Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain

Abstract

The present invention relates to compounds of general formula (I) having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opiod receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein 
         Y is 
       
       
         
           
           
               
               
           
         
         and Z is —CH 2 —, —C(O)— or —CHR 9 — or 
         Y is 
       
       
         
           
           
               
               
           
         
         and Z is —CH 2 — or —CHR 9 —; 
         m is 0 or 1; 
         n is 1, 2 or 3; 
         q is 1, 2, 3, 4, 5 or 6; 
         R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or —(CH 2 ) r —W—R 1′ ; 
         r is 0, 1 or 2; 
         W is —CH 2 O—, —CH 2 C(O)NR 5′ —, —CH 2 C(O)O—, —CH 2 C(O)— or —C(CH 3 ) 2 O—; 
         R 1  is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R 5 ; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 1  or R 1′ , if substituted, also in alkylaryl or alkylheterocyclyl, are substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         X is a bond, —C(O)O—, —C(O)NR 5 —, —C(O)—, —O— or —C(R 4 R 4′ )—; 
         R 2  is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 2 , if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, is substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , —NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, -haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 3  and R 3′  are independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl; 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 3 , also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  or —S(O) 2 R 5 ; 
         R 4  is H, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —COOR 5 , —CONR 5 R 5′ , —NR 5 COR 5′ , —NR 5 R 5′″  or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 4 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 4′  is H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 5 , R 5′  and R 5″  are independently selected from the group consisting of H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl, unsubstituted aryl or unsubstituted alkylaryl; 
         R 5′″  is H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl or -Boc; 
         R 6 , R 6′ , R 7  and R 7′  are independently selected from the group consisting of H, halogen, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, unsubstituted heterocyclyl, unsubstituted aryl and unsubstituted cycloalkyl; 
         R 8  and R 8′  are independently selected from the group consisting of H, —OR 5 , halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 9  is selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted and unsubstituted C 2-6  alkynyl; wherein 
         the alkyl, alkenyl and alkynyl as defined in R 1 , R 1 , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 6 , R 6′ , R 7 , R 7′ , R 8 , R 8′  and R 9 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5 , —S(O) 2 R 5 , C(O)OR 5  and C(O)NR 5 R 5′ ; 
         optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or a mixture of at least two of stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is —(CH 2 ) r —W—R, or R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, or substituted or unsubstituted alkylheterocyclyl. 
     
     
         3 . The compound according to  claim 1 , wherein
 X is a bond; —C(R 4 R 4′ )—; —C(O)O—; —C(O)NR 5 —; —C(O)—; or —O—.   
     
     
         4 . The compound according to  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein
 m is 1, and   n is 2.   
     
     
         6 . The compound according to  claim 1 , wherein
 R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, or —(CH 2 ) r —W—R 1′ , wherein   the aryl is phenyl, naphthyl, or anthracene;   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur;   and   the alkyl is C 1-6  alkyl.   
     
     
         7 . The compound according to  claim 6 , wherein R 1  is substituted or unsubstituted phenyl; substituted or unsubstituted pyridine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, or imidazole; substituted or unsubstituted benzyl; or substituted or unsubstituted alkylheterocyclyl, wherein the heterocyclyl is pyridine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyrane, pyrazole, or imidazole and the alkyl is methyl. 
     
     
         8 . The compound according to  claim 1 , wherein
 R 1′  is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R 5 ; wherein   the aryl is phenyl, naphthyl, or anthracene;   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;   and   the cycloalkyl is C 3-8  cycloalkyl.   
     
     
         9 . The compound according to  claim 8 , wherein R, is substituted or unsubstituted phenyl; substituted or unsubstituted morpholine or tetrahydropyran; or substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         10 . The compound according to  claim 1 , wherein
 R 2  is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; wherein   the aryl is phenyl, naphthyl, or anthracene;   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring;   and   the cycloalkyl is C 3-8  cycloalkyl.   
     
     
         11 . The compound according to  claim 10 , wherein R 2  is substituted or unsubstituted phenyl; substituted or unsubstituted pyridine, piperidine, thiazole, morpholine, tetrahydropyran, pyrazole, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, or pyrimidine; substituted or unsubstituted cyclopropyl; substituted or unsubstituted methyl or isopropyl; substituted or unsubstituted ethenyl, propenyl, butenyl, pentenyl, or hexenyl; or substituted or unsubstituted ethynyl, propynyl, butynyl, pentynyl, or hexynyl. 
     
     
         12 . The compound according to  claim 1 , wherein
 R 3  and R 3′  are independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl, wherein   the alkyl is C 1-6  alkyl;   the cycloalkyl is C 3-8  cycloalkyl;   the aryl is phenyl, naphthyl, or anthracene;   and   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.   
     
     
         13 . The compound according to  claim 12 , wherein the C 1-6  alkyl is methyl or ethyl; the C 2-6  alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl; the C 2-6  alkynyl is ethynyl, propynyl, butynyl, pentynyl, or hexynyl; the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the aryl is phenyl; and the heterocyclyl is imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole, oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole or quinazoline. 
     
     
         14 . The compound according to  claim 1 , wherein
 R 4  is H, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —COOR 5 , —CONR 5 R 5′ , —NR 5 COR 5′ , —NR 5 R5′″, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,   and   R 4  is H or substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl), wherein   the cycloalkyl is C 3-8  cycloalkyl;   the aryl is from phenyl, naphthyl, or anthracene;   and   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.   
     
     
         15 . The compound according to  claim 14 , wherein the C 1-6  alkyl is methyl; the C 2-6  alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl; the C 2-6  alkynyl is ethynyl, propynyl, butynyl, pentynyl, or hexynyl; the heterocyclyl is tetrahydropyran; the aryl is phenyl; and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         16 . The compound according to  claim 1 , wherein
 R 5 , R 5′  and R 5″  are independently H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl, unsubstituted aryl or unsubstituted alkylaryl;   R 5′″  is H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl or -Boc, wherein   the alkyl is C 1-6  alkyl;   and   the aryl is phenyl, naphthyl, or anthracene.   
     
     
         17 . The compound according to  claim 16 , wherein the C 1-6  alkyl is methyl, ethyl, or isopropyl; the C 2-6  alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl; the C 2-6  alkynyl is ethynyl, propynyl, butynyl, pentynyl, or hexynyl; and the aryl is phenyl. 
     
     
         18 . The compound according to  claim 1 , wherein
 R 6 , R 6′ , R 7  and R 7′  are independently selected from the group consisting of H, halogen, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, unsubstituted heterocyclyl, unsubstituted aryl and unsubstituted cycloalkyl; wherein   the cycloalkyl is C 3-8  cycloalkyl;   the aryl is phenyl, naphthyl, or anthracene;   and   the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.   
     
     
         19 . The compound according to  claim 18 , wherein the C 1-6  alkyl is methyl or ethyl; the C 2-6  alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl; the C 2-6  alkynyl is ethynyl, propynyl, butynyl, pentynyl, or hexynyl; the heterocyclyl is tetrahydropyran; the aryl is phenyl or naphthyl; and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         20 . The compound according to  claim 1 , wherein
 R 8  and R 8′  are independently selected from the group consisting of H, —OR 5 , halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl.   
     
     
         21 . The compound according to  claim 20 , wherein R 8  and R 8′  are independently selected from the group consisting of substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; substituted or unsubstituted ethenyl, propenyl, butenyl, pentenyl, or hexenyl; or substituted or unsubstituted ethynyl, propynyl, butynyl, pentynyl, or hexynyl. 
     
     
         22 . (canceled) 
     
     
         23 . The compound according to  claim 1 , which is selected from the group consisting of:
 2-methylene-9-phenethyl-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   4-(2-fluorophenyl)-2-methylene-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   (Z)-4-(2-fluorophenyl)-9-phenethyl-2-((tetrahydro-2H-pyran-4-yl)methylene)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   4-(2-fluorophenyl)-9-phenethyl-2-(propan-2-ylidene)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   4-benzyl-9-(2-methoxyphenethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   12-phenyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(3-nitrophenethyl)-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(2-oxo-2-phenylethyl)-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-(4-methoxybenzyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride;   tert-butyl (4-(2-(13-oxo-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate;   8-(3-nitrophenethyl)-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   tert-butyl (4-(2-(13-oxo-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate;   4-benzyl-9-(2-(pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   4-(2-fluorophenyl)-2-(propan-2-ylidene)-9-(2-(pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   4-(2-fluorophenyl)-9-(2-(4-methylthiazol-5-yl)ethyl)-2-(propan-2-ylidene)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   (Z)-4-(2-fluorophenyl)-2-(3-methoxypropylidene)-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   8-(2-fluorophenethyl)-12-(4-methoxybenzyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-(3-methoxypropyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   N,N-dimethyl-3-[13-oxo-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-12-yl]propanamide;   12-(2-methoxyethyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   methyl 3-(13-oxo-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-12-yl)propanoate;   8-phenethyl-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(2-fluorophenethyl)-12-(2-(trifluoromethyl)pyridin-3-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(2-fluorophenethyl)-12-(3-(trifluoromethyl)pyridin-2-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride;   8-(2-fluorophenethyl)-12-(4-(trifluoromethyl)pyridin-3-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride;   12-(2-Fluorophenyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-phenethyl-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(3-aminophenethyl)-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(3-aminophenethyl)-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   N-[3-(2-{13-oxo-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide;   N-[3-(2-{13-oxo-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]methanesulfonamide;   {3-[2-(13-oxo-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl]phenyl}urea;   N-methyl-3-[13-oxo-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-12-yl]propanamide;   8-(2-hydroxy-2-phenylethyl)-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-(3-hydroxypropyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   4-(2-(4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol;   2-(2-(4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol;   8-[2-(2-aminothiazol-4-yl)ethyl]-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-[2-(2-aminothiazol-4-yl)ethyl]-12-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-(2-hydroxyethyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   3-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)phenol;   9-phenethyl-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   3-(9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)phenol;   2-(methoxymethyl)-9-phenethyl-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   9-(3-methoxyphenethyl)-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   2-(2-(4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol;   3-(2-(4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol;   2-(9-phenethyl-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-2-yl)etanol;   4-benzyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   9-phenethyl-4-(thiazol-4-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   9-(2-methoxyphenethyl)-4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   2-methyl-4-((1-methyl-1H-imidazol-2-yl)methyl)-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   2-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   2-(2-(4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenol;   2-methyl-9-phenethyl-4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   2-methyl-9-phenethyl-4-(2-(pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   9-(4-methoxyphenethyl)-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   4-(3-methoxyphenyl)-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   9-(2-methoxyphenethyl)-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   4-benzyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   9-phenethyl-4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane;   4,9-diphenethyl-1-oxa-4,9-diazaspiro[5.5]undecane;   3-(2-(4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)aniline;   N-(3-(2-(4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)acetamide;   3-methyl-9-phenethyl-4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane;   8-(2,5-difluorophenethyl)-12-(2-(trifluoromethyl)pyridin-3-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(2,5-difluorophenethyl)-12-(4-(trifluoromethyl)pyridin-3-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   8-(2,5-difluorophenethyl)-12-(3-(trifluoromethyl)pyridin-2-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;   12-benzyl-8-(2-(3-fluoropyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane;   8-(2-(3-fluoropyridin-2-yl)ethyl)-12-(3-methylpyridin-2-yl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane;   methyl 3-(12-benzyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)propanoate;   methyl 3-(12-benzyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)propanoate; and   methyl 3-(13-oxo-12-phenyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)propanoate;   optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or in form of a mixture of at least two stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.   
     
     
         24 . A process for the preparation of a compound of formula Ia 
       
         
           
           
               
               
           
         
         wherein 
         Z is —CH 2 — or —CHR 9 —; 
         m is 0 or 1; 
         n is 1, 2 or 3; 
         R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or —(CH 2 ) r —W—R 1′ ; 
         r is 0, 1 or 2; 
         W is —CH 2 O—, —CH 2 C(O)NR 5′ —, —CH 2 C(O)O—, —CH 2 C(O)— or —C(CH 3 ) 2 O—; 
         R 1′  is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R 5 ; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 1  or R 1′  if substituted, also in alkylaryl or alkylheterocyclyl, are substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, haloalkoxy, —SR5, —S(O)R 5  and —S(O) 2 R 5 ; 
         X is a bond, —C(O)O—, —C(O)NR 5 —, —C(O)—, —O— or —C(R 4 R 4′ )—; 
         R 2  is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 2 , if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, is substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , —NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, -haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 3  and R 3′  are independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl; 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 3 , also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 4  is H, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —COOR 5 , —CONR 5 R 5′ , —NR 5 COR 5′ , —NR 5 R 5″  or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl, 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 4 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 4′  is H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 5 , R 5′  and R 5″  are independently selected from the group consisting of H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl, and unsubstituted aryl and unsubstituted alkylaryl; 
         R 5′″  is H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl or -Boc; 
         R 8  and R 8′  are independently selected from the group consisting of H, —OR 5 , halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl and substituted or unsubstituted C 2-6  alkynyl; 
         R 9  is selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl and substituted or unsubstituted C 2-6  alkynyl; wherein 
         the alkyl, alkenyl and alkynyl as defined in R 1 , R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 8 , R 8′ , and R 9 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5 , —S(O) 2 R 5 , C(O)OR 5  and C(O)NR 5 R 5′ ; 
         which comprises the steps of 
         (a) reacting a compound of formula Va 
       
       
         
           
           
               
               
           
         
         with a compound of formula VI 
       
       
         
           
           
               
               
           
         
         wherein LG is a leaving group, 
         to obtain a compound of formula VIIa 
       
       
         
           
           
               
               
           
         
         and 
         (b) Carrying out a cyclisation of the resulting compound in a suitable solvent, in the presence of a strong base and at a temperature comprised between −78° C. and the reflux temperature. 
       
     
     
         25 . A process for the preparation of a compound of general formula Ifx 
       
         
           
           
               
               
           
         
         wherein 
         Z is —CH 2 —, —C(O)— or —CHR 9 —; 
         m is 0 or 1; 
         n is 1, 2 or 3; 
         R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or —(CH 2 ) r —W—R 1′ ; 
         r is 0, 1 or 2; 
         W is —CH 2 O—, —CH 2 C(O)NR 5′ —, —CH 2 C(O)O—, —CH 2 C(O)— or —C(CH 3 ) 2 O—; 
         R 1′  is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R 5 ; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 1  or R 1′ , if substituted, also in alkylaryl or alkylheterocyclyl, are substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, haloalkoxy, —SR5, —S(O)R 5  and —S(O) 2 R 5 ; 
         X is a bond, —C(O)O—, —C(O)NR 5 —, —C(O)—, —O— or —C(R 4 R 4′ )—; 
         R 2  is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 2 , if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, is substituted with substituents selected from the group consisting of —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , —NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, -haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 3  and R 3′  are independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl; 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 3 , also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 4  is H, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —COOR 5 , —CONR 5 R 5′ , —NR 5 COR 5′ , —NR 5 R 5″  or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl, 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 4 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  and —S(O) 2 R 5 ; 
         R 4′  is H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 5 , R 5′  and R 5″  are independently selected from the group consisting of H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl, and unsubstituted aryl or unsubstituted alkylaryl; 
         R 5′″  is H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl or -Boc; 
         R 8  and R 8′  are independently selected from the group consisting of H, —OR 5 , halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl and substituted or unsubstituted C 2-6  alkynyl; 
         R 9  is selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl and substituted or unsubstituted C 2-6  alkynyl; wherein 
         the alkyl, alkenyl and alkynyl as defined in R 1 , R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 8 , R 8′ , and R 9 , if substituted, are substituted with substituents selected from the group consisting of —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5 , —S(O) 2 R 5 , C(O)OR 5  and C(O)NR 5 R 5′ ; 
         and 
         R 7  and R 7′  are hydrogen; 
         which comprises (a) the dehydration of a compound of formula XIXx 
       
       
         
           
           
               
               
           
         
         wherein 
         R 6  and R 6′  are hydrogen; 
         followed by (b) the cyclopropanation of a compound of formula Icx 
       
       
         
           
           
               
               
           
         
       
     
     
         26 . A pharmaceutical composition which comprises the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         27 . A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Y is 
       
       
         
           
           
               
               
           
         
         Z is —CH 2 —, —C(O)— or —CHR 9 —; 
         m is 0 or 1; 
         n is 1, 2 or 3; 
         q is 1, 2, 3, 4, 5 or 6; 
         R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or —(CH 2 ) r —W—R 1′ ; 
         r is 0, 1 or 2; 
         W is —CH 2 O—, —CH 2 C(O)NR 5′ —, —CH 2 C(O)O—, —CH 2 C(O)— or —C(CH 3 ) 2 O—; 
         R 1′  is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R 5 ; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 1  or R 1′  if substituted also in alkylaryl or alkylheterocyclyl are substituted with substituents selected from —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, haloalkoxy, —SR5, —S(O)R 5  or —S(O) 2 R 5 ; 
         X is a bond, —C(O)O—, —C(O)NR 5 —, —C(O)—, —O— or —C(R 4 R 4′ )—; 
         R 2  is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         wherein the aryl, heterocyclyl or cycloalkyl in R 2  if substituted also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl is substituted with substituents selected from —R 5 , —OR 5 , halogen, —CN, —NO 2 , —NR 5 R 5′″ , —C(O)OR 5 , —NR 5 C(O)R 5′ , —C(O)NR 5 R 5′ , —NR 5 S(O) 2 R 5′ , ═O, —OCH 2 CH 2 OH, —NR 5 C(O)NR 5′ R 5″ , —S(O) 2 NR 5 R 5′ , —NR 5 S(O) 2 NR 5′ R 5″ , haloalkyl, -haloalkoxy, —SR 5 , —S(O)R 5  or —S(O) 2 R 5 ; 
         R 3  and R 3′  are independently selected from H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl; 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 3  also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl if substituted are substituted with substituents selected from —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  or —S(O) 2 R 5 ; 
         R 4  is H, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —COOR 5 , —CONR 5 R 5′ , —NR 5 COR 5′ , —NR 5 R 5′″  or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, 
         wherein the aryl, cycloalkyl and heterocyclyl as defined in R 4  if substituted are substituted with substituents selected from —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5  or —S(O) 2 R 5 ; 
         R 4′  is H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2 _6 alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 5 , R 5′  and R 5″  are independently selected from H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl, unsubstituted aryl or unsubstituted alkylaryl; 
         R 5′″  is H, unsubstituted C 1-6  alkyl, unsubstituted C 2-6  alkenyl, unsubstituted C 2-6  alkynyl or -Boc; 
         R 6 , R 6′ , R 7  and R 7′  are independently selected from H, halogen, —OR 5 , substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, unsubstituted heterocyclyl, unsubstituted aryl and unsubstituted cycloalkyl; 
         R 8  and R 8′  are independently selected from H, —OR 5 , halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         R 9  is selected from H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl or substituted or unsubstituted C 2-6  alkynyl; 
         and wherein 
         the alkyl, alkenyl and alkynyl as defined in R 1 , R 1′ , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 6 , R 6′ , R 7 , R 7′ , R 8 , R 8′  and R 9  if substituted are substituted with substituents selected from —OR 5 , halogen, —CN, haloalkyl, haloalkoxy, —SR 5 , —S(O)R 5 , —S(O) 2 R 5 , C(O)OR 5  or C(O)NR 5 R 5′ ; 
         optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
       
     
     
         28 . The method according to  claim 27 , wherein the pain is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain, neuropathic pain, allodynia, and hyperalgesia.