Cytotoxic agents for conjugation to a cell binding molecule

Patent metadata

Field	Value
Publication number	US-9988408-B2
Application number	US-201314914739-A
Country	US
Kind code	B2
Filing date	Sep 2, 2013
Priority date	Sep 2, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention is related to novel cytotoxic agents, pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives, their conjugates with a cell-binding agent, the preparation and the therapeutic uses in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
represents either a single bond or a double bond;
provided that when represents a single bond, U and U′ are the same or different, and independently represent H, R 5 , or an amine protecting moiety, or a linking group L′;
V and V′ are the same or different, and are independently selected from the group consisting of H, OH, —NHOH; —OR 5 ; —OCOR 5 ; —OCOOR 5 ; —NR 5 R 5 ′, —NR 5 COR 5 ′, —NR 5 NR 5 ′NR 5 ″; —OCONR 5 R 5 ′; —NR 5 (C═NH)NR 5 ′R 5 ″; an optionally substituted 5- or 6-membered nitrogen-containing heterocycle selected from the group consisting of piperidine, tetrahydropyrrole, pyrazole, morpholine; —NR 5 CONR 5 ′R 5 ″; —OCSNHR 5 ; —SH; —SR 5 ; —SOR 5 ; —SOOR 5 : —SO 3 , —HSO 3 , —HSO 2 , or a sodium or potassium salt of —HSO 3− , —SO 3 2− , —HSO 2 , or —OSO 3 − ; —NR 5 SOOR 5 ′; H 2 S 2 O 5 or a sodium or potassium salt of —S 2 O 5 2− ; —PO 3 SH 3 , —PO 2 S 2 H 2 , —POS 3 H 2 , —PS 4 H 2 or a sodium or potassium salt of —PO 3 S 3− , —PO 2 S 2 3− , —POS 3 3− , —PS 4 3− ; —(R 5 O) 2 POSR 5 ′; —HS 2 O 3 or a sodium or potassium salt of —S 2 O 3 2− ; —HS 2 O 4 or a sodium or potassium salt of —S 2 O 4 2− ; —P(═S)(OR 5 )(S)(OH) or a sodium or potassium salt thereof; —NR 5 OR 5 ′; —R 5 C(═O)NOH or a sodium or potassium salt thereof; HOCH 2 SO 2 —, or a sodium or potassium salt thereof; —NR 5 COR 5 ′; —N 3 ; a cyano; a halo; a trialkylphosphoramidate (phosphoramidic acid), or triarylphosphonium; and a linking group L′;
and when represents a double bond, U and U′ are absent; V and V′ represent H, a linear or branched alkyl having 1 to 4 carbon atoms;
n and n′ are 0, 1,2, 3,4, 5 or 6; l, m, l′ and m′ are 1 or 2;
X, X′, Y and Y′ are the same or different, and independently, represent CH 2 , CHR 5 , ═CH—, ═CR 5 —, or —C(OR 5 )H—;
Z and Z′ are the same or different, and independently, represent CH, C—R 5 , COH or COR 5 ;
R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, R 3 ′, and R 4 ′ are the same or different and are independently selected from the group consisting of —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl or aryl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(OCH 2 CH 2 ) t R 5 , halogen, —NH(C═NH)NH 2 , —OR 5 , —NR 5 R 5 ′, —NO 2 , —NCO, —NR 5 COR 5 ′, —SR 5 , —SOR 5 , —SO 2 R 5 , —SO 3 ′M + , —SO 3 H, —OSO 3 ′M + , OSO 3 H, —SO 2 NR 5 R 5 ′, cyano, an azido, —COR 5 , —OCOR 5 , —OCONR 5 R 5 ′, CF 3 , OR 5 , aryl, heterocycle, P(O)R 5 R 5 ′R 5 ″, a linking group (L′) with a reactive group, and a cell binding agent bonded thereto; R 2 and R 3 may join together, or R 2 ′ and R 3 ′ may join together to form a ═ (double bond), ═O (ketone), ═S, ═NR 5 , —C(═O)R 5 , or a double bond containing group ═CR 5 R 5 ′; and R 1 and R 2 may join together, or R 1 ′ and R 2 ′ may join together, or R 3 and R 4 may join together or R 3 ′ and R 4 ′ may join together to form an aromatic, heterocyclic, or heteroaryl ring;
R 5 , R 5 ′ and R 5 ″ are independently selected from the group consisting of H, linear, branched or cyclic alkyl, alkenyl alkynyl or aryl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH 2 CH 2 O) r —R 11 , 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 the group consisting of nitrogen, oxygen, and sulfur, and an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from the group consisting of O, S, N and P; R 5 , R 5 ′, and R 5 ″ may be substituted with at least one substituent selected from the group consisting of —N(R 1 )(R 2 ), —CO 2 H, —SO 3 H, —OR 11 , —CO 2 R 11 , —CONR 11 , —PO 2 R 11 R 12 , —POR 11 R 12 R 13 and —PO 3 H, and pharmaceutical salts, R 11 , R 12 , and R 13 being independently a linear, branched or cyclic alkyl having from 1 to 10 carbon atoms;
q=0, 1 or 2;
L and L′ are the same or different and are independently a linker or a linker-cell binding molecule (Q) covalently bound cluster, or a linker which has a functional group on the linker that enables reaction of the compound with a cell-binding agent (CBA), wherein the linker for L has a formula of: -Ww-(Aa)r-Tt-; or -Ww-(Aa)r-Tt-Q; or Q-Ww-(Aa)r-Tt-; wherein: W is a Stretcher unit: w is 0 or 1; Aa is independently an amino acid unit selected from the group consisting of *valine-citrulline*, *alanine-phenylalanine*, *glycine-valine-citrulline* or *glycine-glycine-glycine*, wherein * is a point of attachment; r is an integer ranging from 0 to 100; the Stretcher unit W contains a self-immolative or a non-self-immolative component, a peptidyl unit, a hydrazone unit (—NH—NH—), a disulfide unit (—S—S—), an ester unit (—COO—), an oxime unit (—NH—O—), an amide unit

or a thioether unit (—S—); the self-immolative component is para-aminobenzylcarbamoyl (PAB) unit, 2-aminoimidazol-5-methanol unit, a heterocyclic PAB unit, beta-glucuronide unit, or an ortho or para-aminobenzylacetal unit;

or the self-immolative component has any one of following structures:

wherein the (*) atom is a point of attachment of additional spacer or releasable linker unit, or a cytotoxic agent, and/or a binding molecule (CBA); X 1 , Y 1 , Z 2 and Z 3 are independently NH, or O, or S; Z 1 is H, or NH, or O or S independently; v is 0 or 1; Q 1 is independently H, OH, C 1 -C 6 alkyl, (OCH 2 CH 2 ) n CH 3 , F, Cl, Br, I, OR 5 , or SR 5 , NR 5 R 5′ , N═NR 5 , N═R 5 , NR 5 R 5 ′, NO 2 , SOR 5 R 5 ′, SO 2 R 5 , SO 3 R 5 , OSO 3 R 5 , PR 5 R 5 ′, POR 5 R 5 ′, PO 2 R 5 R 5 ′, OPO(OR 5 )(OR 5 ′), or OCH 2 PO(OR 5 (OR 5 ′), wherein R 5 and R 5 ′ are as defined above;
the non-self-immolative component is any one of following structures:

wherein the (*) atom is a point of attachment of additional spacer or releaseable linker, a cytotoxic agents, and/or a binding molecules; X 1 , Y 1 , Q 1 , R 5 , R 5 ′ are as defined above; r is 0-100; m, n and p are 0-6;
spacer (T) is a linear, branched or cyclic alkyl, alkenyl, alkynyl or aryl having from 1 to 10 carbon atoms, polyethylene glycol (—CH 2 CH 2 O-) spacer, or a cyclization product formed by amide bond hydrolysis of a substituted and unsubstituted 4-aminobutyric acid amide, substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring system, or 2-aminophenylpropionic acid amide; and t is 0, or 1-100;
or L is R 5 , OR 5 , SR 5 , NHR 5 , or NR 5 R 5 ′, thus R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, R 3 ′, or R 4 ′, or U, or U′, or V, or V′ in the Formula (I) may be linked to Q via Stretcher units (Ww) or via Spacer units (Tt) when the compound is used for conjugation to a cell binding agent;
Q is a cell binding molecule (CBA), or a functional group that enables reaction of the compound with a cell-binding agent, or a functional group capable of reacting the compound with a linker attached on a cell binding agent, the function group is selected from the group consisting of a thiol group, an amine group, a hydrazine group, an alkoxylamino group, a disulfide group, a maleimido gro

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P37/02

  Immunomodulators · CPC title