DE1903901A1 - Cardenolideaminodesoxyglycosides for use - as heart stimulants - Google Patents
Cardenolideaminodesoxyglycosides for use - as heart stimulantsInfo
- Publication number
- DE1903901A1 DE1903901A1 DE19691903901 DE1903901A DE1903901A1 DE 1903901 A1 DE1903901 A1 DE 1903901A1 DE 19691903901 DE19691903901 DE 19691903901 DE 1903901 A DE1903901 A DE 1903901A DE 1903901 A1 DE1903901 A1 DE 1903901A1
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- amino
- heavy metal
- glucopyranoside
- cardenolide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000496 cardiotonic agent Substances 0.000 title abstract 3
- 229910001385 heavy metal Inorganic materials 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 4
- -1 tri-O-acetylglucopyranosyl Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229910003439 heavy metal oxide Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- TYYDXNISHGVDGA-UHFFFAOYSA-N Corotoxigenin Natural products CC12CCC3C(CCC4CC(O)CCC34C=O)C1CCC2C5=CC(=O)OC5 TYYDXNISHGVDGA-UHFFFAOYSA-N 0.000 claims 1
- JIUWTCXNUNHEGP-GJHPUSIBSA-N cardenolide Chemical compound C1([C@H]2CC[C@@H]3[C@H]4[C@@H]([C@]5(CCCCC5CC4)C)CC[C@@]32C)=CC(=O)OC1 JIUWTCXNUNHEGP-GJHPUSIBSA-N 0.000 claims 1
- 229930182470 glycoside Natural products 0.000 claims 1
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical compound [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 claims 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract description 15
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 125000002252 acyl group Chemical group 0.000 abstract 1
- FQGYCXFLEQVDJQ-UHFFFAOYSA-N mercury dicyanide Chemical compound N#C[Hg]C#N FQGYCXFLEQVDJQ-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000829 suppository Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ODJLBQGVINUMMR-UHFFFAOYSA-N Strophanthidin Natural products CC12CCC(C3(CCC(O)CC3(O)CC3)C=O)C3C1(O)CCC2C1=CC(=O)OC1 ODJLBQGVINUMMR-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000020094 liqueur Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ODJLBQGVINUMMR-HZXDTFASSA-N strophanthidin Chemical compound C1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@@]5(O)CC4)C=O)CC[C@@]32C)=CC(=O)OC1 ODJLBQGVINUMMR-HZXDTFASSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- XZTUSOXSLKTKJQ-UHFFFAOYSA-N Uzarigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C1=CC(=O)OC1 XZTUSOXSLKTKJQ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- XZTUSOXSLKTKJQ-CESUGQOBSA-N digitoxigenin Chemical compound C1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC4)C)CC[C@@]32C)=CC(=O)OC1 XZTUSOXSLKTKJQ-CESUGQOBSA-N 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008030 superplasticizer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Neue Cardenolid-amino-desoxy-glycoside Die Erfindung betrifft neue Cardenolid-amino-desoxy-glycoside der allgemeinen Formel I, in der entweder m eine Formylgruppe und B eine Hydroxylgruppe oder A eine Methylgruppe und B ein Wasserstoffatom darstellen, sowie ein Verfahren zu ihrer Herstellung.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.
Erfindungsgemäß werden die neuen Verbindungen folgendermaßen nergestellt: Umsetzung eines Gardenolids der allgemeinen Formel II, in der und B wie oben definiert sind, mit einem O-Acyl-glycosylhalogenid der allgemeinen Formel III, in der R1 einen niederen Acylrest, insbesondere den Acetylrest, und Hal ein Chlor- oder Bromatom bedeuten, und anschließende Umesterung einer erhaltenen Verbindung der Formel IV, in der R1, A und B wie oben definiert sind, mit benzylalkoholischem Ammoniak, wobei gleichzeitig die Acylreste abgespalten werden, zu einer Verbindung der Formel V, in der d und B wie eingangs definiert sind, und ansckließende Abspaltung des Dibenzylphosphorylrestes mittels katalytischer Hydrierung.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.
Die Umsetzung erfolgt in Gegenwart eines Schwermetallsalzes oder eines Schwermetalloxides vorzugsweise in einem inerten organischen Lösungsmittel, beispielsweise in Benzol, und vorzugsweise bei der Siedetemperatur des verwendeten Lösungsmittels. Hierbei wird eine lösung einer Verbindung der Formel II zweckmäßigerweise mit einer Suspension eines Schwermetallsalzes oder Scvermetalloxides, vorteilhafterweise mit Quecksilber II cyanid, versetzt und anschließend in der Siedehitze eie Lösung eines O-Acyl-glycosyl-halogenids der Formel III zugetropft.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.
Die anschließende Umesterung erfolgt bei Temperaturen zwischen -20 und +20°C, zweckmäßigerweise bei Raumtemperatur, mit mit Ammoniak bei 60c gesättigtem Benzylalkohol.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.
Die Abspaltung der Dibenzylphosphorylgruppe erfolgt durch Hydrierung in Gegenwart eines Edelmetallkatalysators, z.B.The dibenzylphosphoryl group is split off by hydrogenation in the presence of a noble metal catalyst, e.g.
211adiumkohle, in einem Lösungsmittel, beispielsweise in Methanol, vorzugsweise bei Normaldruck und Raumtemperatur.211adium carbon, in a solvent, for example in methanol, preferably at normal pressure and room temperature.
Die Ausgangsstoffe der Formeln II und III sind literaturbekannt.The starting materials of the formulas II and III are known from the literature.
So lassen sich z.B. die Ausgangsverbindungen der Formel III nach der von L.Zervas und S. Konstas (Chem.Ber. 9D, 435 (1960)) beschriebenen Methode herstellen.For example, the starting compounds of the formula III according to by L. Zervas and S. Konstas (Chem.Ber. 9D, 435 (1960)).
Dle erfindungsgemäß hergestellten neuen Herzglykoside besitzen wertvolle pharmakologische Eigenschaften, insbesondere we-isen sie eine positive inotrope Wirkung am isoliertem Meerschweinchenvorhof auf.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.
Die nachstehenden Beispiele dienen zur näheren Erläuterung der Erfindung: 1. Digitoxigenin-3-(2'-amino-2'-desoxy-ß-D-glucopyranosid) a) Digitoxigenin-3-(2'-desoxy-2'-diphenylphosphorylamino-3',4',6'-tri-O-acetyl-ß-D-glucopyranosid): 0,58 g (1,54 m Mol) Digitoxigenin werden mit 1 g (ca. 4 m Mol) Hg (CN)2 in 40 ml abs. Benzol unter Rühren zum Sieden erhitzt, 0,92 g (1,54 m Mol) 1-Brom-2,3-didesoxy-2-diphenylphosphorylamino-3,4,6-tri-O-acetyl-α-D-glucopyranose zugegeben und 5 Stunden weiter erhitzt. Danach werden noch 0,1 g Bromzucker und 0,1 g Hg (CN)2 zugegeben und weitere 4 Stunden gekocht. Nach dem Abku'hlen, bei dem bereits ein Teil des Produktes auskristallisiert, wird mit 75 ml Chloroform verdünnt, zweimal mit kalter Natriumchloridlösung und viermal mit Eiswasser gewaschen, mit Natriumsulfat getrocknet und eingedampft. Der Rückstand wird aus Benzol umkri'stallisiert.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.
Ausbeute: 1,02 g (74 %); Schmp.: 133 - 135°C. Yield: 1.02 g (74%); M.p .: 133-135 ° C.
α20D: + 6°C (c=0,5; Methanol); dünnschichtchromatographisch rein (Kieselgel, Chloroform/10 % Methanol oder Dichlormethan/ Methanol/Formamid 90:9:1). 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'-desoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranosid): 0,9 g Digitoxigenin-3-(2'-desoxy-2'-diphenylphosphorylamino-3',4',6'-tri-0-acetyl-ß-D-glucopyranosid) werden in 100 ml mit Ammoniak bei OOC gesättigtem Benzylalkohol gelöst und 70 Stunden bei Raumtemperatur aufbewahrt. Ammoniak und Benzylalkohol werden im Vakuum entfernt und der Rückstand schichtchromatographisch auf Kieselgel (Chloroform/Methanol/NH385:14:1) gereinigt. Die Hauptkomponente fällt in einer Ausbeute. von 0,5 g (66 %) in amorphem Zustand an. 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'-desoxy-ß-D-glucopyranosid) 0,68 g Digitoxigenin-3-(2'-desoxy-2'-dibenzylphosphorylaminoß-D-glucopyranosid) werden in 100 ml Methanol mit 0,3 g 10-proz. Palladiumkohle 20 Minuten hydriert. Nach Filtration wird die Phosphorsäure mit Amerlite IRA 400 OH entfernt und die Lösung eingedanpft. Das Produkt wird schichtchromatographisch gereinigt (Kieselgel, Chloroform/Methanol/NH3 80:19:1) und anschließend aus Äthanol/Äther unikristallisiert. 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.
Ausbeute: 0,37 g (81 %); Schmp.: 225 - 2270C; [α]20D: -15° (c=0,5; Methanol). Yield: 0.37 g (81%); M.p .: 225-2270C; [α] 20D: -15 ° (c = 0.5; methanol).
2. Strophanthidin-3-(2'-amino-2'-desoxy-ß-D-glucopyranosid) a) Strophanthidin-3-(2'-desoxy-2'-diphenylphosphorylamino-3',4',6'-tri-O-acetyl-ß-D-glucopyranosid): Die Umsetzung von Strophanthidin (@,46 g, 1,1 m Mol) mit 0,66 g (1,1 m Mol) Bromzucker und 0,66 g (ca. 2,6 m Mol) Hg (CN)2 erfolgt in der in Beispiel 1a beschriebenen Weise. Der nach der Aufarbeitung erhaltene Sirup wird in Äthylacetat heiß gelöst.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.
Beim Abkühlen fällt das Produkt gelartig aus (Ausb.:0,4 g), nach Zugabe von Petroläther erhält man weitere 0,04 g, insges. 50 , der theoret. Ausb..Die zweite Mutterlauge wird auf Kieselgel-Platten (PF, Merck) chromatographiert. Man erhält weitere 0,1 g Produkt und 0,05 g nicht umgesetztes Strophanthidin (Fließmittel Chloroform/Methanol 9:1). Das Produkt kann aus Äthylacetat/Methanol/Petroläther umkristallisiert werden. Schmp.: 177 - 1780C; +150; [α]20400: +36° (c=0,5; Methanol). 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'-desoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranosid): 0,31 g Strophanthidin-3-(2'-desoxy-2'-diphenylphosphorylamino-3',4',6'-tri-0-acetyl-ß-D-glucopyranosid) werden, wie in Beispiel 1b beschrieben, mit Ammoniak in Benzylalkohol umgeestert. Der erhaltene braune Sirup wird auf Kieselgelplatten in Chloroform/Methanol 8:2 schichtchromatographiert. Durch Elution der unteren Zone erhält man 0,12 g (43 ) reines, jedoch nicht kristallines Material. Die ebenfalls im W-sichtbare obere Zone ergab nach der Elution ein sehr uneinheitliches Material, das verworfen wurde. 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'-desoxy-ß-D-glucopyranosid): 1,76 g schichtchromatographisch gereinigtes Strophanthidin-3-(2'-desoxy-2'-dibenzylphosphorylamino-ß-D-glucopyranosid) werden in 200 ml 90-proz. Methanol mit 0,3 g (0-proz.- -alladium/Kohle 30 Minuten hydriert. Dabei wird die berechnete IIenge Wasserstoff aufgenommen. Nach Aufarbeitung wie in Beispiel 1 c beschrieben, erhält man 1,04 g (92 0) amorphes, schaumiges Produkt, das aus Äthanol/Äther kristallisiert (Ausb.:600 mg). Durch Schichtchromatographie der Mutterlauge (Chloroform/Methanol/Ammoniak 75:23:2) erhält. man weitere 90 mg Produkt. Die Gesamtausbeute (nach dem Umkristallisieren) beträgt 780 mg (69 %). Das reinste Produkt erhält man durch -allerdings verlustreiche- Umkristallisation aus Methanol. 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.
Schmp.: 255 - 2650C (Zers.); [α]20D: + 140; tal42000: + 390 (c=0,5; Nethanol).M.p .: 255-2650C (dec.); [α] 20D: +140; valley42000: + 390 (c = 0.5; ethanol).
Zur pharmazeutischen Anwendung können die erfindungsgemäß hergestellten Substanzen in die üblichen Präparate eingearbeitet werden. Die minimalen bzw. maximalen Einzeldosen liegen zwischen 0,125 mg und 2,00 mg. Im folgenden sind einige pharmazeutische Zubereitungsformen angegeben.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) Tabletten 1 Tablette enthält: Digitoxigenin-3-(2'-amino-2'-desoxy-B-D-glucopyranosid) 0,25 mg Milchzucker 85,75 mg Kartoffelstärke 30,0 mg Gelatine 3,0 mg Magnesiumstearat 1,0 mg 120,0 mg Herstellungsverfahren: Die Wirksubstanz wird mit der zehnfachen Menge Milchzucker intensiv verrieben. Man mischt diese Verreibung mit dem restlichen Milchzucker sowie mit Kartoffelstärke und granuliert mit einer 10%igen wässrigen Lösung der Gelatine durch Sieb 1,5 an. Trockung bei 4000. Das getrocknete Granulat wird nochmals durch Sieb 1 mm gerieben und mit Magnesiumstearat vermischt. Aus der Mischung werden Tabletten gepreßt.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.
Tablettengewicht: 120 ing Stempel: 7 mm flach mit Teilkerbe.Tablet weight: 120 ing Stamp: 7 mm flat with Dividing notch.
.B) Dragees 1 Dragéekern enthält: Strophanthidin-3-(2'-amino-2'-desoxy-ß-D-glucopyranosid 0,25 mg Milchzucker 32,25 mg Maisstärke 15,0 mg Polyvinylpyrrolidon 2,0 mg Magnesiumstearat 0,5 mg 50,0 mg Herstellungsverfahren: Die Wirksubstanz wird mit der zehnfachen Menge Milchzucker intensiv verrieben, mit dem restlichen Milchzucker sowie mit der Maisstärke gemischt und mit einer eigen wässrigen Lösung des Polyvinylpyrrolidons durch Sieb 1 mm granuliert..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.
Die bei 400C getrocknete Masse wird nochmals durch obiges Sieb gerieben, mit Magnesiumstearat gemischt und anschließend zu Dragéekernen verpreßt.The mass, dried at 400C, is rubbed through the above sieve again, mixed with magnesium stearate and then pressed into tablet cores.
Eerngewicht: 50 mg Stempel: 5 mm gewölbt.Eern weight: 50 mg Stamp: 5 mm convex.
Die so hergestellten Dragéekerne werden nach bekanntem Verfahren mit einer Hülle überzogen, die im wesentlichen aus Zucker und Talkum besteht. Die fertigen Dragees werden mit Hilfe von Bienenwachs poliert.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.
Dragéegewicht: 85 mg C) Dragees 1 Dragéekern enthält: Digitoxigenin-3-(2'-amino-2'-desoxy-B-D-glucopyranosid) 0,125 mg Milchzucker 32,375 mg Maisstärke 15,0 mg Polyvinylpyrrolidon 2,0 mg Magnesiumstearat 0,5 mg 50,0 mg Herstellungsverfahren: Die Herstellung erfolgt wie oben unter B) angegeben.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) Tropfen Zusammensetzung: 100 ml Tropflösung enthalten: Strophanthidin-3-(2'-amino-2'-desoxyß-D-glucopyranosid 0,0125 g Saccharin-Natrium 0,3 g Sorbinsäure 0,1 g Aethanol 30,0 g Herrenliköressenz (Haarm. & Reimer) 1,0 g Dest. Wasser ad 100,0 g Herstellungsverfahren: Man mischt die Lösung der Wirksubstanz und der Liköressenz in Aethanol mit der Lösung der Sorbinsäure und Saccharin in Wasser und filtriert faserfrei.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 Tropflösung enthält 0,125 mg.1 ml of dropping solution contains 0.125 mg.
E) Ampullen 1 Ampulle enthalt: Digitoxigenin-3-(2'-amino-2'-desoxyß-D-glucopyranosid) 0,25 mg Polyäthylenglykol 600 Weinsäure 150,0 mg Dest. Wasser ad 3,0 ml Herstellungsverfahren: In destilliertem Wasser werden nacheinander Weinsäure, Polyäthylenglykol und die Wirksubstanz gelöst. Man füllt mit destilliertem Wasser auf das gegebene Volumen auf und filtrlert keimfrei.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.
Abfüllung: in weiße 3 ml-Ampullen unter Stickstoffbegasung Sterilisation: 20 Minuten bei 120°C.Filling: in white 3 ml ampoules under nitrogen gas sterilization: 20 minutes at 120 ° C.
F) Suppositoren 1 Zäpfchen enthält: Strophanthidin-3-(2'-amino-2'-desoxyß-D-glucopyranosid 0,25 mg Milchzucker 4,75 mg Zäpfchenmasse (z.B. Witepsol W 45) 1 695,0 mg 1 700,0 mg Herstellungsverfahren: Die Verreibung der Wirksubstanz mit Milchzucker wird mit Hilfe eines Eintauchhomogenisators in die geschmolzene und auf 40°C abgekühlte Zäpfchenmasse eingerührt. Man kühlt auf 37°C ab und gießt in leicht vorgekühlte Formen.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.
Zäpfchengewicht: 1,7 g G) Suppositorien 1 Zäpfchen enthält: Digitoxigenin-3-(2'-amino-2'-desoxyß-D-glucopyranosid) 0,125 mg Milchzucker Zäpfchenmasse (z.B. Witepsol W 45) 1 695,0 mg 1 700,0 mg Herstellungsverfahren: Die Herstellung erfolgt wie oben unter F) angegeben.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).
Die erfindungsgemäß hergestellten neuen Verbindungen der Formel 1 können gegebenenfalls zur pharmazeutischen Anwendung mit anderen Wirksubstanzen, insbesondere mit einem Koronardilatator wie 2,6-Bis(diäthanolamino)-6,8-dipiperidino-pyrimido[5,4-d]pyrimidin, in die üblichen Präparate eingearbeitet werden.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)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691903901 DE1903901A1 (en) | 1969-01-27 | 1969-01-27 | Cardenolideaminodesoxyglycosides for use - as heart stimulants |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691903901 DE1903901A1 (en) | 1969-01-27 | 1969-01-27 | Cardenolideaminodesoxyglycosides for use - as heart stimulants |
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| Publication Number | Publication Date |
|---|---|
| DE1903901A1 true DE1903901A1 (en) | 1970-09-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19691903901 Pending DE1903901A1 (en) | 1969-01-27 | 1969-01-27 | Cardenolideaminodesoxyglycosides for use - as heart stimulants |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2351042A1 (en) * | 1973-10-11 | 1975-04-30 | Dorma Baubeschlag | Spring door stop - has holder device locking mechanism operated by solenoid |
| DE2443444A1 (en) * | 1974-09-11 | 1976-03-25 | Dorma Baubeschlag | Spring door stop - has holder device locking mechanism operated by solenoid |
| DE3521777A1 (en) * | 1984-06-22 | 1986-02-13 | Texas Instruments Italia S.p.A., Aversa, Caserta | DEVICE FOR THE CONTROL OF THE ELECTRICAL SUPPLY AND FOR THE DELAYED LOCKING RELEASE OF THE DOORS OF WASHING MACHINES AND THE LIKE. |
| WO1987004166A1 (en) * | 1986-01-09 | 1987-07-16 | Farmitalia Carlo Erba S.P.A. | Nor-cholanic acid derivatives, a process for their preparation, their use and pharmaceutical compositions containing them |
-
1969
- 1969-01-27 DE DE19691903901 patent/DE1903901A1/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2351042A1 (en) * | 1973-10-11 | 1975-04-30 | Dorma Baubeschlag | Spring door stop - has holder device locking mechanism operated by solenoid |
| DE2443444A1 (en) * | 1974-09-11 | 1976-03-25 | Dorma Baubeschlag | Spring door stop - has holder device locking mechanism operated by solenoid |
| DE3521777A1 (en) * | 1984-06-22 | 1986-02-13 | Texas Instruments Italia S.p.A., Aversa, Caserta | DEVICE FOR THE CONTROL OF THE ELECTRICAL SUPPLY AND FOR THE DELAYED LOCKING RELEASE OF THE DOORS OF WASHING MACHINES AND THE LIKE. |
| WO1987004166A1 (en) * | 1986-01-09 | 1987-07-16 | Farmitalia Carlo Erba S.P.A. | Nor-cholanic acid derivatives, a process for their preparation, their use and pharmaceutical compositions containing them |
| US4895836A (en) * | 1986-01-09 | 1990-01-23 | Farmitalia Carlo Erba S.P.A. | Nor-cholanic acid derivatives, a process for their preparation, their use and pharmaceutical compositions containing them |
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