SE466683B - SPIROKETAL STEROID GLYCOSIDES AND / OR ESTARS THEREOF TO USE AS A MEDICINE - Google Patents

Description

466 683 2 The extensive metabolic effects of prostaglandins allow for many therapeutic uses. Thus, prostaglandins are used in the treatment of asthma and circulatory diseases, as E-type prostaglandins have a vasodilating effect. On the other hand, prostaglandins cause pain and initiate labor so that they can also be used as abortion products if necessary.

It has been known very recently that the effect of some drugs, partly known for several years with analgesic and anti-inflammatory activity, is due to an inhibition of prostaglandin synthetases. This applies, for example, to acetylsalycylic acid, indomethacin and ibuprofen. The strong inhibitory effect of these compounds explains on the one hand their action against inflammatory symptoms but on the other hand the presence of many side effects of which by way of example only the onset of gastric bleeding is mentioned.

The biosynthesis of the prostaglandins is based on membrane phospholipids, which are converted to arachidonic acid and converted to endoperoxide-prostaglandins by acid radicals. From these endoperoxide oxide prostaglandins are formed the relatively stable prostaglandins, thromboxanes and the relatively unstable prostacyclin. The formation of PGE2 and PGF2α from arachidonic acid can be represented by the following formula scheme: (fw 3 466 683 The biological half-life of prostaglandins and in particular prostaglandin precursors is very short.

It is already known that some chemical compounds are strong prostaglandin synthetase inhibitors. These compounds, such as indomethacin or acetylsalicylic acid, are considered inhibitors of PGE2 synthetases and are therefore used to treat inflammatory symptoms of various origins such as rheumatic diseases and arthritis and the like. However, the strongly pronounced inhibitory effect, which not only appears to be restricted to the PGE2 synthetases, also leads to undesirable side effects, such as the triggering of gastrointestinal bleeding, other diffuse bleeding, the occurrence of allergies and the possible effect of a pregnancy.

The object of the present invention is to provide a medicament having the action of a prostaglandin synthetase inhibitor without the known disadvantages.

The invention therefore relates to spiroketal steroid glycosides and / or esters thereof for use as medicaments, and in particular to spiroketal steroid glycosides and / or esters thereof for use as medicaments for the treatment of diseases caused by an excess of prostaglandins.

It has surprisingly been found that spiroketal steroid glycosides and esters thereof are effective inhibitors of prostaglandin Ez and prostaglandin Fza synthetases and nevertheless do not trigger any by side effects of prostaglandin otherwise occurring side effects.

Spiroketal steroid glycosides are the steroid saponins which, in the steroid backbone of aglycone, have a spiroketal moiety attached to carbon atoms 16 and 17. The aglycones can also be different depending on whether they are 5-en-steroidal apogenines or 5-α-steroidal apogenins. The 5-ene compounds include, for example, diosgenin, yamogenin, botogenin and correlogenin, while typical examples of the 5-α compounds are, for example, tigogenin, neotigogenin, hecogenin sisalagenin.

In nature, the aglycones in the saponins occur as glycosides and usually contain 3 or more monosaccharide units in the sugar moiety. For this reason, the relatively sugary compounds are relatively readily soluble in water and often form a soap-like foam.

The spiroketal steroid glycosides have the following general formula z-o / wherein a double bond or an α-hydrogen atom is in the 5-position, and wherein Z represents a mono- or disaccharide, in particular glucose, optionally esterified.

The spiroketal steroid glycosides and esters thereof charged according to the invention can be charged as extracts from plant materials such as enriched extracts or as synthetically produced compounds. The synthesis takes place in a manner known per se, such as with the known Königs-Knorr synthesis for the production of glycosides using the corresponding aglycones, a brominated sugar acetate at carbon atom 1 and silver oxide and silver carbonate.

The spirochetal steroid glycosides, because they are not readily soluble in water, should be given in a sufficiently small particle size for resorption. It is therefore convenient that the spiroketal steroid glycosides used according to the invention are prepared and / or prepared and / or incorporated into pharmaceutical preparations so that liquid or solid solutions, emulsions or solid dispersions are formed, which can be obtained in a manner known per se. by adsorption, absorption or by grinding procedure with or without additives. These methods all aim to reduce the particles and lower the crystallinity so that they are in the form of extremely small amorphous mono- or multimolecular aggregates instead of in the form of crystalline microparticles. The compounds of the invention to be administered are usually introduced with a particle size of about 0.1 mm and preferably 0.06 mm and less. The same applies, despite their slightly better water solubility, to the spiroketal steroid glycosides, which are also used with a particle size of about 0.1 mm and preferably 0.06 mm or less.

The compounds of the invention to be administered are given in a daily dose of about 0.03 to about 10 mg. As a maintenance or prophylactic dose, it is usually given about 0.45-0.1 mg per day. These doses can be divided into three single doses or administered in a single dose with delayed action.

As far as is known, the compounds to be used according to the invention are suitable for the treatment of such diseases in which a reduction of the PGE2 or PGF2a content is required. These are, for example, 1. ulcers, especially in the gastrointestinal tract, 2. endocrine disorders, 3. urogenital disorders, in particular benign prostatic hypertrophies and thereby caused problems, 4. heart disorders and blood pressure disorders, 5. edematous conditions, 6 vascular diseases, thromboses, varicose veins and hemorrhoids, 7. dermatitis and excess histamine reactions, 8. inflammatory disorders, 9. rheumatic diseases and arthritis disorders, 10. allergies, including asthma. 466 685 6 In the same way, the compounds according to the invention which are to be administered can also be used for the treatment of animal diseases. The doses in the control of animal diseases can be calculated in a known manner, ie on a weight basis at an assumed human average weight of 75 kg.

The compounds can be processed in a manner known per se into pharmaceutical specialties such as, for example, powders, pills and tablets, capsules, dragees, emulsions, solutions, injection or infusion solutions, ointments and creams.

The invention is further illustrated by the following examples.

Example 1 Preparation of diosgenin 3-β-D-glucoside. 41.4 g of diosgenin and 55.2 g of silver carbonate are charged to boiling toluene and the mixture is distilled with stirring until the distillate turns anhydrous. Then the stirred boiling solution is added dropwise with a solution of 82.2 g of bromoacetyl glucose in 100 ml of toluene. The mixture is further distilled continuously to remove the water formed during the reaction. During this time, the reaction vessel is protected from light. If necessary, the volume of the reaction mixture is kept constant by the addition of dry toluene. After addition of the acetobromine glucose solution, it is further distilled until the distillate becomes anhydrous. The reaction mixture is then cooled and filtered. The residue is washed with fresh hot toluene. The combined filtrates and washings are evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol or hexane. The yield of diosgenin-3-β-D-glucoside tetraacetate is 25.5 g or 34.3%. 1 g of sodium is dissolved in 100 ml of absolute ethanol. Of this solution, 15 ml are rapidly added with stirring to a solution of 10 g of diosgenin-glucoside tetraacetate in 600 ml of ethanol at 45 ° C.

The mixture is stirred for 1 hour before 2 liters of water are added and the mixture is then stirred again for 1 hour. The precipitated diosgenin-β-D-glucoside is filtered off and washed with water until neutral before being dried in vacuo for 7 g 466 685 12 hours. The yield is 7 g or 90%.

Correspondingly, all the other mentioned spiroketal steroid glycosides can also be prepared.

Example 2 Preparation of pharmaceutical preparations. a) Preparation of lactose-corn starch powder with a content of diosgenin-β-D-glucoside. 15 g of diosgenin-β-D-glucoside are dissolved in 3 liters of a boiling mixture of chloroform and ethanol in a ratio of 3: 1. The solution is then added to 1 kg of lactose with a particle size not exceeding 0.15 mm. The slurry thus formed is evaporated to dryness with constant stirring. The dried, impregnated lactose is decomposed back to the original particle size and finally mixed with 9 kg of corn starch and 50 g of magnesium stearate. This mixture is excellent for filling into capsules. Each capsule may, for example, contain 100 mg of the mixture, which corresponds to a content of 0.15 mg of diosgenin-β-D-glucoside, 10 mg of lactose, 90 mg of corn starch and 0.5 mg of magnesium stearate. b) Preparation of lactose granules with a content of diosgenin-ß-D-glucoside. 5 g of diosgenin-β-D-glucose are dissolved in 5 liters of boiling ethanol.

The solution is then added to 3.32 kg of lactose with a particle size not exceeding 0.15 mm. The slurry is evaporated to constant dryness with constant stirring. The dry, impregnated lactose is decomposed to the original particle size before being processed into granules with a preferred particle size of about 0.7-1.2 mm. This granulated product is also particularly suitable for further processing into capsules, whereby, for example, a capsule with 100 mg of the granulate contains 0.15 mg of diosgenin-B-D-glucoside.

The products under a) and b) can also be prepared using glycosides of the said 3-β-hydroxypirooketal steroids and in particular the β-D-glucosides of tigogenin and hecogenin. Glucose, ascorbic acid or talc as carriers for the glycosides or also the use of other inert pharmaceutically acceptable carriers. The content of active glycoside compound in each capsule can be adjusted to values between 0.01 mg and more. 4. The excipients mentioned in a) and b) may be varied according to the usual pharmaceutical manufacturing procedures. 5. At any stage of the preparation process in a) or b) other pharmaceutically active compounds may be incorporated. c) Preparation of tablets with a content of diosgenin-β-D-glucoside. 1.250 g of diosgenin-β-D-glucoside are dissolved in 1 liter of chloroform and added with 900 g of lactose. The slurry is dried under reduced pressure and constant stirring at room temperature. Then the mixture is added with 2100 g of potato starch and stirred vigorously again. The impregnated lactose-starch mixture is added to 2500 ml of an aqueous solution of 250 g of gelatin and 5 g of glycerin and granulated in a manner known per se. The granules are dried under reduced pressure at room temperature.

The granules are then compressed in a manner known per se into tablets with a total weight of 400 mg. Thus, each tablet contains 0.15 mg of diosgenin-β-D-glucoside, 110.56 mg of lactose, 257.97 mg of potato starch, 30.31 mg of gelatin and 0.61 mg of glycerin. d) Preparation of dragees with a content of hecogenin-ß-D-glucoside.

A solution of 450 mg of hecogenin B-D-glucoside in 2 liters of chloroform is added with 1850 g of lactose and 300 g of sucrose. The slurry is dried at 30 ° C under reduced pressure and then granulated in a manner known per se by adding 1.6 liters of an aqueous gelatin solution with a content of 40 g of gelatin. The granules are dried under reduced pressure at a temperature of 45 ° C. Then mix the granules well with 10 g of magnesium stearate. The mixture thus prepared (2200 g) is pressed into about 3000 cores, which are then coated by known dragee method with a possible colored, thin dragee coating.

Thus, each dragee contains 0.15 mg of hecogenin-β-D-glucoside, 616.67 mg of lactose, 100.00 mg of sucrose, 13.33 mg of gelatin and 3.33 mg of magnesium stearate. e) Preparation of an ointment containing hecogenin-ß-D-glucoside content. 1 g of hecogenin-β-D-glucoside is incorporated into 90 g of emulsifying cetylstearyl alcohol. After adding 105 g of viscous paraffin and 105 g of white petroleum jelly, it was melted on a water bath at 60 ° C.

The melt is added with 699 g of water in small batches at approximately the same temperature. The mixture is stirred until it has cooled, whereby an ointment with a content of 0.1% glucoside is obtained. f) Preparation of a cream with a content of tigogenin-ß-D-glucoside. 1 g of tigogenin-β-D-glucoside is charged into 500 g of wool fatty alcohol and heated on a water bath at about 50 ° C. The mixture is then added with 499 g of water of about the same temperature in small batches.

The cream is stirred until it has cooled, whereby evaporated water is added. The cream has a content of 0.1% glucoside.

Example 3 Pharmacological examination of the spiroketal steroid glycosides.

Investigation of the toxicity of spiroketal steroid glycosides.

When examining acute toxicity in rats, mice, rabbits, dogs and primates, no oral effect could be established after oral administration of, for example, sitosterol B-D glucoside, even at doses of 1-2 g / kg body weight. Even when administered over an extended period of daily doses of 100-200 mg / kg body weight, no toxic and no gout-like conditions could be established in these animal species, so that the tolerability must be described as good. Example 4 Activity of the compounds as prostaglandin synthetase inhibitor.

The action of the compounds as a prostaglandin synthetase inhibitor was demonstrated by the method of A.L. Willis under the experimental conditions described, for example, in the Proceedings of a Workshop held at the Eighth European Rheumatology Congress in Helsinki in 1975.

Siliconized cuvettes for an aggregometer were used as incubators at a temperature of 37 ° C. In the incubation vessel, an arachidonate solution is rapidly added to a prostaglandin synthetase enzyme system, usually prepared from sheep bladder, and stirred. To this solution in the cuvette is then added anticoagulant-treated platelet-containing plasma, which is also heated to 37 ° C. The light transmission through the cuvette is determined immediately after the addition. In the control samples, after a 45 second incubation period, a clear peak in the platelet aggregation is shown, which shows the formation of the prostaglandins PGE2 and PGF2a and the platelet aggregation caused thereby.

In the experimental tests with an addition of 0.00001% sterol glycosides or spiroketal steroid glycosides, the aggregation of the platelets is absent. This clearly shows that the formation of prostaglandins via endoperoxide compounds from arachidonate is inhibited.

Example 5 According to new findings, the prostaglandins PGE and PGF α and the endoperoxide precursors of these compounds play a significant role in triggering rheumatoid arthritis. Therefore, in pharmacological experiments, the effect of the compounds used according to the invention as prostaglandin synthetase inhibitors was investigated.

In a comparison of arthritis after experimental rose, for example in rats with rheumatoid arthritis in humans, a far-reaching agreement of the individual morphological changes can be observed. The investigations were performed according to the instructions of Schulz et al. Beitr. Path. 154, 1-26, 27-51 (1975). The rose-related arthritis in rats can be reproduced with almost 100% certainty by a single injection. In arthritis, more than 6 joints are always altered, namely large and small extremity joints with the same character. In experimental rose, all animals still show high proliferative processes after 3 months.

For the examination of the substances, from that phase, when symptoms occur, the following parameters were used to assess the effect of the preparation: Paw volume Rat arthritis is clinically characterized by a high degree of periarticular edema in animals with a body weight of 150 g from the third day and at a body weight of 200 g from the fifth day.

Kidneys (egg white secretion) Necrosis caused by microtombosis can occur in about 30-40% of the animals on the seventh - eighth day. Eyes Inflammations (clouding) of the cornea at about the eighth day.

External genitals, the tip of the tail Necrosis caused by thrombi from the sixth to the eighth day. êeššâ Between the sixth and eleventh day, fibrin-rich thrombi occur intimately in the rats of the rats. The largest surface area occurs on about the eighth day.

For the study, male Wistar rats weighing between 150 and 180 g were used. The animals were kept in individual cages and given the standard diet for rats (Ssniff R) and water ad libitum. 466 683 12 The room temperature was constant 22 ° C, and the relative humidity between 50 and 60%. The daily lighting time was 12 hours. Before the test started, the animals had an acclimation time of 10 days.

The infection occurred with rosstam T28. The dosage was 2 ml subcutaneously (approximately 100-200 million microorganisms). The compounds to be tested are suspended in sterile physiological saline and given at a dose of 5 mg / kg intraperitoneally. The treatment took place from the day of infection until the end of the experiment or until the animals died 5 times a week.

In the evaluation of the characteristic aortic thrombi, the following values were obtained: control sample: number of points 2.80 hecogenic glucoside: 1.38 diosgenic glucoside: 1.33

Claims (4)

466 683 13 Patent claims Spiroketal steroid glycosides and / or esters thereof for use as medicaments. Spiroketal steroid glycosides and / or esters thereof according to claim 1 for use as medicaments for the treatment of diseases caused by an excessive level of prostaglandins. Spiroketal steroid glycosides according to claim 1, characterized in that they are glucosides of diosgenin, hecogenin and / or tigogenin. Spiroketal steroid glycosides according to one or more of claims 1-3, wherein the particle size of the active substance is in the range below 0.1 mm diameter and in particular about 0.06 mm diameter and smaller.