AMIDE DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN

• US 20170197984A1
• Filed: 06/02/2015
• Published: 07/13/2017
• Est. Priority Date: 06/02/2014
• Status: Active Grant

• Current Assignee: Esteve Pharmaceuticals S.A. (Corporation Quimico Farmaceutica Esteve SA)
• Original Assignee: Laboratories Del Dr Esteve SA (Corporation Quimico Farmaceutica Esteve SA)
• Inventors: VIRGILI-BERNADO, Marina, ALONSO-XALMA, Monica, ALEGRET-MOLINA, Carlos, MERCE-VIDAL, Ramn, ALMANSA-ROSALES, Carmen
• Granted Patent: US 10,065,971 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

The present invention relates to compounds 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.

wherein
Y is

n is 1 or 2;
q is 1, 2, 3, 4, 5 or 6;
X is a bond, —C(O)O—, —C(O)NR₈—, —C(O)—, —O— or —C(R₄R_4′)—;
R₁ is C(O)R₅ or S(O)₂R⁵.

Claims

1-18. -18. (canceled)

19. A compound of formula (I),

20. The compound according to claim 19, wherein

R₃ and R₃′

are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl and substituted or unsubstituted cycloalkyl, with cycloalkyl, if substituted, being substituted by substituents selected from halogen, —

R₉, and —

OR₉;

and

R₄ is hydrogen, —

OR₈, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, —

C(O)OR₉, —

C(O)NR₉R_9′

, —

NR₉C(O)R_9′

, or —

NR₉R<sub>9′

″</sub>

;

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, or a corresponding solvate thereof.

21. The compound according to claim 19, wherein

R₂ is 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, or substituted or unsubstituted heterocyclyl;

with cycloalkyl, aryl, or heterocyclyl, if substituted, being substituted by substituents selected from the group consisting of halogen, —

R₉, —

OR₉, —

NO₂, —

NR₉R<sub>9′

″</sub>

, NR₉C(O)R_9′

, —

NR₉SO2R_9′

, —

S(O)₂NR₉R_9′

, —

NR₉C(O)NR_9′

R_9″

, —

SR₉, —

S(O)R₉, S(O)₂R₉, —

CN, haloalkyl, haloalkoxy, —

C(O)OR₉, —

C(O)NR₉R_9′

, ═

O, —

OCH₂CH₂OH, —

NR₉S(O)₂NR_9′

R_9″

;

R₉, R_9′

and R_9″

are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl;

R<sub>9′

″</sub>

is selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl and -Boc;

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;

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, or a corresponding solvate thereof.

22. The compound according to claim 21, wherein the C_1-6 alkyl is 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;

the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

the aryl is phenyl; and

the heterocyclyl is pyridine, piperidine, thiazole, or morpholine.

23. The compound according to claim 19, wherein

R₃ and R₃′

are independently selected from the group consisting of hydrogen, 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 heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, with cycloalkyl, heterocyclyl or aryl, if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, being substituted by substituents selected from the group consisting of halogen, —

R₉, and —

OR₉;

R₉, and R_9′

are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and 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;

the alkyl is C_1-6 alkyl;

and

the cycloalkyl is C_3-8 cycloalkyl;

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, or a corresponding solvate thereof.

24. The compound according to claim 23, wherein the C_1-6 alkyl is methyl or isopropyl;

the C_2-6 alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl;

the C₂-6 is ethynyl, propynyl, butynyl, pentynyl, or hexynyl;

the cycloalkyl is cyclopropyl;

the aryl is phenyl; and

the heterocyclyl is imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole or quinazoline.

25. The compound according to claim 23, wherein R₃ and R₃, are independently selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl.

26. The compound according to claim 19, wherein

X is a bond, —

C(O)O—

, —

C(O)NR₈—

, —

C(O)—

, —

O—

or —

C(R₄R_4′

)—

, wherein

R_4′

is hydrogen, —

OR₈, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, —

COOR₉, —

CONR₉R₉′

, —

NR₉COR_9′

, or —

NR₉R<sub>9′

″</sub>

;

R_4′

is hydrogen, or substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl or substituted or unsubstituted C_2-6 alkynyl;

R₈ and R₈′

are independently selected from the group consisting of hydrogen, 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 and substituted or unsubstituted heterocyclyl,

R₉, R_9′

and R_9″

are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl;

R<sub>9′

″</sub>

is selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl and -Boc;

wherein

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;

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, or a corresponding solvate thereof.

27. The compound according to claim 26, wherein

the C_1-6 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl;

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 aryl is phenyl; and

the heterocyclyl is imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole or quinazoline.

28. The compound according to claim 19, wherein

R₅ is substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl aryl, substituted or unsubstituted alkyl heterocyclyl, substituted or unsubstituted alkyl cycloalkyl, or —

NR₈R₈, wherein the cycloalkyl, aryl or heterocyclyl groups, if substituted, also in alkyl aryl, alkyl heterocyclyl, alkyl cycloalkyl, are substituted by substituents selected from the group consisting of halogen, —

R₉, —

OR₉, —

NO₂, —

NR₉R<sub>9′

″</sub>

, —

NR₉C(O)R₉, —

NR₉S(O)₂R_9′

, —

S(O)₂NR₉R_9′

, —

NR₉C(O)NR_9′

R_9″

, —

SR₉, —

S(O)R₉, —

S(O)₂R₉, —

CN, haloalkyl, haloalkoxy, —

C(O)OR₉ and —

C(O)NR₉R_9′

;

R₈ and R₈′

are independently selected from the group consisting of hydrogen, 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 and substituted or unsubstituted heterocyclyl;

R₉, R_9″

and R_9″

are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl;

R<sub>9′

″</sub>

is selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl and -Boc;

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 from the group consisting of nitrogen, oxygen and sulfur;

the alkyl is C_1-6 alkyl;

and

the cycloalkyl is C_3-8 cycloalkyl;

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, or a corresponding solvate thereof.

29. The compound according to claim 28, 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;

the cycloalkyl is cyclopropyl;

the aryl is phenyl; and

the heterocyclyl is pyridine, thiazole, tetrahydropyran or piperidine.

30. The compound according to claim 19, wherein

R₆, R_6′

R₇, and R_7′

are independently selected from the group consisting of hydrogen, halogen, —

OR₉, 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;

R₉, R_9′

and R_9″

are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl;

R<sub>9′

″</sub>

is selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl and -Boc;

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;

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, or a corresponding solvate thereof.

31. The compound of claim 30, 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 cycloalkyl is cyclopropyl;

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, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole or quinazoline.

32. The compound of claim 30, wherein R₆, R_6′

R₇, and R_7′

are hydrogen.

33. The compound according to claim 19, wherein

R₁₀ and R_10′

are independently selected from the group consisting of hydrogen, halogen, —

OR₉, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted —

O—

C_1-6 alkyl, substituted or unsubstituted —

O—

C_2-6 alkenyl or substituted or unsubstituted —

O—

C_2-6 alkynyl.

34. The compound according to claim 33, wherein the C_1-6 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl;

the C_2-6 alkenyl is ethenyl, propenyl, butenyl, pentenyl, or hexenyl; and

the C_2-6 alkynyl is ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

35. The compound according to claim 33, wherein R₁₀ and R_10′

are hydrogen.

36. The compound according to claim 19, wherein the compound of formula I is a compound of formula I′

37. The compound according to claim 19, wherein the compound of formula I is a compound of formula I″

38. The compound according to claim 19, wherein the compound of formula I is a compound of formula I′

″

39. The Compound according to 19, which is is selected from the group consisting of:

(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

1-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-phenylethanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-3-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-4-yl)methanone

(4-chloropyridin-2-yl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-methoxyphenyl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-fluorophenyl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

1-(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone

cyclopropyl(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(thiazol-4-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(thiazol-2-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(thiazol-5-yl)methanone

1-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-(pyridin-3-yl)ethanone

1-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone

(3-methoxyphenyl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(tetrahydro-2H-pyran-4-yl)methanone

1-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-(pyridin-2-yl)ethanone

2-cyclopropyl-1-(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-(trifluoromethyl)pyridin-2-yl)methanone

(5-fluoropyridin-2-yl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(5-chloropyridin-2-yl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

(3-fluoropyridin-2-yl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(5-fluoropyridin-3-yl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-(trifluoromethyl)pyridin-2-yl)methanone

(5-fluoropyridin-2-yl)(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(5-chloropyridin-2-yl)(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

8-phenethyl-12-[(pyridin-2-yl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

12-[(5-chloropyridin-2-yl)carbonyl]-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

(3-fluoropyridin-2-yl)(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(5-fluoropyridin-3-yl)(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

(5-chloropyridin-3-yl)(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-(trifluoromethyl)pyridin-3-yl)methanone

(9-(2-(3-chloropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(6-(trifluoromethyl)pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(5-chloropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

6-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)nicotinonitrile

(2-methyl-9-(2-(3-(trifluoromethyl)pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(5-(trifluoromethyl)pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(4-(trifluoromethyl)pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(3-nitropyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(6-aminopyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(2-nitropyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(3-chloropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2,6-difluorophenyl)methanone

(9-(2-(3-chloropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

(9-(2-(3-chloropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-fluorophenyl)methanone

(9-(2-(3-chloropyridin-4-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(3-fluoropyridin-4-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(5-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(2-fluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

1-(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)propan-1-one

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(cyclopropyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(2,6-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

8-(2-(3-chloropyridin-2-yl)ethyl)-12-[(2,6-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

(2-fluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2,6-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-(2-hydroxy-2-phenylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-methoxyphenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

phenyl(9-(2-(pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

9-phenethyl-N-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

cyclopropyl(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

N-methyl-9-phenethyl-N-phenyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(piperidin-1-yl)methanone

phenyl(9-(3-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

phenyl(9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

phenyl(9-(2-(pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-methyl-9-(2-(pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(6-methoxypyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(pyridin-4-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

4-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)benzenesulfonamide

(2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

4-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)-N-methylbenzenesulfonamide

tert-butyl(4-(2-(4-(5-chloropicolinoyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)thiazol-2-yl)carbamate

tert-butyl(4-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)thiazol-2-yl)carbamate

(2-methyl-9-(3-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

(2-methyl-9-(2-nitrophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(3-nitrophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

9-phenethyl-4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane

4-(isopropylsulfonyl)-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane

(2-methyl-9-(3-phenylpropyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-isopentyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(2-methyl-9-(2-(pyridin-2-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-isopropoxyethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-morpholinoethanone

2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-(piperidin-1-yl)ethanone

1-(9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)propan-1-one

(9-(2-(5-chloropyridin-3-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(5-fluoropyridin-3-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

8-(2-fluorophenethyl)-12-[(pyridin-2-yl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

1-(2-isopropyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone cyclopropyl(2-isopropyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-(3-nitrophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-benzyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-hydroxyphenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(3-hydroxyphenyl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-hydroxyphenyl)(9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(9-(2-(2-aminothiazol-4-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-chloropyridin-2-yl)methanone

(9-(2-(2-aminothiazol-4-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(3-aminophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-aminophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(3-aminophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(3-aminopyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

(9-(2-(2-aminopyridin-3-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(phenyl)methanone

1-(3-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl) urea

1-(2-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)urea

N-(3-(2-(4-benzoyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)acetamide

N-(2-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)acetamide

N-(3-(2-(4-benzoyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)acetamide

N-(3-(2-(4-benzoyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenyl)methanesulfonamide

2-methyl-9-phenethyl-4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane

4-(isopropylsulfonyl)-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane

N,N-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

N,N,2-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

N-methyl-9-phenethyl-N-(pyridin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

N-cyclopropyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

9-phenethyl-N-(pyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

N-cyclopropyl-N-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

N-methyl-9-phenethyl-N-(pyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxamide

(R)-(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

(S)-(2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(pyridin-2-yl)methanone

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(2,3-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(2,4-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

2-(2-(12-(2-fluorobenzoyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)nicotinonitrile

8-(2-(3-fluoropyridin-2-yl)ethyl)-12-[(2,5-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

12-[(2-fluorophenyl)carbonyl]-8-(2-(3-methoxypyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

(2-fluorophenyl) (9-(2-(3-fluoropyridin-2-yl)ethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

12-[(3-fluorophenyl)carbonyl]-8-(2-(3-fluoropyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

12-[(4-fluorophenyl)carbonyl]-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-[(2-methoxyphenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

2-(8-(2-(3-fluoropyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane-12-carbonyl)benzonitrile

12-[(2-chlorophenyl)carbonyl]-8-(2-(3-fluoropyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

(2,3-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

8-(2-(3-chloropyridin-2-yl)ethyl)-12-[(2,3-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

12-[(2-fluorophenyl)carbonyl]-8-(2-(6-methoxypyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

methyl 3-(12-(2,6-difluorobenzoyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)propanoate

12-[(2,6-difluorophenyl)carbonyl]-8-(2-(6-methoxypyridin-2-yl)ethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

8-(2,5-difluorophenethyl)-12-[(2,6-difluorophenyl)carbonyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane

(R)-(2-fluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(S)-(2-fluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(R)-(2,6-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(S)-(2,6-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2,3-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2,4-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2,5-difluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(2-chlorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone

(3-fluorophenyl)(9-(2-(3-fluoropyridin-2-yl)ethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone,

optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.

40. A process for the production of a compound of formula I according to claim 19,

41. A process for the preparation of a compound of formula I″

according to claim 37

42. A process for the preparation of a compound of formula I′

″

according to claim 38

43. A pharmaceutical composition which comprises the compound according to claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

44. A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 19.

45. The method according to claim 44, 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 or neuropathic pain, allodynia and hyperalgesia.