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

A method of enriching, for a specific isomer, a tyrphostin of a general formula:

• wherein,
• 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;
• A, D, X and Y are each a nitrogen;
• B is a carbon;
• R1, R2, R3, R5 and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R1 and R2 or R2 and R3 form a 5-7 member ring structure;
• R6 is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, a ryloxy, 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;
• R4 and R8 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 —NR10R11 and, a physiologically acceptable salt or a prodrug thereof;
• R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R10 and R11 form a five- or six-member heteroalicyclic ring;
• and, a physiologically acceptable salt or a prodrug thereof;
• whereas, for each molecule of Compound I, R6 is at position 6 or 7;
• the method comprising:
• (a) chromatographing said tyrphostin through a matrix, thereby separating isomers of said tyrphostin;
• and
• (b) collecting at least one specific isomer.

A method for preparing a pharmaceutical composition for slow release of a tyrphostin comprising the steps of:

• (a) providing a purified tyrphostin of a general formula:
• wherein,
• 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;
• A, D, X and Y are each independently a nitrogen;
• B is a carbon;
• R1, R2, R3, R5 and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R1 and R2 or R2 and R3 form a 5-7 member ring structure;
• R6 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;
• R4 and R8 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 —NR10R11 and, a physiologically acceptable salt or a prodrug thereof;
• R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R10 and R11 form a five- or six-member heteroalicyclic ring;
• and, a physiologically acceptable salt or a prodrug thereof;
• whereas, for Compound I, said R6 is either at position 6 or at position 7;
• (b) dissolving or dispersing a slow release carrier and said purified tyrphostin in an organic solvent for obtaining an organic solution containing said carrier and said purified tyrphostin;
• (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 purified tyrphostin.

A stent comprising a substantially tubular body, the body is made of a material designed for slow release of a purified tyrphostin of a general formula:

• wherein,
• 4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;
• A, D, X and Y are each independently a nitrogen;
• B is a carbon;
• R1, R2, R3, R5 and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R1 and R2 or R2 and R3 form a 5-7 member ring structure;
• R6 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;
• R4 and R8 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 —NR10R11 and, a physiologically acceptable salt or a prodrug thereof;
• R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R10 and R11 form a five- or six-member heteroalicyclic ring;
• and, a physiologically acceptable salt or a prodrug thereof;
• whereas, for Compound I, said R6 is either at position 6 or at position 7.