Phosphonate linkers and their use to facilitate cellular retention of compounds

Patent metadata

Field	Value
Publication number	US-10869929-B2
Application number	US-201716072347-A
Country	US
Kind code	B2
Filing date	Jan 24, 2017
Priority date	Jan 29, 2016
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

Abstract

Phosphonate linkers and their use for delivering compounds with passive cell permeability into a cell wherein the phosphonate group facilitates cellular retention of the compound are described.

First claim

What is claimed:

1. A compound of the formula

wherein
V is selected from O and S;
W is selected from a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
X is selected from a covalent bond; a carbon atom; a heteroatom; an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic; or nucleoside;
Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
Z is a reactive functional group selected from the group consisting of N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, azide, hydrazine, pentafluorophenyl, haloacetamide, maleimide, hydroxylamine, cycloalkyne, heterocycloalkyne, alkyne, diene, and heterocyclic azadience, wherein halo is iodine (I), bromine (Br), fluorine (F), or chlorine (Cl) and hetero is N, O, or S;
D is a therapeutic agent linked to W via a covalent linkage formed via a reaction with a primary amine, a secondary amine, a hydroxyl, a sulfhydryl, a carboxyl, an aldehyde, or a ketone group of the therapeutic agent;
Each occurrence of R is independently hydrogen, an acyl, arylalkyl, aliphatic, aryl, heteroaryl, or heteroaliphatic group; and
n is 1, 2, 3, or 4.

2. The compound of claim 1 , wherein the therapeutic agent is an anti-inflammatory agent.

3. The compound of claim 2 , wherein the anti-inflammatory agent is a glucocorticoid receptor agonist.

4. The compound of claim 2 wherein the anti-inflammatory agent is Cortisol, cortisone acetate, beclometasone, prednisone, prednisolone, methylprednisolone, betamethasone, trimcinolone, budesonide, dexamethasone, fluticasone, or mometasone.

5. The compound of claim 1 , wherein the therapeutic agent is a cytotoxic agent.

Assignees

• Merck Sharp & Dohme

Inventors

• Garbaccio Robert M
• Kern Jeffrey C
• Mulhearn James J
• Brandish Philip E

Classifications

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/548 Primary

  Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544) · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title