Novel compounds

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  represents a hydrogen or fluorine atom or a trifluoromethyl group; 
 R 2  represents a group —X—Y—R 3 ; 
 X and Y each independently represent a bond, an oxygen atom or a group —C(O), —S(O) n , —C(O)NR 4 , —S(O) 2 NR 4 , —NR 4 , 
 
       
         
           
           
               
               
           
         
          or —CR 4 R 5 —, provided that X and Y cannot both simultaneously represent a bond and provided that if X and Y are both other than a bond, then at least one of X and Y represents —CR 4 R 5 —; 
         n is 0, 1 or 2; 
         each R 4  independently represents a hydrogen atom or a C 1 -C 6  alkyl or C 1 -C 6  haloalkyl group; 
         each R 5  independently represents a hydrogen atom, a C 1 -C 6  alkyl or C 1 -C 6  haloalkyl group or ═CH—; 
         R 3  represents a 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system, the ring system itself being optionally substituted by at least one substituent selected from halogen, hydroxyl, cyano, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulphinyl, C 1 -C 6  alkylsulphonyl, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkylcarbonyloxy, C 1 -C 6  alkoxycarbonyl, amino (—NH 2 ), —CON(R 6 ) 2 , C 1 -C 6  alkylamino, di-(C 1 -C 6  alkyl)amino, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, C 3 -C 6  cycloalkylmethyl, —[O] p —(CH 2 ) q —O—R 7  and a 4- to 6-membered saturated or unsaturated heterocyclic ring (optionally substituted with at least one substituent selected from C 1 -C 4  alkyl and C 1 -C 4  alkoxy); 
         each R 6  independently represents a hydrogen atom or a C 1 -C 6  alkyl group; 
         p is 0 or 1; 
         q is 1, 2, 3 or 4; and 
         R 7  represents a C 1 -C 6  alkyl group; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to  claim 1 , wherein R 1  represents a hydrogen atom. 
     
     
         3 . A compound according to  claim 1 , wherein X represents a bond, an oxygen atom or a group —C(O), —S(O) n , —C(O)NR 4 , —S(O) 2 NR 4 , —NR 4 , 
       
         
           
           
               
               
           
         
       
       or —CR 4 R 5 —, and Y represents a bond or —CR 4 R 5 —. 
     
     
         4 . A compound according to  claim 3 , wherein X represents a group —S(O) n , —NR 4 , —CHR 4  or 
       
         
           
           
               
               
           
         
       
       and Y represents a bond or a group —CHR 4 . 
     
     
         5 . A compound according to  claim 4 , wherein each R 4  independently represents a hydrogen atom or methyl group. 
     
     
         6 . A compound according to  claim 1 , wherein, in R 3 , the 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system is selected from phenyl, pyridinyl, oxazolyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, 2,3-dihydrobenzofuranyl, pyrimidinyl, imidazo[1,2-a]pyridinyl, pyrazolyl, thiazolyl and piperidinyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 3  represents an optionally substituted 3- to 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system. 
     
     
         8 . A compound according to  claim 7 , wherein R 3  represents a 5- or 6-membered unsaturated carbocyclic or heterocyclic ring system, the heterocyclic ring system comprising one or two ring heteroatoms independently selected from nitrogen and oxygen, wherein the carbocyclic or heterocyclic ring system is optionally substituted by one, two, three or four substituents independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 2  haloalkyl, C 1 -C 2  hydroxyalkyl, C 1 -C 4  alkoxy, C 1 -C 2  haloalkoxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulphinyl, C 1 -C 4  alkylsulphonyl, C 1 -C 4  alkylcarbonyl, C 1 -C 4  alkylcarbonyloxy, C 1 -C 4  alkoxycarbonyl, amino, carboxamido, C 1 -C 4  alkylamino, di-(C 1 -C 4  alkyl)amino, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyloxy, C 3 -C 6  cycloalkylmethyl, —[O] p —(CH 2 ) q —O—R 7  and a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally substituted by methyl or methoxy. 
     
     
         9 . A compound according to  claim 7 , wherein the optional substituents are selected from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl and methoxy. 
     
     
         10 . A compound of formula (I) as defined in  claim 1  selected from the group consisting of:
 4-Hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one, 
 6-[2-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}pyridazin-3(2H)-one, 
 6-[(4-Chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one, 
 6-[2-(3-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(2-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(3,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one, 
 6-(2-Cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(2-Cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(2-Cyclopentylethyl)-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one, 
 6-[2-(2,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-{2-[3-(Difluoromethyl)phenyl]ethyl}-4-hydroxypyridazin-3(2H)-one, 
 6-Benzyl-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(3-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-(1-phenylcyclopropyl)pyridazin-3(2H)-one, 
 4-[2-(5-Hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)ethyl]benzonitrile, 
 6-[2-(3-Fluoro-4-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(4-Fluoro-3-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(3,4-Dimethoxyphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 
 6-[2-(4-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[2-(2-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 
 6-(4-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(4-(Trifluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(3-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-[1-(4-Fluorophenyl)cyclopropyl]-4-hydroxypyridazin-3(2H)-one, 
 6-[1-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 
 6-((Cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one, 
 6-((Cyclohexylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one, 
 6-(3-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(4-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(Cyclohexylmethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(4-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(2-Chloro-6-fluorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(2-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(3-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(2-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(4-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(3-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one, 
 4-Hydroxy-6-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one, 
 4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one, 
 4-Hydroxy-6-[2-(oxan-4-yl)ethyl]pyridazin-3(2H)-one, 
 6-{[(4-Fluorophenyl)methyl](methyl)amino}-4-hydroxy-pyridazin-3(2H)-one, 
 6-[2-(2,6-Difluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)-one, 
 6-[2-(2-Chloro-6-fluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)-one, 
 6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}-4-hydroxypyridazin-3(2H)-one, and 
 6-(1-Phenylethyl)-4-hydroxypyridazin-3(2H)-one, 
 6-(Cyclopropylmethyl)-4-hydroxy-2,3-dihydropyridazin-3-one. 
 4-Hydroxy-6-{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3-dihydropyridazin-3-one, 
 6-{2-[2-Chloro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 6-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydro-pyridazin-3-one, 
 6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 4-Hydroxy-6-(3-methyl-4-(trifluoromethyl)phenethyl)pyridazin-3(2H)-one, 
 3,4-bis(Benzyloxy)-6-((3-chloro-4-(trifluoromethyl)phenyl)ethyl)-pyridazine, 
 4-Hydroxy-6-{2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazin-3-one, 
 6-{2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 6-{2-[3-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, 
 
       and pharmaceutically acceptable salts thereof. 
     
     
         11 . A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  which comprises
 (i) when X represents a sulphur atom or when X is a bond and Y represents a sulphur atom, reacting a compound of formula (II) 
 
       
         
           
           
               
               
           
         
         in which Hal represents a halogen atom and R 1  is as defined in formula (I), with a compound of formula (III), HS—[Y] t —R 3 , where t is 0 or 1 and Y and R 3  are as defined in formula (I); or 
         (ii) when X represents SO or when X is a bond and Y represents SO, oxidising a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         in which P 1  represents a protecting group and R 1  is as defined in formula (I), with a suitable oxidising agent, followed by reaction with a compound of formula (V), L 1 -[Y] w —R 3 , where w is 0 or 1, L 1  represents a leaving group and Y and R 3  are as defined in formula (I); or 
         (iii) when X represents SO 2  or when X is a bond and Y represents SO 2 , oxidising a compound of formula (IV) as defined in (ii) above with a suitable oxidising agent, followed by reaction with a compound of formula (V) as defined in (ii) above; or 
         (iv) when X represents an oxygen atom or when X is a bond and Y represents an oxygen atom, reacting a compound of formula (II) as defined in (i) above, with a compound of formula (VI), HO—[Y] z —R 3 , where z is 0 or 1 and Y and R 3  are as defined in formula (I); or 
         (v) when X represents C(O) or when X is a bond and Y represents C(O), reacting a compound of formula (II) as defined in (i) above with carbon dioxide, followed by addition of an activating agent and reaction with a compound of formula (Va), M-[Y] w —R 3 , where M is Li or MgR 20 , R 20  represents a halogen atom and w, Y and R 3  are as defined in formula (V) in (ii) above; or 
         (vi) when X represents —C(O)NR 4  or when X is a bond and Y represents —C(O)NR 4 , reacting a compound of formula (VII) 
       
       
         
           
           
               
               
           
         
         in which R 1  is as defined in formula (I), with a compound of formula (VIII), R 4 HN—[Y] g —R 3 , where g is 0 or 1 and Y, R 3  and R 4  are as defined in formula (I); or 
         (vii) when X represents —S(O) 2 NR 4  or when X is a bond and Y represents —S(O) 2 NR 4 , reacting a compound of formula (II) as defined in (i) above with sulphur dioxide, followed by addition of an oxidising-chlorinating agent and then reaction with a compound of formula (VIII) as defined in (vi) above; or 
         (viii) when X represents —NR 4  or when X is a bond and Y represents —NR 4 , reacting a compound of formula (II) as defined in (i) above, with a compound of formula (VIII) as defined in (vi) above; or 
         (ix) when X represents —CR 4 R 5 — or when X is a bond and Y represents —CR 4 R 5 — and R 4  and R 5  each independently represent a C 1 -C 6  alkyl group, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX), L 2 -CR 4′ R 5′ —[Y] h —R 3 , where h is 0 or 1, L 2  represents a leaving group, R 4′  and R 5′  each independently represent a C 1 -C 6  alkyl group and Y and R 3  are as defined in formula (I); or 
         (x) when X represents —CR 4 R 5 — or when X is a bond and Y represents —CR 4 R 5 — and R 4  and R 5  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group but do not both simultaneously represent a C 1 -C 6  alkyl group, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IXa), R 4 C(O)—[Y] h —R 3 , wherein h, Y, and R 3  are as defined in formula (IX) in (ix) above and R 4  is as defined in formula (I) above, followed by a hydrogenation reaction; or 
         (xi) when X and Y each represent —CHR 4 , hydrogenating a compound of formula (X) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 3  and R 4  are as defined in formula (I); or 
         (xii) when X represents —CR 4 R 5 — or when X is a bond and Y represents —CR 4 R 5 — and R 5  is ═CH, reacting a compound of formula (XI) 
       
       
         
           
           
               
               
           
         
         wherein R 22  represents a hydrogen atom or a C 1 -C 6  alkyl group and R 1  is as defined in formula (I), with a compound of formula (IXb), R 24 —CH(R 26 )—[Y] h —R 3 , wherein R 24  represents a phosphonate moiety, R 26  represents a hydrogen atom or a C 1 -C 6  alkyl group and h, Y and R 3  are as defined in formula (IX) in (ix) above; or 
         (xiii) when X represents a group 
       
       
         
           
           
               
               
           
         
          or when X is a bond and Y represents a group 
       
       
         
           
           
               
               
           
         
          reacting a compound of formula (XII) 
       
       
         
           
           
               
               
           
         
         where k is 0 or 1 and Y, and R 3  are as defined in formula (I), with diiodomethane and zinc-copper couple; or 
         (xiv) when X represents a group 
       
       
         
           
           
               
               
           
         
          or when X is a bond and Y represents a 
       
       
         
           
           
               
               
           
         
          group, reacting a compound of formula (XIII) 
       
       
         
           
           
               
               
           
         
         where 1 is 0 or 1 and Y, and R 3  are as defined in formula (I), with diiodomethane and zinc-copper couple; 
         and optionally thereafter carrying out one or more of the following procedures:
 converting a compound of formula (I) into another compound of formula (I) 
 removing any protecting groups 
 forming a pharmaceutically acceptable salt. 
 
       
     
     
         12 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1  and one or more agents selected from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and lithium. 
     
     
         16 . An intermediate compound of formula (XXX) 
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  each independently represent a protecting group, R 20  represents a hydrogen atom or a leaving group and R 1  is as defined in formula (I) of  claim 1 . 
       
     
     
         17 . A method of treating a condition whose development or symptoms are linked to D-amino acid oxidase (DAAO) enzyme activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 . 
     
     
         18 . A method of treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 .