Amphipatic polycarboxylic chelates and complexes with...

Details Amphipatic polycarboxylic chelates and complexes with... Amphipatic polycarboxylic chelates and complexes with...

2001-12-14

2003-11-25

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C564S123000, C564S153000, C564S152000, C564S161000, C564S159000, C562S561000, C562S565000, C424S009323

Reexamination Certificate

active

06652834

ABSTRACT:

FIELD OF THE INVENTION
The present invention addresses novel polycarboxylic ligand molecules and chelated complexes of said ligands with metals; the metals are for instance transition metals, e.g. paramagnetic metals for generating responses in the field of magnetic resonance imaging (MRI)
The present polycarboxylic ligands exhibit outstanding tensioactive properties which make them particularly useful in the form of paramagnetic chelates for making formulations and compositions useful as MRI contrast media of controllable and long lasting activity in the blood pool.
BACKGROUND ART
U.S. Pat. No. 5,466,438 (WO 92/231017) discloses compounds of formulae
in which formulae I-III:
R
1
is independently a substituted or unsubstituted C
7-30
straight chain or cyclic compound;
R
2
is independently a substituted or unsubstituted C
1
-C
30
straight chain or cyclic compound which may be internally interrupted by O, NH, NR
3
or S, where R
3
is a C
1
-C
3
alkyl;
n is 0-1 in formula I and 1-20 in formula III;
m is 1-2;
B is a substituted or unsubstituted C
1
-C
30
straight chain or cyclic compound which may be internally interrupted by O, NH, NR
3
or S.
In formula IV:
R
1
, R
2
are independently H or a substituted or unsubstituted C
7
-C
30
straight chain or cyclic compound;
R
3
, R
4
are independently H or a substituted or unsubstituted C
1
-C
30
straight chain or cyclic compound which may be internally interrupted by O, NH, NR
5
or S, where R
5
is a C
1
-C
3
alkyl;
and in formula V:
R
1
is independently a substituted or unsubstituted C
7
-C
30
straight chain or cyclic compound
R
2
is independently a substituted or unsubstituted C
1
-C
30
straight chain or cyclic compound which may be internally interrupted by O, NH, NR
4
or S, where R
4
is a C
1
-C
3
alkyl;
R
3
is independently a substituted or unsubstituted C
1
-C
30
straight chain or cyclic compound which may be internally interrupted by O, NH, NR
4
or S, where R
4
is a C
1
-C
3
alkyl and
m is 0-12.
The reference also discloses contrast agents obtained with the compounds of the above formulae (I-V), the latter further comprising lipids; the lipids are in the form of emulsions, liposomes or micelles.
U.S. Pat. No. 5,312,617 dicloses a method of imaging comprising administering to patients a contrast agent comprising a complex of a paramagnetic metal and a ligand selected from formulae IV and V disclosed in the foregoing U.S. Pat. No. 5,466,438.
Liposomes incorporating the above chelates are also disclosed as well as the possibility of having the compounds in the form of emulsions or micelles.
The micelles can be prepared by a variety of conventional liposome preparatory techniques; suitable lipids include, for example, monomyristoyl-phosphatidyl-choline, monopalmitoyl-phosphatidylcholine, dibutyroyl-phosphatidylcholine and the like, linoleic acid, oleic acid, palmitic acid, and the like.
Lipid emulsions can be prepared by conventional techniques, for instance a typical method is as follows:
1. In a suitable flask, the lipids are dissolved in ethanol or chloroform or any other suitable organic solvent.
2. The solvent is evaporated leaving a thin layer of lipid at the bottom of the flask.
3. The lipids are resuspended in an aqueous medium, such as phosphate buffered saline, this producing an emulsion
4. Sonication or microfluidization can then be applied to improve homogeneity.
5. The contrast agents can be added to the lipids during preparation of the emulsion, or they may be added to the emulsion afterwards.
6. Useful additives include, for example, soybean lecithin, glucose, Pluronic F-68 and D,L-&agr;-tocopherol; these additives are particularly useful where injectable intravenous formulations are desired.
The foregoing contrast agents may further comprise suspension stabilizers such as polyethyleneglycol, lactose, mannitol, sorbitol, ethyl alcohol, glycerin, lecithin, polyoxyethylene sorbitan monoleate, sorbitan monoleate and albumin. Various sugars and other polymers may also be added, such as polyethylene glycol, polyvinylpyrrolidone, polypropylene glycol and polyoxyethylene.
The contrast agents of this reference have high T
1
and T
2
relaxivity, especially when lipids are also present. Because of the high relaxivity, these contrast media are particularly useful for imaging the blood pool.
SUMMARY OF THE INVENTION
Despite the merit of the paramagnetic polycarboxylic chelates of the prior art as contrast agents for MRI, there was a need for a new range of chelating compounds of further improved properties designed to provide blood-pool contrast agents of outstanding long life in the circulation. In view of their structure including strongly hydrophobic and hydrophilic moieties, the compounds of the present invention achieve a significant step in the right direction.
The novel compounds of the present invention, either racemic or enantiomeric, have the following formulae (†) and (IV)
in which n and m are 1 or 0 but not simultaneously 1, and
when n=m=0, R′ is H, and R* is a C
12-25
linear or ramified, saturated or unsaturated, hydrocarbon radical;
when n=1 and m=0, R* is H or a C
1-3
alkyl or alkylene substituent; and R′ is selected from —NHR
3
, —NR
4
R
5
and —OR
6
where the R
3
to R
6
are independently C
1-25
linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by —CO— and/or —O— and optionally terminated by —NR
7
R
8
in which R
7
and R
8
are independently H or C
12-25
hydrocarbon radicals;
when n=0 and m=1, R* is H or a C
1-3
alkyl or alkylene substituent; and R′ is selected from R
9
and —CH
2
—O—CO—R
9
in which R
9
is a C
10-30
linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by —NH—, —NR
10
—, —CO— or —O—, R
10
being a lower aliphatic hydrocarbon; and
R
12
is H or a C
12-30
hydrocarbon radical optionally interrupted by —NH—, —NR
10
—, —CO— or —O— and optionally terminated by a cholesteryl residue, and the R
13
are —OH; or one or two R
13
are a —NH—R
14
group in which R
14
is a C
2-30
linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by —NH—, —NR
10
—, —CO—, —O—, and/or —OPO(OH)O—, the remaining R
13
being —OH.
The compounds of formulae (†) and (IV) can be used as chelates of paramagnetic metals, preferably Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III) and Er(III) in the preparation of MRI contrast formulations and compositions of outstanding long life in the blood which makes them ideal agents for investigating the circulation in appended organs.
DETAILED DESCRIPTION OF THE INVENTION
Preferred are the compounds encompassed by formula (†), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is an alkylene group, and the other variable groups are the meanings defined above.
Equally preferred are the compounds, encompassed by formula (†), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is H or a C
1-3
alkyl; and R′ is selected from —NHR
3,
or —NR
4
R
5
, where the R
3
to R
5
groups are independently C
12-25
linear or ramified, saturated or unsaturated, hydrocarbon radicals, optionally interrupted by —CO— and/or —O— and optionally terminated by —NR
7
R
8
in which R
7
and R
8
are independently H or C
12-25
hydrocarbon radicals with the same meaning just above defined.
Equally preferred are the compounds encompassed by formula (†), in which n and m are 1 or 0 but not simultaneously 1, and when n=0 and m=1, R* is an alkylene group, and the other variable groups are the meaning defined above.
Equally preferred are the compounds encompassed by formula (†), in which n and m are 1 or 0 but not simultaneously 1, and when n=1 and m=0, R* is H or a C
1-3
alkyl; and R′ is selected from R
9
and —CH
2
—O—CO—R
9
in which R
9
is a C
12-25
linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted

Affiliated with

Also associated with

Rating

Amphipatic polycarboxylic chelates and complexes with... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Amphipatic polycarboxylic chelates and complexes with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amphipatic polycarboxylic chelates and complexes with... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3168803