Abnormal cannabidiols as agents for lowering intraocular pressure

Abstract

The present invention provides a method of treating glaucoma or ocular hypertension which comprises applying to the eye of a person in need thereof an amount sufficient to treat glaucoma or ocular hypertension of a compound of formula I wherein Y, Q, Z, R, R 1 and R 2 are as defined in the specification. The present invention further comprises pharmaceutical compositions, e.g. ophthalmic compositions, including said compound.

1 . A method of treating glaucoma or ocular hypertension, comprising applying to the eye of a person an ophthalmic solution comprising a therapeutically effective amount of a compound of formula I′ 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of H, halogen; and C 1-5  alkyl; 
         R 1  is selected from the group consisting of H or halogen; 
         R 2  is independently selected from the group consisting of H, C 1-5  alkyl, halogen, XC 1-5  alkyl, C 1-5  alkylOR 13 , C 1-5  alkylN(R 13 ) 2 , N(R 13 ) 2 , XC 1-5  alkylN(R 13 ) 2  and XC 1-5  alkylOR 13 ; X is O or S(O) n ; n is 0 or an integer of from 1 to 2; 
         Y is selected from the group consisting of keto and hydroxyl; 
         Y 1  is selected from the group consisting of hydroxyl, halogen and C 1 -C 5  alkyl; 
         Q is a halogen-substituted phenyl; and 
         R 13  is selected from the group consisting of H, C 1-5  alkyl and C 3-8  cyclic alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein said compound is 2-(4-Chlorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         3 . The method of  claim 1 , wherein said compound is 2-(3,5-Difluorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         4 . The method of  claim 1 , wherein said compound is 2-(2,5-Difluorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         5 . The method of  claim 1 , wherein said compound is 2-(3,5-Dichlorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         6 . The method of  claim 1 , wherein said compound is 2-(2,5-Dichlorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         7 . The method of  claim 1 , wherein said compound is 4,5-Dichloro-2-phenylpyridazin-3-one. 
     
     
         8 . The method of  claim 1 , wherein said compound is 4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one. 
     
     
         9 . The method of  claim 1 , wherein said compound is 4,5-Dibromo-2-(2,5-difluorophenyl)pyridazin-3-one. 
     
     
         10 . The method of  claim 1 , wherein said compound is 4,5-Dibromo-2-(2,5-dichlorophenyl)pyridazin-3-one. 
     
     
         11 . The method of  claim 1 , wherein said compound is 2-(3,5-Dichlorophenyl)-5-methoxypyridazin-3-one. 
     
     
         12 . The method of  claim 1 , wherein said compound is 2-(2,5-Dichlorophenyl)-5-methoxypyridazin-3-one. 
     
     
         13 . The method of  claim 1 , wherein said compound is 4-Bromo-2-(3,5-dichlorophenyl)-5-methoxypyridazin-3-one. 
     
     
         14 . The method of  claim 1 , wherein said compound is 4-Bromo-2-(2,5-dichlorophenyl)-5-methoxypyridazin-3-one. 
     
     
         15 . The method of  claim 1 , wherein said compound is 5-Hydroxy-2-(3-trifluoromethylphenyl)-pyridazin-3-one. 
     
     
         16 . The method of  claim 1 , further comprising at least one ingredient selected from the group of an ophthalmically acceptable preservative, buffer system, antioxidant and chelating agent. 
     
     
         17 . The method of  claim 1 , wherein said compound is 4-Bromo-2-(3,5-dichlorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         18 . A method of treating glaucoma or ocular hypertension, comprising applying to the eye of a person an ophthalmic solution comprising a therapeutically effective amount of a compound of formula I′ 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of H, halogen; and C 1-5  alkyl; 
         R 1  is H; 
         R 2  is independently selected from the group consisting of H, C 1-5  alkyl, halogen, C 1-5  alkylOR 13 , C 1-5  alkylN(R 13 ) 2 , OC 1-5  alkylN(R 13 ) 2 , OC 1-5  alkylOR 13 , and N(R 14 ) 2 ; 
         R 13  is selected from the group consisting of H, C 1-5  alkyl and C 3-8  cyclic alkyl; 
         R 14  is selected from the group consisting of C 1-5  alkyl and C 3-8  cyclic alkyl; 
         Y is selected from the group consisting of keto and hydroxyl; 
         Y 1  is selected from the group consisting of hydroxyl, halogen and C 1 -C 5  alkyl; and 
         Q is phenyl. 
       
     
     
         19 . The method of  claim 18 , wherein said compound is 4-Chloro-2-phenyl-5-hydroxy-pyridazin-3-one. 
     
     
         20 . The method of  claim 18 , wherein said compound is 5-Hydroxy-2-phenyl-pyridazin-3-one. 
     
     
         21 . The method of  claim 18 , wherein said ophthalmic solution further comprises at least one ingredient selected from the group of an ophthalmically acceptable preservative, buffer system, antioxidant and chelating agent. 
     
     
         22 . A method of treating glaucoma or ocular hypertension, comprising applying to the eye of a person an ophthalmic solution comprising a therapeutically effective amount of a compound of formula I′ 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of H, halogen; and C 1-5  alkyl; 
         R 1  is selected from the group consisting of H or halogen; 
         R 2  is independently selected from the group consisting of H, C 1-5  alkyl, halogen, XC 1-5  alkyl, C 1-5  alkylOR 13 , C 1-5  alkylN(R 13 ) 2 , N(R 13 ) 2 , XC 1-5  alkylN(R 13 ) 2  and XC 1-5  alkylOR 13 ; X is O or S(O) n ; n is 0 or an integer of from 1 to 2; 
         Y is selected from the group consisting of keto and hydroxyl; 
         Y 1  is selected from the group consisting of hydroxyl, halogen and C 1 -C 5  alkyl; and 
         Q is a compound having the formula 
       
       
         
           
           
               
               
           
         
         wherein a dotted line represents the presence or absence of a double bond and the wavy line represents a direct bond; 
         Z is N or C; 
         R 3  is selected from the group consisting of H, hydroxyl, oxo, C 1-5  alkyl, C 1-5  alkylOR 13  and C 1-5  alkylN(R 13 ) 2 , 
         R 4  is selected from the group consisting of H, C 1-5  alkenyl, C 1-5  alkyl, C 1-5  alkylOR 13  and C 1-5  alkylN(R 13 ) 2 ; 
         R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are independently selected from the group consisting of H, C 1-5  alkyl, C 1-5  alkylOR 13  and OR 13 ; 
         R 13  is selected from the group consisting of H, C 1-5  alkyl and C 3-8  cyclic alkyl. 
       
     
     
         23 . The method of  claim 22 , wherein said ophthalmic solution further comprises at least one ingredient selected from the group of an ophthalmically acceptable preservative, buffer system, antioxidant and chelating agent. 
     
     
         24 . A method of treating glaucoma or ocular hypertension, comprising applying to the eye of a person an ophthalmic solution comprising a therapeutically effective amount of a compound selected from the group 4-Bromo-2-(3,5-difluorophenyl)-5-hydroxypyridazin-3-one, 4-Bromo-2-(2,5-difluorophenyl)-5-hydroxypyridazin-3-one, and 4-Bromo-2-(2,5-dichlorophenyl)-5-hydroxypyridazin-3-one. 
     
     
         25 . The method of  claim 24 , wherein said ophthalmic solution further comprises at least one ingredient selected from the group of an ophthalmically acceptable preservative, buffer system, antioxidant and chelating agent. 
     
     
         26 . A method for treating glaucoma or intraocular pressure which comprises applying to the eye an amount sufficient to treat ocular hypertension of a combination of drugs which include a first drug which is a compound of Formula I′ according to  claim 1 ,  18 , or  22  and a second drug selected from the group consisting of β-blockers, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, chlolinesterase inhibitors, glutamate antagonists, prostamides and prostaglandins. 
     
     
         27 . The method of  claim 26  wherein said second drug is a β-blocker selected from the group consisting of carteolol, levobunolol, metiparanolol, timolol hemihydrate, timolol maleate, and betaxolol, or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         28 . The method of  claim 26  wherein said second drug is an adrenergic agonist selected from the group consisting of epinephrine borate, epinephrine hydrochloride, dipivefrin, apraclonidine and brimonidine or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         29 . The method of  claim 26  wherein said second drug is a carbonic anhydrase inhibitor selected from the group consisting of acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         30 . The method of  claim 26  wherein said second drug is a cholinergic agonist selected from the group consisting of charbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         31 . The method of  claim 26  wherein said second drug is a cholinesterase inhibitor selected from the group consisting of demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         32 . The method of  claim 26  wherein said second drug is a glutamate antagonist selected from the group consisting of memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         33 . The method of  claim 26  wherein said second drug is bimatoprost or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         34 . The method of  claim 26  wherein said second drug is a prostaglandin selected from the group consisting of travoprost, UFO-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost or pharmaceutically acceptable salts or prodrugs thereof.