Oxa-azaspiro compounds having activity against pain

Patent metadata

Field	Value
Publication number	US-2018312479-A1
Application number	US-201615769502-A
Country	US
Kind code	A1
Filing date	Oct 21, 2016
Priority date	Oct 23, 2015
Publication date	Nov 1, 2018
Grant date	—

Abstract

The present invention relates to oxa-azaspiro compounds having pharmacological activity towards the sigma (σ) receptor, 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.

First claim

1 - 16 . (canceled)

17 . A compound of general Formula (I):

wherein
R 1 is

m is 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4 or 5;
p is 0, 1 or 2;
Y is —CH 2 — or —C(O)—;
X is a bond, —C(R x R x′ )—, —O—, —C(O)—, —C(O)NR 7 —, —NR 7 C(O)— or —C(O)O—;
wherein R x is selected from the group consisting of halogen, —OR 7 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;
R x′ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;
R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

R 1′ is selected from the group consisting of 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;
R 2 is 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;
R 3 and R 3′ 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 alkylcycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted alkylheterocyclyl; or
R 3 and R 3′ , together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;
R 4 and R 4′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;
R 5 and R 5′ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl; or
R 5 and R 5′ together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclyl;
R 6 and R 6′ are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, —CHOR 8 and —C(O)OR 8 ;
wherein R 8 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl and substituted or unsubstituted C 2-6 alkynyl;

R n is selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl;
optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or a mixture of at least two stereoisomers, including enantiomers and/or diastereomrers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof;
with the proviso that when Y is —C(O)—; then R 1 is not

18 . The compound according to claim 17 , wherein
X is a bond.

19 . The compound according to claim 17 , wherein
R 1′ is selected from the group consisting of 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.

20 . The compound according to claim 19 , wherein R 1′ is substituted or unsubstituted methyl, substituted or unsubstituted ethyl or substituted or unsubstituted phenyl.

21 . The compound according to claim 17 , wherein
R 2 is 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.

22 . The compound according to claim 21 , wherein R 2 is hydrogen, substituted or unsubstituted isopropyl, substituted or unsubstituted isobutyl or substituted or unsubstituted phenyl.

23 . The compound according to claim 17 , wherein
R 3 and R 3′ , together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl.

24 . The compound according to claim 23 , wherein R 3 and R 3′ form a substituted or unsubstituted cyclopropyl.

25 . The compound according to claim 17 , which is a compound of Formula (I′)

26 . The compound according to claim 17 , which is a compound of Formula (I 2′ )

27 . The compound according to claim 17 , which is a compound of Formula (I 3′ )

28 . The compound according to claim 17 , which is selected from the group consisting of:
(5s,8s)-8-(benzylamino)-12-ethyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-8-(benzylamino)-12-ethyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-12-ethyl-8-[methyl(2-phenylethyl)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-12-ethyl-8-[methyl(2-phenylethyl)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-8-[benzyl(methyl)amino]-12-ethyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-12-ethyl-8-[(2-phenylethyl)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-12-ethyl-8-[(2-phenylethyl)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-8-[benzyl(methyl)amino]-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-8-[methyl(2-phenylethyl)amino]-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-8-(benzylamino)-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-12-phenyl-8-[(2-phenylethyl)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-8-(benzylamino)-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-12-phenyl-8-[(2-phenylethy)amino]-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-8-[benzyl(methyl)amino]-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-8-[methyl(2-phenylethyl)amino]-12-phenyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5r,8r)-8-[benzyl(methyl)amino]-12-ethyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-13-one, (5s,8s)-N-benzyl-12-ethyl-N-methyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-8-amine, (5r,8r)-N-benzyl-12-ethyl-N-methyl-4-oxa-12-azadispiro[2.1.5.3]tridecan-8-amine,

Assignees

• Esteve Labor Dr

Inventors

• Almansa-Rosales Carmen
• Alegret-Molina Carlos

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D265/34 Primary

  condensed with carbocyclic rings · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title