	US 11,787,906 B2
	Biodegradable drug-polymer conjugate
Stephen Lonsdale Birkett, Langwarrin (AU); Andrew Craig Donohue, Bentleigh East (AU); Asha Marina D'Souza, Carnegie (AU); Sarah Man Yee Ng, Berwick (AU); Adrian Sulistio, Glen Iris (AU); Russell John Tait, Balwyn (AU); David Valade, Glenroy (AU); Alan Naylor, Harston (GB); Jason Watling, Cheltenham (AU); and Carmen Vittoria Scullino, Moonee Ponds (AU)
Assigned to POLYACTIVA PTY LTD, Melbourne (AU)
Appl. No. 16/493,252
Filed by POLYACTIVA PTY LTD, Melbourne (AU)
PCT Filed Mar. 14, 2018, PCT No. PCT/AU2018/050234 § 371(c)(1), (2) Date Sep. 11, 2019, PCT Pub. No. WO2018/165711, PCT Pub. Date Sep. 20, 2018.
Application 16/493,252 is a continuation in part of application No. 15/458,546, filed on Mar. 14, 2017, granted, now 10,113,033.
Claims priority of application No. 2017900888 (AU), filed on Mar. 14, 2017.
Prior Publication US 2020/0123322 A1, Apr. 23, 2020
Int. Cl. C08G 73/08 (2006.01); A61K 47/59 (2017.01); A61K 31/5377 (2006.01); A61K 31/5575 (2006.01)

CPC C08G 73/08 (2013.01) [A61K 31/5377 (2013.01); A61K 31/5575 (2013.01); A61K 47/59 (2017.08)]

20 Claims

1. A drug-polymer conjugate, which is a copolymer of (i) at least one monomer of Formula (I):

where:

X may be the same or different at each occurrence and represents a terminal functional group comprising an alkyne or an azide;

R is selected from the group consisting of linear or branched hydrocarbon, optionally substituted aryl and optionally substituted heteroaryl;

D is a releasable drug selected from a prostaglandin analogue according to Formula Xb:

wherein:

represents the point of attachment of the prostaglandin analogue to linker group L;

represents a double or single bond;

Y is optionally substituted C₄to C₁₀hydrocarbyl or optionally substituted C₄to C₁₀hydrocarbyloxy; and

W is hydroxy and U is hydrogen, or W and U are both fluoro, or W and U together form oxo;

L is a linker group;

wherein the drug D is conjugated to the polymer backbone via an ester linkage formed between the drug D and the linker group L;

Q is independently selected at each occurrence and may be present or absent;

wherein when present, Q represents a linking group and is selected from the group consisting of:

wherein

(R) indicates the end of the group attached to the group R and the opposite end is attached to (X);

each of t and v are independently 0 or 1 and at least one of t and v is 1;

R¹, R^1′, R²and R^2′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy and alkoxyalkyl, and wherein one of the pairs of R¹, R^1′ and R², R^2′, may between the members of the pair form a carbocycle or heterocycle of 3 to 6 constituent ring members wherein the heterocycle may comprise from 1 to 3 constituent oxygen heteroatom ring members; and

M is selected from the group consisting of a bond, optionally substituted C₁to C₁₀straight or branched chain aliphatic, the group —O—(C₁to C₁₀straight or branched chain aliphatic), an ether linking group comprising C₁to C₁₀straight or branched chain aliphatic interrupted by a oxygen (—O—), the group —N(R^w)—(C₁to C₁₀straight or branched chain aliphatic) and an amine linking group comprising C₁to C₁₀straight or branched chain aliphatic interrupted by the group N(R^w) wherein R^wis selected from hydrogen and C₁to C₄alkyl;

q is 0 or 1;

s is from 0 to 10;

and

(ii) at least one co-monomer of Formula (IIIa):

J-((OR^a)_m—B-A)_n (IIIa)

wherein

A may be the same or different at each occurrence and represents a group comprising a terminal functional group comprising an alkyne or an azide functionality, wherein the alkyne or azide functionality in the terminal functional group is complementary to the alkyne or azide functionality in a terminal functional group X present on a monomer of formula (I);

J represents a bond, oxygen or linking functional group,

R^ais selected from ethylene, propylene, butylene and mixtures thereof;

m is 1 to 300;

n is 3 to 8;

B is a bond, oxygen, the group of formula -MOC(O)N(H)M′-, -MOC(O)OM′—, MC(O)NHM′-, the group formula selected from (VIa), (VIb), (VIc) and (VId):

wherein M and M′ are independently selected from the group consisting of a bond, optionally substituted C₁to C₁₀straight or branched chain aliphatic, the group —O—(C₁to C₁₀straight or branched chain aliphatic), an ether linking group comprising C₁to C₁₀straight or branched chain aliphatic interrupted by a oxygen (—O—), the group —N(R^w)-(C₁to C₁₀straight or branched chain aliphatic) and an amine linking group comprising C₁to C₁₀straight or branched chain aliphatic interrupted by the group N(R^w) wherein IV′ is selected from hydrogen and C₁to C₄alkyl;

q is 0 or 1; and

wherein in the monomers of formula, (VIa), (VIb), (VIc) and (VId) the groups R³, R^3′, R⁴and R^4′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkyl amino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl wherein one of the pairs of R³, R^3′, R⁴, R^4′, may between the members of the pair form a carbocycle or heterocycle of 3 to 6 constituent ring members wherein the heterocycle may comprise from 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen which nitrogen may optionally be substituted by C₁to C₆alkyl; and

wherein at least one of the groups Q in the monomer of formula (I) and B in the co-monomer of formula (Ma) comprise at least one substituent selected from the group consisting of R¹, R^1′, R², R^2′, R³, R^3′, R⁴and R^4′ which is present and is not hydrogen.