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US5554748A
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Adducts of macrocyclic chelants
Assignee: Amersham Health Salutar Inc
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Filing: 1993-12-30
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Granted: 1996-09-10
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Expires: 2013-12-30
Abstract
Abstract There are provided polychelants and their metal chelates which are useful in diagnostic imaging and in radiotherapy and which comprise a plurality of macrocyclic chelant moieties, e.g. DOTA residues, conjugated to a polyamine backbone molecule, e.g. polylysine. To produce a site-specific polychelate, one or more of the macrocyclic chelant carrying backbone molecules may be conjugated to a site-directed macromolecule, e.g. a protein. For example, adducts of a macrocyclic chelant can be formed by the process of (a) dispersing a carboxylic macrocyclic chelant in a polar, anhydrous solvent, (b) adding a base with a pKa sufficient to remove all carboxyl protons to create an amine salt of the chelant soluble in the solvent, (c) chilling the reaction mixture to between about 5 DEG C. and 55 DEG C. above the freezing point of the solvent, and (d) adding substantial equimolar amount of chilled alkylhaloformate under anhydrous conditions so as to form a slurry containing the mixture carboxycarbonic anhydride of the chelant.
Inventors
- 👤 Paul F. Sieving
- 👤 Alan D. Watson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 02:51
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/06; A61K49/08; A61K49/10; A61K49/14; A61K49/143; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/547; A61K47/62; A61K47/64; A61K47/645; A61K49/085; A61K49/101; A61K49/106; A61K49/12; A61K49/126; A61K49/128; A61K49/146; A61K51/00; A61K51/02; A61K51/04; A61K51/06; A61K51/065; C; C08; C08G; C08G69/00; C08G69/48
Claims Analysis
Total Claims: 6
Claim 1
Independent Claim
143 words
A mixed carboxycarbonic anhydride adduct of a macrocyclic chelant selected from the group consisting of the residues of 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (OTTA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N(2-aminophenethyl)amide formed by a process comprising the following steps: (a) dispersing a carboxylic macrocyclic chelant in a polar, anhydrous solvent; (b) adding a base with a pKa sufficient to remove all carboxyl protons to create an amine salt of said chelant soluble in said solvent; (c) chilling the reaction mixture to between about 5° C. and 55° C. above the freezing point of the solvent; and (d) adding a substantially equimolar amount of chilled alkylhaloformate under anhydrous conditions while approximately maintaining the temperature of step (c) for a period of time sufficient for substantially complete reaction to form a slurry containing the mixed carboxycarbonic anhydride of the chelant.
Claim 2
Dependent Claim
143 words
A mixed carboxycarbonic anhydride adduct of a macrocyclic chelant selected from the group consisting of the residues of 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (OTTA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N(2-aminophenethyl)amide formed by a process comprising the following steps: (a) dispersing a carboxylic macrocyclic chelant in a polar, anhydrous solvent; (b) adding a base with a pKa sufficient to remove all carboxyl protons to create an amine salt of said chelant soluble in said solvent; (c) chilling the reaction mixture to between about 5° C. and 55° C. above the freezing point of the solvent; and (d) adding a substantially equimolar amount of chilled alkylhaloformate under anhydrous conditions while approximately maintaining the temperature of step (c) for a period of time sufficient for substantially complete reaction to form a slurry containing the mixed carboxycarbonic anhydride of the chelant.
Claim 3
Dependent Claim
17 words
An adduct according to claim 1 formed using an aprotic solvent as the solvent of step (a).
Claim 4
Dependent Claim
19 words
An adduct according to claim 1 formed using dry acetonitrile, dimethylacetamide or dimethylformamide as the solvent of step (a).
Claim 5
Dependent Claim
18 words
An adduct according to claim 1 formed using tetramethylguanidine, 1,5-diazabicyclo[4.3.0]non-5-ene, or 1,8-diazabicyclo[5.4.0]undec-7-ene as the base of step (b).
Claim 6
Dependent Claim
15 words
An adduct according to claim 1 formed using isobutylchloroformate as the alkylhaloformate of step (d).
References Cited (Backward Citations)
US4647447A
Cited
US4741900A
Cited
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