Maytansinoid derivatives with sulfoxide linker

Patent metadata

Field	Value
Publication number	US-9156854-B2
Application number	US-201214009957-A
Country	US
Kind code	B2
Filing date	Mar 20, 2012
Priority date	Apr 18, 2011
Publication date	Oct 13, 2015
Grant date	Oct 13, 2015

Abstract

The invention relates to novel maytansinoid compounds having sulfoxide linkers and more specifically to novel maytansinoid compounds of structural formula (I) and (II). The invention also provides conjugates of the maytansinoid compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

First claim

I claim:

1. The compound represented by the following structural formula:

wherein:
D is a maytansinoid;
X is S or Se;
Y′ is —SO 2 —, aryl, aryl, pyridyl or —C(═O)—;
Z is an alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or —N(R b )—R d —;
R b is H or a C 14 alkyl;
R d is a C 14 alkyl; and
M is a linking group that can react with a cell-binding agent to form a covalent bond.

2. The compound of claim 1 , wherein D is represented by the following structural formula:

wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 )—CR 1 R 2 —,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, an alkyl, an alkenyl, a cycloalkyl, a heteroaryl, a heterocyclyl, or an aryl; and
l, m and n are each independently 0 or an integer of from 1 to 5.

3. The compound of claim 2 , wherein R 1 and R 2 are each independently H, C 1-4 alkyl or C 1-4 alkyl substituted with one to six halogens.

4. The compound of claim 3 , wherein R 1 and R 2 are each independently H, methyl, —CF 3 or —CCl 3 .

5. The compound of claim 3 , wherein R 1 and R 2 are both H or methyl.

6. The compound of claim 2 , wherein 1 and m are 0, n is 1, R 1 , R 2 , R 3 and R 4 are all H.

7. The compound of claim 2 , wherein n is 0, 1 and m are both 1, R 5 , R 6 , R 7 and R 8 are all H, R 1 and R 2 are both methyl.

8. The compound of claim 2 , wherein n is 0, 1 and m are both 1, R 5 , R 6 , R 7 and R 8 are all H, R 1 is H and R 2 is methyl.

9. The compound of claim 1 , wherein X is S.

10. The compound of claim 1 , wherein Y′ is SO 2 .

11. The compound of claim 10 , wherein Z is phenyl.

12. The compound of claim 1 , wherein Y′ is pyridyl and Y′ is linked with Z through the pyridyl nitrogen atom.

13. The compound of claim 12 , wherein Z is an alkyl.

14. The compound of claim 1 , wherein Y′ is —C(═O)—.

15. The compound of claim 14 , wherein Z is —N(R b )—R d —.

16. The compound of claim 15 , wherein R b is H and R d is —CH 2 —CH 2 —.

17. The compound of claim 1 , wherein M represents a maleimide, a haloacetamido, —SH, —SSR f , —CH 2 SH, —CH(Me)SH, —C(Me) 2 SH, —NHR g , —CH 2 NHR g , —NR g NH 2 , —COOH or a reactive ester, wherein R f is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl or nitropyridyl and R g is —H or a C 1-4 alkyl.

18. The compound of claim 17 , M represents a maleimide, a haloacetamido, N-hydroxysuccinimde ester, N-hydroxy sulfosuccinimide ester, nitrophenyl ester, dinitrophenyl ester, sulfo-tetraflurophenyl ester or pentafluorophenyl ester.

19. The compound of claim 17 , wherein M represents a N-hydroxysuccinimide ester.

20. A conjugate represented by the following structural formula:

wherein:
CBA represents a cell-binding agent,
D is a maytansinoid;
X is S or Se;
Y′ is —SO 2 —, aryl, pyridyl or —C(═O)—;
Z is an alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or —N(R b )—R d —;
R b is H or a C 1-4 alkyl;
q is an integer from 1 to 20; and
R d is a C 1-4 alkyl.

21. The conjugate of claim 20 , wherein D is represented by the following structural formula:

wherein:
Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 )—CR 1 R 2 —,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, an alkyl, an alkenyl, a cycloalkyl, a heteroaryl, a heterocyclyl, or an aryl; and
l, m and n are each independently 0 or an integer of from 1 to 5.

22. The conjugate of claim 21 , wherein R 1 and R 2 are each independently H, C 1-4 alkyl or C 1-4 alkyl substituted with one to six halogens.

23. The conjugate of claim 22 , wherein R 1 and R 2 are each independently H, methyl, —CF 3 or —CCl 3 .

24. The conjugate of claim 22 , wherein R 1 and R 2 are both H or methyl.

25. The conjugate of claim 21 , wherein 1 and m are 0, n is 1, R 1 , R 2 , R 3 and R 4 are all H.

26. The conjugate of claim 21 , wherein n is 0,1 and m are both 1, R 5 , R 6 , R 7 and R 8 are all H, R 1 and R 2 are both methyl.

27. The conjugate of claim 21 , wherein n is 0,1 and m are both 1, R 5 , R 6 , R 7 and R 8 are all H, R 1 is H and R 2 is methyl.

28. The conjugate of claim 20 , wherein X is S.

29. The conjugate of claim 20 , wherein Y′ is SO 2 .

30. The conjugate of claim 29 , wherein Z is phenyl.

31. The conjugate of claim 20 , wherein Y′ is pyridyl and Y′ is linked with Z through the pyridyl nitrogen atom.

32. The conjugate of claim 31 , wherein Z is an alkyl.

33. The conjugate of claim 20 , wherein Y′ is —C(═O)—.

34. The conjugate of claim 33 , wherein Z is —N(R b )—R d —.

35. The conjugate of claim 34 , wherein R b is H and R d is —CH 2 —CH 2 —.

Assignees

• Fishkin Nathan
• Immunogen Inc

Inventors

• Fishkin Nathan

Classifications

• C07D498/18 Primary

  Bridged systems · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K31/537

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/5365

  ortho- or peri-condensed with heterocyclic ring systems · CPC title