Treatment of tuberous sclerosis associated neoplasms

Abstract

The present invention relates to the use of PDGF receptor tyrosine kinase or bcr-abl tyrosine kinase inhibitors, especially of N-phenyl-2-pyrimidine-amine derivatives of formula I, in which the symbols and substituents have the meaning as defined herein in free form or in pharmaceutically acceptable salt form, in the manufacture of a pharmaceutical composition for the treatment of tuberous sclerosis associated neoplasms; to a method of treatment of warm-blooded animals, including humans, suffering from a tuberous sclerosis associated neoplasms.

What is claimed is:  
     
         1 . A method of treating tuberous sclerosis associated neoplasms, which comprises administering to a subject in need thereof an effective amount of a PDGF receptor tyrosine kinase inhibitor or a bcr-abl tyrosine kinase inhibitor.  
     
     
         2 . A method according to  claim 1  which comprises administering an effective amount of an N-phenyl-2-pyrimidine-amine derivative of the formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is 4-pyrazinyl; 1-methyl-1H-pyrrolyl; amino- or amino-lower alkyl-substituted phenyl, wherein the amino group in each case is free, alkylated or acylated; 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom; or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen;  
 R 2  and R 3  are each independently of the other hydrogen or lower alkyl;  
 one or two of the radicals R 4 , R 5 , R 6 , R 7  and R 8  are each nitro, fluoro-substituted lower alkoxy or a radical of formula II  
 —N(R 9 )—C(═X)—(Y) n —R 10    (II),  
 wherein  
 R 9  is hydrogen or lower alkyl,  
 X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,  
 Y is oxygen or the group NH,  
 n is 0 or 1 and  
 R 10  is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical,  
 and the remaining radicals R 4 , R 5 , R 6 , R 7  and R 8  are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A method according to  claim 2  wherein 
 one or two of the radicals R 4 , R 5 , R 6 , R 7  and R 8  are each nitro or a radical of formula II  
 wherein 
 R 9  is hydrogen or lower alkyl,  
 X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,  
 Y is oxygen or the group NH,  
 n is 0 or 1 and  
 R 10  is an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical,  
 
 and the remaining radicals R 4 , R 5 , R 6 , R 7  and R 8  are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A method according to  claim 3  wherein 
 R 1  is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom,  
 R 2  and R 3  are each hydrogen,  
 R 4  is hydrogen or lower alkyl,  
 R 5  is hydrogen, lower alkyl or trifluoromethyl,  
 R 6  is hydrogen,  
 R 7  is nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein 
 R 9  is hydrogen,  
 X is oxo,  
 n is 0 and  
 R 10  is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C 5 -C 7 alkyl, thienyl, 2-naphthyl or cyclohexyl, and  
 
 R 8  is hydrogen,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . A method according to  claim 4  wherein 
 at least one of the radicals R 4  and R 8  is lower alkyl, and the remaining substituents are as defined in the respective generic claim,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         6 . A method according to  claim 5 , wherein 
 R 1  is pyridyl bonded at a carbon atom,    R 2 , R 3 , R 5 , R 6  and R 8  are each hydrogen,    R 4  is lower alkyl,    R 7  a radical of formula II wherein 
 R 9  is hydrogen,  
 X is oxo,  
 n is 0 and  
 R 10  is 4-methyl-piperazinyl-methyl,  
   or a pharmaceutically acceptable salt thereof.    
     
     
         7 . A method according to  claim 1 , wherein N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3pyridinyl)-2-pyrimidine-amine, or a pharmaceutically acceptable salt thereof, is administered.  
     
     
         8 . A method according to  claim 7 , wherein N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3pyridinyl)-2-pyrimidine-amine, monomesylate salt is administered.  
     
     
         9 . A method of  claim 1  wherein the tuberous sclerosis associated neoplasm is selected from angiomyolipomas, rhabdomyomas, lymphangioleiomyomatosis, subependymal giant cell astrocytomas, angiofibromas and periungual fibromas.  
     
     
         10 . A method of  claim 1  wherein the monomethanesulfonate salt of N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-2-pyrimidine-amine is administered at a daily dose corresponding to 100 to 1000 mg of N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-2-pyrimidine-amine free base.  
     
     
         11 . A method of inhibiting the formation of neoplasms in a patient suffering from tuberous sclerosis, which comprises administering to the patient an effective amount of a PDGF receptor tyrosine kinase inhibitor or a bcr-abl tyrosine kinase inhibitor.  
     
     
         12 . A method according to  claim 11  comprises administering an effective amount of an N-phenyl-2-pyrimidine-amine derivative of the formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is 4-pyrazinyl; 1-methyl-1H-pyrrolyl; amino- or amino-lower alkyl-substituted phenyl, wherein the amino group in each case is free, alkylated or acylated; 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom; or unsubstituted or lower alkyl—substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen;  
 R 2  and R 3  are each independently of the other hydrogen or lower alkyl;  
 one or two of the radicals R 4 , R 5 , R 6 , R 7  and R 8  are each nitro, fluoro-substituted lower alkoxy or a radical of formula II  
 —N(R 9 )—C(═X)—(Y) n —R 10    (II),  
 wherein  
 R 9  is hydrogen or lower alkyl,  
 X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,  
 Y is oxygen or the group NH,  
 n is 0 or 1 and  
 R 10  is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical,  
 and the remaining radicals R 4 , R 5 , R 6 , R 7  and R 8  are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         13 . A method according to  claim 12  wherein 
 one or two of the radicals R 4 , R 5 , R 6 , R 7  and R 8  are each nitro or a radical of formula II  
 wherein 
 R 9  is hydrogen or lower alkyl,  
 X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,  
 Y is oxygen or the group NH,  
 n is 0 or 1 and  
 R 10  is an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical,  
 
 and the remaining radicals R 4 , R 5 , R 6 , R 7  and R 8  are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . A method according to  claim 13  wherein 
 R 1  is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom,  
 R 2  and R 3  are each hydrogen,  
 R 4  is hydrogen or lower alkyl,  
 R 5  is hydrogen, lower alkyl or trifluoromethyl,  
 R 6  is hydrogen,  
 R 7  is nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein 
 R 9  is hydrogen,  
 X is oxo,  
 n is 0 and  
 R 10  is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C 5 -C 7 alkyl, thienyl, 2-naphthyl or cyclohexyl, and  
 
 R 8  is hydrogen,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . A method according to  claim 14  wherein 
 at least one of the radicals R 4  and R 8  is lower alkyl, and the remaining substituents are as defined in the respective generic claim, or a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . A method according to  claim 15 , wherein 
 R 1  is pyridyl bonded at a carbon atom,    R 2 , R 3 , R 5 , R 6  and R 8  are each hydrogen,    R 4  is lower alkyl,    R 7  a radical of formula II wherein 
 R 9  is hydrogen,  
 X is oxo,  
 n is 0 and  
 R 10  is 4-methyl-piperazinyl-methyl,  
   or a pharmaceutically acceptable salt thereof.    
     
     
         17 . A method according to  claim 11 , wherein N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-3-pyrimidine-amine or a pharmaceutically acceptable salt thereof, is administered.  
     
     
         18 . A method according to  claim 17 , wherein N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-3-pyrimidine-amine monomesylate salt is administered.  
     
     
         19 . A method according to  claim 11  wherein the monomethanesulfonate salt of N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-3-pyrimidine-amine is administered at a daily dose corresponding to 100 to 1000 mg of N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridinyl)-3-pyrimidine-amine free base.