Polymeric conjugates of active principles, their process of preparation and their polymeric intermediates

Patent metadata

Field	Value
Publication number	US-9278137-B2
Application number	US-201113877757-A
Country	US
Kind code	B2
Filing date	Nov 18, 2011
Priority date	Nov 19, 2010
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The present invention relates to novel conjugates of active principles grafted to a polymer, to the nanoparticles comprising them, to their preparation and to their polymeric intermediates.

First claim

The inventions claimed is:

1. Conjugate of an active principle and of a copolymer of polyethylene glycol and polylactic acid of formula (I):

in which:
mPEG is a methoxy-polyethylene glycol;
PLA is a polylactic acid;
m is the average molecular weight of the polyethylene glycol fragment (mPEG) and is comprised between 100 and 15 000 (expressed in Da);
n is the average molecular weight of the polylactic acid fragment and is comprised between 1000 and 50 000 (expressed in Da);
AP is an active principle residue;
L is a linker, such that L is a dicarboxylate derivative of succinic acid, glutaric acid or diglycolic acid,
X is a hydrogen atom or an alkyl group optionally substituted by one or more substituents selected from halogen atoms, OR, CN, CF 3 , NRR′ and COOR groups, where R and R′, which are identical to or different from one another, are a hydrogen atom or an alkyl group,

and their pharmaceutically acceptable salts.

2. Conjugate according to claim 1 , such that the AP residue is bonded to L by means of an OH group present in the AP.

3. Conjugate according to claim 1 , such that the said AP is a taxoid.

4. Conjugate according to claim 3 , such that the said taxoid is selected from paclitaxel, docetaxel, cabazitaxel and larotaxel.

5. Conjugate according to claim 1 , such that the said active principle is cabazitaxel, grafted in the 2′ position.

6. Conjugate according to claim 1 , such that the said PLA exhibits, at its optionally remaining free hydroxyl end, a protective group.

7. Conjugate according to claim 1 , corresponding to the formula (Ia):

in which L, AP, and X are as defined according to claim 1 and p is comprised between 1 and 340, and q is comprised between 10 and 700.

8. Conjugate according to claim 1 , corresponding to the following formula (Ib):

in which L, and AP are as defined according to claim 1 and and p is comprised between 1 and 340, and q is comprised between 10 and 700.

9. Process for the preparation of a conjugate according to claim 1 , comprising the coupling of a compound of formula (III):

with a derivative of the said active principle corresponding to the formula:
AP-L-H

where mPEG, m, PLA, n, X, AP and L are defined according to claim 1 .

10. Compound of formula (III):

in which mPEG, PLA, m, n and X are defined according to claim 1 .

11. Process for the preparation of the compound of formula (III) according to claim 10 comprising:
1. the stage of selective monoprotection of a hydroxyl group of the compound of formula (IV):

by means of an appropriate protective group,
2. the coupling of the monoprotected compound thus obtained with a precursor of the (PLA) n group, and
3. the deprotection of the protective group introduced in stage 1,
in which mPEG is a methoxy-polyethylene glycol;
m is the average molecular weight of the polyethylene glycol fragment (mPEG) and is comprised between 100 and 15 000 (expressed in Da);
PLA is a polylactic acid;
n is the average molecular weight of the polylactic acid fragment and is comprised between 1000 and 50 000 (expressed in Da);
and X is a hydrogen atom or an alkyl group optionally substituted by one or more substituents selected from halogen atoms, OR, CN, CF 3 , NRR′ and COOR groups, where R and R′, which are identical to or different from one another, are a hydrogen atom or an alkyl group.

12. Process according to claim 11 , such that the monoprotection is carried out by means of

where Lg represents a leaving group, such as a halogen atom or a trifluoromethanesulphonate group.

13. Process according to claim 11 such that stage 2 is carried out by ring opening polymerization (ROP) by means of the precursor 3,6-dimethyl-[1,4]-dioxane-2,5-dione.

14. Nanoparticles comprising a conjugate according to claim 1 .

15. Pharmaceutical composition comprising a conjugate according to claim 1 .

16. A method for the treatment and/or prevention of cancers in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the conjugate of claim 1 .

Assignees

• Amgoune Abderrhamane
• Bazile Didier
• Bensaid Fethi
• Bourissou Didier
• Didier Eric
• Greco Stephanie
• Lakkireddy Harivardhan Reddy
• Sable Serge
• Veillard Michel
• Sanofi Sa
• Centre Nat Rech Scient
• Univ Toulouse 3 Paul Sabatier

Inventors

• Amgoune Abderrhamane
• Bazile Didier
• Bensaid Fethi
• Bourissou Didier
• Didier Eric
• Greco Stephanie
• Lakkireddy Harivardhan Reddy
• Sable Serge
• Veillard Michel

Classifications

• A61K47/6935

  the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol · CPC title

• A61K47/59

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• A61K47/6907

  the form being a microemulsion, nanoemulsion or micelle · CPC title

• C08G65/3328 Primary

  heterocyclic · CPC title

• A61P35/00

  Antineoplastic agents · CPC title