Diazeniumdiolate cyclohexyl derivatives
View Patent ↗A compound having the structure or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, —OH, —C 1-6 alkyl, —OC 1-6 alkyl, aryl, or halogen, or together with R 7 , forms an oxo group, or together with R 7 and the atom to which they are attached, form a 5-7-membered carbocycle ring or a 5-7-membered heterocyclic ring having 1, 2, or 3 heteroatoms, wherein alkyl and aryl are unsubstituted or independently mono-, di-, or tri-substituted with R 14 ; R 7 is hydrogen, C 1-6 alkyl, —CF 3 , aryl, —O-aryl, —O—C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(R 15 R 16 )OH, a 5-7-membered heteroaryl having 1, 2, 3 or 4 nitrogen atoms, or halogen, or together with R 6 , forms an oxo group, or together with R 6 and the atom to which they are attached, form a 5-7-membered carbocycle ring or a 5-7-membered heterocyclic ring having 1, 2, or 3 heteroatoms wherein alkyl, aryl and heteroaryl are unsubstituted or independently mono-, di- or tri-substituted with R 14 ; R 12 is hydrogen, C 1-6 alkyl, or —(CH 2 ) 1-2 OH, or together with R 13 and the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring containing one nitrogen atom and 0 or 1 oxygen atoms, wherein said ring is unsubstituted or independently mono-, di- or tri-substituted with halogen or —C 1-6 alkyl; R 13 is —C 1-6 alkyl or —(CH 2 ) 1-2 OH, or together with R 12 and the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring containing one nitrogen atom and 0 or 1 oxygen atoms, wherein said ring is unsubstituted or independently mono-, di- or tri-substituted with halogen or —C 1-6 alkyl.
1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen;
R 2 , R 3 , R 4 , R 5 , R 8 , and R 9 are independently hydrogen or —C 1-6 alkyl;
R 6 is hydrogen, —OH, —C 1-6 alkyl, —OC 1-6 alkyl, aryl, or halogen,
or together with R 7 , forms an oxo group,
or together with R 7 and the atom to which they are attached, form a 5-7-membered carbocycle ring or a 5-7-membered heterocyclic ring having 1, 2, or 3 heteroatoms,
wherein alkyl and aryl are unsubstituted or independently mono-, di-, or tri-substituted with R 14 ;
R 7 is hydrogen, C 1-6 alkyl, —CF 3 , aryl, —O-aryl, —O—C 1-6 alkyl,
a 5-7-membered heteroaryl having 1, 2, 3 or 4 nitrogen atoms, or halogen,
or together with R 6 , forms an oxo group,
or together with R 6 and the atom to which they are attached, form a 5-7-membered carbocycle ring or a 5-7-membered heterocyclic ring having 1, 2, or 3 heteroatoms
wherein alkyl, aryl and heteroaryl are unsubstituted or independently mono-, di- or tri-substituted with R 14 ;
R 10 and R 11 are hydrogen;
R 12 is hydrogen, C 1-6 alkyl, or —(CH 2 ) 1-2 OH,
or together with R 13 and the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring containing one nitrogen atom and 0 or 1 oxygen atoms, wherein said ring is unsubstituted or independently mono-, di- or tri-substituted with halogen or —C 1-6 alkyl;
R 13 is —C 1-6 alkyl or —(CH 2 ) 1-2 OH,
or together with R 12 and the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring containing one nitrogen atom and 0 or 1 oxygen atoms, wherein said ring is unsubstituted or independently mono-, di- or tri-substituted with halogen or —C 1-6 alkyl;
R 14 , each time in which it occurs, is independently halogen, —C 1-6 alkyl, —CF 3 , aryl or trimethylsilyl;
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , having the formula Ia:
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 , wherein R 4 is hydrogen or —CH 3 , or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 , wherein R 5 is hydrogen or —CH 3 , or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 , wherein R 8 is hydrogen or —CH 3 , or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , wherein R 9 is hydrogen or —CH 3 , or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 , wherein R 6 is hydrogen, —OH, F, —CH 3 , or —C 6 H 5 ,
or together with R 7 forms an oxo group, or together with R 7 and the atom to which they are attached, forms
or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 , wherein R 7 is hydrogen, F, —CH 3 , —CF 3 , —C 6 H 5 , —CH 2 —C 6 H 5 ,
or a 5-membered heteroaryl ring having 2 or 3 nitrogen atoms,
wherein R 14 , each time in which it occurs, is independently halogen, —CF 3 , aryl or trimethylsilyl,
or together with R 6 forms an oxo group, or together with R 6 and the atom to which they are attached, forms
or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 , wherein R 7 is hydrogen, F, —CH 3 , —CF 3 , —C 6 H 5 ,
or together with R 6 forms an oxo group,
or together with R 6 and the atom to which they are attached, forms
or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 , wherein, R 12 is hydrogen, —CH 3 , or —CH 2 CH 3 , or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 , wherein, R 13 is —C(CH 3 ) 3 , or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 , which is
O 2 -(1,4-dioxaspiro[4.5]decan-8-yl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(4-oxocyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(4-oxocyclohexyl) 1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -(4,4-difluorocyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(4,4-difluorocyclohexyl) 1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -(4-hydroxylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(trans-4-hydroxylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(cis-4-hydroxylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -{trans-4-[3,5-bis(trifluoromethyl)phenoxy]cyclohexyl} 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -{cis-4-[3,5-bis(trifluoromethyl)phenoxy]cyclohexyl} 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(trans-4-{[3,5-bis(trifluoromethyl)benzyl]oxy}cyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(cis-4-{[3,5-bis(trifluoromethyl)benzyl]oxy}cyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(cis-4-hydroxy-4-phenylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(trans-4-hydroxy-4-phenylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(cis-4-phenylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(trans-4-phenylcyclohexyl) 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -{4-[3,5-bis(trifluoromethyl)phenyl]cyclohexyl} 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[trans-4-(1H-pyrazol-1-yl)cyclohexyl] 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[cis-4-(1H-pyrazol-1-yl)cyclohexyl] 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[trans-4-(1H-1,2,3-triazol-1-yl)cyclohexyl] 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[cis-4-(1H-1,2,3-triazol-1-yl)cyclohexyl] 1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(4,4-Dimethylcyclohexyl)-N-tert-butylamino-diazen-1-ium-1,2-diolate,
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a compound of claim 12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a compound of claim 12 , or a pharmaceutically acceptable salt thereof, a diuretic, and a pharmaceutically acceptable carrier.