Complex compounds for diagnosis of vascular diseases

Details Complex compounds for diagnosis of vascular diseases Complex compounds for diagnosis of vascular diseases

1997-07-17

2002-01-29

Jones, Dameron (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C424S009100, C530S300000, C534S014000

Reexamination Certificate

active

06342201

ABSTRACT:

The invention concerns new complex compounds for the diagnosis of vascular diseases, processes for their production as well as diagnostic agents containing these compounds.
Arteriosclerosis is a chronic, progressive disease of the blood vessels, which previously could only be clinically diagnosed at an advanced stage. Vessel change caused through arteriosclerosis are today conventionally determined through arteriography. Here a contrasting agent is applied via a catheter into the vessel of interest and stenosis of the regions of the vessel is detected through X-rays. A disadvantage of this procedure is that only partial regions of the vascular system can be observed. Because arteriography is an invasive procedure, complications can arise upon its application like for example pain, perforation of an artery, arrhythmia, heart attack or stroke, and under unfortunate circumstances even death of the patient.
Furthermore procedures based on the application of ultrasound as well as MR-tomography are also used for the diagnosis of arteriosclerosis.
All the presently used procedures have the great disadvantage in that the arteriosclerotic vessel change is detected through the observation of contracted blood flow or significant changes in the artery wall and therefore detected only at an advanced stage of atherogenesis.
Early detection of arteriosclerosis would be of great significance for example for the control of therapeutical effect of diet, calcium antagonists, lipid- and high blood pressure reducers, the control of restenosis after angioplasty and the diagnosis of coronary heart diseases as well as the detection of thrombotic vessel deposition.
Non-invasive techniques for the diagnosis of arteriosclerosis have been described. Radioactive labeled antibodies or also labeled low density lipoproteins (LDL) are introduced which bind on the arteriosclerotic wall regions (Lees et al. 1993, J. Nucl. Med. 24, 154-156; Kaliman et al. 1985, Circulation, 72, 300; Virgolini et al. 1991, Eur. J. Nucl. Med., 18, 944-947). These methods however have decisive disadvantages, for example the antigenic effect of the antibodies on the organism and the long duration (several days) necessary for the isolation, purification and labelling of LDL from the patient's blood. These large molecules also reveal a long half life in the blood which together with a high background radiation over the whole body making the localization of arteriosclerotic lesions difficult if not impossible.
Shih et al. (1990, Proc. Natl. Acad. Sci., 87, 1436-1440) have synthesized partial sequences of the LDL-protein portions (apo-B-100), which although still bind to arteriosclerotic plaque, reveal an overall shorter half-life in blood and a better signal-noise ratio. Due to their low affinity to plague and/or the low density of binding sites for this apo-B-peptide in the plaque, a successful in vivo diagnosis of arteriosclerosis could not be established.
The object of the invention is to provide new compounds and agents which are suitable for non-invasive diagnostic procedures, especially for the diagnosis of early, but not yet stenotic, vascular diseases.
Endothelines are physiologically active peptides, which perform hormonal as well as neuroregulatory functions in organisms (MacCumber et al. 1989, Proc. Natl. Acad. Sci., 7285-7289; Yanagisawa et al. 1989, Trends Pharmacol. Sci., 10, 374-378; LeMonier die Gouville et al., 1989, Life Scd., 45, 1499-1513; Yanagisawa et al., 1988, Nature, 332, 411-415). Up to now four different isotypes have been identified in humans (Inoue et al., 1989, Proc. Natl. Acad. Sci., 86, 2863-2867). Endotheline 1 is a polypeptide having the following sequence of 21 amino acids:
Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp (Yanagisawa et al., 1988, Nature, 332, 411-415).
From vascular endothelium an inactive precursor of the endotheline, the Big Endotheline, is formed. After a heptadecapeptide is splitted off through the Endotheline-Converting-Enzyme (ECE) endotheline originates, which binds on specific receptors of smooth vascular musculature. There it leads to a Ca
++
-facilitated contraction of the smooth muscle cells (Yanagisawa et al., Nature, 332, 411-415; Takuwa et al. 1991, Contrib. Nephrol., 90, 99-104).
One of the early irreversible changes arising from atherogenesis is, among others, the proliferation of smooth muscle cells of the vessel wall brought about by the growth factor (e-g. PDGF) (Desmoulière and Gabbiani 1992, Cerebrovasc. Dis., 2, 63-71). Through in vitro incubation of human atheromatotic coronary arteries with
125
I-endotheline 1, it could be shown that an increased binding of
125
I-endotheline 1 in the region of Tunica media as well as Vasa vasora region appears (Dashwood et al., 1991, J. Cardiovasc. Pharmacol., 17, 458-462). Through the application of
125
I-endotheline 1 in rabbits, whose abdominal aorta were previously de-endothelisized via a balloon catheter, an increased uptake of
125
I-endotheline 1 in the de-endothelisized regions of the aorta could be shown, which indicates a greater density of binding sites for endotheline 1 in the damaged vessel regions (Kurata et al. 1992, J. Nucl. Med., 33, 845). From this investigation it can be concluded that the proliferated smooth muscle cells also further express endotheline receptors.
Endotheline 1 has a strong vasoconstrictory effect on smooth vascular musculature (A. M. Doherty, 1992, Medical Chemistry, 35, 1493-1508). Therefore, it can only be applied i.v. relative low concentrations into the organism. Higher concentrations can only be applied with partial sequences of endothelines, endotheline derivatives, endotheline analogs or endotheline antagonists, which although bind to the endotheline receptor, but do not lead to such a marked contraction of the smooth muscle cells.
Since endothelines are eliminated very quickly through the kidneys, disturbing background radiation caused by the uptake of endothelines by other organs or tissues is extremely low.
The German patent application P 43 01 871.8 already describes compounds containing endothelines, partial sequences of endothelines, endotheline derivatives, endotheline antagonists or endotheline analogs, which bind to endotheline receptors.
During the search for additional compounds the substance was found which has the general formula I
(K)
z
-(L)
y
-(A
1
)
aa
-(A
2
)
bb
-(A
3
)
cc
-(A
4
)
dd
-(A
5
)
ee
-(A
6
)
ff
-(A
7
)
gg
-(A
8
)
hh
-(A
9
)
jj
-(A
10
)
kk
-(A
11
)
ll
-Ile-Ile-Trp  (I)
in which
aa, bb, cc, dd, ee, ff, gg, hh, jj, kk and ll stand for, independent from one another, the integers 0, 1 or 2,
y and z represent independent from one another the integers 0 or 1,
K depicts a chelate-forming residual having the general formula IIA or IIB
in which
T is a hydrogen atom or a bond at a metal atom or a suitable sulfur protecting group like an alkali metal ion, a C
1-6
-acyl residual, a benzoyl residual, a hydroxyacetyl residual, an acetamidomethyl residual, a p-methoxybenzyl residual, an ethoxyethyl residual, a benzyl residual, an ortho- or para-hydroxybenzyl residual, an ortho- or para-acetoxybenzyl residual, a p-nitrobenzyl residual, a 4-picolyl residual, a 2-picolyl-N-oxid residual, a 9-anthrylmethyl residual, a 9-fluorenyl residual, a ferrocenylmethyl residual, a diphenylmethyl residual, a bis(4-methoxyphenyl)methyl residual, a dibenzosuberyl residual, a triphenylmethyl residual, a diphenyl-4-pyridylmethyl residual, a phenyl residual, a 2,4-dinitrophenyl residual, a tert-butyl residual, a 1-adamantyl residual, a methoxymethyl residual, a isobutoxymethyl residual, a 2-tetrahydropyranyl residual, a benzylthiomethyl residual, a phenylthiomethyl residual, a trimethylacetamidomethyl residual, a benzamidomethyl residual, an acetylmethyl residual, a carboxymethyl residual, a cyanomethyl residual, a 2-nitro-1-phenylethyl residual, a 2-(4′-pyrdyl)ethyl residual, 2-cyanoethyl residual, a 2,2-bis(carboethoxy)ethyl residual, a 1-m-nitrophenyl-2-benzoylethyl residual, a 2-phenylsulfonylethyl residual, a 1-(4-me

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