7-aza-spiro[3,5]nonane-7-carboxylate derivatives, preparation thereof and therapeutic use thereof

Abstract

The present invention is directed to 7-aza-spiro[3.5]nonane-7-carboxylate derivatives of the Formula I. The compounds of the invention are inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The invention also relates to processes for the preparation of compounds of the Formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

1 - 11 . (canceled) 
     
     
         12 . A compound of the formula (III) 
       
         
           
           
               
               
           
         
         in which Z represents a hydrogen atom or a nitro group, R 3  represents a hydrogen atom, fluorine atom, a C 1-6 -alkyl group or a trifluoromethyl group; and R 4  represents a 4-(methylcarbamoyl)-oxazol-2-yl group. 
       
     
     
         13 . A compound of the formula (Ia): 
       
         
           
           
               
               
           
         
         in which R 2  represents a hydrogen atom, fluorine atom, hydroxyl, cyano, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or NR 8 R 9  group; 
         m, n, o and p independently of one another represent a number ranging from 0 to 3; 
         it being understood that 2≦m+n≦5 and that 2≦o+p≦5; 
         R 3  represents a hydrogen atom, fluorine atom, a C 1-6 -alkyl group or a trifluoromethyl group; 
         R 4  represents a 5-membered heterocycle selected from a furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thia-diazolyl, imidazolyl, triazolyl or tetrazoyl group; 
         this heterocycle optionally being substituted with one or more substituents selected from a halogen atom, a C 1-6 -alkyl, C 1-6 -haloalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkylC 1-3 -alkylene, C 1-6 -haloalkoxy, cyano, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 , NR 8 SO 2 R 9 , NR 8 SO 2 NR 8 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , CON(R 8 )(C 1-3 -alkylene-NR 10 R 11 ), SO 2 R 8 , SO 2 NR 8 R 9 , or —O—(C 1-3 -alkylene)-O group; 
         R 8  and R 9  independently of each other represent a hydrogen atom or a C 1-6 -alkyl group; 
         or with the atom or atoms which bear them form, in the case of NR 8 R 9 , a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, azepine, oxazepine or piperazine rings, this ring possibly being substituted with a C 1-6 -alkyl or benzyl group; 
         in the case of NR 8 COR 9 , a lactam ring; in the case of NR 8 CO 2 R 9 , an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR 8 SO 2 R 9 , a sultam ring; and in the case of NR 8 SO 2 NR 8 R 9 , a thiazolidine dioxide or thia-diazinane dioxide ring; and 
         R 10  and R 11  independently of one another represent a hydrogen atom or a C 1-6 -alkyl group; 
         and G represents a covalent bond or C 1-6 -alkylene. 
       
     
     
         14 . A compound of the formula (IIa): 
       
         
           
           
               
               
           
         
         in which R 2  represents a hydrogen atom, fluorine atom, hydroxyl, cyano, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or NR 8 R 9  group; R 8  and R 9  independently of each other represent a hydrogen atom or a C 1-6 -alkyl group; 
         or with the atom or atoms which bear them form, in the case of NR 8 R 9 , a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, azepine, oxazepine or piperazine rings, this ring possibly being substituted with a C 1-6 -alkyl or benzyl group; o and p represent 1, m and n represent 1 or 2, but m and n do not together represent the value 2, G represents a covalent bond or C 1-6 -alkylene, and GP represents a protective group chosen from the group consisting of Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), benzyl and benzhydryl. 
       
     
     
         15 . A compound of the formula (II): 
       
         
           
           
               
               
           
         
         in which m, n, o and p independently of one another represent a number ranging from 0 to 3; it being understood that 2≦m+n≦5 and that 2≦o+p≦5; R 2  represents a hydrogen atom, fluorine atom, hydroxyl, cyano, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or NR 8 R 9  group; 
         R 1  represents a group R 5  optionally substituted with one or more groups R 6  and/or R 7 ; 
         R 5  represents a group selected from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyrid-inyl group; 
         R 6  represents a halogen atom, a cyano, —CH 2 CN, nitro, hydroxyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, C 1-6 -haloalkyl, C 1-6 -haloalkoxy, C 1-6 -halothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkylene, C 3-7 -cycloalkyl-C 1-3 -alkylene-O—, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 , NR 8 SO 2 R 9 , NR 8 SO 2 NR 8 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , SO 2 R 8 , SO 2 NR 8 R 9  or —O—(C 1-3 -alkylene)-O— group; 
         R 7  represents a group selected from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group, the group or group(s) R 7  possibly being substituted with one or more groups R 6  which are identical to or different from one other; 
         R 3  represents a hydrogen or fluorine atom, a C 1-6 -alkyl group or a trifluoromethyl group; 
         R 4  represents a 5-membered heterocycle selected from a furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thia-diazolyl, imidazolyl, triazolyl or tetrazol group; this heterocycle optionally being substituted with one or more substituents selected from a halogen atom, a C 1-6 -alkyl, C 1-6 -haloalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkylC 1-3 -alkylene, C 1-6 -haloalkoxy, cyano, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 , NR 8 SO 9 R 9 , NR 8 SO 2 NR 8 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , CON(R 8 )(C 1-3 -alkylene-NR 10 R 11 ), SO 2 R 8 , SO 2 NR 8 R 9 , or —O—(C 1-3 -alkylene)-O group; 
         R 8  and R 9  independently of each other represent a hydrogen atom or a C 1-6 -alkyl group; 
         or with the atom or atoms which bear them form, in the case of NR 8 R 9 , a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, azepine, oxazepine or piperazine rings, this ring possibly being substituted with a C 1-6 -alkyl or benzyl group; in the case of NR 8 COR 9 , a lactam ring; in the case of NR 8 CO 2 R 9 , an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR 8 SO 9 R 9 , a sultam ring; and in the case of NR 8 SO 2 NR 8 R 9 , a thiazolidine dioxide or thia-diazinane dioxide ring; and 
         R 10  and R 11  independently of one another represent a hydrogen atom or a C 1-6 -alkyl group; 
         and A represents an oxygen atom, with the proviso that R 1  is not a fluorophenyl group. 
       
     
     
         16 . A compound of the formula (IIe): 
       
         
           
           
               
               
           
         
         in which R 2  represents a hydrogen atom, fluorine atom, hydroxyl, cyano, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or NR 8 R 9  group; R 8  and R 9  independently of each other represent a hydrogen atom or a C 1-6 -alkyl group; 
         or with the atom or atoms which bear them form, in the case of NR 8 R 9 , a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, azepine, oxazepine or piperazine rings, this ring possibly being substituted with a C 1-6 -alkyl or benzyl group; o and p represent 1, m and n represent 1 or 2, but m and n do not together represent the value 2, G represents a covalent bond or C 1-6 -alkylene and GP represents a protective group chosen from the group consisting of Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), benzyl and benzhydryl. 
       
     
     
         17 - 20 . (canceled)