Compound

Abstract

The present invention relates to certain spirooxindole derivatives of the formula I, and pharmaceutically acceptable salts thereof, which exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.

1 . A compound of the formula I  
       
         
           
           
               
               
           
         
       
       in racemic form or in the form of an enantiomer, or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is 
 a) H,  
 b) substituted or unsubstituted C 1 -C 6  alkyl,  
 c) C 1 -C 6  alkoxy C 2 -C 6  alkyl,  
 d) C 1 -C 6  alkylthio C 2 -C 6  alkyl,  
 e) halogenated C 1 -C 6  alkyl,  
 f) aryl C 1 -C 6  alkyl,  
 g) C 1 -C 6  alkenyl, or  
 h) C 1 -C 6  cycloalkyl C 1 -C 2  alkyl;  
 
 R 2  is 
 a) H,  
 b) C 1 -C 6  alkyl,  
 c) C 2 -C 4  alkynyl,  
 d) halogen,  
 e) substituted or unsubstituted carbamoyl,  
 f) substituted or unsubstituted carbamoyloxy,  
 g) C 1 -C 6  alkylcarbonyl,  
 h) C 1 -C 6  alkoxycarbonyl,  
 i) C 1 -C 6  alkylcarbonyloxy,  
 j) hydroxy-substituted C 1 -C 6  alkyl,  
 k) cyano,  
 l) nitro,  
 m) amino,  
 n) halogenated C 1 -C 6  alkyl,  
 o) halogenated C 1 -C 6  alkoxy,  
 p) halogenated C 1 -C 6  alkylthio,  
 q) C 1 -C 6  alkylsulfinyl,  
 r) C 1 -C 6  alkylsulfonyl,  
 s) C 1 -C 4  alkylsulfinylalkyl,  
 t) C 1 -C 4  alkylsulfonylalkyl,  
 u) C 1 -C 6  alkylsulfonylamino,  
 v) halogenated C 1 -C 6  alkylsulfonylamino,  
 w) halogenated C 1 -C 2  alkylsulfonyloxy,  
 x) aminosulfonyl,  
 y) aminosulfonyloxy,  
 z) aryl,  
 aa) heteroaryl,  
 bb) arylcarbonyl,  
 cc) heteroarylcarbonyl,  
 dd) arylsulfinyl,  
 ee) heteroarylsulfinyl,  
 ff) arylsulfonyl,  
 gg) heteroarylsulfonyl, in which any aromatic moiety is optionally substituted,  
 hh) C 1 -C 6  alkylcarbonylamino,  
 ii) C 1 -C 6  alkoxycarbonylamino,  
 jj) C 1 -C 6  alkyl-thiocarbonyl,  
 kk) C 1 -C 6  alkoxy-thiocarbonyl,  
 ll) formyl, or  
 mm)alkoxysulfonylamino;  
 
 R 3  is 
 a) H,  
 b) C 1 -C 6  alkyl,  
 c) halogen,  
 d) C 1 -C 6  alkoxy,  
 e) halogenated C 1 -C 4  alkyl,  
 f) halogenated C 1 -C 6  alkoxy,  
 g) halogenated C 1 -C 6  alkylthio,  
 h) C 1 -C 4  alkylsulfinyl,  
 i) C 1 -C 4  alkylsulfonyl,  
 j) C 1 -C 4  alkylsulfinyl C 1 -C 6  alkyl,  
 k) C 1 -C 4  alkylsulfonyl C 1 -C 6  alkyl,  
 l) C 1 -C 4  alkylsulfonylamino,  
 m)halogenated C 1 -C 4  alkylsulfonylamino,  
 n) aminosulfonyl, or  
 o) aminosulfonyloxy;  
 
 R 4  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
 
 R 2  and R 3  may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OH, cyano, amino, C 1 -C 6  alkyl-NH—, (C 1 -C 6  alkyl) 2 —N—, CN, NH 2 SO 2 , NH 2 CO—, or C 1 -C 6  alkyl-CO—;  
 Any amino moiety in R 2 -R 4  can obtionally be substituted with one or two C 1 -C 6  alkyl groups which may be part of a ring;  
 Ar is 
 a) benzene,  
 b) pyridine,  
 c) thiophene,  
 d) pyrazine,  
 e) pyrimidine,  
 f) oxazole,  
 g) thiazole,  
 h) pyrrole,  
 i) pyrazole, or  
 j) furan;  
 
 X is 
 a) —NHCO—,  
 b) —CONH—,  
 c) —NH—SO 2 —,  
 d) —SO 2 NH—,  
 e) —OCH 2 —,  
 f) —NHCH 2 —, or  
 g) —NHCOCH 2 —;  
 
 Y is 
 a) —CH 2 —,  
 b) —CH(C 1 -C 6  alkyl)-,  
 c) —C(C 1 -C 6  alkyl) 2 -, or  
 d) a single bond;  
 
 Z is 
 a) —CH 2 CH 2 CH 2 —,  
 b) —CH 2 CH 2 CH 2 CH 2 —,  
 c) —CH═CHCH 2 —,  
 d) —CH═CHCH 2 CH 2 —, or  
 e) —CH 2 CH═CHCH 2 —;  
 
 provided that when X is —NHCOCH 2 — then Y cannot be —CH 2 —; and  
 excluding the racemic compounds wherein Ar is benzene, R 2 -R 4  is hydrogen, X is NHCO, Y is a single bond, Z is —CH 2 CH 2 CH 2 —, and R 1  is ethyl or n-propyl.  
 
     
     
         2 . A compound according to  claim 1 , wherein 
 R 1  is 
 a) H,  
 b) C 1 -C 4  alkyl,  
 c) C 1 -C 4  alkoxy C 1 -C 4  alkyl,  
 d) C 1 -C 4  alkylthio C 1 -C 4  alkyl,  
 e) fluorinated C 1 -C 4  alkyl,  
 f) aryl C 1 -C 4  alkyl,  
 g) C 1 -C 4  alkenyl, or  
 h) cyclopropylmethyl;  
   R 2  is 
 a) H,  
 b) C 1 -C 4  alkyl,  
 c) C 2 -C 3  alkynyl,  
 d) halogen,  
 e) substituted or unsubstituted carbamoyl,  
 f) substituted or unsubstituted carbamoyloxy,  
 g) C 1 -C 3  alkylcarbonyl,  
 h) C 1 -C 3  alkoxycarbonyl,  
 i) C 1 -C 3  alkylcarbonyloxy,  
 j) hydroxy-substituted C 1 -C 3  alkyl,  
 k) cyano,  
 l) fluorinated C 1 -C 3  alkoxy,  
 m) fluorinated C 1 -C 6  alkylthio,  
 n) C 1 -C 3  alkylsulfinyl,  
 o) C 1 -C 3  alkylsulfonyl,  
 p) C 1 -C 3  alkylsulfinyl C 1 -C 6  alkyl,  
 q) C 1 -C 4  alkylsulfonyl C 1 -C 6  alkyl,  
 r) C 1 -C 3  alkylsulfonylamino,  
 s) halogenated C 1 -C 3  alkylsulfonylamino,  
 t) sulfamoyl,  
 u) sulfamoyloxy,  
 v) aryl,  
 w) heteroaryl,  
 x) heteroarylsulfinyl,  
 y) arylsulfonyl,  
 z) heteroarylsulfonyl, in which any aromatic moiety is optionally substituted,  
 aa) C 1 -C 4  alkylcarbonylamino,  
 bb) C 1 -C 3  alkoxycarbonylamino,  
 cc) C 1 -C 3  alkyl-thiocarbonyl, or  
 dd) C 1 -C 3  alkoxy-thiocarbonyl;  
   R 3  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
   R 4  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen,  
   R 2  and R 3  may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OH, cyano, amino, C 1 -C 6  alkyl-NH—, (C 1 -C 6  alkyl) 2 -N—, CN, NH 2 SO 2 , NH 2 CO—, or C 1 -C 6  alkyl-CO—;    Any amino moiety in R 2 -R 4  can obtionally be substituted with one or two C 1 -C 6  alkyl groups which may be part of a ring;    Ar is 
 a) benzene,  
 b) pyridine,  
 c) thiophene,  
 d) pyrazine,  
 e) pyrimidine,  
 f) oxazole,  
 g) thiazole,  
 h) pyrrole,  
 i) pyrazole, or  
 j) furan;  
   X is 
 a) —NHCO—,  
 b) —CONH—,  
 c) —NH—SO 2 —, or  
 d) —SO 2 NH—;  
   Y is 
 a) —CH 2 —,  
 b) —CH(C 1 -C 6  alkyl)—,  
 c) —C(C 1 -C 6  alkyl) 2 —, or  
 d) a single bond;  
   Z is 
 f) —CH 2 CH 2 CH 2 —,  
 g) —CH 2 CH 2 CH 2 CH 2 —,  
 h) —CH═CHCH 2 —,  
 i) —CH═CHCH 2 CH 2 —, or  
 j) —CH 2 CH═CHCH 2 —;  
   provided that when X is —NHCOCH 2 — then Y cannot be —CH 2 —; and    excluding the racemic compounds wherein Ar is benzene, R 2 -R 4  is hydrogen, X is NHCO, Y is a single bond, Z is —CH 2 CH 2 CH 2 −, and R 1  is ethyl or n-propyl.    
     
     
         3 . A compound according to  claims 1  to  2 , wherein 
 R 1  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) C 1 -C 4  alkoxy C 1 -C 4  alkyl;  
 
 R 2  is 
 a) H,  
 b) C 1 -C 4  alkyl,  
 c) halogen,  
 d) substituted or unsubstituted carbamoyl,  
 e) substituted or unsubstituted carbamoyloxy,  
 f) C 1 -C 2  alkylcarbonyl,  
 g) C 1 -C 3  alkoxycarbonyl,  
 h) cyano,  
 i) fluorinated C 1 -C 2  alkoxy,  
 j) fluorinated C 1 -C 6  alkylthio,  
 k) C 1 -C 3  alkylsulfinyl,  
 l) C 1 -C 3  alkylsulfonyl,  
 m) C 1 -C 2  alkylsulfonylamino,  
 n) C 1 -C 3  alkylcarbonylamino, or  
 o) C 1 -C 3  alkoxycarbonylamino;  
 
 R 3  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
 
 R 4  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
 
 R 2  and R 3  may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OH, cyano, amino, C 1 -C 6  alkyl-NH—, (C 1 -C 6  alkyl) 2 -N—, CN, NH 2 SO 2 , NH 2 CO—, or C 1 -C 6  alkyl-CO—;  
 Any amino moiety in R 2 -R 4  can obtionally be substituted with one or two C 1 -C 6  alkyl groups which may be part of a ring;  
 Ar is 
 a) benzene,  
 b) pyridine,  
 c) thiophene,  
 d) pyrazine,  
 e) pyrimidine,  
 f) oxazole,  
 g) thiazole,  
 h) pyrrole,  
 i) pyrazole, or  
 j) furan;  
 
 X is 
 a) —NHCO—,  
 b) —CONH—,  
 c) —NH—SO 2 —, or  
 d) —SO 2 NH—;  
 
 Y is 
 a) —CH 2 —,  
 b) —CH(C 1 -C 6  alkyl)—,  
 c) —C(C 1 -C 6  alkyl) 2 —, or  
 d) a single bond;  
 
 Z is 
 a) —CH 2 CH 2 CH 2 —,  
 b) —CH 2 CH 2 CH 2 CH 2 —,  
 c) —CH═CHCH 2 —,  
 d) —CH═CHCH 2 CH 2 —, or  
 e) —CH 2 CH═CHCH 2 —;  
 
 excluding the racemic compounds wherein Ar is benzene, R 2 -R 4  is hydrogen, X is NHCO, Y is a single bond, Z is —CH 2 CH 2 CH 2 —, and R 1  is ethyl or n-propyl.  
 
     
     
         4 . A compound according to  claims 1  to  3 , wherein 
 R 1  is H;  
 R 2  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
 
 R 3  is 
 a) H,  
 b) C 1 -C 4  alkyl, or  
 c) halogen;  
 
 R 4  is 
 d) H,  
 e) C 1 -C 4  alkyl, or  
 f) halogen;  
 
 Ar is 
 a) benzene, or  
 b) pyridine;  
 
 X is 
 a) —NHCO—,  
 b) —CONH—, or  
 c) —NH—SO 2 —;  
 
 Y is a single bond;  
 Z is 
 a) CH 2 CH 2 CH 2 —, or  
 b) —CH═CHCH 2 —;  
 
 excluding the racemic compounds wherein Ar is benzene, R 2 -R 4  is hydrogen, X is NHCO, Y is a single bond, Z is —CH 2 CH 2 CH 2 —, and R 1  is ethyl or n-propyl.  
 
     
     
         5 . A compound or a pharmaceutically acceptable salt thereof, according to  claims 1  to  4  being 
 5-Fluorospiro[indolin-3,3′-piperidin]-2-one;  
 5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 (R)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 (S)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 5,7-Difluorospiro[indolin-3,3′-piperidin]-2-one acetate;  
 5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 (S)-5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 1′,5-Dimethylspiro[indolin-3,3′-piperidin]-2-one;  
 5-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one;  
 6-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one;  
 4-Methylspiro[indolin-3,3′-piperidin]-2-one;  
 4-Methyl-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 4-Methyl-1′-propylspiro[indolin-3,3′-piperidin]-2-one;  
 7-Fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one;  
 (S)-(+)-7-Fluorospiro[indolin-3,3′-piperidin]-2-one;  
 Spiro[indolin-3,3′-piperidin]-2-one;  
 1′-Ethylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-Propyl-spiro[indolin-3,3′-piperidin]-2-one;  
 1′-Isopropylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-Allylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-Cyclopropylmethylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-Butylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-s-Butylspiro[indolin-3,3′-piperidin]-2-one;  
 (S)-(+)-1′-Propylspiro[indolin-3,3′-piperidin]-2-one;  
 1′-Propylspiro[4-azaindolin-3,3′-piperidin]-2-one;  
 1′-Butylspiro[4-azaindolin-3,3′-piperidin]-2-one;  
 1′-sec-Butylspiro[4-aza-indolin-3,3′-piperidin]-2-one;  
 1′-Propyl-5-chlorospiro[7-aza-indolin-3,3′-piperidin]-2-one;  
 1′-Propylspiro[7-azaindolin-3,3′-piperidin]-2-one;  
 1′-Propyl-6-methylspiro[7-azaindolin-3,3′-piperidin]-2-one;  
 1′-Propylspiro[isoindolin-3,3′-piperidin]-1-one hydrochloride;  
 1′-Isopropylspiro[indoline-3,3′-piperidine]hydrochloride;  
 2,3-Dihydro-1H-1′-Propylspiro[thieno[3,2-b]pyrrol-3,3′-piperidin]-2-one;  
 2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3′-pyridin]-2-one;  
 2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[5,8-diazaindol-3,3′-pyridin]-2-one;  
 1′,2′,3′,4′-Tetrahydrospiro[indolin-3,3′-(7H)-azepin]-2-one;  
 1′,2′,3′,4′-Tetrahydrospiro[7-azaindolin-3,3′-(7H)-azepin)-2-one;  
 1′-Ethyl-1′,2′,3′,4′-tetrahydrospiro[4-azaindolin-3,3′-(7H)-azepin)-2-one;  
 
     
     
         6 . A compound or a pharmaceutically acceptable salt thereof, according to claims  1 - 4  being 
 (S)-5-Chloro-7-fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one  
 (S)-5-Chlorospiro[indoline-3,3′-piperidin]-2-one.  
 
     
     
         7 . A compound of the formula (S)-5-Chloro-7-fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         8 . A compound of the formula (S)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         9 . A compound of the formula (S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-on or a therapeutically acceptable salt thereof.  
     
     
         10 . A compound of the formula (S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         11 . A compound of the formula (S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         12 . A compound of the formula (S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         13 . A compound of the formula (S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         14 . A compound of the formula (S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         15 . A compound of the formula (S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt thereof.  
     
     
         16 . A compound of the formula (S)-5-Chlorospiro[indoline-3,3′-piperidin]-2-one or a therapeutically acceptable salt thereof.  
     
     
         17 . A process for the preparation of a compound according to any one of  claims 1  to  16  comprising the step of 
 A) cyclizing a compound of the Formula VII  
                     
 wherein L is a halogen or a trifluoromethylsulfonyl group, to give a compound of the general Formula I using palladium as a catalyst under standard conditions;  
 or  
 B) cyclizing a compound of the Formula XII  
                     
 wherein X is and X is —NHCO—, —CONH—, —NH—SO 2 —, or —SO 2 NH—, A is oxygen or nitrogen, and PG is a suitable protecting group, such as Boc or benzyl when A is nitrogen and 4-methoxybenzyl when A is oxygen, to give a compound of the general Formula I using formaldehyde under standard Mannich conditions;  
 or  
 C) cyclizing a compound of the Formula VI  
                     
 to give a compound of the general Formula I using formaldehyde under standard Mannich conditions;  
 or  
 D) cyclizing a compound of the Formula V  
                     
 wherein PG is an amino protecting group, using a ruthenium or molybdene complex as a catalyst under standard reaction conditions to give compounds of the general formula I, wherein Z is CH═CHCH 2 —, or —CH2CH═CHCH 2 —.  
 
     
     
         18 . A pharmaceutical formulation containing a compound according to any one of  claims 1  to  16  as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.  
     
     
         19 . Use of a compound according to any one of  claims 1  to  16  in therapy.  
     
     
         20 . Use of a compound according to any one of  claims 1  to  16  for the manufacture of a medicament for the treatment of pain.  
     
     
         21 . Use of a compound according to any of  claims 1  to  16  for the manufacture of a medicament for the treatment of neuropathic or central pain.  
     
     
         22 . Use of a compound according to any of claims  20  and  21  for the manufacture of a medicament for oral use.  
     
     
         23 . A method for treatment or prophylaxis of pain or discomfort, comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any one of  claims 1  to  16 .  
     
     
         24 . A method for treatment or prophylaxis of neuropathic or central pain, comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound according to any of claims  1 - 16 .  
     
     
         25 . A method according to any of claims  23  and  24  by oral administration.  
     
     
         26 . A pharmaceutical formulation for use in the treatment or prophylaxis of pain or discomfort, comprising a compound of the formula I according to any one of  claims 1  to  16 , in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         27 . A pharmaceutical formulation for use in the treatment or prophylaxis of neuropathic or central pain, comprising a compound according to any of claims  1 - 16 , in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         28 . A pharmaceutical formulation according to any of claims  18 ,  26  and  27  for oral administration