Substituted benzoxazolone derivatives as acid ceramidase inhibitors, and their use as medicaments

Patent metadata

Field	Value
Publication number	US-10213416-B2
Application number	US-201615346457-A
Country	US
Kind code	B2
Filing date	Nov 8, 2016
Priority date	May 12, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present invention relates to substituted benzoxazolone derivatives as acid ceramidase inhibitors, pharmaceutical compositions containing these inhibitors and methods of inhibiting acid ceramidase for the treatment of disorders in which modulation of the levels of ceramide is clinically relevant. The invention also provides substituted benzoxazolone derivatives for use in the treatment of cancer, inflammation, pain, inflammatory pain or pulmonary diseases.

First claim

The invention claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein:
X is a bond, CO, CH(OH) or CH 2 group; wherein X can be attached to any position of the ring to which it is connected;
R, R 1 and R 2 are independently hydrogen or linear or branched C 1-6 alkyl;
n is an integer from 1 to 6;
A is a linear or branched C 1-9 alkyl, C 2-9 alkenyl or C 2-9 alkynyl group or a group:

wherein:
m is 0 or an integer from 1 to 6;
G is a 3-10 membered saturated or unsaturated, aromatic or heteroaromatic, single or fused ring comprising up to three heteroatoms selected from N, O, and S; and R 6 and R 7 are as defined below;
R 3 is hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy or OH; wherein R 3 can be attached to any position of the ring to which it is connected;
R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, OH, CN, NO 2 , fluoro C 1-6 alkyl, fluoro C 1-6 alkoxy, COOR 8 , CONR 9 R 10 , SO 2 NR 9 R 10 , and SO 2 R 11 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, OH, CN, NO 2 , fluoro C 1-6 alkyl, fluoro C 1-6 alkoxy, optionally substituted aryl or heteroaryl, COOR 8 , CONR 9 R 10 , SO 2 NR 9 R 10 , and SO 2 R 11 ;
wherein
R 4 , R 5 , R 6 and R 7 can be attached to any position of the ring to which they are connected;
Y is a bond or a heteroatom selected from the group consisting of O, S, SO, SO 2 and NR 12 ; and
R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from the group consisting of hydrogen and linear or branched C 1-6 alkyl;
with the proviso that when Y is a bond, n+m is ≥4 and A is a group

2. A compound according to claim 1 wherein:
X is a bond, CO, or CH(OH);
R is hydrogen;
R 1 and R 2 are independently hydrogen or linear or branched C 1-6 alkyl;
n is an integer from 1 to 6;
A is a linear C 1-6 alkyl or a group

wherein
m is an integer from 1 to 6;
G is
an aryl selected from naphthyl or phenyl
(C 3 -C 10 )cycloalkyl, or
a heteroaryl which is pyridyl, thiophenyl, pyrimidinyl, furyl, or indolyl;

R 3 is hydrogen or halogen;
R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy, OH, CN, NO 2 , CF 3 , and hydroxy C 1-6 alkyl;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, linear or branched C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, OH, CN, NO 2 , and CF 3 ;
Y is a bond or heteroatom selected from the group consisting of O, S, SO, and SO 2 ;
with the proviso that when Y is a bond, A is a group

and n+m is ≥4.

3. A compound according to claim 1 having the Formula (Ia),

4. A compound according to claim 3 having Formula (Ia) wherein:
X is a bond, CO, or CH(OH); wherein X can be attached to any position of the ring to which it is connected;
R is hydrogen;
R 1 and R 2 are independently hydrogen or methyl;
n is an integer from 2 to 4;
m is an integer from 2 to 4;
G is phenyl, thiophenyl, pyridyl, naphthyl or C 3-7 cycloalkyl;
R 3 is hydrogen or chlorine; wherein R 3 can be attached to any position of the ring to which it is connected;
R 4 is hydrogen;
R 5 is independently selected from the group consisting of halogen, Me, Et, MeO, EtO, OH, CN, NO 2 , and CF 3 ; and
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, Me, Et, MeO, EtO, OH, CN, NO 2 , and CF 3 ;
wherein R 4 , R 5 , R 6 and R 7 can be attached to any position of the ring to which they are connected.

5. A compound according to claim 1 having Formula (Ib)

wherein:
Y is a heteroatom selected from the group consisting of O, S, SO, SO 2 and NR 12; wherein R 12 is hydrogen or linear or branched C 1-6 alkyl.

6. A compound of Formula (Ib) according to claim 5 , wherein
X is a bond, CO, or CH(OH); wherein X can be attached to any position of the ring to which it is connected;
R is hydrogen;
R 1 and R 2 are independently hydrogen or Me;
n is an integer from 1 to 4;
m is 0 or an integer from 1 to 4;
G is phenyl, thiophenyl, pyridyl, naphthyl or C 3-7 cycloalkyl;
R 3 is hydrogen or chlorine; wherein R 3 can be attached to any position of the ring to which it is connected;
R 4 is hydrogen;
R 5 is independently selected from the group consisting of halogen, Me, Et, MeO, EtO, OH, CN, NO 2 , and CF 3 ; and
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, Me, Et, MeO, EtO, OH, CN, NO 2 , and CF 3 ;
wherein R 4 , R 5 , R 6 and R 7 can be attached to any position of the ring to which they are connected.

7. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, of claim 1 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 comprising an additional pharmaceutically active ingredient.

9. The pharmaceutical composition of claim 8 wherein the additional pharmaceutically active ingredient is an anticancer agent, an anti-inflammatory agent, an analgesic compound, an agent for treating pulmonary diseases, or mixtures thereof.

10. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.

Assignees

• Fondazione St Italiano Tecnologia
• Univ California
• The Regents Of The Univ Of Chicago
• Fondazione Istituto Italiano Di Tech

Inventors

• Piomelli Daniele
• Pizzirani Daniela
• Bach Anders
• Scarpelli Rita
• Melzig Laurin
• Mor Marco

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/421 Primary

  1,3-Oxazoles, e.g. pemoline, trimethadione · CPC title

• C07D263/58

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2 · CPC title