Tubulysin analogs and methods of making and use

Patent metadata

Field	Value
Publication number	US-10077287-B2
Application number	US-201514833422-A
Country	US
Kind code	B2
Filing date	Aug 24, 2015
Priority date	Nov 10, 2014
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

Tubulysin analogs of the formula (I)

where R 1 , R 2 R 3 , R 4 , R 5 , R 6 , R 7 , and Y are as defined herein, are anti-mitotic agents that can be used in the treatment of cancer, especially when conjugated to a targeting moiety.

First claim

What is claimed is:

1. A tubulysin analog having a structure represented by formula (I)

wherein
R 1 is

wherein
R 1a is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, CO(C 1 -C 5 alkyl), CO(C 2 -C 5 alkenyl), or CO(C 2 -C 5 alkynyl);
each R 1b is independently H or C 1-3 alkyl;
R 1c is H, Me, or CH(Me) 2 ; and
n is 0, 1, or 2;

R 2 is H, unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH 2 ) 1-2 O(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkynyl), (CH 2 ) 1-2 OC(═O)(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted C(═O)(C 1 -C 10 alkyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, or unsubstituted or substituted alkylaryl;
R 3 is H, unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 2 -C 10 alkenyl, unsubstituted or substituted C 2 -C 10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH 2 ) 1-2 O(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 O(C 2 -C 10 alkynyl), (CH 2 ) 1-2 OC(═O)(C 1 -C 10 alkyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted (CH 2 ) 1-2 OC(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted C(═O)(C 1 -C 10 alkyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkenyl), unsubstituted or substituted C(═O)(C 2 -C 10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, unsubstituted or substituted alkylaryl, or

wherein each R 3a is independently H, NH 2 , NHMe, C 1 , F, Me, Et, or CN;

R 4 is

wherein
R 4a and R 4b are independently H, C 1 -C 5 alkyl, CH 2 (C 5 -C 6 cycloalkyl), CH 2 C 6 H 5 , C 6 H 5 , or CH 2 CH 2 OH; and
W is O or S;

R 5 and R 6 are each Me or combine with the carbon to which they are bonded to form a cyclopropyl ring;
R 7 is H or C 1 -C 3 alkyl; and
Y is H, OH, C 1 , F, CN, Me, Et, NO 2 , or NH 2 ;
or a pharmaceutically acceptable salt thereof.

2. A tubulysin analog according to claim 1 , having a structure represented by formula (Ia):

wherein
R 2 is Me, Et, CH 2 CH 2 CH 3 , CH(Me) 2 , CH(Et) 2 , or

R 3 is H, C 1 -C 5 alkyl, C 1 -C 5 alkenyl, C 1 -C 5 alkynyl, CH 2 OC(═O)C 1 -C 5 alkyl, CH 2 OC(═O)C 1 -C 5 alkenyl, or CH 2 OC(═O)C 1 -C 5 alkynyl; and R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .

3. A tubulysin analog according to claim 1 , having a structure represented by formula (Ia′)

wherein
R 2 is CH(Me) 2 , CH(Et) 2 , or

R 3 is C 1-5 alkyl;
R 4d is Me or NHMe; and
R 7 is H, Me, or Et.

4. A tubulysin analog according to claim 1 , having a structure represented by formula (Ib′)

wherein
R 2 is CH(Me) 2 , CH(Et) 2 , or

R 3 is C 1-5 alkyl;
R 4d is Me or NHMe; and
R 7 is H, Me, or Et.

5. A tubulysin analog according to claim 1 , having a structure represented by formula (Ic)

wherein
R 1 is

R 2 is CH(Me) 2 , CH(Et) 2 , or

R 3 is C 1-5 alkyl;
R 4d is Me or NHMe;
R 5 and R 6 are each Me or combine with the carbon to which they are bonded to form a cyclopropyl ring; and
R 7 is H, Me, or Et.

6. A tubulysin analog according to claim 5 , wherein R 5 and R 6 are each Me.

7. A compound according to claim 1 , having a structure represented by the formula

wherein R 20 , R 21 , and R 22 are as set for the below:

Compound
R 20
R 21
R 22

(Ia-1)

NH 2

(Ia-2)

NH 2

(Ia-3)

Assignees

• Bristol Myers Squibb Co

Inventors

• Perez Heidi L
• Wei Donna
• Borzilleri Robert M
• Gangwar Sanjeev
• Schroeder Gretchen M
• Cheng Heng
• Schmidt Robert J

Classifications

• A61K47/6851

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• A61K47/6813

  the drug being a peptidic cytokine, e.g. an interleukin or interferon · CPC title

• C07K5/06052

  Val-amino acid · CPC title