Processes for preparing water-soluble polyethylene glycol conjugates of macrolide immunosuppressants
AssigneeWyeth
InventorsJianxin Gu, Mark Ruppen, Tianmin Zhu, Mahdi Fawzi
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Abstract
Processes are described for preparing 42-pegylated rapamycins including reacting a rapamycin with an acylating agent in the presence of a lipase to form an acylated rapamycin and reacting the acylated rapamycin with a methoxy poly(ethylene glycol) derivative in the presence of a base. Also described are processes for preparing 32-pegylated tacrolimus and/or ascomycin using these steps.
Claims23
A process for preparing polyethylene glycol conjugates of a rapamycin immunosuppressive macrolide of the following structure:
- wherein:
- R1 is selected from the group consisting of H, and alkyl, alkenyl, aryl, and arylalkyl;
- R2 is selected from the group consisting of H, hydroxyl, and —O-alkyl;
- R3 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, and —C(O)R31;
- R31 is selected from the group consisting of H, alkyl, alkenyl, aryl, and arylalkyl;
- R4 is selected from the group consisting of H, hydroxyl, and —O-alkyl;
- R5 is selected from the group consisting of H, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyaralkyl, and —C(O)R51;
- and
- R51 is selected from the group consisting of hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyaralkyl;
- the process comprising:
- (a) reacting an acylating agent with said rapamycin, said rapamycin being regiospecifically acylated at the 42-position;
- (b) reacting the acylated macrolide with a methoxy poly(ethylene glycol) derivative or thiol-terminated poly(ethylene glycol) derivative in the presence of a base.
A process for preparing polyethylene glycol conjugates of immunosuppressive macrolides of the following structures:
- wherein:
- R7, R8, R9 are independently H or alky;
- R is ethyl or allyl;
- the process comprising:
- (a) reacting an acylating agent with said immunosuppressive macrolides which are regiospecifically acylated at the 32-position;
- and
- (b) reacting the acylated macrolide with a methoxy poly(ethylene glycol) derivative or thiol-terminated poly(ethylene glycol) derivative in the presence of a base.
A process for preparing a pegylated immunosuppressive macrolide selected from the group consisting of formula I, formula II, formula III, formula IV, formula V, and formula VI:
- wherein:
- n is an integer from 10 to 1000;
- X is O or S;
- said process comprising:
- (a) reacting the macrolide with an acylating agent in the presence of a lipase to form an acylated macrolide, wherein said acylating agent is of the structure:
- wherein:
- R6 is H or CH3;
- Y is a leaving group;
- and
- (b) reacting the acylated macrolide with a methoxy poly(ethylene glycol) derivative in the presence of a base, wherein said methoxy poly(ethylene glycol) derivative is of the structure:
- HX—(CH2CH2O)n—CH3
- wherein:
- n is an integer from 10 to 1000;
- and
- X is O or S.
A process for preparing a pegylated rapamycin of the structure:
- wherein:
- n is 105-115;
- wherein said process comprises:
- (a) reacting rapamycin with vinyl bromoacetate in the presence of the Novozym 435™ lipase to form an acylated rapamycin;
- and
- (b) reacting the acylated rapamycin with methoxy poly(ethylene glycol) thiol having an average molecular weight of 5000 in the presence of diisopropylethylamine.
A process for preparing a pegylated everolimus of the structure:
- wherein, n is 105-115 and said process comprises:
- (a) reacting everolimus with vinyl bromoacetate in the presence of the Novozym 435™ lipase to form an acylated everolimus;
- and
- (b) reacting the acylated everolimus with methoxy poly(ethylene glycol) thiol having an average molecular weight of 5000 in the presence of diisopropylethylamine.
A process for preparing a pegylated CCI-779 of the structure:
- wherein, n is 105-115 and said process comprises:
- (a) reacting CCI-779 with vinyl bromoacetate in the presence of the Novozym 435™ lipase to form an mono-acylated or bis-acylated CCI-779;
- and
- (b) reacting the acylated CCI-779 with methoxy poly(ethylene glycol) thiol having an average molecular weight of 5000 in the presence of diisopropylethylamine.
A process for preparing a pegylated tacrolimus of the structure:
- wherein, n is 105-115 and said process comprises:
- (a) reacting tacrolimus with vinyl bromoacetate in the presence of the Novozym 435™ lipase to form an acylated tacrolimus;
- and
- (b) reacting the acylated tacrolimus with methoxy poly(ethylene glycol) thiol having an average molecular weight of 5000 in the presence of diisopropylethylamine.
A process for preparing a pegylated tacrolimus of the structure:
- wherein, n is an integer from 105 to 115, and said process comprises:
- (a) reacting tacrolimus with vinyl bromoacetate in the presence of the Novozym 435™ lipase to form an acylated tacrolimus;
- and
- (b) reacting the acylated tacrolimus with methoxy poly(ethylene glycol) thiol having an average molecular weight of 5000 in the presence of diisopropylethylamine.
Dependencies are inferred from the claim text.