DE1903901A1 - Cardenolideaminodesoxyglycosides for use - as heart stimulants - Google Patents

Abstract

Cardenolideaminodesoxyglycosides for use as heart stimulants Cpds. of general formula: (where R = 21-amino-21-desoxy-B-D-glucopyranoside and B = OH, or A = CH3 and B = H), are synthesised from the corresponding hydroxy cpds. and tri-O-acylglycosyl halides (C6H5CH2O)2PO-NH-G-X, (where G = tri-O-acyl-glycopyranosyl and X = C1 or Br), esp. tri-O-acetylglucopyranosyl derivs., in the presence of a heavy metal salt or oxide, partic. Hg(CN)2, and the resulting intermediate is treated with NH3/benzyl alcohol to remove the acyl groups, followed by catalytic hydrogenation over Pd/C to cleave the dibenzylphosphoryl group. The new derivs. are heart stimulants and intermediates for other similar cpds.

Description

New cardenolide-amino-deoxy-glycosides The invention relates to new cardenolide-amino-deoxy-glycosides of the general formula I, in which either m is a formyl group and B is a hydroxyl group or A is a methyl group and B is a hydrogen atom, and a process for their preparation.

According to the invention, the new compounds are produced as follows: Implementation of a gardenolide of the general formula II, in which and B are as defined above, with an O-acyl glycosyl halide of the general formula III, in which R1 is a lower acyl radical, in particular the acetyl radical, and Hal is a chlorine or bromine atom, and subsequent transesterification of a compound of the formula IV obtained, in which R1, A and B are defined as above, with benzyl alcoholic ammonia, the acyl radicals being split off at the same time, to form a compound of the formula V, in which d and B are as defined at the outset, and subsequent cleavage of the dibenzylphosphoryl radical by means of catalytic hydrogenation.

The reaction takes place in the presence of a heavy metal salt or one Heavy metal oxide preferably in an inert organic solvent, for example in benzene, and preferably at the boiling point of the solvent used. Here, a solution of a compound of the formula II is expediently with a Suspension of a heavy metal salt or Scvermetalloxides, advantageously with Mercury II cyanide, added and then a solution of one in the boiling heat O-acyl glycosyl halide of the formula III was added dropwise.

The subsequent transesterification takes place at temperatures between -20 and + 20 ° C, expediently at room temperature, with saturated with ammonia at 60 ° C Benzyl alcohol.

The dibenzylphosphoryl group is split off by hydrogenation in the presence of a noble metal catalyst, e.g.

211adium carbon, in a solvent, for example in methanol, preferably at normal pressure and room temperature.

The starting materials of the formulas II and III are known from the literature.

For example, the starting compounds of the formula III according to by L. Zervas and S. Konstas (Chem.Ber. 9D, 435 (1960)).

The new cardiac glycosides produced according to the invention have valuable ones pharmacological properties, in particular they have a positive inotropic Effect on the isolated guinea pig forecourt.

The following examples serve to explain the invention in more detail: 1. Digitoxigenin-3- (2'-amino-2'-deoxy-β-D-glucopyranoside) a) Digitoxigenin-3- (2'-deoxy-2'-diphenylphosphorylamino-3 ', 4', 6'-tri-O -acetyl-ß-D-glucopyranoside): 0.58 g (1.54 m mol) of digitoxigenin are mixed with 1 g (approx. 4 m mol) of Hg (CN) 2 in 40 ml Section. Benzene heated to boiling with stirring, 0.92 g (1.54 mol) of 1-bromo-2,3-dideoxy-2-diphenylphosphorylamino-3,4,6-tri-O-acetyl-α-D-glucopyranose added and heated for 5 hours. Then 0.1 g of bromine sugar and 0.1 g of Hg (CN) 2 were added and the mixture was boiled for a further 4 hours. After cooling down, at from which part of the product has already crystallized out, is mixed with 75 ml of chloroform diluted, washed twice with cold sodium chloride solution and four times with ice water, dried with sodium sulfate and evaporated. The residue is recrystallized from benzene.

Yield: 1.02 g (74%); M.p .: 133-135 ° C.

α20D: + 6 ° C (c = 0.5; methanol); thin layer chromatography pure (silica gel, chloroform / 10% methanol or dichloromethane / methanol / formamide 90: 9: 1).

b) Digitoxigenin-3- (2'-deoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranoside): 0.9 g digitoxigenin-3- (2'-deoxy-2'-diphenylphosphorylamino-3 ', 4', 6'-tri-0-acetyl-ß-D-glucopyranoside) are dissolved in 100 ml of benzyl alcohol saturated with ammonia at OOC and 70 hours stored at room temperature. Ammonia and benzyl alcohol are removed in vacuo and the residue by layer chromatography on silica gel (chloroform / methanol / NH385: 14: 1) cleaned. The main component falls in one yield. of 0.5 g (66%) in amorphous State on.

c) Digitoxigenin-3- (2'-amino-2'-deoxy-β-D-glucopyranoside) 0.68 g Digitoxigenin-3- (2'-deoxy-2'-dibenzylphosphorylaminoß-D-glucopyranoside) in 100 ml of methanol with 0.3 g of 10 percent. Palladium carbon hydrogenated for 20 minutes. After filtration the phosphoric acid is removed with Amerlite IRA 400 OH and the solution evaporated. The product is purified by layer chromatography (silica gel, chloroform / methanol / NH3 80: 19: 1) and then unicrystallized from ethanol / ether.

Yield: 0.37 g (81%); M.p .: 225-2270C; [α] 20D: -15 ° (c = 0.5; methanol).

2. Strophanthidin-3- (2'-amino-2'-deoxy-β-D-glucopyranoside) a) Strophanthidin-3- (2'-deoxy-2'-diphenylphosphorylamino-3 ', 4', 6'-tri -O-acetyl-ß-D-glucopyranoside): The conversion of strophanthidine (@, 46 g, 1.1 mol) with 0.66 g (1.1 mol) Bromose sugar and 0.66 g (approx. 2.6 mol) of Hg (CN) 2 are carried out in the procedure described in Example 1a Way. The syrup obtained after working up is dissolved in hot ethyl acetate.

On cooling, the product precipitates like a gel (yield: 0.4 g) Addition of petroleum ether gives a further 0.04 g, a total of 50, of the theoretical. Education second mother liquor is chromatographed on silica gel plates (PF, Merck). Man receives a further 0.1 g of product and 0.05 g of unreacted strophanthidine (superplasticizer Chloroform / methanol 9: 1). The product can be obtained from ethyl acetate / methanol / petroleum ether be recrystallized. M.p .: 177-1780C; +150; [α] 20400: + 36 ° (c = 0.5; Methanol).

b) Strophanthidin-3- (2'-deoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranoside): 0.31 g strophanthidin-3- (2'-deoxy-2'-diphenylphosphorylamino-3 ', 4', 6'-tri-0-acetyl-ß-D-glucopyranoside) are, as described in Example 1b, transesterified with ammonia in benzyl alcohol. The brown syrup obtained is on silica gel plates in chloroform / methanol 8: 2 layer chromatographed. Elution of the lower zone gives 0.12 g (43) pure but not crystalline material. The upper zone also visible in the W after elution gave a very inconsistent material which was discarded.

c) Strophanthidin-3- (2'-amino-2'-deoxy-β-D-glucopyranoside): 1.76 g strophanthidin-3- (2'-deoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranoside) purified by layer chromatography are in 200 ml 90 percent. Methanol with 0.3 g (0 percent alladium / carbon 30 minutes hydrogenated. The calculated I absorbed a lot of hydrogen. After working up as described in Example 1c, 1.04 g (92 0) of amorphous, foamy product which crystallizes from ethanol / ether (yield: 600 mg). By layer chromatography the mother liquor (chloroform / methanol / ammonia 75: 23: 2) is obtained. one more 90 mg Product. The overall yield (after recrystallization) is 780 mg (69%). The purest product is obtained by recrystallization, albeit lossy from methanol.

M.p .: 255-2650C (dec.); [α] 20D: +140; valley42000: + 390 (c = 0.5; ethanol).

For pharmaceutical use, those prepared according to the invention can be used Substances are incorporated into the usual preparations. The minimum and maximum Single doses are between 0.125 mg and 2.00 mg. The following are some pharmaceutical ones Forms of preparation indicated.

A) Tablets 1 tablet contains: Digitoxigenin-3- (2'-amino-2'-deoxy-B-D-glucopyranoside) 0.25 mg lactose 85.75 mg potato starch 30.0 mg gelatin 3.0 mg magnesium stearate 1.0 mg 120.0 mg Manufacturing process: The active substance is tenfold Amount of milk sugar rubbed in intensively. Mix this trituration with the rest Milk sugar as well as with potato starch and granulated with a 10% aqueous Dissolve the gelatin through a 1.5 sieve. Drying at 4000. The dried granules is rubbed through a 1 mm sieve again and mixed with magnesium stearate. From the Mixture, tablets are pressed.

Tablet weight: 120 ing Stamp: 7 mm flat with Dividing notch.

.B) Dragees 1 tablet core contains: Strophanthidin-3- (2'-amino-2'-deoxy-ß-D-glucopyranoside 0.25 mg lactose 32.25 mg corn starch 15.0 mg polyvinylpyrrolidone 2.0 mg magnesium stearate 0.5 mg 50.0 mg Manufacturing process: The active substance is ten times the amount Milk sugar rubbed in intensively with the rest of the milk sugar and corn starch mixed and with an own aqueous solution of the polyvinylpyrrolidone through sieve 1 mm granulated.

The mass, dried at 400C, is rubbed through the above sieve again, mixed with magnesium stearate and then pressed into tablet cores.

Eern weight: 50 mg Stamp: 5 mm convex.

The dragee cores produced in this way are using a known method coated in a shell consisting essentially of sugar and talc. The finished Dragees are polished with the help of beeswax.

Drage weight: 85 mg C) Dragees 1 tablet core contains: Digitoxigenin-3- (2'-amino-2'-deoxy-B-D-glucopyranoside) 0.125 mg lactose 32.375 mg corn starch 15.0 mg polyvinylpyrrolidone 2.0 mg magnesium stearate 0.5 mg 50.0 mg Manufacturing process: The manufacturing takes place as indicated above under B).

D) Drop composition: 100 ml drop solution contain: strophanthidin-3- (2'-amino-2'-deoxyß-D-glucopyranoside 0.0125 g sodium saccharin 0.3 g sorbic acid 0.1 g ethanol 30.0 g men's liqueur essence (Haarm. & Reimer) 1.0 g distilled water to 100.0 g Manufacturing process: Mix the solution of the active substance and the liqueur essence in ethanol with the solution of sorbic acid and saccharin in water and filtered fiber-free.

1 ml of dropping solution contains 0.125 mg.

E) Ampoules 1 ampoule contains: Digitoxigenin-3- (2'-amino-2'-deoxyß-D-glucopyranoside) 0.25 mg polyethylene glycol 600 tartaric acid 150.0 mg dist. Water ad 3.0 ml Manufacturing process: Tartaric acid, polyethylene glycol and the Active substance dissolved. The volume is made up with distilled water up and filter germ-free.

Filling: in white 3 ml ampoules under nitrogen gas sterilization: 20 minutes at 120 ° C.

F) Suppositories 1 suppository contains: strophanthidin-3- (2'-amino-2'-deoxyß-D-glucopyranoside 0.25 mg lactose 4.75 mg suppository mass (e.g. Witepsol W 45) 1,695.0 mg 1,700.0 mg Manufacturing process: The trituration of the active ingredient with milk sugar is carried out with Using an immersion homogenizer in the melted suppository mass cooled to 40 ° C stirred in. It is cooled to 37 ° C. and poured into slightly pre-cooled molds.

Suppository weight: 1.7 g G) suppositories 1 suppository contains: digitoxigenin-3- (2'-amino-2'-deoxyß-D-glucopyranoside) 0.125 mg Milk sugar suppository mass (e.g. Witepsol W 45) 1,695.0 mg 1,700.0 mg Production process: Production takes place as indicated above under F).

The new compounds of formula 1 prepared according to the invention can optionally for pharmaceutical use with other active substances, especially with a coronary dilator such as 2,6-bis (diethanolamino) -6,8-dipiperidino-pyrimido [5,4-d] pyrimidine, be incorporated into the usual preparations.

Claims (7)

Patent claims 1. New cardenolide-amino-deoxy-glycosides of the general formula I, in which either A is a formyl group and B is a hydroxyl group or a methyl group and B is a hydrogen atom. 2. Process for the preparation of new amino-cardenolide glycosides of the above general formula I, in which and B are as defined above, characterized in that a cardenolide of the general formula II, in which A and B are defined as above, with an O-acylglycosyl halide of the general formula III, in which R1 is a lower acyl radical, in particular the acetyl radical, and Hal is a chlorine or bromine atom, is reacted in the presence of a heavy metal salt or a heavy metal oxide and then a compound of the formula tV> in which R1, A and 3 are defined as above, with benzyl alcoholic ammonia to form a compound of the formula V, in the ,; ur.d 3: as defined at the outset, transesterified and then the dibenzylphosphoryl radical is split off by means of catalytic hydrogenation. 3. The method according to claim 2, characterized in that the implementation in a solvent and at the boiling point of the solvent used is carried out. 4. The method according to claims 2 and 3, characterized gekennzeicnnet, that mercury II cyanide is used as the heavy metal salt. 5. The method according to claim 2, characterized in that the catalytic Hydrogenation with palladium carbon at room temperature and at normal pressure in a solvent is carried out. 6. Pharmaceutical preparation forms characterized by a content on mineral-active compounds of the general formula I. 7. Pharmaceutical preparations according to claim 6, characterized in that that in addition to an active substance of the general formula I, other active substances are included.