CH647521A5 - 14-Hydroxy-amino eburnane derivs. and precursors - Google Patents

Abstract

Eburnane derivs. of formula (I), their optical isomers and pharmaceutically acceptable acid addn. salts are new: where R1 and R2 are each 1-6C alkyl). (I) are intermediates for pharmaceuticals e.g.treatment with aq. dia. acid gives a mixt. of esters of vincaminic and apovincaminic acids. (I) also have pharmaceutical activity themselves, esp. as vasodilators for increasing blood flow in the limbs

Description

The present invention relates to indoloquinolizine esters of the formula

K

n

R3OOC

R1OOC

(A)

45!

R OOC

R1OOC

(VII)

(Va)

where m 1 and n are zero and the dashed line represents a C-N single bond, or m is zero and n 1 if the dashed line is a C-N double bond,

X represents the anion of an acid,

Y is hydrogen or a group of the formula

-CH2-CH (COOR ') 2

is in which formula R 'represents a Ci-Có-alkyl radical, R2 represents ethyl and

R3 has the meaning of R1, or, if m = 1 and Y represents hydrogen, R3 represents hydrogen, and the pharmaceutically acceptable acid addition salts of compound 65 of formula A. These compounds can also be present as optically active isomers.

These new compounds can be used to make

(Vb)

OOC

COOR-

3rd

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such as

F ^ OOC

R1OOC

and

X CH-CH2 ^

wherein the meaning of R1 is the same as above, optionally in the presence of a basic catalyst. The hexahydro-indoloquinolizine ester derivatives obtained of the general formula IVa and / or IVb

(IVa)

R ^ OOC

15 1 R OOC

(IVa)

R1OOC

R1OOC

C-CH2 ^

R1OOC ^

CH0 «^

CH

COOR "

+ - V / -

(IVb)

wherein the substituents are defined above.

Preferred embodiments for the preparation of the new compounds of the formula A and the new compounds of the formulas IVa and IVb, Va and Vb and VII, all of which come under the general structural formula A, are described below:

Hexahydro-indoloquinolizine compounds of the general formula II

20th

!! R1OOC. M J I (IVb)

C-CH

1 /\

R00C CH, -I 2

30th CH

1 / i

R OOC COOR

35 wherein the meaning of R1, R2 and X is the same as above, are catalytically hydrogenated. The new octahydro-indoquinolizine ester derivatives of the general formula Va and / or Vb obtained

40

45

(II)

R ^ OOC

50 R1OOC

(Va)

wherein the meaning of R2 is the same as above and X stands for acid residue, with methylene malonic diester derivatives of the general formula III

60 R1OOC

CH2 = C

COOR1

'COOR1

(III)

(Vb)

R1OOC

R1OOC

COOR '

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4th

R1OOC

^ C-CK-T, J-

i / 1 R. ^

10 R OOC CH ^ y COOR '

I.

is R "^ OOC

4. / \

CH0-CH

^ COOR1

COOR '

(IVc)

wherein the meaning of R1 and R2 is the same as above, are subjected to an alkaline treatment, whereby the new octahydro-indo-quinolizine monoester derivatives of the general formula VII

wherein the meaning of R1 and R2 is the same as above. If desired, the base can be released from the compounds of general formulas IVa and IVb obtained during the reaction. The compounds of the general formulas Va, Vb and VII can be converted into salts and / or into their optical antipodes and, if desired, the further reaction steps can be carried out with the corresponding optical antipodes.

The substituents R1 and R2 stand for alkyl groups with 1 -6 carbon atoms, that is for methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl -, n-pentyl, i-pentyl, n-hexyl and i-hexyl group.

The starting compounds of the general formula II, in which R 2 is ethyl and X is an acid residue, can be prepared according to the method described in J.A.C.S. 87 methods described on pages 1580-1589.

The starting compounds of the general formula III are accessible in the manner described in J. Org. Chem. 4,493 (1939), for example by reacting malonic acid ester with paraformaldehyde.

The reaction of the compounds of the general formulas II and III is preferably carried out in an organic solvent which is neutral with regard to the reaction. Examples of suitable organic solvents are halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons such as dichloromethane or chloroform, furthermore alcohols, preferably aliphatic alcohols with 1-6 carbon atoms such as tert-butanol, and also acetonitrile.

The reaction is optionally carried out in the presence of a basic catalyst. As such, for example, aliphatic or cyclic organic amines (di-ethylamine, triethylamine, piperidine, pyridine) or catalytic amounts of alkali metal alcoholates (for example potassium tert-butoxide) are suitable. The reaction is preferably carried out at room temperature. The reaction time depends on the reaction temperature and is usually between a few hours and a few days.

The ratio in which the compounds of the general formulas IVa and IVb form in the reaction mixture depends on the amount of reagent of the general formula III used. If this is used in a large excess, for example, in addition to the compounds of the general formulas IVa and IVb, a compound of the general formula IVc can also be formed in a smaller amount (R1, R2 and X have the same meaning as for the compounds of the general formulas IVa and IVb)). In practice, however, it is advisable to avoid an excessive excess of the compound of the general formula III.

The intermediaries of the general formulas IVa, IVb and IVc are new compounds and also biologically active per se. The corresponding base can be released from them in a manner known per se by alkaline treatment. For the next step of the reaction, it is expedient to use the compounds of the general formulas IVa and IVb in the form of their acid addition salts. 30 For the catalytic hydrogenation of the compounds of the general formulas IVa and / or IVb, metals, for example palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, tungsten and their oxides and sulfides can be used as the hydrogenation catalyst. The catalyst used may also have previously been deposited on the surface of a support. For example, coal, primarily animal charcoal, can be used as a carrier, but silicon dioxide, the sulfates and carbonates of the alkaline earth metals are also suitable. 40 palladium activated carbon or Raney nickel is used most often, but the selection of the most suitable catalyst always depends on the properties of the substance to be hydrogenated and the reaction conditions. The catalytic hydrogenation is preferably carried out in the presence of a solvent which is neutral with respect to the reaction and which dissolves the substance to be hydrogenated well. Examples of suitable solvents are water, aliphatic alcohols with 1-6 carbon atoms, halogenated aliphatic hydrocarbons with 1-6 carbon atoms, ethyl acetate, dioxane, glacial acetic acid or mixtures of the solvents listed. When using platinum oxide as a catalyst, it is preferable to work in a neutral or rather acidic medium. If Raney nickel is used, a neutral reaction medium is advisable. The temperature and pressure of the catalytic hydrogenation depend on the starting materials, as does the reaction time. Is preferably hydrogenated at room temperature under atmospheric pressure until the stoichiometric amount of hydrogen is absorbed.

If a pure compound of the general formula IVa 60 or IVb (i.e. not the mixture of the two)

hydrogenated, the corresponding compound of the general formula Va or Vb is formed. If the starting compounds IVa and IVb are present in a mixture, the mixture of the corresponding compounds of the general formulas Va and Vb is obtained on hydrogenation. If the mixture to be hydrogenated also contains a compound of the general formula IVc, a mixture is formed during the hydrogenation which, in addition to the compounds of the general formulas Va

20th

and Vb still the corresponding compound of the general formula Vc

C-CH,

R OOC CH.

COOR

COOR

R OOC COOR

contains (in which the meaning of R1 and R2 has the meaning given in the general formulas Va and Vb).

The intermediaries of the general formulas Va, Vb and Vc are new compounds and also biologically active in themselves. If desired, the acid addition salt can be formed from the compounds. They can also be separated into their optically active antipodes.

From the mother liquor of the catalytic hydrogenation, after neutralization with the aid of preparative thin layer chromatography, a very small amount of the compound of the general formula VI

R OOC

CH-CH

be isolated, wherein the meaning of R1 and R2 is the same as above. This compound differs from the compound of the general formula Va only in that in the compound Va the hydrogen in the 12b position is a-position and therefore takes a cis position to the also a-substituent R2, while in the Compound of the general formula VI which is 12b-hydrogen in the β-position and is therefore in the trans position to R2. This clearly shows that the catalytic hydrogenation of the compounds IVa and / or IVb stereoselectively forms the cis compounds Va and / or Vb.

The alkaline treatment of the compounds of the general formula Va and / or Vb can be carried out with an inorganic base, preferably with alkali metal hydroxides, for example with potassium or sodium hydroxide. The alkaline treatment is preferably carried out in a neutral organic solvent or in a mixture thereof with water. The alcohols corresponding to the alcoholate group of the general formula R'-O- are preferably used as organic solvents. The reaction can occur at anyone between room tem647521

temperature and the boiling point of the reaction mixture. Depending on the temperature, the reaction usually takes 10 minutes to a few hours.

In the alkaline treatment described, both the compound Va and Vb and Vc, but also from their mixtures, form the half-ester of the general formula VII. In the alkaline treatment of the compound of the general formula Vb, usually forms in the first stage of the reaction the corresponding compound of the general formula Va. The reaction can be followed by thin layer chromatography. It is then possible to separate the compound of the general formula Va from the mixture by interrupting the reaction in good time. The properties of the compound of the general formula Va obtained in this way correspond to those of the general formula Va obtained by catalytic hydrogenation of the compound IVa or of the mixture IVa and IVb.

The compounds of the general formula VII are new and also biologically active per se. Salts can be formed from the compounds of the general formula VII in a manner known per se, or they can be separated into their optical antipodes. The invention also extends to the salts and the optical antipodes.

The three-step process can also be carried out in a single step without the separation, crystallization and identification of the intermediaries.

The reaction mixtures of all steps of the process can be worked up in a manner known per se. The type of workup depends on the starting materials, the end products, the solvents etc. If the reaction product precipitates, it can be separated off by filtration. If the reaction product is in

Solution remains, so they are usually vurhan

which by-products are filtered off, and then the solution can be evaporated, or the product is precipitated from the solution with a suitable solvent.

For example, if the salt is to be precipitated, the appropriate acid or its solution prepared with a suitable solvent is preferably added to the solution. Furthermore, the product can be separated from the solution by means of preparative thin layer chromatography.

When the reaction mixtures of the intermediate steps are worked up, crystalline products are generally obtained. In the event that the product is oily or amorphous, it usually succeeds in crystallizing it with the solvents chosen in organic chemistry and depending on the solubility of the corresponding substance.

The compounds obtained can be further purified, for example by recrystallization.

The following acids can be used, for example, to form the salts of the compounds mentioned above: organic acids, such as hydrogen halides, for example hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, etc., and also organic acids, carboxylic acid, such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, Hydroxymalein acid, fumaric acid, salicylic acid, lactic acid, Zirntsäure, benzoic acid, phenylacetic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, p-aminosalicylic acid, etc., further alkylsulfonic acids, for example methanesulfonic, ethane-sulfonic acid, cycloaliphatic sulfonic acids such as cyclohexyl sulfonic acid, arylsulfonic acids, for example p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, amino acids, for example aspartic acid, glutamic acid.

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example 1

(±) -1 a-ethyl-1 ß- (2 ', 2'-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3-a] quinolizine and (±) -1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -I, 2,3,4,6,7,12,12bcc-octahydro- indolo [2,3-a] quinolizine.

A suspension of 10.00 g (28.4 mmol) of 1-ethyl 1-1,2, -3,4,6,7-hexahydro-12H-indoIo [2,3-a] quinolizine-5-ium-per Chlorate in 60 ml dichloromethane and 3.6 ml (2.60 g; 25.7 mmol) of triethylamine is stirred with the solution of 8.0 ml (8.4 g; 48.8 mmol) of methylene malonate in 10 ml of dichloromethane are added. The reaction mixture is left to stand at room temperature for two days.

The solvent is distilled off in vacuo and the orange oil remaining as evaporation residue is triturated three times with 30 ml of ether and three times with 30 ml of petroleum ether.

In this way, 18 g of a mixture of 1-ethyl-l- (2 ', 2'-diethoxycarbonyl-ethyl) -l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a ] quinolizine-5-ium perchlorate and 1-ethyl-1 - (2 ', 2', 4 ', 4' -tetraethoxycarbonyl-butyl) -1,2,3,4,6,7-hexa-hydro-12H -indolo [2,3-a] quinolizine-5-ium-perchloratin in the form of an oil which can be used for the next reaction step without being purified.

IR (in KBr): 3260 (indole-NH), 1735.1715 (CO), 1615.1520 (C = N) cm "'.

The 18 g oily mixture is dissolved in a mixture of 200 ml of ethanol and 50 ml of dichloromethane and hydrogenated in the presence of 8 g of pre-hydrogenated 10% palladium-carbon catalyst. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and washed first three times with 3 ml of ethanol, then three times with 30 ml of dichloromethane. The filtrate is combined with the washing liquid and evaporated to dryness in vacuo. The evaporation residue is crystallized from 50 ml of ethanol. The product is washed with ethanol and then dried. In this way 9.0 g (±) -1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -1,2,3,4,6,7, Obtained 12.12ba-octahydro-indolo [2,3-a] quinolizine perchlorate, which indicates 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] - quinolisin-5-ium perchlorate based on a yield of 45.3% corresponds. Melting point: 216-218 ° C (ethanol)

Elemental analysis for C33H46N208.HC104 (M = 699.18)

Calc .: C 56.68%; H 6.63%; N 4.01%

Found: C 57.00%; H 6.55%; N 4.10%.

The hydrochloride of the compound melts at 211-212 ° C (ethanol).

MS (m / e,%): 426 (M + -l 72; 6), 425 (3), 411 (0.3), 397 (0.3), 381 (2), 353 (1), 267 ( 100), 253 (3), 237 (5), 197 (8), 185 (6), 184 (6), 170 (10), 169 (10), 156 (6), 144 (5), 127 ( 10), 99 (10).

The (±) -1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -! , 2,3,4,6,7,12, 12ba-octahydro-indolo [2,3-a] quinoli inbase is prepared by dissolving the perchlorate or the hydrogen chloride in dichloromethane, the solution with 5% aqueous sodium carbonate solution shaken out, the organic phase separated, dried over solid magnesium sulfate and evaporated in vacuo.

■ H NMR (CDCb, 5): 7.86 (1H, indole-NH), 4.30-3.85 (8H, m, O-CH;), 1.45-1.0 (15H, m , CH2-CH3).

From the ethanolic mother liquor of (+) - 1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -1,2,3,4,6,7, -12, 12ba-octahydro-indolo [2,3-a] quinoli in perchlorates becomes the

Ethyl alcohol distilled off. The evaporation residue is dissolved in 30 ml dichloromethane. The solution is shaken with 20 ml of 5% aqueous sodium carbonate solution, the organic phase is separated off, dried over solid anhydrous magnesium sulfate and then evaporated in vacuo. The residue is dissolved in 10 ml of ethyl alcohol, the solution is acidified to pH 5 with hydrochloric acid ethanol and then the hydrochloride is precipitated by adding 10 ml of ether. The product is filtered off, washed with ether and then dried.

4 g (±) -l a-ethyl-1 ß- (2 ', 2'-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3- a] Quinolizine hydrochloride are obtained, which is based on 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate in a yield of 30 Corresponds to 4%.

Melting point: 202-204 ° C (ether).

IR (KBr): 3300 (indole-NH), 1720 (CO) cm- '.

MS (m / e,%): 426 (M +, 15), 425 (12), 411 (1), 397 (1), 381 (8), 365 (0.5), 353 (2), 307 ( 0.6), 267 (100), 253 (2), 237 (4), 197 (12), 185 (8), 184 (7), 170 (10), 169 (12), 156 (5), 145 (0.6), 144 (5), 143 (3), 127 (1), 124 (3).

The (±) -l a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -l, 2,3,4,6,7,12ba-octahydro-indolo [2,3-a] quinolizine Base is prepared by dissolving the hydrochloride in dichloromethane, shaking the solution with 5% aqueous sodium carbonate solution, separating the organic phase, drying over solid magnesium sulfate, filtering and then evaporating to dryness.

'H NMR (CDCb, 8: 7.82 (1H, indole-NH), 7.2-6.85 (4H, m, aromatic), 3.90 (4H, q .1 = 7.3 cps, O-CH2), 1.2-0.8 (9H, m, -CH3).

The (±) -la-ethyl-1 ß- (2 ', 2'-diethoxycarbonyl-ethyl) prepared in the described manner -1,2,3,4,6,7,12,12ba-octa-hydro-indolo [2,3-a] Quinolizine base is subjected to preparative thin layer chromatography (KG-60 PF254 + 366 'benzene: methanol = 14: 3, eluting with acetone). After elution and evaporation of the eluate, the evaporation residue is crystallized from ethanol. The product with the higher Rr value is (±) -1 a-ethyl-1β- (2 ', 2'-diethoxy-carbonyl-ethyl) -1,2,3,4,6,7,12,12bß octahydro-indolo [2,3-a] quinolizine.

Yield: 0.25 g (based on 1-ethyl-1,2,3,4,6,7-hexahydro-l 2H-indolo [2,3-a] quinolizine-5-ium perchlorate, based on 2%). Melting point: 127-128 ° C (ethanol).

IR (KBr): 3280 (indole-NH), 1730.1705 (CO) cm1. MS (m / e,%): 426 (M +, 13), 425 (7.1), 411 (0.8), 397 (0.8), 381 (4.2), 366 (0.9) , 353 (1.8), 337 (0.8), 335 (0.5), 307 (0.6), 267 (100).

Example 2

(±) -1 a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3-a] quinolizine and (±) -1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -1,2,3,4,6,7,12,12ba-octahydro- indolo [2,3-a] quinolizine.

5.00 g (14.2 mmol) of l-ethyl-l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium perchlorate are mixed out 30 ml of dichloromethane and 0.080 g (0.715 mmol) of potassium tert-butoxide are suspended. The solution of 3.03 ml (3.12 g, 18.4 mmol) of methylene malonate in 5 ml of dichloromethane is added to the suspension with stirring. The reaction mixture is left to stand at room temperature for one day.

Then the solvent is distilled off in vacuo and the orange oil remaining as evaporation residue is triturated three times with 5 ml of petroleum ether. 9 g of a mixture of l-ethyl-l- (2 ', 2'-diethoxycarbonyl-ethyl) -l, 2,3,4,6,7-hexahydro-12H-indolo [2,3-a] -quinolizine- 5-ium

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647521

Perchlorate and 1-ethyl-1 - (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) - 1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] Quinolizine 5-ium perchlorate is obtained in the form of an oil. This is used for the following reaction step without purification.

IR (KBr): 3260 (indole-NH), 1735, 1715 (CO), 1615.1520 (C = N) cm-1.

The 9 g of oil obtained are dissolved in a mixture of 10 g of ethanol and 25 ml of dichloromethane and hydrogenated in the presence of 6 g of pre-hydrogenated 10% palladium-carbon. After the desired amount of hydrogen has been taken up, the catalyst is filtered off from the solution and washed three times with 3 ml of ethanol, then three times with 10 ml of dichloromethane. The filtrate is combined with the washing liquid, evaporated to dryness in vacuo and the evaporation residue crystallized from 30 ml of ethanol. The product is filtered off, washed with ethanol and then dried.

In this way, 8 g of a mixture of (±) -1 a-ethyl-1 ß- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -1,2,3,4,6,7 , 12,12ba-octahydro-indolo [2,3-a] quinolizine perchlorate and (±) -1 a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -1,2,3 , 4,6,7,12,12ßa-octahydro-indolo [2,3-a] quinolizine perchlorate, which melts at 181-185 ° C.

The salt mixture can - without isolation and separation - be used in the form of the solution obtained after filtering off the catalyst for the following reaction step.

To determine the composition of the perchlorate mixture, 0.8 g of the mixture is dissolved in 6 ml of dichloromethane and the solution is shaken out with 4 ml of 5% aqueous sodium carbonate solution. The organic phase is separated off, dried over solid magnesium sulfate, filtered and the filtrate is evaporated to dryness in vacuo. The evaporation residue is separated into its components by means of preparative thin layer chromatography (aluminum oxide type T, flow agent: dichloromethane and benzene in a ratio of 20: 1, eluent: dichloromethane: methanol 20: 1).

The compound with the higher Rf value is dissolved in 1.2 ml of ethyl alcohol and the solution is acidified to pH 5 with hydrochloric acid ethanol. The hydrochloride is precipitated by adding 1.2 ml of ether, filtered off, washed with ether and then dried. 0.46 g (±) -la-ethyl-lß- (2 ', 2'-dietho-xycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2, Obtain 3-ajchinolizine hydrochloride, which melts at 202-204 ° C (ethyl alcohol, ether). Yield: 70.5%.

The perchlorate is prepared from the substance with the lower Rr value using 70% aqueous perchloric acid and then recrystallized from ethanol. 0.26 g (26%) (+) - 1 a-ethyl-1β- (2 ', 2', 4 ', 4' -tetraäthoxycarbonyl-butyl) -1,2,3,4,6,7, 12, 12a-octahydro-indolo [2,3-a] quinolizine perchlorate are obtained, which melts at 216-218 ° C (ethyl alcohol).

Example 3

(±) -1 a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3-a] quinolizine

600 mg (1 mmol) of the (±) -1 a-ethyl-1β- (2 ', 2', 4 ', 4' -tetraäthoxy carbonyl-butyl) -1,2,3 prepared according to Example 1 or 2, 4,6,7,12,12ba-octahydro-indolo [2,3-a] quinolizins are dissolved in 8 ml of ethanol. The solution of 120 mg of potassium hydroxide in a mixture of 1 ml of water and 1 ml of ethanol is added to the solution. The reaction is followed by thin layer chromatography (aluminum oxide type T, flow agent: dichloromethane: benzene = 3: 1; the Rr value of the diethoxycarbonyl-ethyl derivative is greater than that of the tetraethoxycarbonyl-butyl derivative) and runs within 20 minutes. The reaction mixture is acidified to pH 6 with acetic acid and the solvent is distilled off in vacuo. The evaporation residue is dissolved in 3 ml of water, the solution is made alkaline to pH 9 with 5% aqueous sodium carbonate solution and then extracted three times with 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered off and the solvent is distilled off from the solution in vacuo. The oil obtained as the evaporation residue is dissolved in 3 ml of ethanol and the solution is treated with hydrochloric acid ethanol. The resulting hydrochloride is precipitated with ether.

0.25 g (53%) (±) -1 a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro- indolo [2,3-a] quino-lizine hydrochloride are obtained which melts at 201-204 ° C.

IR (KBr): 3300 (indole-NH), 1720 (CO) cm- '.

Example 4

(±) -1 a-ethyl-1 ß- (2 '-carboxy-2' -ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3- a] quinolizine

0.46 g (1.08 mmol) of the (±) -1 a-ethyl-1β- (2 ', 2' -diethoxy-carbonyl-ethyl) -1.2,3,4 prepared according to Example 1 or 2 , 6,7,12,12ba-octahydro-indolo [2,3-a] quinolizins are dissolved in 3 ml of ethanol, and to the solution is added the solution of 0.067 g (1.2 mmol) of potassium hydroxide in a mixture of 0, 3 ml of water and 0.9 ml of ethanol were added. The reaction mixture is boiled on the water bath for 90 minutes. Then the solvent is distilled off in vacuo. The oil obtained as a residue is dissolved in 3 ml of water and the solution extracted twice with 2 ml of ether. The aqueous phase is acidified to pH 6 with acetic acid. The precipitated white crystals are filtered off, washed with 5 ml of water and then dried.

0.32 g (74%) (±) -la-ethyl-lß- (2'-carboxy-2'-ethoxycar-bonyl-ethyl) -1,2,3,4,6,7,12,12ba- oktahydro-indolo [2,3-ajchinolizin are obtained which melts at 113-115 ° C (from water).

Ri of (±) -1 a-ethyl-1 ß- (2 ', 2' -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3- a] Quinolizine is larger than that of (±> 1 a-ethyl-1 ß- (2 '-carboxy-2' -ethoxy-carbonyl-ethyl) -1,2,3,4,6,7,12,12ba -octahydro-indolo [2,3-a] quinolizins (on silica gel G, benzene: methanol: concentrated ammonia = 15 ml: 5 ml: 2 drops).

IR (KBr): 3360 (indole-NH), 1715 (CO), 1600 (carboxylate) cm- '.

MS (m / e,%): 354 (M + -44, 53), 353 (58), 339 (8), 325 (8.3), 309 (12), 281 (2), 267 (100). .. 44 (1000).

Example 5

(+) - 1 a-ethyl-1 ß- (2 '-carboxy-2' -ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3- a] quinolizine

0.428 g (0.715 mmol) of the (±) -1 a-ethyl-1β- (2 ', 2', 4 ', 4' -tetraethoxycarbonyl-butyl) prepared according to Example 1 or 2 - 1,2,3,4 , 6,7,12,12ba-octahydro-indolo- [2,3-a] quinoli-interest are dissolved in 3 ml of ethanol. To the solution is added the solution of 0.092 g (1.64 mmol) of potassium hydroxide in a mixture of 0.3 ml of water and 0.9 ml of ethanol. The reaction mixture is boiled on the water bath for 45 minutes, then the solvent is distilled off in vacuo. The oil obtained as a residue is dissolved in 3 ml of water and the solution extracted twice with 2 ml of ether. The aqueous phase is acidified to pH 6 with acetic acid. The precipitated white crystals are filtered off, washed with 5 ml of water and then dried.

0.24 g (74%) (±) -1 a-ethyl-1β- (2'-carboxy-2 '-ethoxycar-bonyl-ethyl) -1,2,3,4,6,7,12, 12ba-octahydro-indolo [2,3-a] -quinolizine are obtained which melts at 112-114 ° C.

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Example 6

(±) -l a-ethyl-1 ß- (2 '-carboxy-2' -ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12ba-octahydro-indolo [2,3- a] quinolizine

The starting point is the filtrate which was obtained according to Example 2 after the catalyst had been filtered off. This filtrate contains, dissolved in the mixture of ethanol and dichloroethane, the (±) -la-ethyl-lß- (2 ', 2'-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12, 12a-octahydro-indolo [2,3-a] quinolizine perchlorate and the (±) -la-ethyl-lß- (2 ', 2', 4 ', 4'-tetraethoxycar-bonyl-butyl) -1 , 2,3,4,6,7,12,12ba-octahydro-indolo [2,3-a] -quinolizine perchlorate approximately in a weight ratio of 3: 1.

The solvent is distilled off in vacuo from the filtrate. A perchlorate mixture of oily consistency is obtained as a residue. This is dissolved in 50 ml of dichloromethane, the solution is shaken with 30 ml of 5% aqueous sodium carbonate solution, then the organic phase is separated off, dried over solid magnesium sulfate, filtered and the filtrate is evaporated to dryness in vacuo. The oil obtained as a residue (1.54 g; 2.34 mmol diethoxy and 0.90 mmol tetraethoxy base, total: 3.24 mmol) is dissolved in 16 ml ethanol. 0.24 g (4.28 mmol) of potassium hydroxide in 2 ml of water are added to the solution. The reaction mixture is boiled on the water bath for 1-1.5 hours. Then the solvent is distilled off in vacuo, the residue is dissolved in 10 ml of water and the basic solution is extracted three times with 10 ml of ether. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The 0.4 g of oil remaining as a residue are mainly a mixture of the starting materials.

The pH of the aqueous phase extracted with ether is adjusted to 6 with acetic acid and the excreted organic substance is extracted four times with 15 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtering, evaporated in vacuo. The oil remaining as a residue is triturated with 10 ml of ether, the substance which separates out is filtered off, washed with 5 ml of ether and then dried.

0.76 g (59%) (±) -l a-ethyl-lß- (2'-carboxy-2'-ethoxycar-20 bonyl-ethyl) -1,2,3,4,6,7,12, 12ba-octahydro-indolo [2,3-a] -quinolizine are obtained, which melts at 108-111 ° C. with decomposition.

B

Claims (2)

647521 2nd PATENT CLAIMS 1. Indoquinolizine esters of the formula Hydroxyamino-eburnamine derivatives of the formula (X "J R3OOC 1 R OOC y (I) wherein m 1 and n are zero and the dashed line represents a C-N single bond, or m are zero and n 1 if the dashed line is a C-N double bond, X is the anion of an acid, Y is hydrogen or a group of the formula -CH2-CH (COOR ') 2 is in which formula R1 represents a Ci-Cs-alkyl radical, R2 represents ethyl and R3 has the meaning of R1 or, if m = 1 and Y represents hydrogen, R3 represents hydrogen, and the pharmaceutically acceptable acid addition salts of the compound of the formula A. 2. Indoquinolizine ester according to claim 1, characterized in that they are present as optically active isomers. be used. The compounds of formula I serve as medicaments with vasodilatory effects. 20 The preferred new compounds of the following formulas fall under the formula A given above 25th HOOC R1OOC ' CH-CH 35