CS211399B2 - Method of making the the new xylite derivatives - Google Patents

Abstract

Xylitol derivatives of the general formula <IMAGE> wherein R<1> and R<5> are the same and represent halogen, tosyloxy or mesyloxy, in which case R<2> and R<4> represent hydroxy or R<1> and R<2> as well as R<4> and R<5> together form oxygen bridges, R<3>, whatever the values of R<1>, R<2>, R<4> and R<5>, is hydrogen, alkanoyl, aralkanoyl or aroyl, exhibit cytostatic activity. They can be prepared from xylitol by standard methods. The compounds can be formulated for pharmaceutical use in conventional manner.

Description

The invention relates to a process for the preparation of novel xylite derivatives of the general formula I,

CH 2 -R ¹

AND

CH-R ²

R3-O-CH,

CH — R4

CH 2 —R ⁵ (I) wherein

R 1 and R 5 represent the same substituents and are halogen, tosyloxy or mesyloxy, in which case

R 2 and R 4 hydroxyl, or

R1 and R2 as well as R4 and ^R5 together form an oxygen bridge,

R ^3, independently of the meaning of R ¹ , R 2, R 4 - and R 5, represents a hydrogen atom, a C 2 -C 4 alkanoyl group, optionally substituted by a phenyl group, a benzoyl group or a fewylbenzoyl group.

The compounds of formula I are cytostatically active substances.

Certain compounds containing C 4 and C 6 sugar alcohols are known to have cytastatic properties [(Neoplasma, 17, 15 (1970)]. These compounds are α, ω-dihalogenated or dimesyloxy derivatives of tetrites or. The compounds have the same characteristic that their hydroxyl groups are free, i.e. not blocked by acetal groups [Arzneimittelforschung (Drug. Res.) 14,

668-670 (1964). and Tetrahedrcin Letters, 20, 716, (196IL)].

It has been found that the novel cytostatically active compounds of formula (I) according to the invention can be produced by the method of xylite of formula (II),

CH 2 —OH

CH-OH

HO — CH,

AND

CH-OH

AND

CH2-OH (II) optionally in the presence of acid binding agents, first acylated with an acylating agent

211339 of the formula R ⁵ -R ^7; wherein ^R5 represents a mesyl or tosyl, in which case R ⁷ represents atoi halogen, or R ⁵ represents a halogen atom, and in a case that R ⁷ is hydrogen, and the obtained compound of general · formula III,

R ¹ CHz-

AND

CH-OH

AND

HO — CH,

CH-OH

AND

CH 2 —R ⁵ (III) wherein R ¹ and R ⁵ are as hereinbefore defined, optionally treated with a base acid-binding agent and the dianhydroxylite of formula IV obtained

CH 4 (IV) is optionally acylated in the presence of acid binding agents by an acylating agent of the formula R ⁶ x or (R ⁸ ) 20, where R ⁸ is an alkanoyl group with 2. up to 4 carbon atoms, optionally substituted by phenyl, benzoyl or phenylbenzoyl and the X atom, halogen, and the obtained 3-acyl derivative of the general formula V, ^C ^> 0

CH ^'R8-CH of CH' (V) wherein R ⁸ has the meaning given above, optionally reacted in the presence of acid binding agents a. Acylating agent of formula R ⁵ -R ^7, wherein R ⁵ and R ⁷ are as defined above to give compounds of formula (VI),

CH 2 -R ¹

CH-OH

R 8 -O-CH,

AND

CH-OH

AND

CH 2 -R ⁵ (VI) wherein R ¹ , R ⁵ and R ⁸ are as defined above, or the optionally obtained dianhydroxylite of formula IV is reacted, optionally in the presence of acid-binding agents, with acylating agents of formula R ⁵ -R ⁷ , wherein R ⁵ and R ⁷ are as defined above, and to obtain compounds of formula III.

Compounds of formula (III), (IV), (V) and (VI) are all within the scope of the compounds of formula (I) and form a special group thereof.

The xylites of the formula II can be reacted with the acylating agents of the general formula R ⁵ -R ^{7 by} several methods. If h-allogenic acid is used as the acylating agent, the xylite may optionally be heated under pressure with a concentrated hydrogen halide solution. If R ⁵ -R ⁷ mesyl or tosyl halides are used as acylating agents: the hydrogen halide formed during the reaction must be bound by an acid binding agent. Suitable acid-binding agents are the customary reagents used in organic chemistry. As; examples of acid binding agents are tertiary amines, for example pyridine, picolines, trialkylimines or carbonates, or alkali metal or alkaline earth acid phosphates or carbonates. Preferably, acid-binding agents are used whose salt formed during the reaction is readily removed from the reaction mixture.

¹ Compounds of formula III obtained in the first step are-amotné useful as cytostatic agents and can according to the invention converted into other derivatives of xylitol. When the obtained compounds of formula III are treated with an acid-binding base, the dianhydroxylite of formula IV is formed. In this reaction, any strong organic or inorganic base is suitable as an acid binding agent. As the organic bases, for example, alkali metal or alkaline-earth metal alcoholates or organic nitrogen bases can be used, and inorganic bases alkali metal or alkaline earth hydroxides or their carbonates or acidic carbonates can be used. The reaction can also be carried out using ion exchangers in hydroxyl form.

The dianhydroxylity of formula IV produced by the above reaction can be further reacted by two methods. In one variation, the reaction leading to the compound of formula (I) is reversed by reacting the dianhydroxylite of formula (IV) with an acylating agent - preferably other than used in the first step - of the formula R ⁵ -R ⁷ under the reaction conditions outlined in the first step. When hydrogen halide is used as the acylating agent, the reaction may be carried out under milder conditions by dissolving the dianhydroxylite of formula IV in a concentrated solution of a salt of a hydrohalic acid and an alkali metal, followed by adding a solution of a strong acid such as sulfuric acid. or at a rate such that the pH of the reaction mixture is kept almost neutral (pH 6.5-7), resulting in a compound of the same formula as the product of the first step, i.e. formula III, which cannot be prepared according to the first reaction step. good yield.

The second method further reaction anhydroxylitu Formula IV comprises reacting diainhydroxylitu in the presence of an acid binder with an acylating agent of the formula ^R8 --x or (R ^8] 2 O wherein R ⁸ is as defined above а X is a halogen atom. As the reaction product of the 3-acylderivá.t of formula V wherein R ⁸ is as defined above. as the acid-binding agents can be used such agent commonly used in organic chemistry. When using acetic anhydride as the acylating agent may, however, the acid released к also use an alkali acetate · The acid-binding agent is intended to bind the acid formed during the reaction and thereby shift the equilibrium of the reaction in the direction of the product, thus it is not critical which acid-binding agent is used.

When converting di-anhydroxylitu formula IV to compound of formula III under the above conditions can be obtained 3-acyl derivatives of the general formula V acylated with acylating agents of general formula R ⁵ -R ^7, wherein the obtained compounds of the general formula VI. The acid binding agents used herein are as described above.

The following scheme illustrates the reactions by which various types of compounds of formula (I) are prepared from xylite of formula (II).

(III) (A)

CH, -R ¹ and 2

CH-OH & ¹ RO-CH

CH-OH

CH _Z R *

a] Ascites tumor .KK / Ly in mice

Mice were transplanted with 10 ⁷ cells and treated on the first day with 600 mg / kg, 300 mg / kg and 150 mg / kg intraperitoneally 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxylite. The untreated animals were sent 17 to 23 days after transplantation. In treated animals, on the other hand, 70, 60 and 30% of the animals remained alive (the order corresponds to the order of doses).

After treatment of the animals on day 3 after transplantation with a dose of 700, respectively. 500 mg / kg intraperitoneally remained alive 40 days after transplantation

100% and 60% of the animals, respectively.

In the definitions of R ¹ and R ⁵ , halogen can be any halogen and is especially chlorine, bromine or iodine, preferably bromine. Halogen X is especially chlorine.

Under the tosyloxy and mesyloxy groups, the methylsulfonyloxy group is crude.

Preferred R ³ groups are γ-phenylbutyryl, benzoyl and p-phenylbenzoyl.

The pharmacological activity of the compounds of the formula I according to the invention has been demonstrated in Example 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxylite and 1,2-4,5-dianhydroxylite.

b) Leukemia L 1210 in mice

10 ⁵ cells were transplanted from DBA / 2 strain. Animals were treated with 200, optionally 400 mg / kg intraperitoneally 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxylite at 200, 1 and 4 days after transplantation. Untreated animals came between day 9 and day 11 after transplantation. Treated animals, on the other hand, died only on day 13.

c) Tulmor S 180 in mice

Mice from the CFLP strain were transplanted subcutaneously with tumor, on the 1st, 4th and 10th day after transplantation, the animals were treated intraperitoneally with a dose of 400 or 500 mg / kg of 3- (p-phenyl-benzoyl) - 1,2-4,5-dianhydrioxylite. The average survival time of the untreated animals was 23 days and the treated animals, on the other hand, 33 days.

d) Yoshid-sarcoma in rats

A 7 x 10 7 test tumor tumor was transplanted subcutaneously from rats from the CFY strain. The animals were treated on day 5, 8 and 12 post-transplant with a dose of 200 mg / kg intraperitoneally of 3- (p-phenylbenzoyl) -1,2-4,5-dihydroxyxylate. The tumor size was 55-% smaller compared to the control. -50 -% of control animals died · 20 days after transplantation, when 80% of treated animals were still alive. 20% of the treated animals remained alive on day 25 after the death of the control animals.

e) NK / Ly ascites tumor in mice

The experiment was performed as described under a) except that the test compound was

1,2-4,5-dianhydroxylite, administered at a dose of 20 mg / kg. 60% of the test animals remained on day 60 after transplantation.

(f) Toxicity tests

The intraperitoneal dose of LD 50 in mice was 1000 mg / kg in the case of 3- (p-phenylbenzoyl) oxyllt, and 200 mg / kg in the case of 1,2-4,5-dianhydroxylity, and the latter was 160 mg / kg. .

As can be seen from animal experiments, the novel compounds of the formula I according to the invention have valuable cytostatic properties and can be used as active compounds in cytostatic pharmaceutical preparations. The preparations contain! in addition to the active ingredient (s), extenders, diluents, stabilizers, flavor enhancers and / or formulation aids. However, pharmaceutical preparations, for example tablets, can also be tabletted without additives.

In the manufacture of pharmaceutical preparations, non-toxic, solid, liquid, solid or pressure-liquefied gaseous additives are preferably used. The active substances are processed by carriers into tablets, dragees, granules, powders, capsules, ointments, creams, solutions, sprays. Solutions include various preparations for injection, infusion, oral or topical administration. The active compounds of the formula I can also be processed in the form of crystal ampoules. If necessary - especially in the case of injection - and infusion preparations - additives affecting the cofrooift pressure or stabilizers are added to the solution to be administered. Various buffers and sodium chloride are used for this purpose.

The active compounds according to the invention are administered after 1 to 10 days in a dose of 1 to 30 mg / kg / day, preferably in single doses, the dose being dependent on the severity of the disease to be treated and the individual tolerability of the patient.

The treatment can be carried out with the pharmaceutical preparations containing the active compound according to the invention, but the treatment can be carried out in combination with several active compounds, thus creating a modern treatment system.

Further details of the invention are illustrated by the following examples, without limiting the invention to these examples.

Example 1

1.0 g of xylite is dissolved in 2000 ml of 65-75% concentrated hydrobromic acid and the solution is saturated at 0 ° C with hydrogen bromide gas and kept in a sealed apparatus at 85 ° C for 4 hours. After cooling, sodium bicarbonate was added to the reaction mixture with stirring to pH 6, whereupon the crystalline precipitate was filtered off and recrystallized from ethyl acetate. There are obtained 1390 g of 1,5-dibrymo-1,5-dide-ddydylite. Melting point: 104-106 ° C; Yield: 76.5%, R _f 0.85 (mixture of 62: 62: 30: 23: 20 benzene: methanol: n-amyl alcohol: water: isopropanol.

Example 2

1600 ml of an ion exchanger in hydroxy form - a polystyrene resin with strongly basic amino groups - 222.4 g of 1,5-dibromo-1,5-nidesyydylite and 1600 ml of distilled water are stirred for 15 minutes. The ion exchange resin was removed by filtration and washed with distilled water. The aqueous solutions are concentrated under reduced pressure to 1 liter and the residue is added with stirring to a suspension of 20 liters of ethyl acetate and 2 kg of sodium carbonate. Water was removed from the ethyl acetate phase and the mixture was evaporated to dryness. The crude product is chromatographed on silica gel. 54 g of pure 1,2-4,5-dianhrdrodrile are obtained. Epoxy content in xylite: 98-100%, Rf = 0.05 (95: 5 benzene: ethyl acetate).

Example 3 g of 1,2-4,5-diaihydroxylite are dissolved in ml of water and the solution is added dropwise to 12 ml of concentrated hydrobromic acid while cooling. After 10 minutes, add sufficient sodium carbonate to the solution until a pH of 6 is reached, the precipitated crude product is filtered and recrystallized from ethyl acetate. 3.5 g of 1,5-dibromo-1,5-didesoxyxylite are obtained. Melting point: 104 - 106 ° C.

Example 4 g of 1,2-4,5-dianhydroxylite are dissolved in 2 ml of water and the solution is added dropwise to 15 ml of concentrated hydroiodic acid while cooling. After 10 minutes, the precipitated crude product was filtered and recrystallized from ethyl acetate. 3.1 g of 1,5-diiodo'-1,5-didesoxyxylite are obtained. Melting point: 115-118 ° C, _Rf = 0.865. (Solvent mixture as above.)

Example 5 g of 1,2-4,5-dianhydroxylite are dissolved in 2 ml of water and the solution is added dropwise to 10 ml of concentrated hydrochloric acid while cooling. After 10 minutes, the solution was concentrated in vacuo to dryness. The residue was dissolved in 50 mL of ethyl acetate and shaken with a saturated aqueous solution of sodium bicarbonate. The ethyl acetate phase is dried and concentrated in vacuo. 1.4 g of colorless 1,5-dichloro-l, 5-didesoxyxylitu, R _R = 0.805. (Solvent mixture as above.)

Example 6 g of crude 1,2-4,5-dianhydroxylite (approx. 75% purity) is dissolved in 250 ml of anhydrous benzene and added with stirring 14 ml of anhydrous triethylamine and with stirring for ¹ hour at 45 ^° C 21.6 g p-phenylbenzoyl chloride, then the precipitated product is filtered off and washed with benzene. The benzene solutions are concentrated in vacuo. The syrupy residue is chromatographed on a silica gel mixture of benzene and ethyl acetate. The fractions containing 3- (p-phenylbenzoyl) -1,2-4,5-dianohydroxylite were evaporated in vacuo. The residue was recrystallized from ethanol. 12.5 g of pure product are obtained. Melting point: 86-88 ° C, R _f = 0.344. (Elution agent as in Example 2.)

Example 7

1,16 g of 1,2-4,5-dianhydroxylite are dissolved in 25 ml of anhydrous benzene and 1,4 ml of anhydrous triethylamine at 45 ° C and 1,82 g of χ-phenylbutyrylchloride in 3 ml of anhydrous solution are added dropwise with stirring. benzene. The mixture was stirred for 30 minutes and the precipitated product was filtered off, and washed with benzenes. The combined benzene solutions were concentrated in vacuo. The syrupy residue is chromatographed on a silica gel mixture of benzene and ethyl acetate. The fractions containing 3- (χ-phenyibutyl) -1,2,4,5-dianhydroxylite were evaporated to dryness. 1.4 g of a colorless oil are obtained. R _f = 0.30 eluovadlo same as in Example 2).

Example 8

1.16 g of 1,2-4,5-dianhydroxylite are dissolved in 25 ml of anhydrous benzene and 1.4 g of anhydrous triethylamine are added to the solution. A solution of 0.71 g of anhydrous acetyl chloride in 3 ml of anhydrous benzene was added dropwise at 45 ° C over one hour. The solution was stirred at 45 ° C for 30 minutes and the mixture was further processed as in Example 7. The product was recrystallized from ethyl acetate. 0.88 g of 3-acetyl-1,2-4,5-dianhydroxy lite is obtained. Melting point: 36 - 38 ° C. R _f = 0.25. (Eluent - same as Example 2.)

Example 9

0.5 g of 3- (p-phenylbenzoyl) -1,2, -4,5-dianhydroxilite was dissolved in 1 ml of acetone and the solution was cooled to 0 ° C. The solution was added dropwise to 5 ml of concentrated hydrobromic acid solution cooled below 0 ° C. After 30 minutes the mixture was diluted with 10 ml of water and allowed to stand at 0 ^° C for 8-12 hours. The reaction mixture is filtered and the crystalline precipitate is washed until neutral and the product is recrystallized from benzene. 0.3 g of 3- (p-phenylbenzoyl) -1,5-dibromo-1,5-didesoxyxylite is obtained.

Melting point: 122-125 ° C. R _f = 0.32. (Eluent as in Example 2.)

EXAMPLE 10 g of 1,2-4,5-dianhydroxyliite are dissolved in 75 ml of anhydrous ethyl acetate. benzene. Was added dropwise 4.2 ml of anhydrous triethylamine and at 45 ^Q C solution of 3 ml of benzoyl chloride in 5 ml of anhydrous benzene ^1. The mixture was stirred at 45 ° C for 30 minutes. The mixture was worked up as in Example 8 using a mixture of hexane and ethyl acetate to recrystallize. 3-Benzoyl-1,2,4,5-dianhydroxy lite is obtained in a yield of 2.8 g. Melting point: 39-40 ° C. R _f = 0.28 (eluovadlo same as in Example 2).

The thin-layer chromatography experiments were carried out in each case on the finished silica gel plates in each case on the finished 20 x 20 cm silica gel plates. The 1,2-4,5-dihydro-derivatives were induced by 5% methanolic nitrobenzylpyridine solution and then by heating the .alpha.-5-dihalogen-1,5-didesoxy derivative by inducing the nitrobenzylpyridine solution sprayed with 50% methanol after heating. triethylamine solution.

Claims (12)

SUBJECT OF THE INVENTION A process for the preparation of novel xylite derivatives of the general formula I,> ⁴⁰ CH < BOY CH ^ »o CH ' CH 2 —R 1 AND CH — R2 AND R3—0 — CH, CH — R4 CH 2 —R ⁵ (i) wherein R 1 and R ⁵ represent the same substituents and are halogen, tosyloxy or mesyloxy, in which case R ² and R ⁴ hydroxyl or Ri and R2 as well as R4 and ^R5 together form an oxygen bridge, R 3, independently of R ¹ , R 2, R 4 and R 5, represents a hydrogen atom, a C 2 -C 4 alkanoyl group optionally substituted by a phenyl group, a benzoyl group or a phenylbenzoyl group, characterized in that xylite of the formula II CH2-OH CH-OH HO — CH, AND CH-OH CH2-OH (II), optionally in the presence of acid-binding agent, first acylated acylač.ním reagent of the 'formula R ⁵ -R ^7, wherein R ⁵ represents a mesyl or tosyl · and · in the case of R ⁷ stands. a halogen atom, or R 5 represents a halogen atom, in which case R 7 represents a hydrogen atom, and to the compounds of the general formula III obtained, CH2-Ri AND CH-OH HO — CH, AND CH-OH CH2-R5 (III), wherein R1 and R5 are as hereinbefore defined, optionally treated with an acid-binding base and the dianohydroxylite of formula IV d) optionally acylated in the presence of acid-binding agents with an acylating agent of formula R ^{8 -} X or (R ⁸ J 20, wherein R ⁸ is C 2 -C 4 alkanoyl optionally substituted by phenyl, benzoyl or phenylnenzoyl, and X represents a halogen atom, and the obtained 3-acyl derivative of the general formula of formula V, ¹ R ⁸ -CH (V) wherein R ⁸ is as hereinbefore defined is optionally reacted in the presence of acid binding agents with acylating agents of the general formula R ⁵ -R ⁷ , wherein R ⁵ and R ⁷ are as defined above, and the compounds of formula (VI) are thus obtained, CH 2 —Rf AND CH-OH I r8 — o_ch, CH-OH CH 2 -R 5 (VI), wherein R 1, R 5 and R 8 are as defined above, or the optionally obtained dialkyl hydroxyl of the formula IV is reacted, optionally in the presence of acid binding agents, with acylating agents of the formulas R 5 -R 7, R ⁷ is as defined above to give compounds of formula III. 2. Process according to claim 1, characterized in that the xylite of the formula II is reacted with hydrohalic acids. Process according to Claim 2, characterized in that the reaction is carried out in an aqueous concentrated solution of hydrohalic acid under heating, in particular at a temperature of 85 ° C. 4. Process according to Claims 1 to 3, characterized in that, for the preparation of 1,2-4,5-dianhydroxylite, the following compounds are treated: III, wherein R ⁵ is as defined above, with an acid binding agent. 5. Method according bo du 4 wherein the compound of formula III wherein R ⁵ has the meaning given ishorai, treated ion exchange resin in the hydroxyl form. 6. A process according to any one of claims 2 to 5, characterized in that for the preparation of 1,5-dibromo-1,5-didesoxyxylite, 1,5-diiodo-1,5-didesoxyxyxylite and 1,5-dichloro-1,5 The deoxyxylite discloses the 1,2-4,5-dianhydroxylite of formula IV in reaction with an aqueous solution of hydrobromic acid or hydroiodic acid or hydrochloric acid. 7. Process according to claims 2-6, characterized in that for the production of 3-acyl derivatives of general formula V-dianhydroxylit give 1.2 to 4.5 of formula IV in the presence of acid binding agents react with acylating agents of general formula R ⁸ - X .or ^(R8) 2O, wherein R ⁸ а X are as defined above. 8. The process according to claim 7, wherein the reaction is carried out in the presence of trialkylamines, in particular lower trialkylamines, as acid binding agents. 9. Process according to claim 7 or 8, characterized in that 3- (7-phenylbutyryl) is used for the preparation of 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxy lite. -1,2-4,5-dianhydroxylite or 3-acetyl-1,2,4,5-dianhydroxylite introduces the 1,2-4,5-dlanhydroxylite of formula IV in the presence of an acid-binding agent in reaction with p-phenylbenzoyl chloride; -phenylbutyryl chloride or acetonitrile. 10. The method of CDU-b 2-9, characterized in that the EE for preparing compounds of formula VI wherein R ⁸ and R ⁵ have the meaning indicated above, should give 3-acyl derivative of formula V wherein R ⁸ has the abovementioned meaning optionally in the presence of acid-binding agent ^1, to react with an acylating agent of the formula R ⁵ -R ^7, wherein R ⁵ and R ⁷ They have a meaning given above. 11. Process according to claim 10, characterized in that 3- [p-phenylbenzoyl) -1,2- is obtained for the preparation of 3- [p-phenylbenzoyl] -1,5-dibroimo-1,5-didesoxyoxyylite. 4,5-dianhydroxylite is reacted with hydrobromic acid. 12. A process according to claim 7 or 8, characterized in that, for the preparation of 3-benzoyl-1,2,4,5-dianhydroxylite, 1,2-4,5-dianhydroxylite of the general formula IV is reacted with benzoyl chloride in the presence of a reagent binding agent. acid.