Cytotoxic benzodiazepine derivatives and methods of preparation

Patent metadata

Field	Value
Publication number	US-9534000-B2
Application number	US-201213984762-A
Country	US
Kind code	B2
Filing date	Feb 15, 2012
Priority date	Feb 15, 2011
Publication date	Jan 3, 2017
Grant date	Jan 3, 2017

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds, such as those in formulas (V)-(VII). The invention also provides conjugates of the benzodiazepine 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. The present invention is further directed to methods of preparing a conjugate of a cell-binding agent and a cytotoxic compound. The methods comprise the use of an imine reactive compound to enable efficient conjugations of cytotoxic compounds with cell binding agents.

First claim

I claim:

1. A cytotoxic compound comprising a linking group with a reactive group bonded thereto capable of covalently linking the cytotoxic compound to a cell binding agent (CBA), wherein said cytotoxic compound is represented by the following formula:
or a pharmaceutically acceptable salt 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, or a linear or branched alkyl having 1 to 4 carbon atoms, and when it is a single bond, X is —H or an amine protecting moiety;
Y is —H or a leaving group selected from —OR, —OCOR′, —OCOOR′, —OCONR′R″, —NR′R″, —NR′COR″, —NR′NR′R″, an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, a guanidinum represented by —NR′(C═NH)NR′R″, an amino acid, or a peptide represented by —NRCOP′, wherein P′ is an amino acid or a polypeptide containing between 2 to 20 amino acid units, —SR, —SOR′, —SO 2 M, —SO 3 M, —OSO 3 M, halogen, cyano and an azido; or,
Y is HSO 3 , HSO 2 or a salt of HSO 3 − , SO 3 2− or HSO 2 − formed with a cation, H 2 S 2 O 5 or a salt of S 2 O 5 2− formed with a cation, PO 3 SH 3 , PO 2 S 2 H 2 , POS 3 H 2 , PS 4 H 2 or a salt of PO 3 S 3− , PO 2 S 2 3− , POS 3 3− or PS 4 3− formed with a cation, (R i O) 2 PS(OR i ), R i S—, R i SO, R i SO 2 , R i SO 3 , HS 2 O 3 or a salt of S 2 O 3 2− formed with a cation, HS 2 O 4 or a salt of S 2 O 4 2− formed with a cation, P(═S)(OR k′ )(S)(OH) or a salt thereof formed with a cation, R k′ C(═O)NOH or a salt formed with a cation, HOCH 2 SO 2 − or a salt of HOCH 2 SO 2 − formed with a cation, HOCH 2 SO 2 − Na + , or a mixture thereof, wherein R i is a linear or branched alkyl having 1 to 10 carbon atoms and is substituted with at least one substituent selected from —N(R j ) 2 , —CO 2 H, —SO 3 H, and —PO 3 H; R i can be further optionally substituted with a substituent for an alkyl described herein; R j is a linear or branched alkyl having 1 to 6 carbon atoms; R k′ is a linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, aryl, heterocyclyl or heteroaryl;
M is —H or a pharmaceutically acceptable cation;
R, for each occurrence, is independently selected from the group consisting of —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH 2 CH 2 O) n —R c , an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P;
R′ and R″ are each independently selected from —H, —OH, —OR, —NHR, —NR 2 , —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH 2 CH 2 O) n —R c , and an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms independently selected from O, S, N and P;
R c is —H or a substituted or unsubstituted linear or branched alkyl having 1 to 4 carbon atoms, or the linking group with the reactive group bonded thereto;
n is an integer from 1 to 24;
W is selected from C═O, C═S, CH 2 , BH, SO and SO 2 ;
X′ is selected from —H, an amine-protecting group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH 2 CH 2 O) n —R c , an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P;
Y′ is selected from —H, an oxo group, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, an optionally substituted 6- to 18-membered aryl, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms;
R 6 is —H, —R, —OR, —SR, —NR′R″, —NO 2 , halogen or the linking group with the reactive group bonded thereto;
A and A′ are the same or different, and are independently selected from —O—, oxo (—C(═O)—), —CRR′O—, —CRR′—, —S—, —CRR′S—, —NR 5 and —CRR′N(R 5 )—,
R 5 for each occurrence is independently —H or an optionally substituted linear or branched alkyl having 1 to 10 carbon atoms;
D and D′ are the same or different, and are independently absent or selected from the group consisting of an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, an amino acid, a peptide bearing 2 to 6 amino acids, and a polyethylene glycol unit (—OCH 2 CH 2 ) n —;
L is absent, the linking group with the reactive group bonded thereto, a polyethylene glycol unit (—OCH 2 CH 2 ) n —, a linear, branched or cyclic alkyl or alkenyl having 1 to 10 carbon atoms, a phenyl group, a 3 to 18-membered heterocyclic ring or a 5- to 18-membered heteroaryl ring having 1 to 6 heteroatoms independently selected from O, S, N and P, wherein the alkyl or alkenyl is optionally substituted with the linking group with the reactive group bonded thereto; phenyl or heterocyclic or heteroaryl ring can be optionally substituted, wherein the substituent can be the linking group with the reactive group bonded thereto;
X″ and X′″ are the same or different, and are independently selected from —(CH 2 ) n′ —, —NR′—, —CO—, —BH—, —SO— or —SO 2 —;
Y″ and Y′″ are the same or different, and are independently selected from —O, —(CH 2 ) n′ —, —NR′— or —S—;
Z″ and Z′″ are the same or different, and are independently selected from —(CH 2 ) n′ —, —CR 7 R 8 —, —NR 9 —, —O—, and —S—;
n′ is selected from 0, 1, 2 and 3;
R 7 and R 8 are the same or different, and are each independently selected from —H, —OH, —SH, —COOH, —NHR′, a polyethylene glycol unit —(OCH 2 CH 2 ) n —, an amino acid, a peptide unit bearing 2 to 6 amino acids, an optionally substituted linear, branched or cyclic alkyl having from 1 to 10 carbon atoms;
R 9 is independently selected from —H, an optionally substituted linear, branched or cyclic alkyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(OCH 2 CH 2 ) n —;
R a , R a′ , R b and R b′ are the same or different, and are independently selected from the group consisting of —H, halide, or an optionally substituted branched, linear or cyclic alkyl having 1 to 10 carbon atoms; or R a and R a′ and/or R b and R b′ together form a double bond containing group ═B and ═B′ respectively;
═B and ═B′ are the same or different and independently selected from an optionally substituted branched or linear alkenyl or a carbonyl group;
Q is Q 1 -Ar-Q 2 ;
Q′ is Q 1 ′-Ar′-Q 2 ′;
Q 1 and Q 1 ′ are each independently absent, a linear, branched or cyclic alkyl from 1 to 6 carbon atoms or a —CH═CH unit;
Ar and Ar′ are each independently absent, or represent an aryl group;
Q 2 and Q 2 ′ are each independently selected from —H, the linking group with the reactive group bonded thereto, a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —R c′ —(OCH 2 CH 2 ) n —R c , or a substituent selected from a halogen, guanidinium [—NH(C═NH)NH 2 ], —OR, —NR′R″, —NO 2 , —NCO, —NR′COR″, —SR, a sulfoxide represented by —SOR′, a sulfone represented by —SO 2 R′, a sulfonate —SO 3 M, a sulfate —OSO 3 M, a sulfonamide represented by SO 2 NR′R″,

Assignees

• Chari Ravi V J
• Immunogen Inc

Inventors

• Chari Ravi V J

Classifications

• A61K47/6851

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61K47/545 Primary

  Heterocyclic compounds (A61K47/558 takes precedence) · 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