# US 5,348,954 A · Heterocyclic chelating agents

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- Number: US 5,348,954 A
- Document ID: US5348954A
- Status: Granted
- Kind: A
- Application number: 07/690,975
- Filed: 1991-07-24
- Granted: 1994-09-20
- Earliest claimed: 1989-01-13
- Assignees: Nycomed Imaging AS
- Inventors: Torsten Almen; Arne Berg; Harald Dugstad; Jo Klaveness; Klaus D. Krautwurst; Pal Rongved
- Web page: https://patentgrep.com/patent/US5348954A

## CPC

- C07D 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/547: {Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent}
- A61K 49/06: Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K 51/0478: {complexes from non-cyclic ligands, e.g. EDTA, MAG3}
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 265/30: not condensed with other rings
- C07D 279/12: not condensed with other rings
- C07F 3/003: {without C-Metal linkages}
- C07F 5/003: {without C-Metal linkages}
- C07F 9/94: Bismuth compounds
- C07F 13/005: {Compounds without a metal-carbon linkage}
- A61K 2121/00: Preparations for use in therapy
- A61K 2123/00: Preparations for testing in vivo
- Y10T 436/24: Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Heterocylic chelating agents and salts thereof of formula I: ##STR1## wherein X represents a bond, O or S, or a group CHR.sup.1 or NR.sup.3 ; R.sup.1 represents H, a group OR.sup.3 or NR.sup.3 R.sup.3, or an alkyl or alkoxyalkyl group optionally substituted by a hydroxyl group or by a group NR.sup.3 R.sup.3 or CON.sup.3 R.sup.3 ; each R.sup.2 represents H, or an alkyl or alkoxy group optionally substituted by a hydroxyl or alkoxy group; each R.sup.3 represents H, an optionally hydroxylated alkyl group or a group CH.sub.2 Y; Y represents a group COZ, CON(OH)R.sup.4, POZ.sub.2 or SO.sub.2 Z; Z represents a group OR.sup.4, NR.sup.4 R.sup.4 or ##STR2## where each R.sup.11 is H, a hydroxyl group or an optionally hydroxylated alkyl group, s is 0, 1 or 2, and W is CHR.sup.11, NR.sup.11 or an oxygen atom; and each R.sup.4 represents H, or an optionally mono- or poly-hydroxylated alkyl, alkoxyalkyl or polyalkoxyalkyl group; with the provisos that where s is 0 then W is CHR.sup.11 and that where X represents a bond or CHR.sup.1, at least one group R.sup.1 or R.sup.2 represents other than H or an unsubstituted alkyl group. A process for preparing these agents and methods of heavy metal detoxification using these agents are also described.

## Claims

### Claim 1

A compound of formula I ##STR21## wherein X represents a bond, an oxygen or sulphur atom or a group of formula CHR.sup.1 or NR.sup.3 ;
each R.sup.1 which may be same or different represents a hydrogen atom, a group of formula OR.sup.3 or NR.sup.3 R.sup.3 or a C.sub.1-8 alkyl or (C.sub.1-8 alkoxy)-C.sub.1-8 alkyl group optionally substituted by a hydroxyl group or by a group of formula NR.sup.3 R.sup.3 or CONR.sup.3 R.sup.3 ;
each R.sup.2 which may be the same or different represents a hydrogen atom or a C.sub.1-8 alkyl or C.sub.1-8 alkoxy group optionally mono- or poly-substituted by hydroxyl or C.sub.1-8 alkoxy groups;
each R.sup.3 which may be the same or different represents a hydrogen atom, an optionally mono-or poly-hydroxylated C.sub.1-8 alkyl group or a group of formula CH.sub.2 Y;
Y represents a group of formula COZ, CON(OH)R.sup.4 POZ.sub.2 or SO.sub.2 Z;
Z represents a group of formula OR.sup.4, NR.sup.4 R.sup.4, or ##STR22## where each R.sup.11 which may the same or different is a hydrogen atom, a hydroxyl group or an optionally hydroxylated C.sub.1-8 alkyl group,
s is 0, 1 or 2, and
W is a group CHR.sup.11, NR.sup.11 or an oxygen atom; and
each R.sup.4 which may bet he same or different represents a hydrogen atom or an optionally mono- or poly-hydroxylated C.sub.1-8 alkyl, (C.sub.1-8)alkoxy)-C.sub.1-8 alkyl or poly-(C.sub.1-8 alkoxy)-C.sub.1-8 alkyl group; with the provisos that where is O then in the resultant 5 membered heterocyclic ring W is a CHR.sup.11 group, and that where X represents a bond or a group CHR.sup.1 at least one group R.sup.1 or R.sup.2 represents other than a hydrogen atom or an unsubstituted C.sub.1-8 -alkyl group, or a salt thereof.

### Claim 2 (depends on 1)

A compound of formula I as claimed in claim 1 wherein Z represents a group of formula OR.sup.4 or NR.sup.4.sub.2 and each R.sup.4 which may be the same or different represents a hydrogen atom or an optionally hydroxylated alkyl group, or a salt thereof.

### Claim 3 (depends on 1)

A compound of formula I as claimed in claim 1 wherein at least one group Z is of formula ##STR23## or a salt thereof.

### Claim 4 (depends on 1)

A compound formula I as claimed in claim 1 wherein R.sup.1 represents a hydrogen atom, a hydroxyl group or a hydroxylated alkyl group, R.sup.2 represents a hydrogen atom or a hydroxylated alkyl group, R.sup.3 represents a hydrogen atom or a group of formula CH.sub.2 Y, X represents a bond, an oxygen atom, an optionally hydroxylated methylene group or a group NR.sup.3, Y represents a group of formula COZ and Z represents a hydroxyl group or a group NHR.sup.4, where R.sup.4, represents a hydrogen atom or an optionally hydroxylated alkyl group, or a salt thereof.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 having a formula: ##STR24## where R.sup.5 represents CH.sub.2 COOH, R.sup.6 represents CH.sub.2 COOH, CH.sub.2 CON(CH.sub.3)CH.sub.2 CHOHCH.sub.2, OH, or CH.sub.2 CONHR.sup.7 and R.sup.7 represents a group ##STR25## where W represents an oxygen atom or a group CH.sub.2 or CHOH, s is 0 or 1 and R.sup.11 is hydrogen, or where s is 1 and W is oxygen, each R.sup.11 may also represent a C.sub.1-4 Hydroxylalkyl group,
or a slat thereof.

### Claim 6 (depends on 1)

A compound as claimed in claim 1 wherein each Y group is a carboxyl group or a salt or amide thereof.

### Claim 7 (depends on 1)

A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:
a) reacting a compound of formula II ##STR26## wherein X, R.sup.1 and R.sup.2 are as defined in claim 1 and R.sup.10 represents a hydrogen atom or a group CH.sub.2 Y where Y is as defined in claim 1, with the proviso that at least one hydrogen is nitrogen-attached, with a compound of formula III
L--CH.sub.2 --Y
where L is a nucleophilic leaving group; and
b) converting a compound of formula I into a salt thereof.

### Claim 8 (depends on 1)

A method of heavy metal detoxification practiced on the human or non-human animal body, said method comprising administering to said body a cheleting agent as claimed in claim 1 in the form of a salt with a physiologically a acceptable counterion.