GB2024204A

GB2024204A - Xylitol derivatives, their preparation and pharmaceutical compositions containing them

Info

Publication number: GB2024204A
Application number: GB7916274A
Authority: GB
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1978-05-11
Filing date: 1979-05-10
Publication date: 1980-01-09
Also published as: NO153928B; IL57182A; PL215489A1; DE2917538A1; ATA347779A; ES480869A1; AT361945B; IN150040B; CH641437A5; IL57182A0; BE876166A; FR2425445A1; EG15150A; IT7967984A0; FI67845B; AR222332A1; IT1118485B; SE7904080L; GB2024204B; DD143765A5

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

SPECIFICATION Xylitol derivatives, their preparation and pharmaceutical compositions containing them The present invention relates to newxylitol derivatives of the general formula

wherein R1 and R5 are the same and represent haloaen.tosvloxv or mesvloxv, in which case R2 and R4 represent hydroxy or R1 and R2 as well as R4 and R5 together form oxygen bridges, R3, whatever the values of R1, R2, R4 and R5, is hydrogen or alkanoyl, aralkanoyl or aroyl. The invention also provides a process for the preparation of the compounds of the general formula land pharmaceutical compositions of cytostatic activity containing compounds of the general formula I as active ingredients.

Certain derivatives of C4 or C6 sugar alcohols have been reported to have cytostatic activity [Neoplasma, 17, 15 (1970)]. These compounds were a,w-dihalo- and dimesyloxy derivatives of tetritols and hexitols or diepoxy derivatives thereof. The secondary hydroxy groups of these compounds are free, i.e. not blocked by acetal groups [Arzneimittel-Forschung (Drug. Res.) 14, 668-70(1964) and Tetrahedron Letters, 716 (1961)].

We have now found that the compounds of the general Formula I show a strong cytostatic activity.

The compounds of the general formula I may be prepared by acylating xylitols of the general formula

optionally in the presence of acid binding agents with an acylating agent of the formula R6-R7 (wherein R6 is mesyl ortosyl and R7 is halogen, or R6 is halogen and R7 is hydrogen) optionally followed by treating the resulting compounds of the general formula

which are within the scope of the general formula I, with a basic acid binding agent to obtain a dianhydroxylitol of the formula

and if desired, acylating the dianhydro xylitol product e.g. with an acylating agent of the general formula R8-X or (R8)20 (where 8 is as defined for R3 other than hydrogen) to obtain 3-acyl derivatives of the general formula

One can treat the dian hydro xylitol of the formula IV or 3-acyl derivatives of the general formula V with an acylating agent of the general formula R6-R7 and thus compounds of the general formulae Ill or

may be prepared. All the compounds of the general formulae III, IV, V and VI fall within the scope of the general formula I, forming special groups therein.

Xylitols of the general formula II and the acylating agent of the general formula R6 -R7 may be reacted by various methods. If a hydrogen halide is employed as acylating agent then xylitol may be heated with a concentrated aqueous solution of the hydrohalic acid optionally under pressure. If mesyl ortosyl halides are used as acylating agents of the formula R6-R7, then the hydrogen halide formed in the course of the reaction has to be bound by an acid binding agent. As acid binding agents the usual acid binding agents may be employed, such as organic or inorganic acid binding agents, for example tertiary amines, such as pyridine, picolines, trialkylamines, or alkali metal- and alkaline earth metal carbonates, hydrogen carbonates or phosphates.

It is preferred to select the acid binding agent such that the agent and the salt thereof formed in the course of the acid binding may be readily removed from the reaction mixture.

The compounds of the general formula I obtained in the first step of the reaction may be employed as cytostatic agents themselves but they may be converted to other xylitol derivatives of the general formula I.

If the resulting compounds of the general formula III are treated with a basic acid binding agent, then dianhydro xylitols of the general formula IV are obtained. As basic acid binding agent any strong organic or inorganic base may be used. Preferred examples of organic bases include alkali metal or alkaline earth metal alcoholates or organic nitrogen bases; inorganic bases include alkali metal or alkaline earth metal hydroxides, carbonates and hydrogen carbonates. The reaction may be however carried out with anion exchange resin in the hydroxy form.

Dianhydro xylitols of the general formula IV obtained in the above reaction may be further reacted according to the following two routes. According to one possibility the reaction leading to the compound of the general formula IV may be reversed, i.e. by reacting the dianhydro xylitol of the formula IV with an acylating agent of the general formula R6R7 - possibly different from the acylating agents used in the first reaction step, under the same reaction conditions as given in step 1.When using a hydrogen halide as acylating agent, the reaction may be carried out under milder conditions by dissolving dianhydro xylitol of the formula IV in a concentrated aqueous solution of an alkali metal halide followed by the addition of a strong acid acid, such as sulfuric acid or perchloric acid, at a rate that an approximately neutral reaction mixture of pH = about 6.5-7 is obtained, under steady stirring. The product of these reactions is a compound which may be characterized by the same structural formula as the compound obtained in the first reaction step - i.e. a compound of the general formula Ill- but wherein R6 preferably stands for a different substituent than group R6 of the compound of the general formula 111 obtained in the first reaction step.The above reactions make it possible to obtain such compounds of the general formula Ill which cannot be prepared in good yield in the first reaction step.

Dianhydro xylitols of the general formula IV are further reacted according to another embodiment of the present invention with an acylating agent of the general formula R8-X or (R8)20- wherein R8 represents alkanoyl, aralkanoyl or aroyl and X represents halogen -in the presence of an acid binding agent. As product, a 3-acyl derivative of the general V is obtained-wherein R8 is as given above. In this reaction the conventionally used acid binding agents may be employed. The same acid binding agents are preferred as given above. When using, for example, acetic anhydride as acylating agent an alkali metal acetate may also be used as acid binding agent. The acid binding agent has to bind the acid formed in the course of the reaction in order to shift the reaction equilibrium to the side of the acylated product and as such its type is not critical.

The resulting 3-acyl products of the general formula V may be acylated with acylating agents of the general formula R6-R7 also under the conditions mentioned above, and thuscompounds of the general formula VI are obtained. Suitable acid binding agents and acylating agents are those described above.

The reactions according to the invention for conversion of the compounds of the general formula II to different types of the compounds of the general formula I are illustrated in the reaction scheme below, showing briefly the reactants generally used in the various steps:

Halogen, in the definition of R1 and R5, may be any halogen but preferably chlorine, bromine or iodine and particularly bromine.

Tosyloxy and mesyloxy represent various toluene-sulfonyloxy, particularly p-toluene-sulfonyloxy or methyi sulfonyloxy groups. Alkanoyl group in the definition of R3 may contain 1 to 10, preferably 1 to 6 carbon atoms and may be straight or branched chained and may optionally be substituted by one or more halogens R3 may particularly stand for C14 alkanoyl, particularly acetyl. If R3 stands for aralkanoyl, the alkyl part contains 1 to 10, preferably 1 to 6 carbon atoms, and may be straight or branched chained, substituted on any of the carbon atoms by an optionally substituted C610 aryl, preferably phenyl. The aryl group is preferably unsubstituted. y-Phenylbutyryl group is preferred. Aroyl groups as R3 may be substituted or unsubstituted.The aromatic groups may preferably contain 6 to 10 carbon atoms and similarly to aryl or aralkanoyl groups, may be substituted by one or more halogens, nitro, trifluoromethyi, alkyl, phenyl, amino, sulfonyl. If R3 stands for aroyl, p-phenyl benzoyl is preferred.

Halogens in place of X, R6 or R7 may stand for chlorine, bromine, or iodine, particularly chlorine.

Pharmacological activity of the compounds ofthe general formula I is illustrated by showing the pharmacological activity of 3-(p-phenyl benzoyl)-1 2-4,5-dianhydroxylitol and 1 ,2-4,5-dianhydroxylitol, as follows: a) NKILy ascites tumour in mice Mice were transplanted with 107 tumour cells and treated intraperitoneally on the first day with 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol at doses of 600 mg/kg. 300 mg/kg. and 150 mg/kg. The untreated animals were dead on the 17th to 23rd day after the transplantation. 70, 60 and 30% respectively of the treated animals were however alive on the 50th day after the transplantation. At doses of 700 and 500 mg/kg. intraperitoneally, 100% and 60% respectively of the animals were alive on the 40th day after transplantation.

b) L 1210 leukaemia in mice Mice derived from DBA/2 strain were transplanted intraperitoneally with 105 cancerous cells. The animals were treated intraperitoneally with 3-(p-phenylbenzoyl)-1 ,2-4,5-dianhydroxylitoi at doses of 200 or 400 mg/kg. on the 1st, 4th and 7th day after transplantation. Between the 9th and 1 tth day after the transplantation the untreated animals were dead. The treated animals however were dead only by the 13th day.

c) S 180 solid tumour in mice Mice belonging to CFLP strain were transplanted With a tumour subcutaneously. On the 1st, 4th and 10th day following the tranplantation the mice were treated intraperitoneally with 3-(p-phenylbenzoyl)-1 ,2-4,5- dianhydroxylitol at a dose of 400 or 500 mg/kg. The average survival of the untreated animals was 23 days and that of the treated animals 33 days.

d) Yoshida solid sarcoma in rats Rats belonging to CFY strain were transplanted subcutaneously with test tumour, using 7 x 107 cells. The animals were treated intraperitoneally with 3-(p-phenylbenzoyl)-1 ,2-4,5-dianhydrn-xylkol on the 5th, 8th and 12th day following the transplantation at a dose of 200 mg/kg. The size of the tumour in the treated animals decreased by 55% compared with the control. 50% of the control animals were dead by the 20th day following the transplantation, while 20% of the treated animals were still alive on the 25th day following the death of the control animals.

e) NKlLy ascites tumour in mice The test was carried out by the method given under a) but as test-compound 1 ,2-4,5-dianhydro-xylitol was used which was administered at a dose of 20 mg/kg. 60% of the test-animals were alive on the 60th day following the transplantation.

f) Toxicity tests LD50 dose intraperitoneally in mice is 1000 mg/kg. in the case of 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro.

xylitol and 200 mg/mg. in the case of 1 ,2-4,5-dianhydro-xylitol. LDlo dose of latter compound: 160 mg/kg.

The test results show that compounds of the invention of the general formula I exhibit valuable cytostatic activity and may be used as active ingredients of cytostatic pharmaceutical compositions. Besides the active ingredient the pharmaceutical compositions may contain the conventionally employed filling agents, diluents, flavouring agents, stabilizers and/or formulating excipients. The pharmaceutical compositions containing a compound of the invention, such as tablets may be prepared by compressing the active ingredients into tablets alone without any inert excipients. Other pharmaceutical formalations can be provided in sterile form for admixture with a liquid carrier prior to parenteral administration.

When preparing pharmaceutical compositions non-toxic, solid, liquid, or semi-liquid carriers or gases liquified under pressure may preferably be used. The active ingredients may be formulated by mixing with the above-mentioned additives to form tablets, dragees, granules, powders, capsulated powders, ointments, creams, solutions or sprays. The solutions include injectable solutions, infusions, perorally or topically employed compositions. The compounds of the formula I of the invention may also be formulated in powder ampoules too. The pharmaceutical compositions may, if necessary, contain - mainly in case of injections and infusion compositions - additives which influence the pH-value or the osmotic pressure of the solution or which stabilize it. Various buffers and sodium chloride may be used for this purpose.

The pharmaceutical composition containing the active ingredients according to the invention may be administered at a dose of 1 to 30 mg/kg/day depending upon the severity of the disease, on the tolerance of the patient to be treated, preferably in divided dosage units for 1 to 10 days. Unit doses are e.g. 25-1000 mg.

The treatment may be performed either by using the pharmaceutical compositions containing as active ingredient only the compound of the invention or by using the pharmaceutical composition of the invention in combination with a pharmaceutical composition containing other active ingredients in accordance with modern methods of therapy.

Further details of the invention are illustrated in the following Examples which serve merely as illustration and not for limitation.

Example 1 1.0 kg. of xylitolis dissolved in 2000 ml. of 65-70% hydrobromic acid and the obtained solution is saturated below O"C with hydrogen bromide gas, whereafter the solution is maintained at85'Cfor4 hours in a closed system. After cooling, sodium hydrogen carbonate is added to the reaction mixture under stirring until a pH value of 6 is obtained. The precipitated crystals are filtered and recrystallized from ethyl acetate.

1,5-Dibromo-1,5-didesoxy-xyiitol is obtained. Yield: 1390 g. (76.5 /O); Rf = 0.85 (developing system: 62:62:30:23:20 mixture of benzene:methanol:n-amyl alcohol: : water:isopropanol); m.p. 104-106"C.

Example 2 1600 ml. of VARION AD ion exchange resin in hydroxy form (polystyrene-based resin containing strong basic amino groups, manufactured by Nitrokemia Ipartelepek, Baiatonfüzfö, Hungary) 222.4 g. of 1,5-dibromo-1,5-didesoxy-xylitol and 1600 ml. of distilled water are stirred for 15 minutes. The ion exchange resin is filtered off and washed with distilled water. The aqueous solutions are evaporated to litre at a reduced pressure and added under stirring to a suspension prepared of 20 litres ethyl acetate and 2 kg. of sodium carbonate. The ethyl acetate layer is dried over an hydros sodium sulfate and evaporated to dryness. The obtained crude product is subjected to chromatography on silicagel. 54 g. of pure 1,2-4,5-dianhydro-xylitol are obtained. Xylitol-epoxide content: 98-100%.Rf = 0.05 (developing system: 95:5 mixture of benzene and ethyl acetate).

Example 3 2 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of distilled water and the solution is added dropwise to 12 ml. of concentrated hydrogen bromide solution under cooling. After ten minutes to the solution sodium hydrogen carbonate is added to pH = 6 whereafter the precipitated crude product is filtered off and recrystallized from ethyl acetate. 3.5 g. of 1 ,5-dibromo-1 ,5-didesoxy-xylitol are obtained. M.p.: 104-106 C.

Example 4 2 g. of 1 ,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of distilled water and the solution is added dropwise to 15 ml. of concentrated hydrogen iodide solution under cooling. After 10 minutes the solution is cooled to 0 C and the precipitated crude product is filtered off and recrystallized from ethyl acetate. 3.1 g. of 1 ,5-diiodo-1 ,5-didesoxy-xylitol is obtained. M.p.: 115-118"C. Rf = 0.865 (developing system see Example 1).

Example 5 2 g. of 1,2-4,5-dianhydro-xylitol are dissolved in 2 ml. of distilled water and the solution is added dropwise under cooling to 10 ml. of concentrated hydrochloric acid solution. After ten minutes the solution is evaporated to dryness in vacuo. The residue is dissolved in 50 ml. of ethyl acetate and shaken out with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer is dried and evaporated in vacuo. 1.4 g. of colourless 1 ,5-dichloro-1,5-didesoxy-xyilitol is obtained. Rf = 0.805 (developing system as in Example 1).

Example 6 12 g. of crude 1 ,2-4,5-dianhydro-xylitol (purity of about 75%) are dissolved in 250 ml. of anhydrous benzene and under stirring 14 ml. of anhydrous triethylamine are added whereafter, at 45"C, 21.6 g. of p-phenyl-benzoyl chloride are added within 3 hours under stirring. The mixture is then stirred for 4 hours at 45"C and the precipitated product is then filtered off and washed with benzene. The benzene solutions are evaporated in vacuo. The syrup residue is chromatographed on silicagel with a mixture of benzene and ethyl acetate. Fractions containing 3-(p-phenyl-benzoyl)-1,2-4,5-dianhydro-xylitol are evaporated in vacuo.The residue is recrystallized from ethanol. 12.5 g. of 3-(p-phenylbenzoyl)-1,2-4,5-dianhydro-xylitol are obtained.

M.p.: 86-88"C. Rf = 0.344 (developing system: see Example 2).

Example 7 1.16 g. of 1,2-4,5-dianhydro-xylitol is dissolved in 25 ml. of anhydrous benzene and under stirring 1.4 ml. of anhydrous triethylamine is added, whereafter at 45'C 1.82 g of y-phenylbutyryl chloride in 3 ml. of anhydrous benzene is added dropwise. The reaction mixture is then stirred for 30 minutes whereafter the precipitated product is filtered and washed with benzene. The combined benzene solutions are evaporated in vacuo. The syrup residue is chromatographed on silicagel with a mixture of benzene and ethyl acetate.

The fractions containing 3-(e-phenylbutyryl)-1,2-4,5-dianhydro-xylitol are evaporated to dryness. 1.4 g. of colourless oil is obtained. Rf = 0.30 (developing system is as used in Example 2).

Example 8 1.16 g. of 1,2-4,5-dianhydro-xylitol is obtained. in 25 ml. of anhydrous benzene and 1.4 ml. of triethylamine is added to the solution. At 45"C a solution of 0.71 g. of anhydrous acetyl chloride in 3 ml. of anhydrous benzene is added dropwise within 1 hour. The mixture is stirred for 30 minutes at 45"C, whereafter the mixture is worked up according to Example 7. The product is crystallized from ethyl acetate. 0.88 g. of 3-acetyl-1,2-4,5-dianhydro-xylitol M.p.: 36-380C, Rf = 0.25 (developing system as given in Example 2).

Example 9 0.5 g. of 3-(p-phenylbenzoyl)-1 ,2-4,5-dianhydro-xylitol is dissolved in 1 ml. of acetone and the solution is cooled to 0 C, whereafter the solution is dropped into 5 ml. of concentrated hydrogen bromide cooled below 0C. The mixture is diluted with 10 ml. of water after 30 minutes, whereafter it is allowed to stand at O"C for 8 to 12 hours. The reaction mixture is filtered and the crystals are washed with water to neutral. The reaction product is recrystallized from benzene. 0.3 g. of 3(p-phenylbenzoyl)-1,5.dibromo-1,5-didesoxy-xylitol is obtained. M.p.:122-1 122-125"C. Rf = 0.32 (developing system is the same as used in Example 2).

Example 10 3 g. of 1,2-4,5-dia 1,2-4,5-dianhydro-xylitol are dissolved in 75 ml. of anhydrous benzene and 4.2 ml. of anhydrous triethyl amine are added under stirring. A solution of 3 ml. of benzoyl chloride in 5 ml. of anhydrous benzene is added dropwise. The reaction mixture is stirred at 45"C for 30 minutes. The reaction mixture is then worked up according to Example 8 and a mixture of hexane and ethyl acetate is used for recrystallization. 2.8 g. of 3-benzoyl-1,2-4,5-dianhydro-xylitol is obtained. Melting point: 39-400C. Rf = 0.28 (developing system as given in Example 2).

Thin layer chromatography was carried out in every case on "DC Fertigplatten Kieselgel" plates of size 20 x 20cam. 1,2-4,5-dianhydro derivatives were developed with 9 5% methanolic nitrobenzyl-pyridine solution followed by heating and the 1 ,5-dihalogeno-1 5-didesoxy derivatives were developed by spraying the plates sprayed with nitrobenzyl-pyridine solution after heating with a 50% methanolic triethylamine solution also.

Example 11 50 mg. powder ampoule Active ingredient of granule size 0.06 to 0.32 mm. is filled into powder ampoules under aseptic conditions with a feeder adjusted to 50 mg. It is packed together with a 10 ml. ampoule containing isotonic saline solution.

Example 12 250 mg. tablets 2500 g. of crystalline active ingredient, 450 g. of anhydrous lactose and 170 g. of anhydrous crystalline cellulose are homogenized with a mixture of 80 g. of paraffin oil and 350 ml. of isopropanol. The mass is granulated and dried, To the dry mixture 50 g. of talc is added, the mixture is then homogenized and pressed into tablets weighing 325 mg. Each tablet contains 250 mg. of active ingredient.

Example 13 100 mg. capsules 1000 g. of crystalline active ingredient are homogeriized with a previously thoroughly mixed mixture of 50 g. of Carbowax 6000 and 50 g. of talc. The obtained powder mixture is filled into hard gelatine capsules by using a filling device adjusted to 110 mg.

Example 14 Enterosolvent tablets and capsules Compositions prepared according to Examples 12 or 13 are provided with a known intestineosolvent coating to get an enterosolvent composition.

Claims

1. Compounds of the generaFformula

wherein R' and R5 are the same and represent halogen, tosyloxy or mesyloxy, in which case R2 and R4 represent hydroxy or R1 and R2 as well as R4 and R5 together form oxygen bridges, R3, whatever the values of R1, R2, R4 and R5,-is hydrogen, alkanoyl, aralkanoyl or aroyl.

2. Compounds according to claim 1 wherein R1 and R5 are bromine, p-tosyl or mesyl or together form an oxygen bridge.

3. Compounds according to claim 1 or 2 wherein R3 is hydrogen, CiA alkanoyl; aralkanoyl wherein the aryl moiety is a substituted or unsubstituted aryl group of 6-10 carbon atoms and the alkyl moiety contains 1-6 carbon atoms; or aroyl which is substituted or unsubstituted and contains 6-10 carbon atoms.

4. Compounds according to claim 3 wherein R3 is hydrogen, acetyl, y-phenylbutyryl orp-phenylbenzoyl.

5. 1,5-Dibromo-1,5-didesoxy-xylitol

6. 1 ,5-Diiodo-1 ,5-didesoxy-xylitol

7. 1,5-Dichloro-1,5-didesoxy-xylitol

8. 1 ,2-4,5-dianhydro-xylitol

9. 3-(p-Phenylbenzoyl )-1 ,2-4,5-dianhydro-xylitol 10. 3-(5-Phenylbutyryl)-1 ,2-4,5-dianhydro-xylitol.

11. 3-Acetyl-1,2-4,5-dianhydro-xylitol

12. 3-(p-Phenylbenzoyl)-1 ,5-dibromo-1 ,5-didesoxy-xylitol

13. 3-Benzoyl-1 ,2-4,5-dian hydro-xylitol 14: Compounds according to claim 1, substantially as described herein.

15. Pharmaceutical compositions having cytostatic activity comprising an effective amount of one or more compounds according to any of claims 1-4 and a pharmaceutically acceptable carrier.

16. Pharmaceutical compositions according to claim 15 which comprise a compound of any of claims 5 to 13.

17. Pharmaceutical formulations comprising an effective amount of one or more compounds according to any of claims 1-4 in sterile form, for admixture with a liquid carrier prior to parenteral administration.

18. Formulations according to claim 17 comprising a compound of any of claims 5 13.

19. Compositions or formulations according to any of claims 15-18 in unit dosage form, each unit dose containing 25-1000 mg of said compound.

20. Pharmaceutical compositions and formulations substantially as illustrated in Examples 11-14 herein.

21. A process for making a compound of claim 1 wherein R1 and R5 are halogen, tosyloxy or mesyloxy which comprises reacting a hydrogenhalide, a tosyl halide or a mesyi halide respectively with xylitol or a xylitol derivative of general formula

wherein R3 is as defined in claim 1.

22. A process according to claim 21 wherein xylitol is reacted with a hot concentrated aqueous solution of a hydrogen halide.

23. A process for making a compound of claim 1 wherein R1 and R2 as well as R4 and R5 together form oxygen bridges and R3 is hydrogen which comprises treating a compound of general formula

wherein Re is halogen, toxyloxy or mesyloxy, with a basic acid binding agent.

24. A process according to claim 23 wherein said basic acid binding agent is an anion exchange resin in the hydroxyform.

25. A process for making a compound of claim 1 wherein R3 is other than hydrogen which comprises acylating a compound of general formula (V) as defined in claim 21 (wherein R3 is hydrogen) to introduce a desired alkanoyl, aralkanoyl or aroyl group, and if desired subjecting the product to the process defined in claim 21.

26. A process according to any of claims 21-25, substantially as illustrated in Examples 1-10 herein.

27. Compounds of any of claims 1-14for use as cytostatic agents in human therapy.