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

Abstract

The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid 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 pharmaceutical composition which comprises a compound selected from the group consisting of:
 12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-isopropyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride,   12-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide,   12-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-ethyl-8-(3-nitrophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   tert-butyl (4-(2-(12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate,   methyl 4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate,   12-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(4-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(2-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide,   8-[2-fluorophenethyl]-12-methyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-fluorophenethyl]-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(3-fluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,   (R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   2,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-methyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-(3-aminophenethyl)-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   N-[3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide,   [3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide,   12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,   8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   2,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   10-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,   10-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,   (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-fluorophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(2-fluorophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-cyclopropyl-9-(2,5-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, and   (R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;   or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the compound is (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one. 
     
     
         3 . A method of treating pain in a subject in need thereof, comprising administration of an effective amount of a compound selected from the group consisting of:
 12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-isopropyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride,   12-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide,   12-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-ethyl-8-(3-nitrophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   tert-butyl (4-(2-(12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate,   methyl 4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate,   12-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(4-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(2-methoxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide,   8-[2-fluorophenethyl]-12-methyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-[2-fluorophenethyl]-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(3-fluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,   (R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   2,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   12-methyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-(3-aminophenethyl)-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   N-[3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide,   [3-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea,   4-(2-{12-ethyl-13-oxo-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide,   12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,   8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   2,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one   4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   8-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   10-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,   10-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,   (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   8-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(3-fluorophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   12-ethyl-8-(2-fluorophenethyl)-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,   (R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   4-cyclopropyl-9-(2,5-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   (R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,   and pharmaceutically acceptable salts thereof.   
     
     
         4 . The method according to  claim 3 , wherein the compound is (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one. 
     
     
         5 . The method according to  claim 3 , 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. 
     
     
         6 . A process for the preparation of a compound having the structure 
       
         
           
           
               
               
           
         
         which comprises the steps of
 (a) reacting a compound having the structure 
 
       
       
         
           
           
               
               
           
         
         wherein R 1  is ethyl and R 2  is 2,5-difluorophenethyl, 
       
       with a compound of formula VI 
       
         
           
           
               
               
           
         
         wherein R 3  is hydrogen, R 3′  is methyl, and W and LG are leaving groups, to obtain a compound of formula VII 
       
       
         
           
           
               
               
           
         
       
       and
 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.