US 2016/0095938 A1 · CONJUGATES COMPRISING CELL-BINDING AGENTS AND CYTOTOXIC AGENTS

Abstract

The invention relates to novel cell-binding agent-cytotoxic agent conjugates, wherein the cell-binding agent (CBA) is covalently linked to the cytotoxic agent through an aldehyde group obtained from oxidation of a 2-hydroxyethylamine moiety on the CBA. The invention also provides methods of preparing the conjugates of the present invention. The invention further provides composition and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the conjugates of the invention.

Claims43

Dependent claims

A cell-binding agent-cytotoxic agent conjugate represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
CBA is a cell-binding agent covalently linked to the JCB′ group;
JCB′ is a moiety formed by reacting an aldehyde group on the CBA and an aldehyde reactive group connected to the group L, wherein the aldehyde group is derived from oxidation of a 2-hydroxyethylamine moiety represented by the following structural formula:
wherein the 2-hydroxyethylamine moiety being part of a serine, threonine, hydroxylysine, 4-hydroxyornithine or 2,4-diamino-5-hydroxy valeric acid residue;
L is a spacer or a bond;
JD′ is a linking moiety connecting the cytotoxic agent D with the group L or absent when L is a bond;
D is a cytotoxic agent covalently linked to L through the linking moiety JD′ or to CBA through JCB′ when L is a bond;
and
w is 1, 2, 3 or 4.

6 more elements

A cytotoxic compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
one of LD′, LD″, and LD′″ is represented by the following formula:
—NR5—P—C(═O)—(CRaRb)r—Zd1—(CRaRb)r′-JCB (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, a polyethylene glycol unit —(OCH2CH2)n—Rc, halogen, guanidinium [—NH(C═NH)NH2], —OR, —NR′R″, —NO2, —NR′COR″, —SR, —SOR′, —SO2R′, —SO3H, —OSO3H, —SO2NR′R″, cyano, an azido, —COR′, —OCOR′, and —OCONR′R″;
Zd1 is absent, —C(═O)—NR9— or —NR9—C(═O)—;
P is an amino acid residue or a peptide containing between 2 to 20 amino acid residues;
Ra and Rb, for each occurrence, are independently —H, (C1-C3)alkyl or a charged substituent or an ionizable group Q;
r and r′ are independently an integer from 1 to 6;
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 heterocycle (e.g., piperidine, tetrahydropyrrole, pyrazole, morpholine, etc. attached through the nitrogen atom), a guanidinum represented by —NR′(C═NH)NR′R″, an amino acid, or a peptide represented by —NRCOP′, —SR, —SOR′, halogen, cyano, azido, —OSO3H, sulfite (—SO3H or —SO2H), metabisulfite (H2S2O5), mono-, di-, tri-, and tetra-thiophosphate (PO3SH3, PO2S2H2, POS3H2, PS4H2), thio phosphate ester (RiO)2PS(ORi), RiS—, RiSO, RiSO2, RiSO3, thiosulfate (HS2O3), dithionite (HS2O4), phosphorodithioate (P(═S)(ORk′)(S)(OH)), hydroxamic acid (Rk′C(═O)NOH), and formaldehyde sulfoxylate (HOCH2SO2−) or a mixture thereof, wherein Ri is a linear or branched alkyl having 1 to 10 carbon atoms and is substituted with at least one substituent selected from —N(Rj)2, —CO2H, —SO3H, and —PO3H;
Ri can be further optionally substituted with a substituent for an alkyl described herein;
Rj is a linear or branched alkyl having 1 to 6 carbon atoms;
Rk′ 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 residue,
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 —(CH2CH2O)n—Rc, 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, —NR2, —COR, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)n—Rc, and an optionally substituted 3- to 18-membered heterocyclic ring having 1 to 6 heteroatoms independently selected from O, S, N and P;
Rc 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, a polyethylene glycol unit —(CH2CH2O)n—Rc, 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;
R1, R2, R3, R4, R1′, R2′, R3′ and R4′ 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, a polyethylene glycol unit —(OCH2CH2)n—Rc, halogen, guanidinium [—NH(C═NH)NH2], —OR, —NR′R″, —NO2, —NCO, —NR′COR″, —SR, —SOR′, —SO2R′, —SO3−H, —OSO3H, —SO2NR′R″, cyano, an azido, —COR′, —OCOR′, and —OCONR′R″;
R6 is —H, —R, —OR, —SR, —NR′R″, —NO2, or halogen;
A and A′ are the same or different, and are independently selected from —O—, oxo (—C(═O)—), —CRR′O—, —CRR′—, —S—, —CRR′S—, —NR5 and —CRR′N(R5)—;
R5 and R9 are each independently —H or an optionally substituted linear or branched alkyl having 1 to 10 carbon atoms;
JCB is an aldehyde reactive group.

22 more elements

Dependencies are inferred from the claim text.

Conjugates comprising cell-binding agents and cytotoxic agents

Life of this patent

Conjugates comprising cell-binding agents and cytotoxic agents

Life of this patent

Abstract

Claims43