Pyrrolidine derivatives for vision and memory disorders

Abstract

This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using pyrrolidine derivatives.

We claim;  
     
         1 . A method for treating a vision disorder, improving vision in an animal, treating age related memory impairment or enhancing memory performance, which comprises administering to said animal an effective amount of a pyrrolidine derivative.  
     
     
         2 . The method of    claim 1   , wherein the pyrrolidine derivative is immunosuppressive or non-immunosuppressive.  
     
     
         3 . The method of    claim 1   , wherein the pyrrolidine derivative has an affinity for an FKBP-type immunophilin.  
     
     
         4 . The method of    claim 3   , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         5 . The method of    claim 1   , wherein the vision disorder is selected from the group consisting of visual impairments; orbital disorders; disorders of the lacrimal apparatus; disorders of the eyelids; disorders of the conjunctiva; disorders of the cornea; cataracts; disorders of the uveal tract; disorders of the retina; disorders of the optic nerve or visual pathways; free radical induced eye disorders and diseases; immunologically-mediated eye disorders and diseases; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injury.  
     
     
         6 . The method of    claim 1   , which is improving naturally-occuring vision in an animal, in the absence of any ophthalmologic disorder, disease, or injury.  
     
     
         7 . The method of    claim 1   , wherein the pyrrolidine derivative is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino;  
 X is O, S, CH 2  or H 2 ;  
 Y is O, or NR 2  or a direct bond; and  
 Z is AR 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         8 . The method of    claim 7   , wherein Z and R 1  are lipophilic.  
     
     
         9 . The method of    claim 7   , wherein the compound is selected from the group consisting of: 
 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-prop-2-(E)-enyl (2S)-1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (3,4,5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S) -1-3,3 - dimethyl-1-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3 -dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-cyclohexyl-1-propyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-cyclohexyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    (1R) -1,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1,3-diphenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;    1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         10 . The method of    claim 1   , wherein the pyrrolidine derivative is a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is C 1 -C 9  straight or branched chain alky, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         11 . The method of    claim 10   , wherein R 1  is selected from the group consisting of C 1 -C 9  straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.  
     
     
         12 . The method of    claim 10   , wherein Z and R 1  are lipophilic.  
     
     
         13 . The method of    claim 1   , wherein the pyrrolidine derivative is a compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate or hydrate thereof, wherein: 
 Z′ is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl or unsubstituted Ar 1 , wherein said alkyl is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl;  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl; and  
 Ar 1  is as defined in    claim 10   .  
 
     
     
         14 . The method of    claim 13   , wherein Z′ is lipophilic.  
     
     
         15 . The method of    claim 1   , wherein the pyrrolidine derivative is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 3 -C 6  cycloalkyl or Ar 1 , wherein said alkyl or alkenyl is unsubstituted or substituted with C 3 -C 6  cycloalkyl or Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;  
 X is O, S, CH 2 , or H;  
 Y is oxygen;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl Z is substituted with one or more substituent(s) independently selected from the group consisting of 2-furyl, 2-thienyl, C 3 -C 6  cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C 1 -C 4  alkoxy.  
 
     
     
         16 . The method of    claim 15   , wherein Z and R 1  are lipophilic.  
     
     
         17 . The method of    claim 15   , wherein the compound is selected from the group consisting of: 
 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dloxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl] glyoxyl)pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S) -1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2) -1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         18 . The method of    claim 15   , wherein the compound is selected from the group consisting of: 
 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         19 . The method of    claim 17   , wherein the compound is 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         20 . The method of    claim 1   , wherein the pyrrolidine derivative is an N-glyoxyl prolyl ester.  
     
     
         21 . The method of    claim 1   , wherein the pyrrolidine derivative is a compound of formula V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is O, N, or S;  
 A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR;  
 R is either C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 , wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxyl, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 ;  
 R 1  is C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;  
 X is O, S, CH 2  or H 2 ;  
 Y is O or NR 2 , or a direct bond;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substiuent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstitued or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         22 . The method of    claim 1   , wherein the pyrrolidine derivative is administered to said animal in combination with an effective amount of one or more factor(s) useful in treating vision disorders, improving vision, treating memory impairment, or enhancing memory performance in an animal.  
     
     
         23 . The method of    claim 22   , wherein the one or more factor(s) is/are selected from the group consisting of immunosuppressants for treating autoimmune, inflammatory, and immunologically-mediated disorders; wound healing agents for treating wounds resulting from injury or surgery; antiglaucomatous medications for treating abnormally elevated intraocular pressure; neurotrophic factors and growth factors for treating neurodegenerative disorders or stimulating neurite outgrowth; compounds effective in limiting or preventing hemorrhage or neovascularization for treating macular degeneration; and antioxidants for treating oxidative damage to eye tissues.  
     
     
         24 . A pharmaceutical composition which comprises: 
 (i) an effective amount of a pyrrolidine derivative for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         25 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is immunosuppressive or non-immunosuppressive.  
     
     
         26 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative has an affinity for an FKBP-type immunophilin.  
     
     
         27 . The pharmaceutical composition of    claim 26   , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         28 . The pharmaceutical composition of    claim 24   , wherein the vision disorder is selected from the group consisting of visual impairments; orbital disorders; disorders of the lacrimal apparatus; disorders of the eyelids; disorders of the conjunctiva; disorders of the cornea; cataracts; disorders of the uveal tract; disorders of the retina; disorders of the optic nerve or visual pathways; free radical induced eye disorders and diseases; immunologically-mediated diseases; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injury.  
     
     
         29 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino;  
 X is O, S, CH 2  or H 2 ;  
 Y is O, or NR 2  or a direct bond;  
 Z is AR 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         30 . The pharmaceutical composition of    claim 29   , wherein Z and R 1  are lipophilic.  
     
     
         31 . The pharmaceutical composition of    claim 29   , wherein the compound is selected from the group consisting of: 
 3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-prop-2-(E)-enyl (2S)-1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (3,4,5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S) -1-3,3 - dimethyl-1-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3 -dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3- (4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-cyclohexyl-1-propyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    3-cyclohexyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;    (1R) -1,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1,3-diphenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    (1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;    1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester;    1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         32 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1  is C 1 -C 9  straight or branched chain alky, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar 1  is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, and amino;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         33 . The pharmaceutical composition of    claim 32   , wherein R 1  is selected from the group consisting of C 1 -C 9  straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.  
     
     
         34 . The pharmaceutical composition of    claim 32   , wherein Z and R 1  are lipophilic.  
     
     
         35 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is a compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate or hydrate thereof, wherein: 
 Z′ is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl or unsubstituted Ar 1 , wherein said alkyl is unsubstituted or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl;  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl; and  
 Ar 1  is as defined in    claim 32   .  
 
     
     
         36 . The pharmaceutical composition of    claim 35   , wherein Z′ is lipophilic.  
     
     
         37 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 3 -C 6  cycloalkyl or Ar 1 , wherein said alkyl or alkenyl is unsubstituted or substituted with C 3 -C 6  cycloalkyl or Ar 2 ;  
 Ar 1  and Ar 2  are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;  
 X is O, S, CH 2 , or H 2 ;  
 Y is O, NR 2  or a direct bond;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl Z is substituted with one or more substituent(s) independently selected from the group consisting of 2-furyl, 2-thienyl, C 3 -C 6  cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C 1 -C 4  alkoxy.  
 
     
     
         38 . The pharmaceutical composition of    claim 37   , wherein Z and R 1  are lipophilic.  
     
     
         39 . The pharmaceutical composition of    claim 37   , wherein the compound is selected from the group consisting of: 
 3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dloxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl] glyoxyl)pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2S) -1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;    3,3-diphenyl-1-propyl (2) -1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         40 . The pharmaceutical composition of    claim 39   , wherein the compound is selected from the group consisting of: 
 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;    3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         41 . The pharmaceutical composition of    claim 39   , wherein the compound is 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
     
     
         42 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is an N-glyoxyl prolyl ester.  
     
     
         43 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is a compound of formula V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is O, N, or S;  
 A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR;  
 R is either C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 9  cycloalkyl, C 5 -C 7  cycloalkenyl, or Ar 1 , wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxyl, hydroxy, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 4  alkoxy, C 2 -C 4  alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 ;  
 R 1  is C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl or Ar 1 , wherein said R 1  is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, and Ar 2 ;  
 Ar 1  and Ar 2  are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;  
 X is O, S, CH 2  or H 2 ;  
 Y is O or NR 2 , or a direct bond;  
 Z is Ar 1 , C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substiuent(s) independently selected from the group consisting of Ar 1 , C 3 -C 8  cycloalkyl, and C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl substituted with C 3 -C 8  cycloalkyl; or Z is fragment  
                     
 wherein:  
 R 3  is C 1 -C 9  straight or branched chain alkyl which is unsubstitued or substituted with C 3 -C 8  cycloalkyl or Ar 1 ;  
 X 2  is O or NR 5 , wherein R 5  is selected from the group consisting of hydrogen, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl; and  
 R 4  is selected from the group consisting of phenyl, benzyl, C 1 -C 5  straight or branched chain alkyl, C 2 -C 5  straight or branched chain alkenyl, C 1 -C 5  straight or branched chain alkyl substituted with phenyl, and C 2 -C 5  straight or branched chain alkenyl substituted with phenyl.  
 
     
     
         44 . The pharmaceutical composition of    claim 24   , wherein the pyrrolidine derivative is combined with an effective amount of one or more factors useful in treating vision loss, preventing vision degeneration, or promoting vision regeneration in an animal.  
     
     
         45 . The pharmaceutical composition of    claim 44   , wherein the one or more factor(s) is/are selected from the group consisting of immunosuppressants, wound healing agents, antiglaucomatous medications, neurotrophic factors, growth factors, compounds effective in limiting or preventing hemorrhage or neovascularization, and antioxidants.