# US 2014/0193453 A1 · Immunomodulatory agent-polymeric compounds

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- Number: US 2014/0193453 A1
- Document ID: US20140193453A1
- Status: Published application
- Kind: A1
- Application number: 14/138,601
- Filed: 2013-12-23
- Published: 2014-07-10
- 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/US20140193453A1

## 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 (I):
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; and
R8 is a biodegradable polymer or unit thereof.

### Claim at position 2

2-3. (canceled)

### Claim 4

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 at position 4

5-18. (canceled)

### Claim 19 (depends on 1)

A composition comprising the compound of claim 1.

### Claim 20

(canceled)

### Claim 21 (depends on 1)

A synthetic nanocarrier that comprises the compound of claim 1.

### Claim at position 8

22-24. (canceled)

### Claim 25 (depends on 21)

A composition comprising the synthetic nanocarrier of claim 21.

### Claim 26

(canceled)

### Claim 27 (depends on 1)

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

### Claim 28 (depends on 19)

A composition comprising a vaccine comprising the composition of claim 19.

### Claim 29 (depends on 21)

A composition comprising a vaccine comprising the synthetic nanocarrier of claim 21.

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 19)

A method comprising:
administering the composition of claim 19 to a subject.

### Claim 32 (depends on 21)

A method comprising:
administering the synthetic nanocarrier of claim 21 to a subject.

### Claim 33

(canceled)

### Claim 34

A method for making a conjugate that comprises a structure as in formula (I):
comprising:
1) activating a biodegradable polymer or unit thereof, and exposing the activated biodegradable polymer or unit thereof and a compound comprising a structure as in formula (III) to a base and/or solvent:
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; and
R8 is a biodegradable polymer or unit thereof or
2) exposing a composition comprising a polymer or unit thereof and a compound comprising a structure as in formula (III) to a coupling agent and base and/or solvent:
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; and
R8 is a polymer or unit thereof.

### Claim at position 19

35-37. (canceled)

### Claim 38

A method for making a conjugate that comprises a structure as in formula (II):
comprising:
1) 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; or
2) 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, NH7, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino;
heating the alcohol and compound; and
adding a catalyst; or
3) 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 at position 21

39-57. (canceled)

### Claim 58

A compound that comprises 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.

### Claim at position 23

59-67. (canceled)

### Claim 68

A method for making a compound that comprises a structure as in formula (IV):
comprising:
combining, in the presence of a solvent and/or heat, a compound that comprises a structure as in formula (III):
and
a compound comprising a structure as in formula (V):
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 at position 25

69-76. (canceled)

### Claim 77

A method for making a conjugate that comprises a structure as in formula (VI):
comprising:
1) 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; or
2) combining a diol having the formula (VII):
HO-polymer-OHμ(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;
heating the alcohol and compound; and
adding a catalyst; or
3) 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, NH7, or substituted or unsubstituted alkyl, aryl, heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino.

### Claim at position 27

78-94. (canceled)

### Claim 95

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 at position 29

96-122. (canceled)