Benzimidazole derivatives useful as histamine H3 antagonists
Disclosed are novel compounds of the formula wherein R 1 is optionally substituted benzimidazolyl or a derivative thereof; R 2 is optionally substituted aryl or heteroaryl; M 1 and M 2 are C(R 3 ) or N; and the remaining variables are as defined in the specification; also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating various diseases or conditions, such as allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula I, as well as methods of treating said diseases or conditions using the compounds of formula I in combination with an H 1 receptor antagonist.
1. A compound represented by the structural formula
or a pharmaceutically acceptable salt or solvate thereof, wherein:
the dotted line represents an optional double bond;
a is 0 to 2;
b is 0 to 2;
n is 2;
p is 1, 2 or 3;
r is 0, 1, 2, or 3;
with the proviso that the sum of p and r is 3;
M 1 is N;
M 2 is C(R 3 );
X is a bond or C 1 –C 6 alkylene;
Y is —C(O)—, —C(S)—, —(CH 2 ) q —, —NR 4 C(O)—, —C(O)NR 4 —, —C(O)CH 2 —, —SO 2 —, —N(R 4 )—, —NH—C(═N—CN)— or —C(═N—CN)—NH—; with the provisos that when M 1 is N, Y is not —NR 4 C(O)— or —NH—C(═N—CN)—; when M 2 is N, Y is not —C(O)NR 4 — or —C(═N—CN)—NH—; and when Y is —N(R 4 )—, M 1 is CH and M 2 is C(R 3 );
q is 1 to 5, provided that when both M 1 and M 2 are N, q is 2 to 5;
Z is a bond, C 1 –C 6 alkylene, C 1 –C 6 alkenylene, —C(O)—, —CH(CN)—, —SO 2 — or —CH 2 C(O)NR 4 —;
R 1 is
Q is —N(R 8 )—, —S— or —O—;
k is 0, 1, 2, 3 or 4;
k1 is 0, 1, 2 or 3;
k2 is 0, 1 or 2;
R is H, C 1 –C 6 alkyl, halo(C 1 –C 6 )alkyl-, C 1 –C 6 alkoxy, (C 1 –C 6 )alkoxy-(C 1 –C 6 )alkyl-, (C 1 –C 6 )-alkoxy-(C 1 –C 6 )alkoxy, (C 1 –C 6 )alkoxy-(C 1 –C 6 )alkyl-SO 0-2 , R 32 -aryl(C 1 –C 6 )alkoxy-, R 32 -aryl(C 1 –C 6 )alkyl-, R 32 -aryl, R 32 -aryloxy, R 32 -heteroaryl, (C 3 –C 6 )cycloalkyl, (C 3 –C 6 )cycloalkyl-(C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkyl-(C 1 –C 6 )alkoxy, (C 3 –C 6 )cycloalkyl-oxy-, R 37 -heterocycloalkyl, R 37 -heterocycloalkyl-oxy-, R 37 -heterocycloalkyl-(C 1 –C 6 )alkoxy, N(R 30 )(R 31 )—(C 1 –C 6 )alkyl-, —N(R 30 )(R 31 ), —NH—(C 1 –C 6 )alkyl-O—(C 1 –C 6 )alkyl, —NHC(O)NH(R 29 ); R 29 —S(O) 0-2 —, halo(C 1 –C 6 )alkyl-S(O) 0-2 —, N(R 30 )(R 31 )—(C 1 –C 6 )alkyl-S(O) 0-2 — or benzoyl;
R 8 is H, C 1 –C 6 alkyl, halo(C 1 –C 6 )alkyl-, (C 1 –C 6 )alkoxy-(C 1 –C 6 )alkyl-, R 32 -aryl(C 1 –C 6 )alkyl-, R 32 -aryl, R 32 -heteroaryl, (C 3 –C 6 )cycloalkyl, (C 3 –C 6 )cycloalkyl-(C 1 –C 6 )alkyl, R 37 -heterocycloalkyl, N(R 30 )(R 31 )—(C 1 –C 6 )alkyl-, R 29 —S(O) 2 —, halo(C 1 –C 6 )alkyl-S(O) 2 —, R 29 —S(O) 0-1 —(C 2 –C 6 )alkyl-, halo(C 1 –C 6 )alkyl-S(O) 0-1 —(C 2 –C 6 )alkyl-;
R 2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N—O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R 32 -quinolyl; R 32 -aryl; heterocycloalkyl; (C 3 –C 6 )cycloalkyl; C 1 –C 6 alkyl; hydrogen; thianaphthenyl;
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R 6 ;
R 3 is H, halogen, C 1 –C 6 alkyl, —OH, (C 1 –C 6 )alkoxy or —NHSO 2 —(C 1 –C 6 )alkyl;
R 4 is independently selected from the group consisting of hydrogen, C 1 –C 6 alkyl, C 3 –C 6 cycloalkyl, (C 3 –C 6 )cycloalkyl(C 1 –C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 –C 6 )alkyl, and R 32 -heteroaryl;
R 5 is hydrogen, C 1 –C 6 alkyl, —C(O)R 20 , —C(O) 2 R 20 , —C(O)N(R 20 ) 2 , (C 1 –C 6 )alkyl-SO 2 —, or (C 1 –C 6 )alkyl-SO 2 —NH—;
or R 4 and R 5 , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;
R 6 is 1 to 3 substituents independently selected from the group consisting of —OH, halogen, C 1 –C 6 alkyl-, C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, —CF 3 , —NR 4 R 5 , —CH 2 —NR 4 R 5 , —NHSO 2 R 22 , —N(SO 2 R 22 ) 2 , phenyl, R 33 -phenyl, NO 2 , —CO 2 R 4 , —CON(R 4 ) 2 ,
R 7 is —N(R 29 )—, —O— or —S(O) 0-2 —;
R 12 is independently selected from the group consisting of C 1 –C 6 alkyl, hydroxyl, C 1 –C 6 alkoxy, or fluoro, provided that when R 12 is hydroxy or fluoro, then R 12 is not bound to a carbon adjacent to a nitrogen; or two R 12 substituents form a C 1 to C 2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R 12 is ═O;
R 13 is independently selected from the group consisting of C 1 –C 6 alkyl, hydroxyl, C 1 –C 6 alkoxy, or fluoro, provided that when R 13 is hydroxy or fluoro then R 13 is not bound to a carbon adjacent to a nitrogen; or two R 13 substituents form a C 1 to C 2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R 13 is ═O;
R 20 is independently selected from the group consisting of hydrogen, C 1 –C 6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, —CF 3 , —OCF 3 , hydroxyl, or methoxy; or when two R 20 groups are present, said two R 20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
R 22 is C 1 –C 6 alkyl, R 34 -aryl or heterocycloalkyl;
R 24 is H, C 1 –C 6 alkyl, —SO 2 R 22 or R 34 -aryl;
R 25 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —CN, —NO 2 , —CF 3 , —OH, C 1 –C 6 alkoxy, (C 1 –C 6 )alkyl-C(O)—, aryl-C(O)—, —C(O)OR 29 , —N(R 4 )(R 5 ), N(R 4 )(R 5 )—C(O)—, N(R 4 )(R 5 )—S(O) 1-2 —, R 22 —S(O) 0-2 —, halo-(C 1 –C 6 )alkyl- or halo-(C 1 –C 6 )alkoxy-(C 1 –C 6 )alkyl-;
R 29 is H, C 1 –C 6 alkyl, C 3 –C 6 cycloalkyl, R 35 -aryl or R 35 -aryl(C 1 –C 6 )alkyl-;
R 30 is H, C 1 –C 6 alkyl-, R 35 -aryl or R 35 -aryl(C 1 –C 6 )alkyl-;
R 31 is H, C 1 –C 6 alkyl-, R 35 -aryl, R 35 -aryl(C 1 –C 6 )alkyl-, R 35 -heteroaryl, (C 1 –C 6 )alkyl-C(O)—, R 35 -aryl-C(O)—, N(R 4 )(R 5 )—C(O)—, (C 1 –C 6 )alkyl-S(O) 2 — or R 35 -aryl-S(O) 2 —;
or R 30 and R 31 together are —(CH 2 ) 4-5 —, —(CH 2 ) 2 —O—(CH 2 ) 2 — or —(CH 2 ) 2 —N(R 38 )—(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;
R 32 is 1 to 3 substituents independently selected from the group consisting of H, —OH, halogen, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, R 35 -aryl-O—, —SR 22 , —CF 3 , —OCF 3 , —OCHF 2 , —NR 39 R 40 , phenyl, R 33 -phenyl, NO 2 , —CO 2 R 39 , —CON(R 39 ) 2 , —S(O) 2 R 22 , —S(O) 2 N(R 20 ) 2 , —N(R 24 )S(O) 2 R 22 , —CN, hydroxy-(C 1 –C 6 )alkyl-, —OCH 2 CH 2 OR 22 , and R 35 -aryl(C 1 –C 6 )alkyl-O—, or two R 32 groups on adjacent carbon atoms together form a —OCH 2 O— or —O(CH 2 ) 2 O— group;
R 33 is 1 to 3 substituents independently selected from the group consisting of C 1 –C 6 alkyl, halogen, —CN, —NO 2 , —CF 3 , —OCF 3 , —OCHF 2 and —O—(C 1 –C 6 )alkyl;
R 34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, —CF 3 , —OCF 3 , —OH and —OCH 3 ;
R 35 is 1 to 3 substituents independently selected from hydrogen, halo, C 1 –C 6 alkyl, hydroxy, C 1 –C 6 alkoxy, phenoxy, —CF 3 , —N(R 36 ) 2 , —COOR 20 and —NO 2 ;
R 36 is independently selected form the group consisting of H and C 1 –C 6 alkyl;
R 37 is 1 to 3 substituents independently selected from hydrogen, halo, C 1 –C 6 alkyl, hydroxy, C 1 –C 6 alkoxy, phenoxy, —CF 3 , —N(R 36 ) 2 , —COOR 20 , —C(O)N(R 29 ) 2 and —NO 2 , or R 37 is one or two ═O groups;
R 38 is H, C 1 –C 6 alkyl, R 35 -aryl, R 35 -aryl(C 1 –C 6 )alkyl-, (C 1 –C 6 )alkyl-SO 2 or halo(C 1 –C 6 )alkyl-SO 2 —;
R 39 is independently selected from the group consisting of hydrogen, C 1 –C 6 alkyl, C 3 –C 6 cycloalkyl, (C 3 –C 6 )cycloalkyl(C 1 –C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 –C 6 )alkyl, and R 32 -heteroaryl; and
R 40 is hydrogen, C 1 –C 6 alkyl, —C(O)R 20 , —C(O) 2 R 20 , —C(O)N(R 20 ) 2 , (C 1 –C 6 )alkyl-SO 2 —, or (C 1 –C 6 )alkyl-SO 2 —NH—;
or R 39 and R 40 , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring.
2. A compound of claim 1 wherein a is 0, and the optional double bond is not present.
3. A compound of claim 2 wherein M 2 is C(R 3 ) wherein R 3 is hydrogen or fluorine, b is 0, r is 1, and p is 2.
4. A compound of claim 3 wherein X is a bond.
5. A compound of claim 4 wherein Y is —C(O)—.
6. A compound of claim 5 wherein Z is straight or branched C 1 –C 3 alkyl.
7. A compound of claim 6 wherein R 2 is a six-membered heteroaryl ring, optionally substituted with one R 6 substituent.
8. A compound of claim 7 wherein R 2 is pyrimidyl, R 6− pyrimidyl, pyridyl R 6− pyridyl or pyridazinyl and R 6 is —NH 2 .
9. A compound of claim 8 wherein R 2 is
10. A compound of claim 2 wherein R 1 is
11. A compound of claim 10 wherein R is (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkoxy(C 1 –C 6 )alkoxy, (C 1 –C 6 )alkylthio, heteroaryl or R 32 -aryl; R 25 is halogen or —CF 3 ; and k and k1 are 0 or 1.
12. A compound of claim 11 wherein R is —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —OCH((CH 3 ) 2 , —CH 2 CH 3 , —SCH 3 , —SCH 2 CH 3 , pyridyl, pyrimidyl, pyrazinyl, furanyl, oxazolyl or R 32 -phenyl.
13. A compound of claim 12 wherein R 2 is
14. A compound of claim 1 selected from the group consisting of
15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.
16. A method of treating nasal congestion obesity, somnolence, narcolepsy, attention deficit hyperactivity disorder, Alzheimer's disease, and schizophrenia comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 .
17. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and an effective amount of H 1 receptor antagonist, and a pharmaceutically effective carrier.
18. A method of treating nasal congestion comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 in combination with an H 1 receptor antagonist.
19. The method of claim 18 wherein said H 1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
20. The method of claim 19 wherein said H 1 receptor antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine.
21. The method of claim 20 wherein said H 1 receptor antagonist is selected from: loratadine or descarboethoxyloratadine.
22. The compound having the structure