Derivatives of oxazaphosphorines that are pre-activated, use and method of preparation

Patent metadata

Field	Value
Publication number	US-9428530-B2
Application number	US-201514790634-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Dec 10, 2010
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

The present invention relates to novel derivatives of oxazaphosphorines that are pre-activated, to the methods for preparing same, to the pharmaceutical compositions containing same and to the therapeutic use thereof, in particular for treating cancer.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
X is O or S;
R1, and R2 are independently H, —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl with proviso that at least one group among R1 and R2 is —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl;
R3 is —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl;
R4 is a vectorization or formulation group comprising a linear or branched, unsaturated hydrocarbon group of 5 to 30 carbon atoms, optionally substituted by one or more substituents selected from —OR, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)R, —NRR′, —C(O)NRR′, —NC(O)R, —NRC(O)R′, —SR, halogen, cyano (—CN), aryl, heteroaryl, alkyl and arylalkyl, wherein R is hydrogen or a C 1 -C 3 alkyl and R′ is hydrogen or a C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R4 comprises an unsaturated, branched or linear, hydrocarbon group of 5 to 30 carbon atoms, optionally substituted by one or more hydroxyl groups.

3. The compound of claim 2 , wherein R4 comprises one or more isoprene units.

4. The compound of claim 2 , wherein R4 comprises a squalenyl group.

5. The compound of claim 1 , wherein R4 comprises a branched unsaturated hydrocarbon group of 5 to 30 carbon atoms.

6. The compound of claim 1 , wherein R4 is of formula R5(Y) a wherein:
Y is a spacer;
a is 0 or 1; and
R5 is a linear or branched unsaturated hydrocarbon chain of 5 to 30 carbon atoms, optionally substituted by one or more —OH groups.

7. The compound of claim 6 , wherein Y is selected from the group consisting of —(CH 2 ) m —, —CONH(CH 2 ) m —, —COO(CH 2 ) m — and —OCO(CH 2 ) m — wherein m is an integer ranging from 1 to 10.

8. The compound of claim 6 , wherein R5 is a branched unsaturated hydrocarbon group of 5 to 30 carbon atoms.

9. The compound of claim 8 , wherein R5 comprises one or more methyl groups as branches.

10. The compound of claim 6 , wherein R5 is an unsaturated C 5 -C 30 hydrocarbon group comprising one or more isoprene units.

11. The compound of claim 6 , wherein R5 comprises from 1 to 4 unsaturations and from 1 to 6 branches being methyl groups.

12. The compound of claim 11 , wherein the unsaturations are double bonds.

13. The compound of claim 6 , wherein R5 is selected from the group consisting of:
(a) (CH 3 ) 2 C═CH—CH 2 —CH 2 —[C(CH 3 )═CH—CH 2 —CH 2 ] m — wherein m is an integer ranging from 0 to 5; and
(b) (CH 3 ) 2 C═CH—CH 2 —CH 2 —[C(CH 3 )═CH—CH 2 —CH 2 ] p —[CH═C(CH) 3 —CH 2 —CH 2 ] q wherein p is an integer ranging from 1 to 5 and q is an integer ranging from 1 to 5.

14. The compound of claim 1 , wherein R2 and R3 are both —(CH 2 ) 2 —Cl and R1 is H.

15. The compound of claim 1 , wherein X is O.

16. A nanoparticle formed by a compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a nanoparticle of claim 16 .

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method for treating a patient suffering from a cancer, the method comprising administering said patient with a therapeutically effective dose of a pharmaceutical composition comprising:
a) a compound or claim 1 or a pharmaceutically acceptable salt thereof; or
b) a nanoparticle formed by a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A method for preparing an oxazaphosphorine of formula (I)

wherein:
X is O or S;
R1, and R2 are independently H, —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl with proviso that at least one group among R1 and R2 is —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl;
R3 is —(CH 2 ) 2 —Cl or —CH(CH 3 )—CH 2 —Cl;
R4 is a vectorization or formulation group comprising a linear or branched, unsaturated hydrocarbon group of 5 to 30 carbon atoms, optionally substituted by one or more substituents selected from the group consisting of —OR, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)R, —NRR′, —C(O)NRR′, —NC(O)R, —NRC(O)R′, —SR, halogen, cyano (—CN), aryl, heteroaryl, arylalkyl; wherein R is a hydrogen or a C 1 -C 3 alkyl and R′ is a hydrogen or a C 1 -C 3 alkyl;
said method comprising:
providing a compound of formula (II)

wherein R1, R2 and R3 are as defined in formula (I); and
reacting the compound of formula (II) with R4-XH, wherein X and R4 are defined as in formula (I), in the presence of a Lewis acid.

Assignees

• Roussy Inst Gustave

Inventors

• Paci Angelo
• Martens Thierry
• Rivard Michael
• Couvreur Patrick
• Desmaele Didier
• Caron Joachim

Classifications

• C07F9/65846 Primary

  the phosphorus atom being part of a six-membered ring which may be condensed with another ring system · CPC title

• C07K16/30

  from tumour cells · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title