Biodegradable drug-polymer conjugate

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;

Q is independently selected at each occurrence and may be present or absent and when present, represents a linking group;

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

D is a releasable bicyclic prostaglandin; and

L is a linker group;

and (ii) at least one co-monomer of formula (III):

J-(Y 1 -A) n   (III)

where:

J represents a linking functional group;

n is an integer from 2 to 8;

Y 1 comprises a polyether of formula (OR a ) m wherein each R a is independently selected from ethylene, propylene, and butylene, and m is an integer from 1 to 300, and the polyether is in chain with one or more groups selected from one or more of optionally substituted straight or branched C 1 to C 10 alkylene, amino, ether, ester, amide, carbonate, and carbamate; and

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 said terminal functional group is complementary to the terminal functional group X of formula (I) providing triazole moieties from reaction of X and A.

2 . The drug-polymer conjugate of claim 1 , wherein n is 3 or 4.

3 . The drug-polymer conjugate of claim 1 , wherein the bicyclic prostaglandin D is of formula (X):

wherein:

CE is a 6 or 7 membered cyclic ether or cyclic thioether which may be saturated or include one double bond;

A 1 is oxygen or sulfur;

represents a double or single bond which is independently selected in each case;

R 12 is C 1-6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl, oxo, halo, C 1-4 alkoxy, ring 2, —O-ring 2, and —S-ring 2, wherein ring 2 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings; and

one of R 10 , R 11 , and R 12 is linked to the polymer backbone, wherein:

R 11 and R 12 when linked to the polymer backbone comprise the alcohol residue of an ester or carbonate linking group, and R 10 when linked to the polymer backbone forms the acid residue of an ester or anhydride linking group; and

R 10 when not linked to the backbone is selected from the group consisting of —OH, —O(C 1-6 alkyl), —O—(C 1-6 alkyl)-O—NO 2 , and —NR a R b , where R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 alkylsulfonyl;

R 11 when not linked to the polymer backbone is hydroxyl or halo;

R 13 is selected from halo, C 1-4 alkyl, and C 1-4 alkoxy;

t is 0, 1, or 2; and

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is an integer from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is an integer from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings.

4 . The drug-polymer conjugate of claim 1 , wherein the bicyclic prostaglandin D is of formula (Xa-1):

wherein:

A 1 is oxygen or sulfur;

represents a double or single bond;

W and U are selected from the group consisting of (i) where W and U together form oxo (═O), (ii) where W and U are each halo, and (iii) where W is R 15 and U is hydrogen;

one of R 10 , R 11 , and R 15 is linked to the polymer backbone, wherein:

R 11 and R 15 when linked to the polymer backbone are the alcohol residue of an ester or carbonate linking group and R 1 when linked to the polymer backbone forms the acid residue of an ester or anhydride linking group; and

R 10 when not linked to the backbone is selected from the group consisting of —OH, —O(C 1-6 alkyl), —O—(C 1-6 alkyl)-O—NO 2 , and —NR a R b , where R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 alkylsulfonyl;

R 11 when not linked to the polymer backbone is hydroxy or halo;

when R 15 is not linked to the backbone then W is hydroxy and U is hydrogen, or W and U are each fluoro, or W and U together form oxo;

Y 2 is selected from —CH 2 —, oxygen, and sulfur; and

ring 2 is selected from optionally substituted, aromatic or non-aromatic carboxylic and heterocyclic rings;

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is an integer from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is an integer from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is an integer from 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings.

5 . The drug-polymer conjugate of claim 1 , wherein the bicyclic prostaglandin D is of formula (Xa-2);

wherein:

R 10 is the bond to linker L and is-OH in the released bicyclic prostaglandin;

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is an integer from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is an integer from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings;

represents a double or single bond;

Y 2 is selected from —CH 2 —, oxygen or sulfur; and

ring 2 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings.

6 . The drug-polymer conjugate of claim 1 , wherein the polymer backbone comprises a plurality of biodegradable groups of formula (II):

wherein:

G is independently selected at each occurrence from oxygen and NR 16 where R 16 is hydrogen or C 1 to C 4 alkyl;

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

R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein one of the pairs of R 1 , R 1′ and R 2 , R 2′ may 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 C 1 to C 10 straight or branched chain aliphatic, —O—(C 1 to C 10 straight or branched chain aliphatic), an ether linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by an oxygen (—O—), —N(R w )—(C 1 to C 10 straight or branched chain aliphatic), and an amine linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by N(R w ), wherein R w is selected from hydrogen and C 1 to C 4 alkyl;

q is 0 or 1; and

T is a triazole moiety.

7 . The drug-polymer conjugate of claim 1 , wherein in formula (I) the Q is absent and the co-monomer of formula (III) comprises biodegradable groups.

8 . The drug-polymer conjugate of claim 1 , wherein Q is independently selected from the group consisting of:

wherein:

(R) indicates the end attached to 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;

R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein one of the pairs of R 1 , R 1′ and R 2 , R 2′ may 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 C 1 to C 10 straight or branched chain aliphatic, —O—(C 1 to C 10 straight or branched chain aliphatic), an ether linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by an oxygen (—O—), —N(R w )—(C 1 to C 10 straight or branched chain aliphatic), and an amine linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by N(R w ), wherein R w is selected from hydrogen and C 1 to C 4 alkyl;

q is 0 or 1; and

s is an integer from 0 to 10.

9 . The drug-polymer conjugate according to of claim 1 , wherein the monomer of formula (I) is of formula (IV):

wherein

G is independently selected at each occurrence from oxygen and NR 16 where R 16 is hydrogen or C 1 to C 4 alkyl;

M is selected from the group consisting of a bond, optionally substituted C 1 to C 10 straight or branched chain aliphatic, —O—(C 1 to C 10 straight or branched chain aliphatic), an ether linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by an oxygen (—O—), —N(R w )—(C 1 to C 10 straight or branched chain aliphatic), and an amine linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by N(R w ), wherein R w is selected from hydrogen and C 1 to C 4 alkyl;

X is 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;

L is a linker group; and

D is a releasable bicyclic prostaglandin;

R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkyl amino, dialkylamino, amino-alkyl, alkylamino-alkyl, and dialkylamino-alkyl, wherein one of the pairs of R 1 ,R 1′ and R 2 ,R 2′ may 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 C 1 to C 6 alkyl; and

q is 0 or 1.

10 . The drug-polymer conjugate of claim 1 , wherein the co-monomer of formula (III) has the 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 a is selected from ethylene, propylene, butylene, and mixtures thereof;

m is an integer from 1 to 300;

n is an integer from 3 to 8;

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

wherein M and M′ are independently selected from the group consisting of a bond, optionally substituted C 1 to C 10 straight or branched chain aliphatic, —O—(C 1 to C 10 straight or branched chain aliphatic), an ether linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by an oxygen (—O—), —N(R w )—(C 1 to C 10 straight or branched chain aliphatic), and an amine linking group comprising C 1 to C 10 straight or branched chain aliphatic interrupted by N(R w ), wherein R w is selected from hydrogen and C 1 to C 4 alkyl;

q is 0 or 1;

wherein in the groups (VIa), (VIb), (VIc), and (VId), R 3 , R 3′ , R 4 , and R 4′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkyl amino, dialkylamino, amino-alkyl, alkylamino-alkyl, and dialkylamino-alkyl, wherein one of the pairs of R 3 , R 3′ and R 4 , R 4′ may 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 C 1 to C 6 alkyl.

11 . The drug-polymer conjugate of claim 10 , wherein J is a hydrocarbon of formula:

C z H 2z+2-n

wherein z is an integer from 1 to 8 and n is an integer from 3 to 8.

12 . The drug-polymer conjugate of claim 1 , wherein n is an integer from 3 to 8 and J is selected from the group consisting of:

wherein n is 3; and

wherein n is an integer from 4, 6, or 8.

13 . The drug-polymer conjugate of claim 1 , wherein (OR a ) m is selected from poly(ethylene oxide), poly(propylene oxide), poly(butylene oxide), block copolymers of one or more of poly(ethylene oxide), poly(propylene oxide) and poly(butylene oxide), and block copolymers of two or more of poly(ethylene oxide), poly(propylene oxide) and poly(butylene oxide), wherein (OR a ) m has a molecular weight in the range of from 200 to 10,000.

14 . The drug-polymer conjugate of claim 1 , wherein the co-monomer of formula (III) is of formula (IIIa-1) or (IIIa-2);

wherein J 1 is a straight or branched chain of formula C Z H 2Z-1 and wherein z is an integer from 1 to 8; and

wherein J 2 is a straight or branched chain of formula C Z H 2z-2 and wherein z is an integer from 1 to 8.

15 . The drug-polymer drug conjugate of claim 6 , wherein, R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , and R 4′ are selected from the group consisting of hydrogen, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, and C 1 to C 4 alkoxy-substituted C 1 to C 4 alkyl.

16 . The drug-polymer conjugate of claim 6 , wherein at least one of R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , and R 4′ which is present is not hydrogen.

17 . The drug-polymer drug conjugate of claim 1 , wherein the monomer of formula (I) has the formula (IVa):

wherein:

G is independently selected at each occurrence from oxygen and NR 16 where R 16 is hydrogen or C 1 to C 4 alkyl;

L is a linker group;

D is a releasable bicyclic prostaglandin;

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

R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkyl amino, dialkylamino, amino-alkyl, alkylamino-alkyl, and dialkylamino-alkyl, wherein one of the pairs of R 1 ,R 1′ and R 2 R 2′ may 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 C 1 to C 6 alkyl;

q is 0 or 1;

s is an integer from 0 to 6; and

in the co-monomer of formula (III), A is azide.

18 . The drug-polymer conjugate of claim 1 , wherein R is selected from the group consisting of straight and branched chain hydrocarbon of from 1 to 12 carbon atoms,

19 . The drug-polymer conjugate of claim 1 , wherein the linker group L is of a formula selected from the group consisting of:

(R) —O— (D);

(R) —OC(O)—Ar—O— (D);

(R) —NHC(O)—Ar—O— (D);

(R) —C(O)O—C 1-12 alkylene-O— (D);

(R) —OC(O)O—C 1-12 alkylene-O— (D);

(R) —OC(O)—C 1 -C 12 alkylene-O— (D);

(R) —OC(O)—O— (D);

(R) —OC(O)—Ar—OC(O) —O— (D);

(R) —NHC(O)—Ar—OC(O)—O (D);

(R) —C(O)O—C 1 -C 12 alkylene-OC(O)—O (D); and

(R) —OC(O)—C 1 -C 12 alkylene-OC(O)— (D),

wherein (R) indicates the end bonded to R and (D) indicates the end bonded to D.

20 . A drug-polymer drug conjugate of claim 1 , wherein the linker group L is of a formula selected from:

wherein R 5 is selected from the group consisting of hydrogen and C 1 to C 6 alkyl, and (R) indicates the end bonded to R and (D) indicates the end bonded to D.

21 . The drug-polymer conjugate of claim 1 , wherein the monomer of formula (I) is of formula (IVb):

wherein:

G is oxygen or NR 16 where R 16 is hydrogen or C 1-4 alkyl;

R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, and C 1 to C 6 alkoxy-(C 1 to C 6 alkyl), wherein one of the pairs of R 1 ,R 1′ and R 2 ,R 2′ may 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 be substituted by C 1 to C 6 alkyl; and

wherein at least one of R 1 , R 1′ , R 2 , and R 2′ is other than hydrogen;

s is an integer from 0 to 6;

q is 0 or 1;

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is an integer from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is an integer from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is an integer from 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings;

represents a double or single bond;

Y 2 is selected from —CH 2 —, oxygen, or sulfur; and

ring 2 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings.

22 . The drug-polymer conjugate of claim 1 , wherein the monomer of formula (I) is of formula (IVc):

wherein R 1 , R 1′ , R 2 , and R 2′ are independently selected from the group consisting of hydrogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, and C 1 to C 6 alkoxy-(C 1 to C 6 alkyl), wherein one of the pairs of R 1 , R 1′ and R 2 , R 2′ may 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 be substituted by C 1 to C 6 alkyl; and

wherein at least one of R 1 , R 1′ , R 2 , and R 2′ is other than hydrogen;

s is an integer from 0 to 6;

q is 0 or 1;

R 5 is hydrogen or methyl;

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings;

represents a double or single bond;

Y 2 is selected from —CH 2 —, oxygen, or sulfur; and

ring 2 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings.

23 . The drug-polymer conjugate of claim 1 , wherein the bicyclic prostaglandin D is selected from the following formulae and forms an ester with linker group L and is the carboxylic acid (C═O) residue of the ester:

24 . The drug polymer conjugate of claim 1 , which is a copolymer of:

(i) at least one monomer of formula (I) selected from the group consisting of:

wherein D is of formula:

wherein

CE is a 6 or 7 membered cyclic ether or cyclic thioether which may be saturated or include one double bond;

A 1 is oxygen or sulfur;

represents a double or single bond which is independently selected in each case;

R 11 or R 12 is linked to the polymer backbone, wherein:

R 11 and R 12 when linked to the polymer backbone comprise the alcohol residue of an ester or carbonate linking group;

R 11 when not linked to the polymer backbone is hydroxyl or halo;

R 12 when not linked to the polymer backbone is C 1-6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl, oxo, halo, C 1-4 alkoxy, ring 2, O-ring 2, and —S-ring 2, wherein ring 2 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings;

R 13 is selected from halo, C 1-4 alkyl, and C 1-4 alkoxy;

tis 0, 1 or 2; and

Z is selected from the group consisting of:

—(CH 2 ) m — wherein m is an integer from 1 to 10;

—(CH 2 ) n —CH═CH— wherein n is an integer from 1 to 6;

—(CH 2 ) p -A 1 -CH 2 — wherein A 1 is oxygen or sulfur and p is 1 to 4; and

ring 1, wherein ring 1 is selected from optionally substituted, aromatic or non-aromatic, carbocyclic and heterocyclic rings;

(ii) at least one co-monomer of formula (III) selected from the group consisting of:

wherein n is the number of ethyleneoxy groups and is an integer from 2 to 50.

25 . The drug polymer conjugate of claim 1 , which is a copolymer of:

(i) at least one monomer of formula (I) selected from the group consisting of:

wherein D is of formula:

(ii) at least one co-monomer of formula (III) selected from the group consisting of;

wherein n is the number of ethyleneoxy groups and is an integer from 2 to 50.

26 . An ocular implant comprising the drug polymer conjugate of claim 1 .