Benzenesulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (RORγ(T))

Patent metadata

Field	Value
Publication number	US-10457637-B2
Application number	US-201515537667-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Dec 19, 2014
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

Benzenesulfonamide derivatives of formula (I), the pharmaceutically acceptable addition salts thereof, the hydrates and/or solvates thereof, and the use of same as inverse agonist of retinoid-related orphan receptor gamma (RORγt) are described. A pharmaceutical composition including such compounds, as well as the use thereof for the topical and/or oral treatment of RORγt receptor-medicated inflammatory diseases, in particular acne, psoriasis and/or atopic dermatitis are also described.

First claim

The invention claimed is:

1. A compound of formula (II), or a pharmaceutically acceptable addition salt thereof:

in which:
q denotes zero or a natural integer ranging from 1 to 3,
R 1 represents a linear or branched C 3 -C 5 alkyl radical, a C 3 -C 5 cycloalkyl radical, a linear or branched C 2 -C 5 alkenyl radical,
R 2 represents a hydrogen atom or a halogen atom, a linear or branched C 1 -C 5 alkyl radical, a linear or branched C 2 -C 4 alkenyl radical, a C 1 -C 4 alkoxy radical, a cyano group —CN; the alkyl, alkenyl and alkoxy radicals optionally being substituted with one or more halogen atoms,
R 3 represents a C 1 -C 3 alkyl radical,
R 4 represents a hydrogen atom or a (CHR 5 ) n —(Z) 0 —(CHR′ 5 ) p —R 6 group,
n, o and p, which are identical or different, denote zero or a natural integer ranging from 1 to 3,
Z represents a divalent group chosen from —CH 2 —, —NH— and —O—,
R 5 and R′ 5 , which are identical or different, represent a hydrogen atom, a methyl radical —CH 3 , a hydroxyl radical —OH, a C 1 hydroxyalkyl radical, a carboxylic radical —COOH,
R 6 represents:
a hydrogen or halogen atom,
a heterocyclic radical optionally substituted with one or more halogen atoms, one or more linear or branched C 1 -C 3 alkyl groups, one or more —OH groups, one or more carbonyl functions ═O, one or more linear or branched C 1 -C 4 hydroxyalkyl groups, a pyrrolidine ring, one or more amino groups, one or more —C(═O)R7 groups, one or more S(═O) 2 R 7 groups; wherein the heterocyclic radical is a monocyclic heterocyclic ring having 2-6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom, and an oxygen atom; R 7 representing a linear or branched C 1 -C 3 alkyl radical, a hydroxyl radical —OH, a linear or branched C 1 -C 4 alkoxy radical, or an amino radical N(R 7a )(R 7b ); with R 7a and R 7b , which are identical or different, denoting a hydrogen atom, a linear or branched C 1 -C 3 alkyl radical or a cyclopropyl radical,
a C 3 -C 6 cycloalkyl radical optionally substituted with one or more —OH groups;
an aromatic or heteroaromatic radical optionally substituted with one or more halogen atoms, one or more linear or branched C 1 -C 3 alkyl groups optionally substituted with one or more halogen atoms, one or more C 1 -C 3 alkoxy groups, one or more amino groups —NR 11 R 12 , one or more —COR 11 groups, one or more —OR 11 groups, one or more C 1 -C 4 hydroxyalkyl groups, one or more —COOR 11 groups, one or more amido —CONR 11 R 12 groups, one or more —SOR 11 groups, one or more —SO 2 R 11 groups, one or more —NHCOR 11 groups, one or more —NHCOOR 11 groups, one or more —SO 2 NR 11 R 12 groups or one or more —CN groups; wherein the heteroaromatic radical is a 5- or 6-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom, and an oxygen atom; R 11 and R 12 , which are identical or different, representing a hydrogen atom or a linear or branched C 1 -C 3 alkyl radical optionally substituted with one or more halogen atoms;

A 1 represents a divalent group selected from the group consisting of —NR a , —O—, —S—, —SO—,
—SO 2 —, —SO(═NH)—, —CH 2 —, —C═C—, and —CH(R a )—;
given that:
R a represents a hydrogen atom, a linear or branched C 1 -C 3 alkyl radical or an acetyl radical —C(═O)CH 3 ,
R b represents a hydrogen atom, a linear or branched C 1 -C 3 alkyl radical or a cyclopropyl group,
Q 1 , Q 2 , Q 3 , Q 4 and Q 5 each represent a —CR′ 2 group,
R′ 2 represents a hydrogen atom or a linear or branched C 1 -C 5 alkyl radical,
R a and R 3 can form, together with the carbon atoms to which they are attached, a C 3 -C 4 heterocycloalkyl group comprising one sulfur atom and 0 to 1 nitrogen atom, which are optionally substituted with one or more carbonyl functions, one or more C 1 -C 3 alkyl radicals,
when A 1 represents —NR a —, then R a and R 4 can form, together with the nitrogen atom to which they are attached, a C 2 -C 10 heterocycloalkyl group optionally comprising 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, a nitrogen atom and an oxygen atom; said heterocycloalkyl group being optionally substituted with at least one radical R 14 , and
R 14 represents a linear or branched C 1 -C 3 alkyl radical, a linear or branched C 1 -C 3 alkoxy radical, a halogen atom, a hydroxyl group —OH, a cyano group —CN, a —CONR 15 R 16 group, a —SO 2 R 16 group, a —COR 15 group or an amino group —CONR 15 R 16 group, a —SO 2 R 16 group, a —COR 15 group or an amino group —NR 15 R 16 ; R 15 and R 16 , which are identical or different, representing a hydrogen atom or a linear or branched C 1 -C 3 alkyl radical.

2. The compound of formula (II) as defined by claim 1 , or the pharmaceutically acceptable addition salt thereof, wherein R 6 represents a heterocyclic radical selected from the group consisting of:

in which:
R 7 represents a linear or branched C 1 -C 3 alkyl radical, a hydroxyl radical —OH, a C 1 -C 3 alkoxy radical or an amino radical N(R 7a )(R 7b ),
R 7a and R 7b , which are identical or different, denote a hydrogen atom, a linear or branched C 1 -C 3 alkyl radical or a cyclopropyl radical,
R 8 and R 9 , which are identical or different, represent a hydrogen atom, a linear or branched C 1 -C 3 alkyl radical, a hydroxyl group —OH, a carbonyl group, a (C 1 )hydroxyalkyl radical (CH 2 OH), an amino group —NH 2 ,
R 8 and R 9 can form, together with the carbon atoms to which they are attached, a 5- to 7-membered carbocyclic ring.

3. The compound of formula (II) as defined by claim 1 , or the pharmaceutically acceptable addition salt thereof, wherein R 6 represents an aromatic or heteroaromatic radical selected from the group consisting of

in which:
R 10 represents a hydrogen atom or a halogen atom; a linear or branched C 1 -C 3 alkyl radical optionally substituted with one or more halogen atoms; a carbonyl function (═O), a group OR 11 , a C 1 -C 4 hydroxyalkyl group, an amino group —NR 11 R 12 , a —COR 11 group, a —COOR 11 group, an amido group —CONR 11 R 12 , a —SOR 11 group, a —SO 2 R 11 group, a —NHCOR 11 group, a —NHCOOR 11 group, a —SO 2 NR 11 R 12 group or a cyano group —CN,
R 11 and R 12 , which are identical or different, represent a hydrogen atom or a linear or branched C 1 -C 3 alkyl radical optionally substituted with one or more halogen atoms,
m denotes zero or a natural integer ranging from 1 to 3.

4. The compound as defined by claim 1 , wherein the compound is selected from the group consisting of the following compounds:

imino-1-oxo-4-(tetrahydropyran-4-ylmethyl)-1,2,3,4- tetrahydro-1λ 6 -benzo[1,4]thiazine-7-sulfonic acid (4-ethylphenyl)isobutylamide Compound 1

N-(4-ethylphenyl)-N-isobutyl-3-methanesulfinyl-4- (tetrahydr

Assignees

• Galderma Res & Dev

Inventors

• Musicki Branislav
• Bouix-Peter Claire
• Ouvry Gilles
• Thoreau Etienne

Classifications

• C07D263/20

  attached in position 2 · CPC title

• C07C381/10

  Compounds containing sulfur atoms doubly-bound to nitrogen atoms · CPC title

• C07C311/29

  having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D309/08

  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 to ring carbon atoms · CPC title

• C07D309/04

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title