1,4,7,10-Tetraazacyclododecane butyltriols, processes for...

Details 1,4,7,10-Tetraazacyclododecane butyltriols, processes for... 1,4,7,10-Tetraazacyclododecane butyltriols, processes for...

1999-07-23

2002-06-04

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C424S009400, C424S009500, C424S001650, C534S016000, C540S465000, C540S474000

Reexamination Certificate

active

06399043

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to 1,4,7,10-tetraazacyclodedecane butyltriols, their complexes and complex salts, agents containing these compounds, their use as diagnostic agents and therapeutic agents as well as processes for the production of these compounds and agents.
In European patent application 87730085.5 with the publication number 0 255 471 macrocyclic compounds of general formula I
are claimed, in which
Y is a nitrogen atom or phosphorus atom,
A
1
and A
2
are the same or different and each is a straight-chain or branched alkylene group with 2 to 6 carbon atoms,
U
1
, U
2
, U
3
, U
4
are the same or different and each is a direct bond or a straight-chain or branched alkylene group with 1 to 6 carbon atoms,
D
1
, D
2
, D
3
, D
4
are the same or different and each is an oxygen atom or sulfur atom, an alkylene group with 1 to 6 carbon atoms or a group N-R
7
with R
7
meaning a hydrogen atom, a straight-chain or branched alkylene chain with 1 to 4 carbon atoms, which on the end carries a COOR
1
group, and R
1
stands for a hydrogen atom or a metal ion equivalent.
D
5
has the meaning indicated for D
1
, D
2
, D
3
and D
4
as well as the group
 with R
5
meaning a hydrogen atom or a straight-chain or branched saturated or unsaturated C
1
-C
20
alkylene group, optionally substituted by hydroxy, mercapto, imino and/or amino group(s), optionally containing imino, phenylenoxy, phenylenimino, amide, ester group(s), oxygen atom(s), sulfur atom(s) and/or nitrogen atom(s), which on the end exhibits either a functional group or a macromolecule B bound by it,
s and t represent whole numbers from 0 to 5,
R
2
represents hydrogen, a straight or branched, saturated or unsaturated alkyl, acyl or acylalkyl group with 1 to 16 carbon atoms optionally substituted by one or more hydroxy or lower alkoxy groups,
—CH
2
—X—V with X meaning carbonyl, a straight-chain or branched-chain alkylene group with 0 to 10 carbon atoms, which optionally is substituted by one or more hydroxy or lower alkoxy groups or a straight-chain or branched-chain alkylene group interrupted by oxygen atoms with 2 to 23 hydrocarbon atoms,
 and R
3
and R
4
, independently
 independently of one another, represent hydrogen, a straight or branched alkyl group with 1 to 16 carbon atoms optionally substituted by one or more hydroxy or lower alkoxy groups or R
3
and R
4
together with the nitrogen atom represent a saturated five or six ring optionally containing another heteroatom and R
6
represents hydrogen or a saturated, unsaturated straight-chain or branched-chain or cyclic hydrocarbon radical with up to 16 carbon atoms or an aryl or aralkyl group,
 or
R
2
or R
3
represent a second macrocycle of formula I′—bound by an alkylene chain (K) containing 2 to 20 carbon atoms, which optionally carries carbonyl groups on the ends and optionally is interrupted by one or more oxygen atoms or R
1
carboxymethylimino groups or is substituted by one or more hydroxy, lower alkoxy or carboxy lower alkyl groups—
which can be of a different structure than the parent substance of the first, or
R
2
means B or CH
2
—COB,
provided that, if R
2
stands for B or CH
2
—COB, R
5
means a hydrogen atom, that at least two COOR
1
groups are present in the molecule and that two heteroatoms of the macrocycle are each connected by an alkylene group with at least two carbon atoms, and functional groups existing in the molecule optionally are conjugated with macromolecules and optionally free carboxyl groups are made into salts with organic or inorganic bases or amino acids and basic groups with inorganic or organic acids.
The substances and the solutions prepared from them meet the demands to be made of pharmaceutically usable chelates. They have a strong and adaptable effectiveness, by the selection of suitable metal atoms, on the respective principles of the diagnostic or therapeutic method (x ray, NMR, ultrasound, nuclear medicine).
SUMMARY OF THE INVENTION
Of the many compounds in EP-A-0 255 471, the 1,4,7,10-tetraazacyclodedecane butyltriols of general formula I
A
in which
R
1
means hydrogen or a metal ion equivalent independent of one another and
R
2
means a butyltriol radical
as well as their salts with organic or inorganic bases or amino acids, exhibit such outstanding properties that even in comparison with the structurally very closely related compound disclosed in EP-A 0 255 471 (Example 6), the use of these selected compounds guarantees a substantial advantage.
Compounds of general formula I
A
with R
1
meaning hydrogen are designated as complexing agents and with at least two of substituents R
1
meaning a metal ion equivalent are designated as metal complexes.
The element, which forms the central ion of the physiologically compatible complex salt, can, of course, also be radioactive for desired purpose of use of the diagnostic medium according to the invention.
If the medium according to the invention is intended for use in NMR diagnosis, the central ion of the complex salt has to be paramagnetic. This involves especially the bivalent and trivalent ions of the elements of the atomics numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, the chromium(III), manganese(II), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III) ion. Because of their very strong magnetic moment there are especially preferred the gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) or iron(III) ion.
For use of the media according to the invention in nuclear medicine the central ion has to be radioactive. For example, radioisotopes of the elements copper, cobalt, gallium. germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium and iridium are suitable.
If the medium according to the invention is intended for use in x-ray diagnosis, the central ion has to be derived from an element of higher atomic number to achieve a sufficient absorption of the x rays. It was found that for this purpose diagnostic media, which contain a physiologically compatible complex salt with central ions of elements of the atomic numbers between 21-29, 42, 44, 57-83, are suitable; they are, for example, the lanthanum(III) ion and the above-named ions of the lanthanide series.
Preferred radicals R
2
are 2,3,4-trihydroxybutyl- and the 1-hydroxymethyl-2,3-dihydroxypropyl radical.
If not all acidic hydrogen atoms are substituted by the central ion, one, several or all remaining hydrogen atom(s) can be replaced by cations of inorganic and/or organic bases or amino acids. Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and especially the sodium ion. Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine.
As proof for the above-named surprising and outstanding properties of the compounds according to the invention there are to be indicated the results of animal experimental studies to determine the acute intravenous (LD
50
) as well as neural compatibility (ED
50
) of two butyltriol compounds according to the invention, i.e., of compounds of general formula I
A
in comparison with the compound described in EP-A 0 255 471, which structurally is closest to the two butyltriol macrocycles:
1. Acute Toxicity Determination (LD
50
)
In an individual cage (Rhema/Hofheim company) the contrast medium was administered to mice (weight: 18-22 g) approximately at body temperature in a caudal vein at a rate of 2 ml/min. Also preferred are those of 10-[2-hydroxy-2,2-bis(hydroxymethyl)ethyl)]-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, and 10-[1,1,1-tris(hydroxymethyl)methyl]-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane.
The contrast media were administered to 3

Affiliated with

Also associated with

Rating

1,4,7,10-Tetraazacyclododecane butyltriols, processes for... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 1,4,7,10-Tetraazacyclododecane butyltriols, processes for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,4,7,10-Tetraazacyclododecane butyltriols, processes for... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2940738