found: C, 73.45; 7.20; N, 7.61. Mass Spec: 514.2 (MH+). ##STR00106##

The following Intermediates 27-29 may be used to synthesize Example 78.

Intermediate 27

##STR00107##

2-[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl]-malonic acid diethyl ester: (Scheme 4 (R)) A solution of star[]ting material 1-(5-bromo-pentyl)-2-methyl-4,5-diphenyl-1H-imidazole (0.5 g, 1.3 mmole) in DMF (5 ml) was added to a suspension of Sodium Hydride (63 mg, 1.56 mmole) in DMF (5 ml) at room temperature under Nitrogen. The reaction suspension was let stirred for 30 minutes at room temperature. Diethyl Phenyl Malonate (0.29 ml, 313.5 mg, 1.3 mmole) was added to the reaction suspension dropwise at room temperature under nitrogen. The reaction mixture was let stirred at 45-50° C. for 48 hrs. Analysis by TLC indicated only a trace of starting material remained. The reaction was let cooled to room temperature, then poured into saturated Sodium Chloride solution. The aqueous layer was extracted with Ethyl Acetate (3×25 ml). The organic layers were combined and washed with water (1×30 ml). The organic layer was separated, dried over Sodium Sulfate and filtered. The filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography using Ethyl Acetate/Toluene (2.5:7.5). Product was obtained as a colorless oil (650 mg, 93%). 1H NMR (CDCl3): δ1.12 (m, 4H), 1.20 (t, 6H), 1.47 (m, 2H), 2.16 (t, 2H), 2.46 (s, 3H), 3.66 (t, 2H), 4.22 (m, 4H), 7.15 (m, 1H), 7.26 (m, 4H), 7.32 (m, 5H), 7.43 (m, 5H). 13C NMR (CDCl3): δ13.7, 14.0, 24.2, 26.8, 30.2, 35.7, 43.8, 61.5, 62.5, 125.9, 126.5, 127.5, 127.9, 128.1, 128.2, 128.3, 128.5, 129.0, 131.0, 144.1, 170.6. Anal. Calcd. for C34H38N2O4.0.34 Toluene: C, 76.77; H, 7.20; N, 4.91. Found: C, 76.64; H, 7.27; N, 4.78. Mass Spec: 539.29 (MH+).

Intermediate 28

##STR00108##

2-[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl-malonic acid: (Scheme 4 (S)) A solution of starting material 2-[5-(2-methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl-malonic acid diethyl ester (630 mg, 1.17 mmole) in THF (18 ml) and Sodium hydroxide (2N) (8 ml) was let stirred at 80° C. for 18 hrs. The next day, analysis by TLC indicated no significant change in the reaction. The THF solvent was removed by rotorvap. The residue was diluted in Methanol (20 ml). The reaction solution was let stirred under reflux for 2 hrs. Analysis by TLC indicated consumption of starting material. The organic solvent was removed by rotorvap. The residue was diluted with water (20 ml). The aqueous layer was extracted Diethyl Ether (2×20 ml). The organic layers were combined and extracted with Sodium Hydroxide (10%) (2×10 ml). The basic aqueous layers were combined and acidified with Hydrochloric acid (3N) to pH=1, then extracted with dichloromethane (2×20 ml). The organic layers were combined, dried over Sodium Sulfate and filtered. The resultant filtrate was concentrated in vacuo to provide product as a white solid (580 mg, quantitative yield). Mass Spec: 483.54 (MH+).

Intermediate 29

##STR00109##

7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-2-phenyl-heptanoic acid: (Scheme 4 (T)) A solution of starting material 2-[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-2-phenyl-malonic acid (580 mg, 1.32 mmole)) in glacial Acetic Acid (20 ml) was let stirred under reflux for 18 hrs. The next day, the reaction was let cooled to room temperature and concentrated in vacuo. Product was obtained 398.6 mg, 77.7%). 1H NMR (CDCl3): δ1.11 (b, 4H), 1.42 (bd, 2H), 1.59 (m, 1H), 1.96 (m, 1H), 2.55 (s, 3H), 3.43 (t, 1H), 3.96 (t, 2H), 7.199 (m, 3H), 7.27 (m, 7H), 7.39 (m, 2H), 7.45 (m, 3H), 11.857 (b, 1H), 13C NMR (CDCl3): δ6 12.0, 21.4, 26.1, 26.8, 29.5, 29.7, 33.1, 44.2, 52.2, 127.0, 127.2, 127.4, 128.0, 128.4, 128.4, 128.5, 129.1, 129.3, 129.5, 130.6, 131.0, 133.0, 139.8, 144.1, 175.8, 177.7. Mass Spec: 439.24 (MH+).

EXAMPLE 74

##STR00110##

[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-1-phenyl-hexyl]-carbamic acid 2-fluoro-phenyl ester: (Scheme 4 (U)) Diphenylphosphoryl Azide (0.083 ml, 0.38 mmole) was added to a suspension of starting material 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-2-phenyl-heptanoic acid (140 mg, 0.32 mmole) and Triethylamine (0.14 ml, 1.005 mmole) in Toluene (5 ml) at room temperature. The reaction mixture was let stirred at room temperature for 10 minutes under Nitrogen, then at 108° C. for 90 minutes. The reaction was let cooled to room temperature, to which 2-Fluorophenol (0.03 ml, 0.038 g, 0.338 mmole) was added. The reaction mixture was let stirred at room temperature for 10 minutes, then at 100° C. for 18 hrs. The next day, analysis by TLC (Dichloromethane/Ethyl Acetate 3:1) indicated consumption of starting material. The reaction was let cooled to room temperature, where the solvent was removed by rotorvap. The crude material was purified by flash column chromatography using dichloromethane/Ethyl Acetate (6:1 to 3:1). Product was obtained (58 mg, 33.1%). 1H NMR (CDCl3): δ1.18 (t, 3H), 1.27 (t, 2H), 1.497 (t, 2H), 2.47 (s, 3H), 3.70 (t, 2H), 4.63 (q, 1H), 5.38 (d, J=8.16 mHz, 1H), 7.18 (m, 7H), 7.37 (m, 7H), 7.44 (m, 5H). 13C NMR (CDCl3): δ13.6, 25.4, 26.1, 30.2, 36.0, 43.6, 55.7, 116.5, 116.7, 124.1, 124.3, 124.3, 126.0, 126.4, 126.5, 127.7, 128.0, 128.3, 128.5, 128.8, 129.0, 131.0, 131.7, 134.7, 136.3, 141.6, 144.1, 153.0. Anal. Calcd. for C35H34FN3O2.0.42 H2O: C, 75.71; H, 6.32; N, 7.57. Found: C, 75.75; H, 6.49; N, 7.50. Mass Spec: 548.27 (MH+).

Determination of FAAH Activity

Homogenates of crude membranes were prepared from H4 cells that express transfected human FAAH (H4-FAAH cells). Briefly, cells were grown in DMEM supplemented with 10% FBS and Geneticin at a final concentration of 500 μg/ml (Gibco BRL, Rockville, Md.). Confluent cultures of H4-FAAH cells were rinsed twice with phosphate-buffered saline [138 mM NaCl, 4.1 mM KCl, 5.1 mM Na2PO4, 1.5 mM KH2PO4 (pH 7.5), 37° C.] and incubated for 5-10 min. at 4° C. in lysis buffer [1 mM sodium bicarbonate]. Cells were transferred from plates to polypropylene tubes (16×100 mm), homogenized and centrifuged at 32,000×g for 30 min. Pellets were resuspended by homogenization in lysis buffer and centrifuged at 32,000×g for 30 min. Pellets were resuspended in lysis buffer (15-20 μg protein/ml) then stored at −80° C. until needed. On the day of an experiment, membranes were diluted to 2.67 μg protein/ml in 125 mM Tris-Cl, pH 9.0

Activity of FAAH was measured using a modification of the method described by Omeir et al., 1995 (Life Sci 56:1999, 1995). Membrane homogenates (240 ng protein) were incubated at room temperature for one hour with 1.67 nM anandamide [ethanolamine 1-3H] (American Radiolabeled Chemical Inc., St Louis, Mo.) and 10 μM anandamide (Sigma/RBI, St. Louis, Mo.) in the absence and presence of inhibitors. The reaction was stopped by the addition of 1 volume of a solution of methanol and dichloroethane (1:1). The mixture was shaken and then centrifuged at 1000×g for 15 min. to separate the aqueous and organic phases. An aliquot of the aqueous phase, containing [3H]-ethanolamine was withdrawn and counted by scintillation spectroscopy. Data were expressed as the percentage of [3H]-ethanolamine formed versus vehicle, after subtraction of the background radioactivity determined in the presence of 10 μM arachidonyl trifluoromethyl ketone (ATFMK), an inhibitor of FAAH. IC50 values were determined using a four-parameter logistic equation for dose-response curves. Compounds for which IC50 values are not provided herein showed no FAAH inhibition or marginal FAAH inhibition in preliminary tests.

* A<10 nM; B 10 nM<100 nM; C 100 nM<1,000 nM; D 1,000 nM<10,000 nM

Example No. IC50 (nM)
1 A
2 D
3 D
5 D
6 B
8 C
9 A
10 A
11 A
12 A
13 B
14 A
15 B
16 C
17 C
18 C
19 B
20 A
21 B
22 A
23 B
24 A
25 B
26 B
27 A
28 C
29 B
30 C
31 B
32 B
33 B
34 B
35 B
36 B
37 C
38 B
39 D
40 C
41 A
43 A
44 B
45 C
46 B
47 B
48 B
49 B
50 B
51 B
52 D
53 D
55 C
56 C
57 C
59 C
60 D
61 D
62 D
63 D
64 D
66 D
69 D
70 D
71 A
72 B
73 C
74 C

In vivo results

In FIG. 1., example 1, was active in phase I (acute phase) and phase II (chronic phase) of the rat formalin test. In animals that received 25 mg/kg, i.v, of Example 1, the number of paw flinches was reduced by nearly 40% in the first 10 minutes after administration of formalin. Paw flinches were reduced by approximately 30% over the following 50 minutes. The effect of example 1 was similar to that seen with a 3 mg/kg, i.p. dose of morphine.

In FIG. 2., animals that received Example 1, the latency to paw withdrawal was increased significantly. The present results confirm, the activity of Example 1 against acute pain.

In FIG. 3., Example 1 was examined in the Chung model of neuropathic pain where animals exhibit a pain response (paw withdrawal) to a normally innocuous stimulus (light touch), In animals with a neuropathic injury, the threshold for withdrawal of the injured paw was increased (toward normal) in a dose-dependent fashion by Example 1. The anti-neuropathic effect observed with 20 mg/kg Example 1 exhibited earlier onset of action compared to 100 mg/kg gabapentin (reference compound) with similar peak efficacy.

INVENTORS:

Sit, Sing-Yuen, Xie, Kai

THIS PATENT IS REFERENCED BY THESE PATENTS:
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THIS PATENT REFERENCES THESE PATENTS:
Patent Priority Assignee Title
5648373, Feb 11 1992 SmithKline Beecham Corporation; Johns Hopkins University, The CoA-IT and PAF inhibitors
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