Backbone polysubstituted chelates for forming a metal chelate-protein conjugate
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsOtto A. Gansow, Martin W. Brechbiel
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Abstract
New polysubstituted diethylenetriaminepentaacetic acid chelates and protein conjugates of the same are described together with the methods of preparing such compounds. A method of delivering radiolabelled compound of the present invention to a target site while minimizing the distribution of the compound to non-targeted organs or tissues is also disclosed.
Claims8
Polysubstituted diethylenetriaminepentaacetic acid (DTPA) chelating agent of the following formula 1 or 2 having one side chain attached to the carbon backbone of the DTPA, said side chain being an alkyl-aryl group with n=1-5, and which contains a functional moiety X selected from the group consisting of nitro, N-hydroxysuccininimide ester, N-hydroxysuccininimide isothiocyanate and haloacetamide groups, and which has one or more additional side chains (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) linked to the carbon backbone of the DTPA, said (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) being selected from the group consisting of hydrogen, straight or branched chain alkyl group with 1-15 carbon atoms, aryl group with 1-15 carbon atoms, and mixture thereof, wherein at least one of the additional side chains must contain at least one carbon atom:
- ##STR2##
The polysubstituted diethylenetriminepentaacetic acid chelating agent of claim 15 in which X is a N-hydroxysuccininimide ester group.
A chelating agent selected from the group consisting of:
- 2-(para-nitrobenzyl)diethylenetriaminepentaacetic acid,
- 2-(para-aminobenzyl)diethylenetriaminepentaacetic acid, and
- 2-(para-isothiocyanatobenzyl)diethylenetriaminepentaacetic acid.
A method for preparing polysubstituted diethylenetriaminepentaacetic acid chelating agent of the following formula 1 or 2:
- ##STR4## where the substituents (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) are selected from the group consisting of hydrogen, straight or branched chain alkyl group with 1-15 carbon atoms, aryl group with 1-15 carbon atoms, and mixture thereof, wherein X is hydrogen, alkyl group of 1-15 carbon atoms, alkyl-aryl group of 1-15 carbons atoms, nitro, methoxy or hydroxy and wherein N=1-5, the method comprising the sequential steps of:
- (a) reacting an amino protected alpha amino acid of the following formula 3:
- ##STR5## wherein the protecting group R.sub.5 is tertiary butyl (BOC), benzyl (CBZ), or 9-fluorenylmethyl (Fmoc) and R.sub.6 is selected from said (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) groups with an alpha amino acid amide of the following fomula 4:
- ##STR6## where R.sub.7 is selected from said (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) groups to produce a coupled diamide;
- (b) then deprotecting said diamide prior to reduction by reducing agent to produce a diethylenetriamine substituted with selected substituents;
- and
- (c) then converting said diethylene triamine substituted with selected substituents to polysubstituted diethylenetriaminepentaacetic acid of formula 1 or 2 by an alkylation reaction with haloacetic acid.
A method for preparing polysubstituted diethylenetriaminepentaacetic acid chelating agent of formula 1, 2:
- ##STR7## where the substituents (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) are selected from the group consisting of hydrogen, straight or branched chain, alkyl group with 1-15 carbon atoms, aryl group with 1-15 carbon atoms, and mixture thereof, wherein X is hydrogen, alkyl group of 1-15 carbon atoms, alkyl-aryl group of 1-15 carbons atoms, nitro, methoxy or hydroxy and wherein N=1-5, the method comprising the sequential steps of:
- (a) reacting an amino protected alpha amino acid of the following formula 5:
- ##STR8## where, in the protecting group, R.sub.8 is tertiary butyl (BOC), benzyl (CBZ), or 9-fluorenylmethyl (Fmoc) and R.sub.9 is selected from said (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) with an alpha amino ketone of formula 6:
- ##STR9## where R.sub.10 is selected from said (R.sub.1 -R.sub.4) and (R'.sub.1 -R'.sub.4) groups to produce the resulting keto amide;
- (b) then converting said keto amide to an oxime ether amide by reaction with methoxylamine;
- (c) then deprotecting said amide, prior to reduction, by a reducing agent to produce a diethylenetriamine subsituted with the selected substitutents;
- and
- (d) then converting said diethylene triamine substituted with selected substituents to polysubstituted diethylenetriaminepentaacetic acid of formula 1 or 2 an alkylation reaction with haloacetic acid.
Dependencies are inferred from the claim text.