CH648837A5 - SUGAR ALCOHOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The present invention relates to new sugar alcohol derivatives of the general formula (I), a process for their

Production, as well as the pharmaceutical preparations containing these compounds.

CHz-R1

I.

CH-R2

CH-OR3

[CH-OR4] "

I.

CH-R2

I.

(I) CH2-R1

In the general formula (I):

R1 chlorine, bromine or iodine,

R2 hydroxy or

R1 and R2 together form an oxygen bridge,

R3 methyl,

R4 is hydrogen, methyl, alkanoyl, aralkanoyl or aroyl and n is 0 or 1, with the restriction that if n is 0, the steric position of the groups R2 and OR3, irrespective of their meanings, corresponds to the configuration of xylitol,

n 1 means that the steric position of the groups R2, OR3 and OR4, regardless of their meanings, corresponds to the configuration of dulcite, mannitol or sorbitol.

The compounds of the general formula (I) in which n is 1 are defined by the general formula (IA) and the compounds of the general formula (I) in which n is 0 are defined by the general formula (IB).

CH2-R1

I.

CH-R2 CH2-R1

I I

CH-OR3 CH-R2

I I

CH-OR4 R30-CH

I I

CH-R2 HC-R2

I I

(IA) CH-Ri (IB) H2C-R1

Compounds which are analogous to the compounds of the general formula (IA), but which contain a cyclic ether (dioxane ring) in the 2,3-position, are known, but have no anti-tumor effect (drug research 17, 145-149 [1967] ).

It has now been found that the action of the cytostatically active 1,6-dihalogen or 1,2-4,5-dianhydroxy-lite changes in a favorable direction if the secondary hydroxyl group (s) with alkoxy group (s) - die only need a small space - converted to ether.

The compounds of the general formula (IA) can be prepared by the 1,2-5,6-dianhydro-hexites of the general formula (II)

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

648837

cm

CHOH

(II)

CH-CH2

:>

methylated with a suitable methylating agent under such circumstances that the oxyran rings of the starting compound of the general formula (II) remain undamaged. Depending on the circumstances of the reaction, the monomethyl derivatives of the general formula (III) are formed

CH2

(III)

CHOH

CH «^.

I.

CH2

or the dimethyl derivatives of the general formula (V). CH2 ^

I.

CH '

I.

CHOCHb

I.

CHOCH3

I.

CH-

:O

(V)

CHf the dimethyl-dianhydro-hexites of the general formula (V) with corresponding hydrohalic acids or alkali metal halides and a strong acid to give the compounds of the general formula (VI)

5

CH2X

I.

CHOH

I.

10 CHOR3

I.

CHORUS4

I.

CHOH

I.

(VI) CH2X

15

implements. The diepoxy derivatives of the general formulas (III), (IV) or (V) can be prepared from the compounds of the general formula (VI) using a suitable alkaline acid extracting agent. The compounds of the general formulas (III), (IV), (V) and (VI) belong to the term compounds of the general formula (I), they are the special groups of the compounds according to the invention. 25 The compounds of the general formula (IB) can be prepared by using 1,2-5,6-dianhydro-xylitol of the formula (VII)

30th

(VII)

HiC ^

I ^

HC- ^

I.

HIGH

I.

HC ^

I ^

H2c- ^

: o x>

methylated with a suitable methylating agent under such circumstances that the oxyran rings of the starting compound remain undamaged. This gives 3-methyl-1,2-4,5-dianhydro-xylitol of the formula (VIII)

The compounds of the general formula (III) belonging to the term of the compounds of the general formula (I) can be converted into the compounds of the general formula (V) using suitable methylating agents or, if desired, using an acylating agent of the general formula R4 X - in which X Halogen, preferably bromine - or s0 of the general formula (R4CO) îO to acyl derivatives of the general formula (IV) (VIII)

H2G ^ HC- "'

I.

H3CO-CH

I.

HCV

I ^

H2c- ^

;O

;O

CHOCH3

CH-OR4

and if desired, this compound is added to the compound of the general formula (IX) using corresponding hydrohalic acids or alkali metal halides and a strong acid

60

(IV)

CH-.

I.

CH2-

: o be implemented. One can also proceed in such a way that the monomethyl dianhydro-hexites of the general formula (III) or their acyl derivatives of the general formula (IV) or

65

(IX)

H2C-X

I.

HC-OH

I.

H3CO-CH

I.

HC-OH

I.

H2C-X

around. Treatment of a dihalo compound of the general formula (IX) with a suitable alkaline acid-removing agent gives the compound of the formula (VIII). The compound of formula (VIII) and the compounds of general formula (IX) belong to the term compounds of general formula (I), they are the special groups of the compounds according to the invention.

It has surprisingly been found that the methylation of the dianhydro-hexites of the general formula (II) or of the dianhydro-xylitol of the formula (VII) can be carried out without damage to the oxyran rings with diazomethane, dimethyl sulfate or with methyl halides under anhydrous conditions, namely a) If diazomethane is used as the methylating agent, the procedure can be such that the solution or the suspension of dianhydro-hexitol or that of dianhydro-xylitol is reacted with diazomethane in the presence of a catalyst. The diazomethane can either be introduced into the reaction mixture in the gaseous state, or its solution can be added dropwise to the reaction mixture. The catalyst used is preferably fluoroboric acid, boron trifluoride, alkali metal oxides, alkaline earth metal oxides, aluminum chloride and selenium dioxide, particularly preferably boron trifluoride etherate.

b) The dianhydro-hexites of the general formula (II) and the dianhydro-xylitol of the formula (VII) can also be reacted with dimethyl sulfate under anhydrous conditions in the presence of an alkaline compound. A metal hydride, preferably sodium hydride, can be used as the alkaline compound. Suitable solvents are ether, preferably the ether used in the methylation with diazomethane.

c) The methylation can also be carried out with methyl iodide or with methyl bromide. In this case the catalyst used is a metal oxide or metal hydride, preferably silver oxide, calcium oxide, strontium oxide or barium oxide and / or a metal hydroxide. Dimethylformamide and dimethyl sulfoxide are preferred as solvents.

The compounds of the general formulas (III) and (V) obtained by methylation and the compound of the formula (VIII) can themselves be used as a cytostatic or can be converted into other sugar alcohol derivatives according to the invention which also have a cytostatic effect.

If the monomethyl derivatives of the general formula (III) are reacted with an acylating agent of the general formula R4 X or (R4C0): 0 in the presence of an acid binder, the azyl derivatives of the general formula (IV) are obtained. As acid binders can in the

648837

Organic chemistry generally used acid binders. Such are the organic or inorganic acid binders, e.g. tertiary amines such as pyridine, picolines, tralkylamines, or alkali metal and alkaline earth metal carbonates, hydrocarbonates and phosphates. Preference is given to using those acid binders which, or their salts formed during the acid binding, can be easily removed from the reaction mixture. During acylation with acetic anhydride e.g. an alkali metal acetate can be used as an acid binder. The acid binding agent only has the role of shifting the equilibrium in the direction of the acylated product by binding the resulting acids. So their selection is not critical.

Compounds of the general formulas (III), (IV) and (V) and the compound of the formula (VIII) can with hydrohalic acids or alkali halides - in which the halogen is chlorine, bromine or iodine - and a strong acid to the compounds of the general Formula (VI)

or be reacted to the compound of formula (IX). Here you can proceed in two different ways. The dianhydro compounds can either be reacted with a concentrated solution of the hydrohalic acids in water, or, under gentler reaction conditions, the dianhydro compounds of the general formulas (III), (IV) and (V) and the formula (VIII) are dissolved in the aqueous solution of the Alkali metal salt of hydrohalic acids and this solution is given the concentrated solution of a strong acid, for example that of sulfuric acid or perchloric acid with stirring in such a time,

that the reaction mixture has a neutral reaction (the pH is 6.5-7). The compounds of the general formulas (VI) and (IX) produced by the indicated reactions belong to the term compounds of the general formulas (IA) and (IB).

If desired, the compounds of the general formulas (VI) and (IX) can be reacted with an alkaline acid extractant to give the compounds of the general formulas (III), (IV) or (V) or to the compound of the formula (VIII). All strong organic or inorganic bases are suitable as alkaline acid removal agents. For example, alkali metal or alkaline earth metal alcoholates or organic nitrogen bases; Alkali metal or alkaline earth metal hydroxides, carbonates or hydrocarbonates are preferably used as inorganic bases. The reaction can also be carried out using anion exchange columns (OH ~ form).

The following reactions show the preparation of the compounds of the general formulas (IA) and (IB) from the compounds of the general formula (II) and from the compound of the formula (VII). The preferred reactants are given in the reaction scheme.

5

5

1"

15

20th

25th

30th

35

40

45

50

648 837

6

(II)

CHOCH3

I.

CHOCH3

[OH-]

CHOIR3

I.

CHORUS4

(V)

CH-

I.

CH2 "

:O

CHOH

I.

(VI) CH2X

(VII)

H2c ^

I.

HC ^ "

I.

HIGH

I.

HC ^

I ^

:O

Methylation

H2C \,

I ^

HC- ^

I.

-> HJCO-CH

;O

HC-

I.

(VIII) H2C-

;O

HX

:O

H2C-X

I.

HC-OH

I.

^ H3CO-CH

HC-OH

[OH-] I

(IX) H2C-X

X means chlorine, bromine or iodine. It is preferred if X is bromine.

If R4 is alkanoyl, the alkanoyl groups 4s are straight-chain or branched, and preferably have 2 to 6 carbon atoms.

If R4 represents an aralkanoyl group, the alkyl part preferably has 1 to 6 carbon atoms. These alkyl groups can be straight-chain or branched and contain an optionally substituted, preferably unsubstituted aryl group, preferably a phenyl group, at any point in the alkyl chain. The preferred aralkyl groups are the phenylpropionyl and the phenylbutiryl groups.

If R4 is aroyl, these groups can be substituted ss. or not substituted. The aromatic groups preferably contain 6 to 10 carbon atoms and, as substituents, such as the aryl parts of the aralkanoyl groups, can contain one or more halogen atoms, nitro, trifluoromethyl, alkyl, phenyl, amino or sulfonyl groups. The aroyl group is preferably p-phenylbenzoyl group.

Biological effectiveness

The tumor pharmacological activity of the compounds of general formulas (IA) 65 and (IB) according to the invention is shown by the following compounds:

1,6-dibromo-1,6-dideoxy-3,4-dimethyl-dulcite (DMDBD)

l, 2-5,6-dianhydro-3,4-dimethyl-dulcite l, 2-4,5-dianhydro-3-methyl-xylitol

(DMDAD) (DMDAX)

Toxicity study

The IDso values on mice with intraperitoneal treatment are DMDBD 700 mg / kg DMDAD 680 mg / kg DMDAX 500 mg / kg effect on Walker intramuscular carcinosarcoma

Tumor inhibition

DMDBD lx 50 mg / kg / ip 80%

1 x 100 mg / kg / ip 99%

DMDAD lx 50mg / kg / ip 55%

1 X 100 mg / kg / ip 80%

«0 DMDAX 1 x 100 mg / kg / ip 90%

Effect on S-180 subcutaneous Sarcom

Tumor inhibition

DMDBD 8x50 mg / kg / ip 90%

DMDAD 8 x 50 mg / kg / ip 80%

DMDAX 5 x 50 mg / kg / ip 75%

On the basis of investigations carried out by other tumors (L1210 mouse leukemia, Yoshida sc. Sarcom, P388 ip leukemia), it was found that the compounds of the general formulas (IA) and (IB) according to the invention have significant cytostatic activity and the activity of the compounds according to the invention is greater than that of the basic molecules.

The new compounds of the general formulas (IA) and (IB) according to the invention can be used in several ways in pharmacology, namely:

Per os: The pure active ingredient in itself or the pure active ingredient with auxiliaries used in the manufacture of tablets (starch, lactoz, talc) in the form of tablets.

Intravenous: in aqueous solution or dissolved in physiologically inert organic solvents (glycols). Intramuscular: in the form of solutions or in suspensions in the manner indicated above.

Intraperitoneal: In the form of solutions or suspensions in the manner indicated above.

Intracavital: The pure active ingredient in itself or the pure active ingredient in the form of solutions or suspensions in the manner indicated above.

Local (in loco): The active ingredient is used in itself or with the known antibacterial and wound care agents (sulfonamides, corticoids, vitamins) together on the skin or at the site of the operation.

The active substance concentrations in the various preparations are 1 to 10% for solutions

for suspensions 1 to 70%

for tablets 20 to 90%.

The preparation of the compounds according to the invention and that of the pharmaceutical preparations are explained in more detail by the following examples.

example 1

l, 2-5,6-dianhydro-3-methyl-dulcitol and 1,2-5,6-dianhydro-3,4-dimethyl-dulcitol

12 g (0.032 mol) of 1,2-5,6-dianhydro-dulcite is suspended in 1500 ml of anhydrous ether and diazomethane gas is passed into the reaction mixture with stirring. After the ether has been saturated with diazomethane, a few drops of boron trifluoride etherate in ether are added to the reaction mixture with continuous introduction of diazomethane gas. When the reaction mixture is saturated with diazomethane, the addition of boron trifluoride etherate is always repeated. After the reaction of the 1,2-5,6-dianhydro-dulcite has ended, the saturated aqueous solution of sodium hydrocarbonate required for the decomposition of the added boron trifluoride etherate is added to the reaction mixture and the reaction mixture is stirred for half an hour,

then dried over heated sodium carbonate. The filtered ether solution is evaporated and the residue is chromatographed on a silica gel column with a twentyfold volume in a benzene / ethyl acetate mixture (1: 1). The fractions containing the 1,2-5,6-dianhydro-3-methyl-dulcitol and the 1,2-5,6-dianhydro-3,4-dimethyl-dulcitol are brought to dryness.

4.0 g of l, 2-5,6-dianhydro-3-methyldulcite are obtained in the form of colorless oil. Yield: 30.48%, Rf = 0.47 (eluent: benzene / ethyl acetate = 1: 1).

In addition, 6.0 g of l, 2-5,6-dianhydro-3,4-dimethyl-dulcite are obtained in the form of white crystals. Yield:

648837

42.05%, melting point: 38-40 ° C (hexane), Rr 20.75 (mobile solvent: benzene / ethyl acetate = 1: 1).

Example 2

1,2-5,6-Dianhydro-3,4-dimethyl-dulcite 12 g of 1,2-5,6-dianhydro-dulcite is methylated analogously to Example 1 with diazomethane. The methylation is carried out until the first 1,2-5,6-dianhydro-3-methyl-dulcite is converted to 1,2-5,6-dianhydro-3,4-dimethyl-dulcite. The reaction mixture obtained is worked up analogously to Example 1. Yield: 77.1%, Rf = 0.75 (eluent as in Example 1).

Example 3

l, 2-5,6-Dianhydro-3,4-dimethyl-dulcite 5 g (0.031 mol) of 1,2-5,6-dianhydro-3-methyl-dulcite is methylated analogously to Example 1 with diazomethane. 4.0 g of 1,2-5,6-dianhydro-3,4-dimethyl-dulcite are obtained. Yield: 75%, melting point: 38-40 ° C, Rf = 0.75 (eluent as in Example 1).

Example 4

l, 2-5,6-Dianhydro-3-methyl-4-acetyl-dulcite 1.6 (0.01 mol) l, 2-5,6-dianhydro-3-methyl-dulcite is dissolved in 25 ml of anhydrous benzene and 1.4 ml of anhydrous triethylamine were added to the reaction mixture with stirring. The reaction mixture is then heated to 45 ° C. and 0.78 g of anhydrous acetyl chloride in 3 ml of anhydrous benzene are added dropwise at this temperature over an hour. The reaction mixture is stirred at 45 ° C. for 30 minutes, then the material which has separated out is filtered off with suction and washed with benzene. The combined benzene phases are evaporated in vacuo and the remaining syrup is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (95: 5). The fraction containing the l, 2-5,6-dianhydro-3-methyl-4-acetyl-dulcite is brought to dryness. 1.3 g of colorless oil are obtained. Yield: 63%, Rf = 0.77 (L, as in Example 1).

Example 5

l, 2-5,6-dianhydro-3-methyl-4-benzoyl-dulcite 1.6 gl, 2-5,6-dianhydro-3-methyl-dulcite is dissolved in 25 ml of anhydrous benzene and the reaction mixture 1.4 ml of anhydrous triethylamine are added with stirring. The reaction mixture is heated to 45 ° C. and 1.4 g of benzoyl chloride in 5 ml of anhydrous benzene are added dropwise at this temperature with stirring. The reaction mixture is stirred at 45 ° C. for 30 minutes, then the material which has separated out is filtered off with suction and washed with benzene. The combined benzene phases are evaporated in vacuo and the remaining syrup is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (95: 5). The fraction containing the 1,2-5,6-dianhydro-3-methyl-4-benzoyl-dulcite is brought to dryness. 1.72 g of colorless oil are obtained. Yield: 65%, Rf = 0.88 (eluent as in Example 1).

Example 6

l, 2-5,6-Dianhydro-3-methyl-4- (y-phenylbutyl) -dulcite 1.6 gl, 2-5,6-dianhydro-3-methyl-dulcite is dissolved in 25 ml of anhydrous benzene and the Solution 1.4 ml of anhydrous triethylamine added with stirring. Then 1.82 g of y-phenylbutiryllactone in 5 ml of anhydrous benzene are added dropwise to the reaction mixture at 45 ° C. with stirring. The reaction mixture is stirred at 45 ° C. for a further 30 minutes, then the material which has separated out is filtered off with suction and washed with benzene. The united Ben7

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

648837

zolphases are evaporated in vacuo. The remaining syrup is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (95: 5). The fractions containing the 1,5,6-dianhydro-3-methyl-4- (y-phenil-butiryl) dulcite are brought to dryness. 1.4 g of colorless oil are obtained. Yield: 39%, Rf = 0.92 (eluent as in Example 1).

Example 7

l, 2-5,6-dianhydro-3,4-dimethyl-dulcite

8.78 g of sodium hydride (55 ° suspension) is washed with 3 x 400 ml of anhydrous ether, then stirred in 400 ml of anhydrous ether with 6.2 g of 1,2-5,6-dianhydro-dulcite for one hour at room temperature. 40 drops of anhydrous isopropanol are first added to the reaction mixture thus obtained, then 16 ml of dimethyl sulfate are added dropwise over 2 hours. The reaction mixture is then stirred for 72 hours and 40 ml of anhydrous ethanol are added with stirring, then 100 ml of water. This reaction mixture is then added dropwise to a mixture of 5000 ml of ethyl acetate and 500 g of anhydrous sodium carbonate with vigorous stirring. The reaction mixture is stirred for a further half hour, then filtered and the solution obtained is dried over anhydrous sodium sulfate and then evaporated. The syrup obtained is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (1: 1). The fractions containing the 1,2-5,6-dianhydro-3,4-dimethyl-dulcite are brought to dryness and the crystalline residue is crystallized from hexane. 2.9 g of l, 2-5,6-dianhydro-3,4-dimethyl-dulcite are obtained. Yield: 40%, melting point: 38-40 ° C, Rf = 0.75 (eluent as in Example 1).

Example 8

l, 2-5,6-dianhydro-3,4-dimethyl-dulcite

4.8 g of 1,2-5,6-dianhydro-dulcite is dissolved in 24 ml of anhydrous dimethylformamide and, while stirring, 24 ml of dioxane, 24 g of barium oxide and 8.7 ml of methyl iodide are added, and the reaction mixture obtained is then filtered and the obtained solution mixed with ethyl acetate. The ethyl acetate is poured off from the oil and the oil is washed 2x 10 ml of ethyl acetate. The combined ethyl acetate solution is evaporated and the residue is chromatographed on silica gel column with a fiftyfold volume in benzene / ethyl acetate mixture (1: 1). The fractions containing the l, 2-5,6-dianhydro-3,4-dimethyl-dulcite are evaporated and the product is crystallized from hexane. 2.0 g of 1,2-5,6-dianhydro-3,4-dimethyl-dulcite are obtained. Yield: 35.8%, melting point: 38-40 ° C.

Example 9

l, 2-5,6-dianhydro-3-methyl-D-mannitol and 1,2-5,6-dianhydro-3,4-dimethyl-D-mannitol

12 g (0.082 mol) of 1,2-5,6-dianhydro-D-mannitol is suspended in 1500 ml of anhydrous ether and passed into the reaction mixture with stirring diazomethane gas.

After saturating the ether with diazomethane, a few drops of bortrifuloride etherate in ether are added to the reaction mixture with continuous introduction of diazomethane gas. When the reaction mixture is saturated with diazomethane, the addition of boron trifluoride etherate is always repeated. When the reaction of the 1,2-5,6-dianhydro-D-mannitol has ended, the saturated aqueous solution of sodium hydrocarbonate required to decompose the added boron trifluoride etherate is added to the reaction mixture and the reaction mixture is stirred for half an hour, then over heated sodium carbonate dried. The filtered ether solution is evaporated and the residue is chromatographed on a silica gel column with a twentyfold volume in a benzene / ethyl acetate mixture (1: 1). The fractions containing the l, 2-5,6-dianhydro-3,4-dimethyl-D-mannitol are brought to dryness. 3.5 g of l, 2-5,6-dianhydro-3-methyl-D-mannitol are obtained in the form of a colorless oil. Yield: 26.7%, Rf = 0.43 (eluent as in Example 1).

In addition, 4.9 g of l, 2-5,6-dianhydro-3,4-dimethyl-D-mannitol are obtained in the form of a colorless oil. Yield: io 35%. Rr = 0.74 (eluent as in Example 1).

Example 10 l, 2-5,6-dianhydro-3,4-dimethyl-D-sorbitol 12 g (0.082 mol) 1, -5,6-dianhydro-D-sorbitol is suspended in is 1500 ml of anhydrous ether and in the obtained suspension with stirring diazomethane gas. After the ether has been saturated with diazomethane, a few drops of boron trifluoride etherate in ether are added to the reaction mixture with continuous introduction of diazomethane gas. When the reaction mixture is saturated with diazomethane, the addition of boron trifluoride etherate is always repeated. After completion of the conversion of the first monomethyl compound to the dimeth-yl compound, the saturated aqueous solution of sodium hydrocarbonate required for decomposition of the added boron trifluoride etherate is added to the reaction mixture and the reaction mixture is stirred for half an hour, then dried over heated sodium carbonate. The filtered ether solution is evaporated and the residue was chromatographed on a silica gel column with a 20-fold volume in a benzene / ethyl acetate mixture (1: 1). The fractions containing 1,2,5,6-dianhydro-3,4-dimethyl-D-sorbitol are brought to dryness. 4.8 g of l, 2-5,6-dianhydro-3,4-dimethyl-D-sorbitol are obtained in the form of 35 colorless oil. Yield: 33.6%, Rf = 0.74 (eluent as in Example 1).

Example 11

l, 2-4,5-dianhydro-3-methyl-xylitol 40 20 g (0.17 mol) of 1,2-4,5-dianhydro-xylitol is dissolved in 1500 ml of anhydrous ether and the solution at room temperature with stirring Diazomethane gas saturated. A few drops of boron trifluoride etherate in ether are then added to the reaction mixture with continuous introduction of diazomethane gas. When the reaction mixture is saturated with diazomethane, the addition of boron trifluoride etherate is always repeated. After the completion of the reaction of the 1,2-4,5-dianhydro-xylitol, the saturated aqueous solution of sodium hydrocarbonate required for the decomposition of the added boron tri-50-fluoride etherate is added to the reaction mixture and the reaction mixture is stirred for half an hour, then dried over heated sodium carbonate . The filtered ether solution is evaporated and the residue is distilled in vacuo. 55 g of 15 g of l, 2-4,5-dianhydro-3-methyl-xylitine are obtained in the form of colorless oil. Yield: 67%. Boiling point: 48 ° C / 1.5 Hgmm.

Example 12 1,5-Dibromo-l, 5-diseoxy-3-methyl-xylitol 60 A solution of 1.0 g (0.0077 mol) of 1,2-5,6-dianhydro-3-methyl-xylitol in 2 ml of acetone is added dropwise at a temperature of less than 0 ° C. with stirring, 6 ml of hydrobromic acid solution cooled under 0 ° C., and the reaction mixture is then stirred for half an hour at a temperature less than 0 ° C. Sodium hydrocarbonate is added to the solution thus obtained and the pH is thus adjusted to 6. The separated material is filtered and mixed with 50 ml dichloroethane without drying. The dichlor

9

648 837

Ethane is dried over heated sodium sulfate, then concentrated to 10 ml and mixed with hexane until the solution begins to opalize. After cooling, the separated material is suctioned off and recrystallized from dichloroethane / hexane mixture (1: 1). 1.4 g of 5 are obtained

1,5-dibromo-1,5-dideoxy-3-methyl-xylitol in the form of colorless crystals. Yield: 62%, melting point: 78-80 ° C, Rf = 0.59 (eluent as in Example 1).

Example 13 io

1,5-dichloro-1,5-dideoxy-3-methyl-xylitol A solution of 1.0 g (0.0077 mol) of 1,2-5,6-dianhydro-3-methyl-xylitol in 2 ml of acetone is added at a temperature of less than 0 ° C. with stirring, 8 ml of concentrated hydrochloric acid solution cooled under 0 ° C. are added dropwise, after which the reaction mixture is stirred for half an hour at a temperature of less than 0 ° C. The solution thus obtained is evaporated in vacuo and the oil obtained is chromatographed on a silica gel column with a twentyfold volume in a benzene / ethyl acetate mixture. The combined fractions containing the 1,5-dichloro-1,5-dideoxy-3-20 methyl-xylitol are evaporated. 0.8 g of l, 5-dichloro-l, 5-dideoxy-3-methyl-xylitol is obtained in the form of a colorless oil. Yield: 51%, Rf = 0.52 (eluent as in Example 1).

25th

Example 14 1,5-Diiodo-1,5-dideoxy-3-methyl-xylitol A solution of 1.0 g (0.0077 mol) of 1,2-5,6-dianhydro-xylitol in 2 ml of acetone is added to a Temperature less than 0 ° C. with stirring 8 ml of concentrated iodic hydrochloric acid solution cooled under 0 ° C. were added dropwise, after which the reaction mixture was stirred for half an hour. The crystals which have separated out are filtered off with suction and recrystallized from ethyl acetate. 1.5 g of l, 5-diiodo-l, 5-dideoxy-3-methyl-xylitol are obtained in the form of colorless crystals. Yield 35 50.5%, melting point: 105-106 ° C.

The table below shows the products of Examples 15 to 22 together with their characteristics. The compounds were prepared analogously to the examples given above. 40

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648 837

Example 23 l, 2-5,6-dianhydro-3,4-dimethyl-dulcite 14.4 g of 1,6-dibromo-1,6-dideoxy-3,4-dimethyl-dulcite, 100 ml of water and 100 ml of anion exchanger Varion AD (OH'-form) (polystyrene-based synthetic resin containing strong alkaline amino groups, manufactured by Nitrokémia Ipartelepek, Balatonfüzfö) are stirred for 15 minutes. The anion exchanger is then suctioned off and washed with 3 x 30 ml of distilled water. The aqueous solution is combined with the wash water and the combined solution is evaporated to 40 ml under reduced pressure, then added while stirring the suspension of 1200 ml of ethyl acetate and 120 g of sodium carbonate. After filtering, the ethyl acetate solution is dewatered over heated sodium sulfate and then evaporated to dryness. The residue is recrystallized from hexane. 4.3 g of l, 2-5,6-dianhydro-3,4-dimethyl-dulcite are obtained, yield: 58%, melting point: 38-40 ° C.

Example 24 l, 2-5,6-dianhydro-3-methyl-dulcite 13.8 gl, 6-dibromo-l, 6-dideoxy-3-methyl-dulcite, 100 ml of water and 100 ml of anion exchanger (OH_ form) Varion AD-type are stirred for 15 minutes. The anion exchanger is suctioned off and washed with 3 x 30 ml of distilled water. The aqueous solution and the wash water are combined and this solution is evaporated to 40 ml under reduced pressure, then with stirring

10th

Suspension of 1200 ml of ethyl acetate and 120 g of sodium carbonate added. After filtering, the ethyl acetate solution is dewatered over heated sodium sulfate and then evaporated to dryness. The crude product obtained is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (1: 1). 3.6 g of pure 1,2,5,6-dianhydro-3-methyldulcite are obtained. Yield: 52%.

Example 25

io 1,2-5,6-dianhydro-3-methyl-4- (p-phenylbenzoyl) dulcite 1.6 g (0.01 mol) l, 2-5,6-dianhydro-3-methyl-dulcite dissolved in 25 ml of anhydrous benzene and 1.4 ml of anhydrous triethylamine were added to this reaction mixture with stirring. The reaction mixture is then heated to 45 ° C., at this temperature 2.16 g of p-phenylbenzoyl chloride in 5 ml of anhydrous benzene are added dropwise. The reaction mixture is stirred at 45 ° C. for 30 minutes, then the material which has separated out is filtered off with suction and washed with benzene. The combined benzene phases are evaporated in a vacuum and the remaining syrup is chromatographed on a silica gel column with a thirtyfold volume in a benzene / ethyl acetate mixture (95: 5). The fractions containing the 1,2-5,6-dianhydro-3-methyl-4- (p-phenilbenzoyl) dulcite are brought to dryness and the residue is recrystallized from ethanol. 1.46 g of l, 2-5,6-dianhydro-3-methyl-4- (p-phenylbenzoyl) dulcite are obtained. Yield: 43%, melting point: 75-78 ° C, Rr = 0.9 (eluent as in Example 1).

B

Claims (23)

648837 PATENT CLAIMS 1. Compounds of the general formula (I) CH2-R1 I. CH-R2 I. CH-OR3 I. [CH-OR4] n I. CH-R2 (I) I. CH2-R1 wherein R1 chlorine, bromine or iodine, R2 hydroxy or R 'and R2 together represent an oxygen bridge, R3 is methyl, R4 denotes hydrogen, methyl, alkanoyl, aralkanoyl or aroyl, and n denotes 0 or 1, with the restriction that if n denotes 0, the steric position of the groups R2 and OR3 corresponds to the configuration of xylitol regardless of their meanings, n 1 means that the steric position of the groups R2, OR3 and OR4, regardless of their meanings, corresponds to the configuration of dulcite, mannitol or sorbitol. 2. l, 6-dibromo-l, 6-dideoxy-3,4-dimethyl-dulcite as a compound according to claim 1. 3rd 648837 I. CH - "^ I. CHOCHÎ I. CHOH I. CH \ I. (in) cm- ^ wherein the steric position of the atoms corresponds to the configuration of dulcite, mannitol or sorbitol, with an acylating agent of the general formula R4X or (R4C0) 20, in which R4 has the meaning given above and X is halogen. 3. 1,2-5,6-dianhydro-3,4-dimethyl-dulcitol as a compound according to claim 1. 4 » 45 50 CHOCHs I. CHOH X) (II) (III) CH ^ I. CH2 ' : o in which the steric position of the atoms corresponds to the configuration of dulcite, mannitol or sorbitol - or dianhydro-xylitol of the formula (VII) (VU) HzC- ^ I ^ HC- ^ I. HIGH I. HC \ I ^ mc- ^ :O ;O 55 wherein the steric position of the atoms corresponds to configuration 60 of dulcite, mannitol or sorbitol, methylated with a methylating agent under conditions such that the oxyran rings of the starting compound remain undamaged. 4. 1,2-4,5-dianhydro-3-methyl-xylitol as a compound according to claim 1. 5 that the compound of formula (II) or (VII) is methylated with diazomethane in the presence of a liquid medium and a catalyst. 5. A process for the preparation of the compounds according to claim 1, in which R1 and R2 together represent an oxygen bridge, R3 denotes methyl, R4 denotes hydrogen or methyl and n denotes 0 or 1, characterized in that compounds of the general formula (II) CH2v CH ' I. CHOH I. CHOH I. CH \ I. CH2 " methylated with a methylating agent under such conditions that the oxyran rings of the starting compound remain undamaged. 6. The method according to claim 5, characterized in 7. The method according to claim 6, characterized in that an ether as the liquid medium and as a catalytic 8. The method according to claim 5, characterized in that the compound of formula (II) or (VII) is methylated with dimethyl sulfate in the presence of a base and in an anhydrous medium. ls 9. The method according to claim 8, characterized in that the methylation is carried out in the presence of sodium hydride and an ether as the reaction medium. 10. The method according to claim 5, characterized in that the compound of formula (II) or (VII) with a 10 sator boron trifluoride used. 11. The method according to claim 10, characterized in that the methylation with methyl iodide or 25 -bromide is carried out in the presence of silver, calcium, strontium or barium oxide and / or hydroxide. 12. The method according to claim 11, characterized in that the reaction is carried out in dimethylformamide or dimethyl sulfoxide. 30th 13. The method according to any one of claims 5 to 12, characterized in that mono- and dimethylated products are separated by chromatography. 14. A process for the preparation of the compounds according to claim 1 wherein R1 and R2 together are an oxygen 3s bridge, R3 and R4 each denote methyl and n 1, characterized in that a compound of the general formula (III) 15. A process for the preparation of compounds according to claim 65, wherein R1 and R2 together represent an oxygen bridge, R3 methyl, R4 alkanoyl, aralkanoyl or aroyl and n 1, characterized in that compounds of the general formula (III) 16. The method according to claim 15, characterized in that one carries out the acylation with an appropriate acyl halide or acyl anhydride in the presence of an acid binder in an anhydrous medium. 17. The method according to claim 16, characterized in that one carries out the acylation at a temperature of 0 to 70 ° C and that one uses pyridine, picolines, trialkyl amines, alkali metal and alkaline earth metal carbonates or phosphates as acid binders. 18. A process for the preparation of compounds according to claim 1, in which R 'is chlorine, bromine or iodine and R2 is hydroxy and R3, R4 and n have the meaning given in claim 1, characterized in that a corresponding compound of the formula (I) , in which R1 and R2 together represent an oxygen bridge, with chlorine, Hydrogen bromide or iodine. 19. The method according to claim 18, characterized in that hydrogen bromide is used and the di-epoxide of formula (I) is reacted with a concentrated aqueous solution of hydrobromic acid, or the diepoxide of formula (I) in an aqueous solution of an alkali metal salt of hydrobromic acid dissolved and the hydrobromic acid is freed by adding a strong acid at a pH of 6.5 to 7 and at a temperature of 0 to 60 ° C. 20. A process for the preparation of compounds according to claim 1, wherein R1 and R2 together represent an oxygen bridge and R3, R4 and n have the meaning given in claim 1, characterized in that a corresponding compound of the formula (I) in which R1 Chlorine, bromine or iodine and R2 are hydroxy, reacted with a base. 20 methyl halide is methylated in the presence of a metal oxide and / or hydroxide and under anhydrous conditions. 21. The method according to claim 20, characterized in that the base used is alkali metal alcoholates, organic nitrogen bases, alkali metal hydroxides, carbonates or hydrocarbonates, or anion exchangers used in OH ~ form in aqueous or in organic solvents at a temperature of 0 to 60 ° C used. 22. Pharmaceutical preparation characterized by a content of at least one compound of the general formula (I). 23. Pharmaceutical preparation according to claim 22, characterized by a content of l, 6-dibromo-l, 6-di-deoxy-3,4-dimethyl-dulcite, 1,2-6,5-dianhydro-3,4-di -methyl-dulcit or l, 2-4,5-dianhydro-3-methyl-xylitol.