Patent EA-001681-B1 (EA)
Title: Method for treating and/or preventing macular edemaand age-relatedmacular degeneration
Inventor: HARRIS ALON
IPC: C07D495/04
Filed: 1997-02-25
Abstract: 1. An ophthalmic composition for treating or preventing macular edema or treating or preventing age-related macular degeneration by topical application which comprises an effective amount of a topical carbonic anhydrase inhibitor and an ophthalmically acceptable carrier. 2. The composition according to Claim 1 wherein the carbonic anhydrase inhibitor comprises dorzolarnide, acetazolamide and methazolamide. 3. The composition according to Claim 2 wherein the carbonic anhydrase inhibitor is dorzolamide. 4. The composition according to Claim 1 wherein the carbonic anhydrase inhibitor is a compound of the formula   wherein A together with the two carbon atoms denoted as .alpha. and .beta. is the group   or wherein: X is -S-, -SO-, -SO2- or -CH2-; Y is -S-, -O-, or -NR<3>- wherein R<3> is hydrogen, C1-3 alkyl, or benzyl; n is 1 or 2; R<1>, R<2>, R<3>, R<4> are independently selected from: 1) hydrogen, 2) OR<5> wherein R<5> is: a) hydrogen, b) C1-5 alkyl, either unsubstituted or substituted with -OH, or   wherein R<6> and R<1> are independently hydrogen or C1-5 alkyl, or joined together form a heterocycle with the nitrogen to which they are attached such as piperidino, morpholino, or piperazino. c) C1-5 alkanoyl, either unsubstituted or substituted with -OH, NR<6>R<7>. -NH-COR<8> or -COR<8> wherein R<8> is -OH, -NR<6>R<7> or C1-5 alkoxy, d) -CO-R<9>, wherein R<9> is -NR<6>R<7> or a 5- or 6-membered aromatic heterocycle such as pyridyl, imidazolyl, pyrazinyl, thiazolyl, thienyl, or oxazolyl, 3) -NR<6>R<7>, 4) -NHR<10> wherein R<10> is: a) -SO2NR<6>R<7>, b) -SO2R<11>, wherein R<11> is C C1-5 alkyl, or c) -CONR<6>R<7>, 5) C C1-5 alkyl, either unsubstituted or substituted with a) -OR<5>, b) -CN, c) -NR<6>R<7>, or d) -COR<8>, 6) -SO2R<11>, 7) -SO2NR<6>R<7>, or 8) -halo, such as chloro, bromo or fluoro; R<1> and R<3>, or R<2> and R<4> taken together represent a double bond; R<1> and R<2>, or R<3> and R<4> taken together represent 1) =O, or 2) =NOR<12> wherein R<12> is hydrogen or C1-3alkyl; and one of the -CH2-groups of -(CH2)n- can be substituted with -COR<8>, -CH2R<8>, or -CH2COR<8>; or a pharmaceutically acceptable salt thereof. 5. The composition according to Claim 1 wherein the carbonic anhydrase inhibitor is a compound of the formula   or a pharmaceutically acceptable salt thereof wherein: R1 is H: C1-4 alkyl; C2-4 alkyl substituted optionally with OH,. halogen. C1-4 alkoxy or C(=O)R1; R2 is H; C1-8 alkyl; C2-8 alkyl substituted with OH, NR5R6, halogen, C1-4 a lkoxy or C(=O)R7; C3-7 alkenyl unsubstituted or substituted optionally with OH, NR5R6, or C1-4 alkoxy; C3-7 alkynyl unsubstituted or substituted optionally with OH, NR5R6, or C1-4 alkoxy; C1-3 alkyl substituted with phenyl or heteroaryl which can be unsubstituted or substituted optionally with OH, C(H2)n NR5R6, halogen, C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R7, S(=O)m R8 or SO2 NR5R6, wherein m is 0-2 and n is 0-2; C2-4 alkoxy substituted optionally with NR5R6, halogen, C1-4 alkoxy, o r C(=O)R7; phenyl, or heteroaryl, unsubstituted or substituted optionally with OH, (CH2)n NR5R6, halogen. C1-4 alkoxy, C1-4 haloalkoxy, C(=O)R7, S(=O)m R8 or SO2 NR5R6, wherein m is 0-2 and n is 0-2; provided that R1 and R2 cannot both be H; or R1 and R2, can be joined to form a saturated ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, NR<5>R<6>, halogen, C1-4alkoxy, C(=O)R<7>, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, NR5R6, halogen, C1-4 alkoxy, C(=O)R7 or on nitrogen with NR5R6, C1-4 alkoxy, C(=O)R7,C1-6 alkyl or C2-6 alkyl substituted optionally with OH, NR5R6, halogen, C1-4 alkoxy or C(=O)R7; R<3> is H; halogen; C1-4 alkyl; C1-8 alkoxy; C1-8 alkylthiol; C2-8 alkoxy sub stituted optionally with OH, NR5R6, halogen, C1-4 alkoxy or C(=O)R7; C1-4 alkyl substituted optionally with R4; or R1 and R3 can be joined together with carbon atoms to form a ring of from 5 to 7 members in which said carbon atoms can be unsubstituted or substituted optionally with R4; R<4> is OH; C1-4 alkyl unsubstituted or substituted optionally with OH, NR5R6 halogen. C1-4 alkoxy or C(=O)R7; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH. NR5R6, halogen, C1-4 alkoxy or C(=O)R7, NR5R6 phenyl, or heteroaryl, unsubstituted or substituted optionally with OH, (CH2)n NR5R6, halogen, C1-4 alkoxy, C1-4 haloalkyoxy C(=O)R<7>, S(=O)m R<8> or SO2NR<5>R<6>, wherein m is 0-2 and n is 0-2; provided that when R<3> is in the 4 position and is H or halogen then R<1> and R<2> are not H, C1-6 alkyl substituted optionally with OH. C1-6 alkoxy, C2-6 alkoxycarbonyl, nor are they joined to form a 5,6 or 7 member ring, saturated or unsaturated, comprised of atoms selected optionally from C, O, S, N in which said nitrogen, when saturated is substituted optionally with H or C1-6 alkyl or in which said carbon is substituted optionally with C1-6 alkyl, C1-6 alkoxy or OH and when R3 is in the 5 position and is H, Cl, Br, or C1-3 alkyl then neither R1 nor R2 can be H or C1-4 alkyl; R5 and R6 are the same or different and are H; C1-4 alkyl; C2-4 alkyl substitute d optionally with OH, halogen, C1-4 alkoxy or C(=O)R7; C1-4 alkoxy; C2-4 alkoxy substituted optionally with OH, halogen; C1-4 alkoxy or C(=O)R7; C3-7 alkenyl unsubstituted or substituted optionally with OH; NR5R6, or C1-4alkoxy; C3-7alkynyl unsubstituted or substituted optionally with OH, NR5R6, or C1-4alkoxy; C1-2 alkyl; C1-3 cycloalkyl or R5 and R6 can be joined to form a ring of 5 or 6 atoms selected from O, S, C or N which can be unsubstituted or substituted optionally on carbon with OH, (=O), halogen. C1-4; alkoxy, C(=O)R7, C1-6 alkyl, C1-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R7 or on nitrogen with C1-4 alkoxy, C(=O)R7 S(=O)mR8, C1-6 alkyl or C2-6 alkyl substituted optionally with OH, halogen, C1-4 alkoxy, C(=O)R7 or on sulfur by (=O)m wherein in is 0-2; R7 is C1-8 alkyl; C1-8 alkyl substituted optionally with OH, NR5R6, halogen , C1-4 alkoxy or C(=O)R9, C1-4alkoxy; C2-4 alkoxy substituted optionally with OH, NR5R6, halogen or C1-4 alkoxy; or NR5R6; R8 is C1-4 alkyl; C2-4 alkyl substituted optionally with OH, NR5R6, halogen , C1-4 alkoxy or C(=O)R7; R9 is C1-4 alkyl; C1-4 alkoxy amino, C1-3 alkylamino, or di-C1 3 alkylamin o; and G is C(=O) or SO2. 6. The composition according to Claim 3 wherein the carbonic anhydrase inhibitor is selected from a compound of the formula   or   wherein R is selected from -CH2CH3 or -CH2CH2CH3 and R<1> is selected from CH3O(CH2)2-4 or a pharmaceutically acceptable salt thereof. 7. The composition according to Claim 1 wherein the carbonic anhydrase inhibitor is administered as a 0.01 to 5% solution in an ophthahnologically acceptable carrier. 8. The composition according to Claim 7 wherein the carbonic anhydrase inhibitor is administered as a 0.5 to 2% solution in an ophthahnologically acceptable carrier. 9. The composition according to Claim 7 wherein the carbonic anhydrase inhibitor is administered twice daily. 10. The composition according to Claim 7 wherein the carbonic anhydrase inhibitor is administered three times daily.