CA1127637A - 5-FLUORO-(.beta.-URIDINE OR 2'-DEOXY-.beta.-URIDINE) DERIVATIVES, A PROCESS FOR PRODUCING THE SAME AND A CARCINOSTATIC AGENT CONTAINING THE SAME - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
5-Fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivatives having an acyl group at the 3-position of the molecule. These compounds are useful as carcino-static agent. This disclosure relates to such compounds, a process for producing the same and a carcinostatic agent comprising such a compound.

Description

11~7637 1 This invention relates to a novel 5-fluoro-(Z-uridine or 2'-deoxy-~-uridine) derivative, a process for producing the same, and a carcinostatic agent comprising the same.
Carcinostatic substances which have hitherto been commercially available have problems in both carcinostatic activity and toxicity. Particularly, they induce, after administration, various symptoms such as a depression of leukocyte count, a depression of thrombocyte count, epilation, suppression of bone marrow, nausea and vomiting, diarrhea, and the like, which is considered as a problem in clinical treatments.
On the other hand, 5-fluoro-2'-deoxy-~-uridine, commonlly called FUDR, is already known to exhibit an intense carcinostatic activity in vitro and have a low toxicity (C. ~le:Ldelberger e~ al., E'roc. Soc.
Exp. Biol. Med., 97, 470 (1958)).
In vivo, however, it lacks persistency (in other words, it is excreted rapidly) and it is readily decomposed by nucleotide-phosphorylase to yield 5-fluorouracil (G. D. Birnie, Biochem. Biophys. Actd., 76, 315 (1963)) so that the above-mentioned properties which the time-dependent metabolic antagonist FUDR
originally has cannot be exhibited.
Under such clrcumstances, the present inventors ~2,7~;~7t 1 have conducted e~Lrnest studies with the aim of providing a compound halling an intense carcinostatic activity, a low toxicity and other excellent properties by increas-ing its protein-binding ability, preventing the decompo-sition in a living body and increasing its percistency.
As a resu]t, it has been found that the above-mentioned object can be realized by a compound represented by the general formula (I), which appear hereinafter.
It is an object of this invention to provide a novel 5-fluoro-(~-uridine or 2'-deoxy-~ uridine) derivative havirlg an acyl group at the 3-positl.on of the mo].ecu].e.
It is another object of this invention to provide a novel 5-fluoro-(~-uridine or 2'-deoxy-~-uridlne) derivative having an intense carcinostaticactivity and a low toxici.ty.
It is yet another object of this invention to provide a carcinostatic agent comprlsing a novel. 5-fluoro-(~-urid1rle or 2'-deoxt/-~,-ur:l.dirle) derivallve as its acti.ve ingredient.
It is still another ob~ect of this invention to provide a process for producing a novel 5-fluoro-(~-uri.di.ne or 2'-deoxy-~-uri.di.ne) derivative.
Other objects and advantages of this invention will be apparent from the following description.
According to this invention, there is provided a 5-fluoro-(~-uridine or 2'-deoxy-~-uridine) derivatives represented by the general formula (I):

llZ7637 Rl-N ~ F
o~NY
R2 ~ (I) l ~Iherein Rl represents acyl; R2 and R3, which may be identical or different, represent protected or unprotected hydroxyl; and R represents hydrogen or protected or unprotected hydroxyl, as well as to a process for produc-ing the same and a carcinostatic agent comprising thesame.
In the compounds of this invention represented by the general formula (I), R]- represents acyl. Specific examples of said acyl include aroyl, such as benzoyl, 3,4-methylenedioxybenzoyl, naphthoyl ancl the ].ike;
Cl 18 alkanoyl., such as acetyl., propionyl., butyryl, valeryl, isobutyryl, isovaleryl, pivaloyl., palmitoyl, stearoyl and the like; heterocyclic carbony]. (this heterocyclic ring contains l to 4 hetero atoms selected f`rom 0, S s~nd M), such as thenoyl, furoyl, thlazo]ylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, nicotinoyl and the like; and C2 5 alkenyl such as acryloyl, crotonoyl and the like. All these acyl groups may have one or more substituents selected from halogens, such as fluorine, chlorine, bromine, or iodine; hydroxyl; nitro;

~Z~;3~

1 cyano; amino; carboxyl; Cl 12 acyl, such as formyl, acetyl, propionyl, butyryl, acryloyl, crotonoyl, benzoyl, naphthoyl, furoyl, thenoyl and the like; halogen-sub-stituted derivati.ves of said acyl; Cl 12 acyloxy, such as acetyloxy, propiony]oxy, butyryloxy, acryloyloxy, benzoyloxy, naphthoyloxy, furoyloxy, thenoyloxy and the like; halogen-substituted drivatives of said acyloxy;
Cl 5 alkylamino such as methylamino, ethylamino, butylamino and the like; halogen-substituted derivatives of said alkylamirlo; d:i-Cl 5 al.ky1.amino, such as di.methylamino, diethylamlno, dibutylamino, methy:Lethylamino and the like; halogen-substituted derivatives of said dialkyl-amino; Cl 12 acylamino, such as acetylamino, propionyl-amino and the like; halogen-substituted derivati.ves of said acylam:Lno; Cl 5 alkyl, such as methyl, ethyl, propyl, butyl and the like; halogen-substituted derivatives of said alkyl; Cl 10 alkoxy such as methoxy, ethoxy, propoxy, butoxy, pentoxy, octyloxy and the~ like;
ha1.ogen-substit;uted deriva.ti.vec; of sa:l.cl alkoxy; Cl 5 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbony], butoxycarbonyl and the lilce; halogen-substituted derivatives of said a.lkoxycarbonyl; aryl such as phenyl, naphthyl and the like; halogen-substituted derivatives of said aryl; heterocyclic groups (this heterocyclic ring contains 1 to 4 hetero atoms selected from 0, S and M), such as fur~1, thienyl and the like and their halogen-substittlted derivatives; and the like.
As the protecting group in the protected hydroxyl groups ~Z7637 1 represented oy R-, R3 and R4, there may be employed those groups which are conventionally used for the protec-tion of hydroxy] group. Examples of said protecting group include Cl 10 alkanoyl, such a.s acetyl, propionyl, 5 isopropionyl, butyryl, isobutyryl, sec-butyryl, tert-butyryl and the like; Cl 10 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl and the like; Cl 12 acyloxy-Cl 12 acyl, such as acetyloxymethylcarbonyl, propionyloxymethyl-carbonyl, acetyloxyethylcarbonyl, ~-(acetyloxy)-propionyl, ~-(propionyloxy)-propionyl and the like;
substituted aroyl, such as p-chlorobenzoyl, p-methyl-benzoyl, p-nitrobenzoyl, m,p-dinitrobenzoyl and the like; and mono-, di- and tri-halogeno-C1 10 alkanoyl, such as chloroacetyl, dichloroacetyl, trichloroacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, bromo-acetyl, dibromoacetyl, tribromoacetyl, iodoacetyl, diiodoacetyl, tri.i.odoacetyl and the llke.
Among the above-rnentionecl comEJownds of this invention, preferable i.s a compound in which R is benzoyl substituted by fluorine or chloroacetylamino, or 3,4-methylened:Loxybenzoyl.
Al.l of the crystal forrns and solvates of the compounds represented by formula (I) were involved in the scope of the present invention.
The compound of this invention can be produced by reacting a compound represented by the general formula (II):

~27~37 HN

N
O (II) R5 ~ 0\

1 wherein R5 and R6 represent protected hydroxyl and R7 ~epresents hydrogen or protected hydroxyl wi.th a reactive der:Lvatlve of' a cornpound represented by the general formula (III):

RlOH (III) wherein R1 is as defined above, in the presence or absence of a ba.se, and then optionally subjecting the reaction product to alcoholysis to remove the protecting group from the protected h,ydroxyl group. In the gerleral formula (II), the protectlng groups of' the protected hydroxyl groups represerlted by R5, H6 and R7 may be the same as those of R2, R3 and R4 in the general formula (I). In order to selectively eliminate only the protecting group from t~le protected hydroxyl group after the reaction between the compound represented by the general formula (II) and the reactive derivative of the compound represented by the general formula (III), it is pre-ferable to use an active protectir!g group having an electronega.tlve y,roup. Specific examples of said active ~1;Z7~i37 1 prGtectin~ ~r~oup lnclude substituted benzoyl, such as p-nitrobenzoyl, m,p-dinitrobenzoyl and the like; mono-, di- or tri-halogenoa]kanoyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, fluoroacetyl, difluoro--acetyl, trifluoroacetyl, bromoacetyl, dibromoacetyl,tribromoacetyl, iodoacetyl, diiodoacetyl, triiodoacetyl and the like; trialkyl.silyl such as trimethyl.silyl and the like; and 1,3,2-dioxaphospholanyl such as ll-methyl-1,3,2-dioxaphospholanyl and the like.
In the general formula (III), R represents the same acyl group as mentioned above. Examples of said reactive derivative include acid halides, acid azides, acid cyanides, mi.xed acid anhydrides, active esters, active acid amides and the like. Depending on the kind of the reactive derivative used, an inorgani.c or organic base such as an alkali hydroxide, an alkali carbonate, an alkali acetate, triethylamine, triMethylamine, tributyl-amine, pyridine, N-methylmosphol:Lne or the like rnay be added. It is partlcularly preferable to u-se arl acid hallde such as acid chloride, acid bromide or the like in combination with triethylamine.
Specifical:l.y, the compound of this invention can be produced a;, follows:
A compound represented by the general formula (II) is dissolved or suspended in a solvent inert to the reaction, such as acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylforrnamide, diethyl ether, diiso-propyl ether, ben~ene, to].uene, dichloroethane, methylene ~7637 1 chloride, chlorofor!rl, ethyl acetate, methyl ethyl ketone or the li!~e or a mixtllre of two or more, and reacted with a reactive derivative of the compound represented by the general formula (III) at a temperature of -50C
to +100C, preferably at room temperature or an elevated temperature, in the presence or absence of the base.
The reaction is usually effected for 5 minutes to 24 hours.
In eliminating the protecting group from the protected hydroxyl group after completion of the reaction, alcoholysis is carried out by use of an a].cohol such as methanol, ethanol, proparlol, isoproparlol or the like in the presence of a base or an acid as a catalyst. The said base includes organic bases such as trimethylamine, tirethylamine, tributylamine, pyridine, N-methylmorpholine or the like. The said acid includes organic and inorganic aclds such as hydrogen chloride, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, trichloro-acetic acid, p-toluene sulfuric aci.d and the~ like.
When acyl is used as the pr-otectin~ group, :It is preferred to carry out the alcoholysis with methanol in the presence of triethylarnine as the catalyst. When trialkylsilyl or 1,3,2-dioxaphospholarlyl is used, it is preferred to carry out the alcoholysis with methanol in the presence of hydrogen chloride as the catalyst. This alcoholysis may be carried out either in succession to the above-mentioned reaction or after the product has been i.solated.
It is carried out in the abo~/e--mentioned solvent or a mixture of two or more of said solvents, or an alcohol.

~lZ7t;37 e alcorlol~sis is usuall~ carried out for 5 minutes to 1.2 hours, after which the objective cornpound is isolated by a conventional way, for example, a chemical means for separation and puri.fication such as solvent-extraction and the like.
The carcinostatic effect and acute toxicity of the typical compounds of this inventi.on are as f`ollows:
1. Experiment on the inhibition of Ehrlich solid tumor (a) ExperimentaL procedure Ehrlich ascites carcinoma was subcutaneously inoculclted lnto thc right inguina]. region of ddY mice (5 weeks o]d, malc, 8 mice per group) with 3 x 106 cells per mouse.
24 Hours after the inoculation, a test drug suspended or dissolved in 5% HCO 60 (a product manufactured by Nikkol) was adm:inistered intraperitoneally succes-sively once dai:ly for 7 days. To the control group, the same quantity as above of 5% HC0 60 was ~intraF)eritorlr?ally administered in the same rnanner l~ourte~rl dc~ , aft;er the inoculation, the tumor was excised an-l wei.ghed, from which the average turnor weight ratio between the test group and the control group (T/C) was deterrnined.

~Z763~

~ --=,' ~ __ ... _ . . _ O O a) r r~l 5 ~; ~ co c\ = r_ 5 à) ~ a co c~
O ~-~ o r .

~ a~
,c~ L~ ~ CO CO
~o ~. ~ . . .
r~ r~ \~ ~ o + + I +
_ _ .
hO
r~ \O o O O
C~ ~ ~ r,~l ::r ~ o -- -- t~

C~ ~
o ~, . . .

~Z~t~37 ___ . ._ _ ~ ~ ~s~ ~Y) ~ ~
~r L~ ~ ~ ~ ~
_ . _ ._ _ , = = C~, ,, I
_. . ___ _ =r -=t co ~ c~
.+,~ -~ + + + +
. ~ _ _ ,, o =
,.

~o ~, o l ~1 l o /~ C~ \ ~ H H

._____ _,.________ ______ ~ _._ __ _ =r Lr~ ~ t-L _ _ __ 1' 7~37 r ~ _ . _ _ r~) r~J r~) r~ r~l ~o .. .__ ___ __ _ _ ~ = = . = _ O

_ r-- r~ ~D r~l r\~ ,~
+ ~ ~ ~ +
_ _ _ _ 1~ r~ = _ _ _ __ __ _ ~ _ r .

~ C~ C~ V C~ C~

C~ --~ ~[~ r ¦ ~1 (~ [~

~C O O 1~ O
r~) _____ ~ ._._ ___ ___ _ .. __ _ ~Z7~37 __ ~ ~ _ __ .................. __ r~ ~ ¦ O Lr~ LS \ r o -,- ~ r~ r~ OJ
_~ _ , ._ __ ~ _ _ = _ = _ V

_ ~_ .......................... __ _ r- ~o c~ ~ Lr~ ~r + + + + + +

~d ¦ _ . _ _ ;) o _ _ , _ , ~ ~
,~ - .. _ .

l ~0 ~ O
O l ~ l C~
C~ O C~ O
O ~ /~\_ 0~ ~0 [~ \~ ~) O O O

__ . _ __ __ _ L~ ~ L-- r~ a~ O
r~ r I .-1 r-~ r~ L~l __ ___ ._.. _ ... _ ~L~Z~i3~

~,, __ _ ._ .. ' ~ Ql (~) (Y) __ _ ___ _ _ _ __ __ _ _ _ _ _ _ lL~. _ 1127~;~7 ~__. __ (`\I I:-\J ~ ~
__ _ _ .. _ _ _ ~r ~ ~ ,~
+ l+ + + rl O __ _ _ .,~
,~ ~ ~ , ~ a _ a . ~ a _ ._ __ :1:
o ~ o Z

~127637 1 (b) Experi.lental procedure Ehrlich ascites carcinoma was subcutaneously inoculated into the inguinal region of ddY mice (5 weeks old, male, 8 mice per group) with 3 x 10 cells per mouse. Six days after the inoculation, a test drug dissolved or suspended in 0.5% CMC solution was admini-stered orally to the test group successively once daily for 10 days, while the same quantity as above of 0.5% CMC solution was orally adrninistered to the control group. Twenty one days after the inoculation, the tumor wa; excised and welghed, from which the average tumor weight ratio betwecn the test group and the control group (T/C) was determlned.

Table 2 .__. .. _ Body No. of surviv- T/C
Compound Dose weight ing mice/No. of (No.) (mg/kg) change total mice used (%) ...... _ _ _ ___._ F'UDR 60 -2.7 8/8 11~3.6 5-Fu 30 -3.8 " 39.7

2 60 -0.4 ll 36.8 -Ll.l ll 34.0 27 60 -0.5 ll 30 0.5% CMC _ ~1.2 10/10 _ - ]6 -112~6~7 1 2. Experiment on the inhibition of Sarcoma-180 ascites tumor (a) Experimental procedure Sarcoma-180 ascites tumor was subcutaneously inoculated into the right inguinal region of ddY rnice ~5 weeks oldj male, 8 mice per group) with 3 x 106 cell.s per mouse. Twenty four hours after the inoculation, a test drug dissolved in 10% polyethylene glycol was administered intravenously to the test group successively once daily for 7 days, while the same quantity as above of 10% polyethylene glycol was lntravenously administered to the control group. Ten days after the inoculation, the tumor was excised and weighed, from which the average tumor weight ratio between the test group and the control group (T/C) was determined.

Table 3 Body - No. o r Jur vlv- rl~/c Compound Dose weight lng tnlcc/~lo~ of (No.) (mg/kg) chan~e total m:l.ce u.ed (~) . ._ ___ FODR ]0 +3-9 8/8 56.3 5-Fu 5 ~LI o 8/8 59.7 2 10 +4.1 8/8 46.2 27 10 +4.0 8/8 1~5 3 1 3. Acute toxicity test (a) The test compound was suspended in 0.25% CMC
solution and administered intraperitoneally to SLC~ddY
mice (5 weeks old, male, 6 mice per group). The number of dead mice was counted over the subsequent three weeks.
As a result, no dead mice were observed in the cases of compounds ~lo. 2, 11, 13, 18 and 27 at a dose of 1,000 mg/kg.
(b) The test compound was suspended in 0.25% CMC
solution and administered orally to SLC-ddY mice (5 weeks old, male, 6 mice per group). The number of dead mice was counted over the subsequent 3 weeks.
LD50 value was calculated according to the method o~
Van der Waerden.

I'able 4 Cornpound (No.) LD50 (mg/kg) _ ~ . .
FIJDR l328 5-Fu 259 21 _ 25LI0 27 > 2289 ~2~ 7 l 4. Carcinostatic test Experimental proceclure Ehrlich ascites carcinoma was subcutaneously inoculated into the right inguinal region of ddY mice (5 weeks old, male, 8 mice per group) with 8 x lO
cells per rnouse. Twenty four hours after the inoculation, 5, lO, 20 or Llo mg/kg of a test drug suspended or dissolved in polyethylene glycol was administered orally to the test group successively once daily for lO days, while the same quantity as above of 10% polyethylene glycol was administered orally to the control group. Fourteen days after the lnoculation, the tumor Was excised~ and weighed, from which the average tumor weight ratio between the test group and the control group (T/C) 1.5 was calculated. ED value was determined by the least square method.

Table 5 . . ~
Compound (~lo.) ED~I~ (nlg/kg) 30 (mg/kg) .. ___ ___ . _ FUDR 24 l9 5-Fu 25 ll _ _ l2 6. L~

l~Z7~

1 f'ro;r~ Tables 1, 3 and 5, it is understandable that the compounds of this invention have an excellent carcinostatic activity and exhibit their efficacy at a low dose. ~`rorn Table 2, i.t is understandable that the compounds of this invention are effective even against tumors which are in an advanced stage of growth. The results of acute toxicity tests (a) and (b) demonstrate that the compounds of this invention have much lower toxicity as compared with the control agents.
Carcinostatic agents containing the compounds of this invent:l.orl, i.e. 5-f].uoro-(~-uridi.ne or 2'-deoxy-~-uridine) deri.vat:lves, may be formulated in the usual way into conventional preparation forms such as tablet, capsule, syrup, injection or drip and May be administered either orally or non-orally. The dose is generally 0.1 - 300 mg/kg per day in 1 to 6 portions in the case of adu:Lt, though the dose and the number of repetitions of administration may be appropriately varied.
By way of the follow:Lrlg cxamples, the process for producing the compounds of this invention will be explained.

Example 1 (a) At room temperature, 1..15 ml of triethylami.ne was dropped into a mixture of 3 g of 3',5'-di-0-chloro-acetyl-5-fluoro-2'-deoxy-~-uridine, 1.15 ml of p-chloroben~oyl chloride and 7.5 ml of anhydrous methylene i3~

1 chloride ~ith stirrinG. The resulting mixture was subiected ~o reaction at room temperature for about 5 hours and thereafter washed with 20 ml of water, 20 ml saturated aqueous solution of sodium bicarbonate and 2G ml of water in this order. The organic layer was dried over anhydrous sodium sulfate and the solvent is distilled of`f under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
chloroform) to obtain 3.4 g (yield 95%) of amorphous

3-p-chlorobenzoyl-3',5'-di-O-chloroacetyl-5-fluoro-2'-deoxy-~-uridine.
IR (KBr) cln 1 ~C o ].'780, 1750(sh), 1715, 1670.
(b) In 10 ml of tetrahydrofuran was dissolved 3.4 g of the 3-p-chlorobenzoyl-3',5'-di-O-chloroacetyl-5-fluoro-2'-deoxy-~-uridine obtained in (a), to which 10 ml of methanol was added. While stirring the mixture at room temperature, 0.5 ml of triethylamine was added and the reaction was effected for about one hour.
The reaction mixture was concerltrated under rc~duced pressure and purif'ied by s:l.lica geL colulrlll chr matography (eluent: a 20 : 1 mixture of' chloroform and trlethanol).
The eluate was.concentrated under reduced pressure, and a small q-lantity of ethyl acetate was added to the concentrate. Thus, there was obtained 1.7 g (yield 94%) of' crystalline 3-p-chlorobenzoyl--5-f'luoro-2'-deoxy-~-uridine having a melting point of 152 - 155C.
IR (KBr) cm 1 ~C=0 1740, 1705, 1650 UV (ethanol) nm: ~ 261 llZ7~37 1 Rf value: 0.70 (cleve1oping solvent: eth~l acetate :
formic acid : water = 65 : 5 : 5) ExaMple 2 (a) At room temperature, 1.15 ml of triethylamine was added to a mixture of 3 g of 3',5'-di-0-chloroacetyl-5-fluoro-2'-deoxy-~-uridine, 1.73 g of p-fluorobenzoyl chloride and 7.5 ml of anhydrous methylene chloride with stirring. The resulting mixture was subjected to reaction at room temperature for about 4 hours and thereafter treated i.n the sarne manner as in Exarnple 1 (a). Thus, there was obta-ined ~l.l g (yield 98%) of amorphous 3-p-fluorobenzoy].-3',5'-d:i.-O-chloroacetyl-5-fluoro-2'-deoxy-~-uridine having a decomposition poi.nt of 225 -235C.
IR (KBr) cm 1 vc 0 1735, 1705, 1660 UV (ethanol) nm: ~max 256 Rf value: o.68 (developing solvent: n-hexane :
benzene : ethyl acetate = 1 : 1 : 2) (b) 4.1 g of the 3-p fluorob(~rlzoyl-3',5'-di-()-chloroacetyl-5--fluoro-2'-deoxy-~ ridirle obtained in (a) was dissol~Jed i.n a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of methanol. To the resultin~
mixture waC.; added 0.5 ml of triethylamine, and the reaction was effected at room temperature for 4 hours.
I'hereafter, the reaction mixture was treated in the same manner as in Exam~le 1 (b). Thus, there was obtained 2.38 g (yield 88%) of 3-p-fluorobenzoyl-5-~Z7~37 1 fluoro-2'-deoxy-~-uridirle ln the form of white crystals having a me,ting point of 130 - 133C.
IR (KBr) cm 1 vc 0 1745, 1705, 1660(sh), 1640 UV (ethanol) nm: AmaX 208, 255 Rf value: 0.73 (developing solvent: ethyl acetate :
formic acid : water = 65 : 5 : 5) Example 3 (a) At roorn temperature, 1..15 ml of triet;hylamine was dropped into a mixture of 3 g of 3',5'-di-0-chloroacetyl-5-fluoro-2'-deoxy-~-uridine, 2.1 g of p-chloroacetylaminobenæoyl. ch:loride and 7.5 rnl of anhydrous rnethylerle chloride with stirring, and the resulting mixture was subjected to reaction for about

4 hours. Then the solvent was distilled off under reduced pressure, and the residue was dissolved i.n ethyl acetate and treated ln the same manner as in Example 1 (a).
Thus, there was obtained 3.95 g (yield 90%) of crystal-line 3-p-chloroacetylaminobenæoy]-3',5'-d:L-0-ch].oroacet-.yl.-

5-fluoro-~'-deoxy-~-urldlne hcLvirlrg a rn(:lt:l.nf-~ poi.rlt of IR (KBr) cm l: vc=O 1740, 1710, 16f.~0 UV (ethano:l) nm: An,aX 300 Rf value: 0.43 (del/elol)ing solvent: n-helcclne :
benYene : ethyl acetate = 1 : 1 : 2) (b) In a mixed solvent of 10 ml of tetrahydrofuran and 10 ml of methanol was dissolved 3.95 g of the 3-p-chloroacetylamlnobenzoyl-3',5'-di-O-chloroacetyl-5-1 fluoro-2-deoxy-~-uridine obtained in (a). While stirring the solution at room temperature, 0.5 ml of triethylamine was added and the resulting mixture was subjected to reaction for about 4 hours. Thereafter, the mixture was treated in the same manner as in ~xample 1 (b), except that the eluent for the column chromatography was a 10 : 1 mixture of chloroform and methanol. Thus, there was obtained 2.39 g (yield 80.5%) of crystalline 3-p-chloroacetylaminobenzoyl-5-fluoro-2'-deoxy-~-uridine having a melting point of 133 - 137C.
IR (KBr) cm 1 vc 0 1735, 1700(sh), 1650 UV (ethanol) nm: ~ x 205, 223, 301 ~f` value: 0.~1 (drveloping solvent: ethyl acetate :
formic acid : water = 65 : 5 : 5) Example 4 (a) At room temperature, 1.15 ml Or triethylamine was dropped into a mixture of 3 g of 3',5'-di-O-chloro-acetyl-5-fluoro-2'-deoxy-~-uridine, .7 g of p-dimethyl-aminobenzoyl chloride and 7.5 ml of anhydorus methy]r-rle~
chloride with stirrlrlg. The resulting rnlxturr-.~ was sub~ected to reaction at rc~m temperature for abou-tfive hours and the reaction mixture was then washed with 20 ml of water, 20 ml of` saturated aqueous solution of sodium bicarbonate and 20 ml of water in this order. It was dried over anhydrous sodium sulfate and ~he solvent was distilled off under reduced pressure, after which the residue was purified by silica gel column chromatography ~' - 2l~ -llZ7637 1 ~ith chloroform 2S an eluent to obtain 3.8 g (yield 93%) of amorphous 3-p-dimethylaminobenzoyl-3',5'-di-0-chloroacetyl-5--fluoro-2'-deoxy-~-uridine.
IR (KBr) cm 1 vc 0 1725, 1.680, 1655 (b) In 10 ml of tetrahydrofuran was dissolved 3.8 g of the 3-p-dimethylaminobenzoyl-3l,5'-di-O-chloroacetyl-5-fluoro-2l-deoxy-~-uridine obtained in (a), to which 10 ml of methanol was added. While stirring the solution at room temperature, 0.5 ml of triethylamine was added thereto and the reaction was effected for about one hour.
Then the reaction mixture was concentrated under reduced pressure and the residue was purified by si].i.ca gel column chromatography (eluent: a 20 : 1 mixture of chloroform and methanol). The eluate was concentrated under reduced pressure and a small quantity of ethyl acetate was added to the concentrate. Thus, there was obtained 2.5 g (yield 92%) of crystalline 3-p-dimethyl-aminobenzoyl-5--fluoro-2'-deoxy-~-uridine having a melting point of 152 - 15LlC.
IR (KBr) crn 1 ~C=0 1720~ 1695(r;h), :l.680, 1655 UV (ethanol) nrn: ~rnax 204, 250, 274, 350 Rf value: ~).6LI (developing solvent: ethyl aceta,te :
forrllic acid : water = 65 : 5 : 5) Example 5 The cornpounds listed :in Table 6 were obtained in yiel,ds ranging from about 85% to 100% by carrying out the condensation reaction in the same manner as in Example 1 (a)-- 2~ -11~7637 ~1 _ O O O _ Ic: ~ ~o ~o ~o s ~ ~, ~
o o L~ o L~ o ~ o ~o t-~o _ o^o^ o Lr~ o^
~1 ~ L~ o _r ~O _r ~
~1 ~ ~1 ~r~ _ _ _ ~
~ O ~ ~
~ Z--~ O ~ ~1 L~ O ~oo E-J ~ l ~ ~C,L O ~O ~o ~o O L~ L~ o ~ ~o ~ ~
~ L~ Lr~ C~
C~ ~1~ -1 -r ~1 ~ .___._ _ ___, ____ ._ ~

~ O O O ~
0~\0 ~1 ~ ~ rY~
C~ :C ~
_ ___ _ __ _ 1~27ti37 _ j _ .. __ 0~ ~ 10 ~D~ O

r-l O r-l 1._ 1~ ~O 1-- t--r1 rl~l r I ~1 ~_ L

~ .
o ~o W ~r I r i E-l u~ ~
O O O O
t-- t-- t-- t~
~1 r-l r-1 .
15~ O C~ L~'~ C~
r~: ~ --r ~ r I r-lt__ ~
____ . __ _ _ __ _ T = ~ / ~ ~ ~ J

I____ 2r~ _ 1~27637 1 E~ample 6 The compounds listed in Table 7 were obtai.ned in yields ranging from 85% to 90% by repeating the procedures of Example 1 (a) and (b).

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O X ~ ~J ~J N ~J
r~, ~ ~I Lt~ ~~ ~ r-l .~ 00 L(~\ U~ ~O L~ LJ~\
a, ~ ~ ~ ~ ~ ~ J~
~ ,~ ~ ~ ~ ~ ~ _ cO cr~ ~O L~ Lr~ C~
L~ O O O O O
~U ~ ~I 0~ ~ ~ I
_ _ _ _ O L~ O O O O
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__ __._ __ ~1~7637 ExamplQ 7 In 10 ml of chloroform was suspended 2.46 g (0.01 mole) of 5-fluoro-2'-deoxy-~-uridine, to which 5.5 ml (0.04 mole) of triethylamine and 2.8 ml (0.022 mole) of trimethylsilyl chloride were added in this order.
The mixture was subjected to reaction under reflux for one hour, after which 2.2 g (0.012 mole) of 3,4-methylene-dioxybenzoyl chloride was added thereto and the mixture was refluxed for an additional 30 minutes. While cooling the reaction rnixture wlth ice, 10 ml of 1 N rnethanolic solution of hydrogen chloride was added. The mixture was stirred at that temperature for 30 minutes and then neutralized with triethylamine. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate, after which the resulting solution was wc~shed with dilute hydrochloric acid, saturated aqueous solution of sodium bicarbonate and water in this order, dried over anhy(lrous magnesiuM
sulfate, ancl subJectecl to distll:Lation under reduced pressure to remove the sol~ent. Thereafter, the crystals of the objective compound was obtained by the following procedure (a) or (b):
(a) The residue was mixed with 40 ml of a chloroform-methanol mixture (20 : 1) and the insoluble matter was collected by f`iltration to obtain ,.7 g (yield 94%) of crystalline 3-(3,4-methylenedioxybenzoyl)-5-fluoro-2'-deoxy-~-uridine having a melting point of 133 - 135C.
Rf value: 0.5~ (developing solvent: chloroform :
acetone : methanol = 5 : 5 : 1) ~127~37 Speci.fic rotation [~D0: 50.2 (C=2 in acetone) NMR (CD3COCD3) ~ value:

~-E(g) O

(d ~ ~ ~ CO - N ~
H) o ~ ~E(h) ~ N H(i) H(f) HO H(b) ,~
H(b) H(e) OH H(a) ( c ) a (2.31, q, 2H) f (6.80, d, lH) b (3.88, m, 3H) g (7.4l, d, lH) c (4 37, m, 3H) h (7.63, q, lH) d (6.10, S, 2H) i (8.40, d, lH) e (6.2]. "n, ].~

l (b) Thre :resldue was dissolved in 20 ml of a chloroforrn-methanol mixture (30 : 1). After ultrasonica-tion (150 W; 28 KHz) at 15C f`or 6 hours, 3.9 g (yield 99%) of 3-(3,4-rrletElylenedioxybenzoyl)-5-fluoro-2'-deoxy-~-uridine was obtained by filtratiorl. The Rf value, specific rotation and NMR of thi.s product were identical with those of the product obtained in above (a).

l~LZ7~.~7 1 Example 8 In ]0 ml of' chloroform was suspended 2.46 g (0.01 mole) of 5-fluoro-2'-deoxy-~-uridine, to which 5.5 ml (o 04 rnole) of triethylamine and 2.8 ml (0.022 mole) of trirnethylsilyl chloride were added in this order.
The mixture was subjected to reaction under reflux for one hour, after which 2.2 g (0.012 mole) of 3,4-methylene-dioxybenzoyl chloride was added thereto and the mixture was ref`luxed for an additional 30 minutes. While cooling the reaction mixture with ice, 10 ml of 1 N methanolic solution of hydrogen chloricle was added. The mi.xture was stirred at that temperature f'or 30 minutes and then neutralized with triethylamine. The reaction mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate, after which the resulting solution was washed with di]ute hydrochloric acid, saturated aqueous solution of sodium bicarbonate and water in this order, dried over anhydrous magnesiurrl sulf'at;e, and sut),Jectecl to distillation under re(luced pres.;ure to rernove the solverlt.
Thereafter, the crystals of the objective compound was obtained by the following procedure (a) or (b):
(a) 1'he r~sidue was dissolved in 40 ml of a chloro-form-methanol mixture (20 : 1). This solution was stirred at 40C for 4 hours and then 3.4 g (yield 86%) 25 of' 3-(3,4-nnethylenedioxybenzoyl)-5-f'luoro-2'-deoxy-~-uridine was obtained by filtration.
Specific rotation [~]20: 50.3 (C=2 in acetone) NMR (CD3COCD3) ~ value:

-- Il,o --l~Z~63~

H(g) F

(d) ~ ~ ~ ~ H(i) (f) HO

(b) I ~(e) OH H
(c) (a) a (2.31, q, 2H) f (6.80, d, lH) b (3.88, m, 3H) g (7.41, d, lH) c (4.37, m, 3H) h (7.63, q, lH) d (6.10, S, 2H) i (8.40, d, lH) e (6.21, m, lH) 1 (b) The residue Wa5 di~solved in 20 ml of a chloroform-methanol rnixture (30 : 1). After ultrasenica-tion (150 W; 28 KHz) at 35~ for 6 hours, 3.8 g (yield 97%) of 3-(3,4-methylenedioxybenzoyl)-5-fluoro-2'~
deoxy-~-uridine was obtained by filtration.
The specific rotation and NMR of this product were identical with those of the product obtained in above (a).

~lZ7637 1 Example 9 In 10 ml of chloroform was suspended 2.46 g (0.01 mole) of 5-fluoro-2'-deoxy-~-uridine, to which 5.5 ml (0.04 mole) of triethylamine and 3.1 g (0 022 mole~
of 2-chloro-4-methyl-1,3,2-dioxaphospholane were added in this order. The mixture was sub~ected to reaction at room temperature for 3 hours with stirring. Then, 2.2 g (0.012 mole) of 3,4-methylenedioxybenzoyl chloride was added thereto and the resulting mixture was sub~ected to at room temperature for 4 hours with stirring. After the reaction, ]0 ml of 1 N methanolic solution of hydrogen chloride was added to the reaction mixture.
Thereafter, it was treated in the same manner as in Example 6. Thus, there was obtained 3.5 g (yield 89%) of crystalline 3-(3,4-methylenedioxybenzoyl)-5-fluoro-2'-deoxy-~-uridine having a melting point of 133 - 135C.

Example 10 At room temperature, 0.93 ml of triethylamine was dropped into a mixture of 2 g of 3',5'-di-0-acetyl-5-fluoro-2'-deoxy-~-uridine, 1.3 g of 3,4-methylenedioxy-benzoyl chloride and 5 ml of anhydrous methylene chloride with stirring. After completion of the dropping, the resulting mixture was sub~ected to at room temperature for 5 hours. Then it was washed with 15 ml of water, 15 ml of saturated aqueous solution of sodium bicarbonate and 15 ml of water in this order, and the organic layer 11~7637 1 l~as dried over anhydrous sodium sulfate, and subjected to distillation under reduced pressure to remove the solvent.
lhe residue was purified by silica gel column chromato-graphy (eluent: chloroform) to obtain 2.7 g (yield 94.5%) of amorphous 3-(3,4-methylenedioxybenzoyl)-3',5'-di-O-acetyl-5-fluoro-2'-deoxy-~-uridlne.
IR (KBr) cm 1 vc=O 1745, 1710, 1670 (ethanol) nm: ~max 206, 236, 279, 321 Rf value: 0.47 (developing solvent: n-hexane :
benzene : ethyl acetate = 1 : 1 : 2) Example 11 At room temperature, 0.41 ml of triethylamine was dropped into a mixture of 1.04 g of 2',3',5'-tri-0-chloroacetyl-5-fluoro-~-uridine, 0.49 g of p-methyl-benzoyl chloride and 5 ml of anhydrous methylene chloridewith stirring. After completion of the dropping, the resulting mixture was sub,~ected to react;ion at room temperature for about 5 hours. The react:Lon mixture was washed with 10 ml of water, 10 ml of saturated aqueous solution of sodium bicarbonate and 10 ml of water in thls order, and the organic layer was dried over anhydrous sodium sulfate, and subjected to distilla-tion under reduced pressure to remove the solvent. The residue was dissolved in 5 ml of tetrahydrofuran, to which 5 ml of methanol was added, and 0.25 ml of triethylamine was further added at room temperature with stirring.
The mixture was subjected to reaction for about 10 hours _ 1+3 _ 1 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromato-graphy (eluent: chloroform : methanol = 20 : 1), the eluate was concentrated under reduced pressure, and a small quantity of methylene chloride was added to the concentrate. Thus, there was obtained o.65 g (yield 82%) of crystalline 3-p-methylbenzoyl-5-fluoro-~-uridine having a melting point of 167 - 168C.
IR (KBr) cm 1 vc=O 1740, 1700, 1655 ~V (ethanol) nm: ~max 205, 264 Rf value: 0.63 (developing solvent: ethyl acetate :
formic acid : water = 65 : 5 : 5) Example 12 The compounds listed in Table 8 were obtained in yields ranging from about 80% to 100% by carrying out the reaction in the same manner as in Rxample 11.

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_ L~6 -llZ7~i37 1 T~pical examples of the preparation containing the compounds of this invent'on are as follows:

Preparation Fxample l Into a vial was sealed 200 mg of sterilized 3-(3,4-methylenedioxybenzoyl)-5-fluoro-2'-deoxy-~-uridine. ~rior to use, it was dissolved in lO ml of 5% aqueous glucose solution containng 5 ml of sterile propylene glycol and further diluted with 500 ml of 5% aqueous glucose solution. The dilute solution was used for intravenous drip. (In the case of adult patients, it was sufficient to intravenously drip this preparation once a day.) Preparation Example 2 One handred milligrams of sterilized 3-(3,4-methylenedioxybenzoyl)-5-fluoro-2'-deoxy-~-uridine, 100 mg of potato starch, 70 mg of lactose, ].0 ml of crystalline cellulose and 0.5 my of magnesiurn sl;earate were mixed together and forrned into a capsule.
(In the case of adult patients, it was sufficient to administer orall.y one capsule of the breakfast and supper everyday.)

Claims (36)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a 5-fluoro-(.beta.-uridine or 2' deoxy-~.beta.-uridine) derivative represented by the general formula:

wherein R1 is acyl, R2 and R3, which may be identical or different, represent protected or unprotected hydroxyl, and R4 represents hydrogen or protected or unprotected hydroxyl, which comprises reacting a compound represented by the general formula:

wherein R5 and R6, which may be identical or different, represent protected hydroxyl, and R7 represents hydrogen or protected hydroxyl, with a reactive derivative of a compound represented by the general formula:

wherein R1 is as defined above, in the presence or absence of a base, and then when required subjecting the reaction product to alcoholysis to eliminate the protecting group.

2. A process according to Claim 1, wherein R5, R6 and R7 are mono-, di- or tri-halo acetyloxy.

3. A process according to Claim 1, wherein R5 and R6 are mono-, di-, or tri-halo acetyloxy.

4. A process according to Claim 1, 2 or 3 wherein said reactive derivative is an acid halide.

5. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative represented by the general formula:

wherein R1 represents acyl; R2 and R3, which may be identical or different, represent protected or unprotected hydroxyl; and R4 represents hydrogen or protected or unprotected hydroxyl whenever prepared or produced by a process as claimed in Claim 1 or an obvious chemical equivalent thereof.

6. A 5-fluoro-.beta.-uridine derivative whenever prepared or produced by a process as claimed in Claim 2 or an obvious chemical equivalent thereof.

7. A 5-fluoro-2'-deoxy-.beta.-uridinc derivative whenever prepared or produced by a process as claimed in Claim 3 or an obvious chemical equivalent thereof.

8. A process as claimed in Claim 1 in which R1 is substitut-ed or unsubstituted aroyl or heterocyclic carbonyl.

9. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative of the formula given in Claim 5, wherein R1 is substituted or unsubstituted aroyl or heterocyclic carbonyl whenever prepared or produced by a process as claimed in Claim 8 or an obvious equivalent thereof.

10. A process as claimed in Claim 1 in which R1 is substitut-ed or unsubstituted benzoyl, 3, 4-methylenedioxybenzoyl, furoyl, thenoyl, thiazolycarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl or nicotinoyl.

11. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative of the formula given in Claim 5, wherein R1 is substituted or unsubstituted benzoyl, 3, 4-methylenedioxybenzoyl, furoyl, thenoyl, thiazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl or nicotinoyl whenever prepared or produced by a process as claimed in Claim 10 or an obvious chemical equivalent thereof.

12. A process as claimed in Claim 1 in which R1 is substitut-ed or unsubstituted benzoyl, or 3, 4-methylenedioxybenzoyl.

13. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative of the formula given in Claim 5, wherein R1 is substituted or unsubstituted benzoyl, or 3, 4-methylenedioxybenzoyl whenever prepared or produced by a process as claimed in Claim 12 or an obvious chemical equivalent thereof.

14. A process as claimed in Claim 1 in which R1 is benzoyl substituted by halogen or haloacetylamino, or 3, 4-methylenedio-xybenzoyl.

15. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative of the formula given in Claim 5, wherein R1 is benzoyl substituted by halogen or haloacetylamino, or 3, 4-methylenedioxybenzoyl whenever prepared or produced by a proccss as claimed in Claim 14 or an obvious chemical equivalent thereof.

16. A process as claimed in Claim 1 in which R1 is benzoyl substituted by fluorine or chloroacetylamino, or 3, 4-methylene-dioxyberlzoyl.

17. A 5-fluoro-(.beta.-uridine or 2'-deoxy-.beta.-uridine) derivative of the formula given in Claim 5, wherein R1 is benzoyl substituted by fluorine or chloroacetylamino, or 3, 4-methylenedioxybenzoyl whenever prepared or produced by a process as claimed in Claim 16 or an obvious equivalent thereof.

18. A process as claimed in Claim 16 in which R2 and R3 are both hydroxyl and R4 is hydrogen.

19. A 5-fluoro-2'-deoxy-.beta.-uridine derivative of the formula given in Claim 5 wherein R2 and R3 are both hydroxyl and R4 is hydrogen and R1 is as in Claim 16 whenever prepared or produced by a process as claimed in Claim 18 or an obvious chemical equivalent thereof.

20. A process as claimed in Claim 14 in which R2 and R3 are both hydroxyl and R4 is hydrogen.

21. A 5-fluoro-2'deoxy-.beta.-uridine derivative of the formula given in Claim 5 wherein R2 and R3 are both hydroxyl and R4 is hydrogen and R1 is as in Claim 14 whenever prepared or produced by a process as claimed in Claim 20 or an obvious chemical equivalent thereof.

22. A process as claimed in Claim 12 in which R2 and R3 are both hydroxyl and R4 is hydrogen.

23. A 5-fluoro-2'-deoxy-.beta.-uridine derivative of the formula given in Claim 5 wherein R2 and R3 are both hydroxyl and R4 is hydrogen and R1 is as in Claim 12 whenever prepared or produced by a process as claimed in Claim 22 or an obvious chemical equivalent thereof.

24. A process as claimed in Claim 10 in which R2 and R3 are both hydroxyl and R4 is hydrogen.

25. A 5-fluoro-2'-deoxy-.beta.-uridine derivative of the formula given in Claim 5 wherein R2 and R3 are both hydroxyl and R4 is hydrogen and R1 is as in Claim 10 whenever prepared or produced by a process as claimed in Claim 24 or an obvious chemical equivalent thereof.

26. A process as claimed in Claim 8 in which R2 and R3 are both hydroxyl and R4 is hydrogen.

27. A 5-fluoro-2'-deoxy-.beta.-uridine derivative of the formula given in Claim 5 wherein R2 and R3 are both hydroxyl and R4 is hydrogen and R1 is as in Claim 8 whenever prepared or produced by a process as claimed in Claim 26 or an obvious chemical equivalent thereof.

28. A process as claimed in Claim 1 which comprises refluxing 5-fluoro-2'-deoxy-.beta.-uridine in chloroform and in the presence of triethylamine with trimethylsilyl chloride and then with 3, 4-methylene-dioxybenzoyl chloride and treating the product obtained with a methanolic solution of hydrogen chloride.

29. A process as claimed in Claim 1 which comprises reacting 5-fluoro-2'-deoxy-.beta.-uridine in chloroform in the presence of triethylamine with 2-chloro-4-methyl-1,3,2-dioxaphospholane and then with 3, 4-methylenedioxybenzoyl chloride and the product obtained is treated with a methanolic solution of hydrogen chloride.

30. 3-(3, 4-Methylenedioxybenzoyl)-5-fluoro-2'-deoxy-.beta.-uridine whenever prepared or produced by a process as claimed in Claims 28 or 29 or an obvious chemical equivalent thereof.

31. A process as claimed in Claim 1 which comprises reacting in the presence of triethylamine in anhydrous methylene chloride 3',5'-di-0-acetyl-5-fluoro-2'-deoxy-.beta.-uridine with 3, 4-methylenedioxybenzoyl chloride at room temperature.

32. 3-(3, 4-Methylenedioxybenzoyl)-3',5'-di-0-acetyl-5-fluoro-2'-deoxy-.beta.-uridine whenever prepared or produced by a process as claimed in Claim 31 or an obvious chemical equivalent thereof.

33. A process as claimed in Claim 1 which comprises reacting 3',5'-di-0-chloroacetyl-5-fluoro-2'-deoxy-.beta.-uridine in anhydrous methylene chloride in the presence of triethylamine with p-fluorobenzoyl chloride at room temperature and treating the product obtained in tetrahydrofuran with methanol in the presence of triethylamine.

34. 3-p-Fluorobenzoyl-5-fluoro-2'-deoxy-.beta.-uridine whenever prepared or produced by a process as claimed in Claim 33 or an obvious chemical equivalent thereof.

35. A process as claimed in Claim 1 which comprises reacting 3',5'-di-0-chloroacetyl-5-fluoro-2'-deoxy-.beta.-uridine in anhydrous methylene chloride in the presencc of triethylamine with p-chloroacetylaminobenzoyl chloride at room temperature and treating the product obtained in tetrahydrofuran with methanol in the presence of triethylamine.

36. 3-p-Monochloroacetylaminobenzoyl-5-fluoro-2'-deoxy-.beta.-uridine whenever prepared or produced by a process as claimed in Claim 35 or an obvious chemical equivalent thereof.