Orally available compounds, a process for preparing the same and their uses as anti-adhesive drugs for treating
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.
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 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.
6. 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 2 , R 2 representing 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 β-cyclodextrin of the following formula:
7. 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-2c):
X, n, Z and
R 2 representing 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 β-cyclodextrin of the following formula:
8. Method according to claim 1 , comprising
administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:
and their pharmaceutically acceptable salts.
9. 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, 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 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 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):
with the proviso that said compound is not of the following structure:
its salts.
10. Compound according to claim 9 , of the following formula (I-1):
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 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,
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 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;
and its pharmaceutically acceptable salts,
provided that when R 1 represents CHRa—NH 2 , then Y can only represent the following group (a):
11. Compound according to claim 9 , wherein Y represents:
said compound being of following formula (I-1a):
X, n and R 1 being as previously defined,
or
said compound being of following formula (I-1b):
X, n and R 1 being as defined,
or
Z being as defined,
said compound being of following formula (I-1c):
X, n, Z and R 1 being as defined.
12. Process of preparation of a compound of formula (I-0):
wherein:
X represents NH, O, S or CH 2 ;
n represents an integer being equal to 3, 4, 5, 6 or 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 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):
with the proviso that said compound is not of one of the following structures:
its salts,
comprising the following steps:
when Y represents:
reaction between a compound of formula (1a):
wherein Rp represents an ad hoc hydroxyl protecting group, and a compound of formula (2a):
wherein R 1 is a group R that is optionally protected by one or more ad hoc protecting groups,
in presence of triphenylphosphine, a coupling agent and optionally 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-aza-benzotriazole (HOAt),
to obtain a compound of formula (3a):
cleavage of the Rp protecting groups and of the optional protecting groups of R 1 in said compound of formula (3a), to obtain a compound of formula (I-0) wherein Y represents (a), of following formula (I-0a):
when Y represents:
reaction between a compound of formula (1b):
and a compound of formula (2b):
wherein R 1 is a group R that is optionally protected by one or more ad hoc protecting groups,
to obtain a compound of formula (3b):
cleavage of the Rp protecting groups and of the optional protecting groups of R 1 in said compound of formula (3b), to obtain a compound of formula (I-0) wherein Y represents (b), of following formula (I-0b):
when Y represents:
reaction between a compound of formula (1c):
and a compound of formula (2b):
wherein R 1 is a group R that is optionally protected by one or more ad hoc protecting groups,
to obtain a compound of formula (3b):
cleavage of the Rp protecting groups and of the optional protecting groups of R 1 in said compound of formula (3c), to obtain a compound of formula (I-0) wherein Y represents (c), of following formula (I-0c):