PDGF receptor kinase inhibitory compounds, their preparation, purification and pharmaceutical compositions including same

Abstract

A preparation of a tyrphostin including a compound of a general formula: wherein, for Compound I, the preparation is enriched either for R 6 at position 6 or for R 6 at position 7, or, for Compound II, the preparation is enriched either for R 6 at position 6 or for R 6 at position 8.

What is claimed is:  
     
         1 . A preparation of a tyrphostin comprising a compound of a general formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;  
 A, B, D, X and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
 R 1 , R 2 , R 3 , R 5  and R 7  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R 1  and R 2  or R 2  and R 3  form a 5-7 member ring structure;  
 R 6  is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and a physiologically acceptable salt or a prodrug thereof;  
 R 4  and R 8  are each independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and —NR 10 R 11  and, a physiologically acceptable salt or a prodrug thereof;  
 R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R 10  and R 11  form a five- or six-member heteroalicyclic ring; and, a physiologically acceptable salt or a prodrug thereof;  
 whereas, for Compound I, said preparation is enriched either for R 6  at position 6 or for R 6  at position 7, or, for Compound II, said preparation is enriched either for R 6  at position 6 or for R 6  at position 8.  
 
     
     
         2 . The preparation of  claim 1 , wherein 
 A, D, X and Y are each a nitrogen;    B is a carbon;    R 1  and R 2  are each independently selected from the group consisting of alkyl, alkoxy, halogen, nitro and amine group;    R 3 , R 5  and R 7  are each a pair of electrons;    R 6  is an aryl, selected from the group consisting of phenyl, ferrocene, thiophene, furane, pyrrole, indole, thiazole, imidazole and pyridine.    
     
     
         3 . The preparation of  claim 2 , w herein 
 R 1  and R 2  are each a methyl;    R 4  and R 8  are each a hydrogen.    
     
     
         4 . The preparation of  claim 1 , wherein said preparation is enriched for Compound I in which R 6  is at position 6.  
     
     
         5 . The preparation of  claim 1 , wherein said preparation is enriched for Compound I in which R 6  is at position 7.  
     
     
         6 . The preparation of  claim 1 , wherein said preparation is enriched for Compound II in which R 6  is at position 6.  
     
     
         7 . The preparation of  claim 1 , wherein said preparation is enriched for Compound II in which R 6  is at position 8.  
     
     
         8 . The preparation of  claim 1 , wherein for Compound I, said preparation is purified either for R 6  at position 6 or for R 6  at position 7, or, for Compound II, said preparation is purified either for R 6  at position 6 or for R 6  at position 8.  
     
     
         9 . A pharmaceutical composition comprising, as an active ingredient, the preparation of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said pharmaceutically acceptable carrier is a slow release carrier.  
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said slow release carrier is polylactic acid.  
     
     
         12 . A method of treating or preventing a protein tyrosine kinase related disorder in an organism, the method comprising the step of administering to said organism a therapeutically effective amount of the pharmaceutical composition of  claim 9 .  
     
     
         13 . The method of  claim 12 , wherein said protein tyrosine kinase related disorder is selected from the group consisting of an EGF related disorder, a PDGF related disorder, an IGF related disorder and a met related disorder.  
     
     
         14 . The method of  claim 12 , wherein said protein tyrosine kinase related disorder is selected from the group consisting of a cell proliferative disorder, a fibrotic disorder and a metabolic disorder.  
     
     
         15 . The method of  claim 14 , wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Burkitt's disease, arthritis, rheumatoid arthritis, diabetic retinopathy, angiogenesis, restenosis, in-stent restenosis, vascular graft restenosis.  
     
     
         16 . The method of  claim 14 , wherein said cell fibrotic disorder is selected from the group consisting of pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy, thrombic microangiopathy syndromes, transplant rejection.  
     
     
         17 . The method of  claim 14 , wherein said cell metabolic disorder is selected from the group consisting of psoriasis, diabetes, wound healing, inflammation, and neurodegenerative diseases.  
     
     
         18 . The method of  claim 12 , wherein said protein tyrosine kinase related disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, small-cell lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Burkitt's disease, psoriasis, pulmonary fibrosis, arthritis, rheumatoid arthritis, diabetic retinopathy, restenosis, in-stent restenosis, vascular graft restenosis, hepatic cirrhosis, atherosclerosis, angiogenesis, glomerulonephritis, diabetic nephropathy, thrombic microangiopathy syndromes, transplant rejection, autoimmune disease, wound healing, inflammation, neurodegenerative diseases, diabetes and hyperimmune disorders.  
     
     
         19 . The method of  claim 12 , wherein said organism is a mammal.  
     
     
         20 . The method of  claim 19 , wherein said mammal is a human.  
     
     
         21 . A method of locally treating or preventing a disorder of a tissue of an organism comprising the step of locally applying the pharmaceutical composition of  claim 9  onto said tissue.  
     
     
         22 . The method of  claim 21 , wherein said organism is a human.  
     
     
         23 . The method of  claim 21 , wherein said tissue is selected from the group consisting of blood vessel, lung and skin.  
     
     
         24 . A method of inhibiting cell proliferation comprising the step of subjecting the cells to the tyrphostin preparation of  claim 1 .  
     
     
         25 . The method of  claim 24 , wherein said cells are of an organism, whereas subjecting the cells to said preparation is effected in vivo.  
     
     
         26 . The method of  claim 25 , wherein said organism is a human.  
     
     
         27 . The method of  claim 24 , wherein subjecting the cells to said preparation is effected in vitro.  
     
     
         28 . A method of enriching a preparation of tyrphostins for a specific geometrical isomer, the preparation comprising a compound of a general formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;  
 A, B, D, X and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
 R 1 , R 2 , R 3 , R 5  and R 7  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R 1  and R 2  or R 2  and R 3  form a 5-7 member ring structure;  
 R 6  is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and a physiologically acceptable salt or a prodrug thereof;  
 R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and —NR 10 R 11  and, a physiologically acceptable salt or a prodrug thereof;  
 R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R 10  and R 11  form a five- or six-member heteroalicyclic ring; and, a physiologically acceptable salt or a prodrug thereof;  
 whereas, for each molecule of Compound I; R 6  is at position 6 or 7, or, for each molecule of Compound II, R 6  is at position 6 or 8;  
 the method comprising the steps of:  
 (a) chromatographing said preparation through a matrix, thereby separating isomers in said preparation;  
 (b) collecting at least one specific isomer.  
 
     
     
         29 . The method of  claim 28 , further comprising the step of: 
 (c) crystallizing said at least one specific isomer.    
     
     
         30 . The method of  claim 28 , wherein 
 A, D, X and Y are each a nitrogen;    B is a carbon;    R 1  and R 2  are each independently selected from the group consisting of alkyl, alkoxy, halogen, nitro and amine group;    R 3 , R 5  and R 7  are each a pair of electrons;    R 6  is an aryl, selected from the group consisting of phenyl, ferrocene, thiophene, furane, pyrrole, indole, thiazole, imidazole and pyridine.    
     
     
         31 . The method of  claim 30 , wherein 
 R 1  and R 2  are each a methyl;    R 4  and R 8  are each a hydrogen.    
     
     
         32 . A method for preparing a pharmaceutical composition for slow release of a tyrphostin comprising the steps of: 
 (a) providing an isomer-enriched tyrphostin preparation comprising a compound of a general formula:                           wherein, 
 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;  
 A, B, D, X and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
 R 1 , R 2 , R 3 , R 5  and R 7  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R 1  and R 2  or R 2  and R 3  form a 5-7 member ring structure;  
 R 6  is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and a physiologically acceptable salt or a prodrug thereof;  
 R 4  and R 8  are each independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and —NR 10 R 11  and, a physiologically acceptable salt or a prodrug thereof;  
 R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R 10  and R 11  form a five- or six-member heteroalicyclic ring; and, a physiologically acceptable salt or a prodrig thereof;  
 whereas, for Compound I, said preparation is enriched either for R 6  at position 6 or for R 6  at position 7, or, for Compound II, said preparation is enriched either for R 6  at position 6 or for R 6  at position 8;  
   (b) dissolving or dispersing a slow release carrier and said isomer-enriched tyrphostin preparation in an organic solvent for obtaining an organic solution containing said carrier and said isomer-enriched tyrphostin preparation;    (c) adding said organic solution into an aqueous solution for obtaining an oil-in-water-type emulsion; and    (d) evaporating said organic solvent from said oil-in-water-type emulsion for obtaining a colloidal suspension of particles containing said slow release carrier and said isomer-enriched tyrphostin preparation.    
     
     
         33 . The method of  claim 32 , wherein said slow release carrier is polylactic acid.  
     
     
         34 . A stent comprising a substantially tubular body, the body is made of a material designed for slow release of a tyrphostin preparation, said tyrphostin preparation including a compound of a general formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;  
 A, B, D, X and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;  
 R 1 , R 2 , R 3 , R 5  and R 7  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R 1  and R 2  or R 2  and R 3  form a 5-7 member ring structure;  
 R 6  is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and a physiologically acceptable salt or a prodrug thereof;  
 R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl. N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and —NR 10 R 11  and, a physiologically acceptable salt or a prodrug thereof;  
 R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R 10  and R 11  form a five- or six-member heteroalicyclic ring; and, a physiologically acceptable salt or a prodrug thereof;  
 whereas, for Compound I, said preparation is enriched either for R 6  at position 6 or for R 6  at position 7, or, for Compound II, said preparation is enriched either for R 6  at position 6 or for R 6  at position 8.