Phthalazine Derivatives with Angiogenesis Inhibiting Activity

Abstract

The invention relates to new phthalazine derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof alone or in combination with one or more other pharmaceutically active compounds for the treatment of a disease, especially of a disease that responds to the inhibition of tyrosine kinases, more especially the inhibition of the vascular endothelial growth factor (VEGF) receptor kinase, preferably the treatment of a proliferative disease, such as a tumour disease.

1 . A compound of the formula I, 
     
       
         
         
             
             
         
       
       wherein
 r is 1 or 2, n is 0-3, 
 t is 0, 1 or 2, 
 R1 and R2 
 
       a) are independently in each case a lower alkyl; or 
       b) together form a bridge of subformula 1**, 
     
     
       
         
         
             
             
         
       
       wherein one or two of the ring members T 1 , T 2 , T 3  and T 4  are nitrogen, and the others are in each case CH, and the bond is achieved via atoms T 1  and T 4 ; 
       G is —C(═O)—, —CHF—, —CFr, lower alkylene, ˜6alkenylene, lower alkylene or C 3 -C 6 alkenylene substituted by acyloxy or hydroxy, —CH 2 O—, —CH 2 S—, —CH 2 —NH—, —CH 2 O—CH 2 , —CH 2 —S—CH 2 —, —CH 2 —NH—CH 2 —, oxa (—O—), thia (—S—), imino (—NH—), —CH 2 —O—CH 2 —, —CH 2 —S—CH 2 —, —CH 2 NH—CH 2 —, —(C(R 4 ) 2 ) t —S(O) p -(5-membered heteroaryl)-(C(R 4 ) 2 ) s —, —(C(R 4 ) 2 ) t —C(G 1 )(R 4 )(C(R 4 ) 2 ) s —, —O—CH 2 —, —S(O)—, —S(O 2 )—, —SCH 2 , —S(O)CH 2 —, —CH 2 S(O)— or —CH 2 S(O) 2 , wherein each of p, sand t, independently of the other, is 0, 1 or 2; R 4  is hydrogen, halogen or lower alkyl; and G 1  is —CN, —CO 2 R 3 , —CON(R 6 ) 2  or CH 2 N(R 6 ) 2 , wherein R 3  is hydrogen or lower alkyl and R 6  is hydrogen, alkyl, aryl or aryl-lower alkyl; 
       A, B, D, E and T are independents N or CH subject to the proviso that at least one and not more than three of these radicals are N; 
       Q is either lower alkoxy or O (oxo), with the proviso that if Q is lower alkoxy, the waved line representing the bonding of Q is a single bond and the ring carrying Q has three double bonds, and if Q is O, the waved line representing the bonding of Q is a double bond and for each Q=O, one of the double bonds in the ring is changed to a single bond; and with the proviso that any Q is bonded to a ring C atom; 
       Q′ is halogen, NHR Q , NR Q   2 , OR Q , SR Q , alkyl, aryl-alkyl, cycloalkyl-alkyl, perfluoroalkyl, acyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetaryl, wherein R Q  represents acyl, alkyl, or alkyl substituted by hydroxy, halogen, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; 
       R a  and R a ′ are each independently H, halogen or lower alkyl; 
       X is imino, oxa, or thia; 
       Y is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or unsubstituted or substituted cycloalkyl; and 
       with the proviso that when two groups R 6  are each alkyl and located on the same nitrogen atom, they may be linked by a bond, an O, an S or NR 3  with R 3  as defined above to form a N-containing heterocycle of 5 to 7 ring atoms; 
       or an N-oxide of a compound of formula I, wherein 1 or more N atoms carry an oxygen atom; 
       or a tautomer or mixture of tautomers of a compound of formula I or an N-oxide thereof; 
       or a pharmaceutically acceptable salt of a compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof. 
     
   
   
       2 . A compound of the formula I according to  claim 1 ,
 wherein   r is 1 or 2,   n is 0 to 3,   t is 0,   R1 and R2   a) are independents in each case a lower alkyl;   or b) together form a bridge of subformula 1 **,   wherein one or two of the ring members T 1 , T 2 , T 3  and T 4  are nitrogen, and the others are in each case CH, and the bond is achieved via atoms T 1  and T 4 ;   G is —C(═O)—, —CHF—, —CF 2 —, lower alkylene, C 2 -C 6 alkenylene, lower alkylene or C 3 -C 6 alkenylene substituted by acyloxy or hydroxy, —CH 2 —O—, —CH 2 —S—, —CH 2 NH—, —CH 2 —O—CH 2 —, —CH 2 S—CH 2 —, —CH 2 —NH—CH 2 —, oxa (—O—), thia (—S—), imino (—NH—), —CH 2 O—CH 2 —, —CH 2 S—CH 2 —, —CH 2 NH—CH 2 —, —(C(R 4 ) 2 ) t S(O) p -(5-membered heteroaryl)-(C(R 4 ) 2 ) s —, —(C(R 4 ) 2 ) t —C(G 1 )(R 4 )—(C(R 4 ) 2 ) s —, —O—CH 2 —, —S(O)—, —S(O 2 )—, —SCH 2 , —S(O)CH 2 —, —CH 2 S(O)— or —CH 2 S(O) 2 —, wherein each of p, s and t, independently of the other, is 0, 1 or 2; R 4  is hydrogen, halogen or lower alkyl; and G 1  is —CN, —CO 2 R 3 , —CON(R 6 ) 2  or CH 2 N(R 6 ) 2 , wherein R 3  is hydrogen or lower alkyl and R 6  is hydrogen, alkyl, aryl or aryl-lower alkyl;   A, B, D, E and T are independently N or CH subject to the proviso that at least one and not more than three of these radicals are N;   Q is either lower alkoxy or O (oxo), with the proviso that if Q is lower alkoxy, the waved line representing the bonding of Q is a single bond and the ring carrying Q has three double bonds, and if Q is O, the waved line representing the bonding of Q is a double bond and for each Q=O, one of the double bonds in the ring is changed to a single bond; and with the proviso that any Q is bonded to a ring C atom;   R a  and R a ′ are each independently H, halogen or lower alkyl;   X is imino, oxa, or thia;   Y is hydrogen, aryl, heteroaryl, or unsubstituted or substituted cycloalkyl; and   with the proviso that when two groups R 6  are each alkyl and located on the same nitrogen atom, they may be linked by a bond, an O, an S or NR 3  with R 3  as defined above b form a N-containing heterocycle of 5 to 7 ring atoms;   or an N-oxide of a compound of formula I, wherein 1 or more N atoms carry an oxygen atom;   or a tautomer or mixture of tautomers of a compound of formula I or an N-oxide thereof;   or a pharmaceutically acceptable salt of a compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof.   
   
   
       3 . A compound of formula I according to  claim 1 , wherein Q is O, with the proviso that the waved line representing the bonding of Q is a double bond and for each Q=O, one of the double bonds in the ring is changed to a single bond; and with the proviso that any Q is bonded to a ring C atom; and the other symbols have the meaning described in  claim 1 ; an N-oxide of said compound of formula I, wherein 1 or more N atoms carry an oxygen atom; or a tautomer or mixture of tautomers of said compound of formula I or an N-oxide thereof; or a pharmaceutically acceptable salt of said compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof. 
   
   
       4 . A compound of formula I according to  claim 1  wherein r is 1 and
 either T is NH, each of B, D and E is CH, A is C and Q is O bonded at A via a double bond, with the proviso that the double bond between A and T is absent;   or A is NH, each of B, D and E is CH and T is C and Q is O bonded at T via a double bond;   and the remaining radicals and symbols are as defined in each of  claims 1  to  5 ; or a tautomer or mixture of tautomers of said compound of formula I; or a pharmaceutically acceptable salt of said compound of formula I, or of a tautomer or mixture of tautomers thereof.   
   
   
       5 . A compound of formula I according to  claim 1  wherein r is 1 and
 A is NH, each of B, D and E is CH and T is C and Q is O bonded at T via a double bond;   and the remaining radicals and symbols are as defined in each of  claims 1  to  5 ; or a tautomer or mixture of tautomers of said compound of formula I; or a pharmaceutically acceptable salt of said compound of formula I, or of a tautomer or mixture of tautomers thereof.   
   
   
       6 . A compound of the formula I, an N-oxide thereof, a tautomer or mixture of tautomers of said compound of formula I or an N-oxide thereof; or a pharmaceutically acceptable salt of said compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof according to  claim 1  for use in the therapeutic or diagnostic treatment of the animal or human body. 
   
   
       7 . A pharmaceutical preparation comprising a compound of the formula I, an N-oxide thereof, a tautomer or mixture of tautomers of said compound of formula I or an N-oxide thereof; or a pharmaceutically acceptable salt of said compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof according to  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       8 . The use of a compound of the formula I, an N-oxide thereof, a tautomer or mixture of tautomers of said compound of formula I or an N-oxide thereof; or a pharmaceutically acceptable salt of said compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof according to  claim 1 , for the preparation of a pharmaceutical preparation for the treatment of VEGF receptor tyrosine kinase inhibiting activity, of cell proliferation, of inflammatory rheumatic or rheumatoid diseases, or pain. 
   
   
       9 . A method for treating a warm-blooded animal, including a human, in which an antitumourally effective dose of a compound of formula I, an N-oxide thereof, a tautomer or mixture of tautomers of said compound of formula I or an N-oxide thereof; or a pharmaceutically acceptable salt of said compound of formula I, of an N-oxide or of a tautomer or mixture of tautomers thereof according to  claim 1  is administered to a warm-blooded animal suffering from a tumour disease, of inflammatory rheumatic or rheumatoid diseases, or pain. 
   
   
       10 .- 15 . (canceled)