Substituted aromatic compounds for the treatment pulmonary fibrosis, liver fibrosis, skin fibrosis and cardiac fibrosis

1. A method for slowing progression of and/or treating fibrosis in a subject having a fibrotic disease, wherein the fibrotic disease is selected from pulmonary fibrosis, liver fibrosis, skin fibrosis or cardiac fibrosis, and wherein said method comprises administering, to a subject having at least one of said fibroses, a therapeutically effective amount of a compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein

A is C 5 alkyl, C 6 alkyl, C 5 alkenyl, C 6 alkenyl, C(O)—(CH 2 ) n —CH 3 or CH(OH)—(CH 2 ) n —CH 3 wherein n is 3 or 4;

R 1 is H, OH or F;

R 2 is H, OH, F or CH 2 —OH;

R 3 is H, OH, F or CH 2 Ph;

R 4 is H, OH or F; and

Q is

1) (CH 2 ) m C(O)OH wherein m is 1 or 2,

2) CH(F)—C(O)OH,

3) CF 2 —C(O)OH, or

4) C(O)—C(O)OH.

2. The method according to claim 1 , wherein the pharmaceutically acceptable salt of said compound is sodium, potassium, lithium, ammonium, calcium, magnesium, manganese, zinc, iron, or copper.

3. The method of claim 2 , wherein the pharmaceutically acceptable salt of said compound is sodium.

4. The method according to claim 1 wherein said compound is one of the following compounds:

5. The method according to claim 1 , wherein the fibrotic disease is pulmonary fibrosis.

6. The method of claim 5 , wherein the therapeutically effective amount is between about 1 to about 50 mg/kg, the compound is administered orally, and the subject is human.

7. The method of claim 6 , wherein the therapeutically effective amount is between about 1 to about 20 mg/kg.

8. The method according to claim 5 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis; sarcoidosis; cystic fibrosis; familial pulmonary fibrosis; silicosis; asbestosis; coal worker's pneumoconiosis; carbon pneumoconiosis; hypersensitivity pneumonitides; pulmonary fibrosis caused by inhalation of inorganic dust; pulmonary fibrosis caused by an infectious agent; pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors; drug-induced interstitial lung disease, pulmonary hypertension; or chronic obstructive pulmonary disease.

9. The method according to claim 1 , wherein the fibrotic disease is liver fibrosis.

10. The method of claim 9 , wherein the therapeutically effective amount is between about 1 to about 50 mg/kg, the compound is administered orally, and the subject is human.

11. The method of claim 10 , wherein the therapeutically effective amount is between about 1 to about 20 mg/kg.

12. The method according to claim 10 , wherein the liver fibrosis is resulting from a chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease or non-alcoholic steatohepatitis, obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction or exposure to toxins.

13. The method according to claim 1 , wherein the fibrotic disease is skin fibrosis.

14. The method of claim 13 , wherein the compound is administered topically.

15. The method of claim 14 , wherein the therapeutically effective amount is between about 0.01 to about 10% (w/w) and the subject is human.

16. The method of claim 13 , wherein the compound is administered orally.

17. The method of claim 16 , wherein the therapeutically effective amount is between about 1 to about 50 mg/kg and the subject is human.

18. The method according to claim 14 , wherein the skin fibrosis is scarring, hypertrophic scarring, keloid scarring, dermal fibrotic disorder, wound healing, delayed wound healing, psoriasis or scleroderma.

19. The method of claim 18 , wherein said scarring derives from a wound, a burn, a scar, wrinkles, stretch marks, sun damage, chemical damage, heat damage, cold damage, a trauma, a surgical injury, a radiation or an ulcer.

20. The method of claim 19 , wherein said ulcer is diabetic foot ulcer, venous leg ulcer or pressure ulcer.

21. The method according to claim 1 , wherein the fibrotic disease is cardiac fibrosis.

22. The method of claim 21 , wherein the cardiac fibrosis is cardiomyopathy, or congestive heart failure.

23. A method for antagonizing collagen secretion or collagen deposition in an organ of a mammal comprising administering a therapeutically effective amount of a compound as defined in claim 1 , to the mammal in need thereof, wherein the organ is lung, liver, skin or heart.

24. A method for reducing collagen production in cells, comprising contacting the cells with a therapeutically effective amount of a compound as defined in claim 1 .

25. The method according to claim 1 , wherein the compound is administered in combination with a therapeutically effective amount of a second compound, and wherein the second compound is an immunosuppressive drug, an anti-inflammatory drug, a cytokine, a monoclonal antibody, a multiple receptor tyrosine kinase inhibitor, an antioxidant, an enzyme inhibitor, an integrin inhibitor, a lipid receptor modulator or a thiazolindione.

26. The method according to claim 25 , wherein the fibrotic disease is pulmonary fibrosis, and wherein the compound is administered in combination with a therapeutically effective amount of pirfenidone.

27. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein

A is C 5 alkyl, C 6 alkyl, C 5 alkenyl, C 6 alkenyl, C(O)—(CH 2 ) n —CH 3 or CH(OH)—(CH 2 ) n —CH 3 wherein n is 3 or 4;

R 1 is H, OH or F;

R 2 is H, OH, F or CH 2 —OH;

R 3 is CH 2 Ph;

R 4 is H, OH or F; and

Q is

1) (CH 2 ) m C(O)OH wherein m is 1 or 2,

2) CH(CH 3 )C(O)OH,

3) C(CH 3 ) 2 C(O)OH,

4) CH(F)—C(O)OH,

5) CF 2 —C(O)OH, or

6) C(O)—C(O)OH.

28. The compound of claim 27 , wherein the compound is:

29. The method according to claim 25 , wherein the fibrotic disease is pulmonary fibrosis, and wherein the multiple receptor tyrosine kinase inhibitor is nintedanib.