IP Library › Patent Application 17586495

Patent Application

App. No. 17/586,495

COMPOSITION COMPRISING A POLYMERIC REAGENT

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Patent No.: US None
App. No.: 17/586,495

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Abstract

The present invention provides conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates. The conjugates as well as the polymeric reagents used to form the conjugates include at least one of each the following: an aromatic moiety comprising an ionizable hydrogen atom, a spacer moiety, and a water-soluble polymer. Methods of making polymeric reagents and conjugates, as well as methods for administering conjugates and compositions, are also provided.

Claims (269)

1 . A polymeric reagent of Formula I:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

is an aromatic-containing moiety bearing an ionizable hydrogen atom, H α ;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

2 . The polymeric reagent of claim 1 , of Formula II:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

3 . The polymeric reagent of claim 1 , of Formula III:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

4 . The polymeric reagent of claim 1 , of Formula IV:

wherein:

POLY 2 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

X 3 is a third spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

5 . The polymeric reagent of claim 1 , of Formula V:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

6 . A polymeric reagent of Formula VI:

wherein:

POLY is a water-soluble polymer;

X is a spacer moiety that does not include a

moiety;

is an aromatic moiety bearing an ionizable hydrogen atom, H α ;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

R e , when present, is an electron altering group; and

(FG) is a functional group capable of reacting with an amino group of an active agent to form a degradable linkage.

7 . The polymeric reagent of claim 6 , wherein

8 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein each of POLY 1 and POLY 2 is a poly(ethylene glycol).

9 . The polymeric reagent of claim 6 , wherein POLY is a poly(ethylene glycol).

10 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

11 . The polymeric reagent of claim 6 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

12 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.

13 . The polymeric reagent of claim 6 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.

14 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein the first spacer moiety is selected from the group consisting

of —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —C(O)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—, —NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—, —C(O)—NH—CH 2 —CH 2 —(OCH 2 CH 2 ) 1-3 —NH—C(O)—, —C(O)—NH—(CH 2 CH 2 O) 1-3 —CH 2 —CH 2 —NH—C(O)—, —NH—C(O)—CH 2 —, —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —O—, —O—CH 2 —C(O)—NH—, —CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —O—CH 2 —CH 2 —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—, —NH—C(O)—CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —NH—C(O)—, —C(O)—NH—CH 2 —CH 2 —O—, and —O—CH 2 —CH 2 —NH—C(O)—, and the second spacer moiety is selected from the group consisting

15 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 , 5 and 6 , wherein R 1 is H and R 2 is H.

16 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 , 5 and 6 , wherein the functional group capable of reacting with an amino group of an active agent is selected from the group consisting of carbonates of N-succinimidyl, 1-benzotriazolyl, imidazole, imidazole, halides and phenolates.

17 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 , 5 and 6 , wherein the functional group capable of reacting with an amino group is a carbonate of N-succinimidyl.

18 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein (a) is zero and (b) is zero.

19 . The polymeric reagent of claim 6 , wherein (a) is zero.

20 . The polymeric reagent as in any one of claims 1 , 2 , 3 , 4 and 5 , wherein (a) is one, (b) is zero, and the first electron altering group is selected from the group consisting of halo, lower alkyl, aryl, substituted aryl, substituted arylakyl, alkoxy, aryloxy, alkylthio, arylthio, CF 3 , —CH 2 CF 3 , —CH 2 C 6 F 5 , —CN, —NO 2 , —S(O)R, —S(O)Ar, —S(O 2 )R, —S(O 2 )Ar, —S(O 2 )OR, —S(O 2 )OAr, —S(O 2 )NHR, —S(O 2 )NHAr, —C(O)R, —C(O)Ar, —C(O)OR, and —C(O)NHR, wherein Ar is aryl and R is H or an organic radical.

21 . The polymeric reagent of claim 6 , wherein (a) is one and the electron altering group is selected from the group consisting of halo, lower alkyl, aryl, substituted aryl, substituted arylakyl, alkoxy, aryloxy, alkylthio, arylthio, CF 3 , —CH 2 CF 3 , —CH 2 C 6 F 5 , —CN, —NO 2 , —S(O)R, —S(O)Ar, —S(O 2 )R, —S(O 2 )Ar, —S(O 2 )OR, —S(O 2 )OAr, —S(O 2 )NHR, —S(O 2 )NHAr, —C(O)R, —C(O)Ar, —C(O)OR, and —C(O)NHR, wherein Ar is aryl and R is H or an organic radical.

22 . The polymeric reagent of claim 5 , selected from the group consisting of

wherein, for each structure, each (n) is from 4 to 1500.

23 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

24 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

25 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

26 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

27 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

28 . The polymeric reagent of claim 5 , of the formula:

wherein each (n) is from 4 to 1500.

29 . The polymeric reagent of claim 6 , of the formula:

wherein (n) is from 4 to 1500.

30 . A conjugate of Formula I-C:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

is an aromatic-containing moiety bearing an ionizable hydrogen atom, H α ;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

31 . The conjugate of claim 30 , of Formula II-C:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

32 . The conjugate of claim 30 , of Formula III-C:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

33 . The conjugate of claim 30 , of Formula IV-C:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

X 3 is a third spacer moiety;

Ar 1 is a first aromatic moiety;

Ar 2 is a second aromatic moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

34 . The conjugate of claim 30 , of Formula V-C:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

35 . A conjugate of Formula VI-C:

wherein:

POLY is a water-soluble polymer;

X is a spacer moiety that does not include a

moiety;

is an aromatic-containing moiety bearing an ionizable hydrogen atom, H α ;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

R e , when present, is an electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

D is a residue of a biologically active agent.

36 . The polymeric reagent of claim 35 , wherein

37 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 , wherein each of POLY 1 and POLY 2 is a poly(ethylene glycol).

38 . The conjugate of claim 35 , wherein POLY is a poly(ethylene glycol).

39 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

40 . The conjugate of claim 35 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6,000 Daltons.

41 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.

42 . The conjugate of claim 35 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.

43 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 , wherein the first spacer moiety is selected from the group consisting

44 . The conjugate as in any one of claims 1 , 2 , 3 , 4 , 5 and 6 , wherein R 1 is H and R 2 is H.

45 . The conjugate as in any one of claims 30 , 31 , 32 , 33 , 34 and 35 , wherein Y 1 is O and Y 2 is O.

46 . The conjugate as in any one of claims 30 , 31 , 32 , 33 , 34 and 35 , wherein the biologically active agent is a polypeptide.

47 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 wherein (a) is zero and (b) is zero.

48 . The conjugate of claim 35 , wherein (a) is zero.

49 . The conjugate as in any one of claims 30 , 31 , 32 , 33 and 34 , wherein (a) is one, (b) is zero, and the first electron altering group is selected from the group consisting of halo, lower alkyl, aryl, substituted aryl, substituted arylakyl, alkoxy, aryloxy, alkylthio, arylthio, CF 3 , —CH 2 CF 3 , —CH 2 C 6 F 5 , —CN, —NO 2 , —S(O)R, —S(O)Ar, —S(O 2 )R, —S(O 2 )Ar, —S(O 2 )OR, —S(O 2 )OAr, —S(O 2 )NHR, —S(O 2 )NHAr, —C(O)R, —C(O)Ar, —C(O)OR, and —C(O)NHR, wherein Ar is aryl and R is H or an organic radical.

50 . The conjugate of claim 35 , wherein (a) is one and the electron altering group is selected from the group consisting of halo, lower alkyl, aryl, substituted aryl, substituted arylakyl, alkoxy, aryloxy, alkylthio, arylthio, CF 3 , —CH 2 CF 3 , —CH 2 C 6 F 5 , —CN, —NO 2 , —S(O)R, —S(O)Ar, —S(O 2 )R, —S(O 2 )Ar, —S(O 2 )OR, —S(O 2 )OAr, —S(O 2 )NHR, —S(O 2 )NHAr, —C(O)R, —C(O)Ar, —C(O)OR, and —C(O)NHR, wherein Ar is aryl and R is H or an organic radical.

51 . The conjugate of claim 1 , selected from the group consisting of:

wherein, for each structure, each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

52 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

53 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

54 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

55 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

56 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

57 . The conjugate of claim 30 , of the formula:

wherein each (n) is from 4 to 1500 and D is a residue of a biologically active agent.

58 . The conjugate of claim 35 , of the formula:

wherein (n) is from 4 to 1500 and D is a residue of a biologically active agent.

59 . A method for preparing a polymeric reagent, comprising:

(a) providing an aromatic moiety bearing a first attachment site, a second attachment site

and a third attachment site;

(b) reacting a functional group reagent with the first attachment site to result in the first attachment site bearing a functional group capable of reacting with an amino group of an active agent and resulting in a hydolyzable carbamate;

(c) reacting a plurality of water-soluble polymers bearing a reactive group with the second attachment site and third attachment site to result in (i) the second attachment site bearing a water-soluble polymer through a spacer moiety, and (ii) the third attachment site bearing a second water-soluble polymer through a spacer moiety.

60 . The method of claim 59 , wherein step (b) is performed before step (c).

61 . The method of claim 59 , wherein step (c) is performed before step (b).

62 . A method for preparing a conjugate, comprising reacting under conjugation conditions a polymeric reagent according to any one of claims 1 , 2 , 3 , 4 , 5 or 6 with an amine-containing biologically active agent.

63 . A conjugate prepared by the method of claim 62 .

64 . A pharmaceutical composition comprising a conjugate of claim 63 and a pharmaceutically acceptable excipient.

65 . The pharmaceutical composition of claim 64 , in lyophilized form.

66 . The pharmaceutical composition of claim 64 , further comprising a liquid diluent.

67 . The pharmaceutical composition of claim 66 , wherein the liquid diluent is selected from the group consisting of bacteriostatic water for injection, dextrose 5% in water, phosphate-buffered saline, Ringer's solution, saline solution, sterile water, deionized water, and combinations thereof.

68 . The pharmaceutical composition of claim 64 , in unit dosage form.

69 . The pharmaceutical composition of claim 68 , housed in a glass vial.

70 . A method of delivering a conjugate comprising the step of administering to a patient a therapeutically effective amount of a conjugate according to any one of claims 30 , 31 , 32 , 33 , 34 and 35 .