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-10485811-B2
Application number	US-201515113986-A
Country	US
Kind code	B2
Filing date	Jan 23, 2015
Priority date	Jan 24, 2014
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

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. A pharmaceutical composition comprising, in combination with a pharmaceutically acceptable vehicle:
(i) at least one compound of the following formula (I-0):

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

Z representing O, S or NH;
R representing a moiety selected from the group consisting of:
H
a linear or branched (C 1 -C 7 )-alkyl,
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,
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 amino acid, and
a cyclodextrin,

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 optionally substituted by one or more substituent(s), each independently selected from the group consisting of:
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 consisting of 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 a salt thereof; and
pharmaceutically acceptable salts thereof,

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

with the proviso that said compound is not of the following structure:

and salts thereof; and
(ii) at least one compound selected from the group consisting of antibiotics, anti-inflammatory compounds, glucocorticoids, immunosuppressive compounds and anti-TNF-alpha therapies,
said pharmaceutical composition being used for simultaneous or separate use or use spread over time intended for the treatment of inflammatory bowel disease.

2. The pharmaceutical composition according to claim 1 , wherein said at least one compound of the formula (I-0) is of the following formula (I-1):

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

Z representing O, S or NH;
R 1 representing:
H
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, 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 amino acid,

said (C 1 -C 7 )-alkyl, (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 and CO-aryl being optionally substituted by one or more substituent(s), each independently selected from the group consisting of:
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 consisting of 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; and

pharmaceutically acceptable salts thereof,
provided that when R 1 represents CHRa—NH 2 , then Y can only represent the following group (a):

3. The pharmaceutical composition according to claim 2 , wherein:
Y represents

said at least one compound of the formula (I-0) being of following formula (I-1a):

X, n and R 1 being as previously defined;
or
Y represents

said at least one compound of the formula (I-0) being of following formula (I-1b):

X, n and R 1 being as previously defined;
or
Y represents

said at l

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

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• C08L5/16

  Cyclodextrin; Derivatives thereof · CPC title

• C08B37/0015

  Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title