# US 10,869,929 B2 · Phosphonate linkers and their use to facilitate cellular retention of compounds

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- Number: US 10,869,929 B2
- Document ID: US10869929B2
- Status: Granted
- Kind: B2
- Application number: 16/072,347
- Filed: 2017-01-24
- Published: 2019-01-31
- Granted: 2020-12-22
- Earliest claimed: 2016-01-29
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Robert M. Garbaccio; Jeffrey C. Kern; James J. Mulhearn; Philip E. Brandish
- Web page: https://patentgrep.com/patent/US10869929B2

## CPC

- A61K 47/6889: {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}
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- C07F 9/3839: {Polyphosphonic acids}
- C07F 9/40: Esters thereof
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 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)SO2—, SO2N(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)SO2—, SO2N(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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 1)

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