Quinazoline compounds

Abstract

The invention concerns compounds of the formula (I): wherein ring A is phenyl or a 5- or 6-membered heterocyclic ring as defined herein; Z is —O—, —NH— or —S—; m is an integer from 0 to 5 inclusive; R 1 is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6 (wherein R 5 and R 6 , which may be the same or different, are hydrogen or C 1-3 alkyl); R 2 is hydrogen, hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, amino or nitro; R 3 is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; provided that when ring A is a 5- or 6-membered heterocyclic ring, at least one R 3 is either hydroxy or halogeno; X 1 is —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 —, —NR 7 CO—, —CONR 7 —, —SO 2 NR 7 — or —NR 7 SO 2 —, (wherein R 7 is hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); and R 4 is selected from a number of groups defined herein comprising an C 2-5 alkylene, C 3-5 alkenylene or C 3-5 alkynylene chain wherein each methylene group (other than that of the α-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C 1-4 alkanoyloxy; provisos are as defined herein. The invention also relates to pharmaceutical compositions comprising a compound of formula (I), to the use of a compound of formula (I) in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal and to a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment. The compounds are useful in disease states such as cancer, rheumatoid arthritis and psoriasis.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 ring A is a 5- or 6-membered heterocyclic ring which may be saturated, partially saturated or unsaturated and may be aromatic or non-aromatic and which contains 1, 2 or 3 ring heteroatoms selected from O, N and S;  
 Z is —O—, —NH— or —S—;  
 m is an integer from 0 to 5 inclusive;  
 R 1  is hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6  (wherein R 5  and R 6 , which may be the same or different, are hydrogen or C 1-3 alkyl);  
 R 2  is hydrogen, hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, amino or nitro;  
 R 3  is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; provided that when ring A is a 5- or 6-membered heterocyclic ring, at least one R 3  is either hydroxy or halogeno;  
 X 1  is —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 —, —NR 7 CO—, —CONR 7 —, —SO 2 NR 7 — or —NR 7 SO 2 —, (wherein R 7  is hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 R 4  is selected from one of the following groups: 
 1) —Y 1 X 2 COR 8  [wherein —Y 1 — is a C 2-5 alkylene chain wherein each methylene group (other than that of the α-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C 1-4 alkanoyloxy, provided that there is at least 1 and no more than 3 substituents on the C 2-5 alkylene chain; X 2  is —O— or —NR 9 — (in which R 9  is hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 8  is C 1-3 alkyl, —NR 10 R 11  or —OR 12  (wherein R 10 , R 11  and R 12 , which may be the same or different, are hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl)];  
 2) —Y 2 —X 3 R 13  [wherein Y 2 — is C 2-5 alkylene, C alkenylene or C 3-5 alkynylene wherein each methylene group (other than that of the α-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C 1-4 alkanoyloxy, provided that there is at least 1 substituent and no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; X 3  is —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 7 CO—, —CONR 7 —, —SO 2 NR 7 —, —NR 7 SO 2 — or —NR 7 — (wherein R 7  is as defined above) and R 13  is hydrogen or C 1-3 alkyl, wherein the C 1-3 alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy;  
 3) —Y 1 —X 6 C 1-5 alkylR 14  [wherein Y 1  is as defined above and X 6  is —O—, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 7 —, —SO 2 NR 7 —, —NR 7 SO 2 — or —NR 7 — (wherein R 7  is as defined above) and R 14  is C 3-7 cycloalkyl or a 3 to 7 membered saturated or partially saturated heterocyclic group containing up to 3 ring heteroatoms selected independently from O, S and N, wherein the carbocyclic or heterocyclic group is optionally substituted by one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, (wherein the C 1-4 alkyl group is optionally substituted by 1 or 2 substituents selected from hydroxy, cyano, halogeno, amino, nitro, morpholino, C 3-5 cycloalkyl, piperidin-1-yl and piperazin-1-yl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-3 alkylcarbamoyl,  N,N -di(C 1-3 alkyl)carbamoyl, C 2-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, C 2-4 alkanoylamino,  N —C 1-3 alkyl-C 2-4 alkanoylamino,  N —C 1-3 alkylsulphamoyl,  N,N -di-[C 1-3 alkyl]sulphamoyl, C 1-3 alkanesulphonylamino and  N —C 1-3 alkyl-C 1-3 alkanesulphonylamino, 
 or R 14  is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl,  N —C 1-3 alkylsulphamoyl,  N,N -di-[C 1-3 alkyl]sulphamoyl, C 1-3 alkanesulphonylamino,  N —C 1-3 alkyl-C 1-3 alkanesulphonylamino, —CONR10R 11  and —NR 10 COR 11  (wherein R 10  and R 11  are as defined above)];  
 4) —Y 1 —X 4 C 1-5 alkylX 5 R 15  [wherein Y 1  is as defined above and X 4  and X 5  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 7 —, —SO 2 NR 7 —, —NR 7 SO 2 — or —NR 7 —(wherein R 7 , is as defined above and R 15  is hydrogen or C 1-3 alkyl)]; .  
 5) —Y 1 —O—C 1-3 alkyl (wherein Y 1  is as defined above) provided that X 1  is —O—, —S—, —SO— or —SO 2 —;  
 6) —Y 2 —R 16  {wherein —Y 2 — is as defined above and R 16  is a saturated or partially saturated 3 to 7 membered heterocyclic ring containing up to 3 heteroatoms selected from O, S and N [wherein the heterocyclic ring is optionally substituted by up to 3 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-7 cycloalkyl (wherein C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-7 cycloalkyl are themselves optionally substituted by up to 3 substituents selected from hydroxy, halogeno, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, amino, nitro and R 14  as defined above), C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N—N -di(C 1-4 alkyl)carbamoyl, C 2-4 alkanoyl, C 1-4 alkoxycarbonyl, C 3-7 cycloalkyl, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, C 2-4 alkanoylamino,  N —C 1-3 alkyl-C 2-4 alkanoylamino,  N —C 1-3 alkylsulphamoyl,  N,N -di-[C 1-3 alkyl]sulphamoyl, C 1-3 alkanesulphonylamino and  N —C 1-3 alkyl- C 1-3 alkanesulphonylamino  
 or R 16  is a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group containing 1 to 3 ring heteroatoms independently selected from O, N and S, and wherein the pyridone, phenyl or heterocyclic group is optionally substituted by up to 5 substituents selected from halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl,  N —C 1-3 alkylsulphamoyl,  N,N -di-[C 1-3 alkyl]sulphamoyl, C 1-3 alkanesulphonylamino,  N —C 1-3 alkyl-C 1-3 alkanesulphonylamino, —CONR10R 11  and —NR 10 COR 11  (wherein R 10  and R 11  are as defined above)];  
 7) —Y 2 —X 6 —R 14  (wherein Y 2 , X 6  and R 14  are as defined above); and  
 8) —Y 2 —NR 17 R 18  [wherein Y 2  is as defined above and R 17  and R 18  are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-3 alkoxyC 1-6 alkyl (wherein any alkyl group in R 17  or R 18  is optionally substituted by up to 2 substituents selected from hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro)];  
 
 
 9) —Y 3 —R a  (wherein Y 3  is C 1-5 alkylene, C 2-5 alkenylene or C 2-5 alkynylene wherein each methylene group (other than that of the α-carbon) is optionally substituted by 1 substituent independently selected from hydroxy, halogeno, amino and C 1-4 alkanoyloxy, provided that there are no more than 3 substituents on the alkylene, alkenylene or alkynylene chain; and R a  is C 3-7 cycloalkyl which is substituted by 1 substituent selected from hydroxy, amino and halogeno on the ring carbon linked to y 3  and additionally optionally substituted by up to 3 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl,  N—N -di(C 1-4 alkyl)carbamoyl, C 2-4 alkanoyl, C 1-4 alkoxycarbonyl and C 3-7 cycloalkyl (wherein C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-7 cycloalkyl are themselves optionally substituted by up to 3 substituents selected from hydroxy, halogeno, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and R 14  as defined above)];  
 provided that when:  
 m is an integer from 1 to 3;  
 R 1  is methoxy; R 2  is hydrogen; Z is —NH—;  
 R 3  is halogeno or C 1-3 alkyl; and  
 X 1  is —O—; then  
 R 4  is not selected from one of the following three groups: 
 a) —C 2-5 alkylR 19  (wherein R 19  is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy);  
 b) —C 2-5 alkenylR 19  (wherein R 19  is as defined herein);  
 c) —C 2-5 alkynylR 19  (wherein R 19  is as defined herein);  
 wherein any alkylene, alkenylene or alkynylene chain in groups a) to c) above are optionally substituted by one or more substituents selected from hydroxy, halogeno and amino;  
 or a salt thereof.  
 
 
     
     
         2 . A compound according to  claim 1  wherein R 2  is hydrogen.  
     
     
         3 . A compound according to  claim 1  wherein R 1  is hydrogen or methoxy.  
     
     
         4 . A compound according to  claim 1  wherein ring A is pyridyl.  
     
     
         5 . A compound according to  claim 1  wherein R 3  is hydroxy, halogeno, C 1-2 alkyl, C 1-2 alkoxy, trifluoromethyl, cyano, amino or nitro.  
     
     
         6 . A compound according to  claim 1  wherein m is 2 or 3.  
     
     
         7 . A compound according to  claim 1  wherein X 1  is —O—, —S—, —NR 7 CO— or —NR 7 SO 2 —(wherein R 7  is hydrogen, methyl or ethyl).  
     
     
         8 . A compound according to  claim 1  wherein R 4  is of the formula —Y 2 —R 16 , —Y 2 —NR 17 R 18  or —Y 3 —R a  wherein Y 2 , Y 3 , R a , R 16 , R 17  and R 18  are as defined in  claim 1 .  
     
     
         9 . A compound according to  claim 1  wherein the alkylene, alkenylene or alkynylene chain in Y 1  or Y 2  in R 4  is substituted by hydroxy or acetoxy, wherein Y 1 , Y 2  and R 4  are as defined in  claim 1 .  
     
     
         10 . A compound according to  claim 1  in the form of a pharmaceutically acceptable salt.  
     
     
         11 . A process for the preparation of a compound of the formula (I) as defined in  claim 1  or a salt thereof which comprises: 
 (a) the reaction of a compound of the formula III:                           (wherein R 1 , R 2 , X 1  and R 4  are as defined in  claim 1  and L 1  is a displaceable moiety), with a compound of the formula IV:                           (wherein ring A, Z, R 3  and m are as defined in claim  1 );    (b) where the group of formula IIa:                           (wherein ring A, R 3  and m are as defined in  claim 1)  is a ring carrying one or more hydroxy groups, the deprotection of a compound of formula V:                           (wherein ring A, X 1 , m, R 1 , R 2 , R 3 , R 4  and Z are as defined in  claim 1 , P is a hydroxy protecting group and p 1  is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that m-p 1  is equal to the number of R 3  substituents which are not protected hydroxy);    (c) compounds of formula (I) and salts thereof wherein the substituent X 1  is —O—, —S— or —NR 7 — (wherein R 7  is as defined in  claim 1)  can be prepared by the reaction of a compound of the formula VI:                           (wherein ring A, m, X 1 , R 1 , R 2 , R 3 , and Z are as defined in  claim 1)  with a compound of formula VII:      R 4 -L 1   (VII)     (wherein R 4  is as defined in  claim 1  and L 1  is as defined herein);    (d) the reaction of a compound of the formula VIII:                           with a compound of the formula IX:      R 4 —X 1 —H  (IX)     (wherein ring A, R 1 , R 2 , R 3 , R 4 , Z, m and X 1  are all as defined in  claim 1  and L 1  is as defined herein);    e) compounds of the formula (I) and salts thereof wherein R 4  is a 2-hydroxypropyl chain substituted by —NR 17 R 18  (wherein R 17  and R 18  are as defined in  claim 1)  or a saturated or partially saturated heterocyclic ring containing and linked through a ring nitrogen atom and containing up to 2 additional ring heteroatoms selected from O, S and N, can be prepared by reacting a compound of the formula X:                           (wherein ring A, R 1 , R 2 , R 3 , Z, m and X 1  are all as defined in  claim 1)  with the appropriate amine and analagous reactions may be used to produce compounds of the formula (1) wherein R 4  comprises longer hydroxy-substituted alkylene, alkenylene or alkynylene chains;    f) compounds of the formula (I) and salts thereof wherein the group in R 4  linked to —Y 1 — or —Y 2 — is linked via a N, O or S atom may be prepared by reacting a compound of the formula (XI):                           (wherein ring A, X 1 , R 1 , R 2 , R 3 , Z and m are as defined in  claim 1 , L 1  is as defined herein and Q is —Y 1 — or —Y 2 — (wherein —Y 1 — or —Y 2 — are as defined in  claim 1)  with the appropriate compound containing a HN, HO or HS group;    and optionally preparing a pharmaceutically acceptable salt of a compound of the formula I reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt.    
     
     
         12 . A pharmaceutical composition which comprises a compound of the formula (I) as defined in any one of claims  1 - 6  and  7 - 9  or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.  
     
     
         13 . A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt.