IP Library › Granted Patent US 10,273,313

Granted Patent B2

US 10,273,313 · App. 14/416,529 · Granted Apr 30, 2019

Multimeric mannosides, a process for preparing the same and their uses as a drug

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Quick Facts

Patent No.: US 10,273,313
App. No.: 14/416,529
Granted: Apr 30, 2019
Kind: B2

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Abstract

The present invention relates to multimeric mannosides, a process for preparing the same and their uses in medicine for treating Escherichia coli infections. Exemplary compounds are:

Claims (244)

1. A compound of the following formula (I):

A-X n (I)

wherein:

A is selected from the group consisting of:

wherein

X′ is selected from the group consisting of —OH and -----, wherein ----- represents a bond to X;

R 2 is selected from the group consisting of hydrogen and a linear or branched (C 1 -C 7 )-alkyl;

n is an integer from 6 to 8;

X represents a group according to formula (1):

-W p -L r -Y s —Z (1)

wherein:

p, r, and s are integers independently from each other equal to 0 or 1,

provided that:

when r is equal to 0, p and s are such as the sum p+s is equal to 1,

when r is equal to 1, p and s are such as the sum p+s is equal to 2;

W is selected from the group consisting of:

Y is selected from the group consisting of:

Z is selected from the group consisting of:

L represents a linker having a formula:

m being an integer comprised from 0 to 20,

q being an integer chosen from 6, 7, and 8,

Q and Q′ representing independently from each other NH, O or S;

T representing O, S or CH 2 ;

R′ representing a group selected from the group consisting of:

a linear or branched (C 1 -C 7 )-alkane diyl,

a linear or branched (C 2 -C 7 )-alkene diyl,

a linear or branched (C 2 -C 7 )-alkyne diyl,

a (C 3 -C 7 )-cycloalkane diyl,

a (C 5 -C 7 )-cycloalkene diyl,

a (C 3 -C 7 )-heterocycloalkane diyl,

a (C 5 -C 7 )-heterocycloalkene diyl,

an arene diyl, said arene being an aromatic or heteroaromatic group,

a group -arene 1 -arene 2 - wherein arene 1 and arene 2 are independently to each other an aromatic or heteroaromatic arene; and

a group of the following formula:

said (C 1 -C 7 )-alkane diyl, (C 2 -C 7 )-alkene diyl, (C 2 -C 7 )-alkyne diyl, (C 3 -C 7 )-cycloalkane diyl, (C 5 -C 7 )-cycloalkene diyl, (C 3 -C 7 )-heterocycloalkane diyl, (C 5 -C 7 )-heterocycloalkene diyl, arene diyl, arene 1 and arene 2 being substituted or not 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 and

CN.

2. The compound according to claim 1 , of formula (I):

A-X n (I)

wherein A is a cyclodextrin chosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), n being 6 when A is α-cyclodextrin or a α-cyclodextrin derivative;

n being chosen from 6 and 7 when A is β-cyclodextrin or a β-cyclodextrin derivative;

n being chosen from 6, 7 and 8 when A is γ-cyclodextrin or a γ-cyclodextrin derivative.

3. A pharmaceutical composition comprising, as active substance, a compound according to claim 2 , in association with a pharmaceutically acceptable vehicle.

4. The compound according to claim 2 , wherein the compound of formula (I) is selected from the group consisting of:

(i) a compound of formula (I) wherein Z is of formula (1″):

T representing O, S or CH 2 ;

(ii) a compound of formula (I) wherein X is of formula (1), wherein p equals 0 and Z is of formula (1″), corresponding to the following formula (2a):

wherein Y and q are as defined above, T representing O, S or CH 2 ;

(iii) a compound of formula (I) wherein X is of formula (1), wherein p equals 1 and Z is of formula (1″), corresponding to the following formula (2b):

wherein W, L, Y and q are as defined above, T representing O, S or CH 2 ;

(iv) a compound of formula (I) wherein X is of formula (1), wherein p equals 0, Y represents (1′) and Z is of formula (1″), corresponding to the following formula (2c):

wherein q is as defined in above, T representing O, S or CH 2 ;

(v) a compound of formula (I), wherein X is of formula (1), wherein p equals 1, L is of formula (1 1 ), and Z is of formula (1″), corresponding to the following formula (2d):

wherein W, L, Y, m and q are as defined above, T representing O, S or CH 2 ;

(vi) a compound of formula (I), wherein X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (2e):

wherein L and q are as defined above, T representing O, S or CH 2 ; and

(vii) a compound of formula (I), wherein X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (2f):

wherein m and q are as defined in above, T representing O, S or CH 2 .

5. The compound according to claim 2 , wherein the compound of formula (I) is selected from the group consisting of:

(i) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein Z is of formula (1″), corresponding to the following formula:

wherein p, n, W, L, Y and q are as defined above, T representing O, S or CH 2 ;

(ii) a compound of formula (I), wherein A is a cyclodextrinX is of formula (1), wherein p equals 0 and Z is of formula (1″), corresponding to the following formula (IIa):

wherein n, Y and q are as defined above, T representing O, S or CH 2 ;

(iii) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 1 and Z is of formula (1″), corresponding to the following formula (IIb):

wherein n, W, L, Y and q are as defined above, T representing O, S or CH 2 ;

(iv) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 0, Y represents (1′) and Z is of formula (1″), corresponding to the following formula (IIc):

wherein n and q are as defined above, T representing O, S or CH 2 ;

(v) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 1, L is of formula (1 1 ), and Z is of formula (1″), corresponding to the following formula (IId):

wherein n, W, L, Y, m and q are as defined above, T representing O, S or CH 2 ;

(vi) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (IIe):

wherein n, L and q are as defined above, T representing O, S or CH 2 ;

(vii) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (IIf):

wherein n, m and q are as defined above, T representing O, S or CH 2 ;

(viii) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 0, Y represents (1′) and Z is of formula (1″), corresponding to the following formula (IIg):

wherein n and q are as defined above, T representing O, S or CH 2 ;

(ix) compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (IIh):

wherein n, m and q are as defined above, T representing O, S or CH 2 ;

(x) a compound of formula (I), wherein A is a cyclodextrin derivative, X is of formula (1), wherein p equals 0, Y represents (1′) and Z is of formula (1″), corresponding to the following formula (IIg-bis):

wherein n and q are as defined above, T representing O, S or CH 2 ; and

(xi) a compound of formula (I), wherein A is a cyclodextrin derivative, X is of formula (1), wherein p equals 1, W and Y are of formula (1′), and Z is of formula (1″), corresponding to the following formula (IIh-bis):

wherein n, m and q are as defined above, T representing O, S or CH 2 .

6. The compound according to claim 2 , wherein n is 7.

7. The compound according to claim 1 , wherein

q is 7.

8. The compound according to claim 1 , selected from the group consisting of:

wherein Q and Q′ are as defined above,

wherein Q and Q′ are as defined above.

9. A pharmaceutical composition comprising, as active substance, a compound according to claim 1 , in association with a pharmaceutically acceptable vehicle.

10. A vaccine composition comprising, as active substance, a compound according to claim 1 , in association with a pharmaceutically acceptable adjuvant.

11. A method for the treatment of pathologies caused by Escherichia coli and mediated by interactions between Escherichia coli lectins and host cell surface glycans, comprising administering to a patient in need thereof an therapeutically effective amount of the compound according to claim 1 .

12. The method according to claim 11 , wherein said pathologies belong to the group consisting of:

inflammatory bowel diseases,

urinary tract infections, and

urinary tract infections in patients with a metabolic disease correlated with enhanced apoptosis.

13. The method according to claim 12 , wherein one of said pathologies is Crohn's disease.

14. A process of preparation of a compound of formula (I):

A-X n (I)

wherein:

A is selected from the group consisting of:

wherein

X′ is selected from the group consisting of —OH and -----, wherein ----- represents a bond to X;

R 2 is selected from the group consisting of hydrogen and a linear or branched (C 1 -C 7 )-alkyl;

n is an integer from 6 to 8;

X represents a group of the following formula (1):

—W p -L r -Y s —Z (1)

wherein:

p, r, and s are integers independently from each other equal to 0 or 1,

provided that:

when r is equal to 0, p and s are such as the sum p+s is equal to 1,

when r is equal to 1, p and s are such as the sum p+s is equal to 2;

W is selected from the group consisting of:

Y is selected from the group consisting of:

Z is selected from the group consisting of:

L represents a linker of one of the following formulae:

m being an integer comprised from 0 to 20,

q being an integer chosen from 6, 7, and 8,

Q and Q′ representing independently from each other NH, O or S;

T representing O, S or CH 2 ;

R′ representing a group selected from the group consisting of:

a linear or branched (C 1 -C 7 )-alkane diyl,

a linear or branched (C 2 -C 7 )-alkene diyl,

a linear or branched (C 2 -C 7 )-alkyne diyl,

a (C 3 -C 7 )-cycloalkane diyl,

a (C 5 -C 7 )-cycloalkene diyl,

a (C 3 -C 7 )-heterocycloalkane diyl,

a (C 5 -C 7 )-heterocycloalkene diyl,

an arene diyl, said arene being an aromatic or heteroaromatic group,

a group -arene 1 -arene 2 - wherein arene 1 and arene 2 are independently to each other an aromatic or heteroaromatic arene; and

a group of the following formula:

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 and

CN;

when r=0, said process of preparation comprising a reaction between:

A-(G 1 ) n , wherein A and n are as defined above and G 1 is the first co-precursor of Y or W, and

G 2 -Z, wherein Z is as defined above and G 2 is the second co-precursor of Y or W

to obtain a compound of formula (I) A-(X) n , wherein X corresponds to formula —Y—Z (1a) or —W—Z, G 1 and G 2 having reacted together to form Y or W,

said group G 1 representing —N 3 or

said G 2 group representing respectively

when r=1, said process of preparation comprising:

a) a reaction between:

A-(G 1 ) n , wherein A and n are as defined above and G 1 is the first co-precursor of W;

F 2 -L-F 3 , wherein L is as defined above, F 2 is the second co-precursor of W, and F 3 is a precursor of the first co-precursor F 4 of Y;

to obtain a compound of formula A-(W-L-F 3 ) n ; G 1 and F 2 having reacted together to form W;

b) a reaction starting from A-(W-L-F 3 ) n to obtain A-(W-L-F 4 ) n , wherein F 4 is the first co-precursor of Y;

c) a reaction between:

a. A-(W-L-F 4 ) n , and

b. G 2 -Z, wherein Z is as defined above and G 2 is the second co-precursor of Y,

to obtain a compound of formula (I) A-(X) n , wherein X corresponds to formula (Ib)

—W-L-Y—Z, F 4 and G 2 having reacted together to form Y,

said group G 1 representing —N 3 or

said F 2 group representing respectively

said group F 4 representing —N 3 or

said G 2 group representing respectively

15. The process of preparation according to claim 14 , of a compound of the following formula (IIc):

wherein q is as previously defined, said process of preparation comprising a reaction between:

to obtain aforesaid compound of formula (IIc).

16. The process of preparation according to claim 14 , of a compound of formula (IIf):

wherein m and q are as previously defined,

said process of preparation comprising:

a) a reaction between:

wherein n and m are as defined above, and wherein LG is a leaving group,

to obtain a compound of formula:

b) a reaction between aforesaid compound of formula (IV) and M-N 3 , wherein M is a metal chosen from sodium and potassium,

to obtain a compound of formula (V):

c) a reaction between aforesaid compound of formula (V) and

to obtain aforesaid compound of formula (IIf).

17. The process of preparation according to claim 14 ,

wherein A is a cyclodextrin chosen from α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD);

n is 6 when A is α-cyclodextrin or a α-cyclodextrin derivative;

n is chosen from 6 and 7 when A is β-cyclodextrin or a β-cyclodextrin derivative; and

n is chosen from 6, 7 and 8 when A is γ-cyclodextrin or a γ-cyclodextrin derivative.

18. The process of preparation according to claim 17 , wherein the compound of formula (I) is selected from the group consisting of:

(i) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein Z is of formula (1″), corresponding to the following formula:

wherein p, n, W, L, Y and q are as defined above, T representing O, S or CH 2 ;

(ii) a compound of formula (I), wherein A is a cyclodextrin, X is of formula (1), wherein p equals 0 and Z is of formula (1″), corresponding to the following formula (IIa):