Multivalent fucose derivatives for use as a drug
Disclosed is a compound bearing at least two fucose moieties for its use as a drug in the prevention or treatment of infections caused by Aspergillus spp, the compound having a molecular weight included from 0.6 to 340 kDa, in particular from 0.6 to 2 kDa or from 1 to 7 kDa or from 2 to 10 kDa or from 5 to 340 kDa.
1. A compound bearing at least two fucose moieties and having a molecular weight of 0.6 to 340 kDa,
said compound being of formula (I):
A-[(D) i -B—C] x (I)
wherein
i is equal to 0 or 1,
when i=0 formula (I) does not comprise D and A is linked to B,
when i=1 formula (I) comprises D;
A is selected from
k being equal to 1, or 3 and
when k=1, x is equal to 6,
when k=3, x is equal to 8;
r being an integer of 1 to 30 and x being equal to 2;
s being an integer of 5 to 300 and x being equal to (3s+8);
v being an integer of 0 to 10 and x being equal to 8;
B is of formula
wherein B is of formula B1 when B group is linked to C group through the nitrogen atom of the triazole to form a B—C group of formula
or B is of formula B2 when B group is linked to C group through its carbon atom to form a B—C group of formula
C is of formula
y being equal to 0 or 1;
X being selected from O, S or CH 2 ;
U being selected from
m being an integer of 0 to 8,
n being an integer of 0 to 8,
p being an integer of 1 to 10,
q being an integer of 1 to 10,
or
R 1 , R 2 , R 3 and R 4 being independently from each other selected from H, COCH 3 , NH 2 , NO 2 , NHAc, OH, OMe, COOH, COOMe, CONHMe, Cl, Br, I, F, SMe or Me;
provided that y+n or y+m is different from 0;
D being selected from
j being an integer of 0 to 8.
2. The compound according to claim 1 of formula (I)
A-[(D) i -B—C] x (I)
wherein
i is equal to 0 or 1,
when i=0 formula (I) does not comprise D and A is linked to B,
when i=1 formula (I) comprises D;
A is selected from
k being equal to 1, or 3 and
when k=1, x is equal to 6,
when k=3, x is equal to 8;
r being an integer of 1 to 30 and x being equal to 2;
s being an integer of 5 to 300 and x being equal to (3s+8);
v being an integer of 0 to 10 and x being equal to 8;
B is of formula
wherein B is of formula B1 when B group is linked to C group through the nitrogen atom of the triazole to form a B—C group of formula
or B is of formula B2 when B group is linked to C group through its carbon atom to form a B—C group of formula
C is of formula
y being equal to 1;
X being selected from 0, S or CH 2 ;
U being selected from
m being an integer of 0 to 8,
n being an integer of 0 to 8,
q being an integer of 1 to 10,
R 1 , R 2 , R 3 and R 4 being independently from each other selected from H, COCH 3 , NH 2 , NO 2 , NHAc, OH, OMe, COOH, COOMe, CONHMe, Cl, Br, I, F, SMe or Me;
D being selected from
j being an integer of 0 to 8.
3. The compound according to claim 1 , said compound being of formula (I-A1):
A1-[(D) i -B—C] x ,
wherein A being of formula A1 and having the following structure:
k being equal to 1;
D i , B and C being as defined in formula (I); or
said compound being of formula (I-A2):
A2-[(D) i -B—C] 2 ,
wherein A being of formula A2 and selected from
r being equal to 1;
r being equal to 2;
r being equal to 3;
r being equal to 4;
r being equal to 7;
r being equal to 11;
r being equal to 19;
r being equal to 27;
D i , B and C being as defined in formula (I); or
said compound being of formula (I-A3):
A3-[(D) i -B—C] x ,
wherein A being of formula A3 and selected from
s being equal to 66;
D i , B and C being as defined in formula (I); or
said compound being of formula (I-A4):
A4-[(D) i -B—C] 8 ,
wherein A being of formula A4 and selected from
D i , B and C being as defined in formula (I).
4. The compound according to claim 1 , said compound being of formula (I), wherein B is selected from B1 or B2,
wherein B is of formula B1 when B group is linked to C group through the nitrogen atom of the triazole to form a B—C group of formula
or B is of formula B2 when B group is linked to C group through its carbon atom to form a B—C group of formula
A, D i and C being as defined in formula (I).
5. The compound according to claim 1 , said compound being of formula (I), wherein C is selected from C1, C2 or C3
A, B and D i being as defined in formula (I).
6. The compound according to claim 1 , said compound being of formula (I) wherein i is equal to 0 and said compound is of formula A-[B—C] x , and wherein B—C is selected from the groups consisting of:
[B2-C1],
[B2-C2-1],
[B2-C2-2], and
[B1-C3];
A, B1, B2 and x being as defined in formula (I),
C1, C2-1, C2-2 and C3 being:
7. The compound according to claim 1 , said compound being of formula selected from
A1-[B2-C1] x ,
A1-[B2-C2] x ,
A2-[B2-C1] 2 ,
A3-[B1-C3] x ,
A4-[B2-C1] 8 ,
A4-[B2-C2] 8 ,
A1, A2, A3, A4, B1, B2 and x being as defined in formula (I),
wherein C1, C2 and C3 being
8. A pharmaceutical composition comprising a compound having a molecular weight of 0.6 to 340 kDa,
said compound being of formula (I)
A-[(D) i -B—C] x (I)
wherein
i is equal to 0 or 1,
when i=0 formula (I) does not comprise D and A is linked to B,
when i=1 formula (I) comprises D;
A is selected from
k being equal to 1, or 3 and
when k=1, x is equal to 6,
when k=3, x is equal to 8;
r being an integer of 1 to 30 and x being equal to 2;
s being an integer of 5 to 300 and x being equal to (3s+8);
v being an integer of 0 to 10 and x being equal to 8;
B is of formula
wherein B is of formula B1 when B group is linked to C group through the nitrogen atom of the triazole to form a B—C group of formula
or B is of formula B2 when B group is linked to C group through its carbon atom to form a B—C group of formula
C is of formula
y being equal to 0 or 1;
X being selected from O, S or CH 2 ;
U being selected from
m being an integer of 0 to 8,
n being an integer of 0 to 8,
p being an integer of 1 to 10,
q being an integer of 1 to 10,
or
R 1 , R 2 , R 3 and R 4 being independently from each other selected from H, COCH 3 , NH 2 , NO 2 , NHAc, OH, OMe, COOH, COOMe, CONHMe, Cl, Br, I, F, SMe or Me;
provided that y+n or y+m is different from 0;
D being selected from
j being an integer of 0 to 8.
9. The compound according to claim 1 , wherein said compound is selected from
10. The compound according to claim 1 , said compound being of formula (I), wherein C is selected from C2-1 and C2-2:
A, B and D i being as defined in formula (I).
11. The compound according to claim 1 , said compound being of formula selected from
A1-[B2-C2-1] x ,
A1-[B2-C2-2] x ,
A4-[B2-C2-1] 8 ,
A4-[B2-C2-2] 8 ,
A1, A4, B1, B2 and x being as defined in formula (I),
wherein C2-1 and C2-2 being
12. The compound according to claim 1 , said compound being of formula selected from
A1-1-[B2-C1] 6 ,
A1-1-[B2-C2] 6 ,
A2-4-[B2-C1] 2 ,
A2-5-[B2-C1] 2 ,
A2-6-[B2-C1] 2 ,
A2-7-[B2-C1] 2 ,
A2-8-[B2-C1] 2 ,
A3-1-[B1-C3] x ,
A4-1-[B2-C1] 8 ,
A4-1-[B2-C2] 8 ,
B1, B2 and x being as defined in formula (I),
wherein A1-1, A2-4, A2-5, A2-6, A2-7, A2-8, A3-1, A4-1, C1, C2, C3 being
13. A method of treatment of infections caused by Aspergillus spp, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 .
14. The method according to claim 13 , wherein said compound is formulated in a composition.
15. The method according to claim 13 , wherein said compound is in a composition, formulated for its human and/or animal use.
16. The method according to claim 13 , wherein said compound is in a composition, said Aspergillus spp being Aspergillus section Fumigati, Aspergillus section Flavi, Aspergillus section Nigri, Aspergillus section Nidulantes, Aspergillus oryzae, Aspergillus bombycis, Aspergillus nemius.
17. The method according to claim 13 , wherein said compound is in a composition, said infection being an aspergillosis, or an allergic broncho-pulmonary aspergillosis, an aspergilloma, a chronic pulmonary aspergillosis or an invasive pulmonary aspergillosis.
18. The method according to claim 13 , wherein said compound is in a composition, said compound being used by respiratory route, by oral route or intravenously.
19. The method according to claim 13 , wherein said compound is in a composition, wherein the composition comprises said compound from 1 mg to 1.4 g; or from 200 mg to 10 g; or from 10 mg to 10 g; or from 0.015 to 20 mg/kg; or from 3 mg/kg to 143 mg/kg; or from 0.15 mg/kg to 143 mg/kg.
20. The method according to claim 13 , wherein said compound is in a composition, wherein the composition further comprises an antifungal agent selected from an azole antifungal agent, a polyene antifungal agent or an echinocandin antifungal agent.