Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Patent
1996-03-19
1998-03-24
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
424900, 514 60, 556 69, 556 70, A61K 4904
Patent
active
057309531
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel substituted triphenylbismuth derivatives and, if any, pharmaceutically acceptable salts thereof which have excellent radiographic contrasting ability, processes of producing them and pharmaceutical compositions for medical inspection containing them as an ingredient.
BACKGROUND ART
Radiography, especially X-ray radiography, has long been used widely as a medical technique for diagnosis and analysis of various diseases. However, not a few parts of the body such as the vasculature, the urinary tract, the gallbladder, the bile duct and the cerebrospinal cavity require a contrast medium for a higher resolution. In particular, angiography is almost indispensable to diagnosis of various angiopathies, mainly in the tissues of extremities and the brain, and medical need for angiography is increasing. As contrast media for angiography, 2,4,6-triiodobenzoic acid derivative type compounds represented by iopamidol, iohexol and ioxaglate are now in use. However, contrast media with a higher contrasting ability are required for diagnosis in an increasing number of cases. In addition, under the present the side effects of these media for injection, such as heat and pain at the time of injection due to their osmotic pressures higher than that of the blood, and nausea, vomiting and eruption, which are thought as peculiar to iodine compounds, are regarded as questionable.
As a method of improving contrasting ability, compounds having more iodine atoms introduced per molecule are conceivable, however, they seem to have many problems in practical use due to their chemical instability and difficulties in their production. On the other hand, some compounds containing atoms with a nucleus larger than that of an iodine atom, are expected to exhibit a higher contrasting ability commensurate with their radiation shielding power. However, the enhanced chemical instability accompanied by enlargement of atomic nuclei, difficulties in their production and the toxicity are seriously problematic in practical use of these compounds as a contrast medium.
DISCLOSURE OF INVENTION
As a result of extensive searches, the present inventors found that the tris(substituted phenyl)bismuth derivatives and their pharmaceutically acceptable salts of the present invention, which are different from any compound disclosed in the documents (a) to (c), are all chemically stable and biologically safe, and exhibit an excellent contrasting ability in X-ray radiography, that in particular, the water soluble tris(substituted phenyl)bismuth derivatives having a hydroxyl group at the .omega.-terminal of a substituent on a benzene ring and their pharmaceutically acceptable salts exhibit a high contrasting ability in X-ray radiography and that they can be used as an ingredient to provide a safe and useful contrast medium for X-ray radiography of the vasculature, the urinary tract, the gallbladder, the bile duct or the cerebrospinal cavity which can obviate the problematic side effects of conventional media attributable to iodine. On the basis of these discoveries, the present inventors have achieved the present invention.
The present invention provides tris(substituted phenyl)bismuth derivatives of the general formula (I) or, if any, pharmaceutically acceptable salts thereof: ##STR2## --SO.sub.2 -- or ##STR3## and each of R.sup.1 and R.sup.2 is, independently of each other, a hydrogen atom, a C.sub.1-4 alkyl group or A--Z (wherein A is an alkylene chain which has 2-6 carbon atoms in total and may have a branch having at least two carbon atoms, and Z is OR.sup.3 (wherein R.sup.3 is SiR.sup.4 R.sup.5 R.sup.6 (wherein each of R.sup.4, R.sup.5 and R.sup.6 is, independently of one another, a C.sub.1-4 alkyl group or a phenyl group), a hydrogen atom or a C.sub.1-4 alkyl group) or NR.sup.7 R.sup.8 (wherein each of R.sup.7 and R.sup.8 is, independently of each other, a hydrogen atom or a C.sub.1-4 alkyl group)) provided that the case where R.sup.1 and R.sup.2 are both hydrogen atoms is excepted!, ##STR4## (where
REFERENCES:
patent: 5536424 (1996-07-01), Delfort et al.
Horner et al., Phosphorus Sulfur, 14(2):253-260, (1983).
Gielen et al. Organic Mass Spectrometry 19(12):647-649, (1984).
Polymer, vol. 33, No. 8, pp. 1724-1730, Jan. 1, 1992, F. Ignatious, et al., "Organobismuth Polymers as X-Ray Contrast Materials: Synthesis, Characterization and Properties".
Dental Materials, vol. 8, pp. 54-59, Jan. 1992, H.R. Rawls, et al., "Cytotoxicity Evaluation of a New Radiopaque Resin Additive-Triphenyl Bismuth".
Polymer Preprints, vol 30, No. 2, pp. 185-186, Sep. 1989, Y. Delaviz, et al., "Polymers with Covalently Bound Bismuth as X-Ray Contrast Materials".
Maeda Koichi
Miyaji Katsuaki
Suzuki Hitomi
Tanikawa Keizo
Hollinden Gary E.
Nissan Chemical Industries Ltd.
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