DE2063406B2 - ACYL DERIVATIVES OF PROSCILLARIDIN A, PROCESS FOR THEIR PRODUCTION AND PREPARATIONS CONTAINING THESE - Google Patents

Description

-O-

= 0

OH

R2 is an alkyl group with 1 to 4 carbon atoms, substituted by a halogen atom or a cycloalkyl group, an alkyl group of 2-4 Carbon atoms, a cycloalkyl radical with 3-8 carbon atoms, an aralkyl or Aryl radical, which can optionally be substituted by halogen in the aromatic nucleus, or a methyl group, if R3 has a meaning other than hydrogen, and

R3 is a hydrogen atom, a methyl group or

mean a thenoyl radical.
2. Process for making compounds

of formula I.

R ₃ Ο

40

(I)

OH OCO

R,

wherein Ri, R ₂ and R _{3 have} the meaning given above, characterized in that a compound of the general formula II

Transesterification with an orthoester of the general formula III

R ₂ -C (OR ₄ J ₃ (UI)

where R _{2 has} the meaning given above and R <is a lower alkyl group, initially in a cyclic orthoester of the general formula IV

"° \ R 'CH ₁ XJ' ¹

(IV)

HO

in which Ri, R ₂ and R4 have the meaning given above - whose free OH group can, if desired, also be esterified or etherified - and this intermediate of the general formula IVa

R ₁ O

(IVa)

in which the radicals Ri, R ₂ , R3 and Rt have the meaning given above, partially saponified.

3. Pharmaceutical preparations, characterized by a content of active ingredients of the general Formula I.

HO

CH ₃

1·

¹ C

(H)

45 In the German application P 19 00 898.1 sine acetyl derivatives of proscillaridine are described. However, it was not possible there to prepare the corresponding derivatives of other organic acids by the process proposed there, or to isolate individual pure acyl compounds with the exception of a few acetyl derivatives from the isomer mixture obtained by the process described there. The acyl derivatives of proscillaridine, which are derived from higher acids, are therefore new.

The present invention relates to new compounds of the general formula I.

OH OH

where Ri has the aforementioned meaning through OH OCO

R,

R ₁ the group

H ₃ C

-O-

OH

R _{2 is} an alkyl group with 1-4 C atoms which is substituted by halogen or a cycloalkyl radical; an alkyl group with 2-4 carbon atoms; one, ₅ cycloalkyl radical with 3-8 carbon atoms or an aralkyl or aryl radical, the aromatic nucleus of which can optionally be substituted by halogen, or a methyl group, if R _{3 has} a meaning other than a hydrogen atom, and

R _{3 can represent} a hydrogen atom, a methyl group or a thenoyl group,

and processes for their manufacture. The compounds according to the invention can

expediently produced according to the following process

will be provided:
The starting glycosides of the general formula II

₂ o

(Π)

35

40

where Ri has the meaning given above, are first of all by transesterification with an orthoester general formula III

R ₂ -C (OR ₄ J ₃

(HI)

45

where R2 has the meaning given above and R4 mean lower alkyl groups, in a cyclic orthoester of the formula IV

(IV)

55

160

in which Ri, R ₂ and R4 have the meanings given above, transferred - ^{if desired on the C 4} hydroxyl group by means of an alkyl

or acylating agents of the general formula V

R ₃ X

(V)

where R _{3 has} the meaning given above, except hydrogen, and X is a halogen atom or another easily anionically cleavable radical, can be esterified or etherified - from which then by partial hydrolysis, if desired after previous isolation of the intermediate of the general formula IVa

R, O

(IVa)

in which the radicals Ri, R ₂ , R ₃ and Rt have the meaning given above, the compounds of the formula I according to the invention are formed.

The orthoester of the general formula IV is prepared in the presence of acidic catalysts; If desired, an inert solvent such as tetrahydrofuran, Dioxane, chloroform or methylene chloride can be added. The acidic catalysts are 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; and acidic ion exchangers, such as Amberlite IR 120 or Dowex 50, can be used.

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

The subsequent partial hydrolysis of the intermediate cyclic orthoester of the above given formula IVa takes place, if necessary after resumption in an inert solvent, for example ethyl acetate, in the presence of aqueous acid. It has proven to be particularly favorable that To put the reaction mixture after the transesterification with the aqueous acid and the partial Carry out hydrolysis immediately afterwards. Any aqueous solution can be used as the aqueous acid pH 4 or less can be used. The reaction is stereoselective, so that one in As a rule, of the derivatives that are possible per se, the product with the esterified OH group in Maintains 2 'position. Acylation of the free hydroxyl group can be carried out by any acylation process be carried out as far as the stability of the compound IVa allows. You can with one reactive derivative of the acid, for example an acyl halide, acid anhydride or a mixed one Anhydride from an acid and a carbonic acid monoester at room temperature in one

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, used in a corresponding excess, serve as a solvent at the same time. To the 4-Dimethylaminopyridine can accelerate acylation be used as acylation catalyst with and without the addition of triethylamine. The alkylation the standing free hydroxyl group is preferably mixed with alkyl iodide in the presence of silver oxide Dimethylformamide carried out.

The compound of general formula II used as starting material is proscillaridin A. This is known from the literature and can be obtained, for example, from the white sea onion using customary methods win, e.g. B. according to A. S t o 11 e. a., Helvet. Chim. Acta, 34, page 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 vestibule as well on the heart-lung preparation, which exceeds that of g-strophanthin with significantly lower toxicity. she can be used to treat heart failure. The dosage is 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 powder. 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 milk sugar, 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 usually be coated with cores produced analogously to the tablets Agents used in dragee coatings, for example collidon or shellac, gum arabic, Talc, titanium dioxide or sugar. To achieve a depot effect or to avoid it In the event of incompatibilities, the core can also consist of several layers. Can also do the same the coated tablet shell to achieve a depot effect consist of several layers, the above with the Tablets mentioned excipients can be used.

Juices of the active ingredients or combinations of active ingredients according to the invention can also use a sweetener such as saccharin, cyclamate, or glycerin Sugar, as well as a taste-improving agent, e.g. B. flavorings such as vanillin or orange extract contain. You can also use suspension aids or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

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

Suitable suppositories can be made up, for example, by mixing them with carriers provided for this purpose, such as Manufacture neutral fats or polyethylene glycol or its derivatives.

The following examples serve to illustrate the invention without restricting its scope:

Manufacturing examples
example 1

2'-butyryl proscillaridin A

1 g of proscillaridin A is dissolved in 20 ml of absolute tetrahydrofuran with 50 mg of p-toluenesulfonic acid and 1 ml of triethyl orthobutyrate reacted with stirring at room temperature. After the reaction has ended it is neutralized with triethylamine and the solvent is drawn off in vacuo at a bath temperature of 50 °. The evaporation residue is taken up in 50 ml of chloroform and used to hydrolyze the cyclic Orthoesters shaken with 50 ml of 2η-sulfuric acid. After washing the organic phase twice is dried over anhydrous sodium sulfate, evaporated and the residue is recrystallized from ethyl acetate.

Mp 213-214 ° C; Yield: 910 mg = 80.5% of theory.

Example 2
2'-Benzoyl-proscillaridin A

According to Example 1, 1 g of proscillaridin A is reacted with trimethyl orthobenzoate. For hydrolysis, 2 ml of water and a further 50 mg of p-toluenesulfonic acid are added to the reaction mixture. After the end of the cleavage of the orthoester, the solution is neutralized by adding triethylamine, evaporated in vacuo at a bath temperature of 50 °, and then recrystallized from ethanol.
Mp 236-240 ° C; Yield: 1.015 mg = 84.5% of theory. Th.

The following were produced in an analogous manner:
Example 3

2'-propionyl-proscillaridin A from proscillaridin A and trimethyl orthopropionate according to the example 1.

Mp. 203-207 ⁰ C.

Example 4

2 '- (γ-chlorobutyryl) -proscillaridin A from proscillaridin A and ortho-γ-chlorobutyric acid trimethyl ester according to Example 1.
Mp. 183-184 ⁰ C.

Example 5

2 '- (Cyclopropylcarbonyl) proscillaridin A from proscillaridin A and ortho-cyclopropanecarboxylic acid trimethyl ester according to Example 1.
Mp. 196-210 ⁰ C.

_6c Example 6

2 '- (Cyclopentylcarbonyl) proscillaridin A from proscillaridin A and orthocyclopentanecarboxylic acid trimethyl ester according to example 1.

Mp. 201-203 ⁰ C.

Example 7

2 '- (Cyclohexylcarboxyl-proscillaridin A from proscillaridin A and orthocyclohexanecarboxylic acid-trimethyl-

63 406

ester according to example 1. Mp 218-223 ° C.

Example 8

2 '- (Cyclooctylcarbonyl) proscillaridin A from proscillaridin A and ortho-cyclooctanecarboxylic acid trimethyl ester according to Example 1.

Example 9

2 '- (CyclopentylacetyI) -proscillaridin A from proscillaridin A and ortho-cyclopentylacetic acid trimethyl ester according to example 1.

Mp 159-161 ° C.

Example 10

2 '- (Cyclohexylacetyl) proscillaridin A from proscillaridin A and ortho-cyclohexyl acetic acid trimethyl ester according to example 1.

Mp. 187-190 ° C.

Example 11

2 '- (j9-Phenylpropionyl) -proscillaridin A from Proscillaridin A from ortho-ji-phenylpropionic acid trimethyl ester according to example 1.

NMR: recorded in dimethyl sulfoxide

λ = 7.2 ppm; Singlet (5 protons) - <f \

Λ = 2.77 ppm; Multiple (2 protons) —C-CH ₂ -

Standard: TMS σ

10.00 ppm.

Example 12

2 '- ()> - Phenylbutyryl) -proscillaridin A from proscillaridin A and ortho-y-phenylbutyrate-trimethylester according to example 1.

NMR: recorded in CDCl3

Λ = 2.7 ppm; Singlet (5 protons) - <f \ ή = 7.3 ppm; Singlet (2 protons) - 0-C-CH ₂ -

Example 16

2'-acetyl-4'-methoxy-proscillaridin A

1 g proscillaridin is, according to Example 1, mil Triethyl orthoacetate implemented. According to the Neutralizing the reaction mixture with triethylamine, the solvent is removed in vacuo, dei The residue was dissolved in 30 ml of absolute dimethylformamide and treated with 2 g of silver oxide and 2 ml of methyl iodide for 20 hours stirred in the dark at room temperature. After the solvent has been stripped off, it crystallizes in vacuo to convert the residue from chloroform-ether.

Mp. 140-148 ° C; Yield: 787 mg - 69.5% of theory. Th.

Analogously to Example 16, the following compound was « manufactured:

Example 17

2'-Propionyl-4'-methoxy-proscillaridin A from Proscil laridin A, orthopropionic acid trimethyl ester and Me ethyl iodide / silver oxide. Mp. 154-156 ° C.

Example 18

2'-Cyclopentylformyl-4'-methoxy-proscillaridin A au: Proscillaridin A, ortho-cyclopentanecarboxylic acid trim ethyl ester and methyl iodide / silver oxide.

Mp. 123-134 ° C.

Pharmaceutical Preparations A) Tablets

! The tablet contains:

2 '- (/? - Phenyl propiony I) -

proscillaridin A

Lactose Potato starch

gelatin

Magnesium stearate

0.25 mg

85.75 mg

30.0 mg

3.0 mg

1.0 mg

120.00 mg

Standard .TMSö - 10.00 ppm. Example 13

2 '- (p-fluorobenzoyl) proscillaridin A from proscillaridin A and triethyl ortho-p-fluorobenzoate according to Example 1. SS

Mp; i54 ^ i60 ° C.

Example 14

^ '- (p-ChlorophenylacetylJ-proscillaridin A from Proscil laridin A and triethyl ortho-p-chlorophenylacetate according to Example 1.

M.p. 132-142 "C.

Example 15

2'-Benzoyl-4'-thenoyl-proscillarld! N A from Proscillari-6s din A, orthobenzqesäuretrlmethylester and Then (2) oylchlorld.

Fo. 164-17O ⁰ C.

production method

The active substance is intensively rubbed in with ten times the amount of milk sugar. Mixing this "trituration with the rest of lactose and potato starch mi and granulated with a 10% aqueous solution of the gelatin through sieve 1.5 mm drying at 4O ⁰ C. The dried granules through sieve 1 mm wire again rubbed and stearate with mixed Magnesi . Tablets are pressed from the mixture.

Tablet weight: 120 mg. Stamp: 7 mm flat with partial notch.

B) Dragees 1 coated tablet contains:

2 '"(y-chlorobutyryl)

proscillaridin A

Lactose Mjalskraft Polyvinyl pyrrolidone Mugneslum stearate

0.25 mg

32.25 mg

15.0 mg

2.0 mg

0.5 mg

50.00 mg

production method

The active substance is intensively rubbed with ten times the amount of milk sugar, with the rest

Milk sugar and mixed with the corn starch and with a 15% aqueous solution of polyvinylpyrrolidone Granulated through 1 mm sieve. The mass, dried at 40 ° C., is again passed through the above sieve grated, mixed with magnesium stearate and then pressed into tablet cores.

Core weight: 50 mg.

Stamp: 5 mm waved.

The tablet cores produced in this way are coated with a shell according to a known method, which in the consists essentially of sugar and talc. The finished coated tablets are made with the help of beeswax polished.

Dragee weight: 85 mg.

C) coated tablets 0.125 mg inter B) anj 0.0125 g 1 dragee contains: 32.375 mg 0.3 g 2 '- (cyclopentylcarbonyl) - 15.0 mg composition 0.1g proscillaridin A 2.0 mg 100 ml of drop solution contain: 30.0 g Lactose 0.5 mg 2 '- (ß-phenylpropionyl) - Cornstarch 50,000 mg proscillaridin A 1.0 g Polyvinyl pyrrolidone production method Sodium saccharine 100.0 g Magnesium stearate The production takes place as ι above Sorbic acid D) drops Ethanol Men's liquor essence (Haarm.Ä Reimer) Dist. Water, ad.

E) ampoules
The ampoule contains:

2'-propionyl-proscillaridin A 0.25 mg

Polyethylene glycol 600 700.0 mg

Tartaric acid 150.0 mg distilled water, ad. 3.0 ml

production method

Tartaric acid, polyethylene glycol and the active substance are successively dissolved in distilled water. It is made up to the given volume with distilled water and filtered aseptically.

Filling: into white 3 ml ampoules under nitrogen gas.

Sterilization: 20 minutes at 120 ^° C.

F) suppository suppositories contains:

2'-propionyl proscillaridin A

Lactose

Suppository mass

(e.g. WitepsolW45)

0.25 mg 4.75 mg

1695.0 mg 170ÖÖÖmg

35 Manufacturing Process

The trituration of the active substance with milk sugar is stirred into the melted suppository mass, which has been cooled ^{to 40 ° C., with the aid of an immersion homogenizer.} It is cooled to 37 ° C. and poured into slightly pre-cooled molds.

Suppository weight: 1.7 g.

G) suppositories suppositories contains:

40

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.

2'-acetyl-4'-methoxyproscillaridin A
Lactose
Suppository mass
(e.g. WitcpsolW45)

0.125 mg, 4.875 mg

1695.0 mg 1700,000 mg

45

Connection of the formula Effect absorption

(Meiirsbhwoinchon) (rat)

LD manufacturing process The manufacturing takes place as indicated above under F).

Duration of action liliminulionsgcschWiiuligkuil (Guinea pig) (MLO - = ■ miiilnv l.ciuldosis)

nig / ky i. v.

^ _; l00-R%

CHj-CO / CHj 0.573 cyclo — C ₃ H ₉ —CO / H 0.703 cyclo-CjHj-CO / H v '0.716 CI- / ~ V-CH ₂ -CO / H 0.933 C ₂ H _S -CO / CH ₃ 0.883 H / H (prosellluridine A) 0.465 CH, CO / H (2'-acetyl-Pr.) 0.410

100% 100% 100%

97%

98%

16.5% 55% 55 min
25 min
27 min

63 min

63 min

42 min
92 min

h - tl% MLD / h I68 | * g / kg * h - 24% MLD / h 160 »g / kg · h - 22% MLD / h

89 µκ / kg · h - 9.5% MLD / h

84 μυ / kg · h »9.5% MLD / h

67 µβ / kg · h - 14% MLD / h 27 μβ / kg · h - 6.5% MLD / 1

Claims (1)

Patent claims: 1. Compounds of the general formula I
H (D R ₁ the group H ₃ C