HU176216B - Process for producing terminally bifuntional xylite derivatives of citostatic activity - 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

Certain compounds having a C 4 or C 6 sugar alcohol backbone are known to have cytostatic effects (Neoplasma, 17, 15 (1970)). These compounds are α, ω-dihalo and / or dimethyloxy derivatives derived from tetrites and hexites, These compounds are characterized by the fact that their secondary hydroxy groups are free, i.e. not blocked with acetal groups (Arzneimittel-Forschung (Drug. Rés.) 14,668-70 (1964) and Tetrahedron Letters, 20, 716). (1961)].

These compounds are capable of performing 2 to 2 alkylations in the cell liner depending on the size of the sugar alcohol backbone and are therefore cytostatic by blocking it. Until now, however, derivatives of this type could only be obtained from tetrites and hexites, whereas such derivatives of pentites at different distances between them were not known. As the closest analog, only xylitol halogen derivatives are described in the literature which are protected by secondary hydroxyl groups or protected by an acetal or ether linkage or in which an anhydride ring is formed from the secondary hydroxyl groups. Thus, 1-chloro-1-deoxy-2,5-anhydroxy (Zsurnal Obscsej Minimil, 32, 3617 (1962)), 1,5-dichloro-1,5-dideoxy-3-methyl-2 is known. , 4-methylene xylitol (Zsurnal Obscsej Himii, 36, 1406 (1966)), and derivatives of terminal mono- and diiododyls in which all three hydroxyl groups are protected by acetal or ether [JACS _} 66, 73 (1944), 66, 670 (1944), 72, 561 (1950), 75, 132 (1953), and J. Chem. Soc. Perkin Trans, 1. 38, 1972]. of no importance, they were produced only to gain a better understanding of the chemical behavior of xylitol.

The state of the art cytostatic treatment is not the administration of a compound having a cytostatic effect over a long period of time, but the application of several different cytostatic agents at different levels of 176216. In this way, better therapeutic results can be achieved, reducing the risk of tumor resistance. Until now, this multi-point treatment lacked the sugar alcohol derivatives of the tetrit and hexite derivatives, which were also alkylating. It is an object of the present invention to eliminate this deficiency.

Surprisingly, it has now been found that the novel compounds of Formula I have potent cytostatic activity. We can produce that

a) Xyl derivatives of formula I wherein R ³ is optionally substituted with C 2 -C 4 alkanoyl optionally substituted with phenyl or benzoyl optionally substituted with phenyl, wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above. dianhydroxyl is reacted in the presence of an acid acceptor with an R ⁸ -X or an acylating agent of formula (R ⁸ ) ₂ O, wherein R ^{8 is} a C 2-4 alkanoyl optionally substituted with phenyl or a benzoyl optionally substituted with phenyl, and X is halogen; the resulting 3-acylated xyl derivative of formula V, wherein R ⁸ is as defined above, optionally R ¹ and R ^{5 are} halogen, R ² and R ^{4 are} hydroxy and R ³ 2-4 optionally substituted with phenyl reacting a xyl derivative of the Formula I having a C 1 -C 4 alkanoyl group or a benzoyl group optionally substituted with a phenyl group, or

b) Reaction of dianhydroxyl of formula IV with halogen other than hydrobromic acid to prepare compounds of formula I wherein R ³ is hydrogen, R ¹ and R ⁵ are halogen other than R ² and R ⁴ is hydroxy.

For the acylation according to process variant (a), any acid acceptor commonly used in organic chemistry may be used as the acid acceptor. These include organic or inorganic acid binders such as tertiary amines such as pyridine, picolines, trialkylamines, or alkali and alkaline earth metal carbonates, bicarbonates or phosphates. Preferably, an acid scavenger is used which, or its salt formed during acid scavenging, can be readily removed from the reaction mixture. It is also possible, for example, to use an alkali metal acetate as an acid scavenger when using acetic anhydride as an acylating agent.

The role of the acid scavenger in the reaction is merely to shift the equilibrium of the reaction towards the formation of the desired acylated product by binding the resulting acid, so its selection is not critical.

The 1,5-dihalo derivatives are prepared according to process variants b) and a) by a

Compounds of formula IV and epoxide groups of formula V are reacted with hydrohalic acids. This may be accomplished by heating the reaction mixture consisting of a compound of formula IV or V and a concentrated aqueous solution of hydrochloric acid under pressure. However, it is also possible, under mild conditions, to take a salt thereof instead of the hydrochloric acid, carry out the reaction in a concentrated aqueous solution and liberate the hydrochloric acid with dropwise addition of a strong mineral acid while stirring the reaction mixture. Under these conditions, it can be ensured that the pH of the reaction mixture is approximately neutral (6.5-7.0) during the reaction.

^{R1 and} R in the halogen atom may be any halogen atom. Preferably, I is chlorine, bromine or iodine. It is particularly preferred that R ¹ and R ^{5 are} bromine. The halogen in X is preferably chlorine.

The alkanoyl groups in R ^{3 may} have from 2 to 4 carbon atoms and may be straight or branched and may be optionally substituted with phenyl. It is particularly preferred that R ³ alkanoyl is unsubstituted acetyl or γ-phenylbutyryl. The benzoyl group at R ³ may be unsubstituted or substituted with phenyl. A preferred representative of the latter is p-phenylbenzoyl.

The pharmacological activity of the compounds of formula I according to the invention is exemplified by the example of 3- (p-phenylbenzoyl) -1,2,4,5-dianhydroxyl. The effects of the compounds are well demonstrated in the following animal experiments:

(a) NK / Ly ascites tumor in mice:

Mice were transplanted with 10 ⁷ cell numbers and then, on the first day after transplantation, at doses of 600 mg / kg, 300 mg / kg and 150 mg / kg, except for control animals, intraperitoneally with 3- (p-phenylbenzoyl) -1,2,4,5-dianhydro -xylitol. Untreated animals at post-transplantation were 17-23. days they died. In contrast, treated animals experienced significant survival. At day 50 post-transplant, 70%, 60%, and 30% of the animals were still alive, respectively (according to the above dose sequence).

Significant survival was also observed when animals were treated intraperitoneally with 700 and 500 mg / kg on day 3 post-transplant. In this case, 100 and 60% of the animals survived on the 40th day after transplantation.

b) L 1210 leukemia in mice:

The analysis of DBA / 2 strain mice were intraperitoneally transplanted with 10 ⁵ cell number. Except for control mice, animals were treated with 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxyl at doses of 200 and 400 mg / kg, respectively, on days 1, 4, and 7 after transplantation. Untreated animals died between 9 and 11 days after transplantation. In contrast, treated animals died only on day 13, which shows tumor inhibition.

c) S 180 solid tumor mouse:

Mice of the CFLP strain were transplanted subcutaneously with the tumor. Post-transplant 1,

On days 4 and 10, animals were treated intraperitoneally with 3- (p-phenylbenzoyl) -1,2-4,5-dianhydroxylitol at doses of 400 and 500 mg / kg, except for the control animals. Untreated animals have a median survival time of 23 days, compared with 33 days for your treated animals, demonstrating a significant anti-tumor effect.

(d) in Yoshida solid sarcoma rat:

Rats of CFY strain were transplanted subcutaneously with the test tumor at 7x10 ⁷ cells. Animals were transplanted for 5,

On days 8 and 12, with the exception of those selected for control, 200 mg / kg was administered intraperitoneally with 3- (p-phenylbenzoyl) -1,2,4,5-dianhydroxylite. Due to the high number of cells used for transplantation, the tumor was mature. In treated animals, tumor size was 55% smaller than control. Survival time was also prolonged. 50% of control animals died by day 20 after transplantation, while 80% of the treated animals were still alive. 20% of the treated animals were still alive on the 25th day after the death of the control animals.

(e) Toxicity studies:

The intraperitoneal dose of LD _{50 in} mice is 1000 mg / kg for 3- (p-phenylbenzoyl) -1,2,4,5-dihydroxyl.

As can be seen from animal data, the novel compounds of formula I of the present invention have valuable antitumor activity and can thus be used as active ingredients in cytostatic pharmaceuticals. These pharmaceutical compositions may also contain, in addition to the active ingredient (s), excipients such as fillers, diluents, flavor enhancers, stabilizing and / or formulation aids. However, pharmaceutical compositions containing the active compounds of the present invention, such as tablets, can be prepared by tabletting the active ingredients alone, without the use of any pharmaceutically active additives.

Non-toxic solid, liquid, semi-liquid, liquid or pressure liquefied gaseous additives are advantageously used in the preparation of pharmaceutical compositions. The active compounds may be formulated in the form of tablets, dragees, granules, powders, encapsulated powders or granules, ointments, creams, solutions or sprays. The solutions include formulations for injection, infusion, oral or topical administration. The active compounds of the formula I according to the invention may also be formulated as a powder ampoule. When necessary, pharmaceutical compositions, in particular injection and infusion formulations, may also contain other additives which affect or stabilize the pH or osmotic pressure of the solution for administration. Examples of such additives are various buffers and common salt.

To achieve a cytostatic effect, the pharmaceutical compositions containing the active compounds of the invention are administered in divided doses depending on the severity of the disease being treated and the individual patient's tolerance.

The treatment can be carried out only with pharmaceutical compositions containing the active ingredient of the invention, or by incorporating the treatment with the pharmaceutical composition containing the active ingredient according to the invention into a state-of-the-art treatment system based on the sequential use of several pharmaceutical compositions containing various active ingredients. In the latter way, it is possible to take advantage of the therapeutic effect that the individual active substances have different attack points.

Further details of the invention are illustrated by the following non-limiting examples.

Example 1

1,5-Diiodo-1,5-dideoxoxyl

Dissolve 2 g (0.014 mol) of 1,2- 4,5-dianhydroxyl in 2 ml of distilled water and add dropwise to 15 ml of concentrated iodine hydrochloric acid while cooling with ice-water. After standing for 10 minutes, the solution was cooled to 0 ° C, the precipitated crude product was filtered off and recrystallized from 5 volumes of ethyl acetate. 3.1 g of the expected pure product are obtained. 115-118 ° C. Yield: 59.6%. R _f = 0.865 with benzene-methanol-n-amyl alcohol-water-isopropanol in the ratio 62: 62: 30: 23: 20.

Example 2

1,5-Dichloro-1,5-dideoxyxyl

Dissolve 2 g (0.014 mol) of 1,2- 4,5-dianhydroxyl in 2 ml of distilled water and add dropwise to 10 ml of concentrated hydrochloric acid while cooling with ice-water. After standing for 10 minutes, the solution was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (50 mL) and extracted with saturated aqueous sodium bicarbonate. The ethyl acetate layer was dried and evaporated in vacuo. 1.4 g of the title compound are obtained in the form of a colorless liquid. Rf = 0.805 (Runs as in Example 1)

Example 3

3- (pF-Enylbenzoyl) -1,2-4,5-dianhydroxyl g of crude 1,2- 4,5-dianhydroxyl (about 75% purity) was dissolved in 250 mL of anhydrous benzene and 14 mL of anhydrous triethylamine was added with stirring. To the mixture is stirred for 45 at ⁰ ° C p-21,6g fenilbenzoilkloridot added over the course. After stirring for 4 hours at 45 ° C, the precipitated solid was filtered off and washed with benzene. The combined benzene solutions were evaporated in vacuo. The resulting syrup-like residue was chromatographed on 20 times silica gel with 95: 5 benzene-ethyl acetate. The fractions containing the title product were evaporated in vacuo. The residue was recrystallized from 5 volumes of ethanol. 12.5 g of the expected product are obtained. 86-88 °. Yield: 54.8%. Rf = 0.344 with 95: 5 benzene-ethyl acetate as eluent. Yield: 55.5%. R _f = 0.25 (with the starting material in Example 3).

Example 6

3- (p-Phenylbenzoyl) -1,5-dibromo-1,5-dideoxyxyl

A solution of 0.5 g of 3- (p-phenylbenzoyl) -1,2,4,5-dianhydroxyl in 0 ml of acetone was added dropwise to 5 ml of concentrated hydrobromic acid cooled with salted ice under cooling to 0 ° C. After standing for 30 minutes, the reaction mixture was diluted with 10 ml of water and allowed to stand at 0 ° C for 8-12 hours. Meanwhile, the title compound crystallizes out of the reaction mixture. At this time, the reaction mixture was filtered, the crystalline mass was washed to neutral with water and dried. The crude product obtained is recrystallized from benzene. 0.3 g of the title compound are obtained, m.p. 122-125 ° C. Yield: 38.8%. R _f = 0.32 (with the starting material in Example 3).

Example 4

3- (γ-γ-enylbutyryl) -1,2-4,5-dianhydroxyl

1.16 g of 1,2-4,5-dianhydroxyl are dissolved in 25 ml of anhydrous benzene and 1.4 ml of anhydrous triethylamine are added with stirring. A solution of 1.82 g of γ-phenylbutyryl chloride in 3 ml of anhydrous benzene is added dropwise to the reaction mixture at 45 [deg.] C. with stirring for 1 hour. After the dropwise addition, the reaction mixture was stirred for another 30 minutes at 45 ° C, and the precipitate was filtered off and washed with benzene. The combined benzene solutions were evaporated in vacuo. The resulting syrup-like residue was chromatographed on 20 volumes of silica gel with 95: 5 benzene-ethyl acetate. Fractions containing the title compound were evaporated to dryness. The title compound is obtained in the form of a colorless oil (1.4 g). Yield: 53.4%. R _f = 0.30 (with the starting material in Example 3).

Example 5

3-Acetyl-1.2 to 4.5-dianhidroxilit

1.16 g of 1,2- 4,5,5-dianhydroxyl are dissolved in 25 ml of anhydrous benzene and 1.4 ml of anhydrous triethylamine are added with stirring. The reaction mixture was heated to 45 ° C and a solution of 0.71 g of anhydrous acetyl chloride in 3 ml of anhydrous benzene was added dropwise at this temperature with stirring for 1 hour. After stirring for 30 minutes at 45 ° C, the precipitate was filtered off and washed with benzene. The combined benzene phases were evaporated in vacuo. The resulting syrup-like material was chromatographed on 20 volumes of silica gel with 95: 5 benzene-ethyl acetate. Fractions containing the title compound were evaporated to dryness. The title compound was obtained as a colorless oil (0.88 g).

Example 7

3-Benzoyl-1,2,4,5-dianhydroxyl

3g of 1,2- 4,5-dianhydroxyl is dissolved in 75 ml of anhydrous benzene and 4.2 ml of anhydrous triethylamine are added with stirring. The reaction mixture was then heated to 45 ° C and a solution of 3 ml of benzoyl chloride in 5 ml of anhydrous benzene was added dropwise at this temperature with stirring for 1 hour. After stirring for 30 minutes at 45 ° C, the precipitate was filtered off and washed with benzene.

The combined benzene phases were evaporated in vacuo. The syrup-like residue was chromatographed on 30 volumes of silica gel with 95: 5 benzene-ethyl acetate. Fractions containing the title compound were evaporated to dryness. The title compound was obtained as a colorless oil (2.8 g). Yield:

%. Rf = 0.28 (with the starting material in Example 3).

Thin layer chromatography was performed in each case on Merek's DC Fertigplatten Kieselgel (20 x 20 cm) plates. Development of 1,2-4,5-dianhydro derivatives with 5% methanolic nitrobenzylpyridine followed by followed by heating, and the 1,5-dihalo-1,5-dideoxy derivatives were sprayed with the nitrobenzylpyridine solution sprayed with 50% methanolic triethylamine solution after heating.

Example 8 mg powder ampoule:

The active ingredient with a particle size of 0.06-0.32 mm is aseptically filled into powder vials with a 50 mg dispenser. Packaged with 10ml ampoules of isotonic saline.

Example 9

250 mg tablets:

2500 g of crystalline active ingredient, 450 g of anhydrous lactose and 170 g of anhydrous crystalline cellulose are mixed in a homogenizer with a mixture of 80 g of paraffin oil and 350 ml of isopropanol. The mass is granulated and dried. To the dry matter was added 50 g of talc, homogenized again and compressed into 325 mg tablets. Each tablet contains 250 mg of active ingredient.

Example 10

100 mg capsules:

1000 g of crystalline active ingredient are homogenized with a premixed mixture of 50 g of Carbowax 6000 (a mixture of polyethylene glycols having an average molecular weight of 6000-7500) and 50 g of talc. The resulting mixture is filled into hard gelatine capsules with a 10mg setting using a filling device. Each capsule contains 100 mg of the active substance.

Example 11

Enteric solvent tablets and capsules:

The formulations prepared in Examples 9 and 10 are coated with an intestinal solvent coating known per se. Thus enteric tablets or capsules are obtained.

Claims (10)

Patent claims: A process for the preparation of a novel xylitol derivative of formula I wherein: R ¹ and R ⁵ are the same and are halogen when R ² and R ⁴ are independently hydroxy, or R ¹ and R ² 'together with R ⁴ and R ⁵ together form 1 to 1 oxygen bridges, and R ³ is independently C 2 -C 4 alkanoyl optionally substituted with phenyl or benzoyl optionally substituted with phenyl, independently of R ¹ , R ² , R ⁴ and R ^5; R ³ other than bromine, R ¹ and R ^s may also be hydrogen - for the preparation of a) R ³ stands for an optionally phenyl-substituted C2-4 alkanoyl group or xi lit derivatives of general formula I, optionally with substituted benzoyl phenyl group - wherein R ^ ^{R2, R4 and} R are as described above - for the preparation of formula IV one R ⁸ -X or a ₂ (R ⁸⁾ O acylating formula ⁵ agent dianhidroxilitet optionally acid scavenger - wherein ^R8 is phenyl-substituted C2-4 alkanoyl group, an optionally substituted or an optionally substituted phenyl, benzoyl and X is halogen - and hydrolyzing the resultant, and V representing a particular case of the I θ compounds 3-acylated xylitol derivative of formula - wherein R ⁸ is as defined above - if desired, R ^{1 and} R is halo, R ² and R ⁴ is is hydroxy and R ³ stands for phenyl, optionally substituted ⁵ t C2-4 alkanoyl group, or an optionally reacted I xiljt derivative having phenyl substituted benzoyl preparing a halogénhidrogénsawal or ⁰ b) R ³ is hydrogen, R ^{1 and} R other than bromine halogen atoms and R ² and R ⁴ is for preparing compounds of formula I containing a hydroxy group provider of formula IV dianhidroxilitet different hidrogénbromidtól halogénhidrogénsawal rea ^fifth Process for carrying out the process of claim 1, wherein the acylation reaction is carried out using trialkylamines, preferably θ sen tri / lower alkyl / alkyl amines. Process variant (a) of claim 1 or process of claim 2 for the preparation of 3- (p- ⁵ -phenylbenzoyl) -1,2,4,5-dianhydroxyl, characterized in that the acylation is p-phenyl benzoyl chloride. Process variant (a) of claim 1 or process of claim 2 for the preparation of 3- ^O - (7-phenylbutyryl) -1,2,4,5-dianhydroxyl, characterized in that the acylation is carried out with γ-phenylbutyryl chloride. . A variant of the process of claim 1 a) or a method of implementing the process of claim 2 3- 5-acetyl-1,2- 4,5-dianhydroxyl, characterized in that the acylation is carried out with acetyl chloride. 6. A process for the preparation of process variant (a) of claim 1 for the preparation of 3- (p-phenylbenzoyl) -1,5-dibromo--1,5-dideoxyxyl, characterized in that the resulting 3- (p-phenylbenzoyl) -1, 2-4,5-Dianhydroxyl is reacted with hydrobromic acid. Process variant (a) of claim 1 or embodiment of the process of claim 2 3- 5-benzoyl-1,2,4,5-dianhydroxyl, characterized in that the acylation is carried out with benzoyl chloride. 8. A process for the preparation of process variant b) of claim 1 for the preparation of 1,5-diiodo-1,5-dideoxyxyl, comprising reacting dianhydroxyl of formula IV with an aqueous solution of iodine hydrogen. Process for the preparation of process variant b) according to claim 1 for the preparation of 1,5-dichloro-1,5-dideoxyxyl, characterized in that the dianhyd 5 roxilite was reacted with aqueous hydrochloric acid. 10. Figures 1-9. A process for the preparation of a cytostatic pharmaceutical composition according to any one of claims 1 to 3, characterized in that one or more xylitol derivatives of formula I, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1, are in the preparation of a pharmaceutical composition using conventional excipients such as fillers, diluents and / or formulation.