Combinations of prostaglandins and brimonidine or derivatives thereof

Abstract

The invention concerns combinations of alpha adrenergic agents such as brimonidine and its derivatives as represented by formula (I) below wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R 1 ; R 1 is hydrogen, lower alkyl or oxo; R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates either a single or a double bond with the proviso that when n=1, both bonds from Y to C—R1 cannot be double bonds, and prostaglandins known in the art to cause lowering of intraocular pressure which are useful in compositions, methods of treatment and articles of manufacture for the treatment of glaucoma and alleviation of elevated intraocular pressure and providing neuroprotection.

Having now described the invention, what is claimed is:  
     
         1 . A topical ophthalmic composition useful for controlling elevated intraocular pressure associated with glaucoma and ocular hypertension while providing neuroprotection to the ocular nerves, comprising a combination of a therapeutically effective amount of a prostaglandin and a therapeutically effective amount of an alpha adrenergic agent of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R 1 ; R 1  is hydrogen, lower alkyl or oxo; R 2 , R 3  and R4 are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates a single or double bond, provided that two double bonds are not on the same carbon in the case when n=1, and their pharmaceutically acceptable salts and esters as appropriate.  
     
     
         2 . The composition of  claim 1  wherein the prostaglandin is selected from the group consisting of PGF 2α , PGE 2 , PGE 1 , prostacyclin, 15(S)-methyl-PGF 2α , 16,16-dimethyl-PGF 2α ,15(S)-methyl-PGE 2 ,16,16-dimethyl-PGE 2 ,17,18,19,20-tetranor-16-phenoxy-PGE2,17,18,19,20-tetranor-16-phenoxy-PGF 2α ,18,19,20-trinor-17-phenyl-PGE 2 ,18,19,20-trinor-17-phenyl-PGF 2α , the free acid and lower alkyl esters of PGF 2α , wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, trimoprostil, RS-84-135, rioprostil, S-1033 (15-deshydroxy PGF 2α , sodium salt), S-747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 118182, 13,14-dihydro-ZK 118182, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41 (latanoprost), RO-221327, HR-466, HR-601, ONO-1206, UFO-21, 11-deoxy-PGE 2 , 11-deoxy-PGF 2α , 11-deoxy-16,16-dimethyl-PGE 2 , 11-deoxy-15(S)-methyl-PGE 2 , 11-deoxy-15(S)-methyl-PGF 2α , misoprostol, enisoprost, MDL-646, CL-115,574, CL-115,347, TR4161, TR-4752, TR-4367, CP-27987, sulprostone, gemeprost, alfaprostol, delprostenate, prostalene, fenprostalene, CL-116,069, ONO-995 and RO-229648, and their pharmaceutically acceptable esters and salts, as appropriate.  
     
     
         3 . The composition of  claim 2  wherein the prostaglandin is selected from the group consisting of PGF 2α ,-11-pivalyl ester, the 1-amido-15-methyl ether of PGF 2α , 1-ethylamido-18,19,20-trinor-17-phenyl-PGF 2α , PGF 2α -1-ethyl ester, PGF 2α 1-isopropyl ester, the acid and isopropyl ester derivatives of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, as represented by the structure below:  
       
         
           
           
               
               
           
         
       
       R=H,  i -propyl,  
       RO-229648, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF 2α -1-methyl ester.  
     
     
         4 . The composition of  claim 1  wherein the alpha adrenergic agent is further selected from formula (I) to contain the groups of formula (II) wherein R2 is bromine or methyl and all other variables are defined as in  claim 1 .  
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 3  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         6 . The composition of  claim 4  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         7 . A method of treating a mammal suffering from glaucoma or ocular hypertension, comprising administering to the mammal a therapeutically effective amount of a prostaglandin and a therapeutically effective amount of an alpha adrenergic agent of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R 1 ; R 1  is hydrogen, lower alkyl or oxo; R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates either a single or a double bond, provided that two double bonds are not on the same carbon in the case when n=1, and their pharmaceutically acceptable salts and esters as appropriate.  
     
     
         8 . The method of  claim 7  wherein the prostaglandin is selected from the group consisting of PGF 2α , PGE 2 , PGE 1 , prostacyclin, 15(S)-methyl -PGF 2α , 16,16-dimethyl-PGF 2α , 15(S)-methyl-PGE 2 ,16,16-dimethyl-PGE 2 , 17,18,19,20-tetranor-16-phenoxy-PGE2, 17,18,19,20-tetranor-16-phenoxy-PGF 2α , 18,19,20-trinor-17-phenyl-PGE 2 , 18,19,20-trinor-17-phenyl-PGF 2α , the free acid and lower alkyl esters of PGF 2α wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, trimoprostil, RS-84-135, rioprostil, S-1033 (15-deshydroxy PGF 2α , sodium salt), S747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 118182, 13,14-dihydro-ZK 118182, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41 (latanoprost), RO-221327, HR-466, HR-601, ONO-1206, UFO-21, 11-deoxy-PGE 2 , 11-deoxy-PGF 2α , 11-deoxy-16,16-dimethyl-PGE 2 , 11-deoxy-15(S)-methyl-PGE 2 , 11-deoxy-15(S)-methyl-PGF 2α , misoprostol, enisoprost, MDL-646, CL-115,574, CL-115,347, TR-4161, TR-4752, TR-4367, CP-27987, sulprostone, gemeprost, alfaprostol, delprostenate, prostalene, fenprostalene, CL-116,069, ONO-995 and RO-229648, and their pharmaceutically acceptable esters and salts, as appropriate.  
     
     
         9 . The method of  claim 8  wherein the prostaglandin is selected from the group consisting of PGF 2α -11-pivalyl ester, the 1-amido-15-methyl ether of PGF 2α , 1-ethylamido-18,19,20-trinor-17-phenyl-PGF 2α , PGF 2α -1-ethyl ester, PGF 2α 1-isopropyl ester, the acid and isopropyl ester derivatives of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, as represented by the structure below:  
       
         
           
           
               
               
           
         
       
       R=H,  i -propyl,  
       RO-229648, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF 2α ,-1-methyl ester.  
     
     
         10 . The method of  claim 7  wherein the alpha adrenergic agent is further selected from formula (I) to contain the groups of formula (II) wherein R2 is bromine or methyl and all other variables are defined as in  claim 7 .  
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 9  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         12 . The method of  claim 10  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         13 . The method of  claim 7  wherein the prostaglandin is the 11-pivalyl ester of PGF 2α  and the alpha adrenergic agent is brimonidine.  
     
     
         14 . An article of manufacture comprising packaging material and a pharmaceutical combination of at least one alpha adrenergic agent and at least one prostaglandin and their pharmaceutically acceptable salts and esters as appropriate contained within said packaging material, wherein the pharmaceutical agents are effective in controlling elevated intraocular pressure associated with glaucoma and ocular hypertension and wherein the packaging material comprises a label which indicates that said combination can be used for control of elevated intraocular pressure or in treating glaucoma, and wherein said alpha adrenergic agent is represented by formula (I)  
       
         
           
           
               
               
           
         
       
       wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R 1 ; R 1  is hydrogen, lower alkyl or oxo; R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates a single or double bond, provided that two double bonds are not on the same carbon in the case when n=1.  
     
     
         15 . The article of  claim 14  wherein the prostaglandin is selected from the group consisting of PGF 2α , PGE 2 , PGE 1 , prostacyclin, 15(S)-methyl -PGF 2α , 16,16-dimethyl-PGF 2α , 15(S)-methyl-PGE 2 , 16,16-dimethyl-PGE 2 , 17,18,19,20-tetranor-16-phenoxy-PGE2, 17,18,19,20-tetranor-16-phenoxy-PGF 2α , 18,19,20-trinor-17-phenyl-PGE 2 , 18,19,20-trinor-17-phenyl-PGF 2α , the free acid and lower alkyl esters of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, trimoprostil, RS-84-135, rioprostil, S-1033 (15-deshydroxy PGF 2α , sodium salt), S-747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 118182, 13,14-dihydro-ZK 118182, ZK 110841,13,14-dihydro-ZK 110841, PhXA41 (latanoprost), RO-221327, HR-466, HR-601, ONO-1206, UFO-21, 11-deoxy-PGE 2 , 11-deoxy-PGF 2α , 11-deoxy-16,16-dimethyl-PGE 2 , 11-deoxy-15(S)-methyl-PGE 2 , 11-deoxy-15(S)-methyl -PGF 2α , misoprostol, enisoprost, MDL-646, CL-115,574, CL-115,347, TR-4161, TR-4752, TR-4367, CP-27987, sulprostone, gemeprost, alfaprostol, delprostenate, prostalene, fenprostalene, CL-116,069, ONO-995 and RO-229648, and their pharmaceutically acceptable esters and salts, as appropriate.  
     
     
         16 . The article of  claim 15  wherein the prostaglandin is selected from the group consisting of PGF 2α -11-pivalyl ester, the 1-amido-15-methyl ether of PGF 2α , 1-ethylamido-18,19,20-trinor-17-phenyl-PGF 2α , PGF 2α -1-ethyl ester, PGF 2α 1-isopropyl ester, the acid and isopropyl ester derivatives of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, as represented by the structure below:  
       
         
           
           
               
               
           
         
       
       R=H,  i -propyl,  
       RO-229648, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF 2α -1-methyl ester.  
     
     
         17 . The article of  claim 14  wherein the alpha adrenergic agent is further selected from formula (I) to contain the groups of formula (II) wherein R2 is bromine or methyl and all other variables are defined as in  claim 14 .  
       
         
           
           
               
               
           
         
       
     
     
         18 . The article of  claim 16  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamnine).  
     
     
         19 . The article of  claim 17  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         20 . The article of  claim 14  wherein the prostaglandin is the 11-pivalyl ester of PGF 2α  and the alpha adrenergic agent is brimonidine.  
     
     
         21 . A method of preventing degeneration of the optic nerve and providing protection of the retinal ganglion cells of a mammal suffering from glaucoma or ocular hypertension, comprising administering to the mammal a therapeutically effective amount of a prostaglandin and a therapeutically effective amount of an alpha adrenergic agent of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein each Y is independently selected from the group consisting of N, N—CH3, O, S and C—R 1 ; R 1  is hydrogen, lower alkyl or oxo; R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkenyl; n is an integer from 1 to 3; and a broken line beside a solid line indicates either a single or a double bond, provided that two double bonds are not on the same carbon in the case when n=1, and their pharmaceutically acceptable salts and esters as appropriate.  
     
     
         22 . The method of  claim 21  wherein the prostaglandin is selected from the group consisting of PGF 2α , PGE 2 , PGEL 1 , prostacyclin, 15(S)-methyl -PGF 2α , 16,16-dimethyl-PGF 2α , 15(S)-methyl-PGE 2 , 16,16-dimethyl-PGE 2 , 17,18,19,20-tetranor-16-phenoxy-PGE2, 17,18,19,20-tetranor-16-phenoxy-PGF 2α , 18,19,20-trinor-17-phenyl-PGE 2 , 18,19,20-trinor-17-phenyl-PGF 2α , the free acid and lower alkyl esters of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, trimoprostil, RS-84-135, rioprostil, S-1033 (15-deshydroxy PGF 2α , sodium salt), S-747260, nocloprost, CS-412, YPG-209, K-10134, cloprostenol, fluprostenol, luporstiol, etiproston, tiaprost, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 118182, 13,14-dihydro-ZK 118182, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41 (latanoprost), RO-221327, HR-466, HR-601, ONO-1206, UFO-21, 11-deoxy-PGE 2 , 11-deoxy-PGF 2α , 11-deoxy-16,16-dimethyl-PGE 2 , 11-deoxy-15(S)-methyl-PGE 2 , 11-deoxy-15(S)-methyl-PGF 2α , misoprostol, enisoprost, MDL-646, CL-115,574, CL-115,347, TR-4161, TR-4752, TR-4367, CP-27987, sulprostone, gemeprost, alfaprostol, delprostenate, prostalene, fenprostalene, CL-116,069, ONO-995 and RO-229648, and their pharmaceutically acceptable esters and salts, as appropriate.  
     
     
         23 . The method of  claim 22  wherein the prostaglandin is selected from the group consisting of PGF 2α -11-pivalyl ester, the 1-amido-15-methyl ether of PGF 2α , 1-ethylamido-18,19,20-trinor-l7-phenyl-PGF 2α , PGF 2α -1-ethyl ester, PGF 2α 1-isopropyl ester, the acid and isopropyl ester derivatives of PGF 2α  wherein the omega chain has been replaced with phenylethylsulfonamidomethyl-, as represented by the structure below:  
       
         
           
           
               
               
           
         
       
       R=H,  i -propyl,  
       RO-229648, SQ 27986, ZK 138519, 13,14-dihydro-ZK 138519, ZK 110841, 13,14-dihydro-ZK 110841, PhXA41, and 18,19,20-trinor-17-phenyl-PGF 2α -1-methyl ester.  
     
     
         24 . The method of  claim 21  wherein the alpha adrenergic agent is further selected from formula (I) to contain the groups of formula (II) wherein R2 is bromine or methyl and all other variables are defined as in  claim 21 .  
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 23  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine).  
     
     
         26 . The method of  claim 24  wherein the alpha adrenergic agent is brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinaminne).  
     
     
         27 . The method of  claim 21  wherein the prostaglandin is the 11-pivalyl ester of PGF 2α  and the alpha adrenergic agent is brimonidine.