METHOD OF USING AN INDOLINONE MOLECULE AND DERIVATIVES FOR INHIBITING LIVER FIBROSIS AND HEPATITIS

• US 20150045395A1
• Filed: 08/09/2013
• Published: 02/12/2015
• Est. Priority Date: 08/09/2013
• Status: Active Grant

• Current Assignee: Acclaim BioMed USA LLC
• Original Assignee: Acclaim BioMed USA LLC
• Inventors: Lee, Kenneth Ka-Ho, Kok, Stanton Hon-Lung, Kok, Tsz-Wai, Wong, Sing-Wan, Chan, John Yeuk-Hon
• Granted Patent: US 10,450,295 B2
• Time in Patent Office: Days
• US Class Current: 514/339
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/40 Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention relates to methods of reversing and inhibiting liver fibrosis and hepatitis using a small indolinone molecule Hesperadin and related compounds. Methods of identifying such agents and using them to inhibit the expression of collagens and ECM proteins including MMPs and TIMPs in purified hepatic stellate cells are provided. In vivo data of Hesperadin in inhibiting induced collagen production are presented. This method of specifically targeting drugs to hepatic stellate cells in vivo, provides a novel therapy for liver diseases.

Claims

1. A method for treating a condition associated with a liver disease, comprising:

preparing a compound having a structure according to Formula I;

2. The method according to claim 1, wherein X is carbon, n is 0, R⁵ is NSO₂—

C₂H₅, and the compound is a member selected from the group consisting of;

(Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenylamino)methylene)indolin-5-yl)ethanesulfonamide (Hesperadin)

(Z)-N-(2-oxo-3-(phenyl(phenylamino)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(p-tolylamino)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-chlorophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(morpholinomethyl)phenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(diphenylmethylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(p-tolyl)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-chlorophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenyl)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(morpholinomethyl)phenyl)(phenyl)methylene)-2-oxoindolin-5 yl)ethanesulfonamide

(Z)-N-(3-benzylidene-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-methylbenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-methoxybenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-(dimethylamino)benzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-fluorobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-chlorobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-bromobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-nitrobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(4-(piperidin-1-ylmethyl)benzylidene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-(morpholinomethyl)benzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenylimino)indolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(p-tolylimino)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-chlorophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-((4-(piperidin-1-ylmethyl)phenyl)imino)indolin-5-yl)ethanesulfonamide and

(Z)-N-(3-((4-(morpholinomethyl)phenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide.

3. The method according to claim 1, wherein X is carbon, n is 0, R⁴ is H, R⁵ is H or Br, R⁶ is H, R⁷ is H, and the compound is a member selected from the group consisting of:

(Z)-N-cyclohexyl-2-(2-oxo-3-(phenyl(phenylamino)methylene)indolin-1-yl)-2-phenylacetamide

(Z)-N-cyclohexyl-2-(2-oxo-3-((phenylamino)methylene)indolin-1-yl)-2-phenylacetamide

(Z)-3-benzylideneindolin-2-one

(Z)-3-(4-fluorobenzylidene)indolin-2-one

(Z)-3-(4-chlorobenzylidene)indolin-2-one

(Z)-3-(4-bromobenzylidene)indolin-2-one

(Z)-3-(4-methoxybenzylidene)indolin-2-one

(Z)-3-(4-(dimethylamino)benzylidene)indolin-2-one

(Z)-3-benzylidene-5-bromoindolin-2-one

(Z)-3-(pyridin-2-ylmethylene)indolin-2-one and

(Z)-5-bromo-3-(pyridin-2-ylmethylene)indolin-2-one.

4. The method according to claim 1, wherein X is nitrogen, n is 0, R⁴ is H, R⁵ is H or Br, R⁶ is H, R⁷ is H, and the compound is a member selected from the group consisting of:

(Z)-3-((4-chlorophenyl)imino)indolin-2-one

(Z)-3-((4-bromophenyl)imino)indolin-2-one

(Z)-3-((4-nitrophenyl)imino)indolin-2-one

(Z)-3-(p-tolylimino)indolin-2-one

(Z)-3-(pyridin-3-ylimino)indolin-2-one and

(Z)-3-((furan-2-ylmethyl)imino)indolin-2-one.

5. The method according to claim 1, wherein the compound is (Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenylamino)methylene)indolin-5-yl)ethanesulfonamide.

6. The method according to claim 1, wherein the liver disease is a member selected from the group consisting of hepatitis due to hepatitis B virus, hepatitis due to hepatitis C virus, hepatitis due to chronic alcohol consumption, hepatitis due to metabolic disorder, hepatitis due to autoimmune disorder, hepatitis due to drug-induced injury, hepatitis due to biliary obstruction, liver fibrosis and cirrhosis.

7. The method according to claim 1, wherein the at least one collagen is selected from the group consisting of collagen type I, collagen type III, collagen type IV, collagen type V, collagen type VI and collagen type VII.

8. The method according to claim 5, wherein the liver disease is a member selected from the group consisting of hepatitis due to hepatitis B virus, hepatitis due to hepatitis C virus, hepatitis due to chronic alcohol consumption, hepatitis due to metabolic disorder, hepatitis due to autoimmune disorder, hepatitis due to drug-induced injury, hepatitis due to biliary obstruction, liver fibrosis and cirrhosis.

9. The method according to claim 5, wherein the at least one collagen is selected from the group consisting of collagen type I, collagen type III, collagen type IV, collagen type V, collagen type VI and collagen type VII.

10. A pharmacological composition for treating a condition associated with a liver disease, comprising:

a compound having a structure according to Formula I;

11. The composition according to claim 10, wherein X is carbon, n is 0, R⁵ is NSO₂—

C₂H₅, and the compound is a member selected from the group consisting of;

(Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenylamino)methylene)indolin-5-yl)ethanesulfonamide (Hesperadin)

(Z)-N-(2-oxo-3-(phenyl(phenylamino)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(p-tolylamino)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-chlorophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(morpholinomethyl)phenylamino)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(diphenylmethylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(p-tolyl)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-chlorophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenyl)(phenyl)methylene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenyl)methylene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(morpholinomethyl)phenyl)(phenyl)methylene)-2-oxoindolin-5 yl)ethanesulfonamide

(Z)-N-(3-benzylidene-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-methylbenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-methoxybenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-(dimethylamino)benzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-fluorobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-chlorobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-bromobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-nitrobenzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(4-(piperidin-1-ylmethyl)benzylidene)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-(4-(morpholinomethyl)benzylidene)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(phenylimino)indolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-(p-tolylimino)indolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-methoxyphenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-(dimethylamino)phenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-fluorophenyl)imino)-2-oxoindolin-5-ypethanesulfonamide

(Z)-N-(3-((4-chlorophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-bromophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(3-((4-nitrophenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide

(Z)-N-(2-oxo-3-((4-(piperidin-1-ylmethyl)phenyl)imino)indolin-5-yl)ethanesulfonamide and

(Z)-N-(3-((4-(morpholinomethyl)phenyl)imino)-2-oxoindolin-5-yl)ethanesulfonamide.

12. The composition according to claim 10, wherein X is carbon, n is 0, R⁴ is H, R⁵ is H or Br, R⁶ is H, R⁷ is H, and the compound is a member selected from the group consisting of:

(Z)-N-cyclohexyl-2-(2-oxo-3-(phenyl(phenylamino)methylene)indolin-1-yl)-2-phenylacetamide

(Z)-N-cyclohexyl-2-(2-oxo-3-((phenylamino)methylene)indolin-1-yl)-2-phenylacetamide

(Z)-3-benzylideneindolin-2-one

(Z)-3-(4-fluorobenzylidene)indolin-2-one

(Z)-3-(4-chlorobenzylidene)indolin-2-one

(Z)-3-(4-bromobenzylidene)indolin-2-one

(Z)-3-(4-methoxybenzylidene)indolin-2-one

(Z)-3-(4-(dimethylamino)benzylidene)indolin-2-one

(Z)-3-benzylidene-5-bromoindolin-2-one

(Z)-3-(pyridin-2-ylmethylene)indolin-2-one and

(Z)-5-Bromo-3-(pyridin-2-ylmethylene)indolin-2-one.

13. The composition according to claim 10, wherein X is nitrogen, n is 0, R⁴ is H, R⁵ is H or Br, R⁶ is H, R⁷ is H, and the compound is a member selected from the group consisting of:

(Z)-3-((4-chlorophenyl)imino)indolin-2-one

(Z)-3-((4-bromophenyl)imino)indolin-2-one

(Z)-3-((4-nitrophenyl)imino)indolin-2-one

(Z)-3-(p-tolylimino)indolin-2-one

(Z)-3-(pyridin-3-ylimino)indolin-2-one and

(Z)-3-((furan-2-ylmethyl)imino)indolin-2-one.

14. The composition according to claim 10, wherein the compound is (Z)-N-(2-oxo-3-(phenyl(4-(piperidin-1-ylmethyl)phenylamino)methylene)indolin-5-yl)ethanesulfonamide.

15. The composition according to claim 10, wherein the liver disease is a member selected from the group consisting of hepatitis due to hepatitis B virus, hepatitis due to hepatitis C virus, hepatitis due to chronic alcohol consumption, hepatitis due to metabolic disorder, hepatitis due to autoimmune disorder, hepatitis due to drug-induced injury, hepatitis due to biliary obstruction, liver fibrosis and cirrhosis.

16. The composition according to claim 10, wherein the at least one collagen is selected from the group consisting of collagen type I, collagen type III, collagen type IV, collagen type V, collagen type VI and collagen type VII.

17. The composition according to claim 14, wherein the liver disease is a member selected from the group consisting of hepatitis due to hepatitis B virus, hepatitis due to hepatitis C virus, hepatitis due to chronic alcohol consumption, hepatitis due to metabolic disorder, hepatitis due to autoimmune disorder, hepatitis due to drug-induced injury, hepatitis due to biliary obstruction, liver fibrosis and cirrhosis.

18. The composition according to claim 14, wherein the at least one collagen is selected from the group consisting of collagen type I, collagen type III, collagen type IV, collagen type V, collagen type VI and collagen type VII.