N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Patent metadata

Field	Value
Publication number	US-2016002156-A1
Application number	US-201514857308-A
Country	US
Kind code	A1
Filing date	Sep 17, 2015
Priority date	Mar 17, 2006
Publication date	Jan 7, 2016
Grant date	—

Abstract

The invention relates to N-hydroxysulfonamide derivatives that donate nitroxyl (HNO) under physiological conditions and are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure and ischemia/reperfusion injury. Novel N-hydroxysulfonamide derivatives release NHO at a controlled rate under physiological conditions, and the rate of HNO release is modulated by varying the nature and location of functional groups on the N-hydroxysulfonamide derivatives.

First claim

1 . A compound of the formula (I), (II), (III) or (IV):

wherein:
R 1 is H;
R 2 is H, aralkyl or heterocyclyl;
m and n are independently an integer from 0 to 2;
x and b are independently an integer from 0 to 4;
y is an integer from 0 to 3;
T is an alkyl or substituted alkyl;
Z is an electron withdrawing group;
R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that:
(1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H;
(2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than halo;
(3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than halo, nitro, cyano, alkyl or alkoxy;
(4) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is other than halo;
(5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl or nitro;
(6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than nitro or alkyl;
(7) when R 3 and R 7 are H, R 5 is nitro and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than halo;
(8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than dialkylamino;
(9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than alkyl; and
(10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than dialkylamino;
each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl;
A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with V and W to form ring A;
B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the V and W to form ring B;
V and W are independently C, CH, N or NR 10 ;
Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8 is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 is N, NR 10 , O or S;
C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 is N, NR 10 , O or S;
R 10 is H, alkyl, acyl or sulfonyl,
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein R 2 is H.

3 . The compound of claim 1 , wherein each R 8 and R 9 is independently selected from the group consisting of Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , CH 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO 2 ), propane-2-thiyl (SCH(CH 3 ) 2 ), propane-2-sulfinyl (S(O)CH(CH 3 ) 2 ), morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl.

4 . The compound of claim 1 , wherein the compound is of the formula (I).

5 . The compound of claim 4 wherein the compound is of the formula (I) and at least one of R 3 and R 7 is other than H.

6 . The compound of claim 4 , wherein the compound is of the formula (I) and at least one of R 3 and R 7 is an electron withdrawing group.

7 . The compound of claim 4 , wherein the compound is of the formula (I) and R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl, provided that (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than F; (3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than F, Cl, Br, I, NO 2 , CN, CH 3 or OCH 3 ; (4) when one of R 3 or R 7 is Cl and the R 3 or R 7 that is not Cl is H and one of R 4 or R 6 is Cl and the R 4 or R 6 that is not Cl is H, R 5 is other than Cl; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than SO 2 NHOH, CF 3 or NO 2 ; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than NO 2 or CH 3 ; (7) when R 3 and R 7 are H, R 5 is NO 2 and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than Cl; (8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than a C 1 -C 5 dialkylamino; (9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than CH 3 ; and (10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than a C 1 -C 5 dialkylamino.

8 . The compound of claim 1 , wherein the compound is of the formula (II).

9 . The compound of claim 1 , wherein the compound is of the formula (III).

10 . The compound of claim 1 , wherein the compound is of the formula (IV).

11 . A method of modulating the in vivo nitroxyl levels in an individual in need thereof, the method comprising administering to the individual an N-hydroxysulfonamide that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof.

12 . A method of treating, preventing or delaying the onset or development of a disease or condition that is responsive to nitroxyl therapy, comprising administering to an individual in need thereof an N-hydroxysulfonamide that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof.

13 . The method of claim 12 wherein the method comprises administering to the individual a compound of the formula:

wherein:
R 1 is H;
R 2 is H;
m and n are independently an integer from 0 to 2;
x and b are independently an integer from 0 to 4;
y is an integer from 0 to 3;
T is an alkyl or substituted alkyl;
Z is an electron withdrawing group;
R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that

Assignees

• Cardioxyl Pharmaceuticals Inc
• Univ Johns Hopkins

Inventors

• Toscano John P
• Brookfield Frederick Arthur
• Cohen Andrew D
• Courtney Stephen Martin
• Frost Lisa Marie
• Kalish Vincent Jacob

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title