Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1986-10-16
1990-07-24
Brown, Johnnie R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 51, 536 23, 536 29, 4241951, A61K 3170
Patent
active
049435647
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to intraarterial injection pharmaceuticals of 5-fluoro-2'-deoxyuridine esters.
More particularly, this invention relates to intraarterial injection pharmaceuticals of 5-fluoro-2'-deoxyuridine esters having a remarkably improved properties of selective migration to the tumor tissue and cumulative action comprising highly liposoluble derivatives of 5-fluoro-2'-deoxyuridine having an antitumor activity and oleaginous bases.
BACKGROUND OF THE ART
The difficulty which cancer chemotherapy encounters is that, though cancerous cells differentiate from nontumorous cells, they fundamentally arise from the same cells, and it is difficult to make the drug exercise the selective anticancer effect only on the cancerous cells. Many of the anticancer drugs now used clinically are intended to display the selective anticancer effect by utilizing the difference in the metabolic rates and turnover cycles between cancerous cells and normal cells; however, if enough anticancer effect is expected of the drug according to the dosage form and regimen conventionally adopted, the normal tissues are also affected by the toxicity of the drug too often.
For instance, it is widely known that 5-fluorouracil has a broad range of spectrum for solid tumors, but its half-life period in vivo is short when it is administered to a living body and its toxicity is found affecting the digestive system and hematopoietic system upon its administration intended for the prolonged antitumor activity continuous in time. As the method for selectively administering 5-fluorouracil to the tumor tissue, a report is made as to its hepatic artery injection for curing hepatic cancer (Chirurgia Gastroenterologica, 13, 43 (1979)). However, it is difficult to prepare 5-fluorouracil in the dosage forms of oily preparation, emulsion of oil in water type, or liposime of hold-back type for hepatic artery injection because of its low fat solubility.
On the other hand, 5-fluoro-2'-deoxyuridine, one of the metabolic products of 5-fluorouracil, is known to have the antitumor activity (Cancer Research, 18, 730 (1958)). It is said that when 5-fluoro-2'-deoxyuridine is administered to a living body, it is turned to 5-fluoro-2'-deoxyuridine-5'-monophosphate to display its activity. When administered to a living body, however, 5-fluoro-2'-deoxyuridine can not exercise its anti-tumor activity enough since its half-life period in vivo is very short (Cancer Research, 32, 1045 (1972)).
To correct such faults, various 5-fluoro-2'-deoxyuridine derivatives have been reported (Japanese Patent Laid-Open Publication Nos. 163585/'79; 49315/'83; Biochemical Pharmacology, 14, 1605 (1965)). Though these compounds have been improved in their antitumor activity, it may be said that their properties such as migratory movement to the target cancerous tissue and accumulation are far from the satisfactory improvement.
DISCLOSURE OF THE INVENTION
As the result of a strenuous study made with the object of producing a drug in the form of a preparation in which 5-fluoro-2'-deoxyuridine can be readily turned to activated 5-fluoro-2'-deoxyuridine-5'-monophosphate and can be administered continuatively to exercise the selective effect against the cancerous tissue, the present inventors have found that the object can be achieved by the intraarterial administration of a medicine prepared by dissolving a 5-fluoro-2'-deoxyuridine ester derivative in an oleaginous base, thus completing this invention.
This invention accordingly provides a medicine for intraarterial administration comprising 5-fluoro-2'-deoxyuridine ester expressed by the undermentioned formula (I), or their pharmaceutically permissible salts, and oleaginous bases ##STR1## wherein R.sub.1 indicates an acyl group; and R.sub.2 indicates an acyloxy group or ##STR2## (in which R.sub.3 represents a C.sub.5 -C.sub.26 alkyl group).
The fat solubility of the 5-fluoro-2'-deoxyuridine esters of formula (I) is remarkably improved and accordingly its affinity for an oleaginous base is increased. Pharma
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Fukushima Shoji
Kawaguchi Takeo
Nakano Masahiro
Suzuki Yoshiki
Brown Johnnie R.
Teijin Limited
Wilson James O.
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