Allosteric hemoglobin modifiers with nitric oxide releasing moiety

Patent metadata

Field	Value
Publication number	US-2016326097-A1
Application number	US-201415107962-A
Country	US
Kind code	A1
Filing date	Dec 22, 2014
Priority date	Dec 27, 2013
Publication date	Nov 10, 2016
Grant date	—

Abstract

Allosteric hemoglobin (Hb) modifiers of hemoglobin which contain nitric oxide (NO) moieties allowing for the release of NO in vivo. The compounds retain the oxygen delivery capability of the allosteric hemoglobin modifier to bind Hb and enhance Hb's ability to deliver oxygen to cells and tissues, and also release NO from the NO moiety. Methods of delivering oxygen and/or NO to cells and tissues are also provided.

First claim

We claim:

1 . A compound having the general formula:

wherein
R1 and R2 are the same or different and are CH 3 , Cl, H, OCH 3 , or 5-carbon cyclic incorporating both R1 and R2;
R3 is H, OH, COOH, or OC 2 H 5 ;
R4 and R5 are the same or different and are H, CH 3 , cyclic incorporating both R4 and R5 and containing CH 3 substituents, OCH 3 , C 2 H 5 , phenyl, or unsubstituted phenyl; and
R6 is a NO containing moiety.

2 . The compound of claim 1 wherein R6 is selected from the group consisting of:

3 . The compound of claim 1 having the formula:

4 . A composition, comprising:
one or more compounds as specified in claim 1 ; and a carrier.

5 . The composition of claim 4 wherein said carrier is a liquid, and wherein said one or more compounds are dissolved or distributed in said liquid.

6 . The composition of claim 5 wherein said liquid is an aqueous liquid.

7 . The composition of claim 5 wherein said liquid is an oil.

8 . The composition of claim 4 , wherein said carrier is a solid.

9 . The composition of claim 4 wherein said carrier is a gas.

10 . The composition of claim 9 wherein said gas is air.

11 . A method of delivering one or more of O 2 and NO to cells and tissues of a subject in need thereof comprising administering to said subject a therapeutic amount of one or more compounds having the general formula:

wherein
R1 and R2 are the same or different and are CH 3 , Cl, H, OCH 3 , or 5-carbon cyclic incorporating both R1 and R2;
R3 is H, OH, COOH, or OC 2 H 5 ;
R4 and R5 are the same or different and are H, CH 3 , cyclic incorporating both R4 and R5 containing CH 3 substituents, OCH 3 , C 2 H 5 , phenyl, or unsubstituted phenyl; and
R6 is a NO containing moiety.

12 . The method of claim 11 wherein R6 is selected from the group consisting of

13 . The method of claim 11 wherein at least one of the one or more compounds is

14 . The method of claim 11 , wherein said subject is a non-human animal.

15 . The method of claim 11 wherein said subject is a human.

16 . The method of claim 11 wherein at least one hemoglobin based oxygen carrier (HBOC) is co-administered.

17 . The method of claim 16 further comprising the step of providing to said patient at least one medicinal gas.

18 . The method of claim 17 wherein said step of providing is carried out by exogenous administration.

19 . The method of claim 17 wherein said step of providing includes a step of applying to said subject at least one exogenous stimulus which elicits endogenous production of said at least one medicinal gas.

20 . The method of claim 17 wherein said at least one medicinal gas is selected from the group consisting of NO, CO, H 2 S, N 2 O, SO, SO 2 and O 2 .

21 . A method of treating gas poisoning in a patient in need thereof, comprising the step of co-administering to said patient
i) an allosteric effector of Hb having the general formula:

wherein
R1 and R2 are the same or different and are CH 3 , Cl, H, OCH 3 , or 5-carbon cyclic incorporating both R1 and R2;
R3 is H, OH, COOH, or OC 2 H 5 ;
R4 and R5 are the same or different and are H, CH 3 , cyclic incorporating both R4 and R5 containing CH 3 substituents, OCH 3 , C 2 H 5 , phenyl, or unsubstituted phenyl; and
R6 is a NO containing moiety; and
ii) one or both of a hemoglobin based oxygen carrier (HBOC) and a perfluorocarbon (PFC).

22 . The method of claim 21 wherein R6 is selected from the group consisting of

23 . The method of claim 21 wherein said gas is selected from the group consisting of CO, H 2 S, and NO 2 .

24 . The method of claim 21 wherein said patient is a non-human animal.

25 . The method of claim 21 wherein said patient is a human.

Assignees

• Univ Virginia Commonwealth

Inventors

• Safo Martin K
• Danso-Danquah Richmond
• Ghatge Mohini
• Venitz Jurgen
• Mangino Martin
• Ward Kevin R

Classifications

• A61P33/06

  Antimalarials · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title