Taxane silicate prodrugs and nanoparticles

Patent metadata

Field	Value
Publication number	US-9375484-B2
Application number	US-201214123448-A
Country	US
Kind code	B2
Filing date	May 31, 2012
Priority date	May 31, 2011
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The invention provides silicate prodrugs comprising a therapeutic agent linked to one or more groups of formula (I): —Si(OR) 3 (I); wherein each R independently has any of the values defined herein, as well as nanoparticles comprising such compounds.

First claim

What is claimed is:

1. A compound comprising a taxane linked to one or more groups of formula (I):
—Si(OR) 3   (I)

wherein:
each R is independently selected from (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl.

2. The compound of claim 1 wherein the taxane is a paclitaxel or docetaxel.

3. A compound of formula (Ia):

wherein R 1 is a group of formula (I),
—Si(OR) 3   (I)

wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.

4. A compound of formula (Ib):

wherein R 1 and R 2 are each independently a group of formula (I),
—Si(OR) 3   (I)

wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.

5. A compound of formula (Ic):

wherein R 3 is a group of formula (I),
—Si(OR) 3   (I)

wherein:
each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, wherein each (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 1 -C 20 )alkanoyl, (C 2 -C 20 )alkenylcarbonyl, and (C 2 -C 20 )alkynylcarbonyl, is optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, oxo, halo, or aryl;
or a salt thereof.

6. A compound selected from:

and salts thereof.

7. A compound selected from:

and salts thereof.

8. A composition comprising a compound as described in claim 1 and a PEG-b-PLGA block co-polymer.

9. A composition comprising a compound as described in claim 1 and a pharmaceutically acceptable carrier.

10. A nano-particle comprising a compound as described in claim 1 and a PEG-b-PLGA block co-polymer.

11. A nano-particle comprising a compound as described in claim 1 and one or more targeting moieties.

12. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 1 .

13. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 1 .

14. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 10 .

15. A composition comprising a compound as described in claim 3 and a PEG-b-PLGA block co-polymer.

16. A composition comprising a compound as described in claim 3 and a pharmaceutically acceptable carrier.

17. A nano-particle comprising a compound as described in claim 3 and a PEG-b-PLGA block co-polymer.

18. A nano-particle comprising a compound as described in claim 3 and one or more targeting moieties.

19. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 3 .

20. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 3 .

21. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 17 .

22. A composition comprising a compound as described in claim 4 and a PEG-b-PLGA block co-polymer.

23. A composition comprising a compound as described in claim 4 and a pharmaceutically acceptable carrier.

24. A nano-particle comprising a compound as described in claim 4 and a PEG-b-PLGA block co-polymer.

25. A nano-particle comprising a compound as described in claim 4 and one or more targeting moieties.

26. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 4 .

27. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 4 .

28. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 4 .

29. A composition comprising a compound as described in claim 5 and a PEG-b-PLGA block co-polymer.

30. A composition comprising a compound as described in claim 5 and a pharmaceutically acceptable carrier.

31. A nano-particle comprising a compound as described in claim 5 and a PEG-b-PLGA block co-polymer.

32. A nano-particle comprising a compound as described in claim 5 and one or more targeting moieties.

33. A method to treat cancer in an animal comprising administering to the animal a compound as described in claim 5 .

34. A method to treat restenosis in an animal comprising administering to the animal a compound as described in claim 5 .

35. A method to treat cancer in an animal, comprising administering to the animal a nano-particle as described in claim 31 .

Assignees

• Hoye Thomas R
• Wohl Adam
• Macosko Christopher W
• Panyam Jayanth
• Univ Minnesota

Inventors

• Hoye Thomas R
• Wohl Adam
• Macosko Christopher W
• Panyam Jayanth

Classifications

• A61K31/695

  Silicon compounds · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/5153

  Polyesters, e.g. poly(lactide-co-glycolide) · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title