Nitrooxy cycloalkane derivatives

1. A compound having the general formula I:

or a pharmaceutically acceptable salt thereof, wherein

X is 1;

Z is 1;

Y is selected from the group consisting of —C(O)OR 2 , —(CH 2 ) 1-2 OR 3 , —OH,

R 1 is selected from the group consisting of

1) —ONO 2 ,

2) —O—CH 3 ,

3) —O—aryl,

4) —O—heteroaryl,

5) —O—C 3-8 cycloalkyl,

6) -aryl,

7) -heteroaryl,

8) —C 3-8 cycloalkyl, and

9) halogen;

R 2 is selected from the group consisting of

1) hydrogen

2) —C 1-6 alkyl,

3) -aryl,

4) —CH 2 OC(O)C 1-6 alkyl, and

5) —(CH 2 ) 1-2 N + (R 9 ) 3 ;

R 3 is selected from the group consisting of

1) hydrogen,

2) —C(O)C 1-6 alkyl, and

3) —P(O)(OH) 2 ,

R 5 is selected from the group consisting of hydrogen and —OH;

R 6 is selected from the group consisting of hydrogen and —OH;

R 7 is absent or, when x is 2 or 3, is selected from the group consisting of hydrogen and —OH;

R 8 is selected from the group consisting of hydrogen, —CH(R 10 )COOH,

R 9 in each instance in which it occurs, is independently C 1-3 alkyl; and

R 10 is straight or branched C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted on any carbon atom with halogen, C 1 -C 20 alkyl, CF 3 , NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NO 2 , oxo, CN, N 3 , —OH, —O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C l -C 6 alkyl)S(O) 0-2 —, (C 1 -C 6 alkyl)S(O) 0-2 (C 1 -C 6 alkyl)-, HS(O) 0-2 (C 1 -C 6 alkyl)-, (C 0 -C 6 alkyl)C(O)NH—, H 2 N—C(NH)—, —O(C 1 -C 6 alkyl)CF 3 , HC(O)—, (C 1 -C 6 alkyl)C(O)—, HOC(O)—, (C 1 -C 6 alkyl)OC(O)—, HO(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 (C 1 -C 6 alkyl)-, HC(O) 1-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 —, HOC(O)NH—, (C 1 -C 6 alkyl)OC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle or cyano-heterocyclylalkyl,

wherein aryl is unsubstituted or substituted on any carbon atom with halogen, C 1 -C 20 alkyl, CF 3 , NH 2 , —NH( 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 ,NO 2 ,oxo, CN, N 3 , —OH, —O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkyl)S(O) 0-2 —, (C 1 -C 6 alkyl)S(O) 0-2 (C 1 -C 6 alkyl)-, HS(O) 0-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)S(O) 0-2 , (C 1 -C 6 alkyl)C(O)NH—, HC(O)NH—, H 2 N—C(NH)—, —O(C 1 -C 6 alkyl)CF 3 , (C 1 -C 6 alkyl)C(O)—, HC(O)—, (C 1 -C 6 alkyl)OC(O)—, HOC(O)—, (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl)-, HO(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 —, HC(O) 1-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)OC(O)NH—, HOC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle or cyano-heterocyclylalkyl,

wherein cycloalkyl unsubstituted or substituted on any carbon atom with unsubstituted, or substituted with 1-3 substituent on any one or more carbon atoms, with halogen, C 1 -C 20 alkyl, CF 3 , NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NO 2 ,oxo, CN, N 3 , —OH, —O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkyl)S(O) 0-2 —(C 1 -C 6 alkyl)S(O) 0-2 (C 1 -C 6 alkyl)-, HS(O) 0-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)S(O) 0-2 —, (C 1 -C 6 alkyl)C(O)NH—, HC(O)NH—, H 2 N—C(NH)—, —O(C 1 -C 6 alkyl)CF 3 , (C 1 -C 6 alkyl)C(O)—, HC(O)—, (C 1 -C 6 alkyl)OC(O)—, HOC(O)—, (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl)-, HO(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)O—, (C 1 -C 6 alkyl)C(O) 1-2 (C 1 -C 6 alkyl)-, HC(O) 1-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 —, (C 1 -C 6 alkyl)OC(O)NH—, HOC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle or cyano-heterocyclylalkyl, and

wherein heteroaryl is a a 5 or 6-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms, independently selected from N, O or S, which is unsubstituted, or substituted with 1 substituent on any one or more carbon atoms, with halogen, C 1 -C 20 alkyl, CF 3 , NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 ,NO 2 ,oxo, CN, N 3 , —OH, —O(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkyl)S(O) 0-2 —(C 1 -C 6 alkyl)S(O) 0-2 (C 1 -C 6 alkyl)-, HS(O) 0-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)S(O) 0-2 —, (C 1 -C 6 alkyl)C(O)NH—, HC(O)NH—, H 2 N—C(NH)—, —O(C 1 -C 6 alkyl)CF 3 , HC(O)—, (C 1 -C 6 alkyl)C(O)—, (C 1 -C 6 alkyl)OC(O)—, HOC(O)—, (C 1 -C 6 alkyl)O(C 1 -C 6 alkyl)-, HO(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)O—, (C 1 -C 6 alkyl)C(O) 1-2 (C 1 -C 6 alkyl)-, HC(O) 1-2 (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)C(O) 1-2 , (C 1 -C 6 alkyl)OC(O)NH—, HOC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle or cyano-heterocyclylalkyl, or independently or additionally substituted with 1 substituent on any one or more nitrogen atoms with C 1 -C 20 alkyl, oxo, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, —C(O)C 1-6 alkyl, —C(O)NHC 1 -C 6 alkyl, —C(O) NH 2 , —C 1 -C 6 alkylC(O)NH 2 , or —C 1 -C 6 alkylOC(O)NH 2 , or independently or additionally substituted with 1 substituent on any one or more sulfur atoms, with C 1 -C 20 alkyl, oxo, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or aryl.

2. A compound of claim 1 , wherein R 1 is selected from the group consisting of

1) —ONO 2 ,

2) —O—CH 3 ,

3) —O-aryl,

4) —O-heteroaryl,

5) —O—C 3-8 cycloalkyl, and

6) halogen,

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , wherein Y is selected from the group consisting of —C(O)OR 2 , —(CH 2 ) 1-2 OH, —OH,

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , wherein R 1 is selected from the group consisting of —OCH 3 , —ONO 2 , and F, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4 , wherein R 1 is —OCH 3 , or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , wherein Y is —C(O)OH or —C(O)OCH 3 and R 1 is —O-CH 3 , or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein Y is —C(O)OH or —C(O)OCH 3 , or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 , wherein, R 5 and R 6 are hydrogen, and x is 1, and z is 0, or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 , wherein the compound is of the formula

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 selected from the group consisting of

(1S,3R,4R)-methyl 4-methoxy-3-(nitrooxy)cyclohexanecarboxylate,

(1S,3R,4R)-methyl 3-methoxy-4-(nitrooxy)cyclohexanecarboxylate,

(1S,3R,4R)-methyl 3-methoxy-4-(nitrooxy)cyclohexanecarboxylate,

(1S,3S,4S)-methyl 4-methoxy-3-(nitrooxy)cyclohexanecarboxylate,

(1R,3S,4S)-methyl 4-methoxy-3-(nitrooxy)cyclohexanecarboxylate,

(1R,3R,4R)-methyl 3-methoxy-4-(nitrooxy)cyclohexanecarboxylate,

(1R,3S,4S)-methyl 3-methoxy-4-(nitrooxy)cyclohexanecarboxylate, and

(1R,3R,4R)-methyl 4-methoxy-3-(nitrooxy)cyclohexanecarboxylate,

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12. A method for treating hypertension in a patient which comprises administering to the patient a therapeutically effective amount of the composition of claim 11 .