DE2557033C2 - Acyl derivatives of 1,2-5,6-dianhydro-dulcite, processes for their preparation and anticarcinogenic agents containing these compounds - Google Patents

Description

through a special activity. This illustrates the results obtained when examining tier toxicological and anticarcinogenic properties of the l ^ -S.e-Dianhydro-S ^ -diacetyi-dulcite of the invention in mice and rats with transpiandcrten Tumors of animal origin were obtained.

The tests were carried out with the following compounds ^:!

25th

1,2-5,6-dianhydro-dulcit

1 ^ -5,6-dianhydro-3, * - di - (^ - phenylpropK> nyl> dulcit

1 ^ -5,6-dianhydro-3,4-di- (p-chlorobenzene> <lul «it l ^ -5,6-dianhydro-3,4-di - (^ - phenyl-butyryl) -dulcit DAD

Diac DAD

DS-DAD

FB-DAD

FP-DAD

CA-DAD

DF-DAD

DB-DAD

CB-DAD

P8-DAD

The toxicity of the acyl derivatives of the invention was carried out on normal Swiss mice with ip and po administration. The _{duration of the study - determination of the LD 50} dose - was 21 days after a single dose. The results are given in table!

Table 1

Active ingredient

MG LD ₅₀ ip LD ₅₀ ip LD50 P- 0. mg / kg mmol / kg mg / kg 146 15th 1.03 18th 230 34 1.48 50 374 120 3.20 100 438 110 2.52 100 410 160 3.8 no investigation

Diac DAD

DS-DAD

FB-DAD

FP-DAD

The table shows that the toxicity decreases approximately to the same extent as the MG of the acyl derivative increases and that the animals perish after 5 to 9 days after both the Lp and po administration. This means that all compounds ₍ also in the gastrointestinal tract are well absorbed. '

The determination of the so-called toxic accumulation residue, with which toxic changes are recorded which slowly manifest themselves, lead to damage to the organs and ultimately to the death of the animals, was carried out according to the Druckrey method on groups of 6 or 10 mice with the full or half the LD ₈ O active ingredient dose, respectively, according to 48 or 96 hours was repeated again. The results obtained are shown in Table 2.

Table 2

Active ingredient

dose
mg / kg

mortality % Always 90 9/10 0 0/10 40 4/10 0 0/10 83 5/6 0 0/6 17th 1/6 0 0/6 83 5/6 0 0/6 0 0/6 17th 1/6 83 5/6 0 0/6 0 0/6 17th 1/6

Accumulation remainder

DAD

Diac DAD

DS-DAD

CA-DAD

1 XLDg ₀
Ix 1/2 LD ₈₀ 2XlZiIiD ₈ O

2 X.1 / 2 LD _n

IX LD ₈ O
1X1 / 2 LD «, 2 x 1/2 LD ₈₀ 2XLaLD ₈₀

IXLD ₈₀
lxl / 2 LD ₈₀ 2 X 1/2 LD ₈₀ 2 X 1/2 LD ₄₀

1 X LD ₈₀

1 X 1/2 LD _M

2 X 1/2 LD ₈₀ 2 X 1/2 LD ₈₀

18th + 9/48 ^h +18/48 ^h 9 9 + 9/96 ^h +19/96 ^h 9 38 19th 19th + 55/48 " 19th + 55/96 ^h HO 55 55 + 24/48 " 55 + 55/96 " 48 24 24 55

45

20th

. 0

20th

20th

The table shows that the accumulation with the Diac-DAD (with 17%) is lower than with the DAD (with 40%), but with both compounds the toxic effect takes place within 96 hours, and regeneration begins after 96 hours for the compounds DS-DAD and CA-DAD on the other hand, the toxic effect only manifests itself after 96 hours.

To the effect of the acylderivatc of the invention and the 1.2-5.o-dianhydro-dulcits (DAD) on different To study tumor types, mice implanted with the various tumor types were with the various acyl derivatives given in the individual tables and DAD - as a comparison substance - treated.

To investigate the effect on tumor P 388, a tumor was generated in mice by i.p. injection. 24 hours after the injection, the mice were given the doses given in the table for I and 9 days Treated individual compounds 1 time per day. The results are shown in Table 3. '

Table 3

Active ingredient dose Effect*) mg / kg i.p. p. T / C% Diac DAD 9X6.3 291 9 X 10 196 1X14 190 DAD 9X2 232 9X4.0 S67 1 X 5.1 197

*) T / C '

average survival of the treated animals (days)
Average survival of the untreated control animals (days)

x 100

The table shows that a higher T / C value can be obtained with the Diac-DAD than with the DAD.

The study of the effect on Walker? 56 Carcinosarcoma Intramuscularia was carried out on rats carried out with the animals 24 hours after the injection of the tumor cells at once as shown in the table indicated doses of active ingredient i.p. were injected. To determine the therapeutic index was the lowest dose taken in each case with which a tumor inhibition of more than 90% (EDw) on the 10th day had been achieved. The results obtained are summarized in Table 4.

ED ₉₀ 7th TI LYso 25 57 033 ED ₅₀ 8th LD ₅₀ TI mg / k « ID ₅₀ y mg / kg mg / kg mg / kg LDjo / EDjo Table 4 i. p. LD ₅₀ ED ₉₀ i. p. Table 6 i. ρ. χ 8 i. p. Active ingredient 2.5 mg / kg 12th 17th Gr ₅₀ Active ingredient 2.3 35 15th 2.4 i. p. 11.2 14.5 m * / kg j 9 45 5 7.0 28 10.7 35 i. p. 9 100 Il Diac DAD 80 27 5 400 10 Diac DAD 100 400 4th CA-DAD 13.5 75 13th 105 5.5 CA-DAD 20th 270 13th DS-DAD 11th 400 15.5 70 22.5 Ό DS-DAD 23 150 6.5 DP-DAD 7.5 180 12th 28 400 DP-DAD 15th 120 8.0 DB-DAD 6.6 170 9.5 25th 33 CB-DAD 0.8 15th 19.0 CB-DAD 2.1 91 4.8 3.65 36 FP-DAD FP-DAD 63 48 FB-DAD FB-DAD U 25 ^l5 DAD DAD 3.65

(Lw ₃₅ hTw. Qr _x relate to the values for doses with which the lymphocyte count or the granulocyte count is halved.)

The table shows that the acyl derivatives of the invention are superior to the DAD in terms of the therapeutic index.

To investigate the effect on Harding-Passey s.c. Melanoma was the slow growing, less so Known tumor that can be influenced by s.c. Transplantation of a piece of tumor tissue in mice generated. Treatment was started 24 hours after the transplant. The evaluation took place on 21st day of the attempt. The results obtained are shown in Table 5.

Table 5

Active ingredient ED ₅₀ X 14 MTD / MTDZED ₃₀ HP X 14 ·) mg / kg mg / kg Diac DAD 3.0 7.0 2.3 CA-DAD 6.0 8.0 U DS-DAD 22nd 25th 1.1 DP-DAD 12.5 25th 1.9 DB-DAD 22nd 25th 1.1 DAD U 2.5 1.7

·) MTD / HP x 14 = max. Tolerated dose / Harding-Passey; the The doses indicated in each case are applied 14 times in succession

The table shows that the therapeutic index of Diac-DAD for this slow growing tumor less sensitive to anticarcinogenic agents even with long-term treatment it is better than that of DAD.

To investigate the effect on Sarcoma S 180 the tumor in mice was caused by sx. transplantation a piece of tumor tissue. Treatment started 24 hours after the transplant, was carried out once a day and continued for a total of 8 days. The tumor inhibition was evaluated on! 0. Day made. The results are shown in Table 6.

The results show that the therapeutic index of Diac-DAD »nd of CB-DAD is only slightly below that of DAD, since the toxicity (LD 50) of the acyl derivatives is significantly lower than that of DA D.

In summary, it can be stated that the toxicity of the diacyl derivatives is less than that of 1.2-5,6-Dianhy dro-dulcits is and that the diacyl derivatives not only on different tumor types (tumor P 388, Walker carcinosarcoma. Harding-Passey melanoma. sarcom S 180) exert an anticarcinogenic effect, but that the anticarcinogenic effect is better than that of 1.2-5.6-dianhydro-dulcit. It is surprising that the diacyl derivatives of the invention also have beneficial effects on melanoma, such as the Harding-Passey Melanoma and melanoma B 16 exercise. The new diacyl derivatives do well in the gastrointestinal tract absorbed.

The invention also relates to a process for the preparation of the acyl derivatives of 1,2-5,6-dianhydro-dulcite of the general formula I. According to which the corresponding 1,2-5,6-dianhydro-hexitol is known per se is reacted with a corresponding acid halide, acid anhydride or ester as acylating agent.

In carrying out the method of the invention proceed as follows:

1 mol of 1,2-5,6-dianhydro-dulcit is dissolved in anhydrous, organic solvent, advantageously in benzene or in a benzene homologue, dissolved at a volume / part by weight ratio of 40. Then it is added of the solution 2.0 to 3.01 mol of an organic, acid-binding base or an inorganic, acid binding agent. In individual cases it can bind acid de base (e.g. triethylamine or pyridine) are added in large excess. Then the base has the Function of the solvent. The acid binder containing solution is given in the form of a dilute, about

05 m solution, 2 mol acylating agent at such a rate that the reaction temperature is kept below the boiling point of the reaction mixture. Conveniently, one addition temperature is maintained between 20 and 50 ^0C. After the addition is complete

the reaction mixture is stirred for 10 to 180 minutes at this temperature Hours of stirring at room temperature.

When working up the reaction mixture, two different approaches can be taken, which depends on whether the acylating agent used has been acid halide, acid anhydride or ester a) In the acylation with acid halides - the precipitated salts after the end of the reaction,

or filtered off from the reaction mixture after stirring and washed with an anhydrous organic solvent, preferably benzene. The pure solution is evaporated at 50 ⁰ C to dryness, the residue with methyl alcohol or other solvents (preferably ether, ethyl acetate or other mixtures) were mixed, then cooled. After the crystallization, the product obtained is filtered off. Further crystalline product (2nd generation) can be obtained from the mother liquor by concentration or precipitation with a solvent, a yield of about 10 to 20% of the original product (generation I) still being obtained. The products obtained, both of the 1st and 2nd generation, are optionally purified by recrystallization once or several times (mainly in the case of the 2nd generation).

b) In the acylation with acid anhydrides or Csters, the reaction mixture is after the end of the Reaction evaporated to half of the original volume, the residue obtained in poured 2 to 3 times the volume of ice water and separated the aqueous phase from the organic phase. If the aqueous phase has an acidic pH, the organic phase, preferably by shaking with 5-10% sodium hydrogen carbonate solution washed neutral. After the last wash The following separation, the organic phase is evaporated under reduced pressure and the resulting The residue is continued in the manner indicated under a). (Mixing with solvent, crystallization and, if necessary, one or more times Recrystallize.)

The preparation of the 1.2-5.6-dianhydro-dulcite used as starting material (melting point: 98.5 ° C, [oi] ″ = + 2 ° in water, c = \ 25) is described in the literature (Jarman. M, Ross. W. CJ, The formation of epoxides from substituted hexitols. Carbohydrate Research. 9,139 [1969]).

Anhydrous organic solvents are expediently used as the reaction medium or solvent used, which are inert to the reaction components. Some examples of this are the homologues the aliphatic. Cycloalkyl and aromatic hydrocarbons, halogenated hydrocarbons or organic acid-binding bases, such as triethylamine or pyridine, used in excess. To wash the filtered off salt one takes expediently the amount of anhydrous solvent corresponding to the originally used solvent to the To avoid the formation of a solvent mixture that makes working up the reaction mixture difficult

Suitable acylating agents are those of the general formula

R-CO-X

used in the

R is an optionally substituted by a carbalkoxy group, a halogen atom or a phenyl group substituted Ci-ig-alkanoyl group, optionally one a benzoyl group substituted by a halogen atom, a cyclohexanoyl group or a 5- or 6-membered monocyclic acyl group containing a nitrogen, oxygen or sulfur atom and

X is a halogen atom, the acid anhydride ester or OR '

mean in which R 'is an alkyl, aryl, acyl, or aralkyl group.

The acylation is expediently carried out in the presence of an acid binder. Some examples of this are tert. Amines, trialkylamines, their hortiologists and alkali carbonates. The application is very beneficial of triethylamine, which is the 1,2'5.6-dianhydro-dulcit good

ίο dissolves and from which the salts formed during the acylation can be easily separated.

The acylation is expediently carried out in the temperature range from 20.degree. To 50.degree. An exception form the acid halides, those in the position large have room-filling groups. When using them, at a reaction temperature of 50 ° C is a Reaction time of 1 to 3 hours required to achieve a good yield. The maximal

TciVipcfäiüf ΚΰΠΓι uci »SicucpüfiiU u £ 3 3ngCW € nuCtCn

Solvent or the reaction mixture correspond. The temperature is usually determined by the The rate of addition of the acylating agent is regulated. External cooling is only necessary if at the beginning the rate of addition of the acylation medium is too fast.

It is very important that starting compounds, solvents. Acid binders and reagents (acylating agents) are completely anhydrous. This must be done the reaction must be checked. If necessary, the connections must be subjected to further drainage and cleaning.

The invention also relates to ahticarcinogenic agents containing one or more acyl derivatives of the 1,2-5,6-dianhydric dulcite in general Formula I in addition to customary inert solvents or carriers. Here is

- The pure active ingredient for per os application optionally with those customary for tableting Aids (starch, lactose, talc) mixed in Form of tablets,

- For IV application, the active ingredient in aqueous Solution or in the solution of a physiological inert organic solvent (various Glycols, etc.),

- for intramuscular, intraperitoneal or intracavital application of the active ingredient in solution, as indicated above, or in the form of a slurry sion and

- the pure active ingredient for local application, optionally mixed with the usual antibacterial and for the treatment of wounds agents used (sulfonamides, corticoids,

Vitamins, etc.).

The concentration of active ingredients in the various preparations is appropriate:

in solutions in suspensions in tablets

1-10%, 1-70% and 20-90%.

The preparation of the acyl derivatives of the invention and Their adjustment is illustrated by the following examples

example 1

In a 100 ml three-necked flask equipped with a stirrer, reflux condenser and dropping funnel are added 1.46 g (10 mmol) of 1,2-5,6-dianhydro-dulcit and 60 ml of abs. Benzene and stir 10 minutes at room temperature. 2.8 ml (20 mmol) of abs are added to the solution obtained. Triethylamine (or 2.45 g [20 mmol] of anhydrous potassium carbonate) and 2.45 g or 1.47 ml (2OmMoI) freshly distilled acetyl bromide dissolved in 5 ml of abs. Benzene, stirred for 20 minutes at room temperature, sucks then the precipitated triethylamine hydrobromide on a glass frit G3 and washes it thoroughly with abs. Benzene. The combined filtrates are evaporated in vacuo, 15 ml of abs is added to the syrup obtained as residue. Ether and 5 ml abs. Add methyl alcohol and cool, a crystalline precipitate immediately separating out. That The mixture is left to stand in the refrigerator overnight, and the crystals which have precipitated out are filtered off with suction and crystallized then from methyl alcohol to give white crystal needles.

Yield: 1.65 g (71.7%).

Melting point: 91 ° C.

Rt = 0.63 (benzene to methyl alcohol = 90:15).

Analysis:

calculated: C 67.79 H 5.0%
found: C 67.75 H 5.3%

Example 2

1.2-5.6-DianhydroO ^ -diacetyl-dulcit

In a 100 ml three-necked flask equipped with a stirrer, reflux condenser and dropping funnel, 1.46 g (10 mmol) of 1,2-5,6-dianhydro-dulcite and 60 ml of abs. Benzene (or anhydrous Toiuoi) 'and stir for 10 minutes at room temperature. 2.8 ml (20 mmol) of abs are added to the solution obtained. Triethylamine, 2.04 g or 2.0 ml (20 mmol) of freshly distilled acetic anhydride, dissolved in 5 ml of benzene, stirred for one hour at room temperature, then for a further two hours at 50 ^° C. and the solution was evaporated to dryness. The residue is taken up in 20 ml of water, the solution is shaken out with 30 ml of benzene, the benzene phase is separated off, washed with 10% sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated. 15 ml of abs are added to the syrup obtained as residue. Ether and 5 ml abs. Methanol and cools down, a crystalline precipitate immediately separating out. The mixture is left to stand in the refrigerator overnight, then the precipitated crystals are filtered off with suction and recrystallized from methyl alcohol. White crystal needles are obtained.

Yield: 1.65 g (71.7%).

Melting point: 91 ° C.

Rf = 0.63 (benzene to methyl alcohol = 90:15).

Example 3

Minutes at room temperature. 2.8 ml, 20 mmol) of abs are added to the solution obtained. Triethylamine and 3.62 g (20 mmol) of p-nitro-phenyl acetate, stirred for 6 hours at 50 ° C. and left the resulting solution in overnight Stand at room temperature. The solution containing organic solvents is mixed with 20 ml of water shaken out, dried over magnesium sulfate and evaporated. To the syrup obtained as residue give 15 ml abs. Ether and cool down. The mixture is left to stand in the refrigerator overnight and sucked then the precipitated crystalline precipitate on a glass frit G2.

Yield: 2.5 g.

Melting point: 72-78 "C.

The yellow crystalline product thus obtained is purified as follows: The crystals are dissolved in 20 ml of benzene dissolved and treated with diethylamino-propylamine. After one hour, 10 ml of water are added and the Mix in a separatory funnel, separate the aqueous phase and repeat the operation with 10 ml Water. The benzene solution thus obtained is dried over magnesium sulfate and evaporated. The as The syrup obtained is 15 ml of abs. Ether and 5 ml abs. Methanol, the mixture leaves overnight stand in the refrigerator and then suck off the crystals.

Yield: 1.58 g (69%).

Melting point: 90 ^° C

Rf = 0.63 (benzene to methyl alcohol = 90:18)

Analysis:

calculated:
found:

C 67.79
C 67.75

H 5.0%
H 5.3%

Example 4

35 Into a 200 ml three-necked flask equipped with a stirrer. Reflux cooler and dropping tube are given 5 g (34 mmol) of 1,2-5.6-dianhydulcite and 150 ml of abs. Benzene, stirred for four hours, treated the mixture thus obtained with 10 ml (70 mmol) of abs. Triethylamine (or 5.7 ml of absolute pyridine) and then within about 5 minutes at room temperature 854 g or 6 ml (68 mmol) of freshly distilled chloroacetyl chloride in 5 ml of abs. Benzene too.

The mixture is carried out for 30 minutes at room temperature, then the triethylamine hydrochloride Sucked off a glass frit G3 and washed the precipitate thoroughly with benzene. The combined filtrates one evaporates in a vacuum. gives to that as a residue

syrup obtained in this way 15 ml of abs. Ether and 5 ml abs. Methyl alcohol and cools down, a crystalline precipitate immediately separating out. The mixture is left to stand in the refrigerator overnight, then the crystalline precipitate is filtered off with suction and recrystallized from methyl alcohol. White crystal needles are obtained.
Yield: 4.4 g (43%).
Melting point: 102 ^° C
Rr = 0.68 (benzene to methyl alcohol = 90:15).

60

Analysis:

calculated:
found:

C 40.0
C 40.0

H 4.0%
H 4.4%

1.46 g (10 mmol) of 1,2-5,6-pianhydro-dulcite and 60% abs. Benzo! (Or anhydrous Dichloroethane) and stir 10 Example 5
1,2-5,6-dianhydro-3,4-di-benzoyl-dulcitol

In a 200 ml three-necked flask equipped with a stirrer, reflux condenser and dropping funnel are added 1.46 g (10 mmol)

l ^ -S.ö-Dianhydro-cluIcit and 60 ml abs. Benzene (or 60 ml of anhydrous triethylamine). stirred for 10 minutes at room temperature, 2.8 ml (20 mmol) of abs were added to the mixture. Triethylamine and drip; then within about 10 minutes at room temperature 2.8 g or 2.32 ml (20 mmol) of freshly distilled benzoyl chloride in 5 ml of abs. Benzene too. The mixture is allowed to stand first at room temperature, then stirred for one hour at 5O ⁰ C and overnight at room temperature. The precipitated triethylamine hydrochloride is filtered off with suction on a G3 glass frit and washed with benzene. The combined filtrates are evaporated in vacuo and the crystalline mass obtained as residue with 10 ml abs. Methyl alcohol added, cooled, vacuumed and finally from one

Benzene-to-petroleum ether mixture recrystallized. Yield: 2.7 g (76.2%).
Melting point: 17 Γ C.
R ₁ = 0.75 (benzene to methyl alcohol = 90:15).

Analysis:

calculated:
found:

C 67.79
C 67.8

H 5.0%
H 5.2%

10

Examples 6-13

According to those given in Examples 1 to 5 Methods the 1.2-5,6-dianhydro-3,4-diacyl-dulcite given in Table I were produced. Closer Information about the source material. The reaction conditions and end products are given in Table I.

Table 7

at Output connections Reaction end product yield Own game conditional societies No. worked 1,2-5,6-di-acylating agents Temp. Duration g% M.p. R, anhydro ⁰ C dulcit g mmol g mmol ° C Min.

6 10.6 7.26 acetyl chloride 9.9

7 1.46 10 propionic acid- 1.85

chloride

8 5.84 40 jo-carbometh- 12.2

oxypropionyl chloride

9 5.11 35 jg-phenylpro-11.8

pionyl chloride

10 5.0 34.2 γ-phenyl butter- 12.2

acid chloride

11 1.46 10 / -phenyl butter- 3.6

acid chloride

12 1.46 10 α-furancarbon 2.61

acid chloride

13 1.46 10 cyclohexanes «- 2.93

acid chloride 1.45 25 45 1,2-5,6-dianhydro-14.7 88 91 0.63 3,4-di-acetyl-dulcitol

25 45 1,2-5.6-dianhydro-1.65 63 65 0.68 3,4-di-propionyldulcite

25 60 1,2-5,6-dianhydro-6.3 42.15 79.5 0.62 3,4-di-OS-carbomethoxy-propionyl) -dulcitol

25 60 1,2-5,6-DianhyJro- 11.25 75 105 0.75 3,4-di (0-phenylpropionyl) -dulcitol

68.4 25 60 1,2-5,6-dianhydro- 10.35 69 58 0.78 3,4-di-Q> -phenylbutyryl) -dulcit

25 120 1,2-5,6-dianhydro-2.7 61.5 085 0.78 3,4-di-0? -Phenylbutyliyl) -dulcitol

50 180 1,2-5,6-dianhydro- 2.25 66.45 192 0.6! 3,4-di- (e'-furancarbonyl) -dulctt

50 180 1,2-5,6-dianhydro-1,5 41 186 3,4-di- (hexahydrobenzoyl) -dulcitol

Example 14 50 mg l ^ -S ^ -DianhydroO ^ -diacetyl-dulcit- powder ampoule

1.2-5.6-Dian hydro-3.4-diacetyl-dulcit
Solvent ampoule:
Aqua dest. per inj.

50 mg / powder ampoule
10 ml / ampoule

The drug-quality product is checked by granutometry. If the The product is made into granules of 0.06-032 mm in a manner known per se - expediently by means of a Powder filling device - filled into ampoules under aseptic conditions with a 50 mg setting. In addition to the powder ampoule, the drug pack contains one with distilled water. Water-filled solvent ampoule, which according to the usual regulations rW

pharmaceutical industry.

Example 15

10 mg 1,25,6-dianhydro-3,4-diacetyl-dulcit (Iyophilisiei? E) powder powder

l, 2-5,6-dianhydro-3,4-di- IO mg / powder ampoule acetyl tolerates Solvent ampoule: 300 mg Sorbitol 2 ml / ampoule Aqua dest pro inj. ad

50 g of drug-quality product (the amount corresponding to 100% active ingredient) is placed in a calibrated vessel with a capacity of 101, dissolved in distilled water (injection quality) and made up to a thousand-nu mark. The least. Water has a temperature of 20 ° C. The solution is then sterilized by filtration under aseptic conditions, the sterile solution obtained with a 2 ml setting in Ampuüeo with garment cap and lyophilized in a manner known per se ⁰ C. The powder ampoules are then closed under sterile conditions with rubber stoppers and a suitable metal closure and signed in the usual way. In addition to the powder ampoule, the pack contains a solvent ampoule with an aqueous sorbitol solution (concentration 15 g sorbitol / 100 ml solution) which is known in the pharmaceutical industry.

Example 16 l ^ -S.o-Dianhydro-S / l-diacetyl-duIcit-Tablets

Composition of the tablet:

l ^ -S.ö-Dianhydro-S ^ -diacetyl-dulcit 250 mg Lactose 45 mg

Crystalline cellulose

Talc

Paraffin oil

17njg 5 mg 8 ing

2500 g crystalline! cit (drug quality), 450 g of anhydrous lactose and 170 g of anhydrous crystalline cellulose are kneaded by irian in a homogenizer with a mixture of 80 g of paraffin oil and 350 ml of anhydrous isopropanol. sifts the mass and dries it. That so The dry granules obtained are then mixed with 56 "g of tafcum added, homogenized and with a tablet machine (11 mm) in the usual way to 325 mg TibJettpn pressed

Example 17 100 mg U-S.e-Dianhydro-S ^ diacetyl-dulcit capsules

Composition of the capsule:

l ^ -S.e-Dianhydro-i ^ -diacetyl-dülcit Carbowax6000 '

Talc

5 mg 5 mg

An amount of crystalline product (active ingredient) corresponding to the batch size is mixed with the previously finely mixed mixture of talc and Carbowax homogenized and - if necessary after granulation - with the appropriate device 110 mg setting filled in so-called hard getatine capsules

Example 18 Enterosolvent dragee or capsule

The products described in Examples 16 and 17 are provided with a coating that is soluble in the small intestine in a manner known per se.

Claims (1)

57-33 soluble 1 ^ -5,6-DiarihydroTdulcit the water solubility "reduced and the solubility, in. organic. -solutions _; increased dem, 1,2-5.6-Diänhydro-dulcit 4 a strong acceleration of the biological transport - .. of the acyl denvate from "blood plasma in the tumor, in the muscle as well as in" the organs (liver). and an increased enrichment, but the acyl derivative in the tumor eine.verringerte enrichment ·: tion of Acyiderivatsratien organs ^result:. In mice with modified tumors p. 180, which had been treated with equimolar amounts of 1,25,6-dianhydro-dalcitol or 1,2-Se-dianhydride / t-diacetyl-duicitol, τ was. B, after 4 hours the concentration of 1,25,6-dianhydro-3,4-diacetyl-duIc! T "in the liver and muscles. 2 ^ mak-im Jiimor. On the other hand, 3.5 times as high as that of \ ^ -Se-Dianhydro-duIcit and 'the quotient of Tpiaorkonzentration / Muscle concentration- '20 iration amount for 1,2-5,6-Dianhydro-diaceiy! -dü! cii 3.18, for 1,2-5 , 6-Dianhydro-dulcit on the other hand only 2.16. • Of the acyclic derivatives of the invention stand out. i ^ -S.ö-Dianhydro-S / t-diacetyl-dtilcit, 12-5,6-dianhydro-3,4sii- {ß-caΓbόmethoxy- ' propibnyl) -dulcit, ■ - ^: ' l _r 2-5,6rbianhydro-3,4-di - ^ '- phenylbutyryl) - dulcit 1 ^ -5,6-D! Anhydro-3, + - di- (β-phenylpropionyl) -. dulcit, l ^ -5,6-dianhydro-3,4-di _{(chIoracetyl)} -duIcit, l ^ ^{-5,6-Diarihydro-3,4-di-benzoyl-duIcit,:} ^ ₁ • 12-5,6- Dianhydro-3,4-di-propionyl-dulcit, 12-5,6-dianhydro-3,4-di- (P-phenyl-butyryl!) - dulcit, 12-5,6-dianhydro-3,4-di- (a-furan-carbonyI) - : dulcit and -u i 2-5,6-dianhydro-3,4-di- (hexahydrobenzoyl) - ·. -julrit '■■ ■' ^l