US3745156A - Novel process for partial hydrolysis of glycosides and some products thereof - Google Patents

Novel process for partial hydrolysis of glycosides and some products thereof Download PDF

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US3745156A
US3745156A US00018337A US3745156DA US3745156A US 3745156 A US3745156 A US 3745156A US 00018337 A US00018337 A US 00018337A US 3745156D A US3745156D A US 3745156DA US 3745156 A US3745156 A US 3745156A
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D Satoh
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Shionogi and Co Ltd
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton

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  • the present invention relates to a novel process for partial hydrolysis of glycosides of 2-deoxy-sugar, and some glycosides of Z-deoxy-sugar, and preparations containing the products of the process of the present invention.
  • the process of the present invention is a selective method of hydrolysis which does not atfect on a 2-deoxyglycosyl residue when it is not present at the terminal position of the glycoside linkage.
  • the process of the present invention is a method for selective hydrolysis of glycosides having 2-deoxy-sugar unit in the molecule which is characterized (1) by increasing of sensitivity for hydrolysis of the specified sugar unit to be removed by the result of glycol cleavage reaction; (2) by providing selectivity with utilization of the fact that 2-deoxy-sugar unit which is not located at the terminal position of the glycoside linkage is not susceptible of the reaction of the process of the present invention; (3) by higher yield; (4) by unequivocal chemical procedure; and (5) by mild and easily handled reaction course.
  • the process of the present invention comprises the first step in which the glycosides are subjected to glycol cleavage reaction to afiord dialdehyde or acetals thereof, fo1- lowed by optional reduction of the product to afford dimethylol; andthe second step in which the product of the first step is subjected to hydrolysis under extremely mild condition.
  • the mild condition allows possible existence of unstable group in the other part of the molecule of the glycosides.
  • the starting materials of the process of the present invention are the glycosides of the formula:
  • X represents an oxygen containing hydrocarbon ring group
  • R and R each represents a hydrogen atom, hydroxyl group or acyloxy group
  • R represents a hydrogen atom or acyl group same or difierent for each sugar unit
  • n is an integer 1 or more.
  • oxygen containing hydrocarbon ring represented by X it is exemplified 2- and 3-furyl group and a, 18 and 'y-butenolide residue, butanolide group and the like.
  • acyl group represented by R and that of acyloxy group represented by R and R there is exemplified alkanoyl groups e.g.
  • haloacetyl glycyl, lactyl, hemisuccinyl, phenylpropionyl, cinnamoyl, optionally substituted phenoxyacetyl, etc.; optionally substituted aromatic acyl groups e.g. benzoyl, nitro-benzoyl, methoxybenzoyl, methylbenzoyl, halobenzoyl, naphthalincarbonyl, nicotinyl, furoyl, and the like; or
  • inorganic acyl groups e.g. carbonic, sulfuric, phosphoric acyl groups and the like.
  • the first step of the process of the present invention comprises glycol cleavage of the starting materials mentioned above at the terminal sugar unit, followed by optional reduction.
  • the reaction of the first step is represented by the reaction scheme:
  • the said gly l cleavi g gent may be chromic a id
  • Th'e cleaving agents are used in various solvents.
  • they may be hydrocarbons e.g.
  • lead tetraacetate is used in non-polar solvents and periodic acid and periodates are used in polar solvents. If required, other solvents may be added thereto in order to dissolve the reactants.
  • one of the product, salts of iodic acid separates as crystals in the medium and may be removed by mere filtration.
  • Bases may be added to the reaction medium to neutralize acidic product.
  • the reaction may be carried out at lowered or elevated temperatures.
  • the amount of the glycol cleaving agent to the starting material are preferably one to five mole equivalents, although more reagent may be used without wrong results.
  • the products are isolated in per se conventional methods e.g. dilution, concentration, extraction, filtration, etc., and are purified by conventional methods e.g. recrystallization, chromatography, etc.
  • the products may be subjected to the process of the next step without further purification.
  • the products thus obtained are dialdehyde of the partial Formula 2 or acetals thereof e.g. those represented by Formulae 3 and 4.
  • the said reducing agents for optional following reduction are those capable of reducing dialdehyde of the partial Formula 2 or acetals thereof represented by e.g. partial Formulae 3 and 4 to give dimethylol of the partial Formula 5, provided that they do not exert irreversible changes in the other part of the substrate molecule.
  • Representatives of preferable reducing agents for the process are metal hydrides, for example boron hydride compounds e.g.
  • potassium borohydride sodium borohydride, lithium borohydride, alkylboron hydrides, boron hydride, pyridine borane, alkylamine boranes, etc.
  • aluminum hydride complexes e.g. lithium aluminum hydride, lithium alkylaluminum hydrides, lithium alkoxyaluminum hydrides, sodium aluminum hydride, alkylaluminum hydrides, alkoxyaluminum hydrides, etc.
  • catalytic hydrogenations over various catalysts e.g.
  • cobalt-copper chromite cobalt-copper chromite, ruthenium-charcoal, palladium charcoal, palladium calcium carbonate, etc., Meerwein-Pondorf reduction, Meerwein-Schmidt reduction, and the like.
  • the reduction may be carried out in a solvent e.g. hydrocarbons, halogenated hydrocarbons, ethers, alcohols, esters, carboxylic acids, bases, water, etc., at elevated or lowered temperature.
  • Optional character of reduction in the process of the present invention necessitates amount of the reducing agent used over a range from zero to one mole equivalent or more. Preferable result is obtained when the reducing agent is one to ten mole equivalents of e.g. sodium borohydride.
  • the products thus prepared may be isolated in per se conventional methods e.g. decomposition of adduct, precipitation by addition of insoluble solvents, filtration, dilution, extraction, washing, drying, evaporation of $01- vents, absorption, elution, etc., or their combination.
  • alternate process through reduction is in effect equivalent to direct hydrolysis of the dialdehyde (2) or acetals thereof e.g. compounds of partial formulae 3 and 4, and has superiority to the latter in that the former shows less or acetals thereof e.g. (3) or (4) fl-elimination CH and/or hydrolysis of acetals
  • the dialdehyde (2) or acetals thereof e.g. (3) and (4), and the dimethylol (5) are hydrolyzed by action of various hydrolyzing agents more smoothl than the corresponding 2-nor compounds derived from 2-hydroxylated sugar units.
  • the known methods applying the methods to Z-hydroxylated sugar require carrying out the reaction under stronger condition than that of the process of this invention.
  • the hydrolysis condition of Goldstein is 0.1-0.5 N hydrochloric acid for 6-8 hours at room temperature; that of Du-gan is heating with 5% potassium hydroxide; and that of Kubota (Tetrahedron, vol. 24, page 675 (1968)) is refluxing with 3% potassium hydroxide in ethanol for 1 hour and refluxing at 60 C. with 0.1% toluene-p-sulfonic acid in dioxane for 30 minutes.
  • sensitive groups e.g. 2- deoxy-sugar units, 14-hydroxyl group, 17-unsaturated oxa ring, etc., showed various irreversible changes e.g.
  • the reactivity of the compounds to hydrolysis are in the order dimethylol, dialdehyde and dimethylol diacetate from higher to lower. From these data, it is concluded that in the case of dirnethylol, some participation of free neighbouring hydroxyl group to reaction center is occurring. Higher reactivity of dialdehyde over dimethylol diacetate is presumed to :be result of existence of carbonyl group at ,B-position from the reaction center to be hydrolyzed.
  • the said hydolysis of this step may be eifected by the action of a reagent capable of decomposition of acetals recovering constituent alcohols.
  • the reagent for reaction of this step may be acids, bases or other reagents of equivalent effect e.g.
  • the said acids may be an acid ranging from weak acids e.g. phenols, aromatic or aliphatic carboxylic acids, silica gel, acid salts e.g. sodium hydrogen sulfate, pyridine sulfate, ammonium chloride, etc., to strong acids e.g. hydrochloric acid, nitric acid, phosphoric acid, perchloric acid, etc.
  • the said bases may be bases ranging from weak bases e.g.
  • alumina calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydrogen carbonate, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, pyridine, trialkylamines, etc., to strong bases e.g. potassium hydroxide, sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, etc.
  • the said carbonyl reagents may be hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, carbazide, hydroxylamine, and the like. These reagents for hydrolysis may be brought into contact with the starting materials of this step in the presence hydrolysis of H of a solvent e.g.
  • Pretera-ble concentration of the acids or bases may be 00001- 30% to the solvents.
  • Preferable results have been obtained in the case of 0.1-0.0001 N mineral acid or treatment in an acidic medium of pH 1-4 at room temperature for 0.5 to 48 hours. Higher temperature may shorten the reaction period.
  • the products of this step may be obtained by a conventional method e.g. precipitation, filtration, dilution, extraction, washing, drying, absorption, elution, and the like or combinations thereof, followed by optional purification by e.g. chromatography, recrystallization, etc.
  • preferable results have been obtained in the cases of hydrolysis of the compounds of the partial Formula 2 with acids, bases or ketone reagents, and in the cases of hydrolysis of the compounds of the partial Formula 5 with acids.
  • the compounds prepared by the process of the present invention are the compounds of the formula:
  • the first eight compounds cited above are literary 'known compounds of higher cardiotonic activity, but because of complexed process of preparation, they have not been utilized for practical purposes.
  • the latter eight compounds and esters thereof are novel, safe, mild and strong cardiotonic duretic compounds of the present invention. Both of them are useful as pharmaceutical agent in the treatment of heart diseases for human or veterinary use, in the forms of pharmaceutical composition containing an elfective amount of the compounds and a pharmaceutically acceptable carrier.
  • novel compounds of the present invention are represented by the general formula:
  • R and R each represents a hydrogen atom or hydroxyl group and at least one of R and R is hydroxyl; n' represents an integer l or 2, and lower alkanoates thereof.
  • the aglycone part of these compounds is a group derived from 175-( 3-furyl)-55,14,8-androstane-3fl,12,8,14- triol, 17fl-(3-furyl)-5 8,14fi-androstane-3p,14,16,3-triol or 17p-(3-furyl) 5,8,14/3 androstanefip,12p,14,16fi-tetrol by removing a hydrogen atom from the hydroxyl group at position 3.
  • the sugar part of these compounds is ,B-D- digitoxosyl group or 4-O-(B-D-digitoxosyl) 5 -D-digitoxosyl group.
  • These compounds can be prepared from the corresponding 3,8 tridigitoxosyloxy-17B-(3-furyl)6B, l4p-androstane compounds disclosed in the US. Pat. No. 3,432,486 or 3,8- bisdigitoxosyloxy 17,8-(S-furyl)-5fl,14,B-androstane compounds of this invention by removing one or two digitoxosyl group according to the process of this invention or other methods e.g. Kaiser et a1. cited above.
  • They may also be prepared from the corresponding cardenolide hisor mono-digitoxoside by reduction of butenolide ring to furan ring with action of reducing agent capable of converting butenolide to furyl group such as active aluminum hydride compounds e.g. dialkylaluminum hydrides, lithium dialkylaluminum hydride, etc.
  • active aluminum hydride compounds e.g. dialkylaluminum hydrides, lithium dialkylaluminum hydride, etc.
  • the compounds of the present invention have valuable pharmacological activities. For example, they have strong digitaloid cardiotonic activity. They show inotropic efiect, chronotropic effect, arrhythmia and finally contractile arrest of heart. They increase contractile amplitude of isolated guinea pig atria, isolated rabbit hearts and pigeon hearts, and show electro-cardiogram specific to digitaloid agents, bradycardia, retardation of heart rate, heart fibrillation when tested on pigeon.
  • the Table I shows results of assay on cardiotonoic activity of two of the compounds. Furthermore,
  • the compound is mixed with gum arabicum and powdered finely.
  • the mixture is mixed with Water to make uniform suspension being 5% gum arabicum suspension.
  • the suspension is administered orally to pigeons and median lethal dosis (LDao) is calculated. The results are represented by mg. per kg. body weight.
  • a method of Japanese Pharmacopoeia VII, United States Pharmacopoeia XVI, etc., for assay of digitalis preparations A solution of the compound in ethanol is diluted with suilicient volume of isotonic sodium chloride solution and the resulted solution is injected repeatedly into alar vein of pigeon through cannula at a dose of 1 ml./kg. for each injections, until the pigeon dies of cardiac arrest. The results are represented by mg. per kg. body weight.
  • guinea pig atria up to 200 Some of the compounds showed other pharmacological or physiological activities, for example, antiviral activity and cytotoxic activity in vitro, diuretic activity, respiration stimulating activity and anti-deoxycorticosterone activty.
  • the compounds of the present invention have cardiotonic activity as active as or stronger than digitoxin and corresponding butenolide derivatives. They are stronger than the corresponding tridigitoxosides. Their lethal doses are higher than the butenolide compounds. In other words, their side effects are weaker than corresponding butenolide compounds. The main efiects progress more rapidly than digitoxin but much slower than strospeside. The side effects disappeared more rapidly than the corresponding triglycosides or lactone compounds. Moreover, the appearance of the cardiotonic eifect is mild and general appearances of animals administered with the compounds are mild and preferable. They can be administered orally or they can be absorbed through intestine.
  • Digitoxin the most practical but severe cardiotonic glycoside, tend to accumulate in the body of patient.
  • Other compounds e.g. gitoxin esters tend to show more individual difference of eifects and side effects due to possible hydrolysis in the body.
  • the compounds of the present invention overcome these insufiiciency of the known compounds. As the com pounds can be prepared in three steps process from abundant glycoside of digitalis plants, they are suitably produced in large amounts. Further they are more soluble in various pharmaceutically acceptable solvents than the corresponding lactone compounds or tridigitoxosides. These features show that the compounds of the present invention are strong, safe and mild cardiotonic agents which are easily preparable and suitable for clinical usage.
  • Aforementioned activities show the compounds of the .present invention is useful for its pharmacological activtive heart, acute heart hyposthenia, tonus disorder or the like, in a daily dosis of 0.1 ,ug. to 10 mg. per kilogram body Weight for human and veterinary use.
  • the content of the compounds in drugs are preferably uniform to make a unit dose tablet, pills, capsules or the like to use as maintenance dosis and/or saturation or digiralization.
  • the preparations containing the compounds may also be used as diuretic agents for treatment of some symptoms caused by heart diseases and as respiration stimulating agents in some special cases.
  • These compounds may be utilized in a wide variety of oral or parenteral dosage forms, solely or in admixture with other co-acting compounds. They can be administered with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended.
  • a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended.
  • the solid compositions can take the form of tablets, powders, granules, capsules, pills or the like.
  • the liquid composition may take the form of injections, suspensions, solutions, emulsions, syrups or elixirs. The tablets and granules may be coated.
  • EXAMPLE 1 (A) To a stirred solution of 1 g. of digitoxin in 80 ml. of 95 ethanol is added 1 g. of sodium periodate in 10 ml. of water. After 1 hour, the reaction mixture is filtrated to remove solid material and the filtrate is concentrated at temperature lower than 50 C. The concentrate is extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The white powdery residue of dialdehyde shows single spot on thin-layer chromatogram and amounts 0.99 g.
  • ELAMPLE 2 To a stirred solution of 1 g. of digoxin in a mixture of 20 ml. of chloroform and 60 ml. of methanol is added 10 ml. of aqueous solution of 10% sodium periodate dropwise and stirred for another 1.5 hours at room temperature. The reaction mixture is filtrated to remove solid material and the filtrate is diluted with 10 ml. of water, evaporated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water and dried over anhydrous sodium sulfate and evaporated to leave 1.0 g. of crude dialdehyde. The crude dialdehyde is dissolve in ml. of 95% methanol an mixed with 500 mg.
  • EXAMPLE 3 (A) To a stirred solution of 1 g. of gitoxin in 250 ml. of a mixture of chloroform and methanol (1:1) is added to a solution of 1 g. of sodium periodate in ml. of water at room temperature, and the resulting mixed solution is kept at room temperature for 2 hours. The reaction mixture is filtrated to remove solid material, concentrated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue amounted 980 mg. which reduced Tollen reagent and showed single spot of dialdehyde on thin-layer chromatogram.
  • UV 1553 219 nm. (0 15,300).
  • IR 5359 3500, 1785, 1740, 1030, 1625 cm.-
  • EMMPLE 4 According to a process similar to that of Example 2, diginatin is oxidized with sodium periodate to afford dialdehyde, followed by reduction with sodium borohydride and hydrolysis with diluted hydrochloric acid giving diginatigenin-bis-digitoxoside.
  • EXAMPLE 5 To a solution of mg. of digitoxin-3'-acetate in 8 ml. of 95 ethanol is added 140 mg. of sodium periodate in 1.4 ml. of water, and the mixture is kept at room temperature for 2 hours. The reaction mixture is filtered to remove solid material, concentrated to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to leave 140 mg. of white powdery dialdehyde which reduced Tollen reagent and showed characteristic signal at 0.30T in its nmr. spectrum. A solution of 140 mg. of the crude dialdehyde in 20 ml. of methanol is mixed with 3 ml.
  • EXAMPLE 7 To a solution of 150 mg. of digitoxigenin-bis-digitoxoside in 10 ml. of 95% ethanol is added a solution of 150 mg. of sodium periodate in 2 ml. of water, and the mixture is kept at room temperature for 1 hour. The reaction mixture is filtered to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thin-layer chromatogram and reduced Tollen reagent. The dialdehyde (150 mg.) dissolved in 15 ml. of 95 methanol is mixed with 75 mg.
  • the reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform.
  • the extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromato gram and did not reduce Tollen reagent.
  • the crude dimethylol (135 mg.) dissolved in 12 ml. of methanol is mixed with 1.8 ml. of 0.05 N hydrochloric acid and kept at room temperature for 2 hours.
  • the reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove volatile solvent, and then extracted with chloroform.
  • EXAMPLE 8 To a solution of 50 mg. of digoxigenin-bisdigitoxoside in 3 ml. of 95% ethanol is added a solution of 50 mg. of sodium periodate in 0.5 ml. of water, and the mixture is kept at room temperature for 1 hour. The reaction mixture is filtrated to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thinlayer chromatogram and reduced Tollen reagent. The crude dialdehyde (52 mg.) dissolved in 3 ml. of 95% methanol is mixed with 10 mg.
  • the reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform.
  • the extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromatogram and did not reduce Tollen reagent.
  • the crude dimethylol (45 mg.) dissolved in 2 ml. of methanol is mixed with 0.5 ml. of 0.05 N hydrochloric acid and kept at room temperature for 1 hour.
  • the reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove volatile solvent and then extracted with chloroform.
  • EXAMPLE 9 To a solution of 250 mg. of gitoxigenin-bisdigitoxoside in 20 ml. of 95 ethanol is added a solution of 250 mg. of sodium periodate in 2.5 ml. of water, and the mixture is kept at room temperature for 1.5 hour. The reaction mixture is filtrated to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thin-layer chromatogram and reduced Tollen reagent. The crude dialdehyde (250 mg.) dissolved in 20 ml. of methanol is mixed with 125 mg.
  • the reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform.
  • the extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromatogram and did not reduce Tollen reagent.
  • the crude dimethylol (230 mg.) dissolved in 20 ml. of methanol is mixed with 3.5 ml. of 0.05 N hydrochloric acid and kept at room temperature for 2 hours.
  • the reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove the volatile solvent and then extracted with chloroform.
  • UV age 212 nm. (6 5,280).
  • IR #355 3500-3600 cm.-
  • EXAMPLE 11 remove solid material, diluted with 20 ml. of water, evaporated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to obtain 44 mg. of crude dialdehyde. A solution of 43 mg. of the crude dialdehyde in 3 ml. of 95% methanol is mixed with 20 mg. of sodium borohydride and the mixture is kept at room temperature for 1 hour. The reaction mixture containing crude dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.8 to thymol blue test paper.
  • the extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to obtain 909 mg. of crude dialdehyde.
  • a solution of 900 mg. of the crude dialdehyde in 80 ml. of 95% methanol is mixed with 80 mg. of sodium borohydride and the mixture is kept at room temperature for 1 hour.
  • the reaction mixture containing crude dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.8 to thymol blue test paper. After stirring for 4 hours under nitrogen atmosphere, the solution is neutralized With 5% sodium hydrogen carbonate, concentrated and extracted with chloroform.
  • the extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.
  • extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent to have 103 mg. of crude dialdehyde.
  • the crude dialdehyde is dissolved in 8 ml. of methanol, mixed with 15 mg. of sodium borohydride, and stirred for 0.5 hour at room temperature.
  • the reaction mixture containing dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.4 and kept at room temperature for 3 hours. Then the mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate to pH 7.0, diluted with water, evaporated to remove volatile solvent and extracted with chloroform.
  • the extract solution is washed with water, dried over anyhdrous sodium sulfate and evaporated to remove the solvent.
  • the crude dialdehyde is dissolved in 12 ml. of 95 methanol, mixed with 20 mg. of sodium borohydride, and stirred for 1.5 hours at room temperature.
  • the reaction mixture containing dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.6 and kept at room temperature for 4 hours. Then the mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate to pH 7. 0, diluted with water, evaporated to remove volatile solvent and extracted with chloroform.
  • the extract solution is washed twice with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 106 mg.
  • EXAMPLE 15 To a solution of mg. of digitoxigenin-mono-digitoxoside in 2 ml. of dry tetrahydrofuran cooled at from -20 C. to 25 C. under nitrogen atomsphere is added dropwise 1.20 ml. of a solution of di-isobutylaluminum hydride in tetrahydrofuran (208 mg./ml.). After 45 minutes, the reaction mixture is mixed with 3 m1. of 2 N-sulfuric acid and stirred for 15 minutes at 0 C., and then is extracted with chloroform. The extract solution is.
  • To a stirred solution of 300 mg. of gitoxigenin-bisdigitoxoside in 5 ml. of tetrahydrofuran is added 1.58 ml. of di-isobutylaluminum hydride in dry tetrahydrofuran (1.1 mole equivalent) at 25 C. under nitrogen atmosphere. After 30 minutes, 5 ml. of 2 N sulfuric acid is added into the reaction mixture, and the mixture is stirred under icecooling for minutes, and then the resultant solution is extracted with chloroform.
  • EXAMPLE 18 To a solution of 400 mg. of digitoxin in 20 ml. of dioxane is added 500 mg. of lead tetraacetate, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is filtrated to remove solid material and the filtrate is diluted with 10 ml. of water. The diluted filtrate is evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 358 mg.
  • Example 1(A) The dialdehyde obtained above is dissolved in 95% ethanol and mixed with 10 mg. of sodium borohydride. After 1 hour, the mixture is acidified to pH 2.4 to thymol blue test paper with 1 N sulfuric acid and kept at room temperature for 30 minutes. The reaction mixture is neutralized with 0.1 N sodium carbonate solution, evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.
  • EXAMPLE 19 To a solution of 100 mg. of digitoxin in 4 ml. of chloroform and 4 ml. of carbon tetrachloride cooled at 0 C. is added 100 mg. of powdered ruthenium tetroxide. After 30 minutes stirring, the mixture is mixed with a small amount of methanol, and filtrated to remove solid material. The filtrate is evaporated to dryness to leave 99 mg. of the residue identical with dialdehyde obtained by the process of Example 1(A). The dialdehyde is dissolved in 1 ml. of ethanol, mixed with 8 mg. of sodium borohydride and the mixture is kept at room temperature for 0.5 hour.
  • the reaction mixture containing crude dimethylol is acidified to pH 3.5 to thymol blue test paper with 0.1 N sulfuric acid. After 3 hours, the reaction mixture is neutralized with 5% sodium hydrogen carbonate, concentrated and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue by thin-layer chromatography and recrystallization gives 73 mg. of digitoxigenin-bisdigitoxoside, M.P. 228-230 C. Yield: 89%.
  • EXAMPLE 20 To a solution of 100 mg. of digitoxin in 5 ml. of acetic acid is added 1 ml. of water and 500 mg. of powdered sodium bismuthate. After shaking for 3 hours at room temperature, the mixture is filtered to remove the solid material. The solid material is washed thoroughly with ethyl acetate. Mixture of the filtrate and Washed solvent is evaporated to dryness. The residue is treated with sodium borohydride and diluted sulfuric acid according to the process of Example 1(B-4) to aiford 70 mg. of digitoxigenin-bisdigitoxoside, M.P. 228230 C. Yield: 85%.
  • EXAMPLE 22 A mixture of 9 mg. of 3,3[4-0-(,3-D-digitoxosyl)-fl-D- digitoxosyfloxy 17/3 (3 furyl)-5fl,l4j3-androstane-14, 16B-diol, 0.5 ml. of pyridine and 0.5 m1. of acetic anhydride is kept at room temperature for 5 days. The reaction mixture is poured onto iced water and extracted with chloroform. The extract solution is washed successively with water, aqueous sodium carbonate solution and diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 12 mg.
  • EXAMPLE 23 A tablet is prepared in conventional manner from 0.2 mg. of 3p [4-0-(p-D digitoxosyl)-fl-D-digitoxosyl]oxy- (3-furyl)-5p, l4fi-androstane-14-16y3-diol, 50 mg. of starch and a small amount of magnesium stearate. Six tablets per day for saturation or two tablets per day for maintenance dosage are given to a patient.
  • EXAMPLE 25 wherein X is a furyl, butenolide, or butanolide group; R and R each represents a hydrogen atom; hydroxyl; lower alkanoyloxy; lower alkenoyloxy; lower alkanoyloxy or lower alkenoyloxy substituted by halogen, hydroxy, phenoxy, amino, phenyl, or carboxy; benzoyloxy; naphthalenecarbonyloxy; nicotinoyloxy; furoyloxy; benzoyloxy substituted by halogen, methoxy, nitro, or methyl; or acyloxy group derived from carbonic, sulfuric or phosphoric acid; R is a hydrogen atom; lower alkanoyl; lower alkenoyl; lower alkanoyl or lower alkenoyl substituted by halogen, hydroxy, phenoxy, amino, phenyl, or carboxy; benzoyl; naphthalenecarbonyl; nicotiny
  • a base selected from alumina, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydrogen carbonate, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, pyridine, trialkylamines, potassium hydroxide, sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, or with a carbonyl reagent selected from hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, carbazide, and hydroxylamine.
  • potassium hydroxide sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, or with a carbonyl reagent selected from hydrazine, phenyl-hydrazine, 2,4- dinitriphenylhydrazine, carbazide, and hydroxylamine.
  • glycol cleaving agent is one to five mole equivalents of periodic acid, periodates or lead tetraacetate.

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Abstract

METHOD FOR SELECTIVE PARTIAL HYDROLYSIS OF STEROID GLYCOSIDES OF 2-DEOXY-SUGAR UNITS, WHICH COMPRISES REACTING GLYCOL CLEAVING AGENTS FOLLOWED BY OPTIONAL REDUCTION AND MILD HYDROLYSIS, CARDIOTONIC COMPOUNDS OF THE FORMULA:

17-(FUR-3-YL),16-R,12-R'',14-HO,3-(H-(O-(4-HO,6-CH3-TETRA-

HYDROPYRAN-5,2-YLENE))N''-O-)ANDROSTANE

WHEREIN R AND R'' EACH REPRESENTS A HYDROGEN ATOM OR HYDROXYL GROUP AND N'' IS AN INTEGER OF 1 OR 2, AND ESTERS THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS OR PRODUCTS OF THE PROCESS OF THE PRESENT INVENTION.

Description

United States Patent NOVEL PROCESS FOR PARTIAL HYDROLYSIS 0F GLYCOSIDES AND SOME PRODUCT THEREOF Daisuke Satoh, Nishinomiya, Japan, assignor to Shionogi & Co., Ltd., Osaka, Japan N0 Drawing. Filed Mar. 10, 1970, Ser. No. 18,337 Claims priority, application Japan, Mar. 19, 1969, 44/20,994 Int. Cl. C07c 173/00 US. Cl. 260-2105 8 Claims ABSTRACT OF THE DISCLGSURE Method for selective partial hydrolysis of steroid glycosides of 2-deoxy-sugar units, which comprises reacting glycol cleaving agents followed by optional reduction and mild hydrolysis, cardiotonic compounds of the formula:
compounds or products of the process of the present invention.
The present invention relates to a novel process for partial hydrolysis of glycosides of 2-deoxy-sugar, and some glycosides of Z-deoxy-sugar, and preparations containing the products of the process of the present invention.
The process of the present invention is a selective method of hydrolysis which does not atfect on a 2-deoxyglycosyl residue when it is not present at the terminal position of the glycoside linkage.
Numerous reports are found on the selective hydrolysis of glycosides of 2-deoxy-sugar. Representatives of them include report of A. Stoll (Helvetica Chimica Acta, vol. 18, 120 (1935)) which describes selective enymatic hydrolysis of digilanides to remove glucose unit from the glycoside chain; and reports of F. Kaiser et a1. (Annalen der Chemie, vol. 603, page 75 (1957)) which describes non-selective acid hydrolysis of cardenolide tridigitoxosides with acids followed by repeated tedious partition chromatography. However, these methods are insuflicient for'preparative or industrial use, because of their nonselectiveness, lower yield, complexed techniques, large volume of reaction mixture, similarity of physical constants of the products and other many deficiencies to be cited. In the course of investigation of acetates of digitoxin and gitoxin, the present inventor intended to determine which of the hydroxyl group in the glycosides were acetylated. He should remove sugar residue one by one from terminal and he conceived to use the glycol cleavage reaction for this purpose in order to increase selectivity to hydrolysis of the residue to be removed. He then extended the method to a general procedure for selective hydrolysis of the glycosides containing 2-deoxy-sugar units as the sugar moiety.
The process of the present invention is a method for selective hydrolysis of glycosides having 2-deoxy-sugar unit in the molecule which is characterized (1) by increasing of sensitivity for hydrolysis of the specified sugar unit to be removed by the result of glycol cleavage reaction; (2) by providing selectivity with utilization of the fact that 2-deoxy-sugar unit which is not located at the terminal position of the glycoside linkage is not susceptible of the reaction of the process of the present invention; (3) by higher yield; (4) by unequivocal chemical procedure; and (5) by mild and easily handled reaction course.
Methods for hydrolysis of glycosides by way of similar reaction techniques are presented in some of the known literatures, e.g. F. Smith et al.: Journal of the American Chemical Society, vol. 81, page 2176 (1959); E. L. Jackson and C. S. Hudson: Journal of the American Chemical Society, vol. 58, page 378 (1946); I. J. Goldstein et al.: Methods in Carbohydrate Chemistry, vol. V, page 361 (1965); E. L. Jackson: Organic Reactions, vol. H, page 341 (1944); Dugan: Canadian Journal of Chemistry: vol. 43, page 2033 (1965); P. P. Regna: Journal of the American Chemical Society, vol. 69, page 246 (1947); and reference cited in these literatures. These methods however do not relate to glycosides of 2-deoxy-sugars and further they direct to degradative hydrolysis of glycosides resistant to normal hydrolysis conditions. Hence, the reaction conditions are rather drastic and there is no intention for selective hydrolysis in respect of the sugar units. In other words, the present invention is an extension of these methods into the field of 2-deoxy-sugar and to the field of cardenolide glycosides and their analogues.
The process of the present invention comprises the first step in which the glycosides are subjected to glycol cleavage reaction to afiord dialdehyde or acetals thereof, fo1- lowed by optional reduction of the product to afford dimethylol; andthe second step in which the product of the first step is subjected to hydrolysis under extremely mild condition. The mild condition allows possible existence of unstable group in the other part of the molecule of the glycosides.
The starting materials of the process of the present invention are the glycosides of the formula:
wherein X represents an oxygen containing hydrocarbon ring group, R and R each represents a hydrogen atom, hydroxyl group or acyloxy group, R represents a hydrogen atom or acyl group same or difierent for each sugar unit and n is an integer 1 or more.
As for the oxygen containing hydrocarbon ring represented by X, it is exemplified 2- and 3-furyl group and a, 18 and 'y-butenolide residue, butanolide group and the like. As for the acyl group represented by R and that of acyloxy group represented by R and R there is exemplified alkanoyl groups e.g. formyl, acetyl, propionyl, butyryl, enanthoyl, stearoyl, trimethylacetyl, tert-butylacetyl, cyclohexylcarbonyl, apocamphane-l-carbonyl, adamantanecarbonyl, cyclopentanealkanoyl, and the like; unsaturated aliphatic acyl groups e.g. crotonyl, ethynylacetyl, and the like; substituted aliphatic acyl groups e.g. haloacetyl, glycyl, lactyl, hemisuccinyl, phenylpropionyl, cinnamoyl, optionally substituted phenoxyacetyl, etc.; optionally substituted aromatic acyl groups e.g. benzoyl, nitro-benzoyl, methoxybenzoyl, methylbenzoyl, halobenzoyl, naphthalincarbonyl, nicotinyl, furoyl, and the like; or
inorganic acyl groups e.g. carbonic, sulfuric, phosphoric acyl groups and the like.
Representatives of the starting materials of the process of the present invention involve:
digitoxin,
digoxin,
gitoxin,
diginatin,
digitoxigenin-bisdigitoxoside,
digoxigeuin-bisdigitoxoside,
gitoxigenin-bisdigitoxoside,
diginatigenin-bisdigitoxoside,
3p-(p-D-digitoxosyl-p-D-digitoxosyl-B-D-digitoxosyl) oxy-17,8(3-furyl)-5;8,14,3-androstane-l2,8,14,16,8-triol,
3/3- [4-O-(B-D-digitoxosyl) -fi-D-digitoxosyl] oxy- 17 8- (3-furyl) -5/3, 14B-androstane-l2fi,l4-diol,
3/3-[4-0-(fi-D-digitoxosyl)-p-D-digitoxosyl] -oxy-17fl- (3-furyl) -5/3,14 8-androstane-14,16,8-diol,
and esters thereof with the proviso that the terminal digitoxose residue has two free hydroxyl groups.
The first step of the process of the present invention comprises glycol cleavage of the starting materials mentioned above at the terminal sugar unit, followed by optional reduction. The reaction of the first step is represented by the reaction scheme:
CH3 CH3 1 l g 3 T O cleaving HO- 1 agent A H CH on,
0 and/or OHC 0H0 OH (dialdehyde) (2) CH2 i Q 0 0 and/or OHC I OH: /O
CHOH (3) isolated reducing agent OIIC-CHz o and indentified (optionally) CE (g I CHa-CH-CHOH (4) CH3 CH3 -0 HO CH3 /0 (dlmethyol) HOCH2 The compound of the partial Formula 1 react with glycol cleaving agents more smoothly than the corresponding Z-hydroxylated sugar compounds. The products are dialdehyde (2) and acetals thereof represented e.g. by the partial Formulae 3 and 4. The dialdehyde (2) as well as acetals thereof are reduced to dimethylol (5) by the action of ordinary reducing agent in high yield.
The said gly l cleavi g gent may be chromic a id,
permanganates, nitric acid, persulfuric acid, cupric hydroxide, bismuthates, manganese acetate, iodosobenzene alkanoates, osmium tetra-oxide, ruthenium tetroxide, lead tetraacetate, periodates, periodic acid and the like, in which lead tctraacetate, periodic acid and periodates are preferable. Th'e cleaving agents are used in various solvents. For example, they may be hydrocarbons e.g. petroleum benzine, petroleum ether, heptane, hexane, benzene, toluene, xylene, cyclohexane, etc.; halogenated hydrocarbons e.g. carbon tetrachloride, chloroform, methylene chloride, dichloroethane, tetrachloroethane, etc.; ethers e.g. diethyl ether, methyl butyl ether, tetrahydrofuran, tetrahydropyran, dioxane, ethylene glycol ethers, etc.; esters e.g. ethyl acetate, butyl acetate, etc.; ketones e.g. acetone, methyl eth'- yl ketone, cyclohexanone, etc.; alcoh'ols e.g. methanol, ethanol, butanol, octanol, etc.; carboxylic acids e.g. acetic acid, propionic acid, formic acid, etc.; bases e.g. pyridine, collidine, quinoline, etc.; and other solvents e.g. dimethylformamide, dimethylsulfoxide, water, etc., and mixture thereof. Generally, lead tetraacetate is used in non-polar solvents and periodic acid and periodates are used in polar solvents. If required, other solvents may be added thereto in order to dissolve the reactants. In the cases of periodates or periodic acid being used as the glycol cleaving agent and the solvent used being dilute alcohol, one of the product, salts of iodic acid separates as crystals in the medium and may be removed by mere filtration. Bases may be added to the reaction medium to neutralize acidic product. The reaction may be carried out at lowered or elevated temperatures. The amount of the glycol cleaving agent to the starting material are preferably one to five mole equivalents, although more reagent may be used without wrong results. The products are isolated in per se conventional methods e.g. dilution, concentration, extraction, filtration, etc., and are purified by conventional methods e.g. recrystallization, chromatography, etc. The products may be subjected to the process of the next step without further purification. The products thus obtained are dialdehyde of the partial Formula 2 or acetals thereof e.g. those represented by Formulae 3 and 4. The said reducing agents for optional following reduction are those capable of reducing dialdehyde of the partial Formula 2 or acetals thereof represented by e.g. partial Formulae 3 and 4 to give dimethylol of the partial Formula 5, provided that they do not exert irreversible changes in the other part of the substrate molecule. Representatives of preferable reducing agents for the process are metal hydrides, for example boron hydride compounds e.g. potassium borohydride, sodium borohydride, lithium borohydride, alkylboron hydrides, boron hydride, pyridine borane, alkylamine boranes, etc., aluminum hydride complexes e.g. lithium aluminum hydride, lithium alkylaluminum hydrides, lithium alkoxyaluminum hydrides, sodium aluminum hydride, alkylaluminum hydrides, alkoxyaluminum hydrides, etc., catalytic hydrogenations over various catalysts e.g. cobalt-copper chromite, ruthenium-charcoal, palladium charcoal, palladium calcium carbonate, etc., Meerwein-Pondorf reduction, Meerwein-Schmidt reduction, and the like. The reduction may be carried out in a solvent e.g. hydrocarbons, halogenated hydrocarbons, ethers, alcohols, esters, carboxylic acids, bases, water, etc., at elevated or lowered temperature. Optional character of reduction in the process of the present invention necessitates amount of the reducing agent used over a range from zero to one mole equivalent or more. Preferable result is obtained when the reducing agent is one to ten mole equivalents of e.g. sodium borohydride. The products thus prepared may be isolated in per se conventional methods e.g. decomposition of adduct, precipitation by addition of insoluble solvents, filtration, dilution, extraction, washing, drying, evaporation of $01- vents, absorption, elution, etc., or their combination. The
alternate process through reduction is in effect equivalent to direct hydrolysis of the dialdehyde (2) or acetals thereof e.g. compounds of partial formulae 3 and 4, and has superiority to the latter in that the former shows less or acetals thereof e.g. (3) or (4) fl-elimination CH and/or hydrolysis of acetals The dialdehyde (2) or acetals thereof e.g. (3) and (4), and the dimethylol (5) are hydrolyzed by action of various hydrolyzing agents more smoothl than the corresponding 2-nor compounds derived from 2-hydroxylated sugar units. The known methods applying the methods to Z-hydroxylated sugar require carrying out the reaction under stronger condition than that of the process of this invention. For example, the hydrolysis condition of Goldstein is 0.1-0.5 N hydrochloric acid for 6-8 hours at room temperature; that of Du-gan is heating with 5% potassium hydroxide; and that of Kubota (Tetrahedron, vol. 24, page 675 (1968)) is refluxing with 3% potassium hydroxide in ethanol for 1 hour and refluxing at 60 C. with 0.1% toluene-p-sulfonic acid in dioxane for 30 minutes. Under these conditions, sensitive groups e.g. 2- deoxy-sugar units, 14-hydroxyl group, 17-unsaturated oxa ring, etc., showed various irreversible changes e.g. formation of iso-cardenolides, hydrolysis at undesired position, dehydration, etc. When the hydrolysis was carried out with 0.0065 N hydrochloric acid at room temperature, or 0.1% potassium hydrogen carbonate at room temperature, the compounds (2), (3), (4) and (5) are hydrolyzed in a short time to obtain the compounds of the partial Formula 6. Under the same conditions, the dialdehyde, acetals thereof or dimethylol derived from Z-hydroxylated terminal sugar unit, i.e. those derived from Purpurea glycoside A by reaction with sodium periodate, is not hydrolyzed and the starting material is recovered unchanged. The reactivity of the compounds to hydrolysis are in the order dimethylol, dialdehyde and dimethylol diacetate from higher to lower. From these data, it is concluded that in the case of dirnethylol, some participation of free neighbouring hydroxyl group to reaction center is occurring. Higher reactivity of dialdehyde over dimethylol diacetate is presumed to :be result of existence of carbonyl group at ,B-position from the reaction center to be hydrolyzed. The said hydolysis of this step may be eifected by the action of a reagent capable of decomposition of acetals recovering constituent alcohols. The reagent for reaction of this step may be acids, bases or other reagents of equivalent effect e.g. a carbonyl reagent which converts a fi-oxygenated-carbonyl compound into an 0a,,3-ll11S2ttllI21t6d oxo compound or an acetal into an alcohol and ketone bound with the carbonyl reagent. The said acids may be an acid ranging from weak acids e.g. phenols, aromatic or aliphatic carboxylic acids, silica gel, acid salts e.g. sodium hydrogen sulfate, pyridine sulfate, ammonium chloride, etc., to strong acids e.g. hydrochloric acid, nitric acid, phosphoric acid, perchloric acid, etc. The said bases may be bases ranging from weak bases e.g. alumina, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydrogen carbonate, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, pyridine, trialkylamines, etc., to strong bases e.g. potassium hydroxide, sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, etc. The said carbonyl reagents may be hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, carbazide, hydroxylamine, and the like. These reagents for hydrolysis may be brought into contact with the starting materials of this step in the presence hydrolysis of H of a solvent e.g. water and organic solvents. Pretera-ble concentration of the acids or bases may be 00001- 30% to the solvents. Preferable results have been obtained in the case of 0.1-0.0001 N mineral acid or treatment in an acidic medium of pH 1-4 at room temperature for 0.5 to 48 hours. Higher temperature may shorten the reaction period. The products of this step may be obtained by a conventional method e.g. precipitation, filtration, dilution, extraction, washing, drying, absorption, elution, and the like or combinations thereof, followed by optional purification by e.g. chromatography, recrystallization, etc. In the process of the present invention, preferable results have been obtained in the cases of hydrolysis of the compounds of the partial Formula 2 with acids, bases or ketone reagents, and in the cases of hydrolysis of the compounds of the partial Formula 5 with acids.
The compounds prepared by the process of the present invention are the compounds of the formula:
iel:
wherein X, R R R and n have the same significances as defined above.
Representatives of the products of the process of the present invention involve:
and esters thereof.
The first eight compounds cited above are literary 'known compounds of higher cardiotonic activity, but because of complexed process of preparation, they have not been utilized for practical purposes. The latter eight compounds and esters thereof are novel, safe, mild and strong cardiotonic duretic compounds of the present invention. Both of them are useful as pharmaceutical agent in the treatment of heart diseases for human or veterinary use, in the forms of pharmaceutical composition containing an elfective amount of the compounds and a pharmaceutically acceptable carrier.
The novel compounds of the present invention are represented by the general formula:
wherein R and R each represents a hydrogen atom or hydroxyl group and at least one of R and R is hydroxyl; n' represents an integer l or 2, and lower alkanoates thereof. The aglycone part of these compounds is a group derived from 175-( 3-furyl)-55,14,8-androstane-3fl,12,8,14- triol, 17fl-(3-furyl)-5 8,14fi-androstane-3p,14,16,3-triol or 17p-(3-furyl) 5,8,14/3 androstanefip,12p,14,16fi-tetrol by removing a hydrogen atom from the hydroxyl group at position 3. The sugar part of these compounds is ,B-D- digitoxosyl group or 4-O-(B-D-digitoxosyl) 5 -D-digitoxosyl group.
Representatives of the compounds of the present invention involve:
3 8- (B-D-digitoxosyl)oxy-17/3 (3-fury1)-5 8, 1413- androstane-12B,l4-diol,
3 5- fi D-digitoxosyl oxy- 17,B-( S-furyl) -5 {3, 145- androstane-IZB,14,16p3-triol,
3,B- [4-O-(p-D-digitoxosy1)-,6-D-digitoxosyl]city-1713- (3-furyl)-5,B,14B-androstane-12,3,14-di01,
3c [4-0- B-D-digitoxosyl) --D-digitoxosyl] oxy- 17p- (S-furyD-Sfi,l4B-androstane-14, 16 3-diol,
3,8-[4-O-(p-D-digitoxosyl)-[3-D-digitoxosyl1oxy-17p- (S-furyl)-5,8,14p-androstane-12B,14,l6p -triol,
and the lower alkanoates thereof.
These compounds can be prepared from the corresponding 3,8 tridigitoxosyloxy-17B-(3-furyl)6B, l4p-androstane compounds disclosed in the US. Pat. No. 3,432,486 or 3,8- bisdigitoxosyloxy 17,8-(S-furyl)-5fl,14,B-androstane compounds of this invention by removing one or two digitoxosyl group according to the process of this invention or other methods e.g. Kaiser et a1. cited above. They may also be prepared from the corresponding cardenolide hisor mono-digitoxoside by reduction of butenolide ring to furan ring with action of reducing agent capable of converting butenolide to furyl group such as active aluminum hydride compounds e.g. dialkylaluminum hydrides, lithium dialkylaluminum hydride, etc.
The compounds of the present invention have valuable pharmacological activities. For example, they have strong digitaloid cardiotonic activity. They show inotropic efiect, chronotropic effect, arrhythmia and finally contractile arrest of heart. They increase contractile amplitude of isolated guinea pig atria, isolated rabbit hearts and pigeon hearts, and show electro-cardiogram specific to digitaloid agents, bradycardia, retardation of heart rate, heart fibrillation when tested on pigeon. The Table I shows results of assay on cardiotonoic activity of two of the compounds. Furthermore,
Sp- [4-0- ,B-D-digitoxosyl) -p-D-digitoxosyl] oxy- 17 (3-furyl)-5fi,l4/8-androstane-12B,14-diol,
3/3-(p-D-digitoxosyl)oxy-1713-(3-fury1)6 8,145-
'androstane-12p,14-diol and SQ-(fi-D-digitoxosyhoxy-17,8-(3-furyl)-5{3,14p-
androstane-14,16p-dio1 III at concentration of 10' increased contractile amplitude of TABLE I solated Isolated rab- Disappearguineabit heart b Pigeon ance of pig side atria a 20 g. 40 pg. P.0. 1.1. efieets Digitoxin 69 17 34 7 0. 48 3 Compound I- 44 10 19 -i 2 Compound IL 66 6 17 11. 2 3. 96 2 Compound III. 48 14 21 5. 4 2. 23 1 Compound IV 76 16 24 6. 7 2. 18 1 a The contractile amplitude of isolated guinea pig atria caused by the compound in a Ringers lsolution at concentration of l0- is recorded on kymograph and the results are represented by percent increase against initial value (Magnus method).
b The compound in a Ringers solution is passed through the coronary vessel of isolated rabbit heart in Ringers solution. The movement of the heart is recorded on hymograph and maximum response is represented in percent increase against initial value (Langendorf method).
a The compound is mixed with gum arabicum and powdered finely. The mixture is mixed with Water to make uniform suspension being 5% gum arabicum suspension. The suspension is administered orally to pigeons and median lethal dosis (LDao) is calculated. The results are represented by mg. per kg. body weight.
A method of Japanese Pharmacopoeia VII, United States Pharmacopoeia XVI, etc., for assay of digitalis preparations. A solution of the compound in ethanol is diluted with suilicient volume of isotonic sodium chloride solution and the resulted solution is injected repeatedly into alar vein of pigeon through cannula at a dose of 1 ml./kg. for each injections, until the pigeon dies of cardiac arrest. The results are represented by mg. per kg. body weight.
Time in day required for disappearance of external symptoms of side eflects of the compounds when tested on peigeon.
isolated guinea pig atria up to 200 Some of the compounds showed other pharmacological or physiological activities, for example, antiviral activity and cytotoxic activity in vitro, diuretic activity, respiration stimulating activity and anti-deoxycorticosterone activty.
From these data, it is concluded that the compounds of the present invention have cardiotonic activity as active as or stronger than digitoxin and corresponding butenolide derivatives. They are stronger than the corresponding tridigitoxosides. Their lethal doses are higher than the butenolide compounds. In other words, their side effects are weaker than corresponding butenolide compounds. The main efiects progress more rapidly than digitoxin but much slower than strospeside. The side effects disappeared more rapidly than the corresponding triglycosides or lactone compounds. Moreover, the appearance of the cardiotonic eifect is mild and general appearances of animals administered with the compounds are mild and preferable. They can be administered orally or they can be absorbed through intestine. Digitoxin, the most practical but severe cardiotonic glycoside, tend to accumulate in the body of patient. Other compounds, e.g. gitoxin esters tend to show more individual difference of eifects and side effects due to possible hydrolysis in the body. The compounds of the present invention overcome these insufiiciency of the known compounds. As the com pounds can be prepared in three steps process from abundant glycoside of digitalis plants, they are suitably produced in large amounts. Further they are more soluble in various pharmaceutically acceptable solvents than the corresponding lactone compounds or tridigitoxosides. These features show that the compounds of the present invention are strong, safe and mild cardiotonic agents which are easily preparable and suitable for clinical usage.
Aforementioned activities show the compounds of the .present invention is useful for its pharmacological activtive heart, acute heart hyposthenia, tonus disorder or the like, in a daily dosis of 0.1 ,ug. to 10 mg. per kilogram body Weight for human and veterinary use. The content of the compounds in drugs are preferably uniform to make a unit dose tablet, pills, capsules or the like to use as maintenance dosis and/or saturation or digiralization. The preparations containing the compounds may also be used as diuretic agents for treatment of some symptoms caused by heart diseases and as respiration stimulating agents in some special cases.
These compounds may be utilized in a wide variety of oral or parenteral dosage forms, solely or in admixture with other co-acting compounds. They can be administered with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, granules, capsules, pills or the like. The liquid composition may take the form of injections, suspensions, solutions, emulsions, syrups or elixirs. The tablets and granules may be coated.
The following examples are given by Way of illustration only and are not intended as limitations of the present invention, many apparent variations of which are possible without departing from the spirit and scope thereof. The abbreviations have the conventional meanings.
EXAMPLE 1 (A) To a stirred solution of 1 g. of digitoxin in 80 ml. of 95 ethanol is added 1 g. of sodium periodate in 10 ml. of water. After 1 hour, the reaction mixture is filtrated to remove solid material and the filtrate is concentrated at temperature lower than 50 C. The concentrate is extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The white powdery residue of dialdehyde shows single spot on thin-layer chromatogram and amounts 0.99 g.
(:0.478, methanol). Positive against Tollen reagent.
(B-l) To a solution of 300 mg. of the crude dialdehyde of (A) in 30 ml. of methanol is added 4.5 ml. of 0.05 N-hydrochloric acid and kept at room temperature for 24 hours. The reaction mixture is neutralized with aqueous solution of sodium hydrogen carbonate solution, evaporated to remove volatile solvent at under 50 C., and then extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and evaporated to remove solvent. Purification of 225 m of the crude product by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (2:1) as developing solvent and recrystallization from a mixture of ethyl acetate and nhexane gives 124 mg. of digitoxigenin-bisdigitoxoside, M.P. 228230 C. Yield: 50% from digitoxin.
(c=0.833, methanol).
UV: x232? 217.5 nm. (e 14,200)
Analysis.Calcd. for C H O (percent): C, 66.22; H, 8.57. Found (percent): C, 65.96; H, 8.53.
(3-2) A solution of 200 mg. of the crude dialdehyde of (A) in 20 ml. of acetone containing 0.1% of potassium hydrogen carbonate is kept at room temperature for 24 hours. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 166 mg. of the residue by thinlayer chromatography over silica gel utilizing a mixture of chloroform and acetone (2:1) as developing solvent and recrystallization from a mixture of ethyl'acetate and 10 n-hexane affords 83 mg. of digitoxigenin-bisdigitoxoside, M.P. 227-230 C. Yield: 50% from digitoxin.
(B-3) A solution of 200 mg. of the crude dialdehyde of (A) in a mixture of 2 ml. of chloroform and 6 ml. of benzene is mixed with 8 g. of neutral alumina and kept at room temperature for 20 hours. Then the mixture is filtrated to remove the solid material, and the solid material is washed three times with 100 ml. of a mixture of methanol and chloroform (1:1). The filtrate solution and washed solvent are combined and evaporated to remove the solvent. Purification of 137 mg. of the residue by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (2:1) and recrystallization from aqueous methanol affords 76 mg. of digitoxigenin-bisdigitoxoside, M.P. 227-230 C. Yield: 45% from digitoxin.
(B-4) A stirred solution of 500 mg. of the crude dialdehyde of (A) in 50 ml. of 95% methanol is mixed with 250 mg. of sodium borohydride and kept at room temperature for 1 hour. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, evaporated under reduced pressure and then extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 503 mg. of the residue by thin-layer chromatography gives crude dimethylol of single spot and negative to Tollen reagent. NMR data showed the structure. A solution of 450 mg. of the crude dimethylol in 30 ml. of methanol is mixed with 4.5 ml. of 0.05 N hydrochloric acid and kept at room temperature for 3 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated under reduced pressure, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue by recrystallization from a mixture of ethyl acetate and n-hexane gives 290 mg. of digitoxigenin-bisdigitoxoside. Yield: more than from digitoxin.
(B-S) A mixture of 200 mg. of the crude dialdehyde of (A), 12 ml. of ethanol, 160 mg. of phenylhydrazine hydrochloride, 240 mg. of sodium acetate trihydrate and 4 ml. of water is refluxed for 6 hours. The reaction mixture is concentrated under reduced pressure and extracted with chloroform. The extract solution is washed with 0.5% hydrochloric acid and water, dried and evaporated to give 230 mg. of residue, which gives 32 mg. of digitoxigenin-bisdigitoxoside on recrystallization from a mixture of acetone and hexane, M.P. 227-230 C. Yield: 18.8% from digitoxin.
ELAMPLE 2 To a stirred solution of 1 g. of digoxin in a mixture of 20 ml. of chloroform and 60 ml. of methanol is added 10 ml. of aqueous solution of 10% sodium periodate dropwise and stirred for another 1.5 hours at room temperature. The reaction mixture is filtrated to remove solid material and the filtrate is diluted with 10 ml. of water, evaporated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water and dried over anhydrous sodium sulfate and evaporated to leave 1.0 g. of crude dialdehyde. The crude dialdehyde is dissolve in ml. of 95% methanol an mixed with 500 mg. of sodium borohydride with stirring at room temperature. The mixture containing dimethylol is stirred for another 30 minutes. The mixture is adjusted to pH 2.4 to thymol blue test paper with 0.1 N hydrochloric acid and kept at room temperature for 3 hours. The reaction mixture is neutralized with 5% potassium carbonate solution to pH 6.8-7.0, evaporated to remove volatile solvent, and then is extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 707 mg. of the residue by recrystallization from a mixture UV: rage 218 nm. (6 14,500 IR: .339 3500, 1782 1740, 1525 Omf Analysis.Calcd. for C H .,O (percent): C, 64.59; H, 8.36. Found (percent): C, 64.06; H, 8.46.
EXAMPLE 3 (A) To a stirred solution of 1 g. of gitoxin in 250 ml. of a mixture of chloroform and methanol (1:1) is added to a solution of 1 g. of sodium periodate in ml. of water at room temperature, and the resulting mixed solution is kept at room temperature for 2 hours. The reaction mixture is filtrated to remove solid material, concentrated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue amounted 980 mg. which reduced Tollen reagent and showed single spot of dialdehyde on thin-layer chromatogram.
(B-l) A solution of 200 mg. of the crude dialdehyde of (A) in 20 ml. of acetone containing 0.1% of potassium hydrogen carbonate is kept at room temperature for 24 hours. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification of 148 mg. of the residue by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (1:1) as developing solvent and recrystallization from a mixture of acetone and hexane afiords 69 mg. of pure crystals of gitoxigenin-bisdigitoxoside, M.P. l99-201 C.
(c.=0.59l, methanol). Yield: 40.5% from gitoxin.
(B-Z) A solution of 200 mg. of the crude dialdehyde of (A) in 20 ml. of methanol is mixed with 3 ml. of 0.05 N hydrochloric acid and kept at room temperature for 24 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, concentrated under reduced pressure and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification of 139 mg. of the residue by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone 1:1) as developing solvent and recrystallization from a mixture of acetone and hexane aflfords 62 mg. of gitoxigeninbisdigitoxoside, M.P. 199-20l C. Yield: 36.4% from gitoxin.
(B-3) To a solution of 200 mg. of the crude dialdehyde of (A) in 20 ml. of methanol is added 25 mg. of sodium borohydride and kept at room temperature for 1 hour. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, evaporated under reduced pressure, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue did not reduce Tollen reagent and showed single spot of dimethylol on thinlayer chromatogram. A solution of 200 mg. of the crude dimethylol in 20 ml. of methanol is mixed with 3.0 ml. of 0.05 N hydrochloric acid and kept at room temperature for 2 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydogen carbonate, concentrated under reduced pressure, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of the residue by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (1:1) as developing solvent and recrystallization from a mixture of acetone and hexane affords mg. of gitoxigenin'bisdigitoxoside. M.P. 199-215 C. Yield: 78% from gitoxin. [u] +10 C. (c.=0.59l, methanol).
UV: 1553 219 nm. (0 15,300). IR: 5359 3500, 1785, 1740, 1030, 1625 cm.-
Analysis.-Calcd. for 0 11 0 (percent): C, 64.59; H, 8.36. Found (percent): C, 64.34; H, 8.47.
EMMPLE 4 According to a process similar to that of Example 2, diginatin is oxidized with sodium periodate to afford dialdehyde, followed by reduction with sodium borohydride and hydrolysis with diluted hydrochloric acid giving diginatigenin-bis-digitoxoside.
EXAMPLE 5 To a solution of mg. of digitoxin-3'-acetate in 8 ml. of 95 ethanol is added 140 mg. of sodium periodate in 1.4 ml. of water, and the mixture is kept at room temperature for 2 hours. The reaction mixture is filtered to remove solid material, concentrated to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to leave 140 mg. of white powdery dialdehyde which reduced Tollen reagent and showed characteristic signal at 0.30T in its nmr. spectrum. A solution of 140 mg. of the crude dialdehyde in 20 ml. of methanol is mixed with 3 ml. of 0.05 N hydrochloric acid, and the mixture is kept at room temperature for 24 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification of the 108 mg. of the residue by thin-layer chromatography over silica gel (a mixture of chloroform and acetone (2:1) as developing solvent) and recrystallization from a mixture of acetone and n-hexane affords 58 mg. of digitoxigenin-bisdigitoxoside-fi-acetate, M.P. l40l45 C. Yield: 49.5%.
Analysis.Calcad. for C H O H O (percent): C, 63.96; H, 8.42. Found (percent): C, 63.79; H, 8.76.
EXAMPLE 6 To a solution of 139 mg. of dig itoxin-3"-acetate in 8 m1. of 95% ethanol is added a solution of 139 mg. of sodium periodate in 1.4 ml. of water, and the mixture is kept at room temperature for 3 hours. The reaction mixture is filtered to remove solid material, concentrated to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to leave 146 mg. of white powdery crude dialdehyde which reduced Tollen reagent and showed characteristic signals at 0.22 1' and 0.44 1' in its nmr. spectrum. The crude dialdehyde is dissolved in 24 ml. of methanol, mixed with 3.6 ml. of 0.05 N hydrochloric acid and kept at room temperature for 24 hours. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure, and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 116 mg. of the residue by thin-layer chromatography over silica gel and recrystallization from aqueous methanol gives 62 mg. of digitoxigenin-bis-digitoxoside-3-acetate, M.P. 143-147 C. Yield: 55.5%. x.[ +17.5 (c.=0.258, methanol).
Amalysis.-Calcd. for C H 0 /2H O (percent): C, 64.80; H, 8.38; CH CO, 6.28. Found (percent): C, 64.74; 'H, 8.25; CH CO, 6.01.
EXAMPLE 7 To a solution of 150 mg. of digitoxigenin-bis-digitoxoside in 10 ml. of 95% ethanol is added a solution of 150 mg. of sodium periodate in 2 ml. of water, and the mixture is kept at room temperature for 1 hour. The reaction mixture is filtered to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thin-layer chromatogram and reduced Tollen reagent. The dialdehyde (150 mg.) dissolved in 15 ml. of 95 methanol is mixed with 75 mg. of sodium borohydride, and kept at room temperature for 2 hours. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromato gram and did not reduce Tollen reagent. The crude dimethylol (135 mg.) dissolved in 12 ml. of methanol is mixed with 1.8 ml. of 0.05 N hydrochloric acid and kept at room temperature for 2 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 118 mg. of the residue by recrystallization from a mixture of ethyl acetate and n-hexane gives digitoxigenin-monodigitoxside, M.P. 197-200" C.
UV: LE3? 218 nm. (e 15,090) [a] 5.2 (c.=0.327, methanol). Yield. 76%
EXAMPLE 8 To a solution of 50 mg. of digoxigenin-bisdigitoxoside in 3 ml. of 95% ethanol is added a solution of 50 mg. of sodium periodate in 0.5 ml. of water, and the mixture is kept at room temperature for 1 hour. The reaction mixture is filtrated to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thinlayer chromatogram and reduced Tollen reagent. The crude dialdehyde (52 mg.) dissolved in 3 ml. of 95% methanol is mixed with 10 mg. of sodium borohydride, and kept at room temperature for 1 hour. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromatogram and did not reduce Tollen reagent. The crude dimethylol (45 mg.) dissolved in 2 ml. of methanol is mixed with 0.5 ml. of 0.05 N hydrochloric acid and kept at room temperature for 1 hour. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 44 mg. of the residue by recrystallization from a mixture of ethyl acetate and n-hexane gives digoxigenin-monodigitoxoside, M.P. 210-212 C.
EXAMPLE 9 To a solution of 250 mg. of gitoxigenin-bisdigitoxoside in 20 ml. of 95 ethanol is added a solution of 250 mg. of sodium periodate in 2.5 ml. of water, and the mixture is kept at room temperature for 1.5 hour. The reaction mixture is filtrated to remove the solid material, concentrated to remove volatile solvent and then extracted with chloroform. The extract solution is Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dialdehyde on thin-layer chromatogram and reduced Tollen reagent. The crude dialdehyde (250 mg.) dissolved in 20 ml. of methanol is mixed with 125 mg. of sodium borohydride, and kept at room temperature for 2 hours. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated under reduced pressure and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed single spot of dimethylol on thin-layer chromatogram and did not reduce Tollen reagent. The crude dimethylol (230 mg.) dissolved in 20 ml. of methanol is mixed with 3.5 ml. of 0.05 N hydrochloric acid and kept at room temperature for 2 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, evaporated to remove the volatile solvent and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 207 mg. of the residue by recrystallization from a mixture of ethyl acetate and nhexane gives gitoxigenin-monodigitoxoside, M.P. 216- 218 C.
EXAMPLE 10 To a solution of mg. of 3 3-(B D-digitoxosyl-B-D- digitoxosyl-fl-D-digitoxosyl)ox 17p (3-furyl)-5fi,l4 3- androstan-l4-ol in 12 ml. of 95 ethanol is added 100 mg. of sodium periodate in 1 ml. of water, and the mixture is kept at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue reduced Tollen reagent and showed single spot of dialdehyde on its thin-layer chromatogram. A solution of 98 mg. of the crude dialdehyde in 10 ml. of 95% methanol is added 50 mg. of sodium borohydride, and the mixture is kept at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture is neutralized with 5% aqueous solution of acetic acid, concentrated at room temperature under reduced pressure, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue did not reduce Tollen reagent and showed single spot of dimethylol on its thin-layer chromatogram. A solution of 100 mg. of the crude dimethylol in 5 ml. of methanol is mixed with 0.75 ml. of 0.05 N hydrochloric acid and the mixture is keptv at room temperature for 3 hours. The reaction mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. Purification of 70 mg. of the residue by recrystallization from a mixture of acetone and n-hexane afl ords 59 mg. of pure 3 8-[4-0-(,3-D-digitoxosyl)- 8-D-digitoxosyl]oxy-l7p-(3-furyD-5B,l4B-androstan-14ol, M.P. I199- 200 C. Yield: 74.3%. [a] +1.0 -*;0.8 (c.=0.516, methanol).
UV: age 212 nm. (6 5,280). IR: #355 3500-3600 cm.-
Analysis.-Calcd. for C H O percent: C, 67.93; H, 8.80. Found (percent): C, 67.96; H, 8.97.
EXAMPLE 11 remove solid material, diluted with 20 ml. of water, evaporated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to obtain 44 mg. of crude dialdehyde. A solution of 43 mg. of the crude dialdehyde in 3 ml. of 95% methanol is mixed with 20 mg. of sodium borohydride and the mixture is kept at room temperature for 1 hour. The reaction mixture containing crude dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.8 to thymol blue test paper. After stirring for 4 hours under nitrogen atmosphere, the solution is neutralized with sodium hydrogen carbonate, concentrated and extracted with chloroform. The extract solution is washed with Water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 41 mg. of the crude product by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (2:1) as developing solvent and recrystallization from a mixture of chloroform and ether gives 30 mg. of crystals of 3,8-[4-0-(fl-D-digitoxosyD-B- D-digitoxosyl]oxy-17fi-(3-furyl)-5p,14fi-androstane 1213, 14-diol, M.P. 136-139 C. [u] +0.8:t0.4; [M +'6.3:O.5 (c.=1.016, chloroform).
UV: A553 212 nm. (e 4,640). IR: W
max. cm.
EXAMPLE 12 To a stirred solution of 800 mg. of 3fi-(fl-D-digitoxosyl- ,8 D digitoxosyl 3 D digitoxosyl)oxy 17 8 (3- furyD-Sfi,14,8-androstane-l4,l6B-diol in 60 ml. of ethanol is added dropwise a solution of 800 mg. of sodium periodate in 8 ml. of water at room temperature. After stirring for another 45 minutes, the reaction mixture is filtrated to remove solid material, diluted with 20 ml. of water, evaporated under reduced pressure to remove volatile solvent, and then extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to obtain 909 mg. of crude dialdehyde. A solution of 900 mg. of the crude dialdehyde in 80 ml. of 95% methanol is mixed with 80 mg. of sodium borohydride and the mixture is kept at room temperature for 1 hour. The reaction mixture containing crude dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.8 to thymol blue test paper. After stirring for 4 hours under nitrogen atmosphere, the solution is neutralized With 5% sodium hydrogen carbonate, concentrated and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 724 mg. of the crude product by thin-layer chromatography over silica gel utilizing a mixture chloroform and acetone (2:1) as developing solvent and recrystallization from a mixture of acetone and hexane gives crystals of 3p-[4-O-(B-D-digitoxosyl) ,8 D digitoxosyl1oxy 17,8 (3 furyl) 55,14,8- androstane 14,16,13 diol, M.P. 105135 C. +10.4:0.9 (c.='0.539, methanol).
UV: x513 212 nm. (6 5,080). IR: #3 59 3500, 1603 cm.-
Analysia-Calcd. for C H O %H O (percent): C, 63.58; H, 8.68. Found (percent): C, 63.59; H, 8.71.
EXAMPLE 13 To a solution of 100 mg. of 3,8-[4-O-(p-D-digitoxosyD- 3 D digitoxosyl1oxy 17B (3 furyl) 55,145 androstan-14-ol in 1 0 ml. of 95% ethanol is added 1.0 ml. of 10% aqueous solution of sodium periodate and the mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with Water, evaporated to remove methanol, and then extracted with chloroform. The
extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent to have 103 mg. of crude dialdehyde. The crude dialdehyde is dissolved in 8 ml. of methanol, mixed with 15 mg. of sodium borohydride, and stirred for 0.5 hour at room temperature. The reaction mixture containing dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.4 and kept at room temperature for 3 hours. Then the mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate to pH 7.0, diluted with water, evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed with water, dried over anyhdrous sodium sulfate and evaporated to remove the solvent. Purification of 95 mg. of the crude product by recrystallization from a mixture of methanol and ether gives 77 mg. of the pure crystals of 3,8-(B-D-digitoxosyl) oxy-17fi-(3-furyl) -5 8,14fi-androstan-14-ol, M.P. 95-97 C. [M 10.8:1.4
(c.=0.361, methanol). UV: iggg 212 nm. 6 5,430
IR: 6 259 3400-3600, 1600 CHI-1 Analysis.Calcd. for C H O /2H O (percent): C,-
69.99; H, 9.11. Found (percent): C, 70.30; H, 9.43.
EXAMPLE 14 roform. The extract solution is washed with water, dried.
over anhydrous sodium sulfate and evaporated to remove the solvent, to leave 140 mg. of crude dialdehyde. The crude dialdehyde is dissolved in 12 ml. of 95 methanol, mixed with 20 mg. of sodium borohydride, and stirred for 1.5 hours at room temperature. The reaction mixture containing dimethylol is acidified with 0.1 N hydrochloric acid to pH 2.6 and kept at room temperature for 4 hours. Then the mixture is neutralized with 5% aqueous solution of sodium hydrogen carbonate to pH 7. 0, diluted with water, evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed twice with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 106 mg. of the crude product by recrystallization from a mix ture of methanol and ether affords 70 mg. of the pure crystals of 3 ,6-( ,B-D-digitoxosyDoxy-17B-(3-furyl)-5 5,14 3- androstane-14,l6fi-diol, M.P. 218-219 C. [011 i0; [a] +11.2 *-2.0 (c.=0.403, methanol).
UV: x533 212 nm. (6 5,600). IR: 6
Analysis.Calcd. for C29H44O7 (percent): C, 69.02.; H, 8.79. Found (percent): C, 69.07; H, 8.94.
EXAMPLE 15 To a solution of mg. of digitoxigenin-mono-digitoxoside in 2 ml. of dry tetrahydrofuran cooled at from -20 C. to 25 C. under nitrogen atomsphere is added dropwise 1.20 ml. of a solution of di-isobutylaluminum hydride in tetrahydrofuran (208 mg./ml.). After 45 minutes, the reaction mixture is mixed with 3 m1. of 2 N-sulfuric acid and stirred for 15 minutes at 0 C., and then is extracted with chloroform. The extract solution is.
1 7 (,9 D digitoxosyDoxy 17p (3 furyl) 5 8,145 androstan-14-ol, M.P. 95-97 C. [:1 1 0.8i1.4
(c.=0.361, methanol).
UV: A512? 212 nm. (e 5,430 IR: V319 3400-3500, 1600 cut- EXAMPLE 16 To a solution of 450 mg. of digoxigenin-bis-digitoxoside in 10 ml. of dry tetrahydrofuran cooled at -30" C. is added 8.8 m1. of a solution of di-isobutylaluminum hydride in tetrahydrofuran (258 mg./ml.) in three portions under nitrogen atmosphere. After 45 minutes, the reaction mixture is mixed with 15 ml. of 2 N sulfuric acid and stirred at 0 C. for 15 minutes, and then extracted with chloroform. The extract solution is washed with 5% aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 390 mg. of the crude product by thin-layer chromatography over silica gel utilizing a mixture of chloroform and acetone (2:1) as developing solvent and recrystallization from a mixture of chloroform and ether gives 303 mg. of 3fl-[4-O-(fl-D- digitoxosyl) )3 D digitoxosyl]oxy 17B (3 furyl)- 53,14,8-androstane-125,14-diol, M.P. 136-139 C., [M +0.8:0.4 (c.=1.016, chloroform).
UV: was 212 nm. (6 4,640 IR: 4539* 3500 cut- EXAMPLE 17 To a stirred solution of 300 mg. of gitoxigenin-bisdigitoxoside in 5 ml. of tetrahydrofuran is added 1.58 ml. of di-isobutylaluminum hydride in dry tetrahydrofuran (1.1 mole equivalent) at 25 C. under nitrogen atmosphere. After 30 minutes, 5 ml. of 2 N sulfuric acid is added into the reaction mixture, and the mixture is stirred under icecooling for minutes, and then the resultant solution is extracted with chloroform. The extract solution is washed with an aqueous solution of potassium carbonate and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Purification of the crude product by crystallization from a mixture of ether and pentane gives 108 mg. of 3,8-[4-0-(p-D-digitoxosyD-B-D- digitoxosyl]oxy-l7 8-(3-furyl) 5,8,1413 androstane-14, 16/3-diol, M.P. 105135 C. [a] I-10.4i0.9' (c. =0.539, methanol).
EXAMPLE 18 To a solution of 400 mg. of digitoxin in 20 ml. of dioxane is added 500 mg. of lead tetraacetate, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is filtrated to remove solid material and the filtrate is diluted with 10 ml. of water. The diluted filtrate is evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. Purification of 358 mg. of the residue by thin-layer chromatography over silica gel using a mixture of chloroform and ethyl acetate (1:1) as developing solvent and recrystallization from a mixture of ether and petroleum ether gives the dialdehyde identical with that obtained in Example 1(A). The dialdehyde obtained above is dissolved in 95% ethanol and mixed with 10 mg. of sodium borohydride. After 1 hour, the mixture is acidified to pH 2.4 to thymol blue test paper with 1 N sulfuric acid and kept at room temperature for 30 minutes. The reaction mixture is neutralized with 0.1 N sodium carbonate solution, evaporated to remove volatile solvent and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue by thin-layer chromatography over silica gel using a mixture of chloroform and acetone (2: 1) as developing solvent and recrystallization from a mixture of acetone and n-hexane gives 287 mg. of digitoxigenin-bisdigitoxoside, M.P. 226230 C. Yield: 87%.
EXAMPLE 19 To a solution of 100 mg. of digitoxin in 4 ml. of chloroform and 4 ml. of carbon tetrachloride cooled at 0 C. is added 100 mg. of powdered ruthenium tetroxide. After 30 minutes stirring, the mixture is mixed with a small amount of methanol, and filtrated to remove solid material. The filtrate is evaporated to dryness to leave 99 mg. of the residue identical with dialdehyde obtained by the process of Example 1(A). The dialdehyde is dissolved in 1 ml. of ethanol, mixed with 8 mg. of sodium borohydride and the mixture is kept at room temperature for 0.5 hour. The reaction mixture containing crude dimethylol is acidified to pH 3.5 to thymol blue test paper with 0.1 N sulfuric acid. After 3 hours, the reaction mixture is neutralized with 5% sodium hydrogen carbonate, concentrated and extracted with chloroform. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue by thin-layer chromatography and recrystallization gives 73 mg. of digitoxigenin-bisdigitoxoside, M.P. 228-230 C. Yield: 89%.
EXAMPLE 20 To a solution of 100 mg. of digitoxin in 5 ml. of acetic acid is added 1 ml. of water and 500 mg. of powdered sodium bismuthate. After shaking for 3 hours at room temperature, the mixture is filtered to remove the solid material. The solid material is washed thoroughly with ethyl acetate. Mixture of the filtrate and Washed solvent is evaporated to dryness. The residue is treated with sodium borohydride and diluted sulfuric acid according to the process of Example 1(B-4) to aiford 70 mg. of digitoxigenin-bisdigitoxoside, M.P. 228230 C. Yield: 85%.
EXAMPLE 21 To a solution of 10 mg. of digitoxin in 1 ml. of benzene is added 13 mg. of iodosobenzene diacetate. After stirring for 5 hours, the reaction mixture is washed with aqueous solution of sodium bisulfate and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue showed spot of dialdehyde on its thin-layer chromatogram. The residue is treated with sodium borohydride and diluted sulfuric acid according to the process of Example 1(B-4) to afford digitoxigenin-bisdigitoxoside, M.P. 228-231 C.
EXAMPLE 22 A mixture of 9 mg. of 3,3[4-0-(,3-D-digitoxosyl)-fl-D- digitoxosyfloxy 17/3 (3 furyl)-5fl,l4j3-androstane-14, 16B-diol, 0.5 ml. of pyridine and 0.5 m1. of acetic anhydride is kept at room temperature for 5 days. The reaction mixture is poured onto iced water and extracted with chloroform. The extract solution is washed successively with water, aqueous sodium carbonate solution and diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 12 mg. of the residue by thin-layer chromatography over silica gel using a mixture of ethyl acetate and benzene (1:2) as developing solvent and recrystallization from a mixture of ether and n-hexane gives 3,8 [4 O (fl-D-digitoxosyl)-}3-D-digitoxosyl] oxy-17fl- (3-furyl)-5 8,14B-androstane 14,16 5 diol tetraacetate, M.P. 103-106 C. (amorphous).
EXAMPLE 23 A tablet is prepared in conventional manner from 0.2 mg. of 3p [4-0-(p-D digitoxosyl)-fl-D-digitoxosyl]oxy- (3-furyl)-5p, l4fi-androstane-14-16y3-diol, 50 mg. of starch and a small amount of magnesium stearate. Six tablets per day for saturation or two tablets per day for maintenance dosage are given to a patient.
,EXAMPLE 24 A colored powder consisting of one weight of 3fi-[4-O- (fi-D digitoxosyl)-fi-D-digitoxosyl] oxy 17p (3-furyl)- ;3,14;8-androstane-14,16fi-diol and ten thousand weights of starch.
EXAMPLE 25 wherein X is a furyl, butenolide, or butanolide group; R and R each represents a hydrogen atom; hydroxyl; lower alkanoyloxy; lower alkenoyloxy; lower alkanoyloxy or lower alkenoyloxy substituted by halogen, hydroxy, phenoxy, amino, phenyl, or carboxy; benzoyloxy; naphthalenecarbonyloxy; nicotinoyloxy; furoyloxy; benzoyloxy substituted by halogen, methoxy, nitro, or methyl; or acyloxy group derived from carbonic, sulfuric or phosphoric acid; R is a hydrogen atom; lower alkanoyl; lower alkenoyl; lower alkanoyl or lower alkenoyl substituted by halogen, hydroxy, phenoxy, amino, phenyl, or carboxy; benzoyl; naphthalenecarbonyl; nicotinyl; furoyl; benzoyl substituted by halogen, methoxy, nitro or methyl; or acyl group derived from carbonic, sulfuric, or phosphoric acid, and is same or different for each sugar unit; and n is an integer of 1, 2 or 3 which comprises treating a compound of the formula wherein X, R R R and n have the same significance as defined above, and Z represents a group selected from the radicals defined by the structural formula OHG or acetals thereof, or
noon, on
HOCHg-CH;
in an acidic medium of pH 1-4 with a 0.1-0.0001 N mineral acid, or a base selected from alumina, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydrogen carbonate, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, pyridine, trialkylamines, potassium hydroxide, sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, or with a carbonyl reagent selected from hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, carbazide, and hydroxylamine.
2. A process as claimed in claim 1, wherein X is a butenolide or furyl group.
3. A process for the preparation of a compound of the formula wherein X, R R R and n have the same significances as defined in claim 1, which comprises reacting a compound of the formula wherein X, R R R and n have the same significances as defined above, with a glycol cleaving agent selected from bismuthates, manganese acetate, iodosobenzene alkanoates, osmium tetroxide, ruthenium tetroxide, lead tetraacetate, periodates, and periodic acid, followed by optional treatment with a reducing agent selected from the group of boron hydride compounds, and aluminum hydride compounds, or by catalytic hydrogenation, and then subjecting the compounds obtained to treatment in an acidic medium of pH 1-4, with a 0.1-0.0001 N mineral acid, or with a base selected from alumina, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydrogen carbonate, sodium acetate, potassium acetate, potassium carbonate, sodium carbonate, lithium carbonate, ammonia, pyridine, trialkylamines, V
potassium hydroxide, sodium hydroxide, lithium hydroxide, tetraalkylammonium hydroxides, or with a carbonyl reagent selected from hydrazine, phenyl-hydrazine, 2,4- dinitriphenylhydrazine, carbazide, and hydroxylamine.
4. A process as claimed in claim 3, wherein the glycol cleaving agent is one to five mole equivalents of periodic acid, periodates or lead tetraacetate.
5. A process as claimed in claim 3, wherein the reduction is effected by the action of one to ten mole equivalents of sodium borohydride.
6. SQ-(B-D-digitoxosyDoxy 17p (3-fury1)5fi,14- androstane-12fi,14,16p-trio1.
7. 35-[4 0 (fi-D-digitoxosyl)-fl-D-digitoxosy1]oxy- 175(3-furyl)-5B,14B-androstane-12p,14-dio1.
8. 35-[4 0 '(p-D-digitoxosyl)-p-D-digitoxosy1]oxy- 17B-(3-fury1)-5p,14p-androstane-12p,14,l6p-trio1.
22 References Cited UNITED STATES PATENTS 3,432,486 3/1969 Minato 260-2105 3,471,614 10/1969 Kaiser et a1 260-2105 3,476,742 11/1969 Voigtlander et a1. 260--210.5
LEWTS GO'ITS, Primary Examiner I. R. BROWN, Assistant Examiner US. Cl. X.R. 424-1 82
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