Pharmaceutically effective compounds
The subject invention relates to carboxamidine derivatives, to pharmaceutical compositions containing the carboxamidine derivatives of the invention, and the use thereof for the treatment of vascular diseases and in the preparation of pharmaceutical compositions for the treatment of vascular diseases.
1. A method for treating a vascular disease or vascular disorder comprising administering to a patient in need thereof an effective amount of a compound of formula III as defined below:
wherein R 1 and R 2 are independently hydrogen, straight chained C 1-6 alkyl group optionally substituted with a phenyl group, branched C 1-6 alkyl group optionally substituted with a phenyl group, or
R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups;
A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
n is 0, 1, or 2;
z is 0 or 1;
with the proviso that
if R 1 and R 2 independently represent a hydrogen atom, a straight chained C 1-6 alkyl group optionally substituted with a phenyl group, a branched C 1-6 alkyl group optionally substituted with a phenyl group, or together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, then A is a heteroaromatic ring containing oxygen or sulfur heteroatom or an N-containing heteroaromatic ring having an N-oxide structure on the nitrogen heteroatom and
if A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl or nitro groups or halogen, or is a 5-6 membered N-containing heteroaromatic ring, then R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups;
or a stereoisomer or salt thereof.
2. The method according to claim 1 , wherein the compound is 5,6-dihydro-5-[(1 -piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
3. The method according to claim 1 , wherein the compound is 5,6-dihydro-5-[(4-benzyl-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
4. The method according to claim 1 , wherein the compound is 5,6-dihydro-5-[(2-oxo-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
5. The method according to claim 1 , wherein the compound is (+)-5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
6. The method according to claim 1 , wherein the compound is 5,6-dihydro-5-[(1-oxido-1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
7. The method according to claim 1 , wherein the compound is 5,6-dihydro-5-[(4-hydroxy-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
8. A method for inhibiting or reversing damage to one or more endothelial cells comprising administering to the one or more endothelial cells an effective amount of a compound of formula III as defined below:
wherein R 1 and R 2 are independently hydrogen, straight chained C 1-6 alkyl group optionally substituted with a phenyl group, branched C 1-6 alkyl group optionally substituted with a phenyl group, or
R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups;
A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
n is 0, 1, or 2;
z is 0 or 1;
with the proviso that
if R 1 and R 2 independently represent a hydrogen atom, a straight chained C 1-6 alkyl group optionally substituted with a phenyl group, a branched C 1-6 alkyl group optionally substituted with a phenyl group, or together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, then A is a heteroaromatic ring containing oxygen or sulfur heteroatom or an N-containing heteroaromatic ring having an N-oxide structure on the nitrogen heteroatom and
if A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl or nitro groups or halogen, or is a 5-6 membered N-containing heteroaromatic ring, then R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups;
or a stereoisomer or salt thereof.
9. The method according to claim 8 , wherein the compound is 5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
10. The method according to claim 8 , wherein the compound is 5,6-dihydro-5-[(4-benzyl-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
11. The method according to claim 8 , wherein the compound is 5,6-dihydro-5-[(2-oxo-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
12. The method according to claim 8 , wherein the compound is (+)-5,6-dihydro-5-[(1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
13. The method according to claim 8 , wherein the compound is 5,6-dihydro-5-[(1-oxido-1-piperidinyl)methyl]-3-(1-oxido-3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
14. The method according to claim 8 , wherein the compound is 5,6-dihydro-5-[(4-hydroxy-1-piperidinyl)methyl]-3-(3-pyridyl)-4H-1,2,4-oxadiazine, or a stereoisomer or salt thereof.
15. The method of claim 8 , wherein the compound is administered to one or more of the endothelial cells in culture.
16. The method of claim 8 , wherein the compound is administered to one or more endothelial cells of a patient.
17. A method for increasing vaso-relaxation of a vessel associated with endothelial cells comprising administering to the cells an effective amount of a compound of formula III as defined below:
wherein R 1 and R 2 are independently hydrogen, straight chained C 1-6 alkyl group optionally substituted with a phenyl group, branched C 1-6 alkyl group optionally substituted with a phenyl group, or
R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups;
A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
n is 0, 1, or 2;
z is 0 or 1;
with the proviso that
if R 1 and R 2 independently represent a hydrogen atom, a straight chained C 1-6 alkyl group optionally substituted with a phenyl group, a branched C 1-6 alkyl group optionally substituted with a phenyl group, or together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, then A is a heteroaromatic ring containing oxygen or sulfur heteroatom or an N-containing heteroaromatic ring having an N-oxide structure on the nitrogen heteroatom and
if A is a phenyl group optionally substituted with one or more C 1-4 alkyl, C 1-4 haloalkyl or nitro groups or halogen, or is a 5-6 membered N-containing heteroaromatic ring, then R 1 and R 2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups;
or a stereoisomer or salt thereof.
18. The method of claim 17 , wherein the compound is administered to one or more of the endothelial cells in culture.
19. The method of claim 17 , wherein the compound is administered to one or more endothelial cells of a patient.