Phosphate based linkers for intracellular delivery of drug conjugates

Patent metadata

Field	Value
Publication number	US-10550190-B2
Application number	US-201515301564-A
Country	US
Kind code	B2
Filing date	Mar 30, 2015
Priority date	Apr 4, 2014
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

Phosphate-based linkers with tunable stability for intracellular delivery of drug conjugates are described. The phosphate-based linkers comprise a monophosphate, diphosphate, triphosphate, or tetraphosphate group (phosphate group) and a linker arm comprising a tuning element and optionally a spacer. A payload is covalently linked to the phosphate group at the distal end of the linker arm and the functional group at the proximal end of the linker arm is covalently linked to a cell-specific targeting ligand such as an antibody. These phosphate-based linkers have a differentiated and tunable stability in blood vs. an intracellular environment (e.g. lysosomal compartment).

First claim

What is claimed:

1. A compound comprising the formula

wherein
V is selected from O and S;
W is selected from O, N, and CH 2 ;
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; a carbon atom linked to a trimethylammonium group by a C1-C5 hydrocarbon chain; nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
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 of Y 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;
T is an NR, O, or S;
Z is a cyclooctyne;
D is an anti-inflammatory agent;
Each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety; and
n is 1, 2, 3, or 4.

2. The compound of claim 1 , wherein the anti-inflammatory agent is a glucocorticoid receptor agonist.

3. The compound of claim 1 , wherein the anti-inflammatory agent is Cortisol, cortisone acetate, beclometasone, prednisone, prednisolone, methylprednisolone, betamethasone, trimcinolone, budesonide, dexamethasone, fluticasone, fluticasone propionate, fluticasone furoate, compound 15-5, or mometasone.

4. The compound of claim 1 , wherein the compound has a structure selected from the group consisting of

Assignees

• Merck Sharp & Dohme
• Ambrx Inc

Inventors

• Garbaccio Robert M
• Kern Jeffrey
• Brandish Philip E
• Shah Sanjiv
• Liang Linda
• Sun Ying
• Wang Jianing
• Knudsen Nick
• Beck Andrew
• Manibusan Anthony
• Gately Dennis

Classifications

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07F9/65517

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• C07F9/572

  Five-membered rings · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07F9/2458

  of aliphatic amines · CPC title