FR2463762A1 - NEW CYTOSTATIC GLUCIDAL ALCOHOLS WITH BIFUNCTIONAL TERMINATION, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) OR R IS A HALOGEN; R IS A HYDROXY OR R AND R FORM TOGETHER AN OXYGEN BRIDGE; R IS A METHYL; R IS A HYDROGEN, A METHYL OR AN ACYL; N IS 1 OR ZERO, STATING THAT IF N IS 1, THE STERIC POSITIONS OF THE -R, -OR AND -OR GROUPS CORRESPOND TO THE CONFIGURATIONS OF DULCITOL, MANNITOL OR SORBITOL INDEPENDENT OF THEIR ACTUAL MEANING, IN THE CASE OR N IS ZERO, THE STERIC POSITIONS OF THE -R AND -OR GROUPS CORRESPOND TO THE CONFIGURATION OF XYLITOL INDEPENDENT OF THEIR ACTUAL MEANING, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

Description

The present invention relates to novel compounds

anticarcinogenic compounds of formula I

CH2 -R1

ICH-R2

I

CH-OR3 (I)

  CH 2 -R or R 1 is halogen, R 2 is hydroxy or R 2 and R 2 together form an oxygen bridge, R 3 is methyl, R is hydrogen, methyl or acyl, n is 1 or zero, specifying that in the case one is worth 1, the steric positions of

  groups -R2, -OR3 and -OR4 correspond to the configu-

  dulcitol, mannitol or sorbitol

  depending on their real meaning, in the case where n is zero, the steric positions

  groups -R2 and -OR3 correspond to the confi-

  xylitol irrespective of their mean-

real cation,

  as well as a process for preparing the compounds

  above and the pharmaceutical compositions containing them. The compounds of formula I where n is zero correspond to formula IA while those of n

  is 1 corresponds to the formula IB.

CH -R1 CH -Ri

122 1 2 2

CHR2 CH-R

1 3 30 |

EC-OR (IA) R O-CH (IB)

CH-OR3 HO-R2

1 2 1 1

  The compounds of formulas IA and IB have not yet been described in the literature.

  described analogs of the compounds of formula IA contained

  cyclic ether (a dioxolane ring) in the 3,4-positions, but the di- and end-dioxygen derivatives of 3,4-O-isopropylidene hexytols do not have antitumor activity (Arzneimittel Forschung, 17,

-149 (1967)).

  It has been found that the cytostatic activity of 1,6-dihalo or 1,2-5,6-dianhydrohexytols and that of

  1,6-dihalo and 1,2-4,5-dianhydroxylitols may be

  advantageously by transforming the secondary hydroxy group (s) into ethers by making them

  react with small alkoxy groups.

  Compounds of formula IA can be prepared by methylating 1,2-5,6-dianhydrohexytols of formula

  II with a suitable methylating agent under conditions of

  tions without damaging the oxyrane cores

  of the starting material. Depending on the conditions of the

  action is formed either the monomethyl derivatives of

  mule III is dimethyl derivatives of formula V. The compounds of formula III, which constitute a smaller group of compounds of formula IA can be converted into compounds of general formula V by methylating them with a suitable methylating agent, or, if it is If desired, they can be converted into acyl derivatives of formula IV by acylating them with an acylating agent of formula RX where X represents a halogen, preferably

  bromine, or with an acylating agent of formula (R4CO) 20.

  Monomethyl dianhydrohexytols of formula III or their derivatives of formula IV or dimethyl dianhydro

  Hexytols of formula V can be converted into

  poses of general formula VI by treating them with a

  halohydrate or an alkaline halide. We can trans-

  form the compounds of formula VI into diepoxy compounds of formulas III, IV and V by reacting them with a

  agent displacing the appropriate acids, of a character

  if that. The compounds of the formulas III, IV, V and VI

  The compounds of formula IB can be prepared by methylating 1,2-4,5-dianhydro-xylitols of formula

  VII with an appropriate methylating agent under conditions

  tions without damaging oxirane nuclei

  of the starting material. We can transform 3-methoxY-

  1,2-4,5-dianhydro-xylitols of formula VIII obtained as compounds of formula IX by reacting them with a

  halohydrate or an alkali metal halide if desired.

  The compounds of formula VIII can be prepared in

  both a dihalo compound of formula IX with a

  placing the appropriate acids of basic character. The compounds of formulas VIII and IX correspond to the formula

  1B and constitute particular subgroups.

  It has surprisingly been found that the dianhydroxytols of formula II and the dianhydroxylitols of formula VII can be methylated without damaging their oxirane rings if diazomethane, dimethylsulfate or a methyl halide is used as the

  methylating agent in the absence of water.

  a) If the methylating agent is diazomethane, it can be used to treat a solution or a suspension of a dianhydrohexytol or a dianhydroxylitol in the presence of a catalyst. The reaction mixture can be treated with diazomethane in the form of gas introduced into the mixture or in the form of a solution which is poured therein. The preferred catalysts are fluoroboric acid, boron trifluoride,

  alkali metal or alkali metal oxides

  earthquake, aluminum chloride or

  minium; the most preferred catalyst is trifluoride

of ethereal boron.

  b) The methylation can also be carried out by reacting a dianhydrohexytol of formula II

  or a dianhydro xylitol of formula VII with

  thylsulfate in the presence of a base under conditions

  anhydrous. As a base, it is possible to use a metal hydride

  lic; the preferred base is sodium hydride. The ether type compounds can be used as solvents; the preferred solvents are the ethers employed in the methylation process carried out with

diazomethane.

  c) Halides can also be used

  alkyl as methylating agents; we prefer

  methyl iodide or methyl bromide and, as a catalyst, a metal oxide and / or a metal hydride, preferably silver oxide,

  of calcium, strontium oxide, oxide and / or hy-

  barium droxide. The preferred solvents are dimeric

  thylformamide and dimethylsulfoxide.

  Compounds of formulas III and V obtained

  by methylation and the compounds of formula VIII can

  themselves be used as cytostatic agents but they can also be transformed into other

  derivatives of cytostatic carbohydrate alcohols according to

vention. -5-

  In the case of treating a mono derivative

  Methyl of formula III with an acylating agent of formula R4X or (R4CO) in the presence of an acidic binder, the reaction product obtained is an acyl derivative of formula IV. We can apply any

  which acid binding agent generally used in

  Organic preparative tick. Suitable acidic binding agents are of organic or inorganic nature, for example tertiary amines such as pyridine, picolines, trialkylamines; alkali or alkaline-earth metal carbonates or bicarbonates or phosphates. The preferred acidic binding agents are those which can also be readily removed from the reaction mixture in the form of their formed salts.

  during the acidic bonding reaction.

  It can also be applied as a binding agent

  when, for example, acetic anhydride is used

  as an acylating agent, an alkaline acetate. The acid binding agent simply having the role of displacing

  the balance of the reaction towards the formation of

  acylated products by binding formic acid, it is not

  no critical parameter of the reaction.

  The compounds of the formulas III, IV, V and VIII can be converted into compounds of the formula VI or IX by treating them with a halohydrate or an alkaline halide, where the halogen atom is chlorine, bromine or iodine. . Two reaction pathways are possible

  for this transformation. We can react a

  dianhydro solution with a concentrated aqueous solution of a halide acid, or perform the reaction

  in milder conditions by dissolving a compound

  dianhydro of formula III, IV, V or VIII in the

  aqueous solution of an alkaline salt of the halo acid

  venable, then adding to the solution the solution -

  of a strong acid, for example sulphuric acid

  or perchloric acid, while shaking vigorously

  the addition being carried out in such a way that the reaction mixture remains substantially neutral (pH = 6.5-7). The compounds of formulas VI and IX obtained by the processes indicated above meet

in formula IB.

  If desired, compounds of formulas VI and IX may be converted to compounds of formulas III, IV, V or VIII by treating them with a basic acid displacing agent. In the

  reaction above, it is possible to use

  placement of acids any strong organic or inorganic base. Preferred organic bases are, for example, alkoxides or alkali or alkaline earth metals, or organic bases containing nitrogen; the preferred inorganic bases are, for example, hydroxides, carbonates or bicarbonates of alkali or alkaline earth metals. The reaction can also be carried out using ion exchangers

anionic hydroxy form.

  The reactions according to the invention by which the IA and IB compounds can be prepared from the dianhydrohexytols of the formula II or

  dianhydro xylitols of formula VII are illustrated below.

  below; the most characteristic reagents in each transformation are indicated above the arrows. vc

-7- 2463762

-7- CH2.

I O

CHOH CHO0H methylation

CHOI1>,

I CH C11. I 0

C012 (II)

CH2- / CI

CHOCH3

I CH, I / OZ OH2 C11 G11

01 0

2% CH20 CH / 0

1HOCH3

CHOH 0 H CH2 H-haloid (/ O) / (V)

H2 C'-

Ha / 3 1 lation HC

H (VII) 0

(VZZ) H C-X 2i

> H 3C00-H

(oI / IHC-OH

H2 (V-X

(VII!)

CH2 'Io

C HOCH3

1 O

011-01-OR C11 CH0 (IV) R4X or

(R4) 20

  (III) OH2X CHOH-R CHOR I CHOH 012x (VI)

,, 11C-

lias IIC I I HC I 0 H2C (Ix)

  R can represent any halogen atom

  logène; the preferred halogens are chlorine, bromine

  or iodine, the most preferred halogen being bromine.

  SiR4 does not represent a hydrogen or methyl group, but an acyl group in general, the alkanoyl groups within R have from 2 to 10 carbon atoms, preferably from 2 to 6 carbon atoms. These alkanoyl groups may have straight or branched carbon chains and may be substituted with one or more halogen atoms if desired. If R 4 is an aralkanoyl group, it has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. The carbon chains of the alkyl moieties may be straight or branched and an optionally substituted, preferably unsubstituted, 6 to C atoms aryl group is located on any carbon atom in the carbon chain. Said aryl group is preferably a phenyl group. Preferred aralkanoyl groups are phenylpropionyl groups

and phenyl-butyryl.

  If R4 is an aroyl group, it can be

  substituted or unsubstituted. Aroyl aromatic groups

  ticks are preferably those with 6 to 10 atoms

  carbon that can be substituted by one or more

  In the case of halogen atoms, one or more groups

  trifluoromethyl, alkyl, phenyl, amino or sulphonyl

  fonyle, as well as the aryl moieties of

  killing aralcanoyl. A preferred aroyl group is the

p-phenylbenzoyl group.

  If X is a halogen, it is chlorine,

  bromine or iodine. HaloSdes can be preferably

  chlorides, bromides or iodides.

  Biological efficacy The cytopharmacological activity of the compounds

  formulas IA and IB, compounds which can be prepared

  res according to the invention is specified by giving the

  experimental results obtained by testing the compounds

  listed below: 1,6-dibromo-1,6-dideoxy-3,4-dimethoxy dulcitol (abbreviated as DIMBD), 1,2-5,6-dianhydro-3,4-dimethoy dulcitol (abbreviated as

DMDAD)

  1,2-4,5-dianhydro-3-methyl-xylitol (abbreviated LóqDAX).

Toxicity tests

  LD50 values for mice after administration

  intraperitoneal: DMIDBD 700 mg / kg DMDAD 680 mg / kg -MIDAX 500 mg / kg Activity against Y7alker intramuscular carcinosarcoma Antitumor activity DMDBD I x 50 mg / kg / ip 80% I x 100 mg / kg / ip 99% DMDAD 1 x 50 mg / kg / ip 55% I x 100 mg / kg / ip 80% MIDAX I x 100 mg / kg / ip 90% Activity against subcutaneous sarcoma S-180 DMDBD 8 x 50 mg / kg / ip 90% DMDAD 8 x 50 mg / kg / ip 80%

IMDAX 8 x 50 mg / kg / ip 75%.

  Comparative experiments performed on other tumors (mouse leukemia 11210, sarcoma

  Yoshida sc., leukemia P388 i.p.) gave results

  results similar to those given above;

  on the basis of these results it has been found that

  formulas IA and IB present an activity

  cytostatics and that their cytostatic effect

  tick is higher than that of the basic molecules.

  The new anticarcinogenic compounds of

  formulas IA and IB can be used in therapeutic

tick in various forms.

  Per os: the pure active ingredient without supports or the

  pure active ingredient mixed with general additives

  used in the manufacture of tablets (eg

  example starch, lactose, talc) all formulated as

  winning. Intravenous: dissolved in water or in a pharmacologically inert organic solvent (miscellaneous

glycols, etc.).

  Intramuscularly: in the form of solutions

  mentioned above or in the form of suspensions.

  Intraperitoneally: in the form of solutions

mentioned or suspensions.

  Intracavitary: the pure active ingredient without carriers or the pure active ingredient in the form of

  mentioned solutions or suspensions.

  Locally: the pure active ingredient is applied to the skin or to the part of the body that has been

  operated without supports or mixed with antibacterial

  generally used and to the compounds used

  for the treatment of wounds (sulphonamides,

coXides, vitamins, etc.).

  Preferred levels of active ingredient in various preparations

  parations: Solution 1-10% Suspension 1-70%

Tablet 20-90.

  The preparation and the formulation of the anticarcinogenic compounds according to the invention are specified

by the following examples.

Example 1

  1,2-5,6-dianbydro-3-methoxy-dulcitol and 1,2-5,6-dianyl

  D-5,4-dimethoxy-dulcitol 12 g (0.082 mole) of 10-11-1,2-5,6-dianhydro-dulcitol are suspended in 1500 l of anhydrous ether and gaseous diazomethane is introduced into the mixture. reaction while stirring. When the suspension

  ethereal is saturated with diazomethane, added to the

  Rinse several drops of ethereal boron trifluoride ether solution while simultaneously introducing diazomethane permanently. We

  always repeat the addition of ethereal solution

  boron fluoride when the reaction mixture becomes saturated with diazomethane. When the starting 1,2-5,6-dianhydro-dulcitol is completely transformed,

  adds to the reaction mixture an aqueous solution of

  sodium bicarbonate in sufficient quantity

  to break down the entire trifluoride of

  boron added, then the reaction mixture is stirred

  for 1/2 hour and dried over sodium carbonate

  dium that has been burned. We filter and we make

  evaporate the ethereal solution, then introduce the

  sidu in a column of gel chromatography

  The volume was 20 times higher than that of the residue and eluted with a 1: 1 mixture of benzene and ethyl acetate. Evaporate to dryness

  fractions containing the title compounds.

  4 g (30.48%) of 1,2-5,6-dianhydro-

  3-methoxydulcitol as a colorless oil, Rf = 0.47 (using a 1: 1 mixture of benzene and

of ethyl acetate).

  6 g (42X83%) of 1,2-5,6-dianhydro-

  3,4-dimethoxy dulcitol in the form of white crystals.

  Mp = 58-40 ° C (crystallized from hexene); Rf =

  0.75 (using a 1: 1 mixture of benzene and

ethyl acetate).

Example 2

  1,2-5 6-Dianhydro-3,4-dimetho dulcitol 12 g of 1,2-5,6-dianhydro-dulcitol are methylated

2463? 62

  With diazomethane following the procedure described in Example 1. The methylation is complete when the

  1,2-5,6-dianhydro-3-metphoxydulcitol formed in the first

  The first stage of the reaction is completely converted to 1,2-5,6-dihydro-3,4-dimethoxydulcitol. The reaction mixture is treated as described in Example 1. Yield: 77.1%. Rf = 0.75 (using the same

  solvent mixture as in Example 1).

Example 3

  1 2-5,6-dianhydro-3,4-dimethyl dulcitol

  5 g (0.031 mol) of 1,2-5,6-diisol are

  anhydro-3-methoxy-dulcitol with the following diazomethane

  the process described in Example 1.

  4.0 g of the title compound, whose PF is 38-40 C.

  Yield: 75%. Rf = 0.75 (using the same material

  solvent mixture as in Example 1).

Example 4

  1,2-5,6-dianhydro-3-methyl-4-acetyl dulcitol

  1.6 g (0.01 mole) of 1,2-5,6-

  dianhydro-3-methoxy dulcitol in 25 ml of dry benzene and 1.4 ml of dry triethylamine are added to the solution while stirring. The reaction mixture is then heated to 450 ° C. and a solution of 0.88 g of dry acetyl chloride in 3 ml of dry benzene is added dropwise for 1 hour while stirring and keeping the mixture under control. temperature. The reaction mixture is stirred at 450 ° C. for 30 minutes and then

  the precipitate is filtered off and washed with benzene.

  The benzene extracts are evaporated under vacuum

  combined. The residual syrup is introduced into a

  chromatography column - on silica gel having a volume 30 times greater than that of the residue and is eluted

with a 95: 5 mixture of benzene and ethyl acetate.

  The fractions are evaporated to dryness.

  the title compound. 1.3 g of the compound -13-

  of the title in the form of a colorless oil.

  Yield: 63%. Rf = 0.77 (using the same material

  solvent mixture as in Example 1).

Example 5

  1,2-5,6-dianhydro-3-methyl-benzyl dulcitol

  1.6 g of 1,2,4,6-dianhydro-3-methyl are dissolved

  thoxydulcitol in 25 ml of dry benzene and add

  to the solution while stirring, 1.4 ml of triethyl

  dry amine. The reaction mixture was then heated to 45 ° C. and a solution of 1.4 g of dry benzoyl chloride in 5 ml of dry benzene was added dropwise for 1 hour while stirring and keeping the mixture at the same temperature. The reaction mixture is stirred at 45 ° C for 50 minutes, then the precipitate is filtered off and washed with benzene. We do

  evaporate the combined benzene extracts under vacuum.

  The residual syrup is introduced into a silica gel chromatography column having a volume one times greater than that of the residue and eluted with a 95: 5 mixture of benzene and ethyl acetate. The fractions containing the title compound are evaporated to dryness. 1.72 g of the compound of

  title in the form of a colorless oil.

  Yield: 65%. Rf = 0s88 (using the same material

  solvent mixture as in Example 1).

Example 6

  1 2-56-Dianhydro-3-m-t-butylbenzylbutyrulcitol

  1.6 g of 1,2-5,6-dianhydro-3 are dissolved

  methoxydulcitol in 25 ml of dry benzene and

  add 1.4 ml of dry triethylamine while stirring.

  A solution of 1.82 g of phenylbutyryl chloride in 5 ml of dry benzene is then poured dropwise over 1 hour at 450 ° C. with stirring. When we have

  finished dripping drop still agitates the

  lange reaction for 1/2 hour at 45 C then -14-

  The precipitate formed is filtered off and washed with benzene.

  zene. The benzene solutions are evaporated under vacuum.

  united. The residual syrup is introduced into a silica gel chromatography column having a volume 30 times that of the residue and eluted with a 95: 5 mixture of benzene and ethyl acetate.

  The fractions are evaporated to dryness

  containing the title compound. 1.4 g is obtained

  of the title compound as a colorless oil.

  Yield: 39%. Rf = 0.92 (using the same

  solvent mixture as in Example 1).

Example 7

  12g2.5.6-Dianhydro-3,4-dimethyl dulcitol 8.78 g of sodium hydride (in the form of a 55% oily suspension) are washed three times with

  400 ml portions of anhydrous ether and then

  The solution is triturated in 400 ml of anhydrous ether and stirred with 6 × 2 g of 1,2-5,6-dihydro-dulcitol for 1 hour at room temperature. 40 drops of dry isopropanol are then added to the reaction mixture and 16 ml of dimethyl sulphate are added dropwise thereto.

  2 hours. The reaction mixture is stirred for

  core for 72 hours, then 40 ml of anhydrous methanol are carefully added with stirring, then ml of water is added. The reaction mixture is poured dropwise into a mixture of 5000 ml of ethyl acetate and 500 g of anhydrous sodium carbonate while stirring vigorously. After stirring for 1/2 hour, the reaction mixture is filtered, the solution is dried over anhydrous sodium sulphate and

  evaporate. The residual syrup is introduced into a

  column of silica gel chromatography with a volume 50 times that of the residue and

  with a 1: 1 mixture of benzene and ethyl acetate.

-15- 2463762

-15-

  The fractions are evaporated to dryness.

  the title product and recrystallize the crystalline residue from hexane. 2.9 g of the title compound having a mp of 38-40 ° C are obtained. Yield: 40%. Rf = 0.75 (using the same soil mixture)

only in Example 1).

Example 8

  1,2-5,6-Dianhydro- ?, 4-dimet, dulcitol

  4.8 g of 1,2-5,6-dianhydro dulcide are dissolved

  tol in 24 ml of dry dimethylformamide, then 24 ml of dioxane, 24 g of barium oxide and 8.7 ml are added.

  methyl iodide with stirring and stirring the

  lange for 1/2 hour at 30 C. The mixture is filtered

  reaction and the solution is mixed with 40 ml of

  ethyl cetate. The ethyl acetate is decanted from the oily fraction and the oil is washed twice with 10 ml portions of ethyl acetate. We evaporate

  the ethyl acetate solutions together and introduce

  The residue was taken up in a silica gel column with a volume 30 times that of the residue and eluted with a 1: 1 mixture of benzene and

  of ethyl acetate.

  holding the title product and recrystallized from hexane. Weight of the product obtained is from

  2.0 g. Yield: 35.8%; Mp 38-400.degree.

Example 9

  1,2-5,6-Dianh-3-methyl-D-mannitol and 1,2-5,6-

  dianhydr o-3,4-dimethyl-D-mannitol 12 g (0.082 mole) of 1,2-5,6-dianhydro-D-mannitol are suspended in 1500 ml of dry ether and gaseous diazomethane is introduced into it. in the mix

  reaction while stirring. Where the ethical suspension

  is saturated with diazomethane, several drops of ether solution are added to the reaction mixture.

  of ethereal boron trifluoride while introducing

-16-

  simultaneously diazomethane gas permanently.

  The addition of boron trifluoride ether solution is always repeated when the reaction mixture

  becomes saturated with diazomethane. When the 1,2-5,6-

  Starting dianhydro-D-mannitol was completely converted, a saturated aqueous solution of sodium bicarbonate was added in an amount sufficient to decompose all of the ethereal boron trifluoride, the reaction mixture was stirred for 1/2 hour and then dry on sodium bicarbonate which has been burned. We filter the ethereal solution, we

  evaporates and the residue is introduced into a

  silica gel chromatography column with a volume equal to 30 times that of the residue and eluted with a 1: 1 mixture of benzene and ethyl acetate. The fractions containing

  the title compounds. 3.5 g of 1,2-5,6-

  dianhydro-3-methoxy-D-mannitol in the form of a colorless oil. Yield: 26.7%; Rf = 0.43 (using the same

  solvent mixture as in Example 1).

  1,2-5,6-Dianhydro-3,4-dimetoxr is obtained

  D-mannitol as 4.9 g of colorless oil.

  Yield: 35%. Rf = 0.74 (using the same material

  solvent mixture as in Example 1).

Example 10

  1,2-5,6-dianhydro-3,4-dimeto-D-sorbitol 12 g (0.082 mol) of 1,2-5,6-dianhydro-D-sorbitol are suspended in 1500 ml of ether. anhydrous and introduced gaseous diazomethane into

  the reaction mixture with stirring. When the

  The ethereal solution is saturated with diazomethane, several drops of solution are added to the reaction mixture.

  in ethereal boron trifluoride ether while

  simultaneously producing diazomethane gas

-17-

  permanently. We always repeat the addition of tri-

  boron fluoride when the reaction mixture becomes saturated with diazomethane. When the monomethyl compound formed in the first stage of the reaction has been converted into a dimethyl compound, the mixture is added to the mixture

  a saturated aqueous solution of bicarbonate

  sodium salt in an amount sufficient to decompose

  Add all the ethereal trifluoride borate added, stir the reaction mixture for 1/2 hour and dry over burnt sodium carbonate. The ether solution is filtered, evaporated and the residue is introduced into a silica gel chromatography column one volume higher than the residue and eluted with a 1: 1 solution of benzene and acetate. ethyl. Fractions containing the product are evaporated to dryness

  title product. 4.8 g of 1,2-5,6-dianhydride are obtained.

  3,4-Dimethyl-D-sorbitol in the form of a colorless oil. Yield: 33.6%. Rf = 0.74 (using

  the same solvent mixture as in Example 1).

Example 11

I, 2-5,6-Dianhydro-methylxyxyitol

  20 g (0.17 mol) of 1,2-4,5-

  dianhydroxylitol in 1500 ml of dry ether and

  solution with diazomethane gas while stirring at room temperature. Several drops of solution are then added to the reaction mixture.

  the ethereal boron trifluoride ether while introducing

  at the same time permanently

  methane gas. The addition of solu-

  Ethereal boron trifluoride when the reaction mixture becomes saturated with diazomethane. When the 1,2-5,6-dianhydroxylitol has completely transformed, an aqueous solution is added to the reaction mixture.

  saturated with sodium bicarbonate in sufficient quantity

  In order to decompose all of the ethereal boron trifluoride added, the reaction mixture is stirred.

  for 1/2 hour and dried over sodium carbonate

  dium that has been burned. The filtered clear solution is evaporated and the residue is distilled under vacuum. 15 g of the title compound are obtained under

  form of a colorless oil. Peb: 48 C / 1.5 mm Hg.

Yield: 67%.

Example 12

  1,5-Dibromo-1 to 5-dideoxy-methylpxvylitol

  1 g (0.0077 mole) of 1,2-5,6-

  dianhydro-3-methylxylitol in 2 ml of acetone and the solution is poured dropwise at a temperature below 0 ° C while stirring in 6 ml of hydrobromic acid cooled below 0 C, and stirred

  mixing for 1/2 hour at a lower temperature

  than 00C. The pH of the solution is adjusted to 6 in

  adding sodium bicarbonate.

  formed and mixed without drying with 50 ml of dichloroethane. Dichloroethane is dried on

  sodium sulphate has been

  about 10 ml and hexane is added

  that he begins to trouble himself. The precipitated product is filtered off with cooling and recrystallized.

  from a 1: 1 mixture of dichloroethane and

  Xane. 1.4 g of the title product is obtained in the form of colorless crystals. Mp: 78-80 0. Yield:

  62%. Rf = 0.59 (using the same mixture of sol-

only in Example 1).

Example 13

  1,5-Dichloro-1,5-dideoxy-3-metboxxy xylitol

  I g (0.0077 mole) of 1,2-5,6-

  dianhydro-3-methoxyxylitol in 2 ml of acetone and the solution is poured dropwise at a temperature below 0 C while stirring in 8 ml of concentrated hydrochloric acid solution cooled below 0 C. The reaction mixture is stirred for 1/2 hour

  hour at a temperature below 0 C.

  The solution is evacuated under vacuum and the residual oil is introduced into a silica gel chromatography column having a volume 20 times that of the residue and eluted with an i: 1 mixture of benzene and ethyl acetate. Fractions containing the title product are combined and evaporated. 0.8 g of the title compound is obtained in the form of a colorless oil. Rf = 0.52 (using a 1: 1 mixture of

  benzene and ethyl acetate as solvent).

Yield: 51%.

Example 14

  I, 5-Diiodo-1,5-dideoxy-3-methoxy-xylitol

  I g (0.0077 mole) of 1,2-5,6-

  dianhydro xylitol in 2 ml of acetone and the solution is poured dropwise at a temperature below 0O C, while stirring, into 8 ml of hydroiodic acid

  concentrate cooled below 0 C. The mixture is stirred

  After 30 minutes, the resulting crystals were filtered off and recrystallized from ethyl acetate. We obtain 1.5 g of

  compound of the title in the form of colorless crystals.

Pf 105-106 C. Yield: 50.5%.

  The following eight examples are given in tabular form for clarity. The final product is prepared as described in the example above. The table contains all the essential data and featureso

BOARD

  Example Compound of Dome Name Mrt Quantum Halogenant Agent (gr) Pr o d u i t Quantum Name (Cr) R eport (C)

(%) (C

  m, 1H, 1H, 1H-1,2-5,6-dian-1H-1,6-dibromo-1,6-1,05-one, 130-1,042 -hydro-3-methyl-dideoxy -3-Methoxy-Dullyol Dulcitol 16 1,2-5,6-Dieno-HCl 1,6-Dichloro-1,6-0,71 49,136 -3,88 Hydro-3-metboxy-dideoxy-3-methoxy-Dulcitol Dulcitol 17 1,2-5,6-dianyl-1H-1,6-diiodo-1,6-1,4,542 132,46dig-3-methoxy-dideoxy-3-methoxy duloitol dulcitol 18 1.2-5.6 HBr 1,6-dibromo-1,6- 1,37 71,160 0,8-dian

3,4-hydro-3,4-dideoxy-3,4-di

  methoxydulcitol methoxy-Ydulcitol - R x f o Iv O I M na wu. TABLE (Continued) Example Starting Compound Quantity (g) Halogenating Agent Product Name Quantity (g) Ratio

(%) (C)

  19 1,2-5,6-dian I HI 1,6-diiodo-1,6- 1,66 68 165 0,83

hydro-53,4-dideoxy-3,4-di-

  methoxy duloitol methoxy duloitol 1,2-5,6-dian 1 HBr 1,6-dibromo-1,6-1,4,44 Oil 0.58 hydro-3-methoxy dideoxy-3-methoxy duloitol -4-acetyl duloitol 21 1,2-5,6-dian I HI 1,6-diiodo-1,6- 1,8 77 Oil 0.65

hydro-5-methoxydis-8-ox-3-methyl

  4-Acetyldulthoxy-4-acetylcitol of Loitol 22 1,2-5,6-dihydro-HCO 1,6dichloro-1,6-0,9 65 Oil 0.52 hydro-3-methacyldesoxy-3-methoxy 4-acetyl dul-4-acetyl dulcitol citol w 0% ru R xf N I ') i

-22.- 2463762

-22.-

Example 23

  I, 2-5,6-Dianhydro-, 4-dimethoxy dulcitol. A mixture of

  14.4 g of 1,6-dibromo-1,6-dideoxy-3,4-dimethbOE dulcine

  tol, 100 ml of water and 100 ml of

  VARION AD in OH- form (the resin is a

  strongly basic polystyrene containing amino groups, manufactured by Nitrokémia Ipartelepek, Balatonfizf6, in Hungary). The ion exchange resin is filtered off and washed 3 times with 30 ml portions of distilled water. The aqueous solution is combined with the wash water and evaporated at 40 ml under reduced pressure; the residue is added to a suspension of 1200 ml of ethyl acetate and 120 g of sodium carbonate. The reaction mixture is filtered and the ethyl acetate solution is dried over sodium sulphate which has been burned and then evaporated to dryness. The product of the residual crude title is recrystallized from hexane,

  and 4.3 g of product are obtained. Yield: 58%.

Mp: 38-40o0.

Example 24

  1,2-5,6-Dianhydro-3-methoxydulcitol A mixture of 13.8 g of 1,6-dibromo-1,6-dideoxy-3-mebioxydulcitol, ml of water and 100 ml of water is stirred for 15 minutes. ml of VARION AD anion exchange resin in OH-form. The ion exchange resin is filtered off and washed 3 times with

  50 ml fractions of distilled water. We combine the

  aqueous solution with washing water and evaporated to 40 ml under reduced pressure; the residue is poured into a suspension of 1200 ml of ethyl acetate and g of sodium carbonate. The reaction mixture is filtered and the ethyl acetate solution is dried over sodium sulfate which has been combusted, and then evaporated to dryness. The product of the residual crude title is introduced into a silica gel chromatography column having a volume one times greater than that of the residue and eluted with a 1: 1 mixture of benzene and ethyl acetate. We ob-

  holds 3.6 g of the title product in pure form.

Yield: 52%.

Example 25

  2-5,6-Dianhydro-3-methoxy-p-phenylbenzoyl dulcitol

  1.6 g (0.01 mole) of 1,2-5,6-

  dianhydro-3-methoxydulcitol in 25 ml of dry benzene and 1.4 ml is added to the solution while stirring.

  of dry triethylamine. The reaction mixture is heated

  at 450 ° C. and a solution of 2.16 g of p-phenylbenzoyl chloride in 5 ml is added dropwise thereto.

  of dry benzene for 1 hour at the same temperature.

  The reaction mixture is stirred at 45 ° for 1/2

  hour, and the precipitated material is filtered off.

  and washed with benzene. We evaporate

  under vacuum the benzene solutions united. We introduce

  the residual syrup in a chromatography column.

  silica gel with a volume 50 times higher than

  laughter and that of the residue and we elute with a mixture

  Benzene and ethyl acetate. We evapo-

  reduce the fractions containing the title product to dryness and the crystalline residue is recrystallized

  from ethanol. 1.46 g of product are obtained.

  Mp: 75-78 C. Yield: 43% o Rf = 0.9 (using

  the same solvent mixture as in Example 1).

-24-

- REVEIDICATIONS -

  I - Compounds of formula I CH2-Ri 1 22

CH-R

1H -R

CH-OR3 (I)

/ CH-OR read CH-R

1 1

CH2-R

  R 1 is halogen, R 2 is hydroxy or R 1 and R 2 together form an oxygen bridge, R 3 is methyl, R 4 is hydrogen, methyl or acyl, n is 1 or zero, with the proviso that in the case one is 1, the steric positions of

  groups -R2, -OR3 and -OR4 correspond to the configu-

  dulcitol, mannitol or sorbitol

  depending on their real meaning, in the case where n is zero, the steric positions

  groups -R2 and -OR3 correspond to the configuration

  xylitol irrespective of their significance

cation.

  2 - 1,6-Dibromo-1,6-dideoxy-3,4-dimethyldulcitol.

  3 - 1,2-5,6-Dianhydro-3,4-dimethyloxydulcitol.

  4 - 1,2-4,5-Dianhydro-5-methaxyxylitol.

  5 - Process for the preparation of compounds of formula I o the meanings of n and substituents

  are as defined in claim 1,

  characterized by reacting either a compound of

  formula II o the spatial positions of the corresponding atoms

  in the configuration of dulcitol, mannitol or sorbitol, a dianhydro xylitol

H2 C ,,

1 2 2cs HCI

HO0- CH

HC

H2CI of formula VII (VII)

  with diazomethane, dimethyl sulphate or a halo

  methyl genius in the presence of a catalyst, in that a compound of the formula III is reacted.

CHOCH3

  CHOH i1 (III) CH2 H2O with an acylating agent of formula R4X or (R4COO o R4

  is an acyl group and where X is a halogen in

  acid binding agent to obtain an acyl derivative of formula IV,

CH2 -0

  ## STR2 ##

1 O

  ## STR5 ## R 4 is an alkanoyl, aralkanoyl or aroyl group, and the methyl derivatives of formulas III, IV, V CH 2 0 CH I may be reacted if desired;

1HOCH3

CR (V)

OHOCH3

0H 10 or VIII H2O

I (VIII)

H3O0- CH

  11k I 0 H20 obtained as described above, with a hydrohalide to obtain a compound of formula VI

CH 2 X

CHOH

CHOR3 (VI)

I 4 GHOH

CH 2 X

-27- or IX

H2C - X

  ## STR2 ## where R 5 and R 4 are as defined above, X is a halogen and the spatial positions of the substituents

  compounds of formula VI correspond to the configuration

  mannitol, dulcitol or sorbitol, and, if desired, that a compound of formula VI or IX may be reacted where the meaning and the spatial positions of the substituents are such that

  defined above, with a basic compound to obtain

* nir a compound of formula III, IV, V or VIII.

  6 - Process according to claim 5, characterized

  in which a 1,2-5,6-dianhydrohexytol is used,

  preferably dulcitol, D-mannitol or D-sorbicide

  tol as starting material of formula II and

  1._2-4,5-dianhydro xylitol is used as a

starting material of formula VII.

  7 - Method according to one of claims 5

  and 6, characterized in that it is methylated in an anhydrous medium.

  8 - Process according to one of the claims

  at 7, characterized in that it is methylated with diazo-

  methane in a solvent of the ether type, preferably

  in diethyl ether or dioxane at a temperature of

  0-40 ° C using as the catalyst fluoroboric acid, boron trifluoride, alkali metal oxides, aluminum chloride or selenium dioxide, preferably ethereal boron trifluoride.

  9 - Method according to one of the claims

  at 7, characterized in that it is methylated with dimethyl sulphate in the presence of a basic compound, which is a metal hydride, preferably sodium hydride, in a solvent of the one-time ether type.

10-50C.

  - Method according to one of the claims

  at 7, characterized in that it is methylated with a methyl halide, preferably with iodide of

  methyl or methyl bromide in dimethyl-

  sulfoxide or dimethylformamide at a temperature of 10-50 C using as catalyst an oxide and / or

  or metal hydroxide, preferably the arsenic oxide

  gent, calcium oxide, strontium oxide, oxide

and / or barium hydroxides.

  11 - Process according to claim 5, characterized

  by separating the 3-methoxy-hexyltols from

  mule III of 3,4-dimethoxyhexytols of formula V formed together by column chromatography, if

reveals necessary.

  12 - Process according to claim 5, characterized

  characterized in that an acyl halide of formula R4X or an acid anhydride of formula (R4COO) is used as the acylating agent oR is a straight or branched chain alkanoyl group having 2 to 10 carbon atoms, which may be substituted by one or more halogen atoms, optionally an aralkanoyl group

  substituted with 7 to 20 carbon atoms, which

  holds a straight or branched chain alkyl moiety having 1 to 10 carbon atoms, or an aroyl group

  having from 6 to 10 carbon atoms which can be substituted

  killed by one or more halogens, alkyl, phenyl,

  amino or sulphonyl, X being as defined in the

sales 5.

-29-

  13 - Process according to claim 12,

  characterized in that it is acylated in an anhydrous medium at a temperature of 070 ° C. in the presence of an acid binding agent, preferably pyridine, a picoline, a trialkylamine, a carbonate or a metal phosphate

  alkaline or alkaline earth metal.

  14 - Method according to one of the claims

  & 13, characterized in that diepoxy compounds of the formulas III, IV, V and VII are converted into dihalogen compounds of the formula VI or IX falling within the formulas

  IA and IB respectively, by reaction with a halo

hydrate.

  - Process according to claim 14,

  characterized in that hydrochloric acid, hydrobromic acid or hydroiodic acid, preferably hydrobromic acid, is used as the hydrohalide, and in that the diepoxy derivatives of formulas III, IV, V are either reacted with a concentrated aqueous solution of the hydrohalide or dissolved in an aqueous solution of an alkaline salt of the hydrohalide

  corresponding and in that one releases the halohydrate

  acting with epoxides at pH 6.5-7 at a temperature of

  0-60 ° C by adding a strong acid to the mixture.

  16 - Method according to one of the claims

  5 to 15, characterized in that a dihalogenated compound of formula VI or IX is converted by reacting it with a basic agent displacing the acids, as a

  alkali metal alcoholate, an organic base

  Nitrogen, an alkali metal hydroxide, bicarbonate or carbonate, preferably an OH form anion exchanger, in an aqueous or organic solvent at a temperature of 0-60 C to a diepoxy compound of

  formula III, IV, V or VIII, respectively.

  17 - A pharmaceutical preparation characterized in that it contains as active ingredient at least one compound of formula IA or IB as defined in US Pat.

claim 1.

  18 - Pharmaceutical preparation according to claim 17, characterized in that it contains 1,6-dibromo-1,6-dideoxy-3,4-dimetbcy dulcitol,

  1,2-5,6-dianhydro-3,4-dimethoxy dulcitol or 1,2-

  4,5-dianhydro-3-methoxyxylitol as the active ingredient.

  As a medicament, a compound of formula IA or IB as defined in claim 1.