Dosage regimen for comt inhibitors

Abstract

The invention relates to the use of an oxodiazolyl compound (I) for the preparation of a medicament for the prevention or treatment of central and peripheral nervous system associated disorders, wherein said medicament is administered according to a dosing regimen having a dosing periodicity ranging from about twice a day to about once every other day.

What is claimed is: 
     
         1 . An individual dosage unit comprising 1 to 500 mg of a compound of formula I 
       
         
           
           
               
               
           
         
         where R 1  and R 2  are the same or different and signify hydrogens or groups hydrolysable under physiological conditions, optionally substituted lower alkanoyl or aroyl; X signifies a methylene group; Y represents an atom of oxygen, NH or sulphur; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R 3  signifies a pyridine N-oxide group according to the formula A, B, or C, which is connected as indicated by the unmarked bond: 
       
       
         
           
           
               
               
           
         
         where R 4 , R 5 , R 6  and R 7  are the same or different, and signify hydrogen, lower alkyl, lower thioalkyl, lower alkoxy, aryloxy or thioaryl group, lower alkanoyl or aroyl group, optionally substituted aryl group, amino, lower alkylamino, lower dialkylamino cycloalkylamino or heterocycloalkylamino group, lower alkylsulphonyl or arylsulphonyl group, halogen, haloalkyl, trifluoromethyl, cyano, nitro or heteroaryl group, or taken together signify aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings; the term alkyl means carbon chains, straight or branched, containing from one to six carbon atoms; the term aryl means a phenyl or naphthyl group, optionally substituted by alkoxy or halogen groups; the term heterocycloalkyl represents a four to eight-membered cyclic ring optionally incorporating other atoms of oxygen, sulphur or nitrogen; the term heteroaryl represents a five or six-membered ring incorporating an atom of sulphur, oxygen or nitrogen; the term halogen represents fluorine, chlorine bromine or iodine; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . An individual dosage unit as claimed in 1, wherein the compound of general formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         3 . An individual dosage unit as claimed in  claim 2  which comprises 2 to 300 mg of the to compound of formula I or a pharmaceutically acceptable salt thereof. 
     
     
         4 . An individual dosage unit as claimed in  claim 2  which comprises 3 to 100 mg of the compound of the formula I or a pharmaceutically acceptable salt thereof. 
     
     
         5 . An individual dosage unit as claimed in  claim 2  which comprises 5 to 50 mg of the compound of the formula I or a pharmaceutically acceptable salt thereof. 
     
     
         6 . An individual dosage unit as claimed in  claim 1  in combination with L-DOPA and/or an aromatic L-amino acid decarboxylase inhibitor. 
     
     
         7 . An individual dosage unit as claimed in  claim 2  in combination with L-DOPA and/or an aromatic L-amino acid decarboxylase inhibitor. 
     
     
         8 . Method of treating at least one condition or disease in a patient in need thereof comprising administering to the patient an individual dosage unit according to  claim 1 . 
     
     
         9 . Method of treating at least one condition or disease in a patient in need thereof comprising administering to the patient about twice every day to about once every other day a pharmacologically effective dose of a compound of formula I as defined in  claim 1 . 
     
     
         10 . Method as claimed in  claim 9 , wherein the administration is once daily. 
     
     
         11 . Method as claimed in  claim 9 , wherein the administration is twice daily. 
     
     
         12 . Method as claimed in  claim 9 , wherein the administration is once every other day. 
     
     
         13 . Method as claimed in  claim 9 , wherein the administration is in the morning, mid-day, noon, afternoon, evening, or midnight. 
     
     
         14 . Method as claimed in  claim 9 , wherein the administration is in the evening. 
     
     
         15 . Method as claimed in  claim 9 , wherein the condition or disease is treatable by L-DOPA and AADC inhibitor therapy. 
     
     
         16 . Method as claimed in  claim 9 , wherein the condition or disease is a central or peripheral nervous system associated disorder. 
     
     
         17 . Method as claimed in  claim 16 , wherein the condition or disease is a movement or schizoaffective disorder. 
     
     
         18 . Method as claimed in  claim 17 , wherein the movement disorder is Parkinson's disease. 
     
     
         19 . Method as claimed in  claim 8 , wherein the compound of general formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         20 . Method as claimed in  claim 9 , wherein the compound of general formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         21 . Method as claimed in  claim 9 , wherein the method further comprises the step of to administering L-DOPA to the patient. 
     
     
         22 . Method as claimed in  claim 9 , wherein the method further comprises the step of administering an AADC inhibitor to the patient. 
     
     
         23 . Method for increasing levels of L-DOPA in the brain or plasma of a subject over 24 to 48 hours comprising administering an individual dosage unit as defined in  claim 1  to the subject, wherein the subject is receiving therapy with L-DOPA and an AADC inhibitor. 
     
     
         24 . Method for increasing levels of L-DOPA in the brain or plasma of a subject over 24 to 48 hours comprising administering about twice per day to about once every other day, an effective dose of a compound of general formula I as defined in  claim 1  to the subject, wherein the subject is receiving therapy with L-DOPA and an AADC inhibitor. 
     
     
         25 . Method for decreasing levels of 3-O-methyl-L-DOPA in the brain or in the plasma of a subject over 24 to 48 hours comprising administering an individual dosage unit according to  claim 1  to the subject, wherein the subject is receiving therapy with L-DOPA and an AADC inhibitor. 
     
     
         26 . Method for decreasing levels of 3-O-methyl-L-DOPA in the brain or in the plasma of a subject over 24 to 48 hours comprising administering about twice per day to about once every other day, an effective dose of a compound of general formula I as defined in  claim 1  to the subject, wherein the subject is receiving therapy with L-DOPA and an AADC inhibitor. 
     
     
         27 . Package comprising an individual dosage unit as defined in  claim 1 . 
     
     
         28 . Package comprising an individual dosage unit as defined in  claims 2 . 
     
     
         29 . Package as claimed in  claim 28 , wherein the package further comprises L-DOPA and/or an AADC inhibitor. 
     
     
         30 . A method of reducing end-of-dose wearing off symptoms in a patient suffering from Parkinson's disease who is treated with an effective amount of L-DOPA and carbidopa comprising administering to said patient an effective amount of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol once a day. 
     
     
         31 . A method as claimed in  claim 30  wherein the amount of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol is 5 mgs to 50 mgs. 
     
     
         32 . A method as claimed in  claim 30  wherein the amount of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol is 50 mgs. 
     
     
         33 . A method as claimed in  claim 30  wherein the amount of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol is 5 mgs. 
     
     
         34 . A method as claimed in  claim 30  wherein the administration is oral. 
     
     
         35 . A method as claimed in  claim 31  wherein the administration is oral. 
     
     
         36 . A method as claimed in  claim 32  wherein the administration is oral. 
     
     
         37 . A method as claimed in  claim 33  wherein the administration is oral. 
     
     
         38 . A method as claimed in  claim 30  when administration is in the evening. 
     
     
         39 . A method as claimed in  claim 14  wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         40 . A method as claimed in  claim 15  wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         41 . A method as claimed in  claim 18  wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         42 . A method as claimed in  claim 21  wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 
     
     
         43 . A method as claimed in  claim 22  wherein the compound of formula I is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]-oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.