Pegylated carfilzomib compounds

Patent metadata

Field	Value
Publication number	US-10517954-B2
Application number	US-201715602823-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	May 24, 2016
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

The present invention provides polymeric pegylated carfilzomib compounds, and pharmaceutically acceptable salts thereof, of Formula I

wherein R 1 , R 2 , linker, PEG, n and o are as defined herein. The invention also provides methods of making and using these compounds to treat cancer, and particularly to treat hematological malignancies including multiple myeloma.

First claim

What is claimed is:

1. A pegylated carfilzomib compound having a structure of formula I

or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1-10 alkyl or C 3-7 cycloalkyl;
each R 2 , independently, is C 1-6 alkyl, —OCH 3 or halogen;
o is an integer selected from 0, 1, 2 or 3;
linker is a moiety having the structure of

wherein R 3 is H or CH 3 ;
n is an integer selected from 1, 2, 3 or 4;
p is an integer selected from 0, 1, 2, 3 or 4;
q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9;
r is an integer selected from 0, 1, 2, 3, 4 or 5; and

PEG is a polyethylene glycol polymeric moiety having a molecular weight ranging from about 500 to about 20,000.

2. The compound of claim 1 wherein R 1 is C 1-10 alkyl.

3. The compound of claim 1 wherein each o is 0 or 1 and R 2 is CH 3 or halogen.

4. The compound of claim 1 wherein each o is 0 or 1 and R 2 is CH 3 or F.

5. The compound of claim 1 wherein the linker is a moiety having the structure of

wherein R 3 is H or CH 3 ;
q is an integer selected from 1, 2, 3, 4 or 5; and
r is an integer selected from 0, 1, 2, 3 or 4.

6. The compound of claim 1 wherein the linker is

wherein R 3 is H or CH 3 ;
q is 4; and
r is 2.

7. The compound of claim 2 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl.

8. The compound of claim 1 wherein
R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl; and the linker is

9. The pegylated carfilzomib compound of claim 1 having a structure of Formula II

wherein
R 1 is C 1-10 alkyl or C 3-7 cycloalkyl;
R 2 is C 1-6 alkyl, —OCH 3 or halogen;
linker is a moiety having the structure of

wherein R 3 is H or CH 3 ;
n is an integer selected from 1, 2, 3 or 4;
p is an integer selected from 0, 1, 2, 3 or 4;
q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9;
r is an integer selected from 0, 1, 2, 3, 4 or 5;

X is a counter ion salt selected from a chloride, a bisulfate, a sulfate, a nitrate, a phosphate, an alky-sulfonate or an aryl-sulfonate; and
PEG is a polyethylene glycol polymeric moiety having a molecular weight ranging from about 2000 to about 20,000.

10. The compound of claim 9 wherein R 1 is C 1-10 alkyl.

11. The compound of claim 9 wherein R 2 is H, CH 3 or halogen.

12. The compound of claim 9 wherein R 2 is H, CH 3 or F.

13. The compound of claim 9 wherein the linker is a moiety having the structure of

wherein R 3 is H or CH 3 ;
q is an integer selected from 1, 2, 3, 4 or 5; and
r is an integer selected from 0, 1, 2, 3 or 4.

14. The compound of claim 9 wherein the linker is

wherein R 3 is H or CH 3 ;
q is 4; and
r is 2.

15. The compound of claim 9 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl.

16. The compound of claim 9 wherein
R 1 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl; and
the linker is

17. The compound of claim 1 having the structure of

18. The compound of claim 1 wherein the PEG has a weight ranging from about 2K to about 20K.

19. The compound of claim 1 wherein the PEG has a weight of 2K, 3K, 5K or 20K.

20. The compound of claim 1 that is a pharmaceutically acceptable salt comprising a counter anion selected from a chloride anion, a bisulfate anion, a sulfate anion, a nitrate anion, a phosphate anion, an alky-sulfonate anion or an aryl-sulfonate anion.

21. The compound of claim 20 wherein the counter anion is a chloride anion or an alky-sulfonate anion.

22. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

23. The pharmaceutical composition of claim 22 that is administered orally or by infusion or injection.

Assignees

• Amgen Inc

Inventors

• Luehr Gary
• Anik Shabbir T
• Peng Ge
• DOTSENKO Irina
• Phiasivongsa Pasit
• ROMANINI Dante

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K38/07 Primary

  Tetrapeptides · CPC title

• C08G65/33396

  having oxygen in addition to nitrogen · CPC title