Immune stimulating micelle composition

Patent metadata

Field	Value
Publication number	US-12318481-B2
Application number	US-202017760885-A
Country	US
Kind code	B2
Filing date	Sep 18, 2020
Priority date	Sep 19, 2019
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

The present invention relates to immune stimulating micelle compositions, and their use in treatment of diseases and disorders, such as cancer. In particular, the present invention relates to micelle compositions comprising a TLR7 agonist, such as 1V270.

First claim

The invention claimed is:

1. A micelle composition comprising:
(i) a toll-like receptor 7 (TLR7) agonist of formula (I), formula (II), formula (III) or formula (IV);

or a tautomer thereof;
or a pharmaceutically acceptable salt or solvate thereof, wherein
X 1 is —O—, —S—, or —NR C ;
R 1 is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 6 -C 10 )aryl, substituted (C 6 -C 10 )aryl, (C 5 -C 9 )heterocyclic, or substituted (C 5 -C 9 )heterocyclic;
R C is hydrogen, (C 1 -C 10 )alkyl, or substituted (C 1 -C 10 )alkyl; or R C and R 1 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring;
each R 2 is independently —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b (carbamoyl), halo, nitro, or cyano;
each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 3 -C 5 )cycloalkyl, substituted (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, substituted (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl;
wherein the substituents on any substituted alkyl, aryl or heterocyclic groups are hydroxy, (C 1 -C 6 )alkyl, hydroxy (C 1 -C 6 )alkylene, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy (C 1 -C 6 )alkylene, amino, cyano, halo, or aryl;
n is 0, 1, 2, 3 or 4;
X 2 is a bond or a linking group;
R 3 is a lipid;
X 3 is —N— or —CH—;
R 4 is —CH 2 — or —CH(R 2 )—;
k is 0 or 1;
X 4 is —O—, —S—, —NH—, —N(R 4 )—, —CH 2 —, or —CH(R 2 )—; and
each R d is independently —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, or —C(O)NR a R b (carbamoyl);
wherein the ring system of formula (II) is a piperidine ring with one heteroatom being an N atom and with the N-atom of the piperidine ring adjacent to X 2 , and
wherein the purine group in any of Formula (I), (II), (III), or (IV) is subject to tautomeric rearrangements;
and (ii) an amphiphilic micelle-forming agent,
wherein the average diameter of the micelles in the micelle composition is from 5 nm to 25 nm.

2. The micelle composition according to claim 1 , wherein the TLR7 agonist is of formula (I):

or a tautomer thereof;
or a pharmaceutically acceptable salt or solvate thereof, wherein
X 1 is —O—, —S—, or —NR C ;
R 1 is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 6 -C 10 )aryl, substituted (C 6 -C 10 )aryl, (C 5 -C 9 )heterocyclic, or substituted (C 5 -C 9 )heterocyclic;
R C is hydrogen, (C 1 -C 10 )alkyl, or substituted (C 1 -C 10 )alkyl; or R C and R 1 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring;
each R 2 is independently —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b (carbamoyl), halo, nitro, or cyano;
each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 3 -C 5 )cycloalkyl, substituted (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, substituted (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl;
wherein the substituents on any substituted alkyl, aryl or heterocyclic groups are hydroxy, (C 1 -C 6 )alkyl, hydroxy (C 1 -C 6 )alkylene, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy (C 1 -C 6 )alkylene, amino, cyano, halo, or aryl;
n is 0, 1, or 2;
X 2 is a bond or a linking group; and
R 3 is a lipid; and
wherein the purine group is subject to tautomeric rearrangements.

3. The micelle composition according to claim 1 , wherein the TLR7 agonist is of formula (I):

or a tautomer thereof;
or a pharmaceutically acceptable salt or solvate thereof, wherein
X 1 is —O—, —S—, or —NR C ;
R 1 is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 6 -C 10 )aryl, substituted (C 6 -C 10 )aryl, (C 5 -C 9 )heterocyclic, or substituted (C 5 -C 9 )heterocyclic;
R C is hydrogen, (C 1 -C 10 )alkyl, or substituted (C 1 -C 10 )alkyl; or R C and R 1 taken together with the nitrogen to which they are attached form a heterocyclic ring or a substituted heterocyclic ring;
n is 0;
X 2 is a bond or a linking group; and
R 3 is a lipid;
wherein the purine group is subject to tautomeric rearrangements.

4. The micelle composition according to claim 1 , wherein X 2 is selected from the group consisting of: a bond, —O—, —C(O)-(carbonyl), (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b (carbamoyl); and
each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 3 -C 5 )cycloalkyl, substituted (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, substituted (C 1 -C 6 )alkanoyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl; and wherein
X 1 is —O—, —S—, or —NR C ;
R 1 is hydrogen, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl;
R C is hydrogen, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl; or R C and R 1 taken together with the nitrogen to which they are attached form a heterocyclic ring or a substituted heterocyclic ring.

5. The micelle composition according to claim 1 , wherein R 3 is a lipid selected from the group consisting of: a phospholipid comprising one or two carboxylic esters; a gonane; a saccharolipid; and a glyceride.

6. The micelle composition according to claim 1 , wherein the amphiphilic micelle-forming agent is selected from the group consisting of: a poloxamer, a poloxamine, a PEG-polyester, a PEG-polyanhydride, a PEG-poly-amino acid, a phospholipid, a polysorbate, and a polyoxyethylene alkyl ether.

7. The micelle composition according to claim 1 , wherein the amphiphilic micelle-forming agent is a phospholipid conjugated to polyethylene glycol (PEG).

8. The micelle composition according to claim 7 , wherein the average molecular w

Assignees

• Univ Danmarks Tekniske

Inventors

• Henriksen Jonas Rosager
• Andresen Thomas Lars
• Jensen Simon Skjøde
• Parhamifar Ladan
• Münter Rasmus Dithmar
• Hansen Anders E
• Stavnsbjerg Camilla
• Christensen Esben

Classifications

• A61K39/001186

  MAGE · CPC title

• A61K39/00119

  Melanoma antigens · CPC title

• A61K39/001194

  Prostate specific antigen [PSA] · CPC title

• A61K39/00117

  Mucins, e.g. MUC-1 · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title