DE1418126B - Glucofuranosides, processes for their production and pharmaceutical preparations containing them - Google Patents

Description

are already known. Thus obtained C, T. B i s h o ρ et al, Can, J. Chem. 34, 845 (1956), by treating 3-benzyl-5,6-dimethyl-D-glucofuianose methyl-S-benzyl-S.o-dimethyl-D-glucofuranoside with methanol in the presence of hydrogen chloride and therefrom methyl-2,5,6-trimethyl-D-glucofuranoside by methylation in position 2 and debenzylation, used as a starting material for the synthesis of 2,5,6-trimethyl-D-glucofuranose would. Furthermore, P. S h y 1 u k et al., Can. J. Chem. 34, 575 (1956) from methyl 3,5,6-tribenzyl-D-glucofuranoside the 2-carboxymethyl derivative, which they processed to 2-carboxymethyl-D-glucose. W e y g a η d et al., Ber. 85, 57 (1952), l ^ -Isopropylidene ^ S ^ -tribenzyl-D-glucose reacted with methanolic hydrochloric acid to methyl - 3,5,6 - tribenzyl -D-glucofuranoside, this is methylated in the 2-position and 2-methyl-glucose from it via the methyl-2-methyl-D-glucofuranoside receive. About the biological properties of these D-glucofuranosides obtained as intermediates nothing is reported in this work.

The invention relates to the glucofuranosides of the general formula

R _n OCH ₉ 6

wherein X is a methylene group, preferably the isopropylidene group, _{treated with alcohols of the formula R 1} -OH in the presence of acids, or

b) l-halo-glucofuranoside of the formula
R ₆ OCH ₂

R.OCH

hc;

: CH - shark

CHOIR, - CHOH

R ₅ OCH

HC

\ 3
CHOIR ₃

XHOR ₁
CHOH

wherein R _{1 is} an ethyl, propyl or butyl radical, an oxyethyl or / Jy-dioxypropyl radical, an allyl radical, a cyclopentyl radical, cyclohexyl radical or a benzyl radical and R ₃ , R ₅ and R _{6 are} low molecular weight alkyl radicals, allyl radicals or optionally in the aromatic nucleus are benzyl radicals substituted by methyl or chlorine.

Low molecular weight alkyl radicals are z. B. methyl, ethyl, propyl or butyl.

These compounds have valuable pharmacological and biological properties. So increase They increase the resistance of animal organisms to bacterial and viral infections and increase the Medicinal effects of chemotherapeutic agents, e.g. B. sulfonamides, against infections. You can therefore alone or in combination with other remedies, such as sulfonamides, for prophylaxis or therapy Infections are used. They also show an anti-endotoxin effect. They inhibit the anaphylactic Shock as well as inflammatory processes and can accordingly be used as medication.

Ethyl 3,5,6-tribenzyl-D-glucofuranoside is particularly preferred.

The compounds according to the invention are prepared by each known per se wise

a) Glucofuranoses of the formula

R _n OCH ₂

R _K OCH

in which Hal denotes a halogen atom, with alcohols of the formula R ₁ -OH.

The etherification is carried out in the usual way in sugar chemistry, the acids being Lewis acids, such as hydrochloric acid, sulfuric acid, glacial acetic acid, optionally mixed with hydrochloric acid, toluenesulfonic acid or salts having the character of Lewis acid can be used.

Suitable l-halo-glucofuranosides are, for. B. the 1-chloro or 1-bromine, but also the 1-iodine-glucofuranoside. The implementation takes place in a manner known per se, advantageously by reaction with the Alcohol, expediently in the presence of condensing agents, especially acid-binding agents, such as silver, lead or mercury salts or oxides or tertiary bases.

The starting materials are known or can be obtained by methods known per se. she can optionally also be formed under the reaction conditions.

Compounds according to the invention can be used as medicaments in the form of pharmaceutical preparations find a mixture that is suitable for enteral, topical or parenteral application contain pharmaceutical organic or inorganic, solid or liquid carrier material.

You can e.g. B. as tablets, coated tablets or in liquid form as solutions, suspensions or emulsions administered, which can optionally also be sterilized.

The antiallergic effect of these compounds can e.g. B. can be demonstrated in animal experiments in systemic anaphylactic shock in actively sensitized guinea pigs or in the Arthus phenomenon in actively sensitized rabbits.
So you can z. B. by graduated administration of ethyl-S ^ .o-tribenzyl-D-glucofuranoside (LD ₅₀ 225 mg / kg iv mouse, about 800 mg / kg iv guinea pigs) in guinea pigs sensitized with ovalbumin to those triggered by intravenous injection of ovalbumin and in 16 of 18 control animals clearly influenced fatal anaphylactic shock in terms of a protective effect. This protective effect already occurs with a dose of 10 mg / kg po. At 30 mg / kg po, the protective effect lasts about 3 hours, at 50 mg / kg po about 5 hours. One hour protection can be z. B. also with 30 mg / kg ip of cyclohexyl-S ^ .o-tribenzyl-D-glucofuranoside, ß-OxyäthyW ^ .o-tribenzyl-D-glucofuranoside or ß-oxyethyl-S ^ o-triallyl-D-glucofuranoside and finally achieve 1,3,5,6-tetrabenzyl-D-glucofuranoside with 50 mg.

Likewise, doses of 30 mg / kg i. v. Ethyl 3,5,6-tribenzyl-D-glucofuranoside that on the depilated abdominal skin of sensitized rabbits with intramural

3 4

Cutaneous injection of horse serum-induced Arthus. Fractional distillation allows a fraction

Phenomenon evident during 6 hours. with enriched α-form {[<x] ² o = 38.2 ° in chloro-

The anti-inflammatory effect of compound form) and / J-form ([a] f = - 7.7 ° in chloroform)

gene of the present invention can be obtained with the aid of the.

Turpentine pleurisy tests based on those of 5 The starting material was obtained as follows:

Spector, J. Path. Bact., Vol. 72 p. 367 (1956), from 33 g of monoacetone glucose, 120 cm ^{3 of} carbon tetrachloride

Method worked on rats with intrapentoneal substance and 57 cm ^{3 of} dimethyl sulfate are added dropwise

Administration to be checked. For this, with 127.8 cm ^{3 of} 9.4 N sodium hydroxide solution was added while stirring

Ethyl 3,5,6-tribenzyl-D-glucofuranoside at one dose sets. The temperature rises over the course of 1 hour

from 0.1 g a 33 percent and with a dose of 10 26 to 60 °. Then carbon tetrachloride is distilled off.

0.3 g has a 38 percent anti-inflammatory effect. Now 127.8 cm ^{3 are} 9.4-n. Caustic soda added

detected. . and add drop by drop for 1 hour

That such antiallergic and antiinflammatory stirring 57 cm ^{3 of} dimethyl sulfate was added. Then it will be

Effects with very little toxic sugar derivatives the mixture with stirring for 80 to 45 minutes

can be achieved is surprising and represents 15 90 ° heated. Now it is extracted with chloroform,

an essential enrichment of the technology. the chloroform is removed in vacuo and the return

The production of the connection according to the invention is carried out again in the manner indicated last.

gene is ethylated in more detail by the following examples. Isolation of the reaction product by

purifies. The temperatures are in degrees Celsius. Chloroform extraction and high vacuum distillation

give. For the production of the starting materials, 20 leads to 29 g of the S ^ .o-trimethyl-l ^ -isopropylidene-

protection is not desired here. D-glucofuranose with bp _{0> 03} = 102 to 110 °.

For example example4

9.8g3,5,6-tribenzyl-1,2-isopropylidene-glucofuranose 9.8 g S ^ o-tribenzyl-l ^ -isopropylidene-D-glucofu-

are with 200 cm ³ 1-n. Ethanolic hydrochloric acid over 25 ranose with 200 cm ^{3 of} 1-n benzyl alcohol

Maintained at room temperature overnight. It is then shaken in hydrochloric acid for 24 hours. Then like in the

Evaporated in vacuo below 50 ° and the residue worked up in Example 3. The 1,3,5,6-Te-

300 cm ^{3 of} chloroform added. The chloroform trabenzyl-D-glucofuranoside by Kp. _{0, 2} = 250 to 260 °

Solution is mixed with sodium bicarbonate solution thoroughly as an oil.

washed, dried with calcined sodium sulfate 30 ice sheets 1 5
and evaporated in vacuo. The oily residue

is now distilled with an open flame in a vacuum. 9.8 g of S ^ o-tribenzyl-l ^ -isopropylidene-D-glucofu-Man receives the ethyl-3,5,6-tribenzyl-D-glucoranose with 200 cm ³ for 24 hours. 1-n cyclofuranoside of bp _{1> 2} = 270 to 280 ° and [oc \ f shaken in hexanolic hydrochloric acid and the reaction chloroform = + 8 °. 35 product in the manner described in Example 3

The glucofuranose used as the starting material worked. The cyclohexyl-S ^ o-tri-

was obtained as follows: benzyl-D-glucofuranoside of bp ₀₄ = 240 to 260 °

8.8 g of 1,2-isopropylidene-D-glucofuranose and 50.6 g as an oil; [*] ?? = 18 ° ± 1 ° (in chloroform).
Benzyl chloride are added with cooling and stirring

in portions with a total of 28g potassium hydroxide 40 examples
offset. The mixture is then used for 3 hours

80 to 90 ° stirred. Work-up from chloroform and 6.8 g of S ^ o-TriaUyl-l ^ -isopropylidene-D-glucofura-

Distillation at 0.1 torr and 250 to 260 ° results in ^{noses with 200 cm 3 of} 1-N ethanolic hydrochloric acid

S ^ gl ^ -Isopropylidene-S ^ o-tribenzyl-D-glucofuranose shaken for 24 hours. After processing according to

([«]? In chloroform = - 28 °). 45 game 3 you get the ÄthyW ^ o-triallyl-D-gluco-

_D. -, ο furanoside as a thin fluid oil with b.p. _{o 06} = 180

B e 1 s ρ 1 e 1 2 _{to 19Qa}

9.8 g of S ^ ö-Tribenzyl-l ^ -isopropylidene-D-glucofura- The starting material was obtained as follows:

In 200 cm ^{3 of} 1-N propanolic hydrochloric acid, 11 g of monoacetone glucose, 50 cm ^{3 of} dioxane and

Shaken for 24 hours, then in vacuo 50 16.8 potassium hydroxide are added dropwise with 25.1 cm ³

evaporated and the residue was added to allyl bromide taken up in chloroform. Then I ¹ I ₂ hours at 90 °

men. The chloroform solution is stirred with saturated, the mixture is cooled and again with

Washed sodium bicarbonate solution and mixed with 25.1 cm ^{3 of} sodium allyl bromide, 16.8 g of potassium hydroxide

Trium sulfate dried. The chloroform is now added in portions and the mixture under removed in a water jet vacuum and the residue was kept stirring at 80 to 90 ° for 2 hours. insulation

distilled in a high vacuum. This gives the propyl by chloroform extraction and high vacuum distillation

3,5,6-tribenzyl-D-glucofuranodide as an oil with _{b.p. 0> 2} lation gives 10.8 g of the S ^ o-TriallyJ-l ^ -isopropylidene-

= 270-280 °; [λ] ² = ₀ ° - 24 ° (in chloroform). 'D-glucofuranose as a low viscosity oil with a boiling point of ₄ = 165

υ. . ,,. up to 180 °.
B e1s ρ 1 el 3 _fi

⁶⁰ Example7
10.5 g S ^ o-trimethyl-l ^ -isopropylidene-D-gluco-

furanose are shaken with 105 cm ^{3 of} 1-N ethanolic salt 9.8 g of SS ^ -tribenzyl-l ^ -isopropylidene-D-glucofuric acid overnight. Then in a vacuum nose is ^{evaporated with 200 cm 3 of} a solution of 1N salts and the product is shaken with chloroformic acid in ethylene glycol for 24 hours. Purified after extraction and high vacuum distillation. 65 Working up analogously to Example 3, the oxy-man is obtained in this way, the ÄthyMAo-trimethyl-D-gluco-ethyl-3,5,6-tribenzyl-D-glucofuranoside as an oil from the furanoside in the form of a thin oil with a boiling point of _{o 1} = 240 to 260 °; [oc]% ° = - 18 ° ± 1 ° (in chloro-Kp.o 05 = 98 to 105 °, [<x] f = + 3.0 ° (in chloroform). form).

Example 8

13.6 g of S ^ jö-triallyl-l ^ -isopropylidene-D-glucofuranose are shaken with 400 cm ^{3 of} a solution of hydrochloric acid in ethylene glycol for 24 hours. After working up as in Example 3, the oxyethyl-3,4,6-triallyl-D-glucofuranoside is obtained as a low-viscosity oil with a boiling point of _{0> 04} = 190 to 205 °.

Example 9

9.8 gl ^ -Isopropylidene-S ^ .o-tribenzyl-D-glucofuranose are shaken with 60 cm ^{3 of} glycerol saturated with hydrogen chloride and 60 cm ^{3 of} glacial acetic acid IV for ₂ hours. The solution is then poured into ice water, extracted with chloroform, the chloroform extract is evaporated in vacuo and the residue is distilled in a high vacuum. The result is / ?, γ-dioxypropyl-3,5,6-tribenzyl-D-glucouranoside, _{b.p. oo3} = 260 to 280 °.

B e i s ρ i e 1 10

9.8 g of S.Sjo-triallyl-l ^ -isopropylidene-D-glucofuranose are shaken with 60 cm ^{3 of} glycerol which has been saturated with hydrochloric acid ^{gas and with 60 cm 3 of} glacial acetic acid for 2 hours. This is followed by working up from chloroform as in Example 10. The β, γ-dioxypropyl-S ^ o-triallyl-D-glucofuranoside with a boiling point of _{o 05} = 200 to 220 ° is obtained in this way.

Claims (4)

Patent claims: 1. Glucofuranoside of the general formula
R _R OCH "6 R ₅ OCH HC 30th 35 CHOIR ₁ CHOIR, - CHOH wherein R _{1 is} an ethyl, propyl or butyl radical, an oxyethyl or ^, y-dioxypropyl radical, a 40 denotes allyl radical, a cyclopentyl radical, cyclohexyl radical or a benzyl radical and R ₃ , R ₅ and R ₆ denote lower alkyl radicals, allyl radicals or benzyl radicals optionally substituted in the aromatic nucleus by methyl or chlorine. 2. EthyW.S.oj-tribenzyl-D-glucofuranoside. 3. A process for the preparation of compounds of the formula according to claim 1, wherein R ₁ , R ₃ , R ₅ and R _{8 have} the meanings given in claim 1, characterized in that one is carried out in a manner known per se a) Glucofuranoses of the formula R "OCH" R ₅ OCH -O- HC; : ch - ο CHOIR, —CH -X wherein X represents a methyl group, preferably the isopropylidene group, _{treated with alcohols of the formula R 1} -OH in the presence of acids, or b) 1-halo-glucofuranoside of the formula R ₆ OCH, R ₅ OCH CH - shark CHORUS ₃ - CHOH wherein Hal is a halogen atom, with alcohols of the formula R ₁ -OH. 4. Pharmaceutical preparations, characterized by a content of one mentioned in claim 1 Connection. 'U