Diazeniumdiolate cyclohexyl derivatives

Patent metadata

Field	Value
Publication number	US-9272987-B2
Application number	US-201214115139-A
Country	US
Kind code	B2
Filing date	Apr 27, 2012
Priority date	May 2, 2011
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Ali Amjad
• Lo Michael Man-Chu
• Yan Lin
• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Lo Michael Man-Chu
• Yan Lin

Classifications

• C07C245/24

  Chains of only three nitrogen atoms, e.g. diazoamines · CPC title

• C07C291/08

  Azoxy compounds · CPC title

• C07D317/72

  spiro-condensed with carbocyclic rings · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07B2200/07

  Optical isomers · CPC title