Diazeniumdiolate heterocyclic derivatives

Patent metadata

Field	Value
Publication number	US-9108920-B2
Application number	US-201113881929-A
Country	US
Kind code	B2
Filing date	Oct 25, 2011
Priority date	Oct 29, 2010
Publication date	Aug 18, 2015
Grant date	Aug 18, 2015

Abstract

A compound having the structure: useful for treating hypertension, Pulmonary Arterial Hypertension (PAH), congestive heart failure, conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy.

First claim

What is claimed is:

1. A compound having the formula I:

or a pharmaceutically acceptable salt thereof, wherein
X is O or NR 7 ;
R 1 is hydrogen, —C(O)OC 1-6 alkyl, or —C(O)OH, or together with R 2 , forms ═O;
R 2 is hydrogen, or together with R 1 , forms ═O;
R 3 and R 4 are independently
—C 1-6 alkyl,
—CD 2 C 1-5 alkyl,
—C 2-5 alkylene-OH,
—C 2-5 alkylene-O—C(O)C 1-6 alkyl,
—C 1-6 alkylene-aryl, or
—CH 2 CH═CH 2 ,
or, together with 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 mono-, di- or tri-substituted with halogen or —C 1-6 alkyl;

R 5 and R 6 , which are attached to any available carbon ring atom, are independently hydrogen,
—C 1-6 alkyl,
—C(O)OC 1-6 alkyl,
—C(O)OH,
aryl,
or R 5 and R 6 , when they are attached to the same carbon atom, together form ═O;

R 7 is
hydrogen,
deuterium,
—C 1-6 alkyl,
—C 1-6 alkylene-aryl,
—C 1-6 alkyleneC(O)O—C 1-6 alkyl,
—C 1-6 alkyleneCF 3 ,
—CN,
—C(O)O—C 1-6 alkyl,
—C(O)C 1-6 alkyl,
—C(O)OC 3-6 carbocycle,
—C(O)CHF 2 ,
—C(O)CHF 3 ,
—C(O)CH 2 OH,
—C(O)aryl,
—C(O)C 1-6 alkyleneOHC(O)C 3-6 carbocycle,
—C(O)NH 2 ,
—C(O)NHC 1-6 alkyl,
—C(O)heterocycle,
—C(O)NHC 3-6 carbocycle,
—C(O)N(C 1-6 alkyl)C 1-6 alkyl,
—C(O)NHSO 2 aryl,
—SOC 1-6 alkyl,
—SO 2 C 1-6 alkyl,
—SO 2 CF 3 ,
—SO 2 aryl,
—SO 2 heteroaryl,
aryl,
heteroaryl,
heterocycle, or
—C 3-6 carbocycle;
wherein aryl, alkyl, carbocycle, heteroaryl, and heterocycle are unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from —CN, halogen, —CF 3 , ═O, —C(O)OC 1-6 alkyl or —O—C 1-6 alkyl.

2. A compound of claim 1 , having the formula Ia

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , having the formula Ib

or a pharmaceutically acceptable salt thereof.

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

5. A compound of claim 1 , wherein R 2 is hydrogen, or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 , wherein R 3 is —C(CH 3 ) 3 or —CH 2 CH 3 , or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 , wherein R 4 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH 2 -phenyl, —CD 2 CH 3 , —CH 2 CH 2 OH, or —CH 2 CH 2 OC(O)CH 3
or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 , wherein R 5 is hydrogen, —CH 3 , C(O)OCH 3 , —C(O)OH, phenyl, or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 , wherein R 6 is hydrogen or —CH 3 , or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 , wherein R 5 and R 6 together form ═O, or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, —CH 3 , —CH 2 CF 3 , —CH 2 C 6 H 5 , —CH(CH 3 )C 6 H 5 , —CH(CH 3 )C(O)OCH 2 CH 3 , —CH 2 CH(CH 2 CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —C(CH 3 ) 2 C 6 H 5 , —C(CH 3 ) 3 , —CN, —CH 2 CH(CH 3 ) 2 , or

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —C(O)OC(CH 3 ) 3 , —C(O)CH 3 , —C(O)CF 3 , —C(O)OCH 2 CH 3 , —C(O)OC 6 H 11 , —C(O)CHF 2 , —C(O)C 6 H 5 , —C(O)CH 2 OH, —C(O)C 3 H 5 , —C(O)C(CH 3 ) 3 , —C(O)NH 2 , —C(O)NHC(CH 3 ) 3 , —C(C)NHC 6 H 11 , —C(O)N(CH 3 )C(CH 3 ) 3 , —C(O)SC(CH 3 ) 3 , —C(C)NHSO 2 C 6 H 5 ,

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —SO 2 CH 3 , —SO 2 C 6 Hs, —SO 2 C(CH 3 ) 3 , —SOC(CH 3 ) 3 , —SO 2 CF 3 ,

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is
—C 6 H 5 ,

15. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is

16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —C 6 H 11 or —C 5 H 9 .

17. A compound of claim 1 , which is
O 2 -[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 [1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N,N-diethylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butyl-N-propylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-butyl-N-tert-butylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butyl-N-phenylethylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-[N-tert-butyl-N-(2′-hydroxyethyl)amino]diazen-1-ium-1,2-diolate,
(±)-O 2 [1-(tert-butoxycarbonyl)piperidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(tert-butoxycarbonyl)azetidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 [1-(tert-butoxycarbonyl)azetidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 [(3R)-pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 [(3R)-pyrrolidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -(piperidin-4-yl) 1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-(2-methylpropyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-benzylpyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
(±)-O 2 -[(3R)-1-(1-phenylethyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-(2-phenylpropan-2-yl)pyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-tert-butylpyrrolidin-3-yl]1-(N-tert-butyl-N-methylamino)diazen-1-ium-1,2-diolate,
O 2 -(1-methylpiperidin-4-yl) 1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -[(3R)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -[1-(2,2,2-trifluoroethyl)piperidin-4-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
O 2 -(1-benzylpiperidin-4-yl) 1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolate,
(±)-O 2 -[1-(1-phenylethyl)piperidin-4-yl]1-(N-tert-butyl-N-ethylamino)diazen-1-ium-1,2-diolat

Assignees

• Ali Amjad
• Lo Michael Man-Chu
• Baker Robert K
• Guo Zhiqiang
• Whitehead Brent
• Henderson Timothy J
• Metzger Edward
• Yan Lin
• Shah Shrenik K
• Dellureficio James
• Wang Jun
• Merck Sharp & Dohme

Inventors

• Ali Amjad
• Lo Michael Man-Chu
• Baker Robert K
• Guo Zhiqiang
• Whitehead Brent
• Henderson Timothy J
• Metzger Edward
• Yan Lin
• Shah Shrenik K
• Dellureficio James
• Wang Jun

Classifications

• A61P9/12

  Antihypertensives · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D211/44 Primary

  attached in position 4 · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title