Small molecules that specifically inhibit TNF-induced NF-KB inflammation pathway

Patent metadata

Field	Value
Publication number	US-11858877-B2
Application number	US-202016799130-A
Country	US
Kind code	B2
Filing date	Feb 24, 2020
Priority date	Feb 22, 2019
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

Provided herein are small molecules that specifically inhibit TNF-induced nuclear factor kB (NF-kB) inflammation pathway. Also provided are methods of screening compounds to identify molecules that specifically inhibit a TNF-induced NF-kB inflammation pathway, methods of inhibiting TNF-induced NF-kB inflammation pathway, and methods of preventing formation of mature TNFR1 complex.

First claim

What is claims is:

1. A compound represented by formula (I):

or a salt or hydrate thereof, wherein:
A is an azinic acid;
B is an alkyl sulfonyl;
X 1 and X 3 are independently selected from O, NOH, NO-alkyl, and C(CN) 2 ;
X 2 is selected from O, NH, and NF;
R 1 is H or alkyl and R 2 is an optionally substituted alkyl or cycloalkyl, or R 1 and R 2 together form an optionally substituted 5- or 6-membered heterocycle; and
R 3 is selected from H, F, and an optionally substituted alkyl, where the compound of formula (I) is not:

2. The compound of claim 1 , wherein -NRiR 2 is represented by:

wherein R 4 is an optionally substituted alkyl, alkene, alkyne, or —COOR 5 , where R 5 is an optionally substituted alkyl or cycloalkyl.

3. The compound of claim 1 , wherein X 1 , X 2 and X 3 are O.

4. The compound of claim 1 , wherein R 3 is H.

5. The compound of claim 1 , wherein R 2 is a cyclopentyl or cyclohexyl.

6. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 , wherein the composition is suitable for administration to a human.

8. The pharmaceutical composition of claim 6 , formulated into a dosage form:
(a) selected from the group consisting of liquid dispersions, gels, aerosols, lyophilized formulations, tablets, and capsules;
(b) selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (c) any combination of (a) and (b).

9. The pharmaceutical composition of claim 6 , formulated for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, intravenous, subcutaneous, intramuscular, nebulization, inhalation, ocular, otic, local, buccal, nasal, and topical administration.

10. A method of preventing formation of mature TNFR1 complex, comprising contacting a cell with a compound of formula (I):

or a salt or hydrate thereof, wherein:
A is an azinic acid;
B is an alkyl sulfonyl;
X 1 and X 3 are independently selected from O, NOH, NO-alkyl, CF 3 , and C(CN) 2 ;
X 2 is selected from O, NH, and NF;
R 1 is H or alkyl and R 2 is an optionally substituted alkyl or cycloalkyl, or R 1 and R 2 together form an optionally substituted 5- or 6-membered heterocycle.

11. The method of claim 10 , wherein the cell is a human cell.

12. The method of claim 10 , wherein the method is in vivo or in vitro.

13. The method of claim 12 , wherein the contacting is in vivo in a subject suffering from a disease caused by blockade of TNF-induced signaling or in a subject suffering from a disease caused by inflammation-associated cancers that are potentiated by TNF-induces NFkB signaling.

14. The method of claim 13 , wherein:
(a) the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis; or
(b) the cancer is selected from the group consisting of aggressive diffuse large B-cell lymphoma, metastatic carcinomas, tumors of the colon, tumors of the lung, tumors of the pancreas, and tumors of the brain.

15. A method of inhibiting a TNF-induced nuclear factor kB (NF-kB) inflammation pathway, comprising contacting a cell with a compound of formula (I):

or a salt or hydrate thereof, wherein:
A is an azinic acid;
B is an alkyl sulfonyl;
X 1 and X 3 are independently selected from O, NOH, NO-alkyl, CF 3 , and C(CN) 2 ;
X 2 is selected from O, NH, and NF;
R 1 is H or alkyl and R 2 is an optionally substituted alkyl or cycloalkyl, or R 1 and R 2 together form an optionally substituted 5- or 6-membered heterocycle.

16. The method of claim 15 , wherein the cell is a human cell.

17. The method of claim 15 , wherein the method is in vivo or in vitro.

18. The method of claim 17 , wherein the contacting is in vivo in a subject suffering from a disease caused by blockade of TNF-induced signaling or in a subject suffering from a disease caused by inflammation-associated cancers that are potentiated by TNF-induced NFkB signaling.

19. The method of claim 18 , wherein:
(a) the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis; or (b) the cancer is selected from the group consisting of aggressive diffuse large B-cell lymphoma, metastatic carcinomas, tumors of the colon, tumors of the lung, tumors of the pancreas, and tumors of the brain.

20. A method of treating a subject suffering from a disease caused by blockade of TNF-induced signaling, comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 .

21. The method of claim 20 , wherein the disease caused by blockade of TNF-induced signaling is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Camacho Carlos Jaime
• Lee Robin E C

Classifications

• C07C233/08 Primary

  with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings · CPC title

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• C07C317/48 Primary

  the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups · CPC title

• A61K31/395

  having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins · CPC title

• A61K31/245

  Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60) · CPC title