Composition and Method for Treating Fibrotic Diseases

• US 20070203203A1
• Filed: 05/01/2007
• Published: 08/30/2007
• Est. Priority Date: 04/13/2005
• Status: Abandoned Application

• Current Assignee: Gao Hu, Li Tao, Yuenian Shi
• Original Assignee: Gao Hu, Li Tao, Yuenian Shi
• Inventors: Tao, Li, Hu, Gao, Shi, Yuenian
• Application Number:
  US11/742,664
• Publication Number:
  US 20070203203A1
• Time in Patent Office: Days
• US Class Current: 514/345
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention discloses 5-methyl-1-(substituted phenyl)-2(1H)-pyridones have enhanced anti-fibrotic activities than 5-methyl-1-(non-substituted phenyl)-2(1H)-pyridones. An representative example of 5-methyl-(1-substituted phenyl)-2(1H)-pyridones is 1-(3′-fluorophenyl)-5-methyl-2(1H)-pyridone. Accordingly, there are provided compositions comprising one or more compounds selected from the group consisting of 5-methyl-1-(substituted phenyl)-2(1H)-pyridones and methods of using the same to treat or prevent fibrosis diseases.

Claims

1. A composition comprising one or more 5-methyl-1-(substituted phenyl)-2(1H)-pyridone in an amount effective for treating organ or tissue fibrosis, said 5-methyl-1-(substituted phenyl)-2(1H)-pyridone having a formula of:

wherein n=1 or 2;

R is selected from the group consisting of F, Cl, Br, I, nitro, C₁-C₆ straight-chain alkyl group, C₃-C₆ branched-chain alkyl group, C₁-C₆ straight-chain alkoxy group, C₃-C₆ branched-chain alkoxy group, and halogenated C₁-C₆ alkyl group; and

when n=2, not both R are nitro.

2. The composition of claim 1, wherein the 5-methyl-1-(substituted phenyl)-2(1H)-pyridone is selected from the group consisting of 1-(2′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

- chlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-chlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 5-methyl-1-(2′

-trifluoromethylphenyl)-2(1H)-pyridone, 5-methyl-1-(4′

-trifluoromethylphenyl)-2(1H)-pyridone, 1-(2′

,3′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 5-methyl-1-(2′

-methylphenyl)-2(1H)-pyridone, 1-(3′

-methylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-methoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-methoxyphenyl)-5-methyl-2(1H)-pyridone. 1-(2′

,3′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, and 1-(3′

,5′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone.

3. The composition of claim 1, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 25 mg to about 6,000 mg.

4. The composition of claim 1, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 50 mg to about 2000 mg.

5. The composition of claim 1, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 100 mg to about 1000 mg.

6. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

7. A method of treating organ or tissue fibrosis, comprising administering to a subject an effective amount of a composition comprising one or more 5-methyl-1-(substituted phenyl)-2(1H)-pyridones having a formula of:

wherein n=1 or 2;

R is selected from the group consisting of F, Cl, Br, I, nitro, C₁-C₆ straight-chain alkyl group, C₃-C₆ branched-chain alkyl group, C₁-C₆ straight-chain alkoxy group, C₃-C₆ branched-chain alkoxy group, and halogenated C₁-C₆ alkyl group; and

when n=2, not both R are nitro.

8. The method of claim 7, wherein the 5-methyl-1-(substituted phenyl)-2(1H)-pyridone is selected from the group consisting of 1-(2′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-bromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-chlorophenyl)-5-methyl-2(1H)-pyridone 1-(3′

-chlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dibromophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dichlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 5-methyl-1-(2′

-trifluoromethylphenyl)-2(1H)-pyridone, 5-methyl-1-(4′

-trifluoromethylphenyl)-2(1H)-pyridone, 1-(2′

,3′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone, or 1-(3′

,5′

-bis-trifluoromethylphenyl)-5-methyl-2(1H)-pyridone. 5-methyl-1-(2′

-methylphenyl)-2(1H)-pyridone, 1-(3′

-methylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-dimethylphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-methoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-methoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone, and 1-(3′

,5′

-dimethoxyphenyl)-5-methyl-2(1H)-pyridone.

9. The method of claim 7, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 25 mg to about 6,000 mg.

10. The method of claim 7, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 50 mg to about 2000 mg.

11. The method of claim 7, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 100 mg to about 1000 mg.

12. The method of claim 7, wherein the organ or tissue fibrosis is selected from the group consisting of glomerulus sclerosis, renal interstitial fibrosis, liver fibrosis, pulmonary fibrosis, peridoneal fibrosis, myocardiac fibrosis, fibrosis of skin, post-surgical adhesion, benign prostate hypertrophy, musculoskeletal fibrosis, scleroderma, Alzheimer'"'"'s disease, fibrotic vascular disease, and glaucoma.

13. The method of claim 7, wherein the composition is administered through a route selected from the group consisting of oral administration, parenteral administration, nasal administration, rectal administration, vaginal administration, ophthalmic application, and topical application.

14. The method of claim 7, wherein the 5-methyl-1-(substituted phenyl)-2(1H)-pyridone is 1-(3′

-fluorophenyl)-5-methyl-2(1H)-pyridone.

15. The method of claim 14, wherein the subject experiences less toxicity than treatment with 5-methyl-1-phenyl-2(1H)-pyridone.

16. A compound of 5-methyl-1-(substituted phenyl)-2(1H)-pyridone selected from the group consisting of 1-(2′

-chlorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-chlorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-fluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(4′

-iodophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,3-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(2′

,6′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,4′

-difluorophenyl)-5-methyl-2(1H)-pyridone, 1-(3′

,5′

-difluorophenyl)-5-methyl-2(1H)-pyridone and 1-(3′

,4′

-dichlorophenyl)-5-methyl-2(1H)-pyridone.

17. A pharmaceutical composition comprising one or more of the compound of claim 16 and a pharmaceutically acceptable carrier.

18. A method of treating organ or tissue fibrosis, comprising administering to a subject an effective amount of the composition of claim 17.

19. The method of claim 18, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 25 mg to about 6,000 mg.

20. The method of claim 18, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 50 mg to about 2000 mg.

21. The method of claim 18, wherein the amount effective for treating organ or tissue fibrosis comprises a daily dosage of about 100 mg to about 1000 mg.

22. The method of claim 18, wherein the organ or tissue fibrosis is selected from the group consisting of glomerulus sclerosis, renal interstitial fibrosis, liver fibrosis, pulmonary fibrosis, peridoneal fibrosis, myocardiac fibrosis, fibrosis of skin, post-surgical adhesion, benign prostate hypertrophy, musculoskeletal fibrosis, scleroderma, Alzheimer'"'"'s disease, fibrotic vascular disease, and glaucoma.

23. The method of claim 18, wherein the composition is administered through a route selected from the group consisting of oral administration, parenteral administration, nasal administration, rectal administration, vaginal administration, ophthalmic application, and topical application.

24. The method of claim 18, wherein the subject experiences less toxicity than treatment with 5-methyl-1-phenyl-2(1H)-pyridone.