Tubulysin analogs and methods of making and use

Patent metadata

Field	Value
Publication number	US-2016130299-A1
Application number	US-201514833422-A
Country	US
Kind code	A1
Filing date	Aug 24, 2015
Priority date	Nov 10, 2014
Publication date	May 12, 2016
Grant date	—

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, Cl, 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, Cl, 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 4 , wherein R 5 and R 6 are each Me.

7 . A tubulysin analog-linker compound having a structure represented by formula (IIIa):

or a pharmaceutically acceptable salt thereof;
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;
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;
R 7 is H, Me, or Et;
T is a self-immolating group;
t is 0 or 1;
AA a and each AA b are independently selected from the group consisting of alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine;
p is 1, 2, 3, or 4;
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
r is 1, 2, 3, 4, or 5;
s is 0 or 1; and

8 . A tubulysin analog-linker compound having a structure represented by formula (IIIc):

or a pharmaceutically acceptable salt thereof;
wherein
R 1c is H, Me, or CH(Me) 2 ;
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;
R 4d is Me or NHMe;
R 5 and R 6 are each Me or combine with the carbon to which they are bond

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

• A61K47/6813

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

• C07K5/06026

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

• C07K5/06139 Primary

  with the first amino acid being heterocyclic · CPC title

• C07K16/3046

  Stomach, Intestines · CPC title

• A61K47/6817

  Toxins · CPC title