DE2063406A1 - New acyl derivatives of Proscillandin A and process for their preparation - Google Patents

Description

Case -1/386
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C »Η. .BOEHRINGER SOHH, IWG-EIHBIM AM RIIElN

lieu «acyl derivatives of prosoillaridin A and method too

their manufacture

The German application P 19 00 898.1 describes acetyl derivatives of prosoillaridine. However, it was not possible there to prepare the corresponding derivatives of other organic acids by the process proposed there, or from the isomer mixture obtained by the process described there, with the exception of individual pure acyl compounds Some aoetyl derivatives to _: isolate. The acyl derivatives of proscillaridins, which are derived from higher acids, are therefore new. The present invention relates to new compounds of the general formula I

OH

209839/1183

ORIGINAL INSPECTED

CH

where R · ^ · the Grugae-Q-I

OH

R _{2 is} an alkyl group with 1-4 carbon atoms which is substituted by halogen or a cycloalkyl radical; an alleyl group with 2-4 carbon atoms'; an Oyclaalkylrest with 3 - 8 carbon atoms or an aralkyl- or Arylrest, whose aromatic nucleus can optionally be substituted by halogen. or a methyl group, if R, has a meaning other than a hydrogen atom or an acetyl group and.

R _{5 is} a hydrogen atom, a radical R ₂ -CO- with the meaning given above for R ₂ , an alkyl group with 1-3 carbon atoms or a heteroaroyl group, preferably a thenoyl group , and processes for their preparation.

The compounds according to the invention can expediently after can be produced using the following process:.

The starting glycosides of the general formula II

HO 0 = 2-0 _v R ₁

OH OK

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II

/ 3

ORiGlNAL. SNSPECTEI

where κ, has the meaning given above, are initially by transesterification with an orthoester of the general formula

Ii ₂ - C (OK ₄ J ₃

III

in which Il _{o has} the meaning given above and R. denotes lower alkyl groups in a cyclic orthoester of the formula Iv

IV

in which R _n , R ₀ and R. have transferred the meanings given above - if desired on the C -hydroxyl group by means of an aluylating or acylating agent of the general formula V

/ 4

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2083406

■ where Iw has the meaning given above, except hydrogen, and X denotes an iialogenatom or another easily anionically cleavable radical, be esterified or etherified can. - -what then by partial hydrolysis, if desired after previous isolation of the intermediate product of general formula IVa

1 "Va-

wherein the radicals R ₁

R ₀ , R, and R, which have the abovementioned meaning, the compounds of the formula I according to the invention are formed. - ".

The Grthoester of the general formula IV is prepared in the presence of acidic catalysts; the reaction mixture If desired, an inert solvent such as tetrahydrofuran, dioxane, chloroform or Methylene chloride are added. As acidic catalysts, inorganic and strong organic acids such as Hydrohalic acids, sulfuric acid, p-toluenesulfonic acid, Methanesulfonic acid or trichloroacetic acid; Lewis acids, such as potassium hydrogen sulfate, zinc chloride, Boron trifluoride etherate or copper sulfate; as well as acidic ion exchangers, like Imberlite IR 120 or Dowex 50, can be used.

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BATH ORIGIN * ¹ -

The reaction takes place between ⁰ ° C. and the reflux temperature of the reaction mixture, preferably approximately at room temperature.

The subsequent partial hydrolysis of the intermediate cyclic orthoesters of the above iOrmel IVa takes place, possibly after resuming in an inert solvent, for example ethyl acetate, in the presence of aqueous acid. It has proven to be particularly advantageous to use the reaction mixture to be added after the transesterification with the aqueous acid and the partial hydrolysis to be carried out directly afterwards. As aqueous Acid, any aqueous solution with a pH of 4 or less can be used. The reaction proceeds stereoselectively in such a way that, as a rule, one of the derivatives which are possible per se is uniformly the product with the esterified one OH group in the 2'-position. The acylation of the G.-standing free hydroxyl group can be carried out by any acylation process as long as the stability of the compound IVa allows. You can with a reactive derivative of the acid, for example an acyl halide, acid anhydride or'einem mixed anhydride of an acid and a carbonic acid monoester at room temperature in an inert solvent in the presence of an acid-binding agent. As an acid-binding agent Inorganic or tertiary organic bases can be used, the latter, for example pyridine, can then, in one corresponding excess used, at the same time as a solvent to serve. To accelerate the acylation, 4-diethylaminopyridine can be used as acylation catalyst with and without the addition of Triethylamine can be used. The alkylation of the C «positions free hydroxyl group is preferably present with alkyl iodide carried out of silver oxide in dimethylformamide.

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The compound used as the starting material of the general Formula II is the Proscillaridin A. This is from the literature 'known and can be obtained, for example, from the white sea onion using conventional methods, e.g. according to A. Stoll e.a. Helvet. Chim. Acta 34, p. 1431 (1951).

The new cardiac glycosides produced according to the invention have valuable pharmacological properties, in particular they have a positive inotropic effect on the isolated guinea pig atrium and on the cardiopulmonary preparation which exceeds that of g-ströphanthin with significantly lower toxicity. They can be used to treat heart failure . As a ψ dosage amounts between 0.05. and 5.0 mg, preferably between 0.125 and 2.0 mg suggested.

Suitable application forms are, for example, tablets, capsules, Suppositories, juices, emulsions or dispersible powders-Corresponding tablets can, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, Disintegrants, such as corn starch or magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.

"The tablets can also consist of several layers.

Correspondingly, coated tablets can be made by coating cores produced analogously to the tablets with usually coated tablets means used, for example Kollidon or Shellac, gum arabic, talc, titanium dioxide or sugar will. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several Layers exist. The coated tablet can also be used for

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Achieving a depot effect from several layers "consist, using the excipients mentioned above for the tablets can be.

Shafts of the active ingredients or combinations of active ingredients according to the invention can additionally contain a sweetener, such as saccharin, cyclamate, G-Iy c er in or sugar, and a taste-enhancing agent, for example, flavorings such as vanillin or orange extract Thickeners, v / ie sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

The one or more active ingredients or combinations of active ingredients Capsules containing can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose ι or sorbitol, mixed and encapsulated in gelatin capsules.

G-e suitable suppositories let you mix them, for example with provided carriers, such as iieutralfetten or Manufacture of polyethylene glycol or its derivatives.

The following examples serve to explain the invention, without limit their scope to:

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209839/1183

BATH ORIGINAL

Manufacturing examples

example 1 2 ^l -Butyryl-proscillaridin A

1 g of proscillaridin A is reacted in 20 ml of absolute tetrahydrofuran with 50 mg of p-toluenesulfonic acid and 1 ml of triethyl orthobutyrate with stirring at room temperature. When the reaction has ended, the mixture is neutralized with triethylamine and the solvent is stripped off in vacuo at a bath temperature of 50 °. The evaporation residue is taken up in 50 ml of chloroform and shaken with 50 ml of 2N sulfuric acid to hydrolyze the cyclic orthoester. After washing the organic phase twice, it is dried over anhydrous sodium sulfate and evaporated, and the residue is recrystallized from ethyl acetate.
Pp. 213-214 ⁰ Q Yield: 910 mg = 80.5> d. Th.

.Example 2 ■

2'-Benzoyl-proecillaridin A

According to Example 1, 1 g of proscillaridin A is reacted with trimethyl orthobenzoate. For hydrolysis, 2 ml of water / water and a further 50 mg of p-toluene sulfonic acid are added to the reaction mixture. When the orthoester has been cleaved, the solution is neutralized by adding triethylamine, evaporated in vacuo at a bath temperature of 50 °, and then recrystallized from ethanol. Pp 236 - 24O ⁰ Gj Yield: 1.015 mg = 84.5% d.. Th.

In the same way the following were produced:

Example 3

2'-Propionyl-proscillaridin A from proscillaridin A and trimethyl orthopropionate according to Example 1. P.p. 203-2O7 ° C

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Example 4

2 '- (^ - Ghlorbutyrylj-proBcillaridin k from Proscillaridin Λ and Ortho-Jf-chlorobutyric acid trimethyl ester according to example mp, 185-184 ⁰ O

Example 5 ■

2 '- (Gyolopropylformyl) - proscillaridin A from proscillaridin A and Ortho-cyclopropancar'bonsäure' trimethyl according to Example 1 Ji ¹ P. 196 - 21O ⁰ C

Example 6

2 '- (Gyolopentylformyl) proscillaridin A from proscillaridin A and triethyl orthocyclopentanecarboxylate according to Example 1 ϊρ. 201-203 ° C

Example 7

2 '- (pyclonexylformyl - proscillariain A from proscillaridin A and Qrthocyclohexancar'bonsäure trimethyl according to Example 1. mp 218 -. 223 ⁰ G

Example 8

2 '- (Cyclooctylformyl) - prosoillaridin A from Proscillaridin A and ortho-cyclooctanecarboxylic acid trimethyl ester according to Example 1

Example 9

2 '- (Cyclopentylacetyl) proscillaridin A from proscillaridin A and ortho-cyclopentylacetic acid trimethyl ester according to Example 1', mp. 159 - 161 ⁰ O

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- ίο -

Example 10 . .

2 '- (Cyolohexylaoetyl) -prosoillaridin A from proscillaridin A and ortho-cyclohexylacetic acid trimethyl ester according to Example 1.

Mp. 187 - 19O ⁰ C

Example 11

.2 '- (ß-Phenylpropionyl) -proscillaridin A from Proscillaridin A from ortho-ß-phenylpropionic acid trimethyl ester according to Example 1
MR: taken up in dimethyl sulfoxide

cf = 7.2 ppm; Singlet (5 protons) ~ \ _ /

S = 2.77 ppm; Multiplet (2 protons) -C-CH ₂ -

0 Standard: TMScT = 10.00 ppm

Example 12 ■

2 ^t - (^ - Phenylbutyryl) -proscillaridin A from proscillaridin A and trimethyl ortho-K'-phenylbutyric acid according to Example 1 WI-IR: recorded in CDOL ₅

«F = 2.7 ppm; Singlet (5 protons) - ^ y

, S β 7.3 ppm; Singlet (2 protons) -0-C-CH ₂ -

0 Standard: ÜMStf = 10.00 ppm

Example 15 :. ^: :: ·. "". "■. _; ■ - ..

2 '- (O-Fluorbenzoylj proscillaridin-A from proscillaridin A and Ortho-p-fluorobenzoic acid-triethyl according to Example 1, mp 154 * -. 160 ⁰ C

"■■■" ■. · '/ 11

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- Ii -

.Example 14 ■

2 '- (p-Ctilorphenylacetylj-proscillaridin A from proscillaridin A and ortho-p-chlorophenylacetic acid triethyl ester according to Example 1
Pp. 132-142 ⁰ C '. .

Example 15

2'-propionyl ^ '- oyclopropionyl-proscillaridin A

1 g Proscillaridin A · analogous to Example 1 with orthopropionic acid triethyl ester implemented. After neutralizing it becomes the solution evaporated, the residue dissolved in pyridine and stirring and ice cooling reacted with 1 ml of cyclopropanecarboxylic acid chloride.

After the usual work-up, removal of the solvent, shaking with 2N hydrochloric acid, washing with water, drying over Na ₂ SO. and evaporation is recrystallized from Essige.ster / petroleum ether.
Γρ. 190 to 195 ⁰ C; Yield: = 79, $ d. Th.

The following compounds were produced analogously to Example 15:

Example 16

2 ', 4'-dipropionyl-prosoillaridin A from proscillaridin, Orthopropionsäureiriäthylester and propionyl chloride mp. 135 ⁰ C

Example 17

2 ', 4'-dibutyryl proscillaridin A -aus proscillaridin A, Ortho butyric acid and butyryl chloride triethyl mp. 112 - 122 ⁰ C.

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Example 18

2 ' _t 4' ~ I) ibenzoyl - proscillaridin A from proscillaridin A _T orthobenzoic acid briethyl ester and benzoyl chloride

INiMR j recorded in

- H.

cf = 8.05 ppm; Multiplet (4 protons) ^σ , -χ y

O y == s

cf = 7.55 ppni; Multiplet (6 protons) 0-VJ -E _fc standard: ^r üMScf = 10.00 ppm

Example 19

2 ' _? 4'-J-dicyclopropylformyl-prosoillaridin A from proscillaridin A, orthocyclopropanecarboxylic acid trimethyl ester and cyclopropanecarboxylic acid chloride
Jj ¹ P. 132 - 134 ⁰ C

Example 20

2 '- (y-chlorobutyryl) -4' ~ c yclopropylform.yl-proscillaridin A from proscillaridin A, ortho - ^ - chlorobutyric acid trimethyl ester and glyclopropane carboxylic acid chloride
h m.p. 105-117 ° C

Example 21

2'-Benzoyl-4'-thenoyl-pro ^ sci llari d in A from proscillaridine A, orthobenzoic acid trimethyl ester and then (2) oyl chloride. 164 - 170 ⁰ C ■ - ■. , .

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Example 22

2'-Acety1-4'-methoxy-proscillaridin A

1 g Pro & cillaridin is, according to Example 1, with triethyl orthoacetate implemented. After! Neutralizing the reaction mixture with triethylamine, the solvent is in the Removed vacuum, the residue in 30 ml of absolute dimethylformamide dissolved and with 2 g of silver oxide and 2 ml of methyl iodide for 20 hours im Stirred dark "at room temperature. After removing the solvent the residue is crystallized from chloroform-ether in vacuo

Pp. 140-148 ⁰ G; Yield: 787 mg = 69.5 ⁽ / ° of theory

The following compounds were produced analogously to Example 22:

Example 23

2 '-PropionylH -'- methoxy-proscillariäin Λ of proscillaridin A, Orthopropionsäure trimethyl and methyl iodide / silver oxide Pp 154 -. 156 ⁰ C

Example 24

2 '-Cyclopentylforr;iyl-4' -raetaoxy proscillaridin-A from proscillaridin A, Ortho-cyclopentanecarboxylic acid trimethyl ester and methyl iodide / silver oxide Pp 123-134 ⁰ C.

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Pharmaceutical preparations

A) tablets

1 tablet contains:

2 '- (β-Phenylpropionyl) proscillaridin A 0.25 mg

Lactose 85.75 mg

Potato starch 30.0 mg

Gelatin 3.0 mg

Magnesium stearate 1.0 mg

120.0 mg

Production method:

The active substance is intensively rubbed in with ten times the amount of milk sugar. You mix this trituration with that
remaining milk sugar as well as potato starch and granu ~ profiled with a 10 ^ aqueous solution of the gelatin by ψ sieve 1.5 mm. Drying at 4O ⁰ G. The dried granulate is again rubbed through sieve 1 mm and mixed with magnesium stearate. Tablets are pressed from the mixture.
Tablet weight: 120 mg
Stamp: 7 mm flat with partial notch.

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B) Coated tablets

1 dragee contains:

2 ^l - ( _i ^ -Chlorbutyryl) -proscillaridin A 0.25 mg

Milk sugar 32.25 mg

Corn starch 15.0 mg

Polyvinylpyrrolidone '2.0 mg

Magnesium stearate 0.5 mg

50.0 mg

preparation procedure;

The active substance will be revealed intensely with ten times the amount of milk sugar, with the remaining milk sugar as well as with the Corn starch mixed and granulated with a 15 $ strength aqueous solution of polyvinylpyrrolidone through 1 mm. The at 40 C The dried mass is rubbed through the above sieve again, mixed with magnesium stearate and then made into tablet cores pressed.

Core weight: 50 mg
Stamp: 5 mm domed.

The tablet cores produced in this way are coated by a known method with a shell consisting essentially of sugar and talc. The finished coated tablets are polished with the help of beeswax.
Dragee weight: 85 mg.

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C) coated tablets

1 dragee contains:

2 ^L - (CyGlopentylformyl) proscillaridin A 0.125 mg

Lactose. 32.375 mg

Corn starch 15.0 mg

Polyvinylpyrrolidone 2.0 mg

™ Magnesium stearate 0.5 mg

50.0 mg

Production method:

The production takes place like. given above under B).

D) drops'

Composition;:

100 ml of drop solution contain:

2 ^l - (β-phenylpropionyl) proscillaridin A 0.0125. G

Saccharin sodium 0 »3 g

Sorbic acid 0.1 g

Ethanol 30.0 g

Men's liqueur essence (Haarnu & Reimer) '1.0 g

Distilled water to 100.0 g

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Production method:

The solution of the active substance and the liqueur essence in ethanol is mixed with the solution of sorbic acid and saccharin in water and filtered fiber-free.
1 ml of dropping solution contains 0.125 mg.

E) ampoules

1 ampoule contains:

2 ^f , ^ - Dipropionyl-proscillaridin A 0.25 mg polyethylene glycol 600

Tartaric acid 150.0 mg

De st. V / ater ad 3.0 ml

Production method:

Tartaric acid and polyethylene glycol are successively added to distilled water and the active ingredient dissolved. It is made up to the given volume with distilled water and filtered germ-free.

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

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Ji ¹ ) suppositories

1 suppository contains:

2 ^! -Propionyl-proscillaridin AG, 25 mg

Lactose 4.75 mg

Suppository mass (e.g. Witepsol W 4-5) 169510 rag

1700.0 mg

Production method;

The Verreihung of the active substance with lactose is stirred by means of a Eintauchhomogenisators in the melted and cooled to 40 ⁰ C suppository mass. It is cooled to '37 ⁰ C and poured into slightly chilled molds. Suppository weight: 1.7 g

G) Suppositories

1 suppository contains:

2'Hlcetyl-4 ⁱ -methoxy-proscillaridin AO ₅ 125 mg

Lactose 4.875 mg

Suppository mass (e.g. Witepsol W 45) 1695.0 mg

1700.0 mg

Production method:

The production takes place as indicated above under F). _{,, Q}

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Claims (4)

Patent claims 'ΐ.Υ) new compounds of general formula I. wherein R ^ is the group-0-1 CH OH an alley group with 1-4 C-atoms passing through. Halogen or a cycloalkyl radical is substituted; an alkyl group
E-it 2-4 carbon atoms; a cycloalkyl radical with 3-8 carbon atoms or an aralkyl or aryl radical whose aromatic nucleus can optionally be substituted by halogen; a ethyl group if R_ has a meaning other than a hydrogen atom or an acetyl group; and / 20 209839/1183 , R, a hydrogen atom, a radical Rp-CO- with the above Meaning for Rp, an alkyl group with 1-3 Carbon atoms or an Ileteroaroylgruppe, preferably a 'l'henoylgruppe, can mean. 2.) Process for the preparation of compounds of the formula I. R3O. 0 R- CH, H H OH OCO where R ,, Rp and R, have the meanings given above, characterized in that a compound of the general formula II HO i \ h H ^ O OH η / ι -TT H OH II wherein R _{1 has} the aforementioned meaning, äverao- with an orthoester of the general formula III 209839/1183 -. 21- III wherein R ^ has the meaning given above and R- a means lower alkyl group, initially in a cyclic Orthoester of the general formula IY HO R ₂ O IY where R- ,, Rp and R, have the meaning given above free OH group, if desired, esterified or can be etherified - converted and this intermediate of the general formula IYa 209839/1183 IVa / 22 in which the radicals R-,, R _? , R, and R, which have the meaning given above, partially saponified. 3.) Pharmaceutical preparations, characterized by a content of active ingredients of the general formula I. 4.) Process for the production of pharmaceutical preparations according to claim 3, characterized in that one or
several active ingredients of general formula I with usual
pharmaceutical auxiliaries and / or carriers formulated in the usual way. ". 5.) Treatment of heart failure, characterized by Administration of a pharmaceutical preparation according to claim 3. 209839/1183