DE1943902B2 - -cardenolides and -bufadienolides and processes for their preparation and their use in combating heart disease - Google Patents

Description

R, O

O-R ₁

in which Ri is a steroid radical of the 3-hydroxycardeno-Hd or 3-hydroxybufadienolide series, R _{2 is} an aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, which optionally additionally has one or more double bonds, characterized in that 3- [2 ', 3'-Dideoxy-zl ² '( ³ '> -rhamnopyranosyl] -cardenolide or -bufadienolide with alkyl, cycloalkyl or aralkyl halides, in which the alkyl or cycloalkyl moiety can additionally have one or more double bonds, in the presence of inorganic silver compounds in converts an inert solvent.

2. 3- [2 ', 3' - dideoxy-4 ² '< ³ ') -4'-alkyl-rhamn & pyranosyl] -cardenolide or -bufadienolide of the general formula

R, 0

QR ₁

in the Ri a steroid residue of the 3-hydroxycardenolide or 3-hydroxybufadienolide series, R2 is a methyl group means.

3. Digitoxigenin-3-L- [2 ', 3'-dideoxy-4 ² < ³ >-4'-O-methyl-rhamnoside].

4. Use of a compound according to claim 2 in combating heart disease.

It is already known that cardiac glycosides, which carry one or more ether groups in the glycoside part, have an advantageous positive inotropic effect. For example, the cymarin shows that in the glycoside part Contains digitose-3'-methylether, one opposite K-strophanthin, which is the same as that of Genin Contains K-strophanthidin, significantly better enteral absorption and better lipoid solubility (B. H el wig, Moderne Arzneimittel, 3rd edition [1967], p. 756).

The invention relates to the previously unknown 3- [2 ', 3'-dideoxy-4 ² '< ³ ') -4'-O-methyl-rhamnopyranosyl] -carbenolide or -bufadienolide (in the older literature was for » 2,3-Dideoxy-Zl ^{2 J} - «the term» 2-deoxy-2,3-anhydro «is common), ie compounds which have an ether group in the 4'-position of the glycoside part and their use in combating heart disease.

Another object of the invention is the following manufacturing process.

It has been found that 3- [2 ', 3'-dideoxy-Zl ² ' ( ³ '> R ₃ O

O-R ₁

ι »in which R, a steroid radical of the 3-hydroxycardenolide or 3-hydroxybufadienolide series, R2 an aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, which optionally also has one or more double bonds, can be produced by 3- [2 ', 3' -Dideoxy-4 ² ' ⁽³ '> -rhamnopyranosyl] -cardenolide or -bufadienolide with alkyl, cycloalkyl or aralkyl halides, in which the alkyl or cycloalkyl moiety may have one or more double bonds, in the presence of silver salts in an inert solvent .

The following cardenolides or bufadienolides, for example, can be used as starting compounds:
the 3- [2 ', 3'-dideoxy-4 ² ' ( ³ ') -L or D-rhammoside] of digitoxigenin, gitoxigenin, digoxigenin, periplogenin, ^ -carboxymethylene-periplogenin-S / S-lactone, 19-cyanomethylene -periplogenins, uzarigenins, canarigenins, K-strophanthidins, scillarenins, bufalins, adrost-5-en-3 /? - ol-17 /? - yl - «- pyrons and des androst-5-en-3j3-ol-17j3- yl-butenolids. The production of

jo th steroidal starting compounds are carried out, for example, by reacting the corresponding steroid alcohols with acylated rhamnals and subsequent saponification of the 4-acyl group of the glycoside part, acetyl and benzoyl radicals in particular being considered as acyl radicals, according to the method described in patent application P 17 68 165.1. Silver carbonate, silver bicarbonate or silver oxide, for example, can be considered as silver salts.
The following are preferably used as alkyl, cycloalkyl or aralkyl halides:

Methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl bromide, propyl iodide, butyl iodide, allyl bromide, Allyl iodide, cyclohexyl iodide, cyclohexyl bromide, benzyl iodide, benzyl bromide, benzyl chloride, crotyl iodide, crotyl

4 ^r ) bromide, cyclohexene iodide, cyclohexene bromide.

The solvents which can also serve as water entrainers are preferably chlorinated Hydrocarbons such as dichloroethane, chloroform, ethylene chloride, methylene chloride or Solvents such as benzene, xylene, dimethylformamide or mixtures of the solvents just mentioned used.

To carry out the process according to the invention, the steroidal starting compound is dissolved in one of the solvents just mentioned, preferably in dichloroethane, sets an excess of the Alkyl halide and the silver salts are added and the reaction mixture is then advantageously heated under a nitrogen atmosphere, 30 min. to 24 h. under

bo stirring under reflux, expediently the possibly condensed solvent which has distilled over is preferably carried out by a water-absorbing one Material, for example anhydrous calcium sulfate, can flow back. After the reaction has ended

b5 is worked up by filtering off the insoluble silver salts, evaporating the filtrate and the obtained residue recrystallized from inert solvents or purified by chromatography.

The products of the process have valuable pharmacological properties. Although they are not free Carrying more hydroxyl groups in the glycoside portion, they surprisingly show a high positive inoti'ope action as well as diuretic and antidiarrheal Properties. Furthermore, they are characterized by an increased lipoid solubility.

For example, the digitoxigenin-3-L- [2 ', 3'-dideoxy-, d ² < ³ ') -4 '- (O-methyl) rhamnoside] produced according to the invention surprisingly shows a significantly higher cardiotonic effect than that Digitoxin used therapeutically.

example 1

Digitoxic, in-3-L- [2 ', 3'-dideoxy-zl ² < ³ >4'-O-methyl-rhamnoside]

2 g of dighox'igenin-3-L- [2 ', 3'-dideoxy-A ² V> -rhamno sid] are dissolved in 50 ml of 1,2-dichloroethane, and 40 ml of methyl iodide and 2 g of silver carbonate are added. The reaction mixture is refluxed in a nitrogen atmosphere with stirring for 6 hours, the condensed liquid flowing back through a small thimble containing anhydrous calcium sulfate. After the reaction has ended, the undissolved silver compounds are filtered off and the solvent from the filtrate is distilled off i. Vac. away. The oily residue obtained is crystallized from ether / n-hexane. Digitoxigenin-3-L- [2 ', 3'-dideoxy- <d ² ' ( ³ >-4'-O-methyl-rhamnoside] is obtained in crystallized form with a melting point of 178-179 ° C. (Kofier-Bank Character. IR bands: 3505 (pointed), 1775, 1750 (shoulder), 1735, 1630,1090,1030,1005 cm- ¹ (recorded in KBr).

The output connection is shown as follows:

Digitoxigenin-3- [2 ', 3'-dideoxy-d ² '< ³ ') -L-rhamnoside-4'-acetate]

A solution of 1.1 g digitoxigenin in 9.6 ml absol. Tetrahydrofuran is mixed with 1.8 ml of diacetyl-L-rhamnal and 0.07 ml of phosphorus oxychloride. After stirring for 5 hours at 20-25 ° C (warming the reaction mixture to over 40 ° C should be avoided because of the formation of undesirable, poorly separable by-products and the associated impairment of yield), the reaction mixture is poured into 50 ml of water, the excess NaHCO ₃ contains, extracted exhaustively with chloroform, the extracts were washed with water, dried and the solvents were distilled i. Vac. away. About 2.5 g of oil remains as a residue, which gradually crystallizes through after trituration with ether. Then you filter off the crystals and wash them with a little cold ether. This gives 1.01 g of digitoxigenin-3- (2'-deoxy-2 ', 3'-anhydro-L-rhamnoside-4'-acetate] mp .: 137-140 ⁰ C (Kofler bank).

Characteristic. Ir bands: 3515, 1780, 1750, 1735, 1615, 1230,1020,740 cm- (in KBr).

UV spectrum (methanol): A, _rm = 216-217 ΐημ; ε = 16,600.

Digitoxigenin-3- [2 ', 3'-dideoxy-zl ² ' ( ^J ') -L-rhamnoside]

0.99 g of the crystallized reaction product just obtained are used to saponify the 4'-acetyl group dissolved in 32 ml of methanol and at the boiling point with a solution of 297 mg of potassium bicarbonate in 2.97 ml of water offset. The reaction mixture is boiled for 20 min

Reflux, then it is cooled down to 20 ⁰ C and poured onto 225 ml halbgesättigl: e aqueous sodium chloride solution to give a crystalline product separates. After 16 hours of standing, the crystals are filtered off, washed with water and dried. 0.84 g of digitoxigenin-3- [2 ', 3'-di <Jesoxy-4 ² ' ( ³ ') -L-rh £ imnoside] with a melting point of 188-184 ° C. (Koflerbank), which according to the Recrystallize from acetone / ether-n-He: tan at 198-20 Γ C. [«]» ■ = + 3.0 ° (chloroform; C = 0.5)

ίο (In another approach carried out analogously, [α] 'g ° = +4.6 ^{3 was} found.)

Character. IR bands (recorded in KBr): 3500, 3400, 3040, 1800 (sometimes as shoulder), 1775, 1720, 1620-1625, 1085, 1020, 990, 735cm- '. UV spectrum:

λ ,,,. _Μ . = 216-217 ίτιμ; ε = 15 100 (in methanol).

Example 2

(19-carboxymethylene-periplogenin-5j3-lactone) -3-L- [2 ', 3'-dideoxy-4 ² ' ( ³ ) -4'-O-methyl-rhamnoside]

2 g of (19-carboxymethylene-periplogenin-5 / Macton) -3-L- [2 ', 3'-dideoxy-zl ² ' ^{| 3} ') -rhamnoside] are dissolved in 50 ml of 1,2-dichloroethane and mixed with 40 ml of methyl iodide and 2 g of silver carbonate are added. The reaction mixture is treated and worked up as indicated in Example 1. The residue obtained is crystallized from isopropyl ether. The (^ -carboxymethylene-periplogenin-S / ilactone) -3-L- [2 ', 3'-dideoxy-4 ² ' ( ³ ') -4'-O-methyl-rhamnoside] with a melting point of 165 is obtained -170 ° C (Kofier bench) as a pseudocrystalline precipitate. Character. IR bands (in KBr): 3480, 1775, 1740 (broad), 1700-1710 (broad), 1620,1090,1070,103: 5,1010,735 cm- '.

Preparation of the starting compound

(19-carboxymethylene-periplogenin-5j3-lactone) -3- L- [2 \ 3'-dideoxy- / 4 ² '< ³ ') -rhamnoside]

To a suspension of 345 mg of sodium hydride in 19 ml of abs. Tetrahydrofuran is added dropwise with stirring and cooling 3.2 ml of carmethoxymethyl diethyl phosphonate. After completion of the ^ development one gives this solution to a solution of 2 g of k-strophanthidine in 30 ml of abs. Tetrahydrofuran. Then you rinse with 20 ml abs. Tetrahydrofuran according to. After stirring for 3 hours and 35 minutes at 23 ° C., it is poured the reaction mixture to 400 ml of water, extracted 5 times with chloroform, the extracts washed with water,

so it dries and the solvent is distilled off. The remaining oil is redissolved from acetone / ether. After some time, the product, which is generally again initially oily, then slowly crystallizes completely. The crystals are filtered off and 1.8 g of ^ -carboxymethylene-periplogenin-SjS-lactone with a melting point of 240 ° -245 ° C. (previously sintered) are obtained. UV: A _times = 215 η \ μ, ε = 24 400.
Character. IR bands: 3460 (often also opening bands at 3560cm- ¹ ), 1770, 1710-1730 (wide), 1615, three weak but character. contiguous bands at 1290, 1270 and 1250 cm- ', bands at 2740-2750 cm -> no longer present.

To a solution of 2 g of 19 carboxymethylene periplogenin-5 / Macton in 14 ml of abs. Tetrahydrofuran (if it is sparingly soluble in tetrahydrofuran, a corresponding amount of absolute methylene chloride is added), 2.8 ml of diacetyl-1-rhamnal and 4 drops of phosphorus oxychloride are added. After 4 hours standing or stirring at 20 ⁰ C

the dark colored reaction mixture in 200 ml of water, the excess sodium hydrogen carbonate contains, poured. It is extracted several times with chloroform, the extracts are washed neutral and dried and the solvent is distilled off. The residue obtained in this way is sprayed on with ether, whereby he crystallized through. 3.05 g are obtained

ig-carboxy-methylen-periplogenin-SjJ-lactone-S - ^ '- O - acetoxy-2', 3'-dideoxy-zl ² '< ³ ') -L-rhamnoside] of m.p. 221-23TC, the shows a melting point of 265-267 ° C. after recrystallization from methylene chloride / ether.

Character IR bands: 3485, 1775, 1730-1740, 1615, 1230 (strong), 1020 cm- '.

UV: A _ma »= 215-216 πιμ, ε = 26,500.

For the saponification, 2.2 g of the reaction product obtained according to a) and having a melting point of 265-267 ° C. are added in 70 ml of abs. Dissolved methanol. A solution of 660 mg of potassium hydrogen carbonate in 6.6 ml of water is added at the boiling point and the reaction mixture is refluxed for 15 minutes. It is then poured into 250 ml of water and extracted with chloroform. After the chloroform has been washed and dried, it is distilled off. After digestion with ether, 1.9 g of Ig-carboxymethylene-periplogenin-S / Macton-3- [2 ', 3'-dideoxy- <4 ² '< ³ '> -L-rhamnoside] are obtained from the residue after reprecipitation from acetone / ether one; mp. 202-208 ⁰ C. Fig. Character IR bands: 3450, 1775, 1700-1740 (broad), 1615, 1025 cm- '. UV: A, "" = 215-216 πιμ, ε = 23,300.

[A] T = + 4 ° (c = 0.5: HCCl ₃ ).

Example 3

K-strophanthidin-3-L- [2 ', 3'-dideoxy-4 ² < ³ ) -4'-O-methyl-rhamnoside]

2 g of K-strophanthidin-3-L- [2 ', 3'-dideoxy-4 ² ' ( ³ ') -rhamnoside] are dissolved in 50 ml of 1,2-dichloroethane and mixed with 40 ml of methyl iodide and 2 g of silver carbonate.

The reaction mixture is treated and worked up as indicated in Example 1. The residue obtained is crystallized from diethyl ether. The K-strophanthidin-3-L- [2 ', 3'-dideoxy-4 ² '< ³ >-4'-O-methyl-rhamnoside] with a melting point of 136-139 ° C. (Kofier bank) is obtained.

Character. IR bands (in KBr): 3490, 2745, 1775, 1735, 1710, 1620, 1090, 1025, 1000, 740 cm- '.
A solution of 10 kg of K-strophanthidine in 70 ml

15 ml of L-rhamnal-3 ', 4'-diacetate and 20 drops of phosphorus oxychloride are added to absolute tetrahydrofuran. After 5 hours of stirring between 20-25 ⁰ C, it is poured the reaction mixture to excess sodium bicarbonate containing water and extracted with chloroform. The chloroform extract is washed with water and dried with sodium sulfate. After the solvent has been distilled off, an oil is obtained which is chromatographed on silica gel “Merck” (column: 3 × 25 cm) with first 1.51 of benzene and then with 4 liters of ether as the eluent. After distilling off the solvent from the ether eluate, after spraying with isopropyl ether, 11.2 g of amorphous K-strophanthidine-3-L- [2 ', 3'-dideoxy- / j2' (3 ') - rhamnoside-4' acetate] with the following characteristic IR bands (in KBr): 3500 (pointed), 2750, 1775, 1740, 1715 (shoulder), 1230, 1030, 1005 (shoulder) cm - '.

To saponify the 4'-acetate group, a solution of 5.2 g of K-strophanthidine-3-L- [2 ', 3'-dideoxy- /! ² '( ³ '>-rhamnoside-4'-acetate] in 168 ml of methanol with a solution of 1.6 g of potassium bicarbonate in 15 ml of water and the reaction mixture is refluxed for 25 minutes containing water and extracted with chloroform. After the chloroform has been distilled off, a foam remains, which is sprayed on with isopropyl ether. 4.4 g of amorphous K-strophanthidin-3-L- [2 ', 3'-dideoxy-4 ² ' are obtained. < ³ ') rhamnoside] with uncharacteristic melting behavior (melting range: 150-155 ° C). Character. IR bands (in KBr): 3470, 2750, 1775, 1735, 1710 (shoulder), 1620, 1020, 990 cm- '.

Claims (1)

Patent claims: 1. Process for the preparation of 3- [2 ', 3'-dideoxy-4 ² '< ³ ') -4'-alkyl-rhamnopyranosyl] -cardenoliden and -bufadienoliden of the general formula 4'-O-alkyl-rhamnopyranosyl] cardenolides and bufadienolides the general formula