Pharmacology of visual cycle modulators

Abstract

Described herein are methods for the treatment of an ophthalmic disease or disorder comprising the administration of non-retinoid visual cycle modulators.

1 . A method of treating an ophthalmic disease or disorder comprising administration of a non-retinoid compound resulting in a normalized electroretinogram response from about 5% to about 55% after about 12 hours to about 48 hours post administration of said non-retinoid compound. 
     
     
         2 .- 24 . (canceled) 
     
     
         25 . The method of  claim 1  wherein the non-retinoid compound is selected from a compound of Formula (I) or a tautomer, stereoisomer, geometric isomer or pharmaceutically acceptable solvate, hydrate, salt, polymorph, or N-oxide thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         Z is a bond, —C(R 1 )(R 2 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—, —X—C(R 31 )(R 32 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—C(R 36 )(R 37 )— or —X—C(R 31 )(R 32 )—C(R 1 )(R 2 )—; 
         R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 5  alkyl, fluoroalkyl, —OR 6  or —NR 7 R 8 ; or R 1  and R 2  together form an oxo; 
         R 31  and R 32  are each independently selected from hydrogen, C 1 -C 5  alkyl, or fluoroalkyl; 
         R 36  and R 37  are each independently selected from hydrogen, halogen, C 1 -C 5  alkyl, fluoroalkyl, —OR 6  or —NR 7 R 8 ; or R 36  and R 37  together form an oxo; or optionally, R 36  and R 1  together form a direct bond to provide a double bond; or optionally, R 36  and R 1  together form a direct bond, and R 37  and R 2  together form a direct bond to provide a triple bond; 
         R 3  and R 4  are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3  and R 4  together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3  and R 4  together form an imino; 
         R 5  is C 1 -C 15  alkyl, carbocyclyalkyl, arylalkyl, heteroaryl alkyl or heterocyclylalkyl; 
         R 7  and R 8  are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , SO 2 R 13 , CO 2 R 13  or SO 2 NR 24 R 25 ; or R 7  and R 8  together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
         X is —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 30 )—, —C(═CH 2 )—, —C(═N—NR 35 )—, or —C(═N—OR 35 )—; 
         R 9  and R 10  are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR 19 , —NR 20 R 21  or carbocyclyl; or R 9  and R 10  form an oxo; or optionally, R 9  and R 1  together form a direct bond to provide a double bond; or optionally, R 9  and R 1  together form a direct bond, and R 10  and R 2  together form a direct bond to provide a triple bond; 
         R 11  and R 12  are each independently selected from hydrogen, alkyl, carbocyclyl, —C(═O)R 23 , —C(NH)NH 2 , SO 2 R 23 , CO 2 R 23  or SO 2 NR 28 R 29 ; or R 11  and R 12 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
         each R 13 , R 22  and R 23  is independently selected from alkyl, heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; 
         R 6 , R 19 , R 30 , R 34  and R 35  are each independently hydrogen or alkyl; 
         R 20  and R 21  are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 22 , SO 2 R 22 , CO 2 R 22  or SO 2 NR 26 R 27 ; or R 20  and R 21  together with the nitrogen atom to which they are attached, form an N-heterocyclyl; and 
         each R 24 , R 25 , R 26 , R 27 , R 28  and R 29  is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 
         each R 33  is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4. 
       
     
     
         26 . The method of  claim 25  wherein the compound of Formula (I) has the structure of Formula (II): 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 5  alkyl, fluoroalkyl, —OR 6  or —NR 7 R 8 ; or R 1  and R 2  together form an oxo; 
         R 3  and R 4  are each independently selected from hydrogen or alkyl; or R 3  and R 4  together form an imino; 
         R 7  and R 8  are each independently selected from hydrogen, alkyl, carbocyclyl or —C(═O)R 13 ; or R 7  and R 8 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
         R 9  and R 19  are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR 19 , —NR 20 R 21  or carbocyclyl; or R 9  and R 19  together form an oxo; 
         R 11  and R 12  are each independently selected from hydrogen, alkyl, carbocyclyl or —C(═O)R 23 ; or R 11  and R 12 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; 
         each R 13 , R 22  and R 23  is independently selected from alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl; 
         R 6 , R 19  and R 34  are each independently hydrogen or alkyl; 
         R 29  and R 21  are each independently selected from hydrogen, alkyl, carbocyclyl, —C(═O)R 22 ; or R 29  and R 21 , together with the nitrogen atom to which they are attached, form an N-heterocyclyl; and 
         each R 24 , R 25 , R 26 , R 27 , R 28  and R 29  is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl; 
         R 14  and R 15  are each independently selected from hydrogen or alkyl; 
         R 16  and R 17  are each independently selected from hydrogen, C 1 -C 13  alkyl, halo or fluoroalkyl; or R 16  and R 17 , together with the carbon to which they are attached form a carbocyclyl; 
         each R 33  is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4; and 
         R 18  is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl. 
       
     
     
         27 . The method of  claim 26  wherein the compound of Formula (II) is further defined as
 R 1  and R 2  are each independently selected from hydrogen, halogen, C 1 -C 5  alkyl, or —OR 6 ; 
 R 9  and R 19  are each independently selected from hydrogen, halogen, alkyl, or —OR 19 ; or R 9  and R 19  together form an oxo; 
 R 6  and R 19  are each independently hydrogen or alkyl; 
 R 16  and R 17 , together with the carbon to which they are attached form a carbocyclyl; and 
 R 18  is selected from a hydrogen, alkoxy or hydroxy. 
 
     
     
         28 . The method of  claim 27  wherein the compound of Formula (II) is further defined as R 16  and R 17 , together with the carbon to which they are attached, form a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and R 18  is hydrogen or hydroxy. 
     
     
         29 . The method of  claim 28  wherein the compound of Formula (II) is (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol. 
     
     
         30 . The method of  claim 29  wherein the dose is from about 4 mg to about 100 mg. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 30  wherein the dose is about 7 mg. 
     
     
         36 . The method of  claim 30  wherein the dose is about 5 mg. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 1  wherein the ophthalmic disease or disorder is selected from retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal blood vessel occlusion, retinopathy of prematurity, ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, Sorsby's fundus dystrophy, uveitis, a retinal injury, a retinal disorder associated with Alzheimer's disease, a retinal disorder associated with multiple sclerosis, a retinal disorder associated with Parkinson's disease, a retinal disorder associated with viral infection, a retinal disorder related to light overexposure, myopia, and a retinal disorder associated with AIDS. 
     
     
         42 . The method of  claim 41  wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. 
     
     
         43 . The method of  claim 42  wherein the ophthalmic disease or disorder is dry age-related macular degeneration. 
     
     
         44 . The method of  claim 41  wherein the ophthalmic disease or disorder is diabetic retinopathy. 
     
     
         45 .- 52 . (canceled)