# US 9,872,911 B2 · Alpha-aminoamidine polymers and uses thereof

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- Number: US 9,872,911 B2
- Document ID: US9872911B2
- Status: Granted
- Kind: B2
- Application number: 14/364,028
- Filed: 2012-12-15
- Published: 2014-10-30
- Granted: 2018-01-23
- Earliest claimed: 2011-12-16
- Assignees: Massachusetts Institute of Technology
- Applicants: Massachusetts Institute of Technology
- Inventors: Arturo Jose Vegas; Kathryn Ann Whitehead; Daniel Griffith Anderson; Robert S. Langer; Joseph R. Dorkin
- Web page: https://patentgrep.com/patent/US9872911B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- C08G 12/06: Amines
- C08G 12/34: and acyclic or carbocyclic compounds
- C08G 73/00: Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00 {(polycarbodiimides prepared from isocyanates C08G18/025, C08G18/797)}
- C08L 79/00: Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen or carbon only, not provided for in groups C08L61/00 - C08L77/00
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- 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
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

α-Aminoamidine polymers and methods of preparing a-aminoamidine polymers by reacting by reacting one or more amines with one or more isocyanides and one or more aldehydes are described. Methods of preparing a-aminoamidine polymers from commercially available starting materials are also provided, wherein the starting materials are racemic or stereochemically pure. a-Aminoamidine polymers or salt forms thereof are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems and for other purposes as well such as, for example, coatings, additives, excipients, plastics, and materials, etc. Given the amino moiety of these α-aminoamidine polymers, they are particularly suited for the delivery of polynucleotides. Complexes, micelles, liposomes or particles containing the inventive α-aminoamidine polymers and polynucleotides can be prepared. The inventive α-aminoamidine polymers may also be used in preparing microparticles for drug delivery. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings.

## Claims

### Claim 1

A polymer of Formula (I):
or a pharmaceutically acceptable salt or isomer thereof;
wherein:
R1 is a linking group comprising one or more combinations of substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; optionally interrupted by one or more groups independently selected from —O—, —S—, —OSi(R7R8)O—, —SiR7R8—, and —NR10—;
R2 is hydrogen; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
R3 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
each instance of R4, R5, and R10 is, independently, hydrogen; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; acyl; sulfonyl; or a nitrogen protecting group;
or R4 and R1 optionally form a cyclic structure;
or R5 and R1 optionally form a cyclic structure;
each of R7 and R8 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
each E is independently, hydrogen or a group of formula R4 or R5;
G is
and
n is an integer from 2 to 100, inclusive.

### Claim 2 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 3 (depends on 1)

A particle comprising a polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof.

### Claim 4 (depends on 3)

The particle of claim 3, wherein the particle further comprises one or more stabilizing agents and/or one or more amino acids.

### Claim 5 (depends on 4)

The particle of claim 4, wherein the stabilizing agents are selected from the group consisting of polyethylene glycol (PEG), cholesterol, cholesterol analogs, and poloxamers.

### Claim 6 (depends on 4)

The particle of claim 4, wherein the stabilizing agents are selected from the group consisting of 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DC-cholesterol), PLURONIC® F127 (poloxamer 407), and 2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (DMG-PEG).

### Claim 7 (depends on 4)

The particle of claim 4, wherein the one or more amino acids comprise H (histidine).

### Claim 8 (depends on 1)

A composition comprising a polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the composition is a pharmaceutical composition, a cosmetic composition, a nutraceutical composition, or a composition with non-medical application.

### Claim 10 (depends on 8)

The composition of claim 8, wherein the composition further comprises an agent.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the agent is an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, or an immunological agent.

### Claim 12 (depends on 10)

The composition of claim 10, wherein the agent is a polynucleotide.

### Claim 13 (depends on 9)

The composition of claim 9, wherein the composition is in the form of a particle.

### Claim 14 (depends on 13)

The composition of claim 13, wherein the particle is a nanoparticle or microparticle.

### Claim 15 (depends on 13)

The composition of claim 13, wherein the particle is a micelle, liposome, or lipoplex.

### Claim 16 (depends on 13)

The composition of claim 13, wherein the particle encapsulates an agent.

### Claim 17 (depends on 1)

A method of delivering a polynucleotide to a cell, comprising:
providing a composition comprising an polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, and a polynucleotide; and
exposing the composition to the cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the cell.

### Claim 18 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 19 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 20 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 21 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 22 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 23 (depends on 1)

The polymer of claim 1, wherein the polymer is of the formula:
wherein:
R2 is of the formula:
and R3 is of the formula:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
R2 is of the formula:
and R3 is of the formula:
R2 is of the formula:
and R3 is of the formula:
or R2 is of the formula:
and R3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.

### Claim 24 (depends on 10)

The composition of claim 10, wherein the agent is a polynucleotide that encodes a protein or peptide.

### Claim 25 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic.

### Claim 26 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic interrupted by one or more groups independently selected from —O— and —SiR7R8—.

### Claim 27 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic.

### Claim 28 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R1 is a linking group comprising one or more substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic, and one or more substituted or unsubstituted aryl.

### Claim 29 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R2 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic.

### Claim 30 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

### Claim 31 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R3 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic, or substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 heteroaliphatic.

### Claim 32 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R3 is substituted or unsubstituted aryl.

### Claim 33 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R4 is hydrogen.

### Claim 34 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R4 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic.

### Claim 35 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R5 is hydrogen.

### Claim 36 (depends on 1)

The polymer of claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R5 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C1-20 aliphatic.

### Claim 37 (depends on 12)

The composition of claim 12, wherein the polynucleotide is DNA.

### Claim 38 (depends on 12)

The composition of claim 12, wherein the polynucleotide is RNA.

### Claim 39 (depends on 38)

The composition of claim 38, wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

### Claim 40 (depends on 1)

The polymer of claim 1, wherein:
R1 is
R2 is
R3 is
R4 is hydrogen; and
R5 is hydrogen.