Antifibrotic compounds and uses thereof
AssigneeAngion Biomedica Corp.
InventorsBijoy PANICKER, Rama K. MISHRA, Dong Sung LIM, Lambertus J.W.M. OEHLEN, Dawoon JUNG
Life of this patent
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Abstract
The present invention provides compounds having the general structural formula (I) and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving abnormal or excessive fibrosis.
Claims20
A method for treating a disease or condition from among fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis, liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, and inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency);
- damaged and/or ischemic organs, transplants or grafts;
- ischemia/reperfusion injury;
- pancreatitis;
- stroke;
- cerebrovascular disease;
- myocardial ischemia;
- atherosclerosis;
- renal failure;
- renal fibrosis or idiopathic pulmonary fibrosis, treatment of wounds for acceleration of healing;
- vascularization of a damaged and/or ischemic organ, transplant or graft;
- amelioration of ischemia/reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs;
- normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction;
- development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs;
- fibrotic diseases;
- hepatic disease including fibrosis and cirrhosis;
- lung fibrosis;
- radiocontrast nephropathy;
- fibrosis secondary to renal obstruction;
- renal trauma and transplantation;
- renal failure secondary to chronic diabetes and/or hypertension;
- amyotrophic lateral sclerosis, muscular dystrophy, scleroderma, chronic obstructive pulmonary disease, emphysema, diabetes mellitus, multiple sclerosis, trauma to the central nervous system, a hereditary neurodegenerative disorders, by administering to a subject in need thereof a compound or a pharmaceutical composition comprising a compound as described in Formula (I) below:
- or a pharmaceutically acceptable salt thereof or a prodrug thereof;
- wherein R1 is —COOR5;
- R2 is H or a prodrug moiety, optionally a carbamate or amide;
- R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
- R5 is a lower alkyl group;
- R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR5, NR8R9, or NCOR8 moieties;
- R8 and R9 are independently H or a lower alkyl group;
- A is N or CH, wherein one A is nitrogen;
- and
- B is O or S.
A method reducing fibrosis in a subject in need thereof comprising administering to the subject a compound or a pharmaceutical composition thereof having Formula (I) below:
- or a pharmaceutically acceptable salt thereof or a prodrug thereof;
- where in R1 is —COOR5;
- R2 is H or a prodrug moiety, optionally a carbamate or amide;
- R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
- R5 is a lower alkyl group;
- R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR8, NR8R9, or NCOR8 moieties;
- R8 and R9 are independently H or a lower alkyl group;
- A is N or CH, wherein one A is nitrogen;
- and
- B is O or S.
The method of prevention, treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis comprising administering to a subject in need thereof a compound or a pharmaceutical composition thereof having Formula (I) below:
- or a pharmaceutically acceptable salt thereof or a prodrug thereof;
- where in R1 is —COOR5;
- R2 is H or a prodrug moiety, optionally a carbamate or amide;
- R3 and R4 are independently H, aryl or heteroaryl, which may optionally be independently substituted with one or more lower alkyl, halogen, OR6, NO2, CN, NH2, NR6R7, NR6COR7 or NR6SO2R7 moieties;
- R5 is a lower alkyl group;
- R6 and R7 are independently hydrogen or alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, alkylcycloalkylalkyl, heterocycloalkyl or alkylheterocycloalkyl, which may optionally substituted with alkyl, OR8, COOR8, NR8R9, or NCOR8 moieties;
- R8 and R9 are independently H or a lower alkyl group;
- A is N or CH, wherein one A is nitrogen;
- and
- B is O or S.
Dependencies are inferred from the claim text.