Controlled HNO release through intramolecular cyclization-elimination

Patent metadata

Field	Value
Publication number	US-9676708-B2
Application number	US-201314439800-A
Country	US
Kind code	B2
Filing date	Oct 30, 2013
Priority date	Nov 1, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

Protected HNO donors designed to undergo non-enzymatic release at neutral pH via an intramolecular cyclization-elimination are disclosed. The rate of cyclization, and therefore HNO release, can be controlled by substituents and chain length. Thus, biologically useful HNO donors having tunable HNO release rates are provided.

First claim

That which is claimed:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from the group consisting of 1, 2, and 3;
X 1 is selected from the group consisting of O and NR 1 ;
R and R 1 are each independently selected from the group consisting of H, unsubstituted or substituted linear alkyl, unsubstituted or substituted branched alkyl, and unsubstituted or substituted aryl;

X 2 is a leaving group selected from the group consisting of halogen and L-Y;
L is a bond, —SO 2 —, or —O—;
Y is W, alkyl, monocyclic cycloalkyl, bicyclic cycloalkyl, tricyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which are unsubstituted or substituted with one or more substituent groups selected from W;
W is a substituent group selected from the group consisting of unsubstituted or substituted linear alkyl, unsubstituted or substituted branched alkyl, alkoxyl, perhaloalkyl, hydroxyl, hydroxyalkyl, alkylsulfonyl, alkylsulfanyl, alkylsulfinyl, N-hydroxylsulfonamidyl, carboxyl, carbonyl, carbamoyl, alkylcarbamoyl, halogen, amino, dialkylamino, cycloalkoxyl, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, nitro, nitrile, amide, haloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryloxyl, cycloalkyl, aralkyloxyl, —SO 3 H, acyl, —COR 2 , —COOR 2 , —CONR 2 R 3 , — CH(C(O)R 2 ) 2 , —SO 2 R 2 , and —COX 3 ;
X 3 is halogen; and
R 2 and R 3 are independently unsubstituted alkyl or aryl, or R 2 and R 3 are taken together to form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure:

wherein:
m is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; and

each Y 1 is independently selected from the group consisting of unsubstituted or substituted linear alkyl, unsubstituted or substituted branched alkyl, alkoxyl, perhaloalkyl, hydroxyl, hydroxyalkyl, alkylsulfonyl, alkylsulfanyl, alkylsulfinyl, N-hydroxylsulfonamidyl, carboxyl, carbonyl, carbamoyl, alkylcarbamoyl, halogen, amino, dialkylamino, cycloalkoxyl, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, nitro, nitrile, amide, haloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryloxyl, cycloalkyl, aralkyloxyl, —SO 3 H, and acyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure:

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of methyl, iso-propyl, benzyl, and phenyl.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of methyl, ethyl, sec-butyl, and benzyl.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein n is 1.

8. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following structure:

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of methyl, iso-propyl, tert-butyl, benzyl, phenyl, 4-chlorophenyl, and 4-methoxyphenol.

10. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

11. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A kit comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. The kit of claim 15 , further comprising instructions for use in treating a disease or condition that is responsive to nitroxyl therapy.

17. A compound of the structure

or a pharmaceutically acceptable salt thereof wherein:
R is methyl and R′ is methyl;
R is benzyl and R′ is methyl;
R is iso-propyl and R′ is methyl;
R is phenyl and R′ is methyl;
R is methyl and R′ is ethyl;
R is methyl and R′ is benzyl; or
R is methyl and R′ is sec-butyl.

18. A compound which is:
2-bromo-benzenesulfonamidyl-2-(methylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(benzylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(iso-propylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(tert-butylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(phenylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(4-methoxy-phenylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-2-(4-chloro-phenylamino)-ethyl carbonate hydrochloride;
2-bromo-benzenesulfonamidyl-3-(iso-propylamino)-propyl carbonate hydrochloride; or
a pharmaceutically acceptable salt thereof.

Assignees

• Univ Johns Hopkins

Inventors

• Toscano John P
• Sutton Art D

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · 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

• A61K31/4152

  having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title