IP Library › Granted Patent US 7,910,568

Granted Patent B2

US 7,910,568 · App. 11/915,305 · Granted Mar 22, 2011

Derivatives of 4- or 5-aminosalicylic acid

Assignee: Antibe Therapeutics Inc.

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Quick Facts

Patent No.: US 7,910,568
App. No.: 11/915,305
Granted: Mar 22, 2011
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides new derivatives of 4- or 5-aminosalicylic acid, and a pharmaceutical composition containing these derivatives of 4- or 5-aminosalicylic acid as active ingredients, useful for the treatment of intestinal diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and for the prevention/treatment of colon cancer. More particularly, these derivatives comprise a hydrogen sulfide releasing moiety linked via an azo, an ester, an anhydride, a thioester or an amide linkage to a molecule of 4- or 5-aminosalicylic acid. Furthermore, the present invention provides a process for preparing these compounds and their use for treating IBD and IBS and the prevention/treatment of colon cancer.

Claims (105)

1. A compound of general formula:

A-L-R (I)

where:

A is

where —N═is either at position 4 or 5,

where —NH is either at position 4 or 5,

where —NH 2 is either at position 4 or 5,

where —NH 2 is either at position 4 or 5;

L is either O, O—C═O, S, N or a covalent bond, to form an ester linkage, an anhydride linkage, a thioester linkage, an amide linkage or an azo linkage; and

R is a hydrogen sulfide releasing moiety that releases hydrogen sulfide in tissue selected from the group consisting of:

or a salt thereof.

2. A compound according to claim 1 , selected from the group consisting of:

4- or 5-(1-Carboxy-3-thiocarbamoyl-propylazo)-2-hydroxy-benzoic acid;

2-(4- or 5-Amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

4- or 5-Amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

2-Hydroxy-4- or 5-[3-(1-hydroxymethyl-3-thiocarbamoyl-propyl)-ureido]-benzoic acid;

4- or 5-Amino-2-(2-amino-4-thiocarbamoyl-butyryloxy)-benzoic acid;

4- or 5-(2-Amino-4-thiocarbamoyl-butyrylamino)-2-hydroxy-benzoic acid;

4- or 5-Amino-2-hydroxy-benzoic acid anhydride with 2-amino-4-thiocarbamoyl-butyric acid;

4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate;

4- or 5-Amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-Hydroxy-4- or 5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

4- or 5-Amino-2-hydroxy-benzoic acid thiocarbamoylmethyl ester;

4- or 5-Amino-2-thiocarbamoylmethoxycarbonyloxy-benzoic acid;

2-Hydroxy-4- or 5-thiocarbamoylmethoxycarbonylamino-benzoic acid;

4- or 5-Amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

4- or 5-Amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid;

or a salt thereof.

3. A compound according to claim 1 , selected from the group consisting of:

2-(4- or 5-amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

4- or 5-amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate;

4- or 5-amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-hydroxy 4- or 5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

4- or 5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

4- or 5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid;

or a salt thereof.

4. A compound according to claim 1 , 4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate, or salt thereof.

5. A compound according to claim 1 , 4-thiocarbamoylphenyl-5-amino-2-hydroxybenzoate, or salt thereof.

6. A pharmaceutical composition comprising a compound as claimed in claim 1 , or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

7. A pharmaceutical composition as claimed in claim 6 , wherein the compound is selected from the group consisting of:

2-(4- or 5-amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

4- or 5-amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate;

4- or 5-amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-hydroxy 4- or 5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

4- or 5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono- (2-mercapto-ethyl) ester; and

4- or 5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid.

8. A pharmaceutical composition claim 6 , wherein the compound is 4 thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate.

9. A method of treating an inflammatory condition of the gastrointestinal tract in a subject in need of such treatment, said method comprising administering to the subject an amount effective to treat the inflammatory condition of the gastrointestinal tract of a compound according to claim 1 .

10. The method of treating an inflammatory condition of the gastrointestinal tract as claimed in claim 9 , wherein the compound is selected from the group comprising:

2-(4- or 5-amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

4- or 5-amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate;

4- or 5-amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-hydroxy 4- or 5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

4- or 5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

4- or 5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid.

11. The method of treating an inflammatory condition of the gastrointestinal tract as claimed in claim 9 , wherein the compound is 4-thiocarbamoylphenyl 4- or 5-amino-2-hydroxybenzoate.

12. The method according to claim 9 , wherein the inflammatory condition of the gastrointestinal tract is selected from the group consisting of Crohn's disease, ulcerative colitis and irritable bowel syndrome.

13. A compound according to claim 1 , selected from the group consisting of:

5-(1-carboxy-3-thiocarbamoyl-propylazo)-2-hydroxy-benzoic acid;

2-(5-amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

5-amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

2-hydroxy-5-[3-(1-hydroxymethyl-3-thiocarbamoyl-propyl)-ureido]-benzoic acid;

5-amino-2-(2-amino-4-thiocarbamoyl-butyryloxy)-benzoic acid;

5-(2-amino-4-thiocarbamoyl-butyrylamino)-2-hydroxy-benzoic acid;

5-amino-2-hydroxy-benzoic acid anhydride with 2-amino-4-thiocarbamoyl-butyric acid;

4-thiocarbamoylphenyl 5-amino-2-hydroxybenzoate;

5-amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-hydroxy-5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

5-amino-2-hydroxy-benzoic acid thiocarbamoylmethyl ester;

5-amino-2-thiocarbamoylmethoxycarbonyloxy-benzoic acid;

2-hydroxy-5-thiocarbamoylmethoxycarbonylamino-benzoic acid;

5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid;

or a salt thereof.

14. A compound according to claim 1 , selected from the group consisting of:

5-(1-Carboxy-3-thiocarbamoyl-propylazo)-2-hydroxy-benzoic acid;

2-(5-Amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

5-Amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

2-Hydroxy-5-[3-(1-hydroxymethyl-3-thiocarbamoyl-propyl)-ureido]-benzoic acid;

5-Amino-2-(2-amino-4-thiocarbamoyl-butyryloxy)-benzoic acid;

5-(2-Amino-4-thiocarbamoyl-butyrylamino)-2-hydroxy-benzoic acid;

5-Amino-2-hydroxy-benzoic acid anhydride with 2-amino-4-thiocarbamoyl-butyric acid;

4-thiocarbamoylphenyl 5-amino-2-hydroxybenzoate;

5-Amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-Hydroxy-5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid;

5-Amino-2-hydroxy-benzoic acid thiocarbamoylmethyl ester;

5-Amino-2-thiocarbamoylmethoxycarbonyloxy-benzoic acid;

2-Hydroxy-5-thiocarbamoylmethoxycarbonylamino-benzoic acid;

5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid;

or a salt thereof.

15. A compound according to claim 1 , selected from the group consisting of:

2-(5-amino-2-hydroxy-benzoylamino)-4-thiocarbamoyl-butyric acid;

5-amino-2-(1-carboxy-3-thiocarbamoyl-propylcarbamoyloxy)-benzoic acid;

4-thiocarbamoylphenyl 5-amino-2-hydroxybenzoate;

5-amino-2-(4-thiocarbamoyl-phenoxycarbonyloxy)-benzoic acid;

2-hydroxy 5-(4-thiocarbamoyl-phenoxycarbonylamino)-benzoic acid; 5-amino-2-hydroxy-benzoic acid anhydride with sulfuric acid mono-(2-mercapto-ethyl) ester; and

5-amino-2-(2-mercapto-ethoxysulfonyloxy)-benzoic acid;

or a salt thereof.

16. A compound according to claim 1 , 4-thiocarbamoylphenyl 5-amino-2-hydroxybenzoate, or salt thereof.

17. A compound according to claim 1 , wherein R is selected from the group consisting of:

Assignments (5)

MERGER Recorded Mar 14, 2022

From: ANTIBE AMALCO INC.; ANTIBE THERAPEUTICS INC.

To: ANTIBE THERAPEUTICS INC.

Reel/Frame 059808/0216 →

ARTICLES OF CONTINUANCE & CERTIFICATE OF DISCONTINUANCE Recorded Mar 14, 2022

From: ANTIBE HOLDINGS INC.

To: ANTIBE HOLDINGS INC.