Kinase inhibitors

Abstract

The present invention relates to drug delivery systems comprising ocular implant, which include organic molecules, capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation, in combination with a polymer, which polymer serves to control, modify, modulate and/or slow the release of the therapeutic component into the environment of the eye in which said composite is placed.

1 . A method of treating an ocular condition of an eye of a patient, comprising the step of placing a biodegradable intraocular implant in an eye of the patient, the implant comprising a tyrosine kinase inhibitor and a biodegradable polymer matrix, wherein the implant degrades at a rate effective to sustain release of an amount of the tyrosine kinase inhibitor from the implant effective to treat the ocular condition and wherein said tyrosine kinase inhibitor is a compound represented by the following general formula: 
       
         
           
           
               
               
           
         
         wherein X is O; 
         Y is [C(R 2 ) 2 ] c ; 
         R 1  is selected from the group consisting of halogen, aryl, C 1  to C 8  alkyl, CF 3 , OCF 3 , OCF 2 H, S(O) f R 2 , (CR 3 R 4 ) d C(O)OR 2 , O(CR 3 R 4 ) e C(O)OR 2 , 
         NR 2 (CR 3 R 4 ) d C(O)R 2 , NR 2 (CR 3 R 4 ) d C(O)OR 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, NR 2 (CH 2 ) e N(R 2 ) 2 , O(CH 2 ) e N(R 2 ) 2 , (CR 3 R 4 ) d CN, O(CR 3 R 4 ) e CN, (CR 3 R 4 ) d Ar, NR 2 (CR 3 R 4 ) d Ar, O(CR 3 R 4 ) d Ar, S(O) f (CR 3 R 4 ) d Ar, (CR 3 R 4 ) d SO 2 R 2 , (CR 3 R 4 ) d C(O)N(R 2 ) 2 , NR 2 (CR 3 R 4 ) d C(O)N(R 2 ) 2 , O(CR 3 R 4 ) d C(O)N(R 2 ) 2 , S(O) f (CR 3 R 4 ) e C(O)N(R 2 ) 2 , (CR 3 R 4 ) d OR 2 , NR 2 (CR 3 R 4 ) e OR 2 , O(CR 3 R 4 ) e OR 2 , S(O) f (CR 3 R 4 ) d OR 2 , C(O)(CR 3 R 4 ) d R 3 , NR 2 C(O)(CR 3 R 4 ) d R 3 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , C(O)(CR 3 R 4 ) d N(R 2 ) 2′ NR 2 C(O)(CR 3 R 4 ) d N(R 2 ) 2 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d R 3 , NR 2 (CR 3 R 4 ) d R 3 , O(CR 3 R 4 ) d R 3 , S(O) f (CR 3 R 4 ) d R 3 , (CR 3 R 4 ) d N(R 2 ) 2 , NR 2 (CR 3 R 4 ) e N(R 2 ) 2 , O(CR 3 R 4 ) e N(R 2 ) 2 , S(O) f (CR 3 R 4 ) d N(R 2 ) 2 , N(R 5 ) 2 , OR 5 , C(O)R 5 , S(O) f R 5 ; 
         R 2  is selected from the group consisting of hydrogen, C 1  to C 8  alkyl, C 1  to C 8  alkenyl, C 1  to C 8  alkynyl, C 1  to C 4  alkylol, lower alkylphenyl, phenyl, (CR 3 R 4 ) d Ar, (CR 3 R 4 ) d C(O)OR 2 , (CR 3 R 4 ) d SO 2 R 2 , (CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d OSO 2 R, (CR 3 R 4 ) d P(O)(OR 2 ) 2 , (CR 3 R 4 ) d R 2 , (CR 3 R 4 ) e N(R 2 ) 2 , (CR 3 R 4 ) e NR 2 C(O)N(R 2 ) 2 ; 
         N(R 2 ) 2  may form a 3-7 membered heterocyclic ring, for example, pyrrolidine, 3-fluoropyrrolidine, piperidine, 4-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine. Said heterocyclic ring may be substituted with one or more of R 3 ; 
         [C(R 2 ) 2 ] c  may form a 3-7 membered carbocyclic or heterocyclic ring; 
         R is selected from the group consisting of halogen, C 1  to C 8  alkyl, CF 3 , OCF 3 , OCF 2 H, (CR 3 R 4 ) d CN, NR 2 (CR 3 R 4 ) e CN, O(CR 3 R 4 ) e CN, S(O) f R 2 , (CR 3 R 4 ) d C(O)OR 2 , NR 2 (CR 3 R 4 ) d C(O)OR 2 , O(CR 3 R 4 ) d C(O)OR 2 , S(O) f (CR 3 R 4 ) d C(O)OR 2 , (CR 3 R 4 ) d Ar, NR 2 (CR 3 R 4 ) d Ar, O(CR 3 R 4 ) d Ar, S(O) f (CR 3 R 4 ) d Ar, (CR 3 R 4 ) d SO 2 R 2 , NR 2 (CR 3 R 4 ) d S(O) f R 2 , 
         O(CR 3 R 4 ) d S(O) f R 2 , S(O) f (CR 3 R 4 ) e S(O) f R 2 , (CR 3 R 4 ) d C(O)N(R 2 ) 2 , NR 2 (CR 3 R 4 ) d C(O)N(R 2 ) 2 , O(CR 3 R 4 ) d C(O)N(R 2 ) 2 , S(O) f (CR 3 R 4 ) e C(O)N(R 2 ) 2 , (CR 3 R 4 ) d OR 2 , NR 2 (CR 3 R 4 ) e OR 2 , O(CR 3 R 4 ) e OR 2 , S(O) f (CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d OSO 2 R 2 , NR 2 (CR 3 R 4 ) e OSO 2 R 2 , O(CR 3 R 4 ) e OSO 2 R 2 , S(O) f (CR 3 R 4 ) e OSO 2 R 2 (CR 3 R 4 ) d P(O)(OR 2 ) 2 , NR 2 (CR 3 R 4 ) d P(O)(OR 2 ) 2 , O(CR 3 R 4 ) d P(O)(OR 2 ) 2 , S(O) f (CR 3 R 4 ) e P(O)(OR 2 ) 2 , C(O)(CR 3 R 4 ) d R 3 , NR 2 C(O)(CR 3 R 4 ) d R 3 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , C(O)(CR 3 R 4 ) d N(R 2 ) 2 , NR 2 C(O)(CR 3 R 4 ) d N(R 2 ) 2 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d R 3 , NR 2 (CR 3 R 4 ) d R 3 , O(CR 3 R 4 ) d R 3 , S(O) f (CR 3 R 4 ) d R 3 , HNC(O)R 2 , HN—C(O)OR 2 , (CR 3 R 4 ) d N(R 2 ) 2 , NR 2 (CR 3 R 4 ) e N(R 2 ) 2 , O(CR 3 R 4 ) e N(R 2 ) 2 , S(O) f (CR 3 R 4 ) d N(R 2 ) 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, HN—CH═CH, —N(COR 2 )CH 2 CH 2 , HC═N—NH, N═CH—S, (CR 3 R 4 ) d C═C(CR 3 R 4 ) d R 2 , (CR 3 R 4 ) d C═C(CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d C═C(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d CC(CR 3 R 4 ) d R 2 , 
         (CR 3 R 4 ) d CC(CR 3 R 4 ) e OR 2 , (CR 3 R 4 ) d CC(CR 3 R 4 ) e N(R 2 ) 2 , (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d R 2 , 
         (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d N(R 2 ) 2 , 
         R 3  and R 4  may be selected from the group consisting of H, F, hydroxy, and C 1 -C 4  alkyl or CR 3 R 4  may represent a carbocyclic or heterocyclic ring of from 3 to 6 carbons, alternatively (CR 3 R 4 ) d  and (CR 3 R 4 ) e  may form a 3-7 membered carbocyclic or heterocyclic ring, preferably R 3  and R 4  are H, F, CH 3  or hydroxy; 
         R 5  is Ar—R 1   b    
         R 6  is selected from hydrogen, C 1 -C 8  alkyl, hydroxylmethyl and phenyl; 
         b is 0 or an integer of from 1 to 2; 
         a is 0 or an integer of from 1 to 3; 
         c is an integer of from 1 to 2; 
         d is 0 or an integer of from 1 to 5; 
         e is an integer of from 1 to 4; 
         f is 0 or an integer of from 1 to 2, and further provided said alkyl or aryl radicals may be substituted with one or two halo, hydroxy, lower alkyloxy, lower alkyl amino or cycloalkylamino radicals wherein the cycloalkyl ring can include an enchained oxygen, sulfur or additional nitrogen atom and may be substituted with one or two halo or lower alkyl radicals; 
       
       and pharmaceutically acceptable salts thereof. 
     
     
         2 . The method of  claim 1 , wherein the method is effective to treat a retinal ocular condition. 
     
     
         3 . The method of  claim 1 , wherein the ocular condition is glaucoma. 
     
     
         4 . The method of  claim 1 , wherein the ocular condition is proliferative vitreoretinopathy. 
     
     
         5 . The method of  claim 1 , wherein the implant is placed in the posterior of the eye. 
     
     
         6 . The method of  claim 1 , wherein the implant is placed in the eye with a trocar. 
     
     
         7 . The method of  claim 1 , wherein the implant is placed in the eye with a syringe. 
     
     
         8 . The method of  claim 1 , further comprising a step of administering a therapeutic agent in addition to the tyrosine kinase inhibitor to the patient.