FR2531962A1 - NOVEL DERIVATIVES OF DESOXYURIDINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R AND R ARE HYDROGEN OR A LOWER ALKYL GROUP, R IS A HALOGEN, CHF OR CF, R IS H, F OR OH, X IS L 'OXYGEN OR IMINO AND N MEAN 0 OR 1, THE CARBOHYDRATE BEING AN A OR B RADICAL. THESE COMPOUNDS MAY BE USED AS MEDICINES, ESPECIALLY FOR FIGHTING HERPES VIRUSES.

Description

The subject of the present invention is new derivatives of the

  deoxyuridine, their preparation and their use as medicaments, in particular for

fight herpes viruses.

  The invention relates more particularly to the compounds of formula I

X R

OH Ni? ' C (CH 2) n R 3 (

N R 2

  Wherein R 1 and R 2 each independently of one another is hydrogen or lower alkyl, R 3 is halogen, CHF 2 or CF 3, R 4 is hydrogen, a group hydroxy or fluorine, X represents an oxygen atom or an imino group, and N represents O or 1, the carbohydrate radical linked to the pyrimidine ring being an a or 5 radical,

  in free form or in the form of acid addition salt.

  In accordance with the process of the invention, to prepare the compounds of formula I and their salts a) a compound of formula II ## STR1 ## is reacted with a compound of formula III

HO (III

  or b) replacing the R 3 'group in the side chain of a compound of formula Ia HC 10 H C- (CH 2) n R 3' (Ia)

N R 2

  -HO with a group R 3, in the formulas Ia, II and III R 1, R 2, R 3, R 4, X and n having the meanings given above, R 5 representing a halogen or an acyloxy group, R 3 'representing a hydroxy group in free or protected form, and any hydroxyl group present in the carbohydrate radical may be in protected form, and, where appropriate, eliminating any protective group present in the compound thus bttenu, and recovering the compound as well obtained in free form

  or as an acid addition salt.

  The process a) can for example be carried out by converting the compound of formula II according to

  known methods in trimethylsilyl derivative and in

  reacting the latter with a compound of formula III, the hydroxy groups of which are protected, in a solvent

  as a halogenated hydrocarbon or acetonitrile.

  According to process b) a compound of formula Ia in protected or unprotected form can be dissolved in an inert solvent under the reaction conditions, for example a (lower alkyl) amide of a

  carboxylic acid such as dimethyl

  formamide. The transformation of RL into a halogen atom can be carried out with a compound of formula Ia whose OH groups in the carbohydrate radical are

  free form or protected form.

  When R 3 represents a halogen atom, the reaction may be carried out according to the usual halogenation methods, for example by using carbon tetrachloride or N-bromosuccinimide when R 3 is CHF 2 or CF 3 is a reaction. be carried out according to the usual fluorination methods, for example from a compound of formula Ia after oxidation to aldehyde with dialkylsulfur trifluoride, or after oxidation to carboxylic acid with

sulfur tetrafluoride.

  Examples of protecting groups that may be mentioned are those usually used in reactions of this type, such as p-toluoyl, benzyl, p-nitrobenzoyl and trimethylsilyl groups.

  introduced and removed according to the usual methods.

  The salts can be prepared according to the usual methods from free forms and vice versa. As indicated above, the carbohydrate radical in

  the compounds of formula I and Ia may have the configuration a or 5.

  For the sake of simplicity, the compounds are represented

in formula I in the form f.

  The pyrimidine group in the compounds of formula I and Ia can exist in the following tautomeric forms:

VNH OH / NH

HR

I I

  The invention is not limited to a tautomeric form

  particular, but includes all tautomeric forms of the compounds.

  The compounds of formula I and Ia can also exist in the form of optical isomers or mixtures of isomers which can be separated according to the usual methods. The invention comprises all the isomeric forms and their mixtures, the compounds being present under this method. last form, unless otherwise indicated The lower alkyl groups contain 1

  to 4 carbon atoms, preferably 1 or 2 carbon atoms.

  The starting materials of formula Ia are also new and form part of the invention. They can be prepared analogously to process a), by reaction of a compound of formula I Ia HN (C Ha) C (CH 2) n 3 (He has)

ON R 2

  H in which R 1, R 2, R 3 ', X and N have the given meanings

  higher with a compound of formula III.

  The compounds of formula II, I Ia and III are known or can be prepared analogously to the known processes, for example as illustrated in

examples below.

253 '962

  End products and intermediates can be isolated and purified according to the usual methods. The compounds of formulas I are distinguished by interesting pharmacological properties and can

  therefore be used as medicaments

  In particular, they exert an antiviral action, as

  from their activity against herpes viruses.

  This activity can be demonstrated in vitro and in vivo, for example by reducing the cytopathic effects (CPE) of various viruses, for example herpes simplex I and II in in vitro assays at concentrations of about 0.003 μg / ml. ml and about 300 μg / ml and in vivo tests in mice and guinea pigs using models of systemic, topical and encephalic infection see HE Renis et al in J Med Chem 16 (7) 754 (1973). Owing to this property, the compounds of formula I can therefore be used therapeutically as chemotherapeutic agents, in particular as agents for combating diseases and infections caused by herpes. For their therapeutic use, the compounds of the invention will be administered at a daily dose of between about 200 and 1200 mg, advantageously in divided doses 2 to 4 times per day in the form of unit doses each containing from 50 to 600 mg of substance active, or in a form to

delayed release.

  The compounds of the invention may be used in free form or, when the compound is sufficiently basic, also in the form of a chemotherapeutically acceptable acid addition salt, especially when X is imino; these salts have the same order of activity as the free forms.

  include hydrochloride, hydrogen

  fumarate and naphthalene-1,5-disulfonate.

  The subject of the invention is also the compounds of formula I in free form or in the form of an acid addition salt, for use as medicaments, in particular as chemotherapeutic agents, especially as antiviral agents, especially for combating

herpes viruses.

  The invention also relates to a medicament containing, as active ingredient, a compound of the formula

  free form or in the form of an acid addition salt.

  As medicaments, the compounds may be

  chemotherapeutically acceptable diluents or vehicles, and administered in the form of tablets, capsules or solutions.

part of the invention.

  Examples of particular significance of the substituents R 1, R 2, R 3, R 4, X and n are the following: R 1, R 2 = a) H b) a lower alkyl group, preferably a methyl group or ethyl R 3 = a) a halogen b) chlorine, bromine or iodine X = an oxygen atom n = 1 R 4 = a) H, OH, F b) H, OH, especially H

and their combinations.

  Particular groups of compounds of formula I are for example those a) in which R 1 and R 2 are hydrogen, R 3 is halogen, R 4 is hydrogen, hydroxy or fluorine, X is oxygen atom or imino group and N is 1; b) in which R 1 and R 2 have the meanings given above, R 3 represents a halogen, X represents an oxygen atom, R 4 represents hydrogen, a group

  hydroxy or fluorine and N means 1.

  A particularly preferred compound is

  1- (2-Deoxy-e-D-erythro-pentofuranosyl) -5- (2-chloroethyl)

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione in free form

  or as an acid addition salt.

  In the following examples which illustrate the invention, the temperatures are expressed in degrees Celsius.

Example 1

  1- (2-Deoxy D-erythro-pentofrannosyl) -5- (2-chloroethyl)

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method b)

  200 mg of 1- (2-deoxy-β-erythro-

  pentofuranosyl) -5- (2-hydroxyethyl) - (1 H, 3 H) -pyrimidine

  2,4-dione and 400 mg of triphenylphosphine in 20 ml of anhydrous dimethylformamide; it is reacted with 0.2 ml of carbon tetrachloride and 0.2 ml of anhydrous pyridine and allowed to stand for one hour at room temperature: The solvent is then removed under vacuum with addition of 1-butanol, and chromatography is carried out. silica gel (eluent: chloroform / methanol = 9/1) to give the title compound as colorless crystals F = 166-167 (after crystallization from absolute methanol)

Example 2

  1- (2-Deoxy-α-D-erythro-pentofuranosyl) -5- (2-chloroethyl);

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method b) 1.5 g of 1- (2-deoxy) -3,5-di-O-

  p-toluoyl-α-D-erythro-pentofuranosyl) -5- (2-hydroxyethyl) -

  (1H, 3H) -pyrimidine-2,4-dione in 20 ml of dimethyl

  formamide anhydrous, reacted with 2.3 g of triphenylphosphine, 1 ml of anhydrous carbon tetrachloride and 0.5 ml of anhydrous pyridine and heated at 70 for 10 minutes The solvent is then removed under 0.1 bar and chromatography chromatography the remaining syrup on silica gel (eluent: toluene / ethyl acetate = 2/1)

  obtain 0.5 g of 1- (2-deoxy-3,5-di-O-p-toluoyl-a-D-

  erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -

  pyrimidine-2,4-dione as colorless crystals (mp = 142-144) To remove the p-toluoyl groups, the compound is dissolved in 10 ml of absolute ethanol and reacted with 1.5 ml of lc N solution of sodium ethanolate in ethanol, allowed to stand for minutes at room temperature and reacted with 1.5 ml of 1 N acetic acid. The solvent was then removed in vacuo and treated with water.

  syrup remaining with a mixture of ether and water.

  The aqueous phase is chromatographed on silica gel (eluent: chloroform / methanol = 9/1), which gives the

  compound of the title in the form of colorless crystals.

  F = 140-142 (after crystallization from a mixture

ethanol and chloroform).

Example 3

  1- (5-Deoxy-5-D-erythro-pentofuranosyl) -5- (2-bromo)

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method b)

  1.14 g of 1- (2-deoxy-5-D-

  erythro-pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione in 30 ml of anhydrous dimethylformamide, reacted with 2.3 g of triphenylphosphine and 1.2 g of N -bromosuccinimide and let it stand

  the mixture for 90 minutes at room temperature.

  The solvent is removed in vacuo and evaporated again after adding n-butanol. A yellow syrup is obtained which, after crystallization from a mixture of ethanol and chloroform, gives the title compound

  in the form of colorless crystals F = 161-163.

Example 4

  1- (2-Deoxy-α-D-erythro-pentofuranosyl) -5- (2-bromo)

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method b) In a manner analogous to that described in Example O

  380 mg of 1- (2-deoxy-α-D-erythro-

  pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-

  2,4-dione to give the title compound F = 131-133 (after crystallization from a mixture of ethanol and chloroform).

Example 5

  1- (2-Deoxy-β-erythro-pentofuranosyl) -5- (2-iodoethyl) -

  (1H, 3H) -pyrimidine-2,4-dione (Method b)

  550 mg of 1- (2-deoxy-5-D-erythro-

  pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-

  2,4-dione and 1.1 g of triphenylphosphine in 25 ml of anhydrous dimethylformamide are reacted with 550 g

  of N-bromosuccinimide and 3.3 g of tetrabutyl iodide

  ammonium and allowed to stand for 90 minutes at room temperature. The solvent was then removed.

  under vacuum, after addition of n-butanol, and

  the residue on silica gel (eluent: chloroform /

  methanol = 9/1) to give the title compound.

F = 160-161.

Example 6

  1- (2-Deoxy-5-D-erythro-pentofuranosyl) -5- (2-chloro)

  Ethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method a) 480 mg of 5- (2-chloroethyl) -uracil are suspended in hexamethyldisilazane, reacted with 0, 3 ml of trimethylchlorosilane and heated at reflux for 3 hours The volatiles are then evaporated under vacuum and evaporated twice after addition of anhydrous xylene The remaining syrup is dissolved in 30 ml of anhydrous chloroform and reacted at room temperature.

  room temperature with 1.2 g of 3,5-di-

  O-p-toluoyl-2-deoxy-D-erythro-pentofuranosyl then with

  0.5 ml of trimethylsilyl ester of trifluoro-

  methanesulphonic acid The mixture is left to stand at room temperature for 5 minutes and then it is stirred with 1.5 ml of saturated and cold aqueous KHCO 3. Concentration of the organic phase in vacuo gives a syrup which is chromatographed on silica gel ( eluent: toluene /

  ethyl acetate = 4/1), which gives the 1- (2-deoxygenate)

  3,5-di-O-p-toluoyl -D-erythro-pentofuranosyl) -5- (2-

  chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione (F = 167-169).

  Removal of the p-toluoyl groups is carried out analogously to that described in Example 2.

  thus 1- (2-deoxy-5-D-erythro-pentofuranosyl) -

  - (2-chloroethyl) - (1 H, 3 H) -pyrimidine-2,4-dione as colorless crystals F = 165-166 (after

crystallization in water).

Example 7

  1 - (- D-arabinofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -

pyrimidine-2,4-dione (Method b)

  400 mg of 1- (5-D-arabino)

  furanosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione in 10 ml of anhydrous dimethylformamide, 0.3 ml of tetrachloride are reacted with 0.7 g of triphenylphosphine of carbon and 0.3 ml of pyridine and the mixture is left to stand for 1 1/2 hours at room temperature After addition of 1-butanol the mixture is evaporated to dryness in a rotary evaporator and the syrupy residue is chromatographed on silica gel. silica (eluent: c-chloroform / methanol = 8/1) By concentration of the appropriate fractions, the

  compound of the title in the form of colorless crystals.

  Mp = 182-183 (after crystallization from ethanol).

Example 8

  1- (5-D-arabinofuranosyl) -5- (2-bromoethyl) - (1H, 3H) -

pyrimidine-2,4-dione

  320 mg of 1- (5-D-arabinofuranosyl) -

  - (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione in 5 ml of anhydrous dimethylformamide is reacted with

  650 mg of triphenylphosphine and 300 mg of N-bromo-

  succinimide and allowed to stand at room temperature for 1 1/2 hours After addition of 5 ml of 1-butanol, the mixture is concentrated to dryness in a rotary evaporator and the syrupy residue is chromatographed on silica gel (eluent: chloroform / methanol = 6/1) By concentration of the fractions

  obtains the title compound in the form of crystals

  color F = 1 66-167 (after crystallization in a

  mixture of acetone and chloroform).

Example 9

  1- (2-Deoxy-2-fluoro-5-d-arabinofuranosyl) -5- (2-

  chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione

  200 mg of 1- (2-deoxy-2-fluoro)

  5-D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione in 5 ml of dimethylformamide

  anhydrous and reacted with 300 mg of triphenyl

  phosphine and 0.3 ml of a 1: 1 mixture of anhydrous pyridine and carbon tetrachloride The mixture is stirred for 4 hours at room temperature, 10 ml of 1-butanol are added and the mixture is concentrated to dryness with the addition empty of the oil pump The residue is then chromatographed

  on silica gel (eluent: chloroform / methanol = 9/1).

  Concentration of the fractions gives the title compound as a colorless, strongly hygroscopic powder.

Example 10

  4-amino-5- (2-chloroethyl) -1- (2-deoxy-D-erythro-pento)

furanosyl) -1 H-pyrimidine-2-one

  3.12 g of 4-amino-5- (2-hydroxyethyl) -

  1 H -pyrimidin-2-one are silylated analogously to that described in Example 6 and reacted with 7.76 g

  of 2-deoxy-3,5-di-O-p-toluoyl-D-erythro-

  pentofuranosylate After stirring the mixture with

  100 ml of saturated aqueous KHCO 3, the chloro

  under vacuum and the residue is chromatographed on silica gel (eluent: chloroform / methanol = 9/1), which

  gives 4-amino-1- (2-deoxy-3,5-di-O-p-toluoyl) -D-

  erythro-pentofuranosyl) -5- (2-hydroxyethyl) H-pyrimidine

  For 2 hours at room temperature, 1.4 g of this anomeric mixture is stirred in 20 ml of

Z 531 9652

  dimethylformamide with 1.4 g of triphenylphosphine, 0.6 ml of anhydrous carbon tetrachloride and 0.6 ml of anhydrous pyridine. After addition of 10 ml of 1-butanol, the solvents are removed in vacuo and the residue is mixed with 20 ml of methanol and 5 ml of a 1N solution of methanol sodium methanolate. When the reaction is complete, the mixture is neutralized with 1 N acetic acid and evaporated under vacuum. Treatment of the residue with 30 ml of ethyl acetate and 10 ml of methanol the title compound is obtained in the form of colorless crystals F = 174 (after crystallization

in water).

  The starting materials can be prepared for example as follows:

  A) 1- (2-deoxy-β-erythro-pentofuranosyl) -5- (2-hydroxy-

  ethyl) - (1H, 3H) -pyrimidine-2,4-dione (for Examples 1, 3, 5)

  10.5 g of 5- (2-hydroxy)

  ethyl) -uracil in 60 ml of hexamethyldisilazane, reacted with 3 ml of trimethylchlorosilane and refluxed for 2 hours. All volatiles were removed in vacuo and evaporated twice after addition of anhydrous xylene. The syrup was dissolved. remaining in 400 ml of anhydrous chloroform and reacted at room temperature with 26.2 g of 3,5-di-op-toluoyl-2-deoxy-D-erythro-pentofuranosyl chloride

  then with the trimethylsilyl ester of trifluoro-

  The mixture is then allowed to stand at room temperature for 1 hour and stirred with 100 ml of saturated aqueous KHCO 3. Concentration of the organic phase under vacuum gives a yellow syrup.

  which, by crystallization, gives 5- (2-hydroxy-

  ethyl) -3 ', 5'-di-op-toluoyl-β-2'-deoxyuridine (F = 176-178) The p-toluoyl groups are removed in a manner similar to that described in Example 2, which gives after crystallization in ethanol in

  a refrigerator, the 1- (2-deoxy-β-erythro-

  pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-

  2,4-dione as colorless crystals F = 160-1610.

  B) 1- (2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro)

  pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -

  pyrimidine-2,4-dione (for example 2) proceeding in a similar way to that

  described in Example A) and using 5- (2-hydroxy-

  ethyl) -uracil and 3,5-di-O-p-toluoyl-2- chloride

  deoxy-D-ribofuranosyl, the title compound is obtained

  after fractional crystallization in ethanol.

  C) 1- (2-Deoxy-α-D-erythro-pentofuranosyl) -5- (2-

  hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione (for

example 4)

  The product is obtained in the form of a colorless oil after removal of the toluoyl groups as described in Example 2 and chromatography on silica gel (eluent:

chloroform / methanol = 3/1).

  D) 5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione (for example 6)

  0.5 g of 5- (2-hydroxyethyl) -

  (1H, 3H) -pyrimidine-2,4-dione in 20 ml of dimethyl

  anhydrous formamide and 2.5 g of triphenyl-

  phosphine, 30 ml of carbon tetrachloride and 1 ml of pyridine The solution is left to stand for 1 1/2 to 80 hours, concentrated and the oily residue is taken up in a 9/1 mixture of chloroform and methanol.

  gives the title compound as crystals

  color F = 260-262 (after crystallization from

ethyl acetate).

  E) 1- (f-D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -

  pyrimidine-2,4-dione (for examples 7 and 8)

  5 g of 2,3,5-tri-O-benzyl-1-O-p- are dissolved

  nitrobenzoyl-D-arabinose in 80 ml of anhydrous dichloromethane, which was saturated 1 hour earlier at 0 with HC 1 is stirred for 2 hours at 0 while passing more HC 1 and the p-nitrobenzoc acid which is removed The filtrate is concentrated to dryness and the oily residue is left in a rotary evaporator.

  for another 2 hours under a pressure of 0.0013 bar.

  The residue is dissolved in anhydrous dichloromethane,

  and reacted with a syrup containing 5 (2-

  hexylethylsilazane-free hydroxyethyl) silyl prepared from 2.93 g of 5- (2-hydroxyethyl) -uracil, analogously to that described in Example A) and stirred for 2 days at room temperature. in the presence of 10 g of molecular sieve (4 A) After filtration and washing of the molecular sieve, the filtrate is stirred with saturated and cold aqueous KHCO 3, the aqueous phase is washed once with dichloromethane and the phases are concentrated. The organic compounds were combined in a rotary evaporator to give a partially crystalline syrup. 1 g of Pd C 12 was suspended in 150 ml of methanol and hydrogenated in a Parr apparatus to obtain Pd (H 2), room temperature and under a pressure of 4 atmospheres, for about

  minutes) To this suspension is added the syrup -

  mentioned above dissolved in 100 ml of methanol and the mixture is hydrogenated overnight under a pressure of 4 atmospheres with H 2. A white crystalline precipitate is formed in the hydrogenation flask, the remainder of the product being in solution. precipitates and palladium, the product is dissolved in water, the palladium is removed by filtration, the filtrate is concentrated in a rotary evaporator and the residue is recrystallized from water and the methanolic residue from the hydrogenation is neutralized on Merck II ion exchanger (strongly basic), filtered through active charcoal and concentrated The crystalline residue is recrystallized from water to give the title product in form

  of colorless needles F = 212-215.

  F) 1- (2-Deoxy-2-fluoro-5-D-arabinofuranosyl) -5- (2-

  hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione (for example 9) 3.1 g of 5- (2-acetoxyethyl) -uracil are silylated in a manner analogous to that described in US Pat. Example A) and after further treatment is reacted with 4 g of

  3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-bromide

  arabinofuranosyl in anhydrous dichloromethane After 14 days the mixture is subjected to the subsequent treatment by adding a few ml of methanol, filtered and separated on a column (eluent: chloroform / methanol = 9/1) After removal of the protecting groups (see Example 2 ), the title compound is obtained in the form of

clear crystals F = 177-178.

NMR SPECTRA

  KH = Proton not determinin; in the remaining deoxyribose KH-1 'at, KH-1' = proton in position 1 of the remainder of the hydroxylose,

  the coupling constants and the chemical shift of the proton-

  to determine the Vanomère NMR apparatus: Brucker WH-90,

M Hz.

  Ex 1 Spectra 2.10 (t, 2H, KH); 2.67 Ctg 2 HI, 2 H 2 CH 2 C 12 J = 7 Hz); 3.4-3.9 (ml, 5H, CH 2 H 2 Cl, KH); 4.1-4.4 cm, 1H, KH); 5.03 (t, 1H, J = 5.1 Hz, 5 'OH); 5.24 (d, 1H, J = 4.3 Hz, 3'-OH); 6.17 (tg

  1H, J = 6.7 Hz, KH-1 't 3); 7.83 (s, 1H, H-6); 11.4%, 1H, NH 3.

  Ex 2 Ek 3 Ex 4 Ex 5 1.8-2.7 Cm, 2H, KH); 2.66 Ct, 2H, J = 7 Hz, CH 2 CH CI); 3.43 (d, 2H, KH); 3.69 (t, 2H, J = 7 Hz, CHCH 2 Cl); 4.1-4.93 Cm, 2H, KH); 4.82 Ct, 1H, J = 5.7 Hz, 5'-OH); 5.30 (d 1 H, J = 3.1 Hz, 3'-OH); 6.10 (doubled d, H, J = 7.4 Hz, KH-1 'a); 7.85 Cm, 1H, H-6); 10.9 (1 r, 1H, NH) 2.14 Ct, 2H, KH); 2.79 (t, 2H, J = 7.9 Hz, C CH Br); 3.5-4.0 cm, 5 h, CH 2 CH-2 Br, KH); 4.29 Cd, 1H, KH); 4.76 (Ir, 2H, 31OH, 5'-OH); 6.20 Ct, 1H, J = 6.7 Hz, KH-1 'G); 7.85 (s, 1H,

H-6); 11.4 (s, 1H, NH).

  1.7-2.5 Cmn, 2H, KH) -, 2.71 Ct, 2H, J = 7Hz, PH 2 CH 2 Br);

  3.5 cm, 2 hours, KH); 3.53 Ct, 2H, J e 7 Hz, CH 2 CH 2 R), 4.0-4.3 Cm, 2H, KH); 480 (t, 1H, J = 5.1 Hz, 5'-OH); 5.27 (d, 1H, J = 3.2 Hz, 3'-OH); 6.07 (doubled d, 1H, J = 7.5 Hz, KH-1 Vcl, 7.82).

Ca, 1H, H-: 6); 11.32 cm, 1H, NH).

  2.06 Ct, 2H, KH); 2.72 Ct, 2H, J = 7Hz, CHCH 2 J); 3.4-3.9 cm, 5 hours, CH 2 CH 2 Jp KH); 4.21 (1 r, 1H, KH); 4.99 C, 1H, J = 2.5 Hz, 5'-OH); 5.20 (d, 1H, J = 4Hz, 3'-OH); 6.13 (t, 1H,

  J = 6.5 Hz, KH-1 t 3); 7.77 (s, 1H, H-6); 11.35 Cs, 1H, NH).

  Ex 7 2.66 (t, 2H, J = 7.2 Hz, CH 2 CH 2 Cl); 3.5-3.8 (ml 5H, CH 2 Cl 2 and KH); 3.85-4 1 (ml 2H, K (H), 5.0 (t, 1 HI, J at 5.4 Hz, -OH), 5.36 and 5.45 (I, 1d, J). = 5Hz, 2H, 3'-OH and 5'-OH); 6.02 (d, 1H, J = 5.4, 4Hz, KH-1, t 3); 7.67 (s, 1 H, H-6); 11.32 (s,

1H, NH).

  Ex 8 2.75 (tm 2 H, J = 7.4 Hz, CH 2 CH 2 Br); 3.4-3.8 (m, 5H, CH 2 Br and KH); 3.85-4.1m, 2H, KH); 4.2-5.71 r, 3H, 2'-OH, 3'-OH, 5'-OH); 6.11 (d, 1H, 4.5 Hz, KH-1, 18); 7.66 (s, 1H, H-6);

11.32 (s, 1H, NH).

  Ex 9247 (t, 2H, J = -7 Hz, CH 2 CH 2 Cl); 3.5-4.25 Cm, 7H, CH 2 Cl and KH); 4.25 (dt, 1 HI, H-3 Y, JH 3 = 20.45 Hz, JH-H 4 Hz); 5.05 Cdt, 1H, H2 ', JH-2' F = 52.2 Hz, JH-H = Hz); 6.1 (dd, 1H, H-1 ', H-1H-F = 15.3Hz, J H-H = 4.1Hz); 7.7 (sl,

1H, H-6); 11.55 (s, 1H, NH).

  Ex 10 2.0 Cm, 2H, K (H); 28 (t, 2H, J = 7Hz, CH 2 CH 2 Cl); 3.5-3.9 (m, 5H, CH 2 CI anind KH); 4.2 (1 ru 9, 1H, KH); 5.0-5.2 (1 rs, 2 H, 2 OH); 6.2 (t, 1H, J = 7 Hz, KH-1 '0); 7.3 (s, 2H, NH 2); 7.8 (a,

1H, H-6).

  Ex A 2.1 (t, 2H, KH); 2.3 Ct, 2H, CH 2 CH 2 OH); 3.3-37 cm, 4 h, CH 22 H 20 H, KH); 3.7-3.85 (m, 1H, KH); 4.1-4.4 cm, 1H, KH); 4.54 (t, 1H, J = 5 Hz, CH 2 CH 2 OH); 5.00 (t, 1H, J = Hz, 5'-OH); 5.23 (d, 1H, J = 4.3 Hz, 3'-OH); 6.16 (t, 1H, J =

  7 Hz, KH-1 '6); 7.68 (s, 1H, H-6); 11-11.5 (1H, NH).

  Ex B 2.1-2.4 Cm, 1 IHH, t H 2 O 3 H 2 HOH, K (H); 3, 32 (t, 2H, J = 8Hz, C Hp CHOO H); 4.3-4 7 Cm, 3H, KH, CH 2 CH 2 OIJ); 5.02 cm, 1H, KH); 556 Cd, 1H, KH); 6.23 (doubled, 1H, J = 5 Hz, KH-aoe); 7.28-7, 40 Cm, 4 Htol uoy'i); 7.66 (s, 1H,

* H-6); 7.78-7.98 (m, 4H, toluo AT, 11.32 (s, 1H, NH).

253 196 2

  EXC 1 7-2 p 5 (mt 2 H 9 K Hh 2.31 (t, 2 Hp 37 Hzt -HCH 20 H) v 33 (M '2 H, XH); 4.1 (m, 2H, XH), 4.5 (1H, OH), 4.8 (1 rd, 1 OH), 5.27 (1H, 1H 2 OH), 6H (ddt 1H, KH), 1-a), 7.71 (H-1 H, H-6), 11.0% Hs NH).

Ex D 2? 71 (t 2 H, 1 = -O Hz,

   H-2 CH 2 C '), 3.70 (t 2 H 9 J = 8 Hz.

  C CI); 7 p 16 (dg 1 H, J = 7 Hz, H-6); 10,16 and 10,34 (21 r and lj 2

each 1H, 2 NH).

  1-0 Ex E 2. 36 (t, J = 6.3 Hz, 2 He I-12 CH 20 H); 3.4-3,, 8 (m, 5 H 9 CH H 2 OH 9 KH), 3, 85-4.1 (mg 2 HI, KH), 4.46 (tg J = 5, 4H). ## STR2 ## wherein: ## STR5 ## (5,37 and (45), 5,37 and 4,5 (2d, 1H, 59-OH), , 2'-OH, 3'-OH), 6.61 (dg J = 4.5 Hg)

  1 Hp KH-110), 7.54 1H, H-6) -, 11, 95 (8, 1H, NH).

  2.34 (t, 2H, J = 7Hz, HCHOH) -, 3.3-4.0 (m, 5H, CH 2 HP KH); 4.25 (1 rd, 1H, J = 22.5 Hz, H-31); 4.57 (t, 1H,

H-31-F

  CH 2 OH-); 5105 (dtg 1H, JH-21 F = 51.1 HHz JH-H = 4 Hzq

  H-21); 5.1 (rn, 1H, 51-OH)? 5 (d, 1H, 4H, 4H, 31-OH), -

  6.1 (dd, 1H, 11H-11-F, 16.4Hz, 3H-H = 4.1H, H-11); 7 and 57

1H, H-6); 11.4 (9, 1H, NH).

1 5 Ex F lr = large

Claims (9)

  Compounds of the Formula I x l 1 H C (CH 2) n -R 3 R 2 (I)   HO wherein R 1 and R 2 each independently of one another is hydrogen or lower alkyl, R 3 is halogen, CHF 2 or CF 3, R 4 is hydrogen, hydroxy is or fluorine, X represents an oxygen atom or an imino group, and n represents O or 1, the carbohydrate radical bonded to the pyrimidine ring being a radical a or 5, -   in free form or in the form of acid addition salt.   A compound according to claim 1 wherein R 1 and R 2 are hydrogen, R 3 is halogen, R 4 is hydrogen, hydroxy or fluorine, X is oxygen or a group imino and N means 1,   in free form or in the form of an acid addition salt.   A compound according to claim 1, characterized in that R 1 and R 2 have the meanings given in claim 1, R 3 represents halogen, X represents oxygen, R 4 represents hydrogen, hydroxy group or fluorine and N means 1,   in free form or in the form of an acid addition salt.   4 1- (2-Deoxy-D-erythro-pentofuranosyl) -   - (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione, under   free form or in the form of an acid addition salt.   A process for the preparation of the compounds of formula I specified in claim 1 in free form or acid addition salt form, characterized in that a) a compound of formula II is reacted X R '   H - (CH 2) n -R N R 2 3 II with a compound of formula III (III) 1 HOU   or b) replacing the R 3 'group in the side chain of a compound of formula Ia H 2 (C'2) n R 3' Oa> N R 2 (Ia) HO 1 N (C) -R   by a group R 3, in the formulas Ia, II and III, R 1, R 29, R 3, R 4, X and N having the meanings given in claim 1, R 5 representing a halogen or an acyloxy group, R 3 'representing a hydroxy group and any hydroxy group 2531942-   present in the carbohydrate radical which may be in protected form, and, where appropriate, any protecting group present in the compound thus obtained is removed, and the compound thus obtained is recovered in the form   free or as an acid addition salt.   6 The compounds as specified in one   any of claims 1 to 4, in free form   or in the form of a chemically acceptable acid addition salt for use as drugs.   7 A medicament, characterized in that it contains, as active ingredient, a compound such as   specified in any one of claims 1 to 4,   in free form or in the form of an addition salt   of chemically acceptable acid.   A pharmaceutical composition, characterized in that it contains a compound such as   specified in any one of claims 1 to 4,   in free form or in the form of a chemically acceptable acid addition salt, in combination with a diluent or vehicle   acceptable from a chemotherapeutic point of view. Compounds of formula Ia R   he (a HOH J 2 (CH 2) n R 3 'H Ok e R 2 (Ia) OH   wherein R 1, R 2, R 4, X and N have the meanings given in claim 1, and R 3 has the meaning given in claim 5, the carbohydrate radical attached to the pyrimidine ring being a radical a or B.