# US 10,869,930 B2 · Poly(cyclic imino ether)s

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,869,930 B2
- Document ID: US10869930B2
- Status: Granted
- Kind: B2
- Application number: 16/312,219
- Filed: 2017-07-03
- Published: 2019-08-01
- Granted: 2020-12-22
- Earliest claimed: 2016-07-01
- Assignees: Universiteit Gent
- Applicants: Universiteit Gent
- Inventors: Richard Hoogenboom; Bart Verbraeken
- Web page: https://patentgrep.com/patent/US10869930B2

## CPC

- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61K 48/0008: {characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition}
- C08G 73/0233: {Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups}
- C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- 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)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention relates to invention relates to a statistical copolymer represented by the following formula (I): Ini-[Ox]m-[Oz]n-Nuc (I) wherein: Ini represents a residue of an initiator of cationic polymerization, Nuc represents a residue of a nucleophilic agent, Ox represents N(R1)CHRaCHRa; each R1 independently represents H or C(O)R11; and R11 independently represents optionally substituted C1-12 alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl; Oz represents N(R2)CHRaCHRaCHRa; each R2 independently represents C(O)R21 or H; and R21 independently represents optionally substituted C1-12 alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl; each Ra independently represents H, linear or branched C1-3 alkyl; m≥5; n≥5; m+n≥20; 3:97≤m:n≤97:3. The statistical copolymers of the present invention exhibit useful properties that can be exploited in the medical field, especially in polymer micelles for drug delivery and polyplexes for DNA delivery.

## Claims

### Claim 1

A gradient copolymer represented by the following formula (I):
Ini-[Ox]m-[Oz]n-Nuc (I)
wherein:
(a) Ini represents a residue of an initiator of cationic polymerization;
(b) Nuc represents a residue of a nucleophilic agent;
(c) Ox represents N(R1)CHRaCHRa; each R1 independently represents H or C(O)R11; and R11 independently represents optionally substituted C1-12 alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl;
(d) Oz represents N(R2)CHRaCHRaCHRa; each R2 independently represents C(O)R21 or H; and R21 independently represents optionally substituted C1-12 alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or optionally substituted aryl;
(e) each Ra independently represents H, linear or branched C1-3 alkyl;
(f) m≥5;
(g) n≥5;
(h) m+n≥20;
(i) 3:97≤m:n≤97:3;
wherein the copolymer comprises three fragments of equal size, a fragment adjacent Ini (Ini fragment), a fragment adjacent Nuc (Nuc fragment) and a central fragment that separates the Ini fragment and the Nuc fragments, wherein the monomer ratio [Oz]/[Ox] in the Ini-half of the copolymer is at least 2 times higher or lower than the same ratio in the Nuc-half of the copolymer.

### Claim 2 (depends on 1)

The copolymer according to claim 1, wherein Ra represents H.

### Claim 3 (depends on 1)

The copolymer according to claim 1, wherein 10≤m≤250.

### Claim 4 (depends on 1)

The copolymer according to claim 1, wherein 10≤n≤250.

### Claim 5 (depends on 1)

The copolymer according to claim 1, wherein each R21 independently represents optionally substituted C1-9 alkyl.

### Claim 6 (depends on 1)

The copolymer according to claim 1, wherein each R11 independently represents optionally substituted C1-9 alkyl or cyclopropyl.

### Claim 7 (depends on 1)

A method of preparing a gradient copolymer according to claim 1, comprising cationic ring-opening polymerizing of a monomeric reaction mixture comprising an optionally 2-substituted 2-oxazoline and an optionally 2-substituted 2-oxazine in a molar ratio in the range of 3:97 to 97:3, wherein the optional substituent in the 2-position of the 2-substituted-2-oxazoline is a residue R11 as defined in claim 1, and the optional substituent in the 2-position of the 2-substituted-2-oxazine is a residue R21 as defined in claim 1.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the cationic ring-opening polymerization is carried out in the presence of a cationic polymerization initiator selected from alkyl halides, alkyl sulfonates, acyl halides, oxazolinium salts or sulfonic acids.

### Claim 9 (depends on 7)

The method according to claim 7, wherein the copolymer comprises pendant acyl residues and at least 50% of the pendant acyl residues are removed by hydrolysis.

### Claim 10 (depends on 1)

A micellar drug delivery system comprising a gradient copolymer according to claim 1 and a drug that is non-covalently bound to the copolymer.

### Claim 11 (depends on 1)

A method of preparing a statistical copolymer, said method comprising cationic ring-opening polymerization of a monomeric reaction mixture comprising an optionally 2-substituted 2-oxazoline and an optionally 2-substituted 2-oxazine in a molar ratio in the range of 3:97 to 97:3, wherein the optional substituent in the 2-position of the 2-substituted-2-oxazoline is a residue R11 as defined in claim 1, and the optional substituent in the 2-position of the 2-substituted-2-oxazine is a residue R21 as defined in claim 1, wherein the statistical copolymer that is formed in the reaction mixture comprises pendant acyl residues, and wherein the statistical polymer is hydrolysed by removing at least 50% of the pendant acyl residues.