DE2050072A1 - Salts of 3-acetyl 18-beta glycyrrhetinic - acid - Google Patents

Abstract

Title cpds. in the form of their Bi, Alk. metal, alk. earth metal or a metal of Gp. III of the Periodic Table salts, esp. the K, Mg, Ca, Al and Bi salts, are anti-inflammatory, anti-ulcer agents and antacids.

Description

"New Pharmaceutical Compounds" This invention relates to new ones pharmaceutical compounds.

According to the present invention, it has been found that 3-acetyl-18ß-glycyrrhetinic acid and their salts with certain metals are optimally curative and anti-inflammatory Have properties that deal with malfunctions the digestive tract, such as Wagen and wölffingerdar ulcers, gastritis and gastroduodenitis, in particular however, drug induced disorders are very useful. These substances can about it hindus in the therapy of pharyngitis, pharyngotracheitis, @@ or @ nautical ulcers, Colitis (especially ulcerative @olitis), dermatitis, dormatosis, decubitus ulcers, latent ulcers, cranial vein ulcers, fissures, nemorrhoids and spithelial erosions the sexual genital passages can be used.

The new metal salts of 3-acetyl-18ß-glycyrrhetinic acid, on which By reference, not only possess the curative, anti-ulcer and alone anti-inflammatory properties of the free acid, but also the pharmacological properties Properties, especially the acid-binding effect of the metal in question.

The invention includes the metal salts of 3-acetyl-18ß-glycyrrhetinic acid with bismuth, the alkali metals, alkaline earth metals and metals of group III des periodic system.

The invention also encompasses pharmaceutical preparations having a Content of 3-acetyl-18ß-glycyrrhetinic acid and pharmaceutical preparations which contain the aforementioned metal salts. These preparations include a Diluents or a carrier for the active ingredient and you can add other drugs contain. Customs include starch, talc, sodium alginate, and magnesium stearate. The preparations can be in the form of tablets or suppositories, or as a powder or half. The pharmaceutical preparations can also Anti-hyperacidity agents such as aluminum hydroxide, glycine and aluminum silicate contain.

The preferred metal salts of 3-acetyl-18β-glycyrrhetinic acid are those with potassium, magnesium, calcium, aluminum and bismuth.

he new salts of 3-acetyl-18ß-glycyrrhetinic acid can by reaction between 3-acetyl-18ß-glycyrrhetinic acid and an alcoholaz of the metal in question getting produced.

Lower alcoholates are preferably used, i.e. alcoholates, in which the alkoxy group or groups have from 1 to 4 carbon atoms. The salt formation reaction can be carried out in the usual manner at room temperature or at an elevated level Temperature, preferably carried out in the presence of organic solvents will. As organic solvents, alcohols, ethers, ketones, chlorinated Solvents (methylene chloride, chloroform), ethyl acetate etc.

be used.

If the ITetal has a valence greater than 1, it is possible, a neutral or a basic salt, depending on the ratio of the reaction components Inchnler, to receive.

The basic salts obtained can be obtained by the formula M (Glyc.) X (OR) m-x are shown, in which M represents the metal, m represents the valence of the metal, x is a positive integer with an iert less than m, I; hydrogen or one of the alkoxy groups of the alcoholate used in the preparation of the salt represents the corresponding alkyl group, and x represents a 3-acetyl-18β-glycyrrhetinic acid group is. The alkoxy group-containing basic salts can be obtained by that the salt formation reaction is carried out in the absence of water. If required, these basic salts can form hydroxyl group-containing basic rolls (i.e. PL = i; in the formula above) by bringing the salts into contact with the stoichiometrically required amount of water to be converted. Optionally can the hydroxyl group-containing basic roller can be prepared by carries out the salt formation reaction in the presence of water.

For example, it was possible to use aluminum to replace the aluminum mono-, -di and -tri-3-acetyl-18ß-glycyrrhetinate to get, where im In the case of the mono- and di-salts, the remaining valencies of the aluminum are replaced by hydroxyl and / or alkoxy groups can be saturated.

in many cases the solubility of these new salts is organic Solvents very high, while the solubility in water is generally very high is low.

As a general rule, the solubility of the salts of -3-acetyl-18ß-glycyrrhetinic acid increases with polyvalent metals in organic solvents from the basic salts to the neutral salts: aluminum tri-3-acetyl-18ß-glycyrrhetinate is a lot more soluble in chloroform than aluminum mono-3-acetyl-18ß-glycyrrhetinate.

Pharmacological data In these attempts, reference is made to the following, numbered publications referenced: (1) Litchfield J.T. and Wilcoxon F.J., Pharmacol. exp. Ther.

96, 99, 1942 (2) Shay H., @amarov S.A., Fels S.S., Moranze D., Gruenstein M. and Spilet N .; Gastroenterology 5, 43, 1945 (3) Keyrilainen T.O. and pass M.K., Acta Pharmacol. et toxicol. 13, 22, 1957 (4) Winter C.A., Risley E.A. and Huss G.W; Proc. Exp. Biol.

Med. 3, 544, 1962 (5) Van Arman C.G., Begany A.J., Miller L.H. and Pless K.H .; J. Pharm. Exp. Ther., 150, 328, 1965 (6) Cahen R., Possonier A .; C.R.Soc. Biol. 157, 477, 1963 (7) Bonfils S., Lefesghe S., Rossi C. and Lambling A .; C.R.Soc. Biol. 151, 1149, 1957.

Toxicity This was determined on male rats of the Sprague-Dawley strain examined in weight from 220 to 290 g by oral and intraperitoneal administration, the observation being extended to a period of 10 days.

The LD50 values were determined according to the method of Litchfield and Wilcoxon (1) calculated.

Tables I and II show the oral resp.

LD50 values obtained after intraperitoneal administration.

T a b e l l e I Product Treated LD50 animals mg / kg 3-acetyl-18ß-glycyrrhetinic acid 20> 3300 aluminum tri-3-acetyl-18ß-glycyrrhetinate 23> 3300 T a b e l l e II Product Treated LD50 animals mg / kg 3-acetyl-18ß-glycyrrhetinic acid 40> 3300 aluminum tri-3-acetyl-18β-glycyrrhetinate 4> 3300 anti-ulcer activity This was done by comparing experimental ulcers generated by pyloric ligature Shay (2) examines.

The ligature of the pylorus was performed under light anesthesia with ether carried out in rats that were in Single cages Fasted water ad libitum.

The rats were returned to the cages with no food and no water spent and killed 17 hours later. The stomach was along the lower bend opened and checked to determine the ulcer formation therein, whereby the following, The classification proposed by Keyrilainen and Paasonen (3) was used: Class I - small ulcers 0.2 mm = value 1 Class II - medium ulcers 2-5 mm = value 5 Class III - large ulcers 5-10 mm = value 10 Class IV - very large ulcers> 10 mm = value 20 Perforation = value 20 It was then calculated: The sum of the Values from all classes Ulcer index = number of animals the percentage deviations the ulcer index of the rats in view of the controls and the number of before a perforation of the ulcer protected stomachs, with those that are niciit More than two small ulcers were considered protected.

The administration of the substances was effected by a cart probe and repeated three times, 48 and 24 hours prior to the Pyrolus ligature and immediately after the operation.

Each of the substances tested was administered to groups of 10 to 13 rats administered suspended in gum arabic.

The data obtained are summarized in Table III. T a b e l l e III number of ulcers in the number of dose / kg number of ulcer deviation different classes (2) non-treatment (1) d.Rats index from ulcerative ulcer Index I II III IV V stomachs%% controls (10% aqueous 20 ml 13 138 43 19 23 1 78.6 - -ges gum (138) (215) (190) (460) (20) arabic) 3-acetyl-18ß-glycyr- 436 mg 10 37 16 3 1 0 16.7 -78 30 rhetinic acid (37) (80) (30) (20) aluminum tri-3-acetyl-18ß-glycyr- 436 mg 13 72 9 0 0 0 9 -88 23 rhetinate) 72) (45) Comments (1) Dose administered three times: 48 and 24 hours before pyloric ligation and immediately after surgery; oral Administration.

(2) In brackets, the number of ulcers multiplied by the value of the various classes, described in accordance with the valuation standard in the process.

Activity related to the improvement of gastric ulcer It became the Technique used by Cahen and Pessonier (6).

@ Similar rats;,! it weighing between 180 and 230 g, the lü Having been fed for hours became abstinence during one Duration of 24 hours according to the method of Bonfils et al. (7) subject.

The substances were administered orally, at fixed doses, of each of which was given half in the morning and half in the evening.

As rats were kept as control animals to which the carrier of the Test compounds, namely gum arabic at a concentration of 10% in water was administered.

The treatments were continued for 1 to 8 days.

The animals were divided into groups of 8 simultaneously by separating the Head killed 2 hours, 3, 6 and 9 days after the immobilization was discontinued, 12 hours after the last administration of the drug.

The stomachs were removed from the sacrificed animals immediately after to the Period of immobilization (testing of the ulcerogenic effectiveness of this period) or removed from the aforementioned pages after cessation of abstinence, washed with physiological solution and the mucous membrane checked afterwards.

It was the number of non-healed ulcers (U) and the number the healed ulcer or ulcer in the process of healing drawn.

It was an ulcer index based on the ratio between the Number of ulcers present in the stomachs examined and the number of ulcers in each of the above-mentioned times of animals killed.

T a b e l l e IV Effect of 3-acetyl-18ß-glycyrrhetinic acid and of Aluminum tri-3-acetyl-18ß-glycyrrhetinate induced on the spontaneous regression of immobilization Ulcers Oral doses Ulcer index at the end of immobilization according to the number of treatment mg / kg following number of days (2) of animals (1) 0 1 3 6 9 U UH U UH U UH U UH U U Control experiments 2 tl / 100 0 6.5 0 1.7 0.3 1.7 0.3 0.2 1.1 0 1.6 (gum arabic in concentration v. 10% in water) 3-acetyl-18β-glycyrrhetine-436 8 6.8 0 0.6 4.2 0.2 1.2 0 1.6 0 1.7 acid aluminum-tri-3-acetyl-18β-436 8 6.0 0 0.1 3.0 0 1.6 0 1.5 0 2.3 glycyrrhetinate U - non-healed ulcers UH - healed ulcers (1) doses given in two servings: half in the morning and half in the evening (2) The number of ulcers present in the stomachs divided by the number killed animals Anti-inflammatory activity Studies of anti-inflammatory Activity were carried out on rats, both by carrageenin after Winter et al (4) and induced by egg yeast according to Van Arman et al (5) on the paw Edema was examined. The substances to be tested were administered intraperitoneally.

The results obtained are in Tables V and below VI compiled.

T a b e l l e V Inhibition of Carregeenin-induced edema Doses edema inhibition treatment mg / kg number of d. (ml # L.S.) Edema Rating (1) animals (2)% (3) control vers. - 8 0.31 # 0.007 -3-acetyl-18β-glycyrrhetinic acid 33 8 0.17 # 0.001 45 P <0.001 109 8 0.04 # 0.003 87 P <0.001 control vers. - 8 0.28 # 0.007 - -Aluminum tri-3-acetyl-18ß-glycyrrhetinate 33 8 0.17 # 0.007 39 P> 0.001 109 8 0.14 # 0.01 50 P> 0.001 (1) dose was given intraperitoneally twice administered: 30 minutes before and 1 hour after the subplantar injection of carrageenin (0.1 ml of a 1% suspension).

(2) Average volume of edema measured 3 hours after the carrageenin injection, the time in which the maximum volume of the edema at the control experiments occurred.

(3) Evaluation, derived from the "t" test according to STUDENT, calculated taking into account the average obtained with the control tests.

T a b e l l e VI Incision of the edema caused by brewer's yeast Doses edema inhibition number of d. Evaluation treatment mg / kg (ml # @. S.) of the edema Animals (3) (1) (2)% control vers. - 8 0.31 # 0.003 -3-acetyl-18β-glycyrrhetinic acid 33 8 0.16 # 0.01 48 P <0.001 109 8 0.07 # 0.003 77 P <0.001 control vers. - 8 0.29 # 0.003 - -Aluminum tri-3-acetyl-18β-glycyrrhetinate 33 8 0.13 # 0.003 35 P <0.001 109 8 0.10 # 0.003 65 P <0.001 (1) doses were given intraperitoneally 30 Minutes before the subplantar injection of brewer's yeast (0.1 ml of a 2% suspension) administered.

(2) Average volume of edema measured 1 hour after the Injection of brewer's yeast, the time in which the maximum volume of the edema in the Control attempts occurred.

(3) Rating, derived from the STUDENT "t" test, calculated taking into account the average obtained with the control tests.

The preparation of the salts according to the present invention is described in explained in the following examples.

B e i s p i e l 1 Production of aluminum tri-3-acetyl-18ß-glycyrrhetinate 15.38 g of 3-acetyl-18ß-glycyrrhetinic acid dissolved in 500 ml of chloroform were made into a A solution of 2.04 g of aluminum isopropoxide in 50 ml of chloroform was added.

After 1 hour the chloroform solution was evaporated to dryness and aluminum tri-3-acetyl-18β-glycyrrhetinate obtained as a white powder, melting point 286 to 290 ° C, [α] D20 = 126 ° # 2 ° (c = 1, CHCl3).

B e i s p i e l 2 Manufacture of aluminum tri-3-acetylglycyrrhetinate 4.03 g of aluminum isopropylate, dissolved in 50 ml of methylene chloride, were added to 30.76 g of 3-acetyl-18ß-glycyrrhetinic acid, dissolved in 200 ml of methylene chloride was added. To complete 'the solution was stirred at room temperature, then concentrated to about 50 ml and poured into 200 ml of hexane. Aluminum tri-3-acetyl-18ß-glycyrrhetinate was produced as a white, amorphous, light powder obtained by filtration.

Example 3 Preparation of magnesium mono-methoxy-mono-3-acetyl 18β-glycyrrhetinate A solution of 0.48 g of magnesium turnings in 100 ml of methanol became 103 g of 3-acetyl-18β-glycyrrhetinic acid added in 500 ml of methanol.

After refluxing for 30 minutes the solvent became Evaporated to dryness and magnesium mono-methoxy-mono-3-acetyl-18ß-glycyrrhetinate obtained as a white powder; Melting point 308 to 313 ° C, [α] D20 = + 129 ° # 2 ° (c = 1, CHCl3).

Example 4 Preparation of magnesium mono-hydroxy-mono-3-acetyl-18β-glycyrrhetinate A solution of 0.48 g of magnesium turnings in 100 ml of methanol became 103 g of 3-acetyl-18β-glycyrrhetinic acid added in 500 ml of ethanol.

After refluxing for 30 minutes, 100 ml of methanol, which contained 4 ml of water, added and the Solution under reflux Heated for 15 minutes; the solution was evaporated to dryness and magnesium mono-3-acetyl-18ß-glycyrrhetinate obtained as a white powder; Melting point 320 to 325 ° C (decomp.), [Α] D20 = + 129 ° # 2 ° (c = 1, CHCl3).

The following examples are pharmaceutical formulations that incorporate the Compounds according to the invention contain: tablets aluminum tri-3-acetyl-18ß-glycyrrhetinate 50 mg aluminum hydroxide 400 mg diluents such as sodium alginate, magnesium stearate, Talc and / or starch up to 1.2 g tablets magnesium di-3-acetyl-18ß-glycyrrhetinate 75 mg diluents such as sodium alginate, magnesium stearate, talc and / or starch up to 0.8 g powder aluminum tri-3-acetyl-18ß-glycyrrhetinate 3 g aluminum hydroxide 16 g diluents such as sodium alginate, talc, magnesium stearate, polyoxyethylene stearate, Starch and / or lactose up to 100 g Suppositories aluminum tri-3-acetyl-18ß-glycyrrhetinate 100 mg tri-glyceride of fatty acids up to 1400 pessaries (vaginal balls) magnesium di-3-acetyl-18ß-glycyrrhetinate 100 mg glycerin 200 mg tri-glycerides of fatty acids up to 2400 g ointment aluminum tri-3-acetyl-18ß-glycyrrhetinate 2 Lidocaine hydrochloride 2 Distilled water 14.8 g of methyl p-hydroxybenzoate 0.2 , Thinners such as polyethylene glycol 4000, propylene glycol and / or cetyl alcohol up to 100

Claims (20)

Claims 1. Salt of 3-acetyl-18ß-glycyrrhetinic acid with bismuth, Alkali metals, alkaline earth metals or metals of group III of the periodic Systems. 2. Salt of 3-acetyl-18ß-glycyrrhetinic acid with potassium, magnesium, Calcium, aluminum or bismuth. 3. Aluminum tri-3-acetyl-186-glycyrrhetinate. 4. Aluminum di-3-acetyl-18ß-glycyrrhetinate. 5. Aluminum mono-3-acetyl-18β-glycyrrhetinate. 6. Magnesium di-3-acetyl-18ß-glycyrrhetinate. 7. Magnesium mono-3-acetyl-18ß-glycyrrhetinate 8. Magnesium monohydroxy-mono-3-acetyl-18β-glycyrrhetinate. 9. Pharmaceutical preparation containing 3-acetyl-186-glycyrrhetinic acid and / or a compound according to any one of claims 1 to 8 together with a pharmaceutical acceptable diluents or carriers. 10. Pharmaceutical preparation according to claim 9, characterized in that that they also have a remedy for hyperacidity such as aluminum hydroxide, glycine and aluminum silicate. 11. Pharmaceutical preparation according to claim 9, essentially as described above and illustrated by examples. 12. Process for the preparation of a metal salt of) -AcetylglycyrrhetinsSure, characterized in that 3-acetyl-18-glycyrrhetinic acid is mixed with a metal alcoholate to react. 13. The method according to claim 12, characterized in that the alcoholate is a lower alcoholate. 14. The method according to any one of claims 12 and 13, characterized in that that the reaction is carried out in the presence of an organic solvent. 15. The method according to any one of claims 12 to 14, characterized in that that the metal has a higher valence than 1 and a basic salt through Reaction of the alcoholate and the acid in an equivalent ratio of greater as 1 is obtained. 16. The method according to claim 15, characterized in that the reaction is carried out under anhydrous conditions. 17. The method according to claim 16, characterized in that the obtained Product with water to displace alkoxy groups by hydroxyl groups in Is brought into contact. 18. The method according to claim 15, characterized in that the reaction is carried out in the presence of siasser. 19. The method according to claim 12 essentially as described above and illustrated by examples, with particular reference to any of the examples 1 to 4. 20. Metal salt of 3-acetyl-18ß-glycyrrhetinic acid, provided it is through a method according to any one of claims 13 to 20 is obtained.