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 the tyrosine kinase inhibitor is a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is N; 
 Y is CR 1  or N; 
 R 1  is selected from the group consisting of hydrogen, alkyl, halogen, OR4, CN, NO 2 , COR 4 , (CH 2 ) a OR 4 , (CH 2 ) a N(R 4 ) 2 , C(O)N(R 4 ) 2  and N(R 4 ) 2 ; 
 R 2  is selected from the group consisting of hydrogen, halogen, alkyl, OR 4 , CN, NO 2 , SO 2 N(R 4 ) 2 , COR 4 , (CH 2 ) a OR 4 , (CH 2 ) a N(R 4 ) 2 , C(O)N(R 4 ) 2 , N(R 4 ) 2  and N(R 6 )(CR 7 R 8 ) a R 10 ; 
 R 3  is selected from the group consisting of hydrogen, halogen, alkyl, OR 4 , CN, NO 2 , SO 2 N(R 4 ) 2 , COR 4 , (CH 2 ) a OR 4 , (CH 2 ) a N(R 4 ) 2 , C(O)N(R 4 ) 2 , N(R 4 ) 2  and N(R 6 )(CR 7 R 8 ) a R 10 ; 
 R 4  is hydrogen or C 1  to C 4  alkyl; 
 A is selected from the group consisting of C≡C, CH═CH, CH 2 CH 2 , CH 2 O, CF 2 O, OCH 2 , OCF 2 , O, N(R 4 ), C(O), S(O) e , NR 7 C(O), C(O)NR 7  and N(R 7 )C(O)NR 7 ; 
 B is selected from the group consisting of hydrogen, alkyl and alkyloxyalkyl or B may be a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group; 
 E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl group; 
 E′ is selected from the group consisting of alkyl, CF 3 , 
 
         (CR 7 R 8 ) a C(O)OR 10 , (CR 7 R 8 ) a C(O)N(R 10 ) 2 , (CR 7 R 8 ) a C(O)N(OR 10 )(R 10 ), (CR 7 R 8 ) a (OR 10 ), (CR 7 R 8 ) a N(R 10 ) 2 , and (CR 7 R 8 ) a R 10 ; wherein R 7  and R 8  are selected from the group consisting of H, halogen, hydroxyl, and alkyl or CR 7 R 8  may represent a carbocyclic ring of from 3 to 6 carbons; 
         R 10  is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl, (CR 7 R 8 ) a C(O)OR 6 , (CR 7 R 8 ) a C(O)R 6 , (CR 7 R 8 ) a C(O)N(R 6 ) 2 , (CR 7 R 8 ) a C(O)N(OR 6 )(R 6 ), (CR 7 R 8 ) a (OR 6 ), (CR 7 R 8 ) a N(R 6 ) 2  and (CR 7 R 8 ) a R 6 , wherein R 6  is selected from the group consisting of hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R 6  is a 5 or 6 membered carbocyclic or heterocyclic group;
 a is 0 or an integer of from 1 to 5; 
 b is an integer of from 2 to 5; 
 c is 0 or an integer of from 1 to 4; 
 d is 0 or an integer of from 1 to 5; and 
 e is 0 or an integer of from 1 to 2. 
 
       
     
     
         2 . The method of  claim 1 , wherein said ocular condition is 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. 
     
     
         9 . The implant of  claim 1 , wherein said compound of Formula I is selected from the group consisting of:
 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid;   (S)—N-[(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}propyl)(oxido)phenyl-λ 4 -sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide; and   N-{[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl](oxido)phenyl-λ 4 -sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide; or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The implant of  claim 1 , wherein said implant is characterized by a porous structure wherein the pores are tubularly shaped. 
     
     
         11 . The implant of  claim 1 , wherein said polymeric matrix comprises R207. 
     
     
         12 . The implant of  claim 11 , wherein said polymeric matrix comprises 60%, by weight, R207 
     
     
         13 . The implant of  claim 12 , comprising 20%, by weight of a tyrosine kinase inhibitor. 
     
     
         14 . The method of  claim 1 , wherein said ocular condition is diabetic retinopathy. 
     
     
         15 . The method of  claim 14 , wherein the implant is placed in the posterior of the eye. 
     
     
         16 . The method of  claim 15 , wherein the implant is placed in the eye with a trocar. 
     
     
         17 . The method of  claim 15 , wherein the implant is placed in the eye with a syringe. 
     
     
         18 . The method of  claim 1 , wherein said ocular condition is a vascular disease. 
     
     
         19 . The method of  claim 18 , wherein said vascular disease is a vascular proliferative disorder or choroidal neovascularization.