Mannosylated compounds useful for the prevention and the treatment of infectious diseases

Patent metadata

Field	Value
Publication number	US-9522928-B2
Application number	US-201214358157-A
Country	US
Kind code	B2
Filing date	Nov 14, 2012
Priority date	Nov 15, 2011
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

The present invention relates to new anti-infectious compounds consisting of (i) a polar head having from one to three mannose, dimannose or trimannose moieties, which is coupled through an appropriate linker to (ii) a single lipid chain of at least 17 carbon atoms in length. Pharmaceutical compositions and therapeutic uses thereof are also provided.

First claim

The invention claimed is:

1. A compound of formula (III):

wherein:
LINKER is a bifunctional linker selected from the group consisting of:
i) an amino acid residue,
ii) peptides having from 2 to 10 amino acid residues,
iii) X 1 —(CH 2 )n-Y, wherein n is an integer from 1 to 10 and X 1 and Y 1 are independently selected from —NH—, —S—, —C(═O)—,—O—, —NH—C(═O)—, —C(═O)—NH—,—O—C(═O)—,—C(═O)—O—, —NH—(C═NH)—NH, —NH—(C═O)—NH— and (C═O)—O—(C═O), and
iv) —NH—, —S—, —O—, —C(═O)—, —NH—C(═O)—, —C(═O)—NH—, —O—C(═O)—, —C(═O)—O—, NH—(C═NH)—NH—, —NH—(C═O)—NH—and —(C═O)—O—(C═O)—,

R 1 is a C 17 -C 30 saturated or unsaturated linear hydrocarbon chain, optionally substituted by one or more C 1 -C 3 alkyl radicals,
M 1 is mannosyl, dimannosyl or trimannosyl,
W is selected from —NH—(CH 2 ) f —, —O—(CH 2 ) f — and —S—(CH 2 ) f — wherein f is an integer from 1 to 5,
X′ is —NH—C(O)—(CH 2 ) e — or —O—C(O)—(CH 2 ) e — wherein e is an integer from 1 to 4,
a is an integer from 2 to 10,
and
d is an integer from 2 to 10,
or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein said compound is of formula (IIIa)

wherein:
R 2 is H or α-mannosyl residue,
R 1 is the C 17 -C 30 saturated or unsaturated linear hydrocarbon chain, optionally substituted by one or more C 1 -C 3 alkyl radicals,
a is an integer from 2 to 10, and
d is an integer from 2 to 10.

3. The compound of claim 2 , wherein said compound is selected from the group consisting of:
a compound of formula (IIIa), wherein R 2 is H, R 1 is —(CH 2 ) 16 CH 3 , a is 3 and b is 4;
a compound of formula (IIIa), wherein R 2 is H, R 1 is —(CH 2 ) 23 CH 3 , a is 3 and b is 4; and
a compound of formula (IIIa), wherein R 1 is —(CH 2 ) 8 —C≡C—C≡C—(CH 2 ) 11 —CH 3 , R 2 is H, a is 3, and b is 4.

4. A compound of formula (Ic):

wherein:
M 1 is selected from the group consisting of mannosyl, dimannosyl, and trimannosyl,
M 2 and M 3 are independently selected from the group consisting of mannosyl, dimannosyl, trimannosyl, and therapeutic agent moieties having a molecular weight of at most 800 g/mol −1 ,
Q 1 , Q 2 and Q 3 are independently selected from the group of oligoether-based spacers comprising at least one —(R 8 O) n — moiety wherein R 8 is a linear or branched C 1 -C 4 alkyl, and n is an integer from 2 to 10,
R 1 is a C 17 -C 30 saturated or unsaturated linear hydrocarbon chain optionally substituted by one or more C 1 -C 3 alkyl radicals, and
LINKER is a radical of formula (VI)

wherein:
R 6 is —NH—C(O)— or —O—C(O)—, and
R 3 , R 4 and R 5 are independently selected from —NH—C(═O)—(CH 2 ) n —O— and —O—C(═O)(CH 2 ) n —O— wherein n is an integer from 1 to 10. or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 4 , wherein said compound is of formula (V):

wherein:
R 1 is a C 17 -C 30 saturated or unsaturated linear hydrocarbon chain, optionally substituted by one or more C 1 -C 3 alkyl radicals,
M 1 is mannosyl or dimannosyl,
M 2 and M 3 are independently selected from the group consisting of mannosyl, dimannosyl, and therapeutic agent moieties, having a molecular weight of at most 800 g/mol −1 ,
W 1 , W 2 and W 3 are independently selected from —NH—(CH 2 ) f —, —O—(CH 2 ) f — and —S—(CH 2 ) f — wherein f is an integer from 1 to 5,
X′ 1 , X′ 2 and X′ 3 are independently selected from —NH—C(O)—(CH 2 ) e — and —O—C(O)—(CH 2 ) e — wherein e is an integer from 1 to 4,
a1, a2, a3, d1, d2 and d3 are integers independently selected from integers ranging from 2 to 10, and
1 b1, b2 and b3 are independently selected from 0 and 1, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 4 , wherein the compound is of formula (Va):

wherein:
—R 2 is H or α-mannosyl residue,
R 1 is C 17 -C 30 saturated or unsaturated linear hydrocarbon chain, optionally substituted by one or more C 1 -C 3 alkyl radicals, and
a is an integer from 1 to 10.

7. The compound of claim 6 , wherein the compound is selected from the group consisting of:
a compound of formula (Va), wherein, R 1 is —(CH 2 ) 23 CH 3 , R 2 is H, and a is 3;
a compound of formula (Va), wherein, R 1 is —(CH 2 ) 23 CH 3 , R 2 is α-mannosyl, and a is 3;
a compound of formula (Va), wherein, R 1 is —(CH 2 ) 8 —C≡C—C≡C—(CH 2 ) 11 —CH 3 , R 2 is H, and a is 3; and
a compound of formula (Va), wherein, R 1 is —(CH 2 ) 8 —C≡C—C≡C—(CH 2 ) 11 —CH 3 , R 2 is α-mannosyl and a is 3.

8. A condom coated with a compound according to claim 1 .

9. A pharmaceutical composition comprising (i) a compound according to claim 1 , (ii) at least one pharmaceutically acceptable excipient and (iii) optionally an additional therapeutic agent.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
(i) —(CH 2 ) p CH 3 wherein p is an integer from 16 to 29;
(ii) —(CH 2 ) p -M —(CH 2 ) q —CH 3 wherein M is CH═CH or C═C and p and q are integers from 0 to 27 with the proviso that 14≦p+q<27;
(iii) —(CH 2 ) p —K—(CH 2 ) q -M—(CH 2 ) r —CH 3 wherein K and M are independently selected from CH═CH and C≡C, and p, q and r are integers from 0 to 25 with the proviso that 12≦p+q+r≦25;
(iv) —(CH 2 ) p —K—(CH 2 ) q -M—(CH 2 ) r —P—(CH 2 ) s —CH 3 wherein K, M and P are independently selected from CH═CH and C≡C, and p, q, r and s are integers from 0 to 23 with the proviso that 10≦p+q+r+s≦23; and
(v) —(CH 2 ) p —C═C═C—(CH 2 ) q —CH 3 wherein p and q are integers from 0 to 26 with the proviso that 13≦p+q≦26.

11. The compound of claim 10 , wherein R 1 is —(CH 2 ) p —K—(CH 2 ) q -M—(CH 2 ) r ,—CH 3 and wherein:
K and M are C≡C, and p, q and r are integers from 0 to 25 with q is 0 and with the proviso that 12≦p+q+r≦25.

12. The compound of claim 1 , wherein M 1 is selected from the group consisting of Man α, Man α(1−>2)Man α, Man α(1−>3)Man α, Man α(1−>4)Man α, and Man α(1−>6)Man α.

13. The compound of claim 1 , wherein LINKER is selected from the group consisting of O—C(═O)—, —C(═O)—O—, —NHC(═O)— and —C(═O)NH—.

14. The compound of claim 4 , wherein R 1 is selected from the group consisting of:
(i) —(CH 2 ) p CH 3 wherein p is an integer from 16 to 29;
(ii) —(CH 2 ) p -M—(CH 2 ) q —CH 3 wherein M is CH═CH or C≡C and p and q are integers from 0 to 27 with the proviso that 14≦p+q≦27;
(iii) —(CH 2 ) p —K—(CH 2 ) q -M—(CH 2 ) r —CH 3 wherein K and M are independently selected from CH═CH and C≡C, and p, q and r are integers from 0 to 25 with the proviso that 12≦p+q+r≦25;
(iv) —(CH 2 ) p —K—(CH 2 ) q -M—(CH 2 ) r —P—(CH 2 ) s , —CH 3 wherein K, M and P are independently selected from CH═CH and C≡C, and p, q, r and s are integers from 0 to 23 with the proviso that 10≦p+q+r+s≦23; and

Assignees

• Univ Strasbourg
• Centre Nat Rech Scient

Inventors

• Baati Rachid
• Dehuyser Laure
• Mueller Christopher
• Schaeffer Evelyne
• Wagner Alain

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/18

  for HIV · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title