Cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-9669102-B2
Application number	US-201514843520-A
Country	US
Kind code	B2
Filing date	Sep 2, 2015
Priority date	Sep 3, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VI). 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.

First claim

The invention claimed is:

1. A compound represented by any one of the following formulas:

or a pharmaceutically acceptable salt thereof, wherein:
one of L′, L″, and L′″ is represented by the following formula:
—Z 1 —P—Z 2 —R x -J  (A)

and the other two are the same or different, and are independently selected from —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, —(CH 2 CH 2 O) n —R c , halogen, —NH(C═NH)NH 2 , —OR, —NR′R″, —NO 2 , —NR′COR″, —SR, —SOR′, —SO 2 R′, —SO 3 H, —OSO 3 H, —SO 2 NR′R″, cyano, an azido, —COR′, —OCOR′, and —OCONR′R″;
one of the Z 1 and Z 2 is —C(═O)—, and the other is —NR 5 —;
P is an amino acid residue or a peptide containing between 2 to 20 amino acid residues;
R x is an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;
J is —COOH or —COE, wherein —COE represents a reactive ester and R c1 is —H or linear or branched alkyl having 1 to 4 carbon atoms optionally substituted with halogen, —OH or (C 1 -C 3 )alkoxy;
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 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 monocyclic heterocycle —NR′(C═NH)NR′R″, an amino acid, or a peptide represented by —NRCOP′, —SR, —SOR′, halogen, cyano, azido, —OSO 3 H, —SO 3 H, —SO 2 H, H 2 S 2 O 5 , PO 3 SH 3 , PO 2 S 2 H 2 , POS 3 H 2 , PS 4 H 2 , (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 , HS 2 O 4 , P(═S)(OR k′ )(S)(OH), R k′ C(═O)NOH, and HOCH 2 SO 2 −1 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;
P′ is an amino acid residue or a polypeptide containing between 2 to 20 amino acid residues,
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, —(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, —(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 an optionally substituted linear or branched alkyl having 1 to 4 carbon atoms;
n is an integer from 1 to 24;
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, —(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 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, R 3 ′ and R 4 ′ are each 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, —(CH 2 CH 2 O) n —R c , halogen, —NH(C═NH)NH 2 , —OR, —NR′R″, —NO 2 , —NCO, —NR′COR″, —SR, —SOR′, —SO 2 R′, —SO 3 − H, —OSO 3 H, —SO 2 NR′R″, cyano, an azido, —COR′, —OCOR′, and —OCONR′R″;
R 6 is —H, —R, —OR, —SR, —NR′R″, —NO 2 , or halogen;
G is —CH— or —N—;
A and A′ are the same or different, and are independently selected from —O—, C(═O)—, —CRR′O—, —CRR′—, —S—, —CRR'S—, —NR 5 and —CRR′N(R 5 )—; and
R 5 for each occurrence is independently —H or an optionally substituted linear or branched alkyl having 1 to 10 carbon atoms,
wherein the optional substituent described above is a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon bon atoms, aryl, heteroaryl, heterocyclyl, halogen, —NH(C═NH)NH 2 , —OR 100 , NR 101 R 102 , —NO 2 , —NR 101 COR 102 , —SR 100 , —SOR 101 , —SO 2 R 101 , —SO 3 M, —OSO 3 M, —SO 2 NR 101 R 102 , cyano, an azido, —COR 101 , —OCOR 101 , —OCONR 101 R 102 or (—CH 2 CH 2 O) n R 101 , wherein M is H or a cation; R 101 , R 102 and R 103 are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—CH 2 CH 2 O) n —R 104 , wherein n is an integer from 1 to 24, an aryl having from 6 to 10 carbon atoms, a heterocyclic ring having from 3 to 10 carbon atoms and a heteroaryl having 5 to 10 carbon atoms; and R 104 is H or a linear or branched alkyl having 1 to 4 carbon atoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl in the groups represented by R 100 , R 101 , R 102 , R 103 and R 104 are optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 and unsubstituted linear or branched alkyl having 1 to 4 carbon atoms.

2. The compound of claim 1 , wherein L′ is represented by the following formula:
—NR 5 —P—C(═O)—(CR a R b ) m -J  (B1);

—NR 5 —P—C(═O)—Cy-(CR a R b ) m′ -J  (B2);

—C(═O)—P—NR 5 —(CR a R b ) m -J  (C1), or

—C(═O)—P—NR 5 —Cy-(CR a R b ) m′ -J  (C2),

wherein:
J is —COE;
R a and R b , for each occurrence, are each independently —H, (C 1 -C 3 )alkyl or a charged substituent or an ionizable group Q;
m is an integer from 1 to 6;
m′ is 0 or an integer from 1 to 6; and
Cy is a cyclic alkyl having 5 or 6 ring carbon atoms optionally substituted with halogen, —OH, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, or halo(C 1 -C 3 )alkyl.

3. The compound of claim 1 , wherein L′ is represented by the following formula:
—NR 5 —P—C(═O)—(CR a R b ) m —S—Z s   (B3); or

—C(═O)—P—NR 5 —(CR a R b ) m —S—Z s   (C3),

wherein:
R a and R b , for each occurrence, are each independently —H, (C 1 -C 3 )alkyl or a charged substituent or an ionizable group Q;
m is an integer from 1 to 6;
Z s is —H, —SR d , —C(═O)R d1 or is selected from any one of the following formulas:

wherein:
q is an i

Assignees

• Immunogen Inc

Inventors

• Chari Ravi V J
• Miller Michael Louis
• Shizuka Manami

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title