GB2072164A

GB2072164A - 2%-Deoxy-3%,5%-di-O- alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the derivatives and anti-tumor agents containing the derivatives

Info

Publication number: GB2072164A
Application number: GB8104375A
Authority: GB
Original assignee: Funai Pharmaceutical Industries Ltd
Current assignee: Funai Pharmaceutical Industries Ltd
Priority date: 1980-02-15
Filing date: 1981-02-12
Publication date: 1981-09-30
Also published as: IT8119758A0; ATA69181A; DE3105111C2; ES499443A0; FR2476086B1; CH646715A5; IT1210989B; ES8206550A1; GB2072164B; FR2476086A1; AT374203B; DE3105111A1

Abstract

2%-Deoxy-3%,5%-di-O- alkylcarbonyl-5-fluorouridine derivatives of the general formula: <IMAGE> wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two R groups, the two alkyl moieties of the alkoxy group may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group. The compounds of Formula I are useful as anti-tumor agents.

Description

2,-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the derivatives and anti-tumor agents containing the derivatives The present invention relates to certain 2-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives, a process for their preparation and anti-tumor agents containing them.

The compounds of the invention are 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two groups R are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group.

In the field of chemotherapy, major public attention is now directed to the development of effective anti-tumor agents. Heretofore, various kinds of 5-fluorouridine derivatives have been developed as anti-tumor agents. However, all of these derivatives are quite unsatisfactory as they are either poor in their inherent anti-tumor activity or possess strong toxicity. 2'-Deoxy-5-fluorouridine (referred to hereinafter simply as FUDR) is already used an an anti-tumor agent but this compound has an exceptionally high toxicity and only a narrower safety margin.In addition, this compound is subject to a considerable limitations in actual therapeutic applications since this compound can be administered only by intrarterial injection and cannot be administered orally (Physicians Desk Reference, p. 1387 (1978). 2'-Deoxy-3',5'-0-acetyl-5-fluorouridine (referred to hereinafter simpiy as acetyl--FUDW) is also known as one of the FUDR derivatives. However, this compound is almost equivalent in anti-tumor activity to FUDR and rather poor in effectiveness (Biochem. Pharmacology, 14, 1605 et seq., (1965); Cancer Research, 23 420 et seq. (1963).

3',5'-Dialkyl esters of FUDR have also been reported as derivatives of FUDR but they are still unsatisfactory in respect of their anti-tumor activity and toxicity Biochem. Pharmacology, 14, 1605-1619 (1965), ibid 15, 627-644(1966). Recently derivatives of FUDR and acetyl-FUlDR have been reported which are compounds in which the hydrogen atom bonded to the 3-nitrogen atom on the uracil ring is substituted by a specific aroyl group (UK Patent Appln. No. 2,025,401 published on January 23, 1980 and European Patent Application No. 9,882 published on April 1 6, 1980). However, further enhancement in anti-tumor activity is also desired in these compounds.Thus, there is a great demand for developing new FUDR derivatives which possess strong anti-tumor activity with weak toxicity and are suitable for oral administration without the necessity of troublesome intrarterial or intravenous injection.

We have found surprisingly that the new compounds of the general formula (I) are superior in antitumor activity to the known similar compounds at an equivalent toxicity level.

In the general formula (I), the benzoyl group introduced into 3-position of the uracil ring may be ring-substituted by up to 3 groups R which may be the same or different and each represent an alkyl group, an alkoxy group or a halogen atom. When R is an alkyl group, straight or branched chain C~20 alkyl groups are preferred such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, npentyl, isopentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl and n-octadecyl.Examples of R as an alkoxy group are, for example, straight or branched chain C1~20 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyioxy, noctyloxy, n-decyloxy, n-dodecyloxy, n-hexdecycloxy and n-octadecyloxy groups.

When two vicinal lower alkoxy groups exist as ring-substituents in the benzoyl groups (R= a lower alkoxy group and m=2), the alkyl moieties of the two lower alkoxy groups may be combined to form an alkylene group. In this case, the two vicinal lower alkoxy groups form an alkylenedioxy group. Preferred examples of the alkylenedioxy group include methylenedioxy, ethylenedioxy and propylenedioxy groups.

Examples of R as a halogen atom include fluorine, chlorine, bromine and iodine atoms, with fluorine atoms being preferred.

Preferred compounds of the general formula (I) include: 3-benzoyl-2'-deoxy-3',5-di-0-pentanoyl-5-fluorouridine, 3-benzoyl-2'-deoxy-3',5-di-0-hexanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3',5-di-0-butanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3',5-di-0-pentanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3' ,5'-di-0-hexanoyl-5-fl uoridine, 3-(2,3 or 4-methoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl-5-fl uoridine, 3-(2,3 or 4-methoxy)-benzoyl-2'-deoxy-3',5 -di-0-hexanoyl-S4luorouridine, 3-(3,5-dimethyl)-benzoyl-2'-deoxy-3' ,5'-di-0-pentanoyl or -hexanoyl-5-fl uorouridine, 3-(2,3-dimethoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or-hexanoyl-5-fluorouridine, 3-(2,3 or 4-ethyl)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine, 3-(2,3 or 4-ethoxy)-benzoyl-2'-deoxy-3' ,5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine, 3-(2,3 or 4-propoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine, 3-(2,3 or 4-fluoro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or - hexanoyl-5-fiuorouridine, and 3-(2,4-dichloro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexa noyl-5-fl u orouridi ne.

The new compounds of the general formula (I) of the present invention are prepared by reacting a 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridine of the general formula:

wherein n is an integer of 1 to 14, with a benzoyl halide of the general formula:

wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and Hal is a halogen atom, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two groups R are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group. The reaction is generally carried out in the presence of a reaction medium and an acid-binding agent.

In general, the 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridines of the general formula (II) are known or can readily be prepared by acylating one molar proportion of FUDR with two molar proportions of the corresponding fatty acid, preferably in the form of a reactive functional derivative.

Benzoyl halides of the general formula (Ill) are generally known and readily commercially available, or can be prepared in a manner known per se. The use of the corresponding chloride or bromide is preferred.

The benzoyl halide of the general formula (III) is preferably used in an amount of 1 to 3 molar proportion for the 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridine of the general formula (II).

The reaction between the benzoyl halide of the general formula (III) and the 2'-deoxy-3',5'-di-0alkylcarbonyl-5-fluorouridine of the general formula (II), i.e. the N-acylation reaction of the fluorouridine with the benzoyl halide, is generally carried out in the presence of an organic solvent which is inert to the N-acylation and affords a proper reaction temperature. Illustrative of the preferred organic solvents are aprotic solvents such as diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide and dimethylsulfoxide.

The reaction is normaily carried out in the presence of an acid-binding agent. The reaction of the present invention is usually promoted by neutralizing the hydrogen halide liberated on the N-acylation of the fluorouridine with the benzoyl halide. Thus, organic bases are generally used as the acid-binding agent. Preferred examples of the organic base include aliphatic tertiary amines such as triethylamine and the like lower trialkylamines and aromatic and heterocyclic tertiary amines such as N,Ndialkylanilines and pyridine which may be substituted by a lower alkyl group or groups. These organic bases are usually miscible with the organic solvent used as the reaction medium, but are precipitated when combined with the hydrogen halide.

Accordingiy, these organic bases can readily be separated from the reaction mixture after completion of the reaction.

The organic base is usually used in an amount of 1 to 5 moles per mole of the benzoyl halide. The organic bases per se may be used as the reaction medium in an excess amount for example, an amount of 5 to 20 molar proportions with respect to the benzoyl halide may be used in place of a part or all of the reaction solvent.

The reaction is carried out within a wide range of reaction temperatures, for example, under ice cooling or at a temperature up to the boiling point of the reduction reaction solvent used. As a rule, the reaction time is within a period from 30 minutes to 12 hours. It is possible to shorten the reaction time by warming the reaction mixture at the final stage of the reaction.

After completion of the reaction, the end product can be obtained by subjecting the reaction mixture directly to concentration under reduced pressure or by first filtering the reaction mixture and then concentrating the filtrate under the reduced pressure, and finally recrystallizing the resultant residue or subjecting the residue to chromatography on silica gel. If necessary, the last-mentioned purification treatment by the aid of chromatographic operation or recrystallization may be repeated.

When the end product is isolated as a viscous oily substance, it can be obtained in solid or crystalline form by dissoiving the oily substance in a small amount of dimethylsulfoxide and pouring the solution into water under vigorous agitation.

The products of the present invention possess high anti-tumor activity with weak toxicity as compared with the known similar FUDR derivatives. The anti-tumor activity and toxicity of the new compounds of this invention were evaluated according to the following tests.

(A) Pharmacological tests for measuring anti-tumur activity: About 10,000,000 tumor cells of Sarcoma S--l 80 (successively incubated for several generations in peritoneal cavity of a male mouse of ICR strain), were transplanted subcutaneously into the inguinal region of 5 week-aged male mice of ICR strain. After the lapse of 24 hours, administration of the compounds of this invention started. The administration of the compounds of this invention was forcibly made orally once a day for 7 days. The body weight of each testing animal was measured every day just before the administration. The compounds of this invention were administered in the form dissolved or suspended in polyethylene glycol 400 to each testing animal while polyethylene glycol 400 alone to a control group of the animals.In each case, the same volume of 0.1 ml/1 0 g (body weight) was administered to each animal. Although the exact doses of the compounds of this invention varied according to the sort of the particular compounds used, the doses were approximately within a range from 0.5 to mg/kg to 120 mg/kg. The doses were graded into 3-12 ranks for each testing compound.

At each rank, the compound of this invention was administered to a group consisting of 6 mice. For the control group 1 8 mice were used.

On the 8th day from the transplantation of the tumor ceils, each mouse was put to death by bleeding under ether anesthesia. After the tumor tissue was excised, its weight was immediately measured and recorded. An average value of tumor weights in the teated group (referred to as T) for each test compound and for each dose and an average value of tumor weights in the control group (referred to as C) were calculated, respectively, to estimate a dose corresponding to T/C value of 0.70 or 0.50 for each test compound.

Concerning evaluation of the anti-tumor activity, a T/C value within the range of 0.70-0.51 is regarded to be slightly effective, while a value of less than 0.50 is regarded to be effective [Ohyo-Yakuri, 7, 1277-1292 (1973)]. Accordingly, the anti-tumor activity becomes stronger as the value indicating 0.70 or 0.50 in terms of T/C becomes smaller.

(B) Test for measuring toxicity: Judging from the effects achieved by the compounds of this invention, toxicity values were measured according to the following method, taking accumulative toxicity into consideration.

Groups of 5 weeks old male mice of ICR strain were used for this test, each group consisting of 10 animals. Test compounds were forcibly administered orally once a day for 7 days. The body weight of each animal was measured every day just before the administration. The compounds of this invention were administered in the form dissolved or suspended in polyethylene glycol 400 to each testing animal in the same volume of 0.1 mI/1 0 g (body weight). Although the exact doses of the compounds of this invention varied according to the sort of the particular compounds used, the doses were approximately within a range from 2 mg/kg to 300 mg/kg. The doses were graded into 3-12 ranks for each testing compound. At each rank, the compound of this invention was administered to each group.On the 14th day from the completion of administration, the survival and death of the tested animals were judged and LD10 values were calculated according to the Litchfield-Wilcoxon method.

The same tests as in the above (A) and (B) were performed, using the following known similar compounds: A: 2'-Deoxy-3',5'-di-0-n-propionyl-5-fluorouridine B: 2'-Deoxy-3',5'-di-0-n-butanoyl-5-fluorouridine C: 2'-Deoxy-3',5'-di-0-n-heptanoyl-5-fl uorouridine D: 2'-Deoxy-3',5'-di-0-n-octanoyl-5-fluorouridine E: 2'-Deoxy-3',5'-di-0-n-palmitoyl-5-fl uorouridine F: 2'-Deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine G: 2'-Deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine H: 3-(3-methylbenzoyl)-2'-deoxy-5-fluorouridine I: 3-(3-methylbenzoyl)-2'-deoxy-3',5'-di-0-acetyi-5-fluorouridine J: 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3' ,5'-di-0-acetyl-5-fl uorouridine K: :3-(3,4-methylenedioxybenzoyl)-2'-deoxy-5-fluorouridine L: 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-3',5'-di-0-acetyl-5-fl uorouridine M: 5-Fluorouracil.

(C) Results of the Tests: Results of the above Tests (A) and (B) and therapeutic indices calculated therefrom are shown in Tables 1,2,3 and 4. The therapeutic indices were calculated according to the following equation: Therapeutic index = LD10value -:T/C value TABLE 1

Compound administered Value Value In General Formula indicating indicating L D 10 Therapeutic (R)m n T/C 0,70 (mg/Kg) T/C 0,50 (mg/Kg) (mg/Kg) index 2,3-Dimethoxy 1 25 44 90 20.6 2,3-Dimethoxy 14 41 89 130 14.6 H (unsubst::) 2 23 43 - 3-Methyl 2 8 23 96 4,17 2-Methyl 5 4 11 - 2,3-Dimethoxy 5 6 13 33 1,83 3-Fluoro 5 1 8 24 3.00 2,3-Dimethoxy 6 6 20 36 1.80 3-Fluoro 6 7 21 41 1.95 A 22 72 108 1.50 B 19 45 70 1.55 C 6 15 24 1.60 D 5 12 19 1.58 E 18 55 71 1.29 TABLE 2

Compound administered In General Formula Value indicating LD 10 Therapeutic (R)m n T/C 0,50 (mg/Kg) (mg/Kg) index H (unsubstituted) 3 1 0 8 6 8 6 0 2-Methyl " 2 0 9 5 4 7 5 3-Methyl " 3 6 8 1 2 2 5 3,5-Dimethyl " 6 0 2 2 3 6 7 3-fluoro " 1 3 3 0 2 3 1 2-Chloro " 1 3 3 3 2 5 4 2,4-Dichloro " 1 4 3 1 2 2 1 H (unsubstituted) 4 1 0 9 4 9 4 0 2-Methyl " 5 9 1 3 2 2 0 3-Methyl " 5 7 1 6 2 8 1 4-Methyl " 5 3 1 2 2 2 6 2,4-Dimethyl " 6 3 1 6 2 5 4 3-Fluoro " 5 8 1 7 2 9 3 4-Fluoro- " 6 1 1 8 2 9 5 3-Chloro " 8 6 2 3 2 6 7 4-Bromo " 1 0 2 6 2 6 0 3,5-Dichloro " 1 3 3 7 2 8 5 F 2 8 2 8 1 0 0 G 9 0 1 9 2 1 1 H 6 2 9 1 1 5 0 I 4 1 8 9 2 1 7 TABLE 3

Compound administered in General Formula Value indicating Value indicating LD 10 Therapeutic (R)m n T/C 0.70 (mg/Kg) T/C 0.50 (mg/kg) (mg/Kg) index 2-methoxy 3 3 6 1 0 3 6 3 6 0 3-methoxy " 2 8 8 3 1 9 2 2 9 4-methoxy " 2 5 7 8 1 7 2 2 4 2-ethoxy " 2 4 8 0 3 5 5 0 0 4-ethoxy " 1 2 5 3 2 7 5 0 9 4-n-propoxy " 1 8 7 4 2 4 3 2 4 4-n-butoxy " 1 0 4 0 1 9 4 7 5 2,3-dimethoxy " 2 0 8 1 2 3 2 8 4 3,5-dimethoxy " 3 0 9 7 3 6 3 7 1 2-methoxy " 2 0 7 6 1 7 2 2 4 3-methoxy " 2 1 9 5 2 6 2 7 4 4-methoxy " 0 9 4 2 1 2 2 8 6 2-ethoxy " 0 8 4 1 2 2 5 3 7 4-ethoxy " - 2,8 1 6 5 7 1 4-n-propoxy " 1 1 4 3 2 0 4 6 5 4-n-butoxy " 2 4 8 0 2 0 2 5 0 2,3-dimethoxy " 2 3 8 0 2 3 2 8 8 F 1 4 2 8 2 8 1 0 0 G 3 1 9 0 1 9 2 1 1 J 1 1 3 4 7 0 2 2 4 TABLE 4

Compound administered Value indicating Value indicating L D 10 Therapeutic In General Formula, (R)m n T/C 0,70 (mg/Kg) T/C 0,50 (mg/Kg) (mg/Kg) index 3,4-Methylenedioxy 3 1,8 7,4 12 1,62 3,4-Methylenedioxy 4 2,7 7,6 15 1,94 K 25 70 61 0,87 L 9 37 43 1,16 M 31 67 63 0,94 As is evident from the results shown in Tables 1, 2, 3 and 4, the compounds of the present invention exhibit strong anti-tumor activity at a relatively low level of toxicity, in comparison with the known similar compounds. Thus, the present invention apparently contributes to remarkable improvement in anti-tumor activity and in reduction of toxicity.

In clinical chemotherapy, the compounds of this invention are preferably administered in a daily dose of 1-1000 mg. As a mode of administration, oral administration is preferably applied to the compounds of this invention but parenteral administration such as intravenous injection or intrarectal medication by means of a suppository is also applicable.

As pharmaceutical preparations suitable for oral administration, tablets, capsules (hard capsules and soft capsules), liquids and pills, each unit containing 0.5-500 mg of the compound of this invention as active ingredient, come into question. These preparations may contain, in addition to the active ingredient, other conventional auxiliary components such as milk sugar, corn starch, potato starch, various cane sugar esters of fatty acids, microcrystalline cellulose and polyethylene glycol 4000 as excipients; acacia, gelatine, hydroxypropylcellulose and potato starch as binders; magnesium stearate and talc as lubricants; carboxymethylcellulose calcium, potato starch and corn starch as disintegrating agents.Usual solubilizing agents and suspending agents may also be contained in the preparations, with polyethylene glycol 200-600 being particularly preferred. Examples for a base of suppositories include glycerol, cacao butter, glycerogelatine, polyethylene glycol, laurin and other materials usually employed for this purpose.

Besides the above mentioned additives, materials normally used as carriers for pharmaceutical preparations may also be contained in the anti-tumor agents of the present invention.

The present invention will now be illustrated in more detail by way of examples.

EXAMPLE 1 2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2-benzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 700C for 30 minutes. The reaction liquid is cooled and triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the oily residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is dissolved in about 1 5 ml of dimethyl sulfoxide and the solution is added dropwise to about 400 ml of ice water under vigorous agitation whereupon a precipitate is formed.The resultant precipitate is collected by filtration, washed with water and dried at room temperature under reduced pressure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained.

UV-absorption spectrum: AEtOH 255.5 nm NMR spectra: S(ppm, CDCl3) Uridine moiety: 7.80 (d, H6), 6.19 (broad-t, H1'), near 2.5 (m, H2'), 5.10-5.30 (m, H3'), 4.16-4.42 (m, H4', H5'), 2.10-2.54 (m, 2 x COCH2), 0.98-1.26 (m, 2 x CH3) Benzoyl moiety: 7.63 (d, H6), 7.12-7.56 (m, H3, H4, H5), 2.62 (s, CH3) Elementary analysis (as C23H2sFN2 s) Calc. (%): C 57.98, H 5.29, N 5.88 Found (%): C 57.82, H 5.49, N 5.99 EXAMPLE 2 2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fiuorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluorobenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 600C for 30 minutes.The reaction liquid is worked up in the same manner as described in Example 1 whereby 2.05 g (yield: 71.5%) of powdery 3-(3-fluorobenzoyl)-2'-deoxy-3',5'-di-O- propionyl-5-fluorouridine are obtained.

UV-absorption spectra: #maxEtOH 251.5 mm NMR spectra: S(ppm, CDCl3) Uridine moiety: 7.81 (d, H6), 6.18 (broad-t, H1'), near 2.5 (m, H2'), 5.19-5.36 (m, Hi), 4.24-4.48 (m, H41, Hj), 2.20-2.60 (m, 2 x COCH2), 1.05-1 .3'2 (m, 2 x CH3) Benzoyl moiety: 7.28-7.76 (m, aromatic H) Elementary analysis (as C22H22F2N208): Calc (%): C 55.00, H 4.62, N 5.83 Found (%): C 55.28, H 4.77, N 6.02 EXAMPLE 3 2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 30 minutes and then at 500C for 30 minutes. The reaction liquid is cooled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is allowed to stand overnight at room temperature whereby a part of the substance is crystallized.A small amount of ethanol is added to crystallize the substance wholly and the crystals are collected by filtration whereby 2.3 g (yield: 79.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained. M.P. 84.5-860C.

UV-absorption spectra: AEtOH 264.5, 327 nm NMR spectra: S(ppm, CDCl3) Uridine moiety: 7.72 (d, He), 6.27 (broad-t, Hi,), near 2.5 (m, H2,), 5.16-5.32 (m, H3,), 4.18-4.48 (m, H4,, H5'), 2.14-2.48 (m, 2 x COCH2), 1.05-1.32 (m, 2 x CH3) Benzoyl moiety: 7.46-7.64 (m, H6), 7.10-7.26 (m, H4, H5), 3.86 (s, OCH3), 3.84 (s, OCH3) Elementary analysis (as C24H27FN2O10): Calc. (%): C 55.17, H 5.21,N 5.36 Found (%):C 55.27, H 5.37, N 5.50 EXAMPLE 4 3.0 Grams of 2'-deoxy-3',5'-di-0-myristoyl-5-fluorouridine are dissolved in 20 ml of dry dioxane and the solution is ice cooled. 2.1 Milliliters of triethylamine and 1.4 g of 4-methylbenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 3 hours. The triethylamine hydrochloride formed is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (elution solvent: chloroform).

The resultant purified oily substance is dissolved in ethanol and concentrated under reduced pressure whereupon a crystalline residue is obtained which, after recrystallization from methanol, gives 1.25 g (yield: 35.4%) of 3-(4-methylbenzoyl)-2'-deoxy-3',5'-di-O-myristoyl-5-fluorouridine are obtained. M.P.

76-770C.

UV-absorption spectru,: #maxEtOH 2.63 nm NMR spectra: #(ppm, CDCI3) Uridine moiety: 7.74 (d, H6), 6.26 (broad-t, H1'), near 2.5 (m, H2,), 5.14-5.32 (m, H3), 4.20-4.44 (m, H4,, H5'). 2.20-2.54 (m, 2 x COCH2), 1.04-1.84 (m, 22 x CH2) 0.76-1.00 (m, 2 x CH3) Benzoyl moiety: 7.78 (d, H2, H6), 7.30 (d, H3, H5), 2.42 (s, CH3) Elementary analysis (as C45H69FN2O8): Calc. (%):C 68.85, H 8.86, N 3.57 Found (%):C 68.76, H 8.55, N 3.79 EXAMPLE 5 3.0 Grams of 2'-deoxy-3',5'-di-0-palmitoyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.9 g of 2,3-dimethoxy-benzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 10 minutes and then at 70OC for 90 minutes. The reaction liquid is cooled and the precipitated triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved under heating in ethanol and the solution is allowed to stand whereby crystals are obtained which, after recrystallization from ethanol, affords 2.95 g (yield: 80.2%) of 3-(2,3ai methoxybenzoyl)-2'- deoxy-3',5'-di-0-palmitoyl-5-fluorouridine are obtained.M.P. 77-780C.

UV-absorption spectra: iEtOH 264.5,327 nm NMR spectra:#(ppm, CDCl3) Uridine moiety: 7.76 (d, H6), 7.31 (broad-t, H1'), near 2.4 (m, H2,), 5.18-5.34 (m, H3), 4.22-4.48 (m, H4', H5,), 2.10-2.55 (m, 2 x COCH2), 1.08-1.80 (m, 26 x CH2), 0.76-1.06 (m, 2 x CH3) Benzoyl moiety: 7.59 (dd, H6), 7.12-7.28 (m, H4, H5), 3.90 (broad-s, 2 x OCH3) Elementary analysis (as C50H79FN2O10): Calc. (%): C 67.69, H 8.98, N 3.16 Found (%):C 68.09, H 9.11, N 2.99 EXAMPLE 6 3.0 Grams of 2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine are dissolved in 20 ml of dry dioxane and the solution is ice cooled. 3 Milliliters of triethylamine and 2.0 g of benzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 2 hours. The triethylamine hydrochloride formed is filtered off and the filtrate is concentrated under reduced pressure. The oily residue is purified by column chromatography on silica gel (elution solvent: chloroform) whereby 2.3 g (yield: 60.7%) of 3-benzoyl-2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine are obtained as an oily substance.

UV-absorption spectrum: #maxEtOH 253.5 nm NMR spectra: #(ppm, CDCI3) Uridine moiety: 7.76 (d, H6), 6.27 (broad-t, H1'), near 2.5 (m, H2'), 5.15-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5'), 2.20-2.52 (m, 2 x COCH2), 1.44-1.92 (m, 2 x CH2), 1.86-1.10 (m, 2 x CH3) Benzoyl moiety: 7.36-8.02 (m, aromatic H) Elementary analysis (as C24H27FN2O5): Calc. (%): C 58.77, H 5.55, N 5.71 Found (%): C 58.75, H 5.82, N 5.78 EXAMPLES 7-23 In the same manner as described in Example 6, a 2'-deoxy-3',5'-di-0-alkylcarbonyl-5fluorouridine is reacted with an aroyl chloride.Table 5 shows the resuiting 2'-deoxy-3',5'-di-0alkylcarbonyl-5-fluorouridine derivatives and characteristic physical properties thereof.

TABLE 5

in General Elementary analysis UV Formula (I) Empirical formula #EtOH NMR (CDCl3) #(ppm) Ex. (R)m Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H,N (nm) Uridine moiety Benzoyl moiety 3-methyl C25H29FN2O8 7,75 (d,H6) 8.28 (broad-t,H1') 7.60-7.80 (m, H2, H6) 7 71.6 59.52 5.79 5.55 257 near 2.4 (m, H2') 5.12-5.32 (m, H3') 7.30-7.52 (m, H4, H5) 2 59.59 6.09 5.59 4.29-4.44 (m, H4' H5') 2.12-2.56(m, 2xCOCH2) 2.40 (s, CH3) 1.44-1.92 (m, 2xCH2) 0.84-1.12 (m, 2xCH3) 4-methyl C25H29Fn2O8 7.74 (d, H6) 6.26 (broad-t, H1') 7.79 (d, H2, H5) 8 71.6 59.52 5.79 5.55 263.5 near 2.4 (m, H2') 5.15-5.32 (m, H2') 7.29 (d, H3, H5) 2 59.55 6.82 5.58 4.22-4.45 (m, H4', H5') 2.16-2.52 (m, 2xCOCH3) 2.42 (s, CH3) 1.44-1.92(m, 2xCH2) 0.84-1.08 (m, 2xCH3) 3,4-di- C26H31FN2O10 7.75 (d, H6) 6.26 (broad-t, H1') 7.55 (broad-s, H2) 9 methoxy 56.2 56.72 5.68 5.09 280.5 near 2.5 (m, H2') 5.14-5.32 (m, H3') 7.39 (d, H6) 56.54 5.60 5.14 4.20-4.46 (m, H4', H5') 2,20-2.55 (m, 2xCOCH2) 6.88 (d, H5) 2 315.5 1.50-1.90 (m, 2xCH3) 0.84-1.10 (m, 2xCH3) 3.91 (s, 2xOCH3) 4-fluoro C24H26F2N2O8 7.78 (d, H6) 6.27 (broad-t, H1') 7.96 (dd, H2, H6) 10 71 56.69 5.15 5.51 255 near 2.5 (m, H2') 5.17-5.34 (m, H3') 7.18 (t, H3, H5) 2 56.74 5.29 5.56 4.22-4.48 (m, H4', H5') 2.08-2.60 (m, 2xCOC H2) 1.46-1.96 (m, 2xCH2) 0.84-1.20 (m, 2xCH3) 2-methyl C31H41FN2O8 7.78 (d, h6) 6.27 (broad-t, H1') 7.16-7.68 (m, aromatic H) 11 68.0 63.25 7.02 4.76 255.5 near 2.4 (m, H2') 5.14-5.32 (m, H3') 2.68 (s, CH3) 5 63.31 7.09 4.79 4.18-4.44 (m, H4', H5) 2.16-2.52 (m, 2xCOCH7) 1.08-1.84 (m, 8xCH2) 0.72-1.04 (m, 2xCH3) 2,3-di- C32H43FN2O10 7.80 (d, H6) 6,34 (broad-t, H1') 7.56-7.70 (m, H6) 12 methoxy 89.0 60.56 6.83 4.41 265 near 2.5 (m, H2') 5.20-5.36 (m, H3') 7.18-7.32 (m, H4, H5) 60.60 7.06 4.36 327 4.20-4.59 (m, H4', H5') 2.16-2.56 (m, 2xCOCH2) 3.90 (s, OCH3) 5 1.16-1.88 (m, 8xCH2) 0.76-1.08 (m, 2xCH3) 3.88 (s, OCH3) TABLE 5 (Continued)

in General Elementary analysis UV Formula (I) Empirical formula #'EtOH NMR (CDCl3) #(ppm) Ex. R(m) Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 3-fluoro C20H36F2N2O5 7.85 (d, H6) 6.28 (broad-t, H1') 7.28-7.90 (m, aromatic H) 13 83.6 80.80 6.46 4.73 252 near 2.5 (m, H2') 5.16-5.35 (m, H2') 5 80.77 6.48 4.70 4.20-4.48 (m, H4',H5') 2,20-2,56(m, 2xCOCH2) 1.10-1.84 (m, 8xCH2) 0.76-1.05 (m, 8xCH2) 0.76-1.05 (m, 2xCH3) 2-methyl C33H48FN2O6 7.80 (d, H6) 6.27 (broad-t, H1') 7.64 (d, H6) 14 81.6 64.27 7.35 4.54 255.5 near 2,5 (m, H2') 5.16-5.35 (m, H3') 7.20-7.60 (m, H2, H4, H3) 6 64.23 7.31 4.59 4.22-4.46 (m, H4', H5') 2.18-2.52 (m, 2xCOCH3) 2.68 (s, CH3) 1.16-1.90 (m, 10xCh2) 0.76-1.04 (m, 2xCH3) 2,3-di- C34H47FN2O10 7.76 (d, H6) 6.29 (broad-t, H1') 7.58 (dd, H5) 15 methoxy 67.9 61.62 7.15 4.23 265 near 2.5 (m, H2') 5.16-5.33 (m, H5') 7.14-7.30 (m, H4, H5) 61.69 7.02 4.09 327 4.22-4.59 (m, H4', H5') 2.16-2.54 (m, 2xCOCH2) 3.87 (s, OCH2) 6 1.14-1.98 (m, 10-CH2) 0.72-1.04 (m, 2-CH3) 3.85 (s, OCH3) 3-fluoro C32H42F2N2O8 7.86 (d, H6) 6.30 (broad-t, H1') 7.24-7.92 (m, aromatic H) 16 84.0 61.92 6.82 4.51 251.5 near 2.5 (m, H2') 5.29-5.36(m, H3') 6 61.73 6.72 4.40 4.26-4.50 (m, H4', H5') 2.22-2.58 (m, 2xCOCH2) 1.14-2.00 (m, 10xCH2) 0.74-1.06 (m, 2xCH3) hydrogen C40H50FN2O5 7.80 (d, H5) 8.28 (broad-t, H1') 7.40-8.10 (m, aromatic H) 17 66.9 67.20, 8.32 3.92 253 near 2.5 (m, H2') 5.16-5.35 (m, H2') 10 67.16 8.30 4.00 4.20 4.54 (m, H4', H5') 2.20-2.60 (m, 2xCOCH2) 1.20-2.00 (m, 18xCH2) 0.76-1.06 (m, 2xCH3) 3-methyl C41H61FN2O8 7.79 (d, H6) 6.29 (broad-t, H1') 7.30-8.00 (m, aromatic H) 18 54.9 67.56 8.44 3.84 257.5 near 2.5 (m, H2') 5.16-5.36 (m, H2') 2.38 (s, CH3) 10 67.59 8.41 3.81 4.20-4.45 (m, H4', H5') 2.15-2.60 (m, 2xCOCH2) 1.10-2.00 (m, 18xCH2) 0.70-1.10 (m, 2xCF3) TABLE 5 (Continued)

In General Elementary analysis UV Formula (I) Empirical formula #EtOH NMR (CDCl3) #(ppm) Ex. R(m) Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moietyl 2,4-di- C42H63FN2O10 7.63 (d, H6) 6.26 (broad-t, H1') 8,10 (d, H6) 19 methoxy 34 65.09 8.19 3.61 278 near 2.5 (m, H2') 5.10-5.30 (m, H3') 6.67 (dd, H5) 65.25 8.65 3.79 304 4.16-4.44 (m, H4', H5') 2.20-2.50 (m, 2xCOCH2) 6.36 (d, H3) 10 1.04-1.80 (m, 18xCH2) 0.78-1.04 (m, 2xCH3) 3.83 (s, OCH3) 3.74 (s, OCH3) hydrogen C44H67FN2O8 7.60 (i, H6) 6,07 (broad-t, H1') 7.10-7.85 (m, aromatic H) 20 43.2 68.54 8.76 3.63 253 near 2.4 (m, H2') 5.00-5.16 (m, H3') 12 68.36 8.75 3.87 4.05-4.35 (m, H4',H5) 2.05-2.50 (m, 2xCOCH2) 1.00-1.80 (m, 22xCH2) 0.70-1.00 (m, 2-CH3) 2-fluoro C44H66F2N2O8 7.62 (d, H6) 6.06 (broad-t, H1') 6.80-7.92 (m, aromatic H) 21 42.3 66.98 8.43 3.55 250 near 2.4 (m, H2') 5.00-5.20 (m, H3') 12 66.89 8.32 3.81 4.04-4.44 (m, H4', H5') 2.04-2.48 (m, 2xCOCH2) 0.96-1.80 (m, 22xCH2) 0.72-0.98 (m, 2xCH3) 2-methyl C49H77FN2O8 7.71 (d, H6) 6.16 (broad-t, H1') 7.54 (d, H6) 22 39.2 69.97 9.23 3.33 245.5 near 2.4 (m, H2') 5.06-5.24 (m, H3') 7.07-7.46 (m, H3, H4, H5) 14 69.89 8.84 3.29 4.10-4.40 (m, H4'H5') 2.15-2.45 (m, 2xCOCH2) 2.62 (s, CH3) 1.00-2.00 (m, 26xCH2) 0.75-1.00 (m, 2xCH3) 3-fluoro C48H74F2N2O8 7.74 (d, H6) 6.21 (broad-t, H1') 7.20-7.76 (m, aromatic H) 23 79.8 68.22 8.83 3.31 252 near 2.4 (m, H2) 5.10-5.28 (m, H3') 14 68.17 8.53 3.35 4.20-4.44 (m, H4', H5') 2.16-2.44 (m, 2xCOCH2) 1.12-1.80 (m, 26xCH2) 0.76-1.02 (m, 2xCH3) EXAMPLE 24 To a solution of 7.0 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethylamine and 2.7 g of benzoyl chloride. The mixture was subjected to reacr tion at room temperature for 2 hours and then at 60 C for 30 minutes. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous soution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate.The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform). The resultant oily substance was dissolved in about 80 ml of ethanol and the solution was treated with active carbon. The ethanol was distilled off under reduced pressure and the residue was again purified by column chromatography on silica gel (elution solvent: chloroform). The resultant purified oily substance was dried at room temperature under reduced pressure whereby 7.9 g (90%) of 3-benzoyl-2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine were obtained as an oily substance.

UV (#maxEtOH, nm): 253 NMR #(ppm, CDCl3): Uridine moiety: 7.79 (d, H6), 6.26 (broad t, H1,), near 2.4 (m, H2,), 5.16-5.32 (m, H3), 4.20-4.56 (m, H4,), H5'). 2.08-2.64 (m, 2 x COCH2), 1.16-1.84 (m, 4 xCH2), 0.80-1.08 (m, 2 x CH3) Benzoyl moiety: 7.36-8.02 (m, aromatic H) Elementary analysis (as C26H3aFN208): Calc. (%): C 60.22 H 6.03 N 5.40 Found (%):C 60.33 H 6.08 N 5.55 EXAMPLE 25-29 In the same manner as described in Example 24, the following 2'-dioxy-3',5'-di-O-alkylcarbonyl- 5-fluorouridine derivatives were prepared. The structures, yields and physical characteristics of the end products obtained were shown in Table 6.

TABLE 6

In General Yield Elementary analysis UV Formula I (%) Empirical formula EtOH NMR (CDCl3) #(ppm) Ex. R(m) Calc. (%) C, H, N #max No. n Nature Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 25 H 82 C28H35FN2O8 253 7.79 (d, H6) 6.26 (broad-t, H1') 7.40-8.04 (m, aromatic H) (4) (Oily 61.53 6.45 5.12 near 2.4 (m, H2') 5.16-5.32 (m'H3') sub) 61.71 6.54 5.29 4.20-4.57 (m, H4', H5') 2.07-2.65 (m, 2xCOCH2) 1.19-1.88 (m, 6xCH2) 0.78-1.08 (m, 2xCH3) 26 2-methyl 79 C27H33FN2O8 255 7.76 (d, H6) 6.26 (broad-t, H1') 7.16-7.68 (m, aromatic H) (3) (Oily 60.89 6.25 5.26 near 2.4 (m, H2') 5.15-5.32 (m, H3') 2.68 (S, CH3) sub) 60.72 6.34 5.34 4.20-4.56 (m, H4'; H5') 2.04-2.66 (m, 2xCOCH2) 1.16-1.84 (m, 4xCH2) 0.80-1.08 (m, 2xCH3) 27 3-fluoro 76 C26H30F2N2O8 252 7.79 (d, F6) 6.25 (broad-t, H1') 7.24-7.88 (m, aromatic H) (3) (Oily 58.20 5.64 5.22 near 2.4 (m, H2') 5.10-5.32 (m, H3') sub) 58.01 5.74 5.31 4.20-4.56 (m, H4', H5') 2.05-2.66 (m, 2xCOCH2) 1.15-1.82 (m, 4xCH2) 0.79-1.05 (m, 2xCH3) 28 3-methyl 83 C29H37FN2O8 258 7.76 (d, H6) 6.25 (broad-t, H1') 7.61-7.80 (m, H2, H6) (4) (Oily 62.13 6.65 5.00 near 2.4 (m, H2') 5.12-5.30 (m, H1') 7.24-7.54 (m, H4, H5) sub) 62.08 6.78 4.94 4.20-4.56 (m, H1' H5') 2.04-2.66 (m, 2xCOCH2) 2.40 (S, CH3) 1.12-1.82 (m, 6xCH2) 0.77-1.02 (m, 2xCH3) 29 4-dimethyl 87 C29H37FN2O8 264 7.77 (d, H6) 6.22 (broad-t, H1) 7.70 (d, H2, H6) (4) (Oily 62.13 6.65 5.00 near 2.4 (m, H2') 5.10-5.28 (m, H3') 7.24 (d, H3, H5) sub) 62.39 6.68 5.00 4.16-4.52 (m, H4', H5') 2.00-2.64 (m, 2xCOCH2) 7.24 (d, H3, H5) 1.16-1.80 (m, 6xCH2) 0.76-1.00 (m, 2xCH3) 2.40 (s, CH3) EXAMPLE 30 To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 4.0 ml of triethylamine and 3.4 g of 3-methylbenzoyl chloride. The mixture was subjected to reaction at room temperature for 5 hours and the reaction liquid was concentrated under reduced pressure.The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified two times by column chromatography on silica gel (elution solvent: chloroform).

The resultant purified oily substance was dried at room temperature under reduced pressure whereby 6.0 g (66%) of 3-(3-methylbenzoyl-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.

UV(EmTxH, nm): 258 NMR b(ppm, CDCI3): Uridine moiety: 7.76 (d, H6), 6.26 (broad t, Hí)l near 2.4 (m, H2'), 5.16-5.32 (m, H3,), 4.20-4.56 (m, H4,, h5'), 2.05-2.67 (m, 2 x COCH2), 1.16-1.84 (m, 4 xCH2), 0.80-1.06 (m, 2xCH3) Benzoyl moiety: 7.28-7.56 (m, H4, H5), 7.64-7.88 (m, H2, H4), 2.38 (s, CH3) Elementary analysis (as C2,H33FN208): Calc. (%): C 60.89 H 6.25 N 5.26 Found (%):C 60.87 H 6.46 N 5.30 EXAMPLE 31 Using benzoyl chloride in the same manner as described in Example 30, 7.4 g (84%) of 3-benzoyl 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 24.

EXAMPLE 32 To a solution of 7.5 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of dry dioxane were added 10.7 ml of triethylamine and 3.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified twice by column chromatography on silica gel (elution solvent: chloroform).The resultant purified oily substance was dried at room temperature under reduced pressure whereby 8.1 g (87%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an oily substance.

The physical characteristics of this substance were identical with those of the oily substance obtained in Example 25.

EXAMPLE 33 To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethyl amine and 3.4 g of 3,5-dimethylbenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 600C for 30 minutes. The reaction liquid was cooled and then treated in the same manner as described in Example 24 whereby 6.6 g (71%) of 3-(3,5-dimethylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.

UV (#maxEtOH, nm):263 NMR (ppm, CDCI3): Uridine moiety: 7.79 (d, H8), 6.28 (broad t, H1'), near 2.4 (m', H2,), 5.16-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5'), 2.14-2.52 (m, 2 x COCH2), 1.16-1.84 (m, 4 x CH2), 0.82-1.04 (m, 2 x CH3) Benzoyl moiety: 7.54 (s, H2, H6), 7.30 (s, H4), 2.34 (s, 2x CH3) Elementary analysis (as C28H35FN208): Calc. (%): C 61.53 H 6.45 N 5.12 Found (%): C 61.69 H 6.63 N 5.31 EXAMPLE 34 Using 3-methylbenzoyl chloride in the same manner as described in Example 33, 6.6 g (73%) of 3 (3-methylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an only substance.

The physical characteristics of this substance were identical with those of the oily sunstance obtained in Example 30.

EXAMPLE 35 To a solution of 7.5 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethylamine and 3.2 g of 3-fluorobenzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours and then at 600C for 30 minutes. The reaction liquid was cooled and then treated in the manner as described in Example 30 whereby 7.0 g (73%) of 3-(3 fluorobenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-S4luorouridine were obtained as an oily substance.

UV (#maxEtOH, nm): 252 NMR #(ppm, CDCl3): Uridine moiety: 7.77 (d, H6'), 6.24 (broad t, H1'), near 2.4 (m, H2'), 5.14-5.30 (m, H3'), 4.20-4.56 (m, H4',H5'), 2.04-2.68 (m, 2 x CH2), 1.12-1.82 (m, 6 x CH2), 0.78-1.04 (m, 2 x CH3) Benzoyl moiety: 7.24 7.84 (m, aromatic H) Elementary analysis (as C28H34F2N208): Calc. (%): C 59.57 H 6.07 N 4.96 Found (%): C 59.69 H 6.31 N 5.02 EXAMPLES 36-43 In the same manner as described in Example 35 or in the same manner as described in that Example except that the reaction time was varied,2'-deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as shown in Table 7 were prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 7.

TABLE 7

In General Yield Elementary analysis UV Reaction Formula (%) Empirical formula EtOH NMR (CDCl3) #(ppm) Ex. (R)m Calc. (%) C, H, N #max Room 60 C No. n (nature) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety (hr) (hr) 36 2-methyl 76 C29H37FN2O8 256 7.75 (d, H6) 6.23 (broad-t, H1') 7.12-7.64 (Oily 62.13 6.65 5.00 near 2.4 (m, H1') 5.12-5.28 (m, H3') (m, aromatic H') 4 0.5 (4) subs) 61.98 6.54 5.02 4.18-4.54 (m, H4, H5') 2.00-2.65 (m, 2xCOCH2) 2.68 'S, CH3) 1.16-1.82 (m, 6xCH2) 0.76-1.02 (m, 2xCH3) 37 2,4-di- 58 C30H30FN2O8 265 7.74 (d, H6) 6.23 (broad-t, H1') 7.46 (d, H6) 1 3 methyl 62,70 6.84 4.87 near 2.4 (m, H2') 5.14-5.29 (m, H3') 7.14 (S, H3) (4) (,,) 62.38 6.92 4.81 4.19-4.54 (m, H4, H5') 2.00-2.64 (m, 2xCOCH3) 7.04 (d, H5) 1.16-1.82 (m, 6xCH2) 0.78-1.04 (m, 2xCH3) 2.66 (S, CH3) 38 2-chloro 70 C26H30ClFN2O8 255 7.78 (d, H6) 6.23 (broad-t, H1') 7.90 (d, H5) 1 2 56.47 5.47 5.07 near 2.4 (m, H2') 5.14-5.32 (m, H3') 7.28-7.59 (3) (,,) 56.65 5.55 4.81 4.20-4.56 (m, H4' H5') 2.04-2.68 (m, 2xCOCH2) (m, H3, H4, H5) 1.12-1.81 (m, 4xCH2) 0.80-1.03 (m, 2xCH3) 39 2,4-dichloro 71 C25H29Cl2FN2O8 263 7.76 (d, H6) 6.23 (broad-t, H1') 7.66 (d, H6) 1 2 53.16 4.98 4.77 near 2.4 (m, H2') 5.15-5.30 (m, H3') 7.22-7.54 (3) (,,) 53.24 5.15 4.53 4.22-4.56 (m, H4'; H5') 2.03-2.69 (m, 2xCOCH2) (m, H3 H5) 1.16-18.2 (m, 4xCH2) 0.82-1.10 (m, 2xCH3) 40 4-fluoro 59 CH28H34F2N2O8 256 7.77 (d, H6) 6.24 (broad-t, H4') 7.84-8.06 1 2 59.57 6.07 4.96 near 2.4 (m, H2') 5.14-5.30 (m, H3') (m, H2H6) (4) (,,) 59.42 5.90 5.03 4.20-4.56 (m, H4' H5') 2.06-2.66 (m, 2xCOCH2) 7.16 (t, H3, H5) 1.14-1.84 (m, 6xCH2) 0.78-1.06 (m, 2xCH3) 41 3-chloro 68 C28H34ClFN2O8 255 7.80 (d, H6) 6.26 (broad-t, H1') 7.24-7.94 1 1 57.88 5.90 4.82 near 2.4 (m, H2') 5.16-5.32 (m, H3') (m, aromatic H) (4) (,,) 57.73 5.78 4.61 4.20-4.60 (m, H4' H5') 2.06-2.70 (m, 2xCOCH2) 1.16-1.66 (m, 6xCH2) 0.80-1.06 (m, 2xCH3) TABLE 7 (Continued)

in General Yield Elementary analysis UV Reaction Formula (%) Empirical formula EtOH NMR (CDCI3) #(ppm) Ex. (R)m Calc. (%) C, H, N #max Room 60 C No. n (nature) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety (hr) (hr) 42 4-Bromo 62 C28H34BrFN2O8 267 7.78 (d, H6) 6.23 (broad-t, H1') 7.52-7.84 1 1 53.77 5.46 4.48 near 2.4 (m, H2') 5.12-5.30 (m, H3') (m, aromatic H) 53.71 5.42 4.30 4.20-4.56 (m, H4', H5') 2.04-2.68 (m, 2xCOCH2) 1.14-1.84 (m, 6xCH2) 0.76-,1.04 (m, 2xCH3) 43 3,3,5-dichloro 73 C28H33Cl2FN2O8 258 7.80 (d, H6) 6.24 (broad-t, H4') 7.72-7.86 1 2 54.64 5.40 4.55 near 2.4 (m, H2') 5.16-5.32 (m, H1) (m, H2, H6) (4) (,,) 54.61 5.32 4.46 4.16-4.60 (m, H4', H5') 2.08-2.70 (m, 2xCOCH2) 7.60-7.72 1.16-1.84 (m, 6xCH2) 0.80-1.06 (m, 2xCH3) (m, H4) EXAMPLE 44 To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry acetonitrile were added under ice cooling 7.8 ml of triethylamine and 2.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 3 hours and then at 50--600C for 10 minutes. The reaction liquid was cooled and then concentrated under reduced pressure and the residue was purified twice by column chromatography on silica gel (elution solvent: chloroform).The resultant purified oily substance was dried at room temperature under reduced pressure whereby 7.0 g (79 Ó) of 3-benzoyl-2'-deoxy-3',5'-di-0-n-pentanoyi-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 24.

EXAMPLE 45 To a solution of 7.5 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 50 ml of dioxane were added 5.2 ml of triethylamine and 2.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 2 hours and then at 50--600C for 30 minutes. The reaction liquid was cooled and filtered to remove insoluble matters. The filtrate was treated in the same manner as described in Example 44 whereby 7.1 g (76%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-S4luornuridine were obtained as an oily substance. The physical characteristics of this substance were identical with those obtained in Example 25.

EXAMPLE 46 Using 2-methylbenzoyl chloride in the same manner as described in Example 44, 6.8 g (75%) of 3 (2-methylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fI uorouridine were obtained as an oily substance.

The physical characteristics of this substance were identical with those of the oily substance obtained in Example 26.

EXAMPLE 47 To a solution of 1.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-S4luorouridine in 10 ml of dry dioxane were added under ice cooling 0.52 ml of triethylamine and 0.54 g of benzoyl bromide. The mixture was subjected to reaction at room temperature for 1 5 minutes and then at 700C for 30 minutes. The reaction liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with an aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of edible salt and treated in the same manner as described in Example 30 whereby 0.75 g (60%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with the oily substance obtained in Example 24.

EXAMPLE 48 To a solution of 7.5 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 40 ml of ethyl acetate were added 4.6 ml of triethylamine and 2.7 g of 3-fluorobenzoyl chloride. The mixture was subjected to reaction at room temperature for 3 hours and then at 5060oC for one hour. The reaction liquid was cooled and washed with a 0.1-N aqueous solution of the caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated in the same manner as described in Example 30 whereby 6.0 g (63%) of 3-(3-fluorobenzoyl)-2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine were obtained as an oily substance.The physical characteristics of this substance were identical with those of the oily substance obtained in Example 35.

EXAMPLE 49 To a solution of 7.0 g of 2'-deoxy-3t,5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 6.3 ml of triethylamine and 5.7 g of 3,5-dimethylbenzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours The reaction liquid was treated in the same manner as described in Example 30 whereby 5.9 g (63%) of 3-(3-,5-dimethylbenzoyl)-2'-deoxy-3',5'di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 33.

EXAMPLE 50 To a solution of 4.1 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 20 ml of dry dioxane were added 2.1 ml of triethylamine and 2.6 g of 2,3-dimethoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 6000 for one hour. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aquecuasolution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform).The resultant oily substance was dissolved in about 30 ml of ethanol and the solution was treated with active carbon. The ethanol was distilled off under reduced pressure and the residue was again purified by column chromatography on silica gel (elution solvent: chloroform) whereby 4.7 g (81.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5- fluorouridine were obtained as an oily substance.

UV (#maxEtOH, nm): 265, 327 NMR #(ppm, CDCl3): Uridine moiety: 7.72 (d, H6), 6.26 (broad t, H1,), near 2.4 (m, H2,), 5.16-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5,), 2.02-2.68 (m, 2 x COCH2), 1.20-1.84 (m 4xCH2), 0.82-1.06(m, 2xCH3) Benzoyl moiety: 7.50-7.62 (m, H60), 7.10-7.22 (m, H4, H5), 3.88 (s, CH3O), 3.86 (s, CH30) Elementary analysis (as C28N35FN2O10): Calc. (%): C 58.13 H 6.10 N 4.84 Found (%): C 57.85 H 6.20 N 4.67 EXAMPLES 51-53 In the same manner as described in Example 50, 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives were prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 8.

TABLE 8

In General Yield Elementary analysis UV Formula (%) Empirical formula EtOH NMR (CDCI3) # (ppm) Ex. (R)m Calc. (%) C, H, N #max No. (n) Nature Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 51 2-ethoxy 8.50 C28H35FN2O9 259 7.69 (d, H6) 6.28 (broad-t, H1') 8.09 (dd, H6) 59.78 6.27 4.98 near 2.4 (m. H2') 5.14-5.30 (m, H3') 7.55 (td, H4) (3) Oily 59.92 6.44 5.04 324 4.18-4.54 (m, H4', H5') 2.00-2.64 (m, 2xCOCH2) 7.04 (t, H5) sub 1.12-1.82 (m, 4xCH2) 0.80-1.06 (m, 2xCH3) 6.92 (d, H3) 4.02 (q, CH2O) 1.26 (t, CH3) 52 2,3- 7.12 C30H39FN2O10 213 7.74 (d, H6) 8.26 (broad-t, H1') 7.48-7.60 (m, H6) dimethoxy Oily 59.40 6.48 4.62 near 2.4 (m, H2') 5,16-5,30 (m, H3') 7.08-7.22 (m, H4, H5) sub 58.89 6.56 4.35 265 4.20-4.46 (m, H4', H5') 2.10-2.54 (m, 2xCOCH2) 3.86 (2xCH3O) (4) 1.20-1.78 (m, 6xCH2) 0.78-1.02 (m, 2xCH3) 326 53 4-methoxy 7.90 C27H33FN2O9 220 7.73 (d, H6) 6.23 (broad-t, H1') 7.84 (d, H2, H6) Oily 59.12 6.08 5.11 near 2.4 (m, H2') 5.12-5.28 (m, H3') 6.93 (d, H3H5) (3) sub: 58.89 6.23 4.98 286 4.16-4.54 (m, H4', H5') 2.00-2.62 (m, 2xCOCH35 3.86 (s, CH3O) 1.12-1.80 (m, 4xCH2) 0.78-1.04 (m, 2xCH3) EXAMPLE 54 To a solution of 2.0 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of chloroform were added 0.95 ml of triethylamine and 1.08 g of 4-n-propoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 50 -60 C for 30 minutes. The reaction liquid was cooled and washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate.The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform). The resultant purified oily substance was dried at room temperature under reduced pressure whereby 2.1 g (77.8%) of 3-(4-n-propoxybenzoyl)-2'-deoxy-3',5'di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.

V(#maxEtOH, nm): 220,288 NMR 8(ppm, CDCI3): Uridine moiety: 7.78 (d, H6), 6.24 (broad-t, H1'), 5.16-5.28 (m, H3') 4.24-4.52 (m, H4', H5'), 2.24-2.46 (m, 2xCOCH3), 1.20-1.92 (m, 6 x CH2), 0.82-1.10 (m, 2 x CH3) Benzoyl moiety: 7.86 (d, H2, H6), 6.92 (d, H3, H5), 3.99 (t, CH2O), near 1.7 (m, CH2), near 1.0 (m, CH3) Elementary analysis (as C31H41FN2O9): Calc. (%): C 61.58 H 6.83 N 4.63 Found (%): C 61.35 H 6.98 N 4.43 EXAMPLE 55 To a solution of 2.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 30 ml of chloroform were added 1.0 ml of triethylamine and 0.98 g of 2-methoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 5 hours.The reaction liquid was treated in the same manner as described in Example 54 whereby 2.1 g (79.8%) of 3-(2-methoxybenzoyl)-2'-deoxy-3',5'-di O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.

UV(EtOH, nm): 259, 322 NMR b(ppm, CDCI3): Uridine moiety: 7.69 (d, H6), 6.16 (broad-t, H1,), near 2.4 (m, H2,), 5.14-5.28 (m, H3,), 4.18-4.40 (m, H4,, H6,), 2.18-2.46 (m, 2 x COCH2), 1.14-1.80 (m 4 x CH2), 0.84-0.98 (m, 2 x CH3) Benzayl moiety: 8.06 (dd, H6), 7.52 (td, H4), 7.04 (t, H5), 6.92 (d, H3), 3.78 (s, CH3O) Elementary analysis (as C27H33FN2O9): Calc. (%): C 59.12 H 6.06 N 5.11 Found (%):C 58.68 H 6.02 N 4.80 EXAMPLE 56 To a solution of 2.0 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 30 ml of chloroform were added 1.0 ml of triethylamine and 1.2 g of 2,3-dimethoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 50-60 C for 2 hours. The reaction liquid was cooled and then treated in the same manner as described in Example 54 whereby 4.6 g (79.3%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 50.

EXAMPLE 57 To a solution of 4.1 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 10 ml of pyridine were added 4.3 g of 4-n-butoxybenzoyl chloride. The mixture was subjected to reaction at 50-60 C for 12 hours. The reaction liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was subjected, as in Example 50, to the column chromatography and the treatment with an active carbon whereby 4.6 g (78.0%) of 3-(4-n-butoxybenzoyl)-2'-deoxy-3',5'-di-O-npentanoyl-5- fluorouridine were obtained as an oily substance.

UV (#maxEtOH, nm):221,289 NMR b(ppm, CDCI3): Uridine moiety: 7.76 (d, H6), 6.27 (broad-t, H,'), near 2.4 (m, H2,), 5.16-5.32 (m, H3,), 4.20-4.58 (m, H4,, H5,), 2.04-2.69 (m, 2 x COCH2), 1.15-1.96 (m, 4xCH2), 0.82-1.12 (m, 2xCH3) Benzoyl moiety: 7.88 (d, H2, H6), 6.95 (d, H3, H5), 4.06 (t, CH2O), near 1.7 (m, 2xCH2), near 1.0 (m, CH3) Elementary analysis (as C30H39FN209): Calc. (%): C 61.01 H 6.66 N 4.74 Found (%):C 61.00 H 6.74 N 5.16 EXAMPLE 58 To a solution of 4.1 g of 2'-deoxy-3',5')di-0-n-pentanoyl-5-fluorouridine in 20 ml of dioxane were added under ice cooling 2.1 ml of triethylamine and 2.1 9 of 4-n-butoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 5060oC for 2 hours. The reaction liquid was treated in the same manner as described in Example 50 whereby 5.0 g (84.6%) of 3 (4-n-butoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 57.

EXAMPLE 59 To a solution of 2.0 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 40 ml of diethyl ether were added 0.95 ml of triethylamine and 0.93 g of 3-methoxybenzoyl chloride. The. mixture was subjected to reaction at room temperature for 10 hours. The reaction liquid was cooled and then treated in the same manner as described in Example 54 whereby 1.6 g (61.5%) of 3-(3-methoxybenzoyl)-2'deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an only substance.

UV (-maxEtOH, nm): 220,261,318 NMR #(ppm, CDCl3): Uridine moiety: 7.76 (d, H6), 6.24 (broad-t, H,'), near 2.4 (m, H2,), 5.14-5.28 (m, H3'), 4.26-4.44 (m, H4,, H6,), 2.18-2.50 (m 2 x COCH2), 1.20-174 (m, 6 x CH2), 0.82-0.96 (m, 2 x CH3) Benzoyl moiety: 7.12-7.50 (m, aromatic H), 3.86 (s, CH3O) Elementary analysis (as C29H37FN2O9): Calc. (%): C 60.41 H 6.47 N 4.86 Found (%): C 60.15 N 6.52 N 4.71 EXAMPLE 60 To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of acetonitrile were aded 3.5 ml of triethylamine and 3.4 g of 4-methoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 6 hours.The reaction liquid was concentrated under reduced pressure and the residue as dissolved in ethyl acetate.

The ethyl acetate solution was treated in the same manner as described in Example 54 whereby 4.5 g (78.0%) of 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an oily substance.

UV (#maxEtOH, nm): 221,287 NMR (ppm, CDCI3): Uridine moiety: 7.75 (d, H6), 6.24 (broad-t, H,'), near 2.4 (m, H2,), 5.08-5.34 (m, H3,), 4.18-4.54 (m, H4,, H5,), 2.04-2.84 (m, 2 X COCH2), 1.18-1.90 (m, 6 x CH2), 0.76-1.06 (m, 2 x CH3) Benzoyl moiety: 7.87 (d, H2, H6), 6,93 (d, H3, h5), 3.86 (s, CH3O) Elementary analysis (as C29H37FN209): Calc. (%): C 6-0.41 H 6.47 N 4.86 Found (%): C 60.78 H 6.59 N 4.69 EXAMPLE 61 To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of acetonitrile were added 3.5 ml of triethylamine and 4.0 g of 2,3-dimethoxybenzoyl chloride.The mixture was subjected to reaction at room temperature for 2 hours and then at 50-60 C for one hour. The reaction liquid was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was trated in the same manner as described in Example 54 whereby 3.9 g (64.3%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluoruridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 52.

EXAMPLE 62 To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 20 ml of dioxane were added 2.1 ml of triethylamine and 2.2 g of 4-n-propoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 600C for 30 minutes. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by' distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform).The resultant purified oily substance was dried at room temperature under reduced pressure whereby 5.1 g (84.3%) of 3-(4-n-propoxybenzoyl-2'-deoxy-3' ,5'-di-O-n-pentanoyl-5- fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 54.

EXAMPLES 63-70 In the same manner as described in Example 62, 2'-deoxy-3',5'-di-0-n-alkylcarbonyl-5- fluorouridine derivatives are prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 9.

TABLE 9

In General Elementary analysis UV Formula I Empirical formula EtOH NMR (CDCl3) # (ppm) Ex. (R)m Yield Calc. (%) C, H, N #max (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 63 3,5-di- 74.3 C28H33FN2O10 217 7.76 (d, H6) 6.24 (broad-t, H1') 6.96-7.08 (m, H2, H6) methoxy 58.13 6.10 4.84 near 2.4 (m, H2') 5.15-5.30 (m, H3) 6.68-6.76 (m, H4) (3) Oily 57.91 6.25 5.09 274 4.20-4.44 (m, H4',H5') 2.16-2.52 (m, 2xCOCH1) 3.82 (s, 2xCH3O) sub 1.16-1.76 (m, 4xCH2) 0.80-1.04 (m, 2xCH3) 335 64 4-ethoxy 79.8 C30H39FN2O9 220 7.78 (d, H6) 6.28 (broad-t, H2') 7.88 (d, H2, H6) (4) 61.01 6.66 4.74 near 2.4 (m, H2') 5.14-5.32 (m, H3') 6.95 (d, H3, H5') Oily 60.82 6.84 4.98 289 4.22-4.58 (m, H4', H5') 2.04-2.63 (m, 2xCOCH3) 4.13 (q, CH2O) sub 1.14-1.86 (m, 6xCH2) 0.78-1.04 (m, 2xCH3) near 1.4 (m, CH3) 65 4-n-butoxy 78.0 C32H43FN2O9 220 7.75 (d, H6) 6.29 (broad-t, H1') 7.87 (d, H2, H5) (4) 82.12 7.00 4.53 near 2.4 (m, H2') 5.16-5.34 (m, H3') 6.95 (d, H3, H5) 4.07 (t, CH2O) Oily 82.27 7.38 4.78 289 4.22-4.60 (m, H4', H5') 2.06-2.70 (m, 2xCOCH2) near 1.7 (m, 2xCH2) sub 1.16-1.92 (m, 6xCH2) 0.80-1.16 (2xCH3) near 1.0 (m, CH3) 66 2-methoxy 7.85 C29H37FN2O9 259 7.69 (d, H6) 6.18 (broad-t, H1') 8.06 (dd, H6) 60.41 6.47 4.86 near 2.4 (m, H2') 5.14-5.30 (m, H3') 7.52 (td, H4) (4) Oily 60.51 6.17 4.87 322 4.18-4.52 (m, H4', H5'), 2.14-2.44 (m, COCH2) 7.03 (t, H5) sub 1.14-1.80 (m, 6xCH2) 0.80-0.96 (2xCH3) 3.78 (s, CH3O) 67 3-methoxy 71.1 C27H32FN2O6 220 7.76 (d, H6) 6.25 (broad-t, H1') 7.12-7.48 59.12 6.06 5.11 261 near 2.4 (m, H2') 5.15-5.30 (m, H3) (m, aromatic H) (3) Oily 59.26 6.16 5.40 318 4.24-4.46 (m, H4', H5') 2.18-2.46 (m, 2xCOCH2) 3.86 (s, CH3O) sub 1.12-1.80 (m, 4xCH2) 0.82-1.02 (m, 2xCH3) 68 2-ethoxy 61.5 C30H39FN2O9 259 7.69 (d, H5) 6.28 (broad-t, H1') 8.09 (dd, H6) 61,01 6.66 4.74 near 2.4 (m, H2') 5.15-5.30 (m, H3') 7.55 (td, H4) (4) Oily 61.22 6.84 4.56 324 4.18-4.54 (m, H4', H5') 2.04-2.68 (m, 2xCOCH2) 7.04 (t, H5) sub 1.14-1.86 (m, 6xCH2) 0.80-1.04 (m, 2xCH3) 6.92 (d, H3) 4.02 (q, CH2O) near 1.3 (m, CH3) TABLE 9 (Continued)

In general Elementary analysis UV Formula I Empirical formula EtOH NMR (CDCL3) # (ppm) Ex. (R)m Yield Calc. (%) C, H, N #max No. (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 69 4-ethoxy 73.3 C28H35FN2O9 220 7.76 (d, H6) 6.28 (broad-t, H1') 7.88 (d, H2, H6) 59.78 6.27 4.98 near 2.4 (m, H2') 5.14-5.30 (m, H3') 8.95 (d, H3, H5) (3) Oily 59.61 6.27 5.21 288 4.20-4.56 (m, H4', H5') 2.04-2.68 (2xCOCH2) 4.14 (q, CH2O) sub 1.12-1.82 (m, 4xCH2) 0.78-1.06 (m, 2xCH3) 1.35 (t, CH3) 70 4-n-propoxy 76.4 C29H37FN2O9 220 7.78 (d, H6') 6.26 (broad-t, H1') 7.86 (d, H2, H6) 60.41 6.47 4.86 near 2.4 (m, H2') 5.16-5.20 (m, H3') 6.92 (d, H3, H5) Oily 60.73 6.21 4.89 289 4.20-4.58 (m, H4', H5') 2.25-2.46 (m, 2xCOCH2) 4.00 (t, CH2O) sub 1.16-1.96 (m, 4xCH2) 0.82-1.10 (m, 2xCH3) near 1.7 (m, CH2) near 1.0 (m, CH3) EXAMPLE 71 Using 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine and 4-methoxybenzoyl chloride, the reaction and after-treatments were carried out in the same manner as described in Example 60.The resultant oily substance was recrystallized from ethanol whereby 3-(4-methoxybenzoyl)-2'-deoxy-3',5'di-0-n-hexanoyl-5-fluorouridine having a melting point of 81-82 C was obtained (yield: 75.0%) as white needle crystals.

UV (#maxEtOH, nm): 221,287 NMR #(ppm, CDCl3): Uridine moiety: 7.75 (d, H6), 6.24 (broad-t, H1), near 2.4 (m, H2,), 5.08-5.34 (m, H3,), 4.18-4.54 (m, H4', H5'), 2.04-2.64 (m, 2 x COCH2), 1.16-1.90 (m, 6 x CH2), 0.76-1.06 (m, 2 x CH3) Benzoyl moiety: 7.87 (d, H2, H6), 6.93 (d, H3, H5), 3.86 (s, CH2O) Elementary analysis (as C29H37FN2O9): Calc. (%): C, 60.41; H, 6.47; N, 4.86 Found (%):C, 60.30; H, 6.73; N, 4.80 EXAMPLES 72-74 The oily substances obtained in Examples 53, 64 and 69 were recrystallized from ethanol in the same manner as described in Example 71 whereby 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n- pentanoyl-5-fluorouridine having a melting point of 84-85 C (yield: 74.0%), 3-(4-ethoxybenzoyl)-2' deoxy-3',5'-di-O-n-haxanoyl-5-fluorouridine having a melting point of 90-91 C OC (yield: 75.0%) and 3 (4-ethoxybenzoyl)-2'-deoxy-di-O-n-pantanoyl-5-fluorouridine having a melting point of 88-89 C (yield: 86.0%) were obtained, respectively, as white needle crystals. The physical characteristics of these substances were identical in UV-adsorption spectra, NMR spectra and elementary analytical data with those of the corresponding oily substances obtained in Examples 53, 64 and 69.

EXAMPLE 75 To a solution of 3.0 g of 2'-deoxy-di-O-n-pantanoyl-5-fluorouridine in 30 ml of dry dioxane were added 2.0 ml of triethylamine and 1.6 g of 3,4-methylenedioxybenzoyl chloride. The mixture was subjected to reaction at 700C for one hour. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was dissolved in a small amount of chloroform and filtered to remove insoluble matter.

The filtrate was purified by column chromatography on silica gel (elution solvent: chloroform) whereby 1.2 g (29.0%) of 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-di-O-n-pantanoyl-5-fluorouridine were obtained as an oily substance.

UV (,AEmTxH, nm): 206, 236, 278, 321 NMR (ppm, CDCI3): Uridine moiety: 7.78 (d, H6), 6.28 (broad-t, H1,), near 2.4 (m, H2,), 5.18-5.32 (m, i 13), 4.24-4.56 (m, H4,, H5'). 2.20-2.52 (m, 2 x COCH2) 1.18-1.84 (m, 4 x CH2), 0.88-1.00 (m, 2 x CH3) Benzoyl moiety: 7.52 (dd, H6), 7.38 (d, H5). 6.86 (d, H2), 6.08 (s, CH2) EXAMPLE 76 Using 2'-deoxy-di-O-n-hexanoyl-5-fluorouridine and 3,4-methylenedioxybenzoyl chloride, the reaction and aftertreatments were carried out in the same manner as described in Example 75 whereby 1.3 g (32.0%) of 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5 fluorouridine were obtained.

UV (#maxEtOH, nm): 206, 236, 278, 321 NMR #(ppm, CDCl3): Uridine moiety: 7.74 (d, H6), 6.26 (broad-t, H1'), 5.18-5.28 (m, H3,) 4.24-4.42 (m, H4,, H5,), 2.18-2.50 (m, 2 x COCH2), 1.18-1.76 (m, 6 x GH2), 0.82-0.98 (m, 2 x CH3) Benzoyl moiety: 7.50 (dd, H6), 7.36 (d, H5), 6.86 (d, H2), 6.06 (s, OH2) The preparation of the anti-tumor agents of the present invention will now be illustrated in more detail by way of the following typical preparation examples.

(A) Hard capsule preparations: 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5- fluoridine 100mg milk sugar 160mg crystalline cellulose 27 mg hydroxypropylcellulose of a low degree of substitution 10 mg magnesium stearate 3 mg total 300 mg Capsules (No. 2) are formed according to a conventional method so that each capsule may contain the above dose of ingredients. In general 3-9 capsules per day can be administered orally to adult patients.

Recipe 2: The compound of the present invention 80 mg cane sugar esters of fatty acids 20 mg milk sugar 165 mg crystalline cellulose 24 mg hydroxypropylcellulose of a low degree of substitution 8 mg magnesium stearate 3 mg total 300 mg The following compounds can be used as the compounds of the present invention for the above recipe:' 3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine 3-(2,3-methoxybenzoyl)-2'-deoxy-di-O-n-propionyl-5-fluorouridine Capsules are formed according to a conventional method so that each capsule may contain the above dose of ingredients. In general, 3-9 capsules can be administered orally to adult patients.

Recipe 3: The compound of the present invention 80 mg polyethylene glycol 6000 20 mg milk sugar 161 mg crystalline cellulose 21 mg hydroxypropylcellulose 8 mg carboxymethylcellulose 5 mg talc 5 mg total 30C mg The following compounds can be used as the compound of the present invention for the above recipe: 3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine 3-(4-ethoxybenzoyl)-2'-deoxy-di-O-n-pentanoyl-5-fluorouridine First, pills are formed according to a usual method, using the compound of the present invention, polyethylene glycol 6000, milk sugar, crystalline cellulose and hydroxypropylcellulose. The pills are then incorporated with carboxymethylcellulose and talc and the mixture is worked up according to a conventional method to capsules (No. 2) in such a manner that each capsule may contain the above dose of ingredients.As a rule, 3-9 capsules per day can be administered orally to adult patients.

(B) Soft Capsuie preparations Recipe: the compound of the present invention 50 mg polyethylene glycol 400 250 mg propylene glycol 10 mg bleached beeswax 10 mg total 320 mg The following compounds can be used as the compound of the present invention for the above recipe: 3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine 3-(3-benzoylbenzoyl)-2'-deoxy-di-O-n-palmitoyl-5-fluorouridine 3-(2-methylbenzoyl)-2'-deoxy-di-O-n-pentanoyl-5-fluorouridine 3-(3-methylbenzoyl)-2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine 3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine 3-(4-n-propoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fl uorouridine Capsules are formed according to a conventional method so that each capsule may contain the above dose of ingredients.As a rule, 3-9 capsules per day can be administered orally to adult patients.

(C) Syrup preparations Recipe 1: A vial containing the under-mentioned ingredients 3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5 fluorouridine 10 mg Carboxymethylcellulose calcium 4 mg white sugar 486 mg total 500 mg Recipe 2: An ampoule containing the under-mentioned ingredients polyethylene glycol 400 3000 mg purified water 1000 mg total 4000 mg On oral administration, the solution in the ampoule is added to the vial and the mixture is well shaken. The resultant syrup corresponds to a unit dose and can be administered orally 3-9 times per day.

It is understood that the preceding representative examples may be varied within the scope of the present specification both as to reactants and reaction conditions, by one skilled in the art to chieve essentially the same results.

As many widely different embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be construed that this invention is not limited to the specific embodiments thereof except as defined in the appended claims.

Claims

1. 2'-Deoxy-3',5'di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two R groups are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members in alkylenedioxy group.

2.2'-Deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as claimed in claim 1, wherein in the general formula (I) is a methyl, methoxy, ethoxy, or propoxy group, or a fluorine athom.

3. 2'-Deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives as claimed in claim 1, wherein R in the general formula (I) is a methoxy group and m is 2.

4. 4.2'-Deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as claimed in any one of the preceding claims wherein n is 3, 4 or 5.

5. 3-Benzoyl-2'-deoxy-3',5'-di-0-pentanoyl-5-fluorouridine.

6. 3-Benzoyl-2'-deoxy-3',5'-di-0-hexanoyl-5-fluorouridine.

7. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine.

8. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl-5-fluorouridine.

9. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-0-hexanoyl-5-fluorouridine.

10. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl-5-fluorouridine.

11. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-hexanoyl-5-fluorouridine.

12.3-(2,3-Dimethyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl or -hexanoyl-5-fluorouridine.

13. 3-(2,3-Dimethoxy)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl or-hexanoyl-5-fluorouridine.

14. 3-(2,3 or 4-Ethyl)-benzoyl-2'-deoxy-3',5'-di-O-pen tanoyl or -hexanoyl-S4luorouridine.

15. 3-(2,3 or 4-Ethoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine.

16. 3-(2,3 or 4-P ropoxy)-benzoyl-2'-deoxy-3' ,5-di-0-pentanoyl or -hexanoyl-5-fluorouridine.

17. 3-(2,3 or 4-Fluoro)-benzonyl-2'-deoxy-3',5'-di-O-pentanoyl or -hexanoyl-5-fluorouridine.

18. 3-(2,4-Dichloro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or-hexanoyl-5-fluorouridine.

19. A process for the preparation of 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives of the general formula

wherein R, m and n are as defined in claim 1 which comprises reacting a 2'-deoxy-3',5-di-0alkylcarbonyl-5-fluorouridine of the general formula:

wherein n is as defined above, with a benzoyi halide of the general formula:

wherein R and m are as defined above and Hal is a halogen atom.

20. A process as claimed in claim 19 wherein Hal in the general formula (III)i is a chlorine atom.

21. A process as claimed in claim 19 or claim 20 wherein the reaction is carried out in the presence of an acid-binding agent.

22. A process as claimed in claim 21 wherein the acid-binding agent is an aliphatic tertiary amine, an aromatic tertiary amine o a heterocyclic tertiary amine.

23. A process as claimed in claim 22 wherein the tertiary amine is triethylamine.

24. A process as claimed in any one of claims 1 9 to 23 wherein the reaction is carried out in the presence of an organic solvent.

25. A process as claimed in claim 24 wherein the solvent is diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide or dimethylsulfoxide.

26. A process as claimed in any one of claims 19 to 21, 23 or 25 wherein the reaction is carried out under ice cooling or at a temperature up to 700C in dioxane in the presence of triethylamine.

27. A process as claimed in claim 24 substantially as hereinbefore described with reference to any one of the Examples.

28. A 2'-Deoxy-3',5'-di-o-alkylcarbonyl-5-fluorouridine derivative as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 1 9 to 27.

29. An anti-tumor agent containing as an active ingredient thereof one or more 2'-deoxy-3',5-di O-alkylcarbonyl-5-fluorouridine derivatives as claimed in any one of claims 1 to 18, or claim 28.

30. An anti-tumor agent as claimed in claim 29 which includes pharmaceutically acceptable carrier or excipient.

31. An anti-tumor agent as claimed in claim 30 wherein the carrier is polyethylene glycol or a cane sugar ester of a fatty acid.

32. An anti-tumor agent as claimed in claim 29 substantially as hereinbefore described.