# US 9,006,254 B2 · Immunomodulatory agent-polymeric compounds

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- Number: US 9,006,254 B2
- Document ID: US9006254B2
- Status: Granted
- Kind: B2
- Application number: 14/138,601
- Filed: 2013-12-23
- Published: 2014-07-10
- Granted: 2015-04-14
- Earliest claimed: 2009-05-27
- Assignees: Selecta Biosciences, Inc.
- Applicants: Selecta Biosciences, Inc.
- Inventors: Charles Zepp; Grayson B. Lipford; Yun Gao; Lloyd Johnston; Fen-ni Fu; Mark J. Keegan; Sam Baldwin
- Web page: https://patentgrep.com/patent/US9006254B2

## CPC

- A61K 39/385: Haptens or antigens, bound to carriers
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 39/0013: {Therapeutic immunisation against small organic molecules, e.g. cocaine, nicotine}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6925: {the form being a microcapsule, nanocapsule, microbubble or nanobubble}
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/34: Tobacco-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07D 471/04: Ortho-condensed systems
- C07D 473/34: attached in position 6, e.g. adenine
- C08G 63/06: derived from hydroxycarboxylic acids
- C08G 63/08: Lactones or lactides
- C08G 63/912: {derived from hydroxycarboxylic acids}
- C08G 64/42: Chemical after-treatment
- C08J 3/24: Crosslinking, e.g. vulcanising, of macromolecules (mechanical aspects B29C35/00; crosslinking agents C08K)
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55544: {Bacterial toxins}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- A61K 2039/6093: {Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine}
- A61K 2039/62: {characterised by the link between antigen and carrier}
- A61K 2039/627: {characterised by the linker}
- C08J 2367/04: Polyesters derived from hydroxy carboxylic acids, e.g. lactones (C08J2367/06 takes precedence)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08J: WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H (working, e.g. shaping, of plastics B29)

## Abstract

This invention relates to compositions, and related compounds and methods, of conjugates of immunomodulatory agents and polymers or unit(s) thereof. The conjugates may be contained within synthetic nanocarriers, and the immunomodulatory agents may be released from the synthetic nanocarriers in a pH sensitive manner.

## Claims

### Claim 1

A compound that comprises a structure as in formula (II):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X═C, N, O, or S;
R6 and R7 are each independently absent, H, or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino.

### Claim 2

A method for making a conjugate that comprises a structure as in formula (II):
comprising:
combining an alcohol, a catalyst, and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; and
heating the alcohol, catalyst, and compound.

### Claim 3

A method for making a conjugate that comprises a structure as in formula (VI):
comprising:
combining a catalyst, a diol having the formula (VII):
HO-polymer-OH (VII),
and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; and
heating the alcohol, catalyst, and compound

### Claim 4

A compound that comprises a structure as in formula (VI):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the polymer or unit thereof comprises a polyester, polycarbonate, polyamide, or a polyether, or unit thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the polymer or unit thereof comprises poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), polycaprolactone, or poly(ethylene glycol), or unit thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the polymer is biodegradable.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is H, R2 is isobutyl, Y is C, and R3 and R4 are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is ethoxymethyl, R2 is hydroxyisobutyl, Y═C, and R3 and R4 are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is ethoxymethyl, R2 is methanesulfonamidoisobutyl, Y═C, and R3 and R4 are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is OH, R2 is benzyl, Y═N, R3 is absent, and R4 is butoxy.

### Claim 12 (depends on 1)

The compound of claim 1, wherein Y is N, R1 is OH, R2 is benzyl, R3 is absent, and R4 is butylamino.

### Claim 13 (depends on 1)

The compound of claim 1, wherein Y is N, R1 is OH, R2 is benzyl, R3 is absent, and R4 is butoxy.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Y is N, R1 is OH, R2 is benzyl, R3 is absent, and R4 is benzylamino.

### Claim 15 (depends on 1)

The compound of claim 1, wherein Y is N, R1 is OH, R2 is benzyl, R3 is absent, and R4 is pentyl.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the polymer is insoluble in water at pH=7.4 and at 25° C.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the polymer has a weight average molecular weight ranging from 800 Daltons to 10,000 Daltons, as determined using gel permeation chromatography.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the polymer or unit thereof does not comprise polyketal or unit thereof.

### Claim 19 (depends on 1)

A composition comprising the compound of claim 1.

### Claim 20 (depends on 1)

A synthetic nanocarrier that comprises the compound of claim 1.

### Claim 21 (depends on 20)

A composition comprising the synthetic nanocarrier of claim 20.

### Claim 22 (depends on 1)

A composition comprising a vaccine comprising the compound of claim 1.

### Claim 23 (depends on 1)

A method comprising:
administering the compound of any of claim 1 to a subject.

### Claim 24

A method for making a conjugate that comprises a structure as in formula (II):
comprising:
combining an alcohol and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino;
heating the alcohol and compound; and
adding a catalyst.

### Claim 25

A method for making a conjugate that comprises a structure as in formula (II):
comprising:
combining an alcohol, a catalyst, and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino.

### Claim 26

A method for making a conjugate that comprises a structure as in formula (VI):
comprising:
combining a diol having the formula (VII):
HO-polymer-OH (VII),
and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino;
heating the alcohol and compound; and
adding a catalyst.

### Claim 27

A method for making a conjugate that comprises a structure as in formula (VI):
comprising:
combining a catalyst, a diol having the formula (VII):
HO-polymer-OH (VII),
and a compound comprising a structure as in formula (IV):
wherein R1═H, OH, SH, NH2, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino;
R2═H, alkyl, or substituted alkyl;
Y═N or C;
R3 is absent if Y═N; or is H, alkyl, substituted alkyl, or combined with R4 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected if Y═C;
R4 is H, or substituted or unsubstituted alkyl, alkoxy, alkylthio, or alkylamino when not combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected; or is combined with R3 to form a carbocycle or heterocycle with the carbon atoms of the pyridine ring to which they are connected;
R5 is a polymer or unit thereof;
X is C, N, O, or S;
R6 and R7 are each independently H or substituted; and
R9, R10, R11, and R12 are each independently H, a halogen, OH, thio, NH2, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino.