Macrocyclic benzodiazepine dimers, conjugates thereof, preparation and uses

Patent metadata

Field	Value
Publication number	US-9688694-B2
Application number	US-201615189388-A
Country	US
Kind code	B2
Filing date	Jun 22, 2016
Priority date	Jun 23, 2015
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

Macrocyclic benzodiazepine dimers having a structure represented by formula I

where A and B are independently according to formulae Ia or Ib

and the other variables in formulae I, Ia, and Ib are as defined in the application. Such dimers are useful as anti-cancer agents, especially when used as the drug component in an antibody-drug conjugate (ADC).

First claim

What is claimed is:

1. A compound having a structure represented by formula I

X is

X 1 is CH 2 , O, NH, S(O) 0-2 , 3- to 7-membered cycloalkylene or heterocycloalkylene unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , or 5- to 6-membered arylene or heteroarylene unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ;
each X 2 is independently Me, CO 2 H, NH 2 , NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2 , SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), N(CH 2 CH 2 ) 2 NH, NHNH 2 , or C(═O)NHNH 2 ;
Y is (CH 2 ) 4-6 CH═CH(CH 2 ) 4-6 , (CH 2 ) 4-6 X 1 (CH 2 ) 4-6 , or (CH 2 ) 2 (OCH 2 CH 2 ) 2-3 ;
each R 1 and R 2 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2 , or NO 2 ;
each double line in a diazepine ring system independently represents a single bond or a double bond;
each R 3 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;
each R 4 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;
A and B are independently according to formula Ia or Ib

wherein, in formula Ia
Y′ and Y″ are independently absent, CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that Y′ and Y″ are not both absent;
each G is independently C or N, with the proviso that no more than two Gs are N; and
each R 5 , R 6 , R 7 , and R 8 is independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2 , F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,

or where a R 5 , R 6 , R 7 , or R 8 is attached to a G that is N, such R 5 , R 6 , R 7 , or R 8 is absent;

and
wherein, in formula Ib,
the dotted lines indicate the optional presence of a C1-C2, C2-C3, or C2-R 10 double bond;
R 10 is H, ═O, ═CH 2 , ═CH(C 1 -C 5 alkyl), CH═CH(CH 2 ) 1-5 X 2 , C≡C(CH 2 ) 1 —X 2 , C 1 -C 5 alkyl, OH, O(C 1 -C 5 alkyl), cyano, NO 2 , F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , 4- to 7-membered cycloalkyl, or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ; and
R 9 is absent if a C1-C2, C2-C3, or C2-R 10 double bond is present and otherwise is H;

wherein a heterocycloalkyl group has 1 to 2 carbons replaced with a heteroatom independently selected from N, O, or S, where the N and S optionally may be oxidized and the N optionally may be quaternized; and
wherein a heteroaryl group has 1 to 4 heteroatoms independently selected from N, O, or S, where the N and S optionally may be oxidized and the N optionally may be quaternized;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , having a structure represented by formula IIa:

wherein
x is 3 or 5;
Y is (CH 2 ) 7-12 , (CH 2 ) 2 (OCH 2 CH 2 ) 1-3 , (CH 2 ) 2-4 NH(CH 2 ) 2-4 or (CH 2 ) 2-4 NH((CH 2 ) 0-1 phenyl)(CH 2 ) 2-4 where the phenyl group is optionally substituted with NH 2 ;
A is A1, A2, or A3

B is B1, B2, or B3

3. A compound according to claim 1 , having a structure represented by formula IIb:

wherein
x is 3 or 5;
each Y′ is independently absent or CH 2 ;
Y is (CH 2 ) 7-12 , (CH 2 ) 2 (OCH 2 CH 2 ) 1-3 , (CH 2 ) 2-4 NH(CH 2 ) 2-4 or (CH 2 ) 2-4 NH((CH 2 ) 0-1 phenyl)(CH 2 ) 2-4 where the phenyl group is optionally substituted with NH 2 ; and
R 40 and R 41 are independently H, Cl, Br, OH, O(C 1-3 alkyl), NH 2 , or C 1-3 alkyl.

4. A compound according to claim 1 , having a structure represented by formula IIc

wherein
x is 3 or 5;
Y is (CH 2 ) 7-12 , (CH 2 ) 2 (OCH 2 CH 2 ) 1-3 , (CH 2 ) 2-4 NH(CH 2 ) 2-4 or (CH 2 ) 2-4 NH((CH 2 ) 0-1 phenyl)(CH 2 ) 2-4 where the phenyl group is optionally substituted with NH 2 ; and
R 42 and R 43 are independently H, OMe, NH 2 , OCH 2 CH 2 OMe, N(CH 2 CH 2 )O, N(CH 2 CH 2 )NMe, or N(CH 2 CH 2 )NH.

5. A compound according to claim 1 , having a structure represented by formula IIb-6, IIc-8, IIc-9, IIc-10, IIc-11, IId-1, IId-2, or IId-3

6. A compound having a structure represented by formula III:

wherein
R 60 is according to formula IIIa, IIIa′, or IIIa″

Y is (CH 2 ) 6-10 ;
x is 3 or 5;
each y is independently 2, 3, or 4;
A and B are independently according to formula Ia or Ib

wherein, in formula Ia
Y′ and Y″ are independently absent, CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that Y′ and Y″ are not both absent;
each G is independently C or N, with the proviso that no more than two Gs are N; and
each R 5 , R 6 , R 7 , and R 8 is independently H, Cl, Br, C 1-3 alkyl, NO 2 , CN, NH 2 , O(C 1-3 alkyl), or (OCH 2 CH 2 ) 1-2 O(C 1-3 alkyl);
or where a R 5 , R 6 , R 7 , or R 8 is attached to a G that is N, such R 5 , R 6 , R 7 , or R 8 is absent;

and
wherein, in formula Ib,
the dotted lines indicate the optional presence of a C1-C2, C2-C3, or C2-R 10 double bond;
R 9 is absent if a C1-C2, C2-C3, or C2-R 10 double bond is present and otherwise is H;
R 10 is H, Cl, Br, ═CH 2 , ═CH(C 1-5 alkyl), C 1-3 alkyl, NO 2 , CN, or NH 2 ;

A′ is

R 50 is H, Cl, Br, C

Assignees

• Bristol Myers Squibb Co

Inventors

• Zhang Yong
• Borzilleri Robert M
• Tebben Andrew J
• Stang Erik M
• Donnell Andrew F
• Schroeder Gretchen M
• Perez Heidi L
• Wei Donna D

Classifications

• C07D498/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61K47/6869

  the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate · CPC title

• C07K16/3046

  Stomach, Intestines · CPC title

• A61K47/6851

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

• A61K47/6863

  the tumour determinant being from stomach or intestines cancer cell · CPC title