Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating E. coli induced inflammatory bowel diseases such as crohn's disease

Patent metadata

Field	Value
Publication number	US-10632135-B2
Application number	US-201916548704-A
Country	US
Kind code	B2
Filing date	Aug 22, 2019
Priority date	Jan 24, 2014
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating E. coli induced inflammatory bowel diseases such as crohn's disease.

First claim

The invention claimed is:

1. Method of treatment of inflammatory bowel disease, or Crohn disease or ulcerative colitis, comprising administering to a subject in need thereof an effective amount of a compound of the following formula (I):

wherein:
X represents NH, O, S or CH 2 ;
n represents an integer comprised from 3 to 7, or n being equal to 5;
Y represents a group selected from:

Z representing O, S or NH;
R representing:
H,
a linear or branched (C 1 -C 7 )-alkyl, or methyl, ethyl, isopropyl or isobutyl,
a group of formula —(CH 2 ) i —X′—(CH 2 ) j —H, wherein X′ represents O, S or NH, i is an integer from 1 to 7, and j is an integer from 0 to 7, or a group —CH 2 —O—CH 3 ,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, said aryl being an aromatic or heteroaromatic group,
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
a CO 2 H,
a CO 2 —(C 1 -C 7 )-alkyl,
a CONH—(C 1 -C 7 )-alkyl,
CF 3 ,
adamantyl,
CHRa—NH 2 , wherein Ra represents the side chain of a proteinogenic aminoacid,
a cyclodextrin, or a cyclodextrin chosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and their derivatives, or alkylated α-cyclodextrins, alkylated β-cyclodextrins and alkylated γ-cyclodextrins, or a cyclodextrin of one of the following formulae:

said (C 1 -C 7 )-alkyl, group of formula —(CH 2 ) i —X′—(CH 2 ) j —H, (C 2 -C 7 )-alkenyl, (C 2 -C 7 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 5 -C 7 )-cycloalkenyl, (C 3 -C 7 )-heterocycloalkyl, (C 5 -C 7 )-heterocycloalkenyl, CO—(C 1 -C 7 )-alkyl, CO 2 —(C 1 -C 7 )-alkyl, CONH—(C 1 -C 7 )-alkyl, aryl, alkyl aryl, CO-aryl and cyclodextrin being substituted or not by one or more substituent(s), each independently selected from:
a linear or branched (C 1 -C 7 )-alkyl,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, wherein the aryl is an aromatic or heteroaromatic group
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CHO,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
a CO 2 H,
a CO 2 —(C 1 -C 7 )-alkyl,
a CONH—(C 1 -C 7 )-alkyl,
a halogen selected from the group comprising F, Cl, Br, and I,
CF 3 ,
OR a , wherein R a represents:
H, a linear or branched (C 1 -C 7 )-alkyl, a (C 3 -C 7 )-cycloalkyl, CO—(C 1 -C 7 )-alkyl, or CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
NR b R c , wherein R b and R c represent independently from each other:
H, a linear or branched (C 1 -C 7 )-alkyl, a (C 3 -C 7 )-cycloalkyl, CO—(C 1 -C 7 )-alkyl, or CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
NO 2 ,
CN,
SO 3 H or one of its salts, or SO 3 Na;

and its pharmaceutically acceptable salts,
provided that when R represents CHRa—NH 2 , then Y can only represent the following group (a):

2. Method according to claim 1 , comprising administering to a subject in need thereof an effective amount of a compound formula (I), wherein R is R 1 , R 1 representing:
H
a linear or branched (C 1 -C 7 )-alkyl, or isopropyl,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, said aryl being an aromatic or heteroaromatic group,
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
a CO 2 H,
a CO 2 —(C 1 -C 7 )-alkyl,
a CONH—(C 1 -C 7 )-alkyl,
CF 3 ,
Adamantyl,
CHRa—NH 2 , wherein Ra represents the side chain of a proteinogenic aminoacid.

3. Method according to claim 1 , comprising administering to a subject in need thereof an effective amount of a compound formula (I), wherein Y represents:

of following formula (I-1a):

X and n being as previously defined,
R 1 representing:
H
a linear or branched (C 1 -C 7 )-alkyl, or isopropyl,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, said aryl being an aromatic or heteroaromatic group,
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
a CO 2 H,
a CO 2 —(C 1 -C 7 )-alkyl,
a CONH—(C 1 -C 7 )-alkyl,
CF 3 ,
Adamantyl,
CHRa—NH 2 , wherein Ra represents the side chain of a proteinogenic aminoacid.

4. Method according to claim 1 , comprising administering to a subject in need thereof an effective amount of a compound formula (I), wherein Y represents:

of following formula (I-1b):

X and n being as previously defined,
R 1 representing:
H
a linear or branched (C 1 -C 7 )-alkyl, or isopropyl,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, said aryl being an aromatic or heteroaromatic group,
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an aromatic or heteroaromatic group,
a CO 2 H,
a CO 2 —(C 1 -C 7 )-alkyl,
a CONH—(C 1 -C 7 )-alkyl,
CF 3 ,
Adamantyl,
CHRa—NH 2 , wherein Ra represents the side chain of a proteinogenic aminoacid.

5. Method according to claim 1 , comprising administering to a subject in need thereof an effective amount of a compound formula (I), wherein Y represents:

of following formula (I-1c):

X, Z and n being as previously defined,
R 1 representing:
H
a linear or branched (C 1 -C 7 )-alkyl, or isopropyl,
a linear or branched (C 2 -C 7 )-alkenyl,
a linear or branched (C 2 -C 7 )-alkynyl,
a (C 3 -C 7 )-cycloalkyl,
a (C 5 -C 7 )-cycloalkenyl,
a (C 3 -C 7 )-heterocycloalkyl,
a (C 5 -C 7 )-heterocycloalkenyl,
an aryl, said aryl being an aromatic or heteroaromatic group,
an alkyl aryl, wherein the aryl is an aromatic or heteroaromatic group,
a CO—(C 1 -C 7 )-alkyl,
a CO-aryl, wherein aryl is an arom

Assignees

• Centre Nat Rech Scient
• Univ Dauvergne
• Univ Des Sciences Et Technologies De Lille 1
• Univ Nantes
• Inst Nat Sante Rech Med
• Michaud Jean Eric
• Michaud Pierre Yohan
• Michaud Vincent

Inventors

• Bouckaert Julie
• Gouin Sebastien
• Sivignon Adeline
• Darfeuille-Michaud Arlette
• Bilyy Rostyslav
• Alvarez-Dorta Dimitri
• Yamakawa Nao
• Dumych Tetiana

Classifications

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• C07H7/02

  Acyclic radicals · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/70 Primary

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title