Heterocyclic H3 antagonists
View Patent ↗Compound of formula (I) wherein W, X, Y, Z is —C(R 1 )═ or N; R 1 is hydrogen or alkyl, V is N or C (i.e. carbon), A is a bond or an alkylene linker with 1 to 3 carbon atoms, with the proviso that when A is a bond, V must be CH, R is ethyl, propyl, a branched C 3-6 alkyl or a cyclic C 3-8 alkyl, m and n is 1-3, D is heteroaryl optionally substituted with halogen, hydroxy, cyano, alkyl, cycloalkyl, alkoxy, —(CH 2 ) 0 —(C═O) p —NR 2 R 3 , or D is aryl optionally substituted with one or more of the groups independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, alkylsulfinyl, heterocyclyl, heterocyclylalkyl, heterocyclyl-alkoxy, heterocyclylcarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarboxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, arylcarbonylamino, aryl-carbonylaminoalkyl, heteroarylcarbonylamino or heteroarylcarbonylaminoalkyl, —(CH 2 ) 0 —(C═O) p —NR 2 R 3 , wherein o is 0-3, p is 0 or 1, and R 2 and R 3 independently are hydrogen, alkyl or cycloalkyl; or R 2 and R 3 , can together with the attached nitrogen form a heterocyclyl group, and salts and solvates thereof have binding affinity for the histamine H3 receptor.
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
W is —CH═;
X is ═CH—;
Y is ═N—;
Z is —CH═;
R is isopropyl, cyclobutyl, cyclopentyl, or 3-pentyl;
V is >CH—;
m is 2;
A is a bond or —CH 2 —; and
D is:
(i) phenyl substituted by one or two substituents selected from the group consisting of formyl, acetyl, anilino, amino, cyano, diisopropylcarbonyl, ethylsulfonyl, flouro, methyl -carbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, N,N-diethylaminocarbonyl, N,N-diethylaminomethyl, N,N-di -methylaminocarbonyl, N,N-dimethylaminomethyl, N,N-dimethylaminosulfonyl, piperidinylsulfonyl, pyrrolidinylcarbonyl, pyrrolidinylethyl, and pyrrolidinylmethyl, or, if substituted on two different carbon atoms in the phenyl ring, methylenedioxy; or
(ii) pyridyl substituted by a methyl or an oxo group.
2. The compound of claim 1 , where D is phenyl substituted by one or two substituents selected from the group consisting of formyl, acetyl, anilino, amino, cyano, diisopropylcarbonyl, ethylsulfonyl, flouro, methylcarbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, N,N-diethylaminocarbonyl, N,N -diethylaminomethyl, N,N-dimethylaminocarbonyl, N,N-dimethylaminomethyl, N,N-dimethylaminosulfonyl, piperidinylsulfonyl, pyrrolidinylcarbonyl, pyrrolidinylethyl, and pyrrolidinylmethyl, or, if substituted on two different carbon atoms in the phenyl ring, methylenedioxy.
3. The compound of claim 1 , where D is pyridyl substituted by a methyl or an oxo group.
4. The compound of claim 1 , where the compound is a compound selected from the group consisting of:
5-[1,3-Benzodioxol-5-yl]-1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-2,4′-bipyridine;
1′-Isopropyl-5-(4-morpholin-4-ylphenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridine;
1-Isopropyl-2″-methyl-1,2,3,4,5,6-hexahydro-[4,2′;5′,4″]terpyridine;
5-(4-Ethanesulfonylphenyl)-1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridine;
4-(1′-Isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-N,N-dimethylbenzamide;
[2-Fluoro-4-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]pyrrolidin-1-yl -methanone;
3-(1′-Isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-N,N-dimethylbenzamide;
N,N-Diethyl-4-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)benzamide;
[4-(1′-Isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]-(4-methylpiperazin-1-yl)methanone;
[4-(1′-Isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]pyrrolidin-1-yl-methanone;
1′-Isopropyl-5[4-(piperidine-1-sulfonyl)phenyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridine;
[4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]-(4-methylpiperazin-1-yl)methanone;
4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-N,N-dimethylbenzamide;
4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-N,N-diethylbenzamide;
[4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]pyrrolidin-1-yl-methanone;
1′-Cyclobutyl-5-(4-ethanesulfonylphenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridine;
4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-N,N-dimethylbenzene-sulfonamide;
1-Cyclobutyl-2″-methyl-1,2,3,4,5,6-hexahydro-[4,2′;5′,4″]terpyridine;
[4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)benzyl]pipethylamine;
1′-Cyclobutyl-5-(4-pyrrolidin-1-ylmethylphenyl)-1′,2′,3 ′,4′,5′,6′-hexahydro-[2,4′]bipyridine;
[4-(1′-Cyclobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)benzyl]dimethylamine;
{4-[6-(1-Cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]phenyl}-(4-methylpiperazin-1-yl)-methanone;
4-[6-(1-Cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]-N,N -dimethylbenzenesulfonamide;
6-(1-Cyclobutylpiperidin-4-ylmethyl)-2′-methyl-[3,4′]bipyridine;
4-[6-(1-Cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]-N,N -dimethylbenzamide;
{4-[6-(1-Cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone;
{4-[6-(1-Cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]benzyl}dimethylamine; and
2-(1-Cyclobutylpiperidin-4-ylmethyl)-5-(4-ethanesulfonylphenyl)pyridine;
or a pharmaceutically acceptable salt thereof.
5. A compound where the compound is [4-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]-(4-methylpiperazin-1-yl)methanone or a pharmaceutically acceptable salt thereof.
6. A compound where the compound is [4-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)phenyl]pyrrolidin-1-ylmethanone or a pharmaceutically acceptable salt thereof.
7. A compound where the compound is 6-(1-cyclobutylpiperidin-4-ylmethyl)-2′-methyl[3,4′]bipyridine or a pharmaceutically acceptable salt thereof.
8. A compound where the compound is {4-[6-(1-cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]phenyl}morpholin-4-ylmethanone or a pharmaceutically acceptable salt thereof.
9. A compound where the compound is {4-[6-(1-cyclobutylpiperidin-4-ylmethyl)pyridin-3-yl]benzyl}dimethylamine or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
11. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier or diluent.
12. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier or diluent.
13. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier or diluent.
14. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier or diluent.
15. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier or diluent.
16. A method of treating obesity in a human comprising: administering to a human in need thereof a compound of claim 1 .
17. A method of inducing weight loss in a human comprising: administering to a human in need thereof a compound of claim 1 .
18. A method of suppressing appetite in a human comprising: administering to a human in need thereof a compound of claim 1 .
19. A method of inducing satiety in a human comprising: administering to a human in need thereof a compound of claim 1 .
20. A compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
W is —CH═;
X is ═CH—;
Y is ═N—;
Z is —CH═;
R is isopropyl, cyclobutyl, cyclopentyl, or 3-pentyl;
V is >N—;
m is 2;
A is —CH 2 —; and
D is:
(i) phenyl substituted by one or two substituents selected from the group consisting of formyl, acetyl, anilino, amino, cyano, diisopropylcarbonyl, ethylsulfonyl, flouro, methyl -carbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, N,N-diethylaminocarbonyl, N,N-diethylaminomethyl, N,N-di -methylaminocarbonyl, N,N-dimethylaminomethyl, N,N-dimethylaminosulfonyl, piperidinylsulfonyl, pyrrolidinylcarbonyl, pyrrolidinylethyl, and pyrrolidinylmethyl, or, if substituted on two different carbon atoms in the phenyl ring, methylenedioxy; or
(ii) pyridyl substituted by a methyl or an oxo group.
21. The compound of claim 20 , where D is phenyl substituted by one or two substituents selected from the group consisting of formyl, acetyl, anilino, amino, cyano, diisopropylcarbonyl, ethylsulfonyl, flouro, methylcarbonylamino, 4-methylpiperazinylcarbonyl, morpholin-4-yl, morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, N,N-diethylaminocarbonyl, N,N -diethylaminomethyl, N,N-dimethylaminocarbonyl, N,N-dimethylaminomethyl, N,N-dimethylaminosulfonyl, piperidinylsulfonyl, pyrrolidinylcarbonyl, pyrrolidinylethyl, and pyrrolidinylmethyl, or, if substituted on two different carbon atoms in the phenyl ring, methylenedioxy.
22. The compound of claim 20 , where D is pyridyl substituted by a methyl or an oxo group.
23. The compound of claim 20 , where the compound is a compound selected from the group consisting of:
4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]-N,N -dimethylbenzamide;
4-[6-(4-Isopropylpiperazin1-ylmethyl)pyridin-3-yl]-N,N -dimethylbenzamide;
1-Cyclobutyl-4-[5-(4-ethanesulfonylphenyl)pyridin-2-ylmethyl]piperazine;
1-[5-(4-Ethanesulfonylphenyl)pyridin-2-ylmethyl]-4-isopropylpiperazine;
{4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]phenyl}-(4-methylpiperazin 1yl)-methanone;
{4-[6-(4-Isopropylpiperazin-1-ylmethyl)pyridin-3 -yl]phenyl}-(4-methylpiperazin-1yl)-methanone;
1-Cyclobutyl-4-{5-[4-(2-pyrrolidin-1-ylethyl)phenyl]pyridin-2-ylmethyl}piperazine;
1-Isopropyl-4- {5-[4-(2-pyrrolidin-1-ylethyl)phenyl]pyridin-2-ylmethyl}piperazine;
1-Cyclobutyl-4-[5-(4-pyrrolidin-1-ylmethylphenyl)pyridin-2-ylmethyl]piperazine;
4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]benzonitrile;
4-[6-(4-Isopropylpiperazin-1-ylmethyl)pyridin-3-yl]benzonitrile;
4-[6-(4-Cyclobutylpiperazin-1-ylmethyl)pyridin-3-yl]benzaldehyde; and
1-Isopropyl-4[5-(4-pyrrolidin-1-ylmethylphenyl)pyridin-2-ylmethyl]piperazine;
or a pharmaceutically acceptable salt thereof.
24. A compound where the compound is 4-[6-(4-isopropylpiperazin-l-ylmethy) ppyridin-3-yl]-N,N-dimethylbenzamide or a pharmaceutically acceptable salt thereof.
25. A compound where the compound is 1-isopropyl-4- {5-[4-(2-pyrrolidin-l-ylethyl) phenyl]pyridin-2-ylmethyl}piperazine or a pharmaceutically acceptable salt thereof.
26. A compound where the compound is 4-[6-(4-isopropylpiperazin-1 -ylmethyl) pyridin-3-yl]benzonitrile or a pharmaceutically acceptable salt thereof.
27. A compound where the compound is 1-isopropyl-4-[5-(4-pyrrolidin-l-ylmethylphenyl) pyridin-2-ylmethyl]piperazine or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
29. A pharmaceutical composition comprising a compound of claim 24 and a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable carrier or diluent.
31. A pharmaceutical composition comprising a compound of claim 26 and a pharmaceutically acceptable carrier or diluent.
32. A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable carrier or diluent.
33. A method of treating obesity in a human comprising: administering to a human in need thereof a compound of claim 20 .
34. A method of inducing weight loss in a human comprising: administering to a human in need thereof a compound of claim 20 .
35. A method of suppressing appetite in a human comprising: administering to a human in need thereof a compound of claim 20 .
36. A method of inducing satiety in a human comprising: administering to a human in need thereof a compound of claim 20 .