Ophthalmic compositions for treating ocular hypertension

Abstract

This invention relates to potent potassium channel blocker compounds of Formula I or a formulation thereof for the treatment of glaucoma and other conditions which leads to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

1 . A compound of the structural formula I: 
       where 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof: wherein, 
         R represents hydrogen, or C 1-6  alkyl; 
         X represents —(CHR 7 ) p —, or —(CHR 7 ) p CO—; 
         Y represents —CO(CH 2 ) n —, (CH 2 ) n , —CH(OR)—, OR 6 , or SR 6 ; 
         Z=O or S; 
         M1, M2, and M3 are independently CH or N; 
         Q represents CR y , or N, provided that when Q is N then R 2  is not alkyl; 
         R y  represents H, C 1-6  alkyl, —(CH 2 ) n C 3-8  cycloalkyl, —(CH 2 ) n C 3-10  heterocyclyl, —(CH 2 ) n C 5-10  heteroaryl, or —(CH 2 ) n C 6-10  aryl; 
         R w  represents H, C 1-6  alkyl, —C(O)C 1-6  alkyl, —C(O)OC 1-6  alkyl, —SO 2 N(R) 2 , —SO 2 C 1-6  alkyl, —SO 2 C 6-10  aryl, NO 2 , CN or —C(O)N(R) 2 ; 
         R 2  represents hydrogen, C 1-10  alkyl, OH, C 2-6  alkenyl, C 1-6  alkylSR, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 1-6  alkoxy, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8  cycloalkyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8 cycloalkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10  heterocyclyl, —N(R) 2 , —COOR, or —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10  aryl, said alkyl, cycloalkyl, heterocyclyl, or aryl optionally substituted with 1-5 groups selected from R a , 
         R 3  represents hydrogen, C 1-10  alkyl, C 2-6  alkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8  cycloalkyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m cycloalkenyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10  heterocyclyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m COOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10  aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHR 8 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R) 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 ) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHCOOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 )CO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m N(R 8 )COR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m NHCOR, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONH(R 8 ), aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 1-6  alkoxy, CF 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m SO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m SO 2 N(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CON(R) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONHC(R) 3 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m CONHC(R) 2 CO 2 R, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m COR 8 , nitro, cyano or halogen, said alkyl, cycloalkyl, alkoxy, heterocyclyl, or aryl optionally substituted with 1-5 groups of R a ; 
         or, when Q equals CR y  or N, R 2  and R 3  taken together with the intervening CR y  or N form a 3-10 membered carbocyclic or heterocyclic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds, and optionally substituted by 1-3 groups selected from R a ; 
         R 4  and R 5  independently represent hydrogen, C 1-6  alkoxy, OH, C 1-6  alkyl, C 1-6  alkyl-S, C 1-6  alkyl-CO—, C 1-6  alkenyl, C 3-8  cycloalkoxy, C 3-8  cycloalkyl, C 3-8  cycloalkyl-S, C 3-8  cycloalkyl-CO—, COOR, SO 3 H, —O(CH 2 ) n N(R) 2 , —O(CH 2 ) n CO 2 R, —OPO(OH) 2 , CF 3 , —N(R) 2 , nitro, cyano, C 1-6  alkylamino, or halogen; 
         R 6  represents hydrogen, C 1-10  alkyl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10  aryl, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 5-10  heteroaryl, NR c R d , —NR—(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10  aryl, 
         —N—((CH 2 ) n (CHR 7 ) q (CH 2 ) m C 6-10  aryl) 2 , —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10  heterocyclyl, —NR—(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10  heterocyclyl, —N—((CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-10  heterocyclyl) 2  (C 6-10  aryl)O—, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m C 3-8  cycloalkyl, —COOR, —C(O)CO 2 R, said aryl, cycloalkyl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1-3 groups selected from R a ; 
         R c  and R d  independently represent H, C 1-6  alkyl, C 2-6  alkenyl, —(CH 2 ) n C 6-10  aryl, —(CH 2 ) n C 5-10  heteroaryl, C 1-6  alkylSR, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n C 1-6  alkoxy, or —(CH 2 ) n C 3-8  cycloalkyl; 
         or R c  and R d  taken together with the intervening N atom form a 4-10 membered heterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds, and optionally substituted by 1-3 groups selected from R a ; 
         R 7  represents hydrogen, C 1-6  alkyl, —(CH 2 ) n COOR or —(CH 2 ) n N(R) 2 , 
         R 8  represents —(CH 2 ) n C 3-8  cycloalkyl, —(CH 2 ) n 3-10  heterocyclyl, C 1-6  alkoxy or —(CH 2 ) n C 5-10  heteroaryl, —(CH 2 ) n C 6-10  aryl said cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups selected from R a ; 
         R a  represents F, Cl, Br, I, CF 3 , N(R) 2 , NO 2 , CN, —COR 8 , —CONHR 9 , —CON(R 8 ) 2 , —O(CH 2 ) n COOR, —NH(CH 2 ) n OR, —COOR, —OCF 3 , —NHCOR, —SO 2 R, —SO 2 NR 2 , —SR, (C 1 -C 6  alkyl)O—, —(CH 2 ) n O(CH 2 ) m OR, —(CH 2 ) n C 1-6  alkoxy, (aryl)O—, —OH, (C 1 -C 6  alkyl)S(O) m —, H 2 N—C(NH)—, (C 1 -C 6  alkyl)C(O)—, (C 1 -C 6  alkyl)OC(O)NH—, —(C 1 -C 6  alkyl)NR w (CH 2 ) n C 3-10  heterocyclyl-R w , —(C 1 -C 6  alkyl)O(CH 2 ) n C 3-10  heterocyclyl-R w , —(C 1 -C 6  alkyl)S(CH 2 ) n C 3-10  heterocyclyl-R w , —(C 1 -C 6  alkyl)-C 3-10  heterocyclyl-R w , —(CH 2 ) n -Z 1 -C(=Z 2 )N(R) 2 , —(C 2-6  alkenyl)NR w (CH 2 ) n C 3-10  heterocyclyl-R w , —(C 2-6  alkenyl)O(CH 2 ) n C 3-10  heterocyclyl-R w , —(C 2-6  alkenyl)S(CH 2 ) n C 3-10  heterocyclyl-R w , —(C 2-6  alkenyl)-C 3-10  heterocyclyl-R w , —(C 2-6  alkenyl)-Z 1 -C(=Z 2 )N(R) 2 , —(CH 2 ) n SO 2 R, —(CH 2 ) n SO 3 H, —(CH 2 ) n PO(OR) 2 , —(CH 2 ) n OH, —(CH 2 ) n (CHR 7 ) q (CH 2 ) m OPO(OR) 2 , C 3-10  cycloalkyl, C 6-10  aryl, C 3-10  heterocyclyl, C 2-6  alkenyl, and C 1 -C 10  alkyl, said alkyl, alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groups selected from C 1 -C 6  alkyl, CN, NO 2 , —(CH 2 ) n OH, —(CH 2 ) n OPO(OR) 2 , CON(R) 2  and COOR; 
         Z 1  and Z 2  independently represents NR w , O, CH 2 , or S; 
         m is 0-3; 
         n is 0-3; 
         p is 0-3 and 
         q is 0-1. 
       
     
     
         2 . A compound according to  claim 1  wherein Q is —N— and Y is —CO(CH 2 ) n . 
     
     
         3 . A compound according to  claim 2  wherein n=0, Z is S, and R 6  is C 1-6  alkyl, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, (CH 2 ) n C 3-10  heterocyclyl, NR c R d  or (CH 2 ) n C 3-8  cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         4 . A compound according to  claim 3  wherein M1, M2 and M3 are CH, X is —(CHR 7 ) p CO—, p is 1-3, R 2  is C 1-10  alkyl or C 1-6  alkylOH and R 3  is (CH 2 ) n C 3-10  heterocyclyl, said heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         5 . A compound according to  claim 1  wherein Q is —CRy, n=0, Z is S, and R 6  is C 1-6  alkyl, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, (CH 2 ) n C 3-10  heterocyclyl, NR c R d  or (CH 2 ) n C 3-8  cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         6 . A compound according to  claim 2  wherein n=0, Z is O, and R 6  is C 1-6  alkyl, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, (CH 2 ) n C 3-10  heterocyclyl, NR c R d  or (CH 2 ) n C 3-8  cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         7 . A compound according to  claim 6  wherein M1, M2 and M3 are CH, X is —(CHR 7 ) p CO—, p is 1-3, R 2  is C 1-10  alkyl or C 1-6  alkylOH and R 3  is (CH 2 ) n C 3-10  heterocyclyl, said heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         8 . A compound according to  claim 1  wherein Q is —CRy, n=0, Z is O, and R 6  is C 1-6  alkyl, (CH 2 ) n C 6-10  aryl, (CH 2 ) n C 5-10  heteroaryl, (CH 2 ) n C 3-10  heterocyclyl, NR c R d  or (CH 2 ) n C 3-8  cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyl optionally substituted with 1 to 3 groups of R a . 
     
     
         9 . A compound according to  claim 1  wherein Q equals —CRy, or N, R 2  and R 3  taken together with the intervening CRy or N form a 3-10 membered carbocyclic or heterocyclic ring or fused ring optionally interrupted by 1-2 atoms of O, S, C(O), or NR and optionally having 1-5 double bonds, and optionally substituted with 1 to 3 groups of R a . 
     
     
         10 . A compound according to  claim 1  where a free hydroxyl group is present, said hydroxyl group optionally derivatized to give a phosphate group represented as —OPO(OH) 2 . 
     
     
         11 . A compound which is:
 or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.   
     
     
         12 . A method for the treatment ocular hypertension or glaucoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of structural formula I of  claim 1 . 
     
     
         13 . A method for the treatment of macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administering to a patient in need thereof a therapeutically effective amount of a compound of structural formula I of  claim 1 . 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A composition comprising a compound of formula I of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition according to  claim 16  wherein the compound of formula I is applied as a topical formulation, said topical formulation administered as a solution or suspension and optionally contains xanthan gum or gellan gum. 
     
     
         18 . A composition according to  claim 17  wherein one or more of an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympatho-mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof, hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist is optionally added. 
     
     
         19 . A composition according to  claim 18  wherein the β-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathomimetic agent is epinephrine, brimonidine, iopidine, clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S1033, the hypotensive lipid is lumigan, the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is 1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.