CA1173436A

CA1173436A - 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: CA1173436A
Application number: CA000370765A
Authority: CA
Inventors: Setsuro Fujii; Bompei Yasui; Tomohisa Miyamoto; Masatoshi Shiga; Kazuko Ando; Iwao Hashimoto; Masahiro Kawasaki; Yoichiro Kawai; Yuji Mino
Original assignee: Funai Pharmaceutical Industries Ltd
Current assignee: Funai Pharmaceutical Industries Ltd
Priority date: 1980-02-15
Filing date: 1981-02-12
Publication date: 1984-08-28
Also published as: KR830005260A; PH18444A; US4503045A; KR840001673B1; JPS56115799A

Abstract

2'-DEOXY-3',5'DI-O-ALKYLCARBONYI,-5-FLUOROURIDINE DERIVATIVES, A PROCESS FOR
THE PREPARATION OF THE DERIVATIVES AND
ANTI-TUMOR AGENTS CONTAINING THE DERIVATIVES

ABSTRACT OF THE DISCLOSURE
2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives possessing strong anti-tumor activity with weak toxicity and represented by the qeneral formula:

Description

~7~36 BACKGROUND OF THE INVENTION

Field of the Invention The present invention relatec; to 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 as active ingredients thereof.
More particularly, the present invention relates to new 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

~3 \NJ~
(R)m o~N
CH3(CH2)nCOO ~ O

CH3(CH2)nC

- wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and _ for an integer of 1, 2 or 5-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's 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 as a whole, a process for the preparation of the derivatives wherein a 2'-deoxy-3', 5'-di-O-alkylcarbonyl-5-fluorouridine is reacted with a benzoyl halide derivative, and anti-tumor agents containing the 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives as active ingredients thereof.

- 2 - ~

- ~'7~3~6 Descrl~ion of the Prlor Arts In the field of chemotherapy, the major public attention is now directed to the development of effective anti-tumor agents.
Heretofore, various kinds of 5-fluorouridine derivatives have been develo~ed as anti-tumor agents. ~lowever, all of these derivatives are quite unsatisfactory as they are either poor in the inherent anti-tumor activity or strong toxicity. 2'-Deoxy-5-fluorouridine (referred to hereinafter simply as FUDR)is already used as an anti-tumor agent but this compound is exceptionally high in toxicity for ~o medication and narrower in safety region. In addition, this com-pound is subject to a considerable limitation in actual therapeutic applications since the mode of administering this compound is limited only to intraarterial injection, or in other words, this compound cannot be administered orally (Physiciansl Desk Reference, p. 1387 (1978)].
~ eretofore, extensive researches have been made by C. Heidel-berger et al. on the mechanism of anti-tumor activity of FUDR and a variety of studies have also been made by ~hem to develop new FUDR
derivatives which are devoid of such drawbacks and possess a high level of anti-tumor ac~ivity of chemical modification gf ~D~. As a result of the studies 2'-deoxy-3',5'-di-O~cetyl-5-fluorouridine (referred to hereinafter simply as acetyl-FUDR) as one of the new chemically modified FUDR derivatives was found to possess such a property that this compound is hardly decomposed in living body, thus suggesting possiblity of oral administration [Cancer Research, 23, 49 et seq. (1963)]. As a result of experiments made on anti-tumor activity of the acetyl-FUDR, however, this compound is evalu-ated to be almost equivalent in anti-tumor activity to FUD~ or rather poor in effectiveness [Biochem. Phaxmacology, 14, 1605 et 30 seq., ~1965); Cancer Research, 23, 420 et seq. (1963)3. Thus, the E~J

7~ 36 acetyl-FuDR is still unsa-tisfaetory as a practically effective an-ti tumor agent.
, A number of researches have thus been made on FUD~ derivatives and results of the researches are summarized, for example, as a 'correlation between the chemical strueture and the anti-tumor activity of FUDR and its derivatives in Cancer Research, 30, 1555-6 (1970).
In this reference, three enzymatie activities which were found to be a key to development of anti-tumor activity as a result of elarifying the mechanism of anti-tumor activity exhibited by FUDR
are taken up as subjects and an explanatory dlagram is given to show what position and what strueture of FUDR moleeule are neees-sary for exhibiting anti-tumor aetivity. In this reference, how-ever, there is described that the nitrogen atom in 3-position of f the uracil (pyrimidine or pyrimidione) ring of FUDR should not be substituted.

3',5'-Dialkyl esters of FUDR are also reported as derivatives of-F~DR but they are still unsatisfaetory in respects of anti-tumor aetivity and toxieity [~iochem. Pharmaeology, 14. 1605-1619 (1965), ~ibid. 15, 627-6~4 (1966)]. Recently, reported FUDR and acetyl-FUDR
derivatives are such compounds that the hydrogen at~m bonded to the 3-nitrogen atom on the uraeil ring is substituted by a specific aroyl group (~K Paten~ Appln. No. 2,025,401 published on January 23, 1980 and ~uropean Patent Appln. No. 9,882 published on ~pril 16, 1980). However, further enhancement in anti-tumor aetivity is desired also 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 suited for oral administration without necessity of troublesome intraarterialor intravenous injec-3Q tion.

~ L3~
'BRIEF SUM~RY OF TEIE I~V~NTION
Accordingly, it is an object of the present invention to pro-vide new 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine deriva-,tives of the general formula (I) possessing strong anti-tumor 5 11, activity with a low level of toxicity.
It is another object of the present invention to provide a ,process for the preparation of the new 2'-deoxy~3', 5 ' -di-O-alkyl-carbonyl-5-fluorouridine derivatives of the general formula (I).
It is further ob~ect of the present invention to provide the use of the new 2'-deoxy-3',5'-di-O-alkylcarbonyl~5-fluorouridine derivatives of the general formula (I) as anti-tumor agents.
It is still another object of the present invention to provide ~anti-tumor agents containing the new compounds of the general for-mula (I) as active ingredient.
It is still further object of the present invention to provide anti-tumor agents useful for both injection and oral administration.
; It is yet further object of the present invention to provide the use of the anti-tumor agents for chemotherapy of tumors.
` Other objects, features and advantages of the present inven-tion will become apparent more fully from the following descrip-tion.
' .
DETAILED DESCRIPTIOI`~ OF T~E INVENTION
I
With a view to developing new 2'-deoxy-3',5'-di-O-alkylcar-bonyl-5-fluorouridine derivatives possessing a high level of anti-tumor activity with weak toxicity, the present inventors have made ~extensive researches on new classes of 2'-deoxy-3',5'-di-O-alkyl-carbonyl-S-fluorouridine derivatives prepared from various 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridines.
~ s a result of the extensive researches, it has now been found surprisingly that the new compounds of the general formula (I) are .

' 3Ç~
superior in anti-tumor activity to the known similar compounds at an equivalent toxicity level. The present invention has been accomplished on the basis of the above finding.
In accordance with one embodiment oE the present invention, there is provided new 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

~R)m o~N

I (I) CH3(CH2)nCOO

3( 2)nC

wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and n for an integer of 1, 2 or 5-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's 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 as a whole.
In the general formula (I), the benzoyl group introduced into 3-position of the uracil ring may be ring-substituted by up to 3 radicals R's which may be the same or diEferent and each represent an alkyl group, an alkoxy group or a halogen atom. When R stands for an alkyl group, straight or branched chain Cl 20 alkyl ., ~1.'7;~'~3~;
groups come into question, such as methy]., ethyl, n-propyl, isopropyl, n-butyl, sec butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl and n-octadecyl. Illustrative of R in case of an alkoxy group are, for example, straight or branched chain Cl 20 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, - 6a -:~'7;~

n-hexyloxy, n-octyloxy, n-decyloxy, n-dodecyloxy, n-hexadecyloxy and n-octadecyloxy groups.
~ hen -two vicinal lower alkoxy groups exist as ri.ng-substituents in the benzoyl group (R = a lower alkoxy group and m = 2), the 'jalkyl moieties of the two lower alkoxy groups may be combined to form an alkylene gxoup. In this case, the two vicinal lower alkoxy groups form an alkylenedioxy group as a whole. Preferable examples of the alkylenedioxy group include methylenedioxy, ethylenedioxy and propylenedioxy groups.
Examples of R in case of a halogen atom include fluorine, chlorine, bromine and iodine atoms, with the fluorine atom being preferred.
The hydroxy groups in 3'- and 5'-positions of 2'-deoxy-5-fluorouridine are esterified with the same fatty acid of the formula CH3(CH2)nCOOH wherein n has the same meanings given above.
The number n is preferably 1, 2, 5, 6, 10, 12 and 19. More precisely, residues of fatty acids occupying the 3'- and 5'-posi-tions propionyl, butanoyl, heptanoyl, octanoyl, dodecanoyl, myristyl and palmitoyl groups.
Preferred compounds of the general formula (I) include:

3-benzoyl-2'-deoxy-3',5'-di-O-buta~oyl or -dodecyl-5-fluorouridine, 3-(2,3 or 4-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl or -butanoyl-5-~luorouridine, 3-(2,3 or 4-methylbenzoyl)-2'-deoxy-3',5'-di-O-octanoyl or -dodecyl-5-fluorouridine, 3-(2,3- or 3,4-dimethoxybenzoyl)-2'-deoxy-3',5~-propionyl or -butanoyl-5-fluorouridine, 3-(2,3 or 3,4-dimethoxybenzoyl)-2'-deoxy-3',5'-octanoyl or -dodecyl-5-fluorouridine, 3-(2,3- ox 4-fluorobenzoyl)-2'-deoxy-3l,5'-propionyl or -butanoyl 5 fluorourldine, and ._..

3-(2,3 or 4~fluorobenzoyl)-2'-deoxy~3',5' myristoyl or -palmitoy].-5 fluorouridine.
In accordance with another embodiment of the present invention, there is provided a process for the preparation oE new 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

~
(R)m o~N
I (I) CH3(CH2)nC ~ ~
1~
CH3(CH2)nC

wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and n for an integer of 1, 2 or 5-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's 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 as a whole, characterized by reacting a 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluoro-uridine of the general formulao o HN
ol N ~
~II) CH3~CH2)nCOO ~ O ~
\l ' ;
CH3~CH2)nCOO

3~31~;

wherein n has the meaning as given above r with a benzoyl halide of the general formula:

- 8a -~.i ~:~t73~3~

Q -CO - Hal (III) (R)m wherein R and m have the same meanings 2S given above and Hal for a halogen atom.
In general, 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-flurouridines of the general formula (II) are known or can easily be prepared by acylating one molar proportion of FUDR with two molar proportion of the corresponding fatty acid preferably in the form of a reactive functional derivative. Benzoyl halides of the general formula ~III) are generally kno~n and easily commercially available or can be prepared in a manner known per se. The use of the corresponding chloride or bromide is preferable.
The benzoyl halide of the general iormula (I~I) is preferably used in an amount of 1-3 molar proportion f or the 2i-deoxy-3',5'-di-O-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-O-alkylcarbonyl-5-fluorouridine of the general formula (II), i.e. N-acylation reaction of the fluoro-uridine with ~e benzoy~lide is carried out as a rule in the presence of an organic solvent which is inert to the N-acylation and affords a proper reaction temperature. Illustrative of the preferable organic solven~ are aprotic solvents such as diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide and dimethylsulfoxide.
The reaction is carried out normally in the presence of an acid-binding agent. The reactlon of the present invention is usually promoted by neutralizing a 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. Prefer-red examples of the organic base include aliphatic tertiary amines ' - -~73~36 such as triethy~amine and the like lower trialkylarnines and aro-matic and heterocyclic tertiary amines such as N,l~-dialkylanilines and pyridine which may be substituted by a lower alkyl group or groups. These organic bases are usua:Lly miscible with the organic solvent used as tne reaction medium but are precipitated when combines with the hydrogen halide. Accordingly, these organic bases can easily be separated from the reaction mixture after completion of the reaction.
The organic base is used usually in an amount of 1-5 moles per mole o~ the benzoyl halide. As the organic bases per se may be used as the reaction medium, an excess amount of the organic bases, for example, in an amount of 5-20 molar pro~ortion for the benzoyl halide may be used in place of a part or all of the reactiol, solvent.
The reaction is carried out within a wide range of reaction temperature, for example, under ice cooling or at a temperature up to the boiling point of the reaction solvent used. As a xule, 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 comple~ion of the reaction, the end product can be obtained by subjecting the reaction mixture directly to concentra-tion under reduced pressure or by first filtering the reaction mixture and then concentrating the filtrate under the reduced pres-sure, and finally recrystallizing the resultant residue or subject-ing the residue to chromatography on silica gel. If necessary, the last-mentioned purification tr~tment by the aid of chromatographic operation or recrystallization ;~-?.y be repeated. ~hen the end product is isolatecl as a viscousoil~ substance, it can be obtained as a solid or crystalline form by dissolving the oily substance in B~

3~36 a small amount of dimethylsulfoxide and pouring the solution into water ~nder 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 com-pounds of this invention were evaluated according to the following tests.
(A) Pharmacological tests for measuring anti-tumor activity:
About 10,000,000 tumor cells of Sarcoma S-180 (successively incubated for several generations in peritoneal cavity of a male mouse of IC~ strain) were transplanted subcutaneously into the in-guinal region of 5 week-aged male mice of ICR strain. After the lapse of 24 hours, administration of the compounds of this inven-tion started. The administration of the compounds of this inven-tion was forcibl~ 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 adminis-tered in the form dissolved or suspended in polyethylene glycol 400 to each testing animal whi~e polyethylene glycol 400 alone to a control group of the animals. In each case, the same volume of 0.1 m~/10 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.S mg/kg to 120 mg/kg.
The doses were gra~ed 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. As the control group 18 mice'were used.
On the 3th day from the transplantation of the tumor cells 3G each ~ouse was put to death by bleeding under ether anes~hesia.

:~'7~3436 After the tumor tissue was excised, its weight was immed~ately measured and recorded. An average value of tumor weights in the treated 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 effec-tive, while a value of less than 0.50 is regarded to be ef~ective[Ohyo-'~akuri, 7, 1277-1292 (1973)]. ~ccordingly, the anti-tumor activity becomes stronger as the value indicating 0.70 or 0.50 in terms of T/C becomes smaller.
(B) Test Lor measuring toxicity:
Judging fro~ the effects achieved by the compounds of this invention, toxicity values were measured according to the followin~3 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 admin-istration. 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 mQ~10 g (body weight).
Although the exact doses of the compounds o~ this invention varied according to the sort of the particular compounds used, the doses were approximately within a ranse from 10 mg/kg to 300 mg/kg. The doses were graded into 5 ranks for each testina compound. At each rank, the compound of this invention was administered to each group. On the 14th day from the completion of administration, the ~3~36 survival and death of the tested animals were judged and LDlo 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-propi.onyl-5-fluorouridine s: 2'-Deoxy-3',5'-di-0-n-butanoyl-5-fluorouridine C: 2'-Deoxy-3',5'-di-0-n-heptanoyl-5-fluorouridine D: 2'-3eoxy-3',5'-di-0-n-octanoyl-5-fluorouridine E: 2'-Deoxy-3',5'-d.i-0-n-palmitoyl-5-fluorouridine F: 3-(3,4-methyleneclioxybenzoyl)-2'-deoxy-5-fluorouridine G: 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-3',5'-di-0-acetyl-5-fluorouridine H: 5-Eluorouracil.
(C) Results of the Tests:
Results of the above Tests (A) and ~B) and therapeutic indices calculated therefrom are shown in Table l. The thexapeutic indices were calculated according to the following equation:
Therapeutic index = LD1o value . T/C 0.50 value ~1 ~7343~;
__ ....... _ . _ .
.~
~ .
~ X u~ ~ o o u~ o u~ o o~
h O o ~r I ~1 I co o co G~ In u~ o~
r~ c N ,~ ~ i~1 O ~1 _ .. _ .--__ - - .. __~

o o ~ ~ ~ ~ ~ oo o c~ r ,~
~ . .. . ^--- --I
~ .
-( ~
~a o r~ 11') . ~r a~ ~ (~ .-1 co co o ~ t~ ) o 1~
o ~ ~ I~ o O
~ _ -__ ----~
,~ ,:
. _ ~0~
~ ~r ~ ~ ~ ~D ~ ~D 1~ ~ ~ I

a) ~ E~ .

E~ _ . _ . _ .
, ..
~ ~ D

~ a) ~O ~ O
o _, E E ~ ~ ~ E ~ ~ ~
a. ~ ~S ~l O ~( O
o ~ c~ a ~ a ~ ~ ~ ~ ~q o a ~) c ~ ~ -- ~ ~ ~ ~ ~
., ~ .. --Compound of the present known Compound invention .__ .. __ . ..... _~ _~

.~- ~

~73~3~

As is evident from the res~llts shown in Table 1, 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 contrib-utes to remarkable improvement in anti-tumor activity and in reduc-tion of toxicity.
According to s-till another embodiment of the present invention, there is provided anti-tumor agents containing one or more of the new 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula (I) as active ingredients.

.. ..
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 administratio~-i-s-preferably applied to the compounds of this invention but-pare~e~a-l-~dministration such as . . .
intravenous in~ection or intrarectal medicat1on by means of a sup-~
pository is also applicable.
As pharmaceutical preparations suitable for oral administra-tion, 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 ac-tive ingredient, other conventional auxiliary components such as milk sugar, corn starch, potato starch, various ca~e sugar esters of ~atty acids, microcrystalline cellulose and pol~yethylene glycol 4000 as excipi-ents; acacia, gelatine, hydroxypropylcellulose and potato starchas binders; magnesium stearate and talc as lubricants; carboxy-methylcellulose calcium, potato starch and corn starah as disinte-grating agents. Usual solubilizing agents and suspending agnets may also be contained in the preparations, with polyethylene glycol 200 - 600 being particularly preferred. Examples for a base of ,j . I
.

7~4~
suppositories include g]ycerol, cacao butter, glycerogelatine, polyethylene glycol, laurin and o-ther materials usually employed for this purpose.
Besides the above mentioned additives, materials normally used as carriers for pharmaceutica:L preparations may also be con-tained in the anti-tumor agents of the present invention.
The present invention will now be illustrated in more detaiL
by way of examples.

~6 -~!

:~'7~9~36 Example 1 2.0 Gr~s of 2'-deoxy-3',5'-di-9-propionyl-5-fluorouridine a~e dissolved in 25 mR of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2imethy ~ nzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 70C
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 The purified oily substance is dissolved in about 15 mQ of dimethyl sulfoxide and the solution is added dropwise to about 400 mQ of ice water under vigorous a~itation whereupon a precipitate is formed. Tlle resultant precipitate is collected by filtration, washed with ~ater and dried at room temperature under reduced pres-sure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)- -2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained.
W-absorption spectrum: AmatOH 255.5 nm NMR-spectra: ~(ppm, CDCQ3) Uridine moiety: 7.80 (d, H6), 6.19 (broad-t, Hi), near 2.5 (m, H2), 5.10 - 5.30 (m, H3), 4.16

4.42 (m, ~14, ~15~, 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 C23H25FN2O8):
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-o-propionyl~5-fluorouridine Bi 3~3~i are dissolved in 25 mQ of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluoro-ben~oyl chloride are added to the solution and the mixture is subjected to reaction at room ternperature for 15 minutes and then at 60C for 30 minutes. The reaction liquid is worked up in the saMe r;lanner 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: ~max 251.5 nm NMR spectra: ~(ppm, CDCQ3) Uridine moiety: 7.81 (d, H6), h.l8 (broad-t, H1), near 2.5 (m, ~2)' 5.19 - 5.36 (m, H3), 4.24-4.48 (m, H4, H'), 2.20 - 2.60 (m, 2 x COCiI2), 1.05 - 1.32 (m, 2 x CH3) senzoyl moiety: 7.28 - 7.76 (m, aromatic H) Elementary analysis (as C22~22F2N2O8):
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-O-propionyl-5-fluorouridine are dissolved in 25 mQ 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 a~d the mixture is subjected to reaction at room temperature for 30 minutes and then at 50C for ~25 30 minutes. The reaction liquid is c~oled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromato-graphy on silica gel (elution solvent: chIoroform). The purified oily substance is allowed to stand overni~ht at room temperature 3~ whereby a part of the substance is crystallized. ~ small amount of ~3~3~;

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. 84.5-86C
W-absorption spectra: ~a 264.5, 327 nm N~IR spectra: ~(ppm, CD'Q3) Uridine moiety: 7.72 (d, H6), 6.27 (broad-t, Hi), near 2.5 (m, H2), 5.16 - 5.32 (m, Ha)~ 4.18 -4.48 ~m, H4', H5), 2.14 - 2.98 (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, 1~5), 3.~6 (s, OCH3), 3.84 (s, OCH3) ~le~entary analysis (as C24H27FN2Olo) Calc. (%): ~ 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-O-myristoyl-5-fluorouridine are dissolved in 20 mQ of dry dioxane and the solution is ice cooled.
2.1 ~Iilliliters 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 hydro-chloride formed is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromato-graphy 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 ethanol, gives 1.25 g (yield:

35.4~) of 3-(4-methylbenzoy~-2'-deoxy~3',5'-di-O-myristoyl-5-fluorouridine. M.P. 76-77RC
UV-absorption spectrum: ~matil 263 nm ,. ~,, ~ -- 19 . ~ , ~` ~

73~36 spectra: ~(ppm, CDCQ3) ~ridlne moiety: 7.74 (d, H6), 6.26 (broad-t, Hi), near 2.5 (m, H2), 5.14 - 5.32 (~, H3'), 4.20 -4.44 tm, 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~ 1~5), 2-42 (s, CH3) Elementary analysis (as C45H69FN2O~):
Calc. (%): C 68.85, H 8.86, N 3.57 Found (~): C 68.76, H 8.55, W 3.79 Example 5 3.0 Grams of 2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine are dissolved in 25 mQ of dry dioxane and the solution is ice cool-ed. 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 70C 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 recrystalliza-tion from ethanol, affords 2.95 g (yield: 80.2%j of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-palMitoyl-5-fluorouridine.
M.P. 77-78-C.
W-ahsorption spectra: ~max 264.5, 327 nm NMR-spectra: ~(ppm, CDC~3) ~ridine moiety: 7.76 (d, U6), 7.31 (broad-t, Hi), near ~.4 (m, H2), 5.18 - 5.34 (m, H3~, 4.22 -4.48 ~m, H4, H5), 2.10 - 2.55 (m, 2 x Bi s ~a73436 COCH2), 1.08 - 1.80 (m, 26 x CH2), 0.76 - 1.06 (m, 2 x CH3) Benzoyl moiety: 7.59 (dcl, H6), 7.12 - 7.2~ (m, H4, H5), 3.90 (broad-s, 2 x OCH3) Elementary analysis (as C50H7C~FN2O10~
, . . .. . .
Calc. (~): C 67.69, H 8.98, N 3.16 Found (%): C 68.09, H 9.11, rl 2.99 Example 6 3.0 Grams of 2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridlne are dissolved in 20 m~ of dry dioxane and the solution is ice cooled.
~- 3 Milliliters of triethylamine and 2.0 ~ of benzoyl chloride are adde~d to the solu-tion and the mixture is subjected to reaction at `~~~~`~~-- room tempera-ture for 2 hours. The triethylamine hydrochloride formed is filtered off and -the Liltrate is concentrated under ~ ...~r. ' reduced pressure. The oily residue is purified by column chromato-graphy on silica gel (elution solvent: chloroform) whereby 2.3 g (yield: 60.--7~) of 3-benzoyl-2'-deoxy-3',5l-di-O-butanoyl-5-fluorouridine are obtained as an oily substance.
UV-absorption spectrum: AmaXoH 253.5 nm N~vlR-spectra: ~(ppm, CDCQ3) Uridine moiety: 7.76 (d, H6), 6.27 (broad-t, Hll, near 2-5 ~m~ ~l2), 5-15 ~ 5-32 (m, H3'j, 4.20-4.46 (m, H4, H5), 2.20 - 2.52 (m, 2 x COCH2), 1.44 ~ 1.92 (m, 2 x CH2), l.g6 ~
~25 1.10 (m, 2 x CH3) Benzoyl moiety: 7.36 - 8.02 (~, aromatic ~1 Elementary analysis (as C H FN O ) Calc. (~): C 58.77, H 5.55, N 5.71 ~ ~ Found (~j: C 58.75, H ~5.~2, N 5.78 Examples 7 ~ 23 - 21 ~

7~

In the same manner as described in ~xample 6, a 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine is reacted with an aroyl chloride. Table 5 shows~the-resulting 2'-deoxy-3',5'-di-0-alkyl-carbonyl-5-fluorouridine derivatives and characteristic physical . properties thereof.

_ 22 -, -.

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3~
~ r~clr.~tL<)~ th~ r-ltL-t;~ ol acJer~Ls ~: L~ s~lt l~v~, -tion will llOW be ilLustrated in more cletail by way of the following typical preparation e~amples:
(A) Hard capsule preparations Recipe:

3-(2,3-dimethoxybenzoyl-2'-deoxy-3',5'-di-O-n-propionyl-5-fluorouridine 80 mg aliphatic acid ester of sucrose20 mg milk sugar 165 mg crystallinecellulose 24 mg hydroxypropylcellulose of a low degree of substitution 8 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 ahove dose of ingredients. In general 3 - 9 capsules 2er day can be administered orally to adult patients.
(B) Soft capsule preparations Recipe:

3-(3-fluorobenzoyl-2'-deoxy-3',5' -di-O-n-palmitoyl-5-fluorouridine 50 mg polyethylene glycol 400 250 mg propylene glycol 10 mg bleached beeswax 10 mCJ

total 320 mg Capsules are formed according to a conventional method so that each capsule may contain the above dose of ingredients. As a r~le, 3 - ~ capsules per day can be administered orally to adult patients.

It is understood that the preceding representative examples may be varied within th~e scope of the present specification both as to reactants and reaction condltions, by those skilled in the art to achieve essentially the same results.

- ~7 -As many widely different embodiments of this invention may be made withou-t departing from the spirit and scope thereof, it is construed that the present invention is not limited to the specific embodiments thereof except as defined in the appended claims.

:

:
: ~ :

.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:
(I) wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and n for an integer of 1, 2 or 5-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's 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 as a whole, which process comprises reacting a 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine of the general formula:

(II) wherein n has the same meaning as given above, with a benzoyl halide of the general formula:

(III) wherein R and m have the same meanings as given above and Hal stands for a halogen atom.

2. A process according to claim 1, wherein Hal in the general formula (III) is chlorine atom.

3. A process according to claim 1, wherein the reaction is carried out at a temperature from ice cooling to 70°C
in an organic solvent in the presence of an acid-binding agent.

4. A process according to claim 3, wherein the organic solvent is dioxane and the acid-binding agent is triethylamine.

5. A process according to claim 1 which comprises reacting said compound of formula (II) with a compound of formula (III) in which m is 0.

6. A process according to claim 1 which comprises reacting said compound of formula (II) with a compound of formula (III) in which m is other than 0 and R is methyl.

7. A process according to claim 1 which comprises reacting said compound of formula (II) with a compound of formula (III) in which m is 2 and R is methoxy.

8. A process according to claim 1 which comprises reacting said compound of formula (II) with a compound of formula (III) in which m is other than 0 and R is fluorine.

9. A process according to claim 1 which comprises reacting a compound of formula (II) in which n is 2 with said compound of formula (III).

10. A process according to claim 1 which comprises reacting a compound of formula (II) in which n is 1 with said compound of formula (III).

11. A process according to claim 1 which comprises reacting a compound of formula (II) in which n is 5 with said compound of formula (III).

12. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:

(I) wherein R stands for an alkyl group, an alkoxy group or a halogen atom, m for zero or an integer of 1-3, and n for an integer of 1, 2 or 5-14, with the proviso that when m is 2 or 3, R's may be the same or different and that when m is 2 and the adjacent two R's 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 alkylene-dioxy group as a whole; whenever prepared by the process according to claim 1 or an obvious chemical equivalent thereof.

13. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein m in the general formula (1) stands for zero; whenever prepared by the process according to claim 5 or an obvious chemical equivalent thereof.

14. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein R in the general formula (1) stands for methyl group and m is other than O;

whenever prepared by the process according to claim 6 or an obvious chemical equivalent thereof.

15. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein R in the general formula (1) stands for methoxy group; and m is 2; whenever prepared by the process according to claim 7 or an obvious chemical equivalent thereof.

16. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein R in the general formula (1) stands for fluorine atom and m is other than O; whenever prepared by the process according to claim 8 or an obvious chemical equivalent thereof.

17. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein n is 2; whenever prepared by the process according to claim 9 or an obvious chemical equivalent thereof.

18. 2'-Deoxy-3',5'-fi-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein n is 1; whenever prepared by the process according to claim 10 or an obvious chemical equivalent thereof.

19. 2'-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives according to claim 1, wherein n is 5; whenever prepared by the process according to claim 11 or an obvious chemical equivalent thereof.