Benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-9265841-B2
Application number	US-201414316105-A
Country	US
Kind code	B2
Filing date	Jun 26, 2014
Priority date	Feb 5, 2009
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepines of formula (I) and (II), in which the diazepine ring (B) is fused with a heterocyclic ring (CD), wherein the heterocyclic ring is bicyclic or a compound of formula (III), in which the diazepine ring (B) is fused with a heterocyclic ring (C), wherein the heterocyclic ring is monocyclic. The invention provides cytotoxic dimers of these compounds. The invention also provides conjugates of the monomers and the dimers. 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. The invention further relates to methods of using the compounds or conjugates for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

First claim

We claim:

1. A compound represented by formula (VI):

or a pharmaceutically acceptable salt, optical isomer, racemate, diastereomer, or enantiomer thereof, wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is H, and when it is a single bond, X is H;
Y is selected from —OR, —OCOR′, —OCOOR′, —OCONR′R″, —NR′R″, —NRCOR′, —NRCOP, wherein P is an amino acid or a polypeptide containing between 2 to 20 amino acid units, —SR′, —SOR′, —SO 2 R′, —SO 3 , —OSO 3 , a halogen, cyano, and an azido, wherein R, R′ and R″ are the same or different and are selected from H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—OCH 2 CH 2 ) n , wherein n is an integer from 1 to 2000, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, wherein the optional substituent is selected from halogen, OR 7 , NR 8 R 9 , NO 2 , NRCOR′, SR 10 , SOR′, —SO 2 R′, —SO 3 , —OSO 3 , SO 2 NRR′, cyano, an azido, —COR 11 , —OCOR 11 or —OCONR 11 R 12 , wherein R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—OCH 2 CH 2 ) n , wherein n is an integer from 1 to 2000, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, and R 10 is optionally SR 13 or COR 13 , wherein R 13 is selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, optionally R 11 is OR 14 , wherein R 14 has the same definition as R, optionally R″ is OH;
W is C═O;
R 6 is OR, SR or NRR′, wherein R and R′ have the same definition as given above, optionally R 6 is a linking group;
X′ is selected from CH 2 ;
Y′ is O;
Z′ is CH 2 ;
A and A′ are the same or different and are O, —CRR′O, S, —CRR′S, —NR 15 or CRR′NHR 15 , wherein R and R′ have the same definition as given above and wherein R 15 has the same definition as R;
D and D′ are same or different and independently selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, each of which can be optionally substituted with any one of halogen, OR 7 , NR 8 R 9 , NO 2 , NRCOR′, SR 10 , SOR′, —SO 2 R′, —SO 3 , —OSO 3 , SO 2 NRR′, cyano, an azido, —COR 11 , OCOR 11 or OCONR 11 R 12 , wherein the definitions of R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined above, or (—OCH 2 CH 2 ) n , wherein n is an integer from 1 to 2000;
L is absent, an optionally substituted phenyl group, or a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P that is optionally substituted, wherein the optional substituent is a linking group that enables linkage to a cell binding agent via a covalent bond, or the optional substituent is selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, optionally substituted with any one of halogen, OR 7 , NR 8 R 9 , NO 2 , NRCOR′, SR 10 , SOR′, —SO 2 R′, —SO 3 , —OSO 3 , SO 2 NRR′, cyano, an azido, —COR 11 , OCOR 11 or OCONR 11 R 12 , wherein R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined above, or (—OCH 2 CH 2 )n, wherein n is an integer from 1 to 2000; optionally, L itself is a linking group that enables linkage to a cell binding agent via a covalent bond; provided that the compound has no more than one linking group that enables linkage to a cell binding agent via a covalent bond.

2. The compounds of claim 1 , wherein:
the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is H, and when it is a single bond, X is H;
Y is selected from —OR, NR′R″, —SO 3 , or —OSO 3 , wherein R is selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—OCH 2 CH 2 ) n , wherein n is an integer from 1 to 2000, an aryl having from 6 to 10 carbon atoms, and a heterocyclic ring having from 3 to 10 carbon atoms;
W is C═O;
X′ is selected from CH 2 ;
Y′ is O;
Z′ is CH 2 ;
A and A′ are each O;
D and D′ are the same or different and independently selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
L is absent, an optionally substituted phenyl group, or a heterocycle ring having from 3 to 10 carbon atoms that is optionally substituted, wherein the optional substituent is a linking group that enables linkage to a cell binding agent via a covalent bond, or the optional substituent is selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, optionally substituted with any one of halogen, OR 7 , NR 8 R 9 , NO 2 , NRCOR′, SR 10 , SOR′, —SO 2 R′, —SO 3 , —OSO 3 , SO 2 NRR′, cyano, an azido, —COR 11 , OCOR 11 or OCONR 11 R 12 , or (—OCH 2 CH 2 )n, wherein n is an integer from 1 to 2000; optionally, L itself is a linking group that enables linkage to a cell binding agent via a covalent bond.

3. The compounds of claim 1 , wherein one of R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, R 3 ′, R 4 ′, L′, L″, L′″ is a linking group independently selected from:
—O(CR 20 R 21 ) m (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—O(CR 20 R 21 ) m (CR 26 ═CR 27 ) m′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—O(CR 20 R 21 ) m (alkynyl) n′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—O(CR 20 R 21 ) m (piperazino) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—O(CR 20 R 21 ) m (pyrrolo) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—O(CR 20 R 21 ) m A″ m″ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m (CR 26 ═CR 27 ) m′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m (alkynyl) n′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m (piperazino) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m (pyrrolo) t′ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—S(CR 20 R 21 ) m A″ m″ (CR 22 R 23 ) n (OCH 2 CH 2 ) p (CR 40 R 41 ) p″ Y″(CR 24 R 25 ) q (CO) t X″,
—NR 33 (C═O) p″ (CR 20 R 21 )

Assignees

• Immunogen Inc

Inventors

• Li Wei
• Fishkin Nathan Elliott
• Zhao Robert Yongxin
• Miller Michael Louis
• Chari Ravi V J

Classifications

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/6849

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

• C07K16/46

  Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00) · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D263/06

  with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms · CPC title