Maytansinoid derivatives, conjugates thereof, and methods of use

Patent metadata

Field	Value
Publication number	US-9950076-B2
Application number	US-201715414537-A
Country	US
Kind code	B2
Filing date	Jan 24, 2017
Priority date	Jan 25, 2016
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

Provided herein are maytansinoid compounds, derivatives thereof, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is arylene or heteroarylene;
L is a linker;
BA is a binding agent; and
k is an integer from 1 to 30.

2. The compound of claim 1 , wherein
A is:

R 1 , independently at each occurrence, is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro,

 or azido;
R A is alkyl;
n is an integer from 0 to 4; and

each is a bond from A to —NH—.

3. The compound of claim 2 , wherein
R 1 , independently at each occurrence, is alkyl, alkoxy, halo, haloalkyl, or heterocycloalkyl.

4. The compound of claim 2 ,
wherein:
A is:

and
n is 0, 1, 2, or 3.

5. The compound of claim 2 , wherein R 1 , independently at each occurrence, is methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, pyrrolidinyl, or morpholinyl.

6. The compound of claim 2 , wherein R 1 is methyl.

7. The compound of claim 2 , wherein R 1 , independently at each occurrence, is fluoro, chloro, or bromo.

8. The compound of claim 2 , wherein R 1 is chloro.

9. The compound of claim 2 , wherein R 1 is trifluoromethyl.

10. The compound of claim 2 , wherein R 1 is methoxy.

11. The compound of claim 2 , wherein R 1 , independently at each occurrence, is methyl, morpholinyl, or pyrrolidinyl.

12. The compound of claim 2 , wherein A is

13. The compound of claim 2 , wherein A is

14. The compound of claim 2 wherein A is

15. The compound of claim 1 , wherein L is:

wherein:
SP is a spacer;

is one or more bonds to the binding agent;

is a bond to —NH-A;
AA 1 is an amino acid; and
AA 2 is an amino acid.

16. The compound of claim 1 , wherein L is:

wherein:
SP is a spacer;

is one or more bonds to the binding agent; and

is a bond to —NH-A.

17. The compound of claim 15 , wherein AA 1 -AA 2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, asparagine-alanine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine.

18. The compound of claim 1 , wherein L is:

wherein:
SP is a spacer;

is one or more bonds to the binding agent;

is a bond to —NH-A;
R AA1 is an amino acid side chain; and
R AA2 is an amino acid side chain.

19. The compound of claim 18 , wherein L is:

wherein:
SP is a spacer; and

is one or more bonds to the binding agent; and

is a bond to —NH-A.

20. The compound of claim 15 , wherein SP comprises a C 5-7 alkylene.

21. The compound of claim 15 , wherein SP is:

wherein:
b, independently in each instance, is an integer from 2 to 8;

is one or more bonds to the binding agent; and

is a bond to —NH-A.

22. The compound of claim 1 , wherein L is

wherein:
b is an integer from 2 to 8;

is one or more bonds to the binding agent; and

is a bond to —NH-A.

23. The compound of claim 22 , wherein L is

wherein

is a bond to the binding agent and

is a bond to —NH-A.

24. The compound of claim 1 wherein L is

wherein

is a bond to the binding agent and

is a bond to —NH-A.

25. The compound of claim 1 , wherein the compound is:

Assignees

• Regeneron Pharma

Inventors

• Nittoli Thomas
• Markotan Thomas P

Classifications

• C07K16/32

  against translation products of oncogenes · CPC title

• A61K47/6851 Primary

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

• C07D498/18

  Bridged systems · CPC title

• A61K47/68 Primary

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07K16/40

  against enzymes · CPC title