Alkoxylation methods

Patent metadata

Field	Value
Publication number	US-2016200867-A1
Application number	US-201615075750-A
Country	US
Kind code	A1
Filing date	Mar 21, 2016
Priority date	Nov 18, 2009
Publication date	Jul 14, 2016
Grant date	—

Abstract

Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.

First claim

1 - 50 . (canceled)

51 . A method comprising the step of alkoxylating in a suitable solvent a previously isolated alkoxylatable oligomer to form an alkoxylated polymeric material, wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 300 Daltons.

52 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has a known and defined weight-average molecular weight of greater than 500 Daltons.

53 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product are soluble in the suitable solvent.

54 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer is prepared by (a) alkoxylating a precursor molecule having a molecular weight of less than 300 Daltons to form a reaction mixture comprising an alkoxylatable oligomer, and (b) isolating the alkoxylatable oligomer from the reaction mixture.

55 . The method of claim 51 where the alkoxylation utilizes ethylene oxide as an alkoxylation agent.

56 . The method of claim 54 , wherein the precursor molecule is selected from the group consisting of glycerol, diglycerol, triglycerol, hexaglycerol, mannitol, sorbitol, pentaerythritol, dipentaerthitol, and tripentaerythritol.

57 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has from one to eight primary hydroxyl groups.

58 . The method of claim 57 , wherein each of the one to eight primary hydroxyl groups is the result of an alkoxylation reaction.

59 . The method of claim 57 , wherein the neither the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product has a hydroxyl group of the precursor molecule.

60 . The method of claim 51 , wherein both the previously isolated alkoxylatable oligomer and the alkoxylated polymeric product each has a branched structure.

61 . The method of claim 60 , wherein the branched structure is a 4- to 8-arm branched structure.

62 . The method of claim 61 , wherein the branched structure is a 4-arm branched structure.

63 . The method of claim 61 , wherein the branched structure is a 5-arm branched structure.

64 . The method of claim 61 , wherein the branched structure is a 6-arm branched structure.

65 . The method of claim 61 , wherein the branched structure is an 8-arm branched structure.

66 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:

wherein the average value of n within the structure is from 2 to 50.

67 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:

wherein the average value of all the instances of n within the structure is from 10 to 1000.

68 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:

wherein the average value of all instances of the value of n within the structure is from 2 to 35.

69 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:

wherein the average value of all instances of the value of n within the structure is from 10 to 750.

70 . The method of claim 51 , wherein the previously isolated alkoxylatable oligomer has the following structure:

wherein the average value of all instances of the value of n within the structure is 2 to 35.

71 . The method of claim 51 , wherein the alkoxylated polymeric material has the following structure:

wherein the average value of all instances of the value of n within the structure is 10 to 600.

72 . The method claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 400.

73 . The method claim 67 , wherein the average value of all instances of the value of n within the structure is from 50 to 300.

74 . The method of claim 66 , wherein all values of n are within three standard deviations of each other.

75 . The method of claim 66 , wherein all values of n are within two standard deviations of each other.

76 . The method claim 66 , wherein all values of n are within one standard deviation of each other.

77 . The method of claim 51 , wherein the suitable solvent include organic solvents selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), toluene, benzene, xylenes, mesitylene, tetrachloroethylene, anisole, and mixtures of the foregoing.

78 . The method of claim 51 , wherein the suitable solvent is selected from the group consisting of toluene, xylene, mesitylene, tetrahydrofuran (THF), and mixtures of foregoing.

79 . The method of claim 51 , wherein the suitable solvent is toluene used in quantities that after ethoxylation the solvent consists more than 25 wt % and less than 75 wt % of the reaction mixture.

80 . The method of claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions, wherein the alkoxylation conditions include the presence of a strong base.

81 . The method of claim 80 , wherein the strong base is selected from the group consisting of one or more alkali metals.

82 . The method of claim 80 , wherein the strong base is selected from the group consisting of metallic potassium, metallic sodium, sodium-potassium alloys, and a hydroxide.

83 . The method of claim 82 , wherein the hydroxide is NaOH, KOH and mixtures thereof.

84 . The method of claim 82 , wherein the strong base is a sodium-potassium alloy.

85 . The method of claim 80 , wherein the strong base is an alkoxide of a previously isolated alkoxylatable oligomer.

86 . The method of claim 80 , wherein the strong base is present in a catalytic amount.

87 . The method of claim 86 , wherein the catalytic amount is from 0.001 to 10.0 weight percent strong base based upon the weight of the total reaction mixture.

88 . The method of claim 86 , wherein the catalytic amount is from 0.01 to about 6.0 weight percent strong base based upon the weight of the total reaction mixture.

89 . The method of claim 51 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 20 ppm.

90 . The method of claim 89 , wherein the step of alkoxylating is carried out under alkoxylating conditions wherein the amount of water present is less than 14 ppm.

91 . The method of claim 90 ,

Assignees

• Nektar Therapeutics

Inventors

• Kozlowski Antoni
• Mcmanus Samuel P
• Tipnis Sachin
• Lavaty Greg
• Swallow David
• Handley John R
• Schaefer Anthony G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• C08L2203/02

  for biomedical use · CPC title