Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Patent
1995-09-18
1998-06-16
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
424 94, 424 945, 424 9451, 554223, 554227, 554225, 554226, C07C 5900
Patent
active
057672997
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/00375 filed Feb. 25, 1994.
This invention relates to X-ray contrast agents.
It has been proposed to improve the detection of lesions in the liver and spleen by the use of contrast agents which accumulate in these organs. A useful survey entitled "Particulate Suspensions as Contrast Media" can be found in Radiocontrast Agents (Handbook of Experimental Pharmacology vol. 73), ed. M. Sovak, pub. Springer Verlag Berlin/Heidelberg, 1984 at page 543. The authors report on the use of inorganic particulate contrast media, organic particulate contrast media and emulsified contrast media.
Of the inorganic particulate contrast media the most well known is thorium dioxide. Use of this medium has been discontinued because of its chronic toxicity.
Organic particulate contrast media have included various iodinated compounds preferably containing three or more iodine atoms to maximise opacity, attached to an aromatic ring for chemical stability. However, compounds such as the ethyl esters of iodipamide and iothalamate are not sufficiently metabolically labile and would be expected to be retained in the liver for some time (see also Violante et. al., Investigative Radiology 16, pages 40-45, 1981).
Other organic particulate contrast media have been proposed in WO89/00988 and WO90/07491 with a view to overcoming the difficulties experienced with earlier organic media.
Emulsified contrast media in general comprise iodinated lipids such as iodinated poppyseed oil. A major disadvantage is that the iodine is aliphatic and hence more chemically reactive, particularly towards blood components.
Another possibility is to use liposomes containing water soluble iodinated contrast agents (Havron et al., Radiology, 140, p. 507, 1981). However, since only a limited amount of iodine can be incorporated in each liposome, it is necessary to administer relatively large amounts of lipids in order to attain adequate contrast enhancement. This tends to cause emboli in the lung capillaries. Furthermore, liposomes have been found to be relatively unstable on storing (Shulkin et al., J. Microencapsul., 1, p. 73, 1984).
Cholesteryl iopanoate has been proposed as a lipid-soluble contrast agent (Longino et al., Investigative Radiology 18, pages 275-278, 1983). However the compound has too long a liver retention time for human use.
Contrast agents based on the naturally occurring lipid triglyceride structure have been proposed in U.S. Pat. Nos. 4,873,075, 4,957,729 and 5,093,042 of Counsell et al. However, compounds of this type do not achieve a good enough rate of degradation within the body, and/or an acceptable rate of excretion from the body.
It has now been found according to the present invention that triglyceride-based contrast agents possessing a rapidly enzymatically degradable group between the glycerol backbone and the iodinated moiety possess advantages of good biodegradation to products of low toxicity which may be rapidly excreted from the body following imaging. The biodegradable groups are rapidly degraded in vivo by esterase enzymes but are stable in the absence of such enzymes.
Accordingly a first aspect of the invention provides compounds of formula (I) ##STR3## wherein R.sup.1, R.sup.2 and R.sup.3 are independently selected from: (i) saturated or unsaturated fatty acyl groups, preferably having from 14 to 24 carbon atoms, more preferably of a type found in nature; ##STR4##
wherein R.sup.4 and R.sup.5 are independently selected from hydrogen atoms, C.sub.1-4 alkyl groups and aryl groups, preferably C.sub.6-10 aryl groups, n represents the integers 0 or 1, A represents either a chemical bond or a straight or branched C.sub.1-6 alkylene chain and R.sup.6 is a group ##STR5##
wherein at least three of R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are iodine atoms and those of said groups R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 which are not iodine atoms are selected from hydrogen atoms, halogen atoms other than iodine, hydroxyl groups, C.sub.1-6 alkoxy groups, amino groups, C.sub.1-6 alky
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patent: 4567034 (1986-01-01), Charles et al.
Patent Abstracts of Japan, vol. 013, No. 236 (C-602) 30 May 1989.
Chemical Abstracts, vol. 110, No. 25, 19 Jun. 1989, 231292c.
DATABASE WPI, Section Ch, Week 8944, Derwent Publications Ltd., London.
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Wolff, M.E., Ed., Burger's Medicinal Chemistry, 4th ed., part 3, 1979, 1147-1203.
Klaveness Jo
Strande Per
Carr Deborah D.
Geist Gary
Nycomed Imaging AS
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