Heterocyclic compounds with affinity to muscarinic receptors
The present invention relates to heterocyclic compounds of the formula (I) or a pharmaceutically acceptable salt, a solvate or hydrate thereof.
1. A heterocyclic compound of the formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
the heterocycle comprises two double bonds, which may be present at varying positions, and which are represented by the dashed lines (—);
the heterocycle contains two heteroatoms,
W is N or NH;
Y is CH, O or NH, wherein
if Y is O, X1 is CH and X2 is C—Z—R2 or C—R3, wherein Z is NH, O, or S; and
if Y is CH or NH, one of X1 and X2 is CH or N, wherein if X1 is CH or N, X2 is C—Z—R2 or C—R3, and if X2 is CH or N, X1 is C—Z—R2 or C—R3, wherein Z is NH or S;
R1 is structure (a):
R2 is chosen from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and
R3 is chosen from (C 4 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen;
and optionally, when R2 is an unbranched (C 2 -C 8 )alkyl, R2 links to formula (Ia)
or a pharmaceutically acceptable salt thereof,
through the X 1 a or X 2 a of formula (Ia), wherein if X 1 is CH or N, X 1 a is CH or N and X 2 a is C-Za-, or
if X1 is C—Z—R2, X 1 a is C-Za- and X 2 a is CH or N, wherein X 1 a or X 2 a having Za links to R2;
wherein
Wa is N or NH;
Ya is CH, O or NH;
Za is NH, O , or S; and
R 1 a is chosen from structure (a):
2. The compound of claim 1 , wherein R2 is chosen from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 8 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen.
3. The compound of claim 2 , wherein R2 is chosen from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, tetrahydrofuranyl and phenyl, wherein the phenyl group is optionally substituted with halogen.
4. The compound of claim 3 , wherein R2 is chosen from (C 1 -C 8 )alkyl and (C 2 -C 8 )alkenyl, optionally substituted with one or more substituents chosen from halogen and (C 1 -C 6 )alkoxy.
5. The compound of claim 1 , wherein R3 is chosen from (C 4 -C 10 )alkyl,(C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally substituted with a substituent chosen from (C 5 -C 7 )cycloalkyl and phenyl, wherein the phenyl group is optionally substituted with halogen.
6. The compound of claim 1 , wherein R1 has the structure (a).
7. The compound of claim 1 , wherein W is N and Y is NH.
8. A heterocyclic compound of the formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
the heterocycle comprises two double bonds, which may be present at varying positions, and which are represented by the dashed lines (—);
the heterocycle contains two heteroatoms,
W is N;
Y is NH;
X1 is CH and X2 is C—Z—R2 or C—R3, wherein Z is O or S;
R1 is structure (a):
R2 is chosen from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and
R3 is chosen from (C 4 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen;
and optionally, when R2 is an unbranched (C 2 -C 8 )alkyl, R2 links to formula (Ia)
or a pharmaceutically acceptable salt thereof,
through the X 1 a or X 2 a of formula (Ia), wherein X 1 a is CH or N and X 2 a is C-Za-;
wherein
Wa is N or NH;
Ya is CH, O or NH;
Za is NH, O , or S; and
R 1 a is chosen from structure (a):
9. The compound of claim 8 , wherein X2 is C—Z—R2.
10. The compound of claim 9 , wherein Z is S.
11. A heterocyclic compound of the formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
the heterocycle comprises two double bonds, which may be present at varying positions, and which are represented by the dashed lines (—);
the heterocycle contains two heteroatoms,
W is N or NH;
Y is O;
X1 is CH and X2 is C—Z—R2 or C—R3 wherein Z is O or S; and
R1 is structure (a):
R2 is chosen from (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, oxo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; and
R3 is chosen from (C 4 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally independently substituted with one or more substituents chosen from halogen, hydroxy, cyano, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkenyloxy, (C 1 -C 6 )alkenylthio, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle optionally substituted with halogen, phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen;
and optionally, when R2 is an unbranched (C 2 -C 8 )alkyl, R2 links to formula (Ia)
or a pharmaceutically acceptable salt thereof,
through the X 1 a or X 2 a of formula (Ia), wherein if X 1 is CH or N, X 1 a is CH or N and X 2 a is C—Za-, or
if X1 is C—Z—R2, X 1 a is C-Za- and X 2 a is CH or N, wherein X 1 a or X 2 a having Za links to R2;
wherein
Wa is N or NH;
Ya is CH, O or NH;
Za is NH, O , or S; and
R 1 a is chosen from structure (a):
12. The compound of claim 11 , wherein Z is S.
13. A compound chosen from
3-(4-Pentyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(Furan-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-(5-Butylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Benzylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(4,4,4-trifluoro-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
N-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-butyramide;
3-(4-Methylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Propylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
Butyl-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-amine;
3-(4-Pentylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Ethylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Butyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Allylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-[3-(1-Methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-ylsulfanyl]-propionitrile;
3-[4-(3-Methyl-butylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(3-Phenyl-propoxy)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hexylsulfanyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-But-3-enyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hexylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Butylsulfanyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Oct-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hept-1-ynyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hex-1-enyl-isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hept-1-ynyl-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Non-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hex-1-ynyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-{4-[2-(3-Fluoro-phenyl)-vinyl]-1H-pyrazol-3-yl}- 1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(5-Cyclohexyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
Bis-[3-(1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazol-4-yl]-2-sulfanylethyl]-methane;
3-[4-(5-Phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Oct-1-enyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(3-Phenyl-propylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(4,4-Difluoro-but-3-enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(3-Phenyl-allylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Hexyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methyl pyridine;
3-(4-Pentyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methyl pyridine;
3-[4-Pent-4-enylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-(2-Ethoxy-ethylsulfanyl)-1H-pyrazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Heptyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Heptyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-(4-Pent-4-enyloxy-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
3-[4-[2-(2-Methoxy-ethoxy)-ethylsulfanyl]-1H-pyrazol-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine;
3-(5-Hexylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; and
3-(5-Pentylsulfanyl-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound as claimed in claim 1 , and at least one other pharmacologically active substance.
15. A pharmaceutical composition comprising the compound as claimed in claim 1 , and a pharmaceutically acceptable auxiliary.