CS220403B1 - Acyl derivatives of dianhydrohexitol and method of preparing same - Google Patents

Abstract

Compounds of the formula I in which the substituents Q1 and Q2 are the acyl radicals given in Claim 1 have anticarcinogenic properties. These compounds are prepared by acylating corresponding 1,2-5,6-dianhydrohexitols. <IMAGE>

Description

SUMMARY OF THE INVENTION The present invention provides acyl derivatives of 1,3-5,6-palohydroheeitsl to counteract anticorrosive activity and a method for producing them. The present invention also provides pharmaceutical compositions containing the above compounds as active ingredients.

It is known that diepoxide types of alcohol dihydroxide derivatives, such as L-1,3,3,4-diepsoxy-butanol, in particular 6 atomic alcohols such as 1,2-5,6-danrhydro-D-marcinol, The 2,5,6-dihydropyridine is highly effective. (Jaiman, M, Rosa, - W.. CJ: Epoxy Formation in Subs Tipped Hexites, Carbolhrdrate - Reseerch -, st. 139, 1969; Ja.man, - M, Ross, WCJ: Origin 1,3-5,6 D-Hydroxy-D-octyl of 1,6-dibromo- and 1,6-dimethanesulfonyl-1,6-dihydroxy-D-mercuryl, Chem., Ind., 42, 1, 789 (1967); Eison, A. L, Jaroan M, Ross, W.C.: Tooicity, haematological effect, and ring-coat efficacy of epoxides derived from disubstituted heeitols (Eur. J. Cancar, J. 61: 7, 1968). these are 1, 2-5,6-dianhydr.odlcctol (Németh L, LотО L, Sornfai S, Gál F., Pályi I., Sugár -J, Csuka C ·, Szentimay Z, - Keeiner B, FarmaaoSogické vlast ^ o The effect of dieposddlcollol) was observed. (1, 2-5,6-diarthrdedroglaatitol, N5C-132313). Crniceř Chemotherapy Rep. I. 56. st. 593, 1972; Institóis L, Nemme L., Sornmai S., Gál - F., Hercsel I., ZaaaS., Keeiner B .: Investigation of the Correlation of Cytostatic Efficacy with Diepoxide In Vitro in Some Heterools Subscribed to Endpoints atoms, Neiplasma Г7, 1, st. 15-24, However, as a result of the presence of free hydroxyl groups and intaancleral reactions between epoxide reactions, even in the absence. These compounds cause changes in buffered and aqueous solutions. From a cytoatatic point of view, these actions give rise to unfavorable or toxic metabolites.

To protect these compounds from the undesired conversion, protecting groups can be introduced which are cleaved under biological conditions and the diepoxide compound is formed as a

224443 active metabolite. In addition, the solubility of the extremely water-soluble diepoxyhexitol is in many cases favorably influenced by hydroxyl-linked protecting groups, thereby increasing the cytoetatic activity of the compound. Animal experiments carried out with some of these compounds show that they have further advantageous effects; for example, a strong decrease in toxicities and changes in the tumor spectrum that can be achieved with these agents.

Antitumor and toxicological activity of 1,2,5,6-dianhydro-3,4-di-o-acyldulcitol compounds.

The anti-tumor efficacy of diepoxydiacyldulcitol derivatives of the invention was investigated in transplanted tumors in animals. Each of the produced compounds inhibited the growth of the transplanted tumors to a dose-dependent extent. Toxicological and antitumor efficacy of 4,6-diepoxydiacyldulcitol and parent 1,2-5,6-dianhydrodulcitol (DAD) in different experimental systems were compared.

Explanation of symbols

DAD = 1,2-5,6-dianhydrodulcitol

Diac-DAD = 1,2-5,6-dianhydro-3,4-di-o-acetyldulcitol

DS-DAD = 1,2-5,6-dianhydro-3,4-di-o - (R-methoxycarbonylpropionyl) -dulcitol

FB-DAD = 1,2-5,6-dianhydro-3,4-di-o- (γ-phenylbutyryl) -dulcitol

FP-DAD = 1,2-5,6-dianhydro-3,4-α-o - (R-phenylpropionyl) -dulcitol

CA-DAD = 1,2-5,6-dianhydro-3,4-di-o- (chloroacetyl) -dulcitol

Acute toxicity ·

Acute toxicity was investigated in mice of Swiss origin. Single dose mortality was assessed over 21 days.

Compound molecular weight ≥ 50 * P * mg / kg LDjq i. Mmoles / kg LD ₅₀ to mg / kg DAD 146 15 Dec 1.03 18 Diac-DAD 230 34 1, 48 50 DS-DAD 347 120 3.20 100 ALIGN! FB-DAD 438 110 2.52 100 ALIGN! FP-DAD 410 160 3.8 not identified

Toxicity is approximately inversely proportional to molecular weight increases. Death occurs as a result of intraperitoneal as well as oral toxicity from day 5 to day 9. It also follows that all of these substances can be well absorbed by the digestive tract.

Accumulation in organism

Compound dose mg / kg i.p. death count % cumulative remainder % DAD 'x' and ¹⁸ 9/10 90 - ^1xLD 80/2 9 0/10 0 ^2хШ 80/2 ^{9 + 9 / 48Ь} 0/10 0 45 ^2xLD 80/2 ^{9 + 9 / 9B} 4/10 40 0

Compound dose mg / kg i.p. deaths, number % the rest of the rest, % -ívc-DA— 1x1-80 38 . 5/6 83 ¹ ^ 0/2 0/6 0 ^2xLD 80/2 19 + 1 9/48h 1/6 17 20 May ^2xW 80/2 19 + 19 / 96h 0/6 0 and DS-DAD 1x ^ 80 110 5/6 83 ^{, xW8} ° / ² 55 0/6 0 ^2xLD 80/2 55 + 55/48 ^hrs 0/6 0 0 ^2xL— 80/2 55 + 55/96 ^hrs 1/6 17 20 _y CA-DAD IxL-80 5/6 83 ^{, XLD 80/2} 24 0/6 0 ^2xLD 80/2 24+ ² 4/48 ^hrs 0/6 0 ' 0 ^2xLD ^ ^0/2 55 + 55/96 ^hrs 1/6 17 20 May

Antitumor activity against transplant tumors

a) Ehrlich's Vscitic Carcinoma,

The tumor was transferred intraperioinally to a mouse of 5 million tumor cells. Treatment was started 24 hours after implantation and continued every day for the next 6 or 8 days.

Compound dose mg / kg tumor inhibition (on day 10) extension of life —Ívc-DA— 6x2 87 175 FB-DAD 6 'x 25 98 8x15 222 DS-DAD 6 x 25 97 8xJ5 40 FP-DAD 4 'x 40 100 ALIGN! 8 x 25 192 DAD 6 x 2.5 100 ALIGN! . 208 6 x 1.25 89 300 - ' control

b) Weber's carcinosarcoma 256

Implantation of 20 million tumor cells was followed by a single treatment. In determining the therapeutic index, the smallest dose that produced more than 90% inhibition of the nation at day 10 evaluation was used.

Compound dose inhibic. Nations% e therapeutic index w ^ / ED ⁰ threshold value mg Diac-DAD 1 x 5 97 1 x 2.5 94 7.6 1 x 1.75 94 1 x 1.25 4 34 / 1.75 «19.4 FB-DAD 1 x 30 92 1 x 15 92 22nd 1 x 10 97 110/10 = 11 1 x 7.5 73 1 x 5.0 51 DS-DAD 1 x 30 95 1 x 15 90 120 / 7.5 «16 19 Dec 1 x 7.5 94 1 x 6.0 53 FP-DAD 1 x 30 98 < 1x15 98 1 x 10 100 ALIGN! 160 / 7.5 = 21 18 1x75 90 1 x 5.0 88 DAD 1 x 40 92 1 x 2.0 98 1x15 96 1 x 1.25 80 15/1,5 = 10 ю, 3 1 x 1.0 53 1 X 0.75 79 CA-DAD 1 x 10 98 1 x 5 91 45 / 2.5 = 18 s, 3 1 x 2.5 96 1 x 1.25 4 VSechna The drugs studied are very effective. Therapy index. of the novel compounds according to of the invention is better than the therapeutic index of unsubstituted DAD; therapeutic index Diac- -DAD '' and CA-DAD is 8-10 mM, for DS-DAD, FB-DAD a FP-DAD is doubled. Significant reduction

Toxic diacyldiepoxides is accompanied only by a slight decrease in antitumor activity.

Effect on Harding-Passey subcutaneous melanoma

The slowly growing, only mildly sensitive tumor was transferred to the mouse organism by transplantation of a piece of tumor tissue. Treatment started 24 hours after transplantation. The results were. evaluated on the 21st day after the start of the experiment.

Compound Dose Tumor inhibition weight Control Changes in spleen weight Number of deaths Evaluation day mg % DAD 5 x 2.5 / 72 ¹¹ 181 43 320 -30 0/6 21 16 x 2.5 / 24 ^h 73 85 493 -42 0/6 25 12 x 5/96 ^hrs - 100 ALIGN! 493 -30 1/6 20 May Diac-DAD 14 x 8/24 ^hrs 248 90 2 555 -78 2/6 20 May 13 x 6/24 ^hrs 197 76 812 -62 0/6 18 14 x 4/24 ^hrs 697 73 2 555 -63 0/6 20 May 13 x 4/24 ^hrs 278 66 812 -29 0/6 18 14 x 2/24 ^hrs 1 085 58 2 555 -66 0/6 20 May CA-DAD 16 x 8/24 ^hrs 387 88 3 317 -72 0/6 24 15 x 10/24 ^hrs 215 86 1 527 -54 2/6 23 FB-DAD 13 x 20 425 73 1 572 - 6 0/6 18 DS-DAD 8 x 30/24 ^hr 323 90 3 317 -20.0 0/2 24 FP-DAD 16 x 25/24 ^hr 430 87 3 317 -60 1/6 24 5 x 30/24 ^hrs 208 87 1 572 -11 1/6 24

The novel compounds of the present invention have been shown to be more effective against this slow-melt, only slightly sensitive tumor than the original diepoxide compounds with which they are compared.

Effect on Guérin's carcinoma

Compound Dose mg / kg Time Mass S nád Inhibition of% ore Spleen weight Body weight change % mg % change Diac-DAD 8 x 8/24 ^hrs 4.65 1 087 75.2 +1, 8 +25.4 * 3.16 +308 8 x 8/24 ^hrs 6.07 857 67.7 -19 ^, 8 +23 +5,5 + 90 Diac-DAD 8 x 4/24 ^hrs 18.0 943 3.0 -12.0 +14 5.5 +165

Compound Dose Hmoonost Inhybice% walnut Hnmtnoot spleen Body weight change % mm / kg time G over mg % change control - 10.7 1 068 - - +29 +9.4 +355 FB-DAD 14 x 20/24 ^hr 4.3 480 89.0 -65.0 +48 - +2,8 FP-DAD 14 x 20/24 ^hr 1.74 435 96.0 -68.0 -1.2 +1, 1 DS-DAD 14 x 20/24 ^hr 2.88 '543 93.0 -60 -6.7 +2,6 control - 39.18 1 370 - - +29 +10.1

The effect of Diac-DAD is directly proportional to the dose used. The effect of other compounds is at the same. large dose equally favorable.

In summary, the diepoxyfluoroacetol derivatives of interest are less toxic than the original epoxide. The antitumor efficacy of these agents could be dernoontreated on a number of transplantable tumors (Ehrlich's ascetic carcinoma, Walker's carcinosarcoma, Harding-Passey melanoma, Gurrin carcinoma); the compounds of the invention have proven to be more effective than the parent compound in some cases. Therapeutic indexes were calculated based on the effect of the individual compounds on Waaker's carcinosarcoma. The compounds of the invention were absorbed without difficulty by the digestive tract.

The invention relates to novel and not yet produced compounds and to a process for their preparation; It also discloses pharmaceutical compositions comprising the compounds of the invention as active ingredients.

So far, the derivatives of 1,2-5,6-dian-di-o-di-o-Dm-1-ol and 1,2,5,6-dianhydroouucetol have not been monoocylated at the 3 or 4 position. or diacylated at positions 3 and 4 as described in 1Herature. Diacyl derivatives may have two identical or different acyl groups. With regard to the order of introduction of acyloxy groups and cyclization, two methods are theoretically possible. These are:

a) gradual build-up of epoxy rings from 3,4-diacyl derivatives,

b) acylation of 1,2-5,6-dianhydrohexoxols

Since cyclization after acylation is problematic, since it is carried out in an alkaline medium and may be cleaved by sub-substituents, process b), i.e. acylation of 1,2-5,6-dianhydroheeitol with the acylaine iinide of formula

R - COX where

R is C 1 -C 3 alkyl, optionally substituted C 1 -C 2 alkoxycarbonyl, halogen or phenyl, phenyl, cyclohexyl, or fluoro, and X is halogen, or a group of formula OR wherein R is as defined above.

The acylain reaction of the process of the invention is carried out according to the following reaction scheme:

CH ----- OH

AND

CH ----- OH acylation

СН ₂ '

where

Q represents a C 1 -C 4 alkanoyl group optionally substituted by a C 1 -C 2 alkoxycarbonyl radical, a halogen atom or a phenyl radical, a benzoyl group, a cyclohexanecarbonyl group or a furoryl group.

The process according to the invention for obtaining new compounds having antitumor activity is as follows:

One mole of 1,2-5,6-dihydrohydroelitol is dissolved in an organic solvent, preferably benzene or its homogeneities, in a ratio of 40 parts by volume per 1 mol of mono. Then 2.0 to 3.1 moles of organic base and / or inorganic agent are added to the solution obtained as acid binders. In some cases, acid binders can be used in large excess (e.g., methyl, pyridine), and the excess serves as a solvent. Approximately 2 moles of the acvlaine reagent in 0.5M solution are added portionwise to the solution of the acid-binding agent diaihydro-oitolite to keep the reaction salt temperature below the boiling point of the salt. The most preferred temperature is 20 to 50 ° C. The reaction mixture is stirred at this temperature for 10 to 180 minutes. In some cases, it may also be necessary to stir the reaction mixture for 10 to 24 hours after the addition of the acylaine reagent. Further processing depends on the type of acylating agent used.

a) as acid acylaine reagent, filter the resulting salt from the reaction salt and wash with an anhydrous organic solvent, preferably benzene. The solution is to bend a little ^bj of interest in te ^ o ^ below ⁵⁰ ° C then diluted methanoleo · n ^e bo ro jnýo ^^ štědleo (preferably in sO ^ s ^ s. With ether ooeitylacetáteo etc.) And cooled. The precipitated crystalline product is separated. By concentrating the mother liquor or by using a precipitating solvent, a second generation of crystals of the product can be obtained which can be 10 to 20% of the original. product.

Both the first and second generation products are purified by recrystallization. The second generation product usually requires repeated recrystallization.

b) When using anhydrides or acid esters as the acylating agent, the reaction mixture is concentrated to approximately half its original volume after the reaction is completed, then added to about two to three times the volume of the ice / water mixture with stirring. The aqueous phase is separated from the organic phase. If the aqueous phase is acidic, the organic phase is washed until neutral and extracted with 5-10% aqueous sodium bicarbonate. After separation of the organic phase from the working solution, this phase is evaporated to dryness under reduced pressure. Further processing is carried out according to paragraph a.). ·

The starting materials used are 1,2-5,6-dianhydromannitol, m.p. 64-66 ° C, [lambda] = + 40 [deg.], Water, c = 1.25) or 1,2-5,6-dianhydrodulcitol (melting point 93). 5 ° C, = + 2 ° in water, c = 1.25). They are obtained by methods known per se. CJarman M., Ross W.

C. J .; Formation of epoxides from substituted hexitols, Carbohydrate Research p. 139, 1969; Jarman M., Ross W. G. J .: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dimethanesulfonoxy-1,6-didesoxy-D-mannitol, Chem. Indian. 42, p. 1 789, 19673.

Anhydrous organic solvents which do not chemically react with the reactants may be used as the reaction medium or solvent. Preferred solvents are homologues of aliphatic, cycloalkyl and aromatic hydrocarbons and halogenated hydrocarbons. Also, the organic base used to bind an acid, such as triethylamine or pyridine, can serve as a solvent when used in an appropriate excess. The filtered salt may be washed with an anhydrous solvent, which is expediently the same solvent as previously used, to avoid the formation of solvent mixtures that could cause difficulties in the preparation of the reaction mixture.

Acylating agents which may be used are acid halides, acid anhydrides, mixed acid anhydrides or esters, preferably a compound of the formula I is used.

R - COX where

R is C 1 -C 3 alkyl optionally substituted with C 1 -C 2 alkoxycarbonyl, halogen or phenyl, phenyl, cyclohexyl or furyl, and X is halogen or OR wherein R is as defined above.

As acid binding agents, tertiary amines, trilkylamines, their homologs or alkali metal carbonates can be used. The preferred acid binding agent is triethylamine because the 1,2-5,6-dienhydrohexitol and the precipitated salts are readily soluble therein.

With respect to the reaction conditions, the acylation can generally be carried out at a temperature of 20 to 50 ° C, except when using halides of acids substituted in the α-position by large groups, where the reaction time must be 1 to 3 hours at 50 ° C. good yield was ensured. The reaction temperature must not be higher than the boiling point of the solvent. The temperature is generally controlled by the rate of addition of the acylating agent. External cooling is only required when the acylation reagent is added too quickly. It is important that starting materials, solvents, acid scavengers and acylating agents be absolutely anhydrous. Before use, they must be checked for this purpose and, if necessary, distilled and purified.

The novel acyl derivatives of 1,2-5,6-dianhydrohexitols, which have an antitumor effect, can be used in treatments in various forms:

Per os: The active ingredient, or a mixture thereof, with commonly used ingredients such as lactose, starch or talc, for example in the form of tablets; intravenously; in solution or suspension; intraperitoneally, intracevitally: as a solution or as a suspension; topically: it is applied to the skin or to an appropriate site by itself or together with conventional antibacterial and wound-healing substances (sulfamides, corticoids, viaamines).

Concentration of active ingredient in the individual compositions:

in solutions: 1 to 10% in suspensions: 1 to 70% · in tablets: 20 to 90%.

The following examples illustrate the preparation and formulation of the compounds of the invention without limiting the scope thereof:

Example I

Preparation of 1,2-, 5, 6-isopropanol, 4-dP-o-ascyl-1-acetonitrile using a tylbrooid as acylating agent.

In a 100 ml flask equipped with a stirrer, condenser, and dropping funnel, 1.46 g (10 mmol) of 1 - 2, 5-.beta.-Piazdol / decol in 60 l of beige benzene was stirred at room temperature for 10 minutes. To the solution obtained, 2.8 ml (20 ml) of ethanol, 4 g (20 ml) of anhydrous potassium carbonate and a freshly distilled solution of ethyl bromide are added. The reaction mixture was stirred at 50 ° C for 20 minutes in anhydrous benzene. The crystals are then filtered off through a fractionated glass filter G3 and washed thoroughly with benzene. The combined filtrates were concentrated under reduced pressure, and 15 L of anhydrous ether and 5 L of anhydrous molar ethanol were added to the residue. The reaction mixture was then cooled to precipitate crystals. The reaction mixture is left in the refrigerator overnight, whereupon the crystals are filtered off and recrystallized from omanol. Give 1 II - g title compound as white needles, · a temperature ^T .ní 91 ° C. The recovery ^from an 71 ^to clarified / W% of theory. ^Rf = ^{0.63 (with E b} enzenu mmehanolu 90 and 15).

Analysis calculated: 67.79% C, 5.0% H; Found:% C, 67.75;% H, 5.3%.

EXAMPLE 2

Preparation of 1,2-5,6-Pianhdd POoЗ, 4-dp-o-ascZyldplcCol using an acylating agent as acylating agent.

In a 100-L three-necked flask equipped with a stirrer, a cooler and a dropping funnel, stir 1.46 g (10 oro) of diazo in 60 L of anhydrous benzene or anhydrous for 10 minutes at room temperature. toluene. To this solution was added 2.8 ol (20 m ^ timers) and freshly trietyLSΘoinl dzsti0ovazý solution of 2.4 g (2 ml, 20 Omoo) acetanthyridu 5 O. benzene, and ^p is Soeste míctó TEPO ^p s ^p o ^ mísZnoo ^{1 H} Odin, ^kp, and ^p and s ⁵⁰ ° C; ^{P d} by an additional hour. The reaction mixture was then evaporated to dryness under reduced pressure, the residue was dissolved in 1 L of water and extracted with 30 L of benzene. The benzene phase was promX! ^With 10% aqueous sodium hydrogen carbonate solution, dried with magnesium sulphate, filtered and heated. To the residue was added 15 L of dry ether and 5 L of dry oothanol. The mixture was cooled to precipitate crystals. The crystal / mother liquor mixture is left in a refrigerator overnight, after which the crystals are filtered off and recrystallized from methanol. 1.65 g (71.7% of theory) of the title ^{compound, melting} ep ^l o ^t ½ ^{of 1} point: 9 ° C as white ^{needles: Rf} = 0 3 ^{6 (mixture} of benzene and methanol 9 ⁰ ^) .

Example '3

Preparation of 1, 2-5,6-diaohyddrl ^3-44di ooaaetySdužcitolž using p-oitroteoylacetátu as the acylating agent.

In a 100 ml three-necked flask equipped with a stirrer, condenser and dropping funnel, 1.46 g (10 min.) Of diazoidone was stirred for 10 minutes at 0 ° C in anhydrous benzene or 60 ml of anhydrous trichloroethane. . To this solution was added 2.8 ml (20 MuMu trteUhyaooiož anhydrous and 3.62 g (20 ошоН) p and the resulting solution oitrotenylacttátž ball ^hook te ^p s ^p lot.ě 50 DEG ^C for ^{6 h odio, and} oače with ^p Oneco ^{hook BC overnight} s te ^p ture míísnoši. the reaction mixture was extracted with 20 ml water and dried over magnesium sulfate. the residual syrup was added 15 ml of anhydrous ether and the mixture was cooled and left overnight in a refrigerator. After indents, the precipitated crystals through a filter of G3 fi ^ i ^ ooan ^ e ^ i ^ of the glass. the crude product yield of ^p te ture mp 72-78 ° C is ^2, 5 ^g. ZIS ^to an ^e ^ s ^^ ute ' ^crystals are then ^p RECIST follows:

To the crystals were added 20 ml of benzene and di-thyao-10-propyl. After 1 hour the solution was extracted with 10 ml of water and after separation of the aqueous phase the extraction was repeated. The benzene phase is dried with magnesium sulfate and concentrated. To the remaining syrup was added 15 ml of anhydrous ether and 5 ml of anhydrous methanol. The mixture is left in the refrigerator overnight and the crystals are filtered off. Give ^1, 5 ^{8 g (9%} of theory, ⁶ in said ziáhlaví ^ ^p roducts of te ^p lo ^I point ^{of 90} ° C. ^Rf = ^0.63 jsměs benzene meehanolu 90: 15)

Analysis calculated: 67.79% C, 5.0% H; naležeho:. 67.75% C, 5.0% H.

Example 4

Preparation 1 dian'luddro ^2-5,6'-3, 44-di-O chUoraaeeySddžcitolž

In a three-necked 100-ml flask equipped with a condenser, stirrer and dropping funnel, 5 g (34 ml) of disodium salt was stirred for 4 hours in 150 ml of anhydrous benzene. 10 ml (70 mol) of anhydrous triethylamine or 5.7 ml of anhydrous pyridine are then added to the obtained solution, and a solution of 6 ml of freshly distilled chloroacetyl chloride in 6 ml of anhydrous benzene is added dropwise over 5 minutes. The mixture was stirred at room temperature for 30 minutes and then filtered through a glass filter G3, which was thoroughly triturated with benzene. The combined filtrates were heated under reduced pressure and 15 ml of anhydrous ether and 5 ml of anhydrous methanol were added to the remaining syrup. The reaction mixture was then cooled to precipitate crystals. The mixture of crystals and mother liquor is left in a refrigerator overnight, after which the crystals formed are filtered off and taken up in methanol. 4,4.g yield (43%) of title ^{compound, melting} Nina ^ ep ^ ^l o ^t of mp ¹⁰² ° C ^{b F} Orme Ilych River ^h ^ jew-IE. ^{Rf = 0.68}

Analysis calculated: 40.0% C, 4.0% H; Found: 40.0% C, 4.4% H.

Example '5

Preparing 1,2 “5,6-dianhSld0l ³ з44dd-o-btncolSdjcitolž

In a 200 ml three-necked flask with stirrer, condenser and dropper, funnel, 1.46 g (mmol) of dianhydrodulcitol in 60 ml of anhydrous benzene was stirred at room temperature for 10 minutes. Anhydrous triethylamine (2.8 mL, 20 mmol) was then added to the solution and 5 mL of a freshly distilled solution of 2.8 g (20 mmol, 2.32 mL) of benzoyl chloride in anhydrous benzene was added dropwise over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour and then for another hour at 50 ^U C, then left overnight at room temperature. The resulting triethylamine hydrochloride crystals are filtered off using a glass filter 43 and washed thoroughly with benzene. The combined filtrates were concentrated under reduced pressure and 10 ml of anhydrous methanol was added to the resulting syrup. The reaction mixture is then cooled and the crystals formed are filtered off and then recrystallized from a mixture of benzene and petroleum ether. 2.7 g (76.2% of theory) of the title compound of melting point 171 DEG C. are obtained. Rf = 0.75 (90: 15 benzene / methanol).

Analysis calculated: 67.79% C, 5.0% H; found: 67.8% C, 5.2% H.

Examples 6 to 13

The following compounds were prepared as described in the previous examples. The characteristics of these compounds are shown in the following table.

CM IA oo 00 40 ί- t— ί- O ο O ο

Dianhydro- Starting material acylating agent Reaction product dulcitol g шшо1. compound amount temp. time compound quantity temp g mmol. (° C) (min ') yield. thaw

and-

M · ia rn

IA

IA o? t- IA O OO IA IA oo IA IA AND OJ IA 04 / * xt C- . 40 40

cn

IA IA OJ <n. t- 1— O CM E-

r4 1 1 н 1 гЧ 1 S о> » 1 O 3 О О Р и a Й Й Ф P й 0 XJ ф 1 0 1 * 0 ^ 4 чЧ • 0 Л Ч 4ч гЧ 0 гЧ >> 1 о 3 i О 1 1 & > » 3 0 гЧ 3 >> С 0 Р Д • H к Д C P 5 2 3 3 р чЧ 0 O O 3 Ф Ό 3 ф гЧ 1 Ф о чЧ 1 л чЧ • H Л 1 чЧ 1ч О • Н Л гЧ Ό P cx Ό 1 н Ό 1 Р * 0 1 0 1 Φ O гЧ 1 O 1 0 no 1 о »0 40 rn and Й O 40 1 3 40 1 о 40 1 гЧ 1 1 and P чЧ о * чЧ гЧ * чЧ IA O O H -H IA Ό • н ΙΑ Ό 5 ΙΑ Ό 1ч 1 Й P >> O 1 1 л. 1 1 Ό 1 1 >> OJ Ό Φ and H cm xt · о CM хГ Н СМ Р O 3 > й ·> « >> О » 0 - 3 1 л Ό * - cn сх - m й - СП Я

ΙΑ IA о О о О Xt х * 40 40 40 см ΙΑ 1А 1А 1А 1А LA OJ СМ СМ СМ СМ СМ ΙΑ xt xt О О О 00 О СМ 00 AND- 40 см 1А СП ОО СМ 00 см 40 as • г— OI »- см СП 1 й 0 1 • 0 -М о * ΰ 1 чЧ ръ 1 й чЧ 0 · Ό й к о and й Л чЧ 1 о AND о чЧ Ό н о гЧ. й Η н гЧ Л (X чЧ н ь ° with 2 > » Р О Й 3 2 д н а о 1 • 0 3 * 0 ф й О ф о ф 2 ф гЧ гЧ чЧ О Ή а and н 4ч н * ч о Ч · tb й чЧ Ь 1 и 2 1 1 С ¹ 1 й Р о and о 0 0 3 s S 0 >> ф гЧ О гЧ Р 3 н Р о § « Р Р о 2 й 2 Ф Ф чЧ 3> » Ф 0 0 о and о л л 3 45 л to Р л л 40 см СМ 1А О ř— О о СП cn · - xt 40 xt ί- х * СО * - 40 о ο ΙΛ м · » • 1А ΙΑ 40 с— ОО (No. Ο -

AND

Dianhydro starting material acylating reagent Reaction product dulcitol g mmol. compound amount temp. time compound quantity temp.

OJ cn ir

U4

>> 1 rH O. O O at b P 1 1 *and tH 1 ^ h 1 O • H 1 • H rH Ό ΟΊ 0 Ό m CD 3 1 1 * - < rH 1 1 No. Ό \O O rH O 40 o Ф rH h ¢ 0 P * Й X! >> AND 1 • rH li \ Ό < O 1 OJ of O 1 o rH cm W ³ 0 1 N Й «4 C • H 5 * c • H Ф - 3 Ό - CD Ό AND

o oo o d \ o

CM i

CM what about ir \ o CM σ \

CM

AND

O CD | X rH Ό Φ >> Ό <P • H X5 d -H 1 β O O β what O rH O <* H rH Λ4 Й rH rH Xí >> CD Λ CD O O O

OJ

Example 14

Preparation of 1,2,5,6-dianyhydro-3-o-ethyl-dd1-dulcitol

1.46 g (10 moles) of 112d616drodecyl acetate is suspended in 80 ml of ethyl acetate, and 1.4 ml (10 moles) of anhydrous trihydrin is added dropwise at room temperature while being ignited. ^p where the ^p s te ^p ture of 45 ° C-Heo ^{EXAMPLE IB} draws one hour ^1p say ^p e srněs ^0, 94 ol (10 rnmolů) aróhrdridi acid -acetic 25 RNL ethdlaeetáti and the resulting srněs the rníehá the 24 ^ n ¹ when t e ^p lot, of ⁴⁵ ° C. Evaporative ^ to precipitate the pressure ^p s oaairnální ^ ^ EPCO of 4 ° C from srněsi ethlCaeetát removed and the oily residue on a column ehromaCoorafuje siliCageCi 50 násobnérn objernovérn ooooisví in ethdlaeetáti. A different product was obtained.

(Rf = 0.62 in ethyl acetate) which is bound to the bed. 0.6 g of a colorless product is obtained. Yield 31.9% Rf = 0.67.

For C ₁₂ H ₁₂ O 4 (molecular potency = 188) calculated: 51.06% C, 6.38% H;

Found: C, 50.84; H, 6.44.

Example 15

The powder ampoules, each containing 50 µg of Dic-DA-, are read as follows:

Diac-DAD 50 og / aopulka arnica with solvent restitated water at injection 10 ol / aopulka

The particle size of the crystalline active ingredient is determined. If the grain is in the range of 0.06 to 0.32 m, the active ingredient is introduced into a powdered powder, which is known per se, preferably by means of a filler of the device, under conventional conditions. The dose is 50 rng in each amouUct. Then, the caps are sealed behind the cushion pad with a rubber stopper and a suitable metal closure. The marking is carried out in the usual manner. The granulation of the active ingredient, which is known in the art, is carried out in a suitable apparatus and the desired granulation in the abovementioned range is obtained by sieving. Likewise, the water-containing water is prepared by the usual procedures for the addition of water and is then added. k powder and F F p p U Uee.

EXAMPLE 16

Lyophilic powder cppuUCk11 each having a content of 10 rng -1сс - сГ, se. prepare as follows:

Diac-DA— 10 µg Powder Powder Avoid Solvent Soobbtol 300 pp _I Wood Water for Injections up to 2 µl / ml

LátkC contained ¹ ^^ IC50 op · ^c ^ ^l 1o VO ^and p. The rozkutí ^^ ^p ^ s ^ PLT 2 ⁰ C fostHované dioxide-free water in lhULČiééUo1 jaktsti · suitable for injection in a 101-carburised sludge vessel and a solution of The solution is then filled to the mark and sterilized under aseptic conditions by filtration. A 2 liter dose of this solution is filled into a rubber capped capsule, whereupon the cover is known in the urine crystal device. After the solution is performed zoznnuí sublioace ice at C-tuttkteikýr now running under ЬоГ- ^ then the product is dried at Tepi 'Cote 3 ⁰ · ^p and ^k ^ y appjLi sealed ^rubber žovýoi ttaoi ^ and V ^ n ^ i . ^ui, or ^e ry · · aseptakých under conditions and marks as usual.

A solution containing 15 g of orbitol in 100 l of an aqueous sorbent solution is prepared in a conventional manner and then packaged in a powdered solution.

PPíkl a d 17

Tablets, each containing 250 mg of active ingredient, are prepared as follows:

Diac-DiD 4 lactose * 250 mg 45 mg cellulose crystal 17 mg maatek 5 mg paraffin oil 8 mg

ingredients, anhydrous · lactose (450 g) and anhydrous,

The crystalline product contained 2,500 g of active crystalline cellulose (170 g) was thoroughly mixed in a mixture of paraffin oil (80 g) and anhydrous isopropanol (350 ml). The resulting mixture was passed through a sieve and the resulting granulate was dried. Subsequently, 50 milligrams of g weight are added, the mixture is mixed, and then 11 mm, each having a weight of 325 mg, are pressed in a tabletting machine. The tablets are packaged as usual.

Example

Capsules, each containing 100 mg Diac-DAD, are obtained as follows:

Diac-DAD 100 mg Carboway 6000 5 mg maatek 5 mg

of

First, a homogeneous mixture of Carbowey and a powder mask is prepared. appropriate mini-crystalline active ingredient is admixed thereto, then the mixed mixture is passed through a sieve and filled into hard gelatin capsules. Each capsule contains 110 mg s ^ Oss.

P-Fig. A d 19

The products obtained in cases 17 and 18 are scalded with suitable coatings to produce enteric coatings or capsules.

Claims (1)

Acyl derivatives of dianhydroheeitols of the general formula I H _O C ² I HC AND HC. AND HC I HC i H ₂ C 0Q Wherein Q is a C 1 -C 4 alkanoyl group optionally substituted with a C 1 -C 2 alkoxycarbonyl radical, a halogen atom or a phenyl radical, a benzoyl group, a cyclohexanecarbonyl group or a furoyl group. 2. 3. 4. 5. 6. 7. ’ 8. 9. 10. 11. 1,2- 5, б-dhtfdOl3,4-dd-OlacyylddŽcito] L. 1- (b-dianhydro-1,4-di-1- (beta-methylcarbonylproplonine) -dititol). 1.2- _{5,6-dičnhrdd0l3>} 4-di-0- (g8čm-čefelbutylryl) -ddžcitll. 11- (4'-dihydro-4'-di-Ol (tert-enenolrololyl)) -. 1,2-5,6-dl-ddo-1,4-di-0l (cycloacetyl) -critol. 1,2- 5,6-Dichloro-3,4-di-O-benzol-ditcitrate. 1.2- _{5,6-dičnhydrl-3>} 4-di-O-proliornl <idžcit-l. ¹ J¾- ^{5, 6} - ^d ICN yddOl3 _J ^L 4-di-0 l ^(e BE AC ^- lbutylryl ee ⁿ⁾ - ^d u ^Ž citll. 1.2- ^5,6-d dičnhy d0l3,4-dd-0 l (ACFC-fžrčnkačboonl) - džcitll. 2. A process for the preparation of acylalkyl derivatives of the formula I according to claim 1, characterized in that 1,2,5,6-dihydrohydroitol-1 is acylated with an acylating Uinide of the formula R-COX. where R represents an alkyl group having 1 to 3 carbon atoms, optionally substituted by an alkoxycarbonyl group having 1 to 2 carbon atoms in the alkoxy moiety, a halogen atom or a phenyl moiety, a phenyl group, a cyclohexyl group or a furyl group, and, X represents a halogen atom or a group of the formula OR wherein R is as defined above. . 12. The process of claim 11, wherein the starting materials used are 1,2-5,6- or 1, 2-5,6-disulphine dimethyl mannitol. 13. A process according to claim 11 or 12, wherein the reaction is carried out in the presence of an acid-binding agent, such as thiamine, pyridine and anhydrous potassium carbonate.