IP Library › Granted Patent US 8,119,806

Granted Patent B2

US 8,119,806 · App. 12/509,698 · Granted Feb 21, 2012

Cicletanine derivatives

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Quick Facts

Patent No.: US 8,119,806
App. No.: 12/509,698
Granted: Feb 21, 2012
Kind: B2

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Abstract

A compound having the structure wherein X is selected from the group consisting of: a bond, —NHCH 2 (CH 2 ) n CH 2 OC(O)—, —CH 2 NHC(O)CH 2 NHC(O)—, —CH 2 OC(O)—, —OCH(CH 3 )OC(O)—, —OCH 2 OC(O)—, —O—, —NR 1 —, —CR 1 R 3 —, —(CH 2 ) p —, —(CH 2 ) q NR 1 C(O)—, —CHR 5 NR 2 C(O)—, —(CH 2 ) q C(O)—, —(CH 2 ) q C(O)NR 1 —, or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating hypertension.

Claims (136)

1. A compound having the general formula I:

wherein

X is selected from the group consisting of:

a bond, —NHCH 2 (CH 2 ) n CH 2 OC(O)—, —CH 2 NHC(O)CH 2 NHC(O)—, —CH 2 OC(O)—,

—OCH(CH 3 )OC(O)—, —OCH 2 OC(O)—,

—O—, —NR 1 —, —CR 1 R 3 —, —(CH 2 ) p —, —(CH 2 ) p NR 1 C(O)—, —CHR 5 NR 2 C(O)—, —(CH 2 ) q C(O)—, —(CH 2 ) q C(O)NR 1 —,

R 1 , R 2 , R 7 and R 8 , each instance in which they occur, are independently selected from the group consisting of hydrogen and C 1-7 alkyl;

R 3 is hydrogen, C 1-4 alkyl, —CH 2 ONO 2 , or —ONO 2 ;

R 5 and R 9 are independently selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OH, —CH(OH)CH 3 , and —CH 2 C 6 H 5 ;

g is 0 or 1;

p is 0, 1, 2, 3, 4, 5, 6, or 7;

q is 1, 2, 3, 4, or 5;

v and w are independently selected from the group consisting of 0, 1, 2, and 3, provided that

v+w is 1, 2, 3 or 4;

R is selected from the group consisting of

—(CH 2 ) x CH(ONO 2 )(CH 2 ) y CH 3 ,

—(CH 2 ) x CH(ONO 2 )(CH 2 ) y CH(ONO 2 )(CH 2 ) z CH 3 ,

—(CH 2 ) x CH(ONO 2 )(CH 2 ) y CH 2 (ONO 2 ),

—(CH 2 ) x CH(ONO 2 )(CR 1 R 2 )CH 2 (ONO 2 ),

—CR 1 R 2 R 3 , with the proviso that R 3 is —CH 2 ONO 2 or —ONO 2 ,

—(CH 2 ) x (ONO 2 ),

—O—C(O)—(CH 2 ) x CH(ONO 2 )(CH 2 ) y CH 2 (ONO 2 ),

with the proviso that X is CR 1 R 3 and R 3 is —CH 2 ONO 2 or —ONO 2 ,

provided that when R is

—O—C(O)—(CH 2 )—CH(ONO 2 )(CH 2 ) y CH 2 (ONO 2 ) or

then X is selected from the group consisting of a bond,

—NR 1 —, —CR 1 R 3 —, —(CH 2 ) p —, —(CH 2 ) q NR 1 C(O)—,

—CHR 5 NR 2 C(O)—, —(CH 2 ) q C(O)—, —(CH 2 ) q C(O)NR 1 —,

h, j, and k are independently selected from the group consisting of 0, 1, and 2;

m, n, x, y, and z are independently selected from the group consisting of 0, 1, 2, 3, and 4;

r and s are independently selected from the group consisting of 0, 1, 2, and 3, provided that

r+s is 1, 2, 3 or 4.

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

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

3. A compound of claim 1 , wherein X is selected from the group consisting of

—NHCH 2 (CH 2 ) n CH 2 OC(O)—, wherein n is 0, 1, 2, or 3,

—CH 2 NHC(O)CH 2 NHC(O)—, —CH 2 OC(O)—, —OCH(CH 3 )OC(O)—, —OCH 2 OC(O)—,

—CH 2 CH 2 C(O)NH—, —(CH 2 ) 5 —, a bond, —C(CH 3 ) 2 —, —CH(CH 3 )—, —C(CH 3 )(CH 2 ONO 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 —,

—CH 2 —, —CH 2 CH 2 NHC(O)—, —CH 2 NHC(O)—, —CH(CH 2 C 6 H 5 )NHC(O)—, —CH(CH 3 )NHC(O)—,

—CH(CH(CH 3 ) 2 NHC(O)—, —O—, —CH 2 N(CH 3 )C(O)—,

4. A compound of claim 1 , wherein R is

—ONO 2 , —O—CO—(CH 2 ) 3 CH(ONO 2 )CH 2 (ONO 2 ),

with the proviso that X is CR 1 R 3 and R 3 is —CH 2 ONO 2 or —ONO 2 ,

—(CH 2 ) 4 ONO 2 , —CH 2 ONO 2 , —(CH 2 ) 2 ONO 2 , —(CH 2 ) 3 ONO 2 , —(CH 2 ) 2 CH(CH 3 )ONO 2 ,

—CH 2 —CH(ONO 2 )—C(CH 3 ) 2 —CH 2 ONO 2 ,

—CH 2 CH(ONO 2 )CH(CH 3 )ONO 2 , —(CH 2 ) 2 CH(ONO 2 )CH 2 ONO 2 , —(CH 2 ) 3 CH(ONO 2 )CH 2 (ONO 2 ),

—(CH 2 ) 4 CH(ONO 2 )CH 2 (ONO 2 ),

5. A compound of claim 1 , wherein —X—R is selected from the group consisting of

—(CH 2 ) 5 ONO 2 , —C(CH 3 ) 2 CH 2 ONO 2 , —CH(CH 3 )(CH 2 ) 2 ONO 2 , —C(CH 3 )(CH 2 ONO 2 )CH 2 ONO 2 ,

—C(CH 3 ) 2 (CH 2 ) 3 ONO 2 , —(CH 2 ) 2 CH(CH 3 )ONO 2 , —(CH 2 ) 2 CH(ONO 2 )CH(CH 3 )ONO 2 ,

—CH 2 NHC(O)(CH 2 ) 2 CH(ONO 2 )CH(ONO 2 )CH 3 , CH 2 NHC(O)(CH 2 ) 3 CH(ONO 2 )CH 2 ONO 2 ,

—CH 2 N(CH 3 )C(O)(CH 2 ) 3 CH(ONO 2 )CH 2 ONO 2 , —O(CH 2 ) 4 CH(ONO 2 )CH 2 ONO 2 , —O(CH 2 ) 3 ONO 2 ,

—CH(ONO 2 )—CH(CH 3 ) 2 , —CH(ONO 2 )—C(CH 3 ) 3 , —NHCH 2 (CH 2 ) n CH 2 OC(O)—R,

—CH 2 NHC(O)CH 2 NHC(O)—R,

wherein n is 0, 1, 2 or 3.

6. A compound of claim 1 , wherein —X—R is selected from the group consisting of

—(CH 2 ) 5 ONO 2 , —C(CH 3 ) 2 CH 2 ONO 2 , —CH(CH 3 )(CH 2 ) 2 ONO 2 , —C(CH 3 )(CH 2 ONO 2 )CH 2 ONO 2 ,

—C(CH 3 ) 2 (CH 2 ) 3 ONO 2 , —(CH 2 ) 2 CH(CH 3 )ONO 2 , —O(CH 2 ) 4 CH(ONO 2 )CH 2 ONO 2 , —O(CH 2 ) 3 ONO 2 ,

or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , selected from the group consisting of

(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-{[(1r,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]amino}-4-oxobutanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1r,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3R)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2,2-dimethyl-3-(nitrooxy)propanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-methyl-4-(nitrooxy)butanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-methyl-3-(nitrooxy)-2-[(nitrooxy)methyl]propanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 3-(nitrooxy)cyclopentanecarboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2,2-dimethyl-5-(nitrooxy)pentanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-(nitrooxy)pentanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl[1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]acetate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl cis-4-(nitrooxy)cyclohexanecarboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2,2-dimethyl-5-(nitrooxy)pentanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3R,4R)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(4R,5R)-4,5-bis(nitrooxy)hexanoate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl cis-3-(nitrooxy)cyclobutanecarboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl trans-3-(nitrooxy)cyclobutanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1r,2R,3S)-2,3-bis[(nitrooxy)methyl]cyclopropanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl N-{[(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]carbonyl}glycinate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl N-{[(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]carbonyl}-D-alaninate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl N-{[(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]carbonyl}-D-leucinate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl N-{[1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]carbonyl}-D-phenylalaninate,

(1r,3R,4S)-3,4-Bis(nitrooxy)cyclopentyl (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl carbonate,

5,6-Bis(nitrooxy)hexyl 3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl carbonate,

3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 3-(nitrooxy)propyl carbonate,

(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-yl 4-{[(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentyl]carbonyl}piperazine-1-carboxylate,

(S)—((S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)2-cyclohexyl-2-(nitrooxy)acetate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-(4,7,7-trimethyl-3-(nitrooxy)bicyclo[2.2.1]heptan-2-yl)acetate,

(R)—((S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)3-methyl-2-(nitrooxy)butanoate,

(S)—((S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl)3,3-dimethyl-2-(nitrooxy)butanoate,

(6R,6aS)-6-((3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yloxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)piperidine-1-carboxylate,

3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-(nitrooxy)piperidine-1-carboxylate,

(S)-((3R,3aR,6R,6aR)-6-(((S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yloxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl)5,6-bis(nitrooxy)hexanoate,

(R)-((3S,3aR,6S,6aR)-6-(((S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yloxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl)5,6-bis(nitrooxy)hexanoate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3R,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl carbonate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-yl(3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl carbonate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3S,3aR,6S,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl carbonate,

3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-(nitrooxy)butanoate,

(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-(nitrooxy)butanoate,

(3R)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-(nitrooxy)butanoate,

1-[({[(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy}carbonyl)oxy]ethyl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl-oxycarbonyloxymethyl(1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl-oxycarbonyl (1s,3R,4S)-3,4-bis(nitrooxy)cyclopentanecarboxylate,

[3-(4-chlorophenyl)-6-methyl-5-oxido-1,3-dihydrofuro[3,4-c]pyridin-5-ium-7-yl](3S,4R)-3,4-dinitrooxycyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3R)-3-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3S)-3-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3R,4R)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3S,4S)-3-ethoxy-4-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3S,4R)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1S,3R,4R)-3-tert-butoxy-4-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3R,4R)-3-fluoro-4-(nitrooxy)cyclopentanecarboxylate,

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1S,3S,4R)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate, and

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1S,3S,4R)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(R)-3,3-dimethyl-2,4-bis(nitrooxy)butyl carbonate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl succinate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3R,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl succinate,

(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(3S,3aR,6S,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl succinate,

2,3-bis(nitrooxy)propyl(S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl succinate,

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

8. A compound of claim 7 , which is

(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl(1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate,

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

9. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier.

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

11. A pharmaceutical composition comprising a compound of claim 1 , a diuretic, 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 10 .

Assignments (5)

CHANGE OF NAME Recorded Aug 29, 2012

From: SCHERING CORPORATION

To: MERCK SHARP & DOHME CORP.

Reel/Frame 028866/0511 →

MERGER Recorded Aug 27, 2012

From: MERCK SHARP & DOHME CORP.

To: SCHERING CORPORATION

Reel/Frame 028850/0515 →

CHANGE OF NAME Recorded Jan 27, 2010

From: MERCK & CO., INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 023852/0595 →

CORRECTIVE ASSIGNMENT TO CORRECT THE THE SPELLING OF 11TH INVENTORS' FIRST NAME. IT CURRENTLY READS "FERRARIO, MISSIMILIANO" IT SHOULD READ "FERRARIO, MASSIMILIANO" PREVIOUSLY RECORDED ON REEL 023268 FRAME 0729. ASSIGNOR(S) HEREBY CONFIRMS THE "FERRARIO, MASSIMILIANO". Recorded Oct 7, 2009

From: ALI, AMJAD; BAKER, ROBERT K.; NARGUND, RAVI P.; YAN, LIN; SEBHAT, IYASSU K.; RUPPRECHT, KATHLEEN M.; SHEN, DONG-MING; HUO, PEI; FRANKLIN, CHRISTOPHER; NICOTRA, ALESSIA; FERRARIO, MASSIMILIANO; BIONDI, STEFANO; ALMIRANTE, NICOLETTA

To: MERCK & CO., INC.; NICOX S.A.

Reel/Frame 023340/0023 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 21, 2009

To: MERCK & CO., INC.; NICOX S.A.

Reel/Frame 023268/0729 →