US2006155120A1PendingUtilityA1

Optically pure and enriched isomers of chelating ligands and contrast agents

Individually held — no corporate assignee on recordPriority: May 23, 2003Filed: May 20, 2004Published: Jul 13, 2006

Est. expiryMay 23, 2023(expired)· nominal 20-yr term from priority

Inventors:John Amedio Peter Caravan Vincent Jacques Kevin Zhou Stuart B. Levy Shirley Kalogeropoulos Matthew Greenfield

A61K 49/085A61K 49/106A61K 49/14A61K 49/10C07D 257/02

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Claims

Abstract

Organic chelating ligands, organic chelating ligand precursors, and metal chelates are disclosed. Methods for synthesizing the same are also described, including methods for preparing optically-enriched or optically-pure compositions of the same.

Claims

exact text as granted — not AI-modified

1 . A composition comprising an organic chelating ligand having a formula selected from the group consisting of:

where n can range from 1 to 4, and wherein said composition has an enantiomeric excess of greater than 50% of an (R) isomer at the 2 position of said chelating ligand.

2 . A composition comprising an organic chelating ligand having a formula selected from the group consisting of:

where n can range from 1 to 4, and wherein said composition has an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of said chelating ligand.

3 . A composition comprising an organic chelating ligand according to claim 1 , wherein said composition has an enantiomeric excess of greater than 85% of said (R) isomer at the 2 position.

4 . A composition comprising an organic chelating ligand according to claim 2 , wherein said composition has an enantiomeric excess of greater than 85% of said (S) isomer at the 2 position.

5 . The composition of claim 1 , wherein said composition has an enantiomeric excess of about 97% or more of said (R) isomer at the 2 position.

6 . The composition of claim 2 , wherein said composition has an enantiomeric excess of about 97% or more of said (S) isomer at the 2 position.

7 . A composition comprising a metal chelate having a structure:

said composition having an enantiomeric excess of greater than 50% of an (R) isomer of said chelate at the 2 position, wherein n can range from 1 to 4, and wherein M can be selected from the group consisting of: Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Ho(III), Er(III), Eu(III), Tb(II), Tb(III), Ce(III), Pr(III), Yb(III), Tm(III), Nd(III), and Tb(IV).

8 . A composition comprising a metal chelate having a structure:

said composition having an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of said chelate, wherein n can range from 1 to 4, and wherein M can be selected from the group consisting of: Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Ho(III), Er(III), Eu(III), Tb(II), Tb(III), Ce(III), Pr(III), Yb(III), Tm(III), Nd(III), and Tb(IV).

9 . The composition of claim 7 , wherein said composition has an enantiomeric excess of greater than 85% of the (R) isomer at the 2 position.

10 . The composition of claim 8 , wherein said composition has an enantiomeric excess of greater than 85% of the (S) isomer at the 2 position.

11 . The composition of claim 7 , wherein said composition has an enantiomeric excess of about 97% or more of the (R) isomer at the 2 position.

12 . The composition of claim 8 , wherein said composition has an enantiomeric excess of about 97% or more of the (S) isomer at the 2 position.

13 . An MRI contrast agent comprising the composition of any one of claims 7 - 12 .

14 . An MRI contrast agent comprising the composition of any one of claims 7 - 12 , wherein said contrast agent comprises one or more TBMs.

15 . A composition comprising an organic chelating ligand precursor having a structure selected from the group consisting of:

where n can range from 1 to 4, and wherein said composition has an enantiomeric excess of greater than 50% of an (R) isomer at the 2 position of said precursor.

16 . A composition comprising an organic chelating ligand precursor having a structure selected from the group consisting of:

where n can range from 1 to 4, and wherein said composition has an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of said precursor.

17 . A method for synthesizing an organic chelating ligand precursor comprising:
a) reacting a starting material compound having the structure: said starting material compound having an L-stereochemistry at the Cat carbon, where n can range from 1 to 4, to form a lactone; b) opening said lactone to yield a hydroxy-dioic acid ester; c) activating said hydroxy group of said hydroxy-dioic acid ester; and d) reacting said activated hydroxy group with an amine compound under conditions capable of alkylating said amine compound at one or more amine moieties to form an organic chelating ligand precursor, said organic chelating ligand precursor comprising one or more amine moieties.

18 . The method according to claim 17 , further comprising converting said organic chelating ligand precursor to an organic chelating ligand.

19 . The method according to claim 18 , further comprising chelating a metal ion to said organic chelating ligand to form a metal chelate.

20 . The method according to claims 17 , 18 , or 19 , wherein said method yields an enantiomeric excess of more than 50% of the (R)-isomer at the 2 position of said organic chelating ligand precursor, said organic chelating ligand, or said metal chelate, respectively.

21 . A method for synthesizing an organic chelating ligand precursor comprising:
a) reacting a starting material compound having the structure: said starting material compound having a D stereochemistry at the Cα carbon, where n can range from 1 to 4, to form a lactone; b) opening said lactone to yield a hydroxy-dioic acid ester; c) activating said hydroxy group of said hydroxy-dioic acid ester; and d) reacting said activated hydroxy group with an amine compound under conditions capable of alkylating said amine compound at one or more amine moieties to form an organic chelating ligand precursor, said organic chelating ligand precursor comprising one or more amine moieties.

22 . The method according to claim 21 , further comprising converting said organic chelating ligand precursor to an organic chelating ligand.

23 . The method according to claim 18 , further comprising chelating a metal ion to said organic chelating ligand to form a metal chelate.

24 . The method according to claim 21 , 22 , or 23 , wherein said method yields an enantiomeric excess of more than 50% of the (S)-isomer at the 2 position of said organic chelating ligand precursor, said organic chelating ligand, or said metal chelate, respectively.

25 . The method according to claim 13 , wherein said amine compound is selected from the group consisting of cyclen, ethylenediamine, and diethylenetriamine.

26 . The method according to claims 18 or 22 , wherein said conversion comprises providing a carboxylic acid ester having a leaving group located at the α-carbon, and reacting said carboxylic acid ester with said organic chelating ligand precursor under conditions in which one or more of said one or more amine moieties of said precursor are alkylated to result in said organic chelating ligand.

27 . A method for converting an organic chelating ligand comprising one or more carboxylic acid esters to a metal chelate comprising:
a) providing said organic chelating ligand; b) deprotecting one or more of said one or more carboxylic acid esters of said organic chelating ligand to yield one or more carboxylic acid moieties; and c) chelating a metal ion to result in said metal chelate; wherein said deprotection and said chelating steps are performed without purification of intermediates.

28 . A method for converting an organic chelating ligand precursor to a metal chelate comprising:
a) providing said organic chelating ligand precursor, said organic chelating ligand precursor comprising one or more amines; b) providing a carboxylic acid ester having a leaving group located at the α-carbon; c) reacting said carboxylic acid ester with said precursor under conditions in which one or more of said one or more amines of said precursor are alkylated to form an organic chelating ligand; and d) chelating a metal ion to said organic chelating ligand to result in a metal chelate; wherein said reacting and said chelating steps are performed without purification of intermediates.

29 . A composition comprising an activated ester of an organic chelating ligand, said activated ester having a structure selected from the group consisting of:

wherein n can range from 1 to 4, wherein X is selected from the group consisting of:

and wherein said composition has an enantiomeric excess of greater than 50% of an (R) isomer at the 2 position of said chelating ligand.

30 . A composition comprising an activated ester of an organic chelating ligand, said activated ester having a structure selected from the group consisting of:

wherein n can range from 1 to 4, wherein X is selected from the group consisting of:

and wherein said composition has an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of said chelating ligand.

31 . A composition comprising an activated ester of a metal chelate having the following general formula:

where n can range from 1 to 4 and X can be selected from the group consisting of:

and wherein said composition has an enantiomeric excess of greater than 50% of an (R) isomer at the 2 position of said activated ester metal chelate.

32 . A composition comprising an activated ester of a metal chelate having the following general formula:

where n can range from 1 to 4 and X can be selected from the group consisting of:

and wherein said composition has an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of said activated ester metal chelate.

33 . A composition comprising a compound having the structure of Compound 26, 28, or 30, wherein said composition has an enantiomeric excess of greater than 50% of an (R) isomer at the 2 position of each conjugated chelating ligand or metal chelate.

34 . A composition comprising a compound having the structure of Compound 26, 28, or 30, wherein said composition has an enantiomeric excess of greater than 50% of an (S) isomer at the 2 position of each conjugated chelating ligand or metal chelate.

35 . The composition of claim 33 , wherein said composition comprises Compound 30 and wherein said composition has an enantiomeric excess of about 97% or more of the (R) isomer at the 2 position of each of the four conjugated metal chelates.

36 . A pharmaceutically acceptable salt of the composition of claims 7 , 8 , 31 or 32 .

37 . The pharmaceutically acceptable salt of claim 36 , wherein the salt is sodium.

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