NO- and H2S-releasing compounds

Patent metadata

Field	Value
Publication number	US-10450260-B2
Application number	US-201715605195-A
Country	US
Kind code	B2
Filing date	May 25, 2017
Priority date	Aug 15, 2011
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

This disclosure relates to compounds containing both an NO-releasing moiety and an H2S-releasing moiety and the use of such compounds in treating inflammatory diseases, including cancers.

First claim

What is claimed is:

1. A compound of formula (II):

wherein
each of p and q, independently, is 0 or 1;
each of L 1 and L 2 , independently, is a linker, the linker being —C(O)—, —(CH 2 ) m —, —(CH 2 ) m —O—, —(CH 2 ) m —C(O)—, —(CH 2 ) m —C(O)O—, —(CH 2 ) m —OC(O)O—, —C(O)—(CH 2 ) m —O—, —C(O)—(CH 2 ) m —C(O)—, —OC(O)—(CH 2 ) m —O—, —OC(O)—(CH 2 ) m —C(O)—, or —OC(O)—(CH 2 ) m —C(O)O—, in which m is 1, 2, 3, 4, 5, 6, or 7;
X is a H 2 S-releasing moiety or a NO-releasing moiety;
Y is a NO-releasing moiety or a H 2 S-releasing moiety, provided that X and Y are not simultaneously H 2 S-releasing moieties or NO-releasing moieties;
the NO-releasing moiety is —NO, —C(O)—(CH 2 ) n —ONO 2 , —O—(CH 2 ) n —ONO 2 , —(CH 2 ) n —ONO 2 , —C(O)—CH 2 —C(CH 3 ) 2 —SNO, —NH—CH 2 —C(CH 3 ) 2 —SNO, —CH 2 —C(CH 3 ) 2 —SNO,

in which n is 1, 2, 3, 4, 5, 6, or 7; R a is H, C 1 -C 10 alkyl, aryl, S(O) 2 -aryl, CN, or CON(R b ) 2 ; and each R b , independently, is H or C 1 -C 10 alkyl; and
the H 2 S-releasing moiety is

2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is H; and R 7 is CH 3 .

3. A compound having the formula:

4. A method of treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (II):

wherein
each of p and q, independently, is 0 or 1;
each of L 1 and L 2 , independently, is a linker, the linker being —C(O)—, —(CH 2 ) m —, —(CH 2 ) m —O—, —(CH 2 ) m —C(O)—, —(CH 2 ) m —C(O)O—, —(CH 2 ) m —OC(O)O—, —C(O)—(CH 2 ) m —O—, —C(O)—(CH 2 ) m —C(O)—, —OC(O)—(CH 2 ) m —O—, —OC(O)—(CH 2 ) m —C(O)—, or —OC(O)—(CH 2 ) m —C(O)O—, in which m is 1, 2, 3, 4, 5, 6, or 7;
X is a H 2 S-releasing moiety or a NO-releasing moiety;
Y is a NO-releasing moiety or a H 2 S-releasing moiety, provided that X and Y are not simultaneously H 2 S-releasing moieties or NO-releasing moieties;
the NO-releasing moiety is —NO, —C(O)—(CH 2 ) n —ONO 2 , —O—(CH 2 ) n —ONO 2 , —(CH 2 ) n —ONO 2 , —C(O)—CH 2 —C(CH 3 ) 2 —SNO, —NH—CH 2 —C(CH 3 ) 2 —SNO, —CH 2 —C(CH 3 ) 2 —SNO,

in which n is 1, 2, 3, 4, 5, 6, or 7; R a is H, C 1 -C 10 alkyl, aryl, S(O) 2 -aryl, CN, or CON(R b ) 2 ; and each R b , independently, is H or C 1 -C 10 alkyl; and
the H 2 S-releasing moiety is

5. The method of claim 4 , wherein the inflammatory disease is cancer, rheumatoid arthritis, intestine inflammation, stomach ulcer, a cardiovascular disease, or a neurodegenerative disease.

6. A pharmaceutical composition comprising a compound of formula (II):

wherein
each of p and q, independently, is 0 or 1;
each of L 1 and L 2 , independently, is a linker, the linker being —C(O)—, —(CH 2 ) m —, —(CH 2 ) m —O—, —(CH 2 ) m —C(O)—, —(CH 2 ) m —C(O)O—, —(CH 2 ) m —OC(O)O—, —C(O)—(CH 2 ) m —O—, —C(O)—(CH 2 ) m —C(O)—, —OC(O)—(CH 2 ) m —O—, —OC(O)—(CH 2 ) m —C(O)—, or —OC(O)—(CH 2 ) m —C(O)O—, in which m is 1, 2, 3, 4, 5, 6, or 7;
X is a H 2 S-releasing moiety or a NO-releasing moiety;
Y is a NO-releasing moiety or a H 2 S-releasing moiety, provided that X and Y are not simultaneously H 2 S-releasing moieties or NO-releasing moieties;
the NO-releasing moiety is —NO, —C(O)—(CH 2 ) n —ONO 2 , —O—(CH 2 ) n —ONO 2 , —(CH 2 ) n —ONO 2 , —C(O)—CH 2 —C(CH 3 ) 2 —SNO, —NH—CH 2 —C(CH 3 ) 2 —SNO, —CH 2 —C(CH 3 ) 2 —SNO,

in which n is 1, 2, 3, 4, 5, 6, or 7; R a is H, C 1 -C 10 alkyl, aryl, S(O) 2 -aryl, CN, or CON(R b ) 2 ; and each R b , independently, is H or C 1 -C 10 alkyl; and
the H 2 S-releasing moiety is

and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 6 , wherein the compound is

8. The compound of claim 1 having the structure

9. The method of claim 4 wherein the compound is

Assignees

• Univ City New York Res Found

Inventors

• Kashfi Khosrow
• Kodela Ravinder

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07C327/48

  having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C203/04 Primary

  having nitrate groups bound to acyclic carbon atoms · CPC title

• C07D339/04

  having the hetero atoms in positions 1 and 2, e.g. lipoic acid · CPC title

• C07C331/28

  having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings · CPC title