Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-18
1999-08-24
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 48, A61K 31435, C07D49122
Patent
active
059425180
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel antitumor compound, and a process for producing the antineoplastic compound.
BACKGROUND TECHNIQUE
Camptothecin is an alkaloid isolated from Camptotheca acuminata (Wall, et al: J. Am. Chem. Soc., 88, 3888-3890 (1966)), and is known to exhibit antineoplastic activity by inhibiting nucleic acid synthesis (Lown, et al.: Biochem. Pharmacol., 29, 905-915, (1989)). However, as the results of the clinical tests in the United States, the development thereof as a medicine was discontinued because of its toxicity. Thereafter, derivatives of camptothecin are being studied to reduce the toxicity or to increase the activity, yet the problem of the high toxicity has not been solved. For example, irinotecan hydrochloride (Sawada, et al.: Chem. Pharm. Bull., 39, 1446-1454 (1991)), which is the most advanced antineoplastic medicine of camptothecin derivatives, involves problems of side effects of marrow inhibition as well as gastrointestinal toxicity which is considered to be caused by choline esterase inhibition resulting from the carbamoyl structure of the prodrug moiety introduced for making the compound water-soluble (Kawato, et al.: Kiso to Rinsho, 24, 229-234 (1990)).
As another example, 10,11-methylenedioxy-20-O-glycylcamptothecin, which has been reported recently as a water-soluble camptothecin derivative (Wall, et al: J. Med. Chem., 36, 2689 (1993)), has the structure analogous to the compound of the present invention, but has not yet been reported to have antineoplastic activity against solid tumor, and is highly toxic.
Furthermore, most of the camptothecin derivatives are hardly soluble in water, and is not suitable for intravenous administration as general clinical method, which is the great problem in development as a medicine. A fluoroethylcamptothecin derivative was disclosed (JP-A-5-17479) which is derived by changing the ethyl group on 20-position of a camptothecin derivative to a 2-fluoroethyl group having lower toxicity without impairing the antineoplastic activity. Such a compounds is also hardly soluble in water, and development thereof as the injectant is difficult.
DISCLOSURE OF THE INVENTION
Under such circumstances, comprehensive studies have been made by the inventors of the present invention to find a water-soluble fluoroethylcamptothecin derivative which has high antineoplastic activity and is less toxic than known camptothecin derivatives. Consequently, it was found that a glycidyl ester of 10-ethoxy-7-ethyl-18-fluorocamptothecin at hydroxyl group of 20-position has much more excellent antineoplastic activity and much higher safety than known camptothecin derivatives, and has water-solubility for use for intravenous administration. Based on the findings, the present invention has been completed.
The present invention provides a compound represented by Formula (1), and salts thereof: ##STR1##
The compound of the present invention can be produced through the process exemplified by Reaction Formula 1 below.
More specifically, the compound represented by Formula (1) can be produced by reaction of Compound (2) with a glycine derivative having a protected nitrogen in a solvent such as a halogenated hydrocarbon like dichloromethane, and chloroform; an ether like tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether; an aromatic hydrocarbon like benzene, and toluene; an amide like N,N-dimethylformamide, and N,N-dimethylacetamide; acetonitrile; or ethyl acetate, by use of a condensing agent, if necessary, such as N,N'-dicyclohexylcarbodimide, 1-ethyl-3-(3-dimethylpropyl)carbodiimide hydrochloride, and carbodiimidazole, in the presence of an amine such as triethylamine, diisopropylamine, pyridine, 4-(N,N-dimethylamino)pyridine, 1,8-diazabicylclo-7-undecene, and subsequent deprotection by action of an acid or a base, or by catalytic reduction. The reaction is conducted usually at -78.degree. C. to 120.degree. C., preferably from 0.degree. C. to 120.degree. C., for 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
The acid
REFERENCES:
patent: 4943579 (1990-07-01), Vishnuvajjala et al.
Journal of Medicinal Chemistry, Sep. 1983, vol. 36, (Wall, et al) "Plant Antitumor Agents 30.Synthesis and Structure Activity of Novel Camptothecin Analogs" (pp. 2689-2700).
Asahina Yoshikazu
Oomori Yasuo
Huang Evelyn Mei
Kyorin Pharmaceutical Co. Ltd.
Nissen McAulay
LandOfFree
Water-soluble fluoroethylcamptothecin derivative and process 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 Water-soluble fluoroethylcamptothecin derivative and process for, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Water-soluble fluoroethylcamptothecin derivative and process for will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-467216