Pegylated carfilzomib compounds

Patent metadata

Field	Value
Publication number	US-10675353-B2
Application number	US-201916675134-A
Country	US
Kind code	B2
Filing date	Nov 5, 2019
Priority date	May 24, 2016
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

The present invention provides a method of treating multiple myeloma using 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.

First claim

What is claimed is:

1. A method of treating multiple myeloma, the method comprising: administering to a patient having multiple myeloma, a therapeutically effective amount of a 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 method of claim 1 , wherein R 1 is C 1-10 alkyl.

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

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

5. The method 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 method of claim 1 , wherein the linker is

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

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

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

9. The method of claim 1 , wherein the compound has 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 method of claim 9 , wherein R 1 is C 1-10 alkyl.

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

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

13. The method 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 method of claim 9 , wherein the linker is

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

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

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

17. The method of claim 1 , wherein the compound has the structure

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

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

20. The method of claim 1 , wherein the compound 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 method of claim 20 , wherein the counter anion is a chloride anion or an alky-sulfonate anion.

22. The method of claim 1 , wherein the compound is in a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient, carrier or diluent.

23. The method of claim 22 , wherein the pharmaceutical composition is administered orally or by infusion or injection.

24. The method of claim 1 wherein the multiple myeloma is relapsed, refractory or relapsed and refractory multiple myeloma.

25. The method of claim 1 wherein the multiple myeloma is newly diagnosed multiple myeloma.

Assignees

• Amgen Inc

Inventors

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

Classifications

• 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

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K47/60 Primary

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

• C08G2230/00

  Compositions for preparing biodegradable polymers · CPC title

• C07D405/12

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