Peripherally restricted GABA positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system

Patent metadata

Field	Value
Publication number	US-10844070-B2
Application number	US-202016789841-A
Country	US
Kind code	B2
Filing date	Feb 13, 2020
Priority date	Jun 26, 2014
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The present invention provides compounds and compositions which are positive allosteric modulators of GABA-A receptors that selectively target the peripheral nervous system and organs of the body, and which do not pass through the blood-brain barrier. The compounds and compositions of the present invention are useful for treatment of diseases or disorders which are mediated by GABA-A neuronal activity, such as, for example, visceral pain, gut motility, irritable bowel syndrome, functional abdominal pain, functional idiopathic diarrhea, inflammatory bowel diseases, drug induced pain, bile salt malabsorption, lactase or other carbohydrate intolerance.

First claim

The invention claimed is:

1. A pharmaceutically acceptable salt of a compound selected from the group consisting of:

2. The salt of claim 1 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, a zinc salt, an acetic acid salt, a benzenesulfonic acid salt, a benzoic acid salt, a camphorsulfonic acid salt, a citric acid salt, an ethanesulfonic acid salt, a fumaric acid salt, a gluconic acid salt, a glutamic acid salt, a hydrobromic acid salt, a hydrochloric acid salt, an isethionic acid salt, a lactic acid salt, a maleic acid salt, a malic acid salt, a mandelic acid salt, a methanesulfonic acid salt, a mucic acid salt, a nitric acid salt, a pamoic acid salt, a pantothenic acid salt, a phosphoric acid salt, a succinic acid salt, a sulfuric acid salt, a tartaric acid salt, and a p-toluenesulfonic acid salt.

3. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

4. The salt of claim 3 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, and a zinc salt.

5. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

6. The salt of claim 5 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, and a zinc salt.

7. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

8. The salt of claim 7 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, and a zinc salt.

9. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

10. The salt of claim 9 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, and a zinc salt.

11. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

12. The salt of claim 11 , wherein the salt is selected from the group consisting of an acetic acid salt, a benzenesulfonic acid salt, a benzoic acid salt, a camphorsulfonic acid salt, a citric acid salt, an ethanesulfonic acid salt, a fumaric acid salt, a gluconic acid salt, a glutamic acid salt, a hydrobromic acid salt, a hydrochloric acid salt, an isethionic acid salt, a lactic acid salt, a maleic acid salt, a malic acid salt, a mandelic acid salt, a methanesulfonic acid salt, a mucic acid salt, a nitric acid salt, a pamoic acid salt, a pantothenic acid salt, a phosphoric acid salt, a succinic acid salt, a sulfuric acid salt, a tartaric acid salt, and a p-toluenesulfonic acid salt.

13. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

14. The salt of claim 13 , wherein the salt is selected from the group consisting of an acetic acid salt, a benzenesulfonic acid salt, a benzoic acid salt, a camphorsulfonic acid salt, a citric acid salt, an ethanesulfonic acid salt, a fumaric acid salt, a gluconic acid salt, a glutamic acid salt, a hydrobromic acid salt, a hydrochloric acid salt, an isethionic acid salt, a lactic acid salt, a maleic acid salt, a malic acid salt, a mandelic acid salt, a methanesulfonic acid salt, a mucic acid salt, a nitric acid salt, a pamoic acid salt, a pantothenic acid salt, a phosphoric acid salt, a succinic acid salt, a sulfuric acid salt, a tartaric acid salt, and a p-toluenesulfonic acid salt.

15. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

16. The salt of claim 15 , wherein the salt is selected from the group consisting of an acetic acid salt, a benzenesulfonic acid salt, a benzoic acid salt, a camphorsulfonic acid salt, a citric acid salt, an ethanesulfonic acid salt, a fumaric acid salt, a gluconic acid salt, a glutamic acid salt, a hydrobromic acid salt, a hydrochloric acid salt, an isethionic acid salt, a lactic acid salt, a maleic acid salt, a malic acid salt, a mandelic acid salt, a methanesulfonic acid salt, a mucic acid salt, a nitric acid salt, a pamoic acid salt, a pantothenic acid salt, a phosphoric acid salt, a succinic acid salt, a sulfuric acid salt, a tartaric acid salt, and a p-toluenesulfonic acid salt.

17. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

18. The salt of claim 17 , wherein the salt is selected from the group consisting of an acetic acid salt, a benzenesulfonic acid salt, a benzoic acid salt, a camphorsulfonic acid salt, a citric acid salt, an ethanesulfonic acid salt, a fumaric acid salt, a gluconic acid salt, a glutamic acid salt, a hydrobromic acid salt, a hydrochloric acid salt, an isethionic acid salt, a lactic acid salt, a maleic acid salt, a malic acid salt, a mandelic acid salt, a methanesulfonic acid salt, a mucic acid salt, a nitric acid salt, a pamoic acid salt, a pantothenic acid salt, a phosphoric acid salt, a succinic acid salt, a sulfuric acid salt, a tartaric acid salt, and a p-toluenesulfonic acid salt.

19. The salt of claim 1 , wherein the salt is a pharmaceutically acceptable salt of the following compound:

20. The salt of claim 19 , wherein the salt is selected from the group consisting of an aluminum salt, an ammonium salt, a calcium salt, a copper salt, a ferric salt, a ferrous salt, a lithium salt, a magnesium salt, a manganic salt, a manganous salt, a potassium salt, a sodium salt, and a zinc salt.

Assignees

• Univ Johns Hopkins
• Lieber Inst Inc

Inventors

• Pasricha Pankaj
• Huang Yifang
• Barrow James

Classifications

• A61K45/06

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

• C07D243/12

  1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines · CPC title

• A61P1/12

  Antidiarrhoeals · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title