FI73429B - SOM MELLANPRODUKT VID FRAMSTAELLNING AV THERAPEUTISKT ANVAENDBARA HYDROXIAMINO-EBURNANDERIVAT ANVAENDBARA INDOLOKINOLIZINDERIVAT. - Google Patents

Description

1 73429 Indole-quinolizine derivatives used as intermediates in the preparation of therapeutically useful hydroxyamino-eburnan derivatives 5 Separated from patent application 801757

The invention relates to novel indoloquinolizine derivatives of the formula io f '----------

jt I f N

T '' Ί Vili HOOC H 1) 15 R1OOC ^ h r2 1 2 wherein R and R represent C1-6 alkyl and their salts.

The compounds of the invention are used as intermediates in the preparation of therapeutically useful hydroxyamino-eburnan derivatives of the formula R OOC <* νν'ΛΛ / Τ \.

I ^ R2 NH R

OH

1 2 30 wherein R and R are C 1-6 alkyl. The preparation and therapeutic properties of these compounds are described in EI Patent Application 850114.

The compounds of the formula I can be used as vasodilators and in particular have a circulatory-enhancing effect on raw materials.

The compounds of formula I may also be used as intermediates in the preparation of other therapeutically useful compounds.

Hungarian Patent Application No. 634 (corresponding JP Kokai 78/147100 is referenced in Chemical Abstracts, Vol. 90 (1979) 187199 v) describes a process for the preparation of compounds of formula (I). In this known method, a pentacyclic compound, an E-homoeburnan derivative, which also contains a 7-membered ring, is used as a starting material. This starting material is much more complicated than the compound of the invention. The pentacyclic starting material of the known method is prepared tetracyclically from an indoloquinolizine derivative by a multi-step synthesis.

By using the tetracyclic indo-quinolizine compound of the invention, the compounds of the formula I can be prepared directly, the process comprising fewer process steps than the known process and thus being much simpler.

U.S. Pat. No. 3,755,333 discloses hexa- and octahydroindolo [2,3-a] quinolizines having two ethyl groups in the 1-position, one having two substituents, namely acyl and acyloxy or hydroxy. In the compounds of the present invention, the 1-ethyl group is substituted with alkoxycarbonyl and hydroxycarbonyl, so that they are clearly different in structure from the known compounds mentioned. In addition, the compounds of U.S. Patent 3,755,333 are used as intermediates in the complex multi-step synthesis of vinaminic acid esters, while the compounds of the present invention are used as intermediates in the simple synthesis of other eburnan-type compounds, namely apovincaminic acid esters.

U.S. Patent 4,089,856 discloses octahydroindolo (2.3-3) quinolizines having two ethyl groups in the 1-position, one of which is monosubstituted with an ester group. These compounds are thus clearly different in structure from the compounds of the present invention. Said known compounds have a vasodilatory effect

II

3 73429 and are used as active ingredients in pharmaceutical compositions. Their use as intermediates is not mentioned in the publication.

The indoloquinolizine derivatives 5 of the invention and their salts can be prepared as a compound of the formula ry-n.

10 Vxn / V- X- H (II) R2 2 15 wherein R is as defined above and X is an acid residue, is reacted, optionally in the presence of a basic catalyst, with a diester derivative of methylenemalonic acid of the formula ^ COOR1 20 ch2 = c (III) ^ COOR1 wherein R '' 'has the same meaning as above, and the hexahydroindolequinolizine ester derivative of formula 25

OlXX, * - 30 r'-ooc H (iva) j ^ ch-ch9 ^ ^ R ^ R1OOC "35 or 4 73429 CX Ό ·· 5 1 I" Ί 1 ^ J (ivt) R OOC. ./ j> C-CH- 1 I 2 P2 R 00C CH,

10, CH

R1OOC ^ ^ COOR1 • 1 2 wherein R, R and X have the same meaning as above, are catalytically hydrogenated. The octahydroindoloquinolines-15-sine ester derivative of the formula thus obtained

QjQ

1 H {] (Va) R OOC ^ ^ ch-ch '! /

25 R 00C

or 30;

3 H

R1OOC - ^^ (Vt>)> 9-CH2 k2 R ooc

35 CH

1 \ 1

RiOOC COOR

5 73429 1 2 wherein R and R are as defined above, is treated with a base to give an octa-hydroquinolizine monoester derivative of formula VIII.

The starting compounds of formula II can be prepared according to J. Am. Chem. Soc. 87, 1580-1589.

Compounds of formula III can be prepared according to J. Org. Chem. 4, 493 (1939), for example by reacting a malonic acid ester with para-10 formaldehyde.

The reaction between the compounds of formulas II and III is carried out in an inert organic solvent. As the inert organic solvent, for example, a hydrocarbon, a halogenated hydrocarbon, an alcohol, acetonitrile or the like can be used. Halogenated hydrocarbons such as dichloromethane and chloroform as well as C 1-8 aliphatic alcohols such as tert-butanol have proven to be particularly advantageous. The reaction may be carried out in the presence of a basic catalyst such as an aliphatic or cyclic amine (e.g. diethylamine, triethylamine, piperidine or pyridine). Catalytic amounts of alkali metal alcoholates such as potassium tert-butoxide can also be used for the same purpose. The reaction is preferably carried out at room temperature.

Depending on the temperature, the reaction time varies from a few hours to a few days.

The relative amounts of compounds of formulas IVa and IVb formed depend on the amount of compound of formula III used. When a large amount of more than 30 compounds of the formula III is used, in addition to the compounds of the formulas IVa and IVb, some compound of the formula 6 73429 is also formed ζχχχ χ- 5 ι * ι "Ί

ROOC. J

.C-CH, ^ (IVC) R1OOC // 'R2 j * 2 COOR1 10 C - CH ~ - CH2 \ I COOR1 R1OOC ^ COOR1 1 2.

wherein R, R and X have the same meaning as above. In practice, however, it is not recommended to use an excessive excess of the compound of formula III.

The compounds of formulas iva, IVb and IVc are novel compounds. The compounds of the formulas IVa, IVb and IVc can be converted into the free bases in a manner known per se by treating the salts with a base. Although the next step in the synthesis can also be performed with free bases, it is preferred to use the acid addition salts of formula IVa and / or IVb as starting materials for the catalytic hydrogenation.

In the next step of the synthesis, the compounds of formula IVa and / or IVb are catalytically hydrogenated. Hydrogen transfer metals such as palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum or tungsten or their oxides and sulfides can be used as hydrogenation catalysts. A supported catalyst can also be used in the Hyd-30 stripping step. Examples of carriers which may be mentioned are carbon (primarily activated carbon), silica, sulphates of alkaline earth metals and carbonates of alkaline earth metals. Palladium on activated carbon or Raney nickel is most often used as the catalyst, but the catalyst should always be selected on the basis of the properties of the substance to be hydrogenated and the reaction conditions. The catalytic hydrogenation is carried out in an inert solvent in which the starting material is highly soluble, such as water, a C 1-8 aliphatic alcohol, a halogenated C 1-8 aliphatic hydrocarbon, ethyl acetate, dioxane, glacial acetic acid or a mixture thereof. If platinum oxide is used as a catalyst, the hydrogenation is preferably carried out in a neutral or slightly acidic medium, whereas if Raney nickel is used, it is preferable to carry out the reaction in a neutral medium. Depending on the properties of the starting materials and other reaction parameters (time and pressure), the reaction temperature can vary over a wide range. The catalytic hydrogenation is preferably carried out at room temperature and atmospheric pressure until a calculated amount of hydrogen is bound.

When a compound of formula IVa and IVb is hydrogenated, a compound of formula Va or Vb is formed. When a mixture of compounds of formulas IVa and IVb is hydrogenated, a corresponding mixture of compounds of formulas Va and Vb is formed.

If the mixture to be hydrogenated also contains a compound of the formula IVc, in addition to the compounds of the formulas Va and Vb, the corresponding reduced compound of the formula Vc is also obtained as a reaction product.

HJ

1 H

R OOC i. J

'0 (Vc) .9-CH2 r2 30 r1 ° oc CH1 Γ 2. COOR1

C - CH „- CH

1 / \ 1 COOR1

R 2 OOC 'COOR

35 • 1 2 where R and R have the same meaning as above.

8 73429

The intermediates of formulas Va, Vb and Vc are novel compounds. If desired, these compounds can be converted into acid addition salts or, if desired, the racemic compounds can be divided into optical isomers in a manner known per se.

When the mother liquor obtained in the catalytic hydrogenation is neutralized and subjected to preparative plate chromatography, small amounts of the compound of formula 10 are also obtained. j -li Γ "1 15 ^ OOC H, vn XZH-CH- d2

i / Δ K

Where R and R have the same meaning as above.

The compound of formula VI is the structural isomer of the compound of formula Va. In the compounds of formula Va, hydrogen has the -PC 'configuration with respect to carbon atom 12b and 2 is thus in the cis position with respect to the substituent R, while in the compounds of general formula VI hydrogen has the A configuration with respect to carbon atom 12b, so that its relative configuration to the substituent R is trans. This unequivocally proves that the catalytic hydrogenation of a compound of formula IVa or IVb results in stereoselective reduction to give the corresponding cis compound of formula Va or Vb.

30 In the next step of the synthesis, the formula Va and / or

The compounds of Vb are treated with a base. For this purpose, an inorganic base, preferably an alkali metal hydroxide such as potassium or sodium hydroxide, can be used.

The reaction is carried out in an inert organic solvent or a mixture of such solvents. As the organic

II

As the solvent, it is preferable to use an alcohol corresponding to the R 2 O group of the starting material. The reaction can be carried out at any temperature between room temperature and the boiling point of the reaction mixture. Depending on the temperature used, the reaction takes place in 10 minutes to 1.5 hours.

Treatment of a compound of formula Va, Vb or Vc with a base or a mixture thereof gives a half ester of formula VIII. When a compound of formula Vb is used as a starting material, it is initially converted to the corresponding compound of formula Va by the action of a base. The reaction may be monitored by thin layer chromatography and, if desired, may be stopped at an appropriate stage to separate the compound of formula Va from the mixture.

The compound of formula Va obtained is identical to the compound 15 obtained by hydrogenation of a compound of formula IVa or a mixture of compounds of formula IVa and IVb.

The compounds of formula VIII can be converted into acid addition salts in a known manner.

The use of the indoloquinolizine derivatives of the invention as intermediates in the preparation of hydroxyamino-eburnan derivatives of formula I is effected by reacting a compound of formula VIII with a nitrosating agent in an acidic medium to give a compound of formula I.

The following examples illustrate the invention.

Preparation of intermediates according to the invention

Example 1 (+) - 1x-ethyl-1H-3 '- (2', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bX-octahydro-indolo [2,3-b] quinolizine and (+) - 10 C-ethyl-1- (2 *, 2 *, 4 *, 4 * -tetraethoxycarbonylbutyl) -1,2,3,4,6,7,12,12b9 ('- octahydro-indolo / 2 3- £ 7kinolitsiini

A solution of 8.0 mL (8.8 g, 48.8 mmol) of methylenimalonic acid diethyl ester in 10 mL of dichloromethane is added to a stirred suspension of 10.00 g (28.4 mmol) of 35 1-ethyl-1, 2,3,4,6,7-hexahydro-12H-indolo [2 ', 3'-quinolizin-5-iumperchlorate in 60 mL of dichloromethane and 3.6 mL (2.6 g, 25.7 mmol ) triethylamine. The reaction mixture is allowed to stand at room temperature for two days.

10 73429

The solution is evaporated in vacuo and the orange-red oil residue is triturated three times with 30 ml of ether and three times with 30 ml of petroleum ether.

18 g of oil are obtained, which is 1-ethyl-1- [2- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a " / Quinolizine-5-iumperchlorate and 1-ethyl-1- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7-hexahydro-12H-indolo / JT A mixture of 3-α / quinolizine-5-iumperchlorate This mixture is used directly, i.e. without purification, in the next step of the synthesis.

IR (KBr): 3260 (indole NH), 1735, 1715 (CO), 1615 and 1520 (C = N) cm -1.

an oily mixture (18 g) prepared as described above is dissolved in a mixture of 200 ml of ethanol and 50 ml of dichloromethane and the mixture is hydrogenated in the presence of a pre-hydrogenated 10% palladium-on-carbon catalyst in an amount of 8 g. After uptake of the required amount of hydrogen, the catalyst is filtered off and washed three times with 3 ml of ethanol and then three times with 30 ml of dichloromethane.

The filtrate and washings are combined, evaporated to dryness in vacuo and the residue is crystallized from 50 ml of ethanol.

9.0 g of (+) - λλ'-ethyl-1 - 5- (2 1, 2 1, 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7, 12,12b * -octahydro-indolo [2,3-a] quinolizine perchlorate, corresponding to 45.3% calculated for 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine Yield of 5-iumperchlorate.

Melting point of the product after crystallization from ethanol

Analysis for CH 2 Cl 2 / N 2 Og. HClO 4 (molecular weight 699.18) calculated: C 56.68 H 6.63 N 4.01% found: C 57.00 H 6.55 N 4.10%.

(+) - 1-X-ethyl-1 H - (2 *, 2 *, 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12 42b-octahydro- indolo [2,3-b] quinolizine hydrochloride has a melting point of 211-212 ° C (from ethanol).

Mass spectrum (m / e,%): 426 (M + -172; 6), 425 (3), 411 35 (0.3), 397 (0.3), 381 (2), 353 (1), 267 ( 100), 253 (3), 237 (5), 197 (8), 185 (6), 184 (6), 170 (10), 156 (6), 144 (5), 127 (10), 99 ( 10).

(+) - LX-ethyl-N- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl) -113,3429 butyl) -1,2,3,4,6,7,12,12bx-octahydroindole The quinolizine base can be prepared by dissolving either the hydrochloride or perchlorate in dichloromethane, shaking the solution with 5% aqueous sodium carbonate solution, separating the organic phase, which is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.

1 H-NMR (CDCl 3, δ δ): 7.86 (1H, indole NH), 4.30 - 3.85 (8H, m, OCH 2), 1.45 - 1.0 (15H, m, CH 2 -CH 3) ) ppm.

Ethanol is distilled off from the ethanolic mother liquor obtained from (+) - 1H-ethyl-1 · '' - (2 ', 2 1, 4', 4 1 -tetraethoxycarbonylbutyl) -1,2,3,4,6 After removal of the perchlorate of 7,12,12b-octahydro-indolo [3,3-a] quinolizine, the residue is dissolved in 30 ml of dichloromethane and the solution is shaken with 20 ml of 5% aqueous sodium carbonate solution. The organic phase is separated, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 10% ethanol and the solution is acidified to pH 5 with ethanolic hydrochloric acid. The hydro-20 chloride is precipitated from solution in 10 ml of ether, the solid is filtered off, washed with ether and dried.

4.0 g of (+) - 10- (ethyl-1H-(2 ', 2'-di-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12b0t-octahydro-indole) are obtained. hydrochloride of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [3,3-a] quinolizine, corresponding to 30.4% calculated Yield of 5-iumperchlorate.

The product has a melting point of 202-204 ° C (from ether).

IR (KBr): 3300 (indole NH), 1720 (CO) cm-1.

Mass spectrum (m / e,%): 426 (M +, 15), 425 (12), 411 30 (1), 397 (1), 381 (8), 365 (0.5), 353 (2), 307 (0.6), 267 (100), 253 (2), 237 (4), 197 (12), 184 (8), 170 (10), 169 (12), 156 (5), 145 (0), 6), 144 (5), 143 (3), 127 (1), 124 (3).

(+) - 1H-Ethyl-1H- (2,2,2-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo (-octahydro-indolo [2,3-a] quinolizine-35 base) is prepared by dissolving the hydrochloride in dichloromethane, shaking the solution with 5% aqueous sodium carbonate solution, separating the organic phase, drying over anhydrous magnesium sulphate, filtering 12 73429 and evaporating the filtrate to dryness.

1 H-NMR (CDCl 3, δ): 7.82 (1H, indole NH), 7.2-6.85 (4H, m, aromatic protons), 3.90 (4H, q, J = 7.3 cps, O-CH 2), 1.2-0.8 (9H, m, -CH 3) ppm.

5 (+) - 1 H -ethyl-1 H - (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b / 11α-octahydroindolo [T' The 3-α / quinoline base prepared as described above is subjected to thin-layer chromatography on silica gel KG-60 PF254 + 366 using a 14: 3 mixture of benzene and methanol and acetone as eluent. After evaporation of the eluent and crystallization of the residue from ethanol, the product with a higher Rf value was isolated.

There was thus obtained 0.25 g of (+) -1H-ethyl-1H, - (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b, 1-octahydroindole. 15 [2,3-a] / quinolizine, corresponding to a calculated yield of 2% of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [1,3-a.? Kino li t-sin-S-iunperchlorate.

Sp. 127-128 ° C (from ethanol) IR (KBr): 3280 (indole NH), 1730, 1705 (CO) cm -1 Mass spectrum (m / e,%): 462 (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 H -ethyl-1H - (2 ', 21-diethoxycarbonylethyl) -25 1,2,3,4,6,7,12,12bo (-octahydro-indolo / 2,3) -α / quinolizine and (+) -1 <x -ethyl-1A- (2 '2', 4 ', 4'-tetraethoxycarbonylbutyl) -1,2,3,4,6,7,12,12b' X-octahydro-indolo /? -? - 3-quinolizine

A solution of 3.03 mL (3.12 g, 18.4 mmol) of methylenimalonic acid diethyl ester in 5 mL of dichloromethane is added to a stirred suspension of 5.00 g (14.2 mmol) of 1-ethyl-1 , 2,3,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-iumperchlorate in 30 ml of dichloromethane and 0.080 g (0.715 mmol) of potassium tert-butoxide. The reaction mixture is allowed to stand at room temperature for one day.

The solvent is then evaporated off under vacuum and the orange-red oily residue is triturated three times with 5 ml of petroleum ether.

73429

The result is 9 g of an oily substance which is 1-ethyl-1- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine -5-iumperchlorate and 1-ethyl-1- (2 ', 2', 4 ', 41-tetraethoxycarbonyl-butyl-5'L) -1,2,3,4,6,7-hexahydro-12H-indolo Mixture of 2,3-α7-quinolizin-5-iumperchlorate. This mixture is used directly, i.e. without purification, in the next step of the synthesis.

IR (KBr): 3260 (indole NH), 1735, 1715 (CO), 1615, 1520 (C = N) cm-1.

The oily residue obtained as described above is dissolved in a mixture of 10 ml of ethanol and 25 ml of dichloromethane and the solution is hydrogenated in the presence of 6 g of a prehydrated 10% palladium-on-carbon catalyst. After the required amount of hydrogen has been taken up, the catalyst is filtered off and washed three times with 3 ml of ethanol and then three times with 10 ml of dichloromethane. The filtrate and washings are combined, evaporated to dryness in vacuo and the residue is crystallized from 30 ml of ethanol. The separated material is filtered off, washed with ethanol and dried. 8.0 g of a mixture of (±) -1 <X-ethyl-1 / 3- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3 are obtained. , 4,6,7,12,1 2bCc-octa-hydro-indolo [2,3-a] quinolizine perchlorate and (±) -1H-ethyl-1 / 3- (2 ', 2'-diethoxycarbonylethyl) -1, 2,3,4,6,7,12,12bOt-octahydro-indolo [2,3-a] quinolizine perchlorate; 25 sp. 181-185 ° C.

This salt mixture can be used directly in the next step of the synthesis as a solution of ethanol in dichloromethane obtained after filtration of the catalyst.

To determine the composition of the perchlorate-salt mixture, 0.8 g of the mixture is dissolved in 6 ml of dichloromethane, the solution is shaken with 4 ml of 5% aqueous sodium carbonate solution, the organic phase is separated, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated to dryness. The residue is subjected to 35 preparative thin-layer chromatography (adsorbent: alumina type T, solvent: 3: 1 mixture of dichloromethane and 14 73429, benzene, eluent: 20: 1 mixture of dichloromethane and mc-methanol).

The substance with a higher R 1 value is dissolved in 1.2 ml of ethanol and the solution is acidified to pH 5 with 5 ml of ethanolic hydrochloric acid. The hydrochloride is precipitated with 1.2 ml of ether, filtered, washed with ether and dried.

0.46 g of (t) -10fc-ethyl-11H- (2 ', 2', diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bOCoctahydro indolo / 2,3-a / quinolizine hydrox 1 or i.dia, corresponding to 1 0 70.5% yield. Sp. 202-204 ° C (from ethanol and ether).

The substance with a lower Rf value is converted to perchlorate with 70% aqueous perchloric acid and the salt is crystallized from ethanol.

The result is 0.26 (±) -1α-ethyl-1 / 3- (2 1, 2 ', 4', 4 '-1 5 tetraethoxycarbonyl-1-butyl) -1,2,3,4, 6,7,12,12b <X-octa-hydro-indolo [2,3-a] quinolizine perchlorate, corresponding to a yield of 26%. Mp 216-218 ° C (from ethanol).

Example 3 (±) -ία-e-style-1 / 3- (2 ', 2'-diethoxycarbonyl) -20 1,2,3,4,6,7,12,1 2b <X-octahydro- indolo [2,3-b] quinolizine 600 mg (1 mmol) (±) -1 (X-ethyl-1 / 3- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1, 2,3,4,6,7,12,1 2bCX-Octahydro-indolo [2,3-a] quinolizine prepared as in Example 1 or 2 is dissolved in 8 ml of ethanol and a solution of is 120 mg of potassium hydroxide in 1 ml of water and 1 ml of ethanol.

Thin layer chromatography using alumina (type T) as the adsorbent and a 3: 1 mixture of dichloromethane and benzene as the solvent shows the reaction time to be 30 minutes at room temperature. In this system, (±) -10t-ethyl-1 - 3- (2 ', 2 1, diethoxycarbonyl) -1,2,3,4,6,7,12,12bOt-octahydro-indolo / The R 2 value of '2,3-alkyololizine' is higher than that of (i) -1C-ethyl-1H-(2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3 , 4,6,7,12,1 2bOt-octahydro-indolo / 2,2-αJ-35 quinolizine Rf value. The reaction mixture is neutralized to pH 6 with acetic acid and the solvent is distilled off in vacuo. The residue 73429 is dissolved in 3 ml of water, the solution is made alkaline (pH-9) with 5% aqueous sodium carbonate solution and then extracted three times with 5 ml of dichloromethane. The organic solutions are combined, dried over anhydrous magnesium sulphate, filtered and the solvent is evaporated off under vacuum, the oily residue is dissolved in 3 ml of ethanol, ethanolic hydrochloric acid is added to the solution and the hydrochloride thus formed is crystallized from ether.

0.25 g of (±) -10t-ethyl-1 / 3- (2 ', 2'-10-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b <X-octahydro- indolo [1,3-a] quinolizine hydrochloride, corresponding to a yield of 53%. Sp. 201-204 ° C (from ether).

IR (KBr): 3300 (indole NH), 1720 (CO) cm-1.

Example 4 (1) -10C-Ethyl-1 H - (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12bOfc-octahydro-indolo / ' 2,3-oxazin-a.7kinolit

A solution of 0.067 g (1.2 mmol) of potassium hydroxide in 0.3 ml of water and 0.9 ml of ethanol is added to a solution of 0.46 g (1.08 mmol) of (±) -106-ethyl -1 / 5- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bOCoctahydroindolo [2,3-a] quinolizine prepared as in Example 1 or 2.3 ml of ethanol. The reaction mixture is boiled in a steam bath for 1.5 hours. The solvent is then evaporated off under vacuum, the oily residue is dissolved in 3 ml of water and the aqueous solution is extracted twice with 2 ml of ether. The aqueous phase is neutralized to pH 6 with acetic acid. The separated white crystalline substance is filtered off, washed with 5 ml of water and dried.

0.32 g of (±) -1Ct-ethyl-1 / 3- (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,1 2b0t- octa-hydro-indolo [2,3-a,] quinolizine, corresponding to a yield of 74%. Sp. 113-116 ° C (from water).

For thin-layer chromatography on a KG-6 silica-35 gel plate using 15 ml of benzene, 5 ml of methanol and two drops of concentrated aqueous ammonia 16 73429 as solvent, 10E-ethyl-1 / 3- (2 ', 2'-diethoxycarbonylethyl) -1,2 , 3,4,6,7,12,1 2b0t-octahydro-indolo [2,3-a] quinolizine has an Rf value higher than (±) -110 (-ethyl-1 / 3- (2'-carboxy-2) '-ethoxycarbonyl) -1,2,3,4,6,7,12,12bb-octahydro-indolo [2,3-a] quinolizine.

IR (KBr): 3360 (indole NH), 1715 (CO), 1600 (COO_) -1 cm

Mass spectrum (m / e,%): 354 (M + -44: 53), 353 (58), 339 (8), 325 (0.3), 309 (12), 281 (2), 267 (100), .. 44 1 0 (1 000).

Example 5 (±) -1 (X-ethyl-1/3 '(2'-carboxy-2'-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12b-octahydro- indolo / 2,3-α-7-quinol itin A solution of 0.092 g (1.64 mmol) of potassium hydroxide in 0.3 ml of water and 0.9 ml of ethanol is added to a solution of 0.428 g ( 0.715 mmol) (±) -1- (X-ethyl-1- / 5- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12 .Beta.-octahydro-indolo [2,3-a] quinolizine prepared as in Example 1 or 2.3 in ethanol. The reaction mixture is boiled on a steam bath for 0.75 hours. The solvent is then evaporated off under vacuum and the oily residue is dissolved in 3 to 1 ml of water and the resulting solution are washed twice with 2 ml of ether, the aqueous solution is neutralized to pH 6 with acetic acid, the separated white crystalline substance is filtered off, washed with 5 ml of water and dried.

0.24 g of (±) -1-ethyl-1 / 3- (2'-carboxy-2'-ethoxycarbonylmethyl) -1,2,3,4,6,7,12,12bQ-octahydroxy indolOif2,3-alkyolizine, corresponding to 74% yield. Sp. 112-114 ° C.

Example 6 (i) -10L-ethyl-1,3- (2'-carboxy-2'-ethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12b-octahydro-indolo / 2 The 3-α / quinolizine 35 The starting material used is the filtrate obtained in Example 2 when the reaction mixture of (±) -10t-ethyl-1 H - (2 ', 2'-di-17,7429 ethoxycarbonylethyl) -1,2 , 3,4,6,7,12,1 2b <X-octahydro-in-Dolo [1,3-a] quinolizine perchlorate and (±) -1 <X-ethyl-1 / 3- (2 *, 2, (4,4,4 * -tetraethoxycarbonylbutyl) -1,2,3,4,6,7,12,12bOt-octahydro-indolo [2,3-a] quinolizine perchlorate 5 in ethanol-dichloromethane and containing the two salts in a weight ratio of about 3: 1, the catalyst has been removed.

The solvent is evaporated in vacuo and the resulting oily salt mixture is dissolved in 50 ml of dichloromethane. 30 ml of 5% aqueous sodium carbonate solution are added, the mixture is shaken, the organic phase is separated, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo. 1.54 g of an oily residue, a mixture of 2.34 mmol of diethoxy base and 0.9 mmol of tetraethoxy base, are dissolved in 16 ml of ethanol and 0.24 g (4.23 mmol) of potassium hydroxide dissolved in 2 ml of water are added. The reaction mixture is boiled for 1-1.5 hours on a steam bath. The solvent is then evaporated off under vacuum, the residue is dissolved in 10 ml of water and this alkaline solution is extracted three times with 10 ml of ether. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residue is 0.4 g of an oily substance which contains mostly the starting material mixture. The pH of the aqueous phase is adjusted to six with acetic acid and the separated organic matter is extracted four times with 15 ml of di-25 chloromethane. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo, the oily residue is triturated with 10 ml of ether, the precipitate filtered off, washed with 5 ml of ether and dried.

0.76 g of (±) -1 <X-ethyl-1 / 3- (2 1 -carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12bCtokta is obtained. -hydro-indolo [2,3-a] quinolizine, corresponding to a yield of 59%. Sp. 108-111 ° C (decomposes).

18 73429

Manufacture of finished products

Example I

(±) -cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (3ocH, 1baEt) A solution of 0.39 g (3.65 mmol) of sodium nitrite in 5 ml of water is added to a solution of 0.75 g (1.885 mmol) of (i) -10C-ethyl-1H-(2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12 , 12bo E-octohydroindolo [2,3-a] quinolizine prepared as in Example 6.15 in 10 glacial acetic acid. The reaction takes place at room temperature within one hour. The reaction mixture is made alkaline (pH = 11) with 30% aqueous sodium carbonate solution under very vigorous cooling on ice and the separated organic matter is extracted four times with 40 ml of dichloromethane. The dichloro-15 methane extracts are combined, washed with 10 ml of water, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The resulting solid residue (0.60 g) is triturated with 5 ml of dichloromethane, the precipitate is filtered off, washed with 3 ml of dichloromethane and dried.

0.52 g of (±) -cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (3 H, 16aEt) are obtained, corresponding to a yield of 72%. Sp. 156-158 ° C (from dichloromethane).

When thin layer chromatography on a silica gel 25 KG-6 plate using a 14: 3 mixture of benzene and methanol, the R 2 value of (±) -cis-14-ethoxycarbonyl-14-hydroxyaminoeburnan (3 H, 16 6 EtE) is higher than that of the element used. (±) -1 <X-ethyl-1 / 3- (2 1 -carboxy-2 1-ethoxybronylethyl) -1,2,3,4,6,7,12,1 2b <X -octahydro-indolo / 2, 3 -a / k inolizine 30 R.-value. r

The title compound did not cause a decrease in melting point as a mixture with (±) -cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (30tH, 16 <XEt) prepared according to UA Patent Application No. RI-634 and identical to the latter 35. with respect to all its physical and chemical properties.

73429 19 IR (KBr): 3400 (NH, OH), 1700 (CO) cm -1.

1 H-NMR (CDCl 3, δ): 8.3 (1H, NH), 4.0 (2H, q, J = 7.3 cps, COOCH 2 CH 3), 1.18 (3H, t, J = 7.3 cps, COOCH2CH3) ppm.

Mass spectrum (m / e,%): 383 (M +, 98), 382 (59), 366 (100), 354 (10), 338 (7.7), 310 (31), 292 (29), 278 (8.5), 267 (40), 253 (92), 237 (15), 211 (18).

Example II

(-) -3 «S, 16otS-14-ethoxycarbonyl-14-hydroxyamino-10 eburnan

To give the title compound, (±) -cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (3H, 16 (XEt) is dissolved in di-benzoyl-D-tartaric acid, mp 169-171 ° C (from dichloromethane). ~ "56.1 ° (c = 1.05, in dimethylformamide).

15 Example III

(ί) -cis-14-methoxycarbonyl-14-hydroxyamino-eburanane (3 <XH, 16ocEt)

Proceed according to Examples 2, 6 and 7, with the difference that 8 ml of methylenemalonic acid diester are replaced by a corresponding amount of methylenemalonic acid dimethyl ester. The melting point of the title substance is 179 ° C (from methanol).

IR (KBr): 3420 (NH, OH), 1710 (CO 2 CH 3) cm -1.

1 H-NMR (CDCl 3, δ): 8.05 (1H, NH), 7.6-7.0 (4H, m, aromatic protons), 3.5 (3H, s, CO 2 CH 3), 1.1 (3H , t, 25 CH 2 CH 3) ppm.

Mass spectrum: m / e 70 eV, M + = 369.

Analysis for C 21 H 27 N 3 O 3 (MW 369.14): Calculated: C 68.27 H 7.36 N 11.38% Found: C 68.58 H 7.29 N 11.28%

30 Example IV

(±) -cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (3otH, 160 (Et) 8.00 g of (±) -10C-ethyl-1 H} - (2 ', 2 1-diethoxycarbonyl- ethyl) -1,2,3,4,6,7,12,12b0t-octahydro-indolo [2,3-a] quino-35 lysine and (i) -1ot-ethyl-1 H - (2 ', 2 ', 4', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12,12bbt-octahydro-indolo-20 7 3 4 2 9 [2,3-a] quinolizine perchlorates the mixture prepared according to Example 2 is dissolved in 80 ml of dichloromethane, the solution is shaken with 40 ml of 5% aqueous sodium carbonate solution, the organic phase is separated, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo. The oily residue is dissolved in 80 ml of ethanol, 1.00 g of potassium hydroxide dissolved in 4 ml of water are added and the reaction mixture is allowed to stand at room temperature for 3.5 hours.

The solvent is then evaporated off under vacuum, the oily residue is dissolved in 16 ml of water and the solution is extracted twice with 8 ml of benzene.

32 ml of glacial acetic acid are added to the aqueous phase, the mixture is cooled in an ice bath and 2.00 g of sodium nitrite dissolved in 4 ml of water are added dropwise over 10 minutes. The mixture is allowed to stand at room temperature for one hour, after which the pH of the mixture is adjusted to 9 with 30% aqueous sodium hydroxide solution while cooling vigorously on ice. The resulting mixture is extracted three times with 50 ml of ethyl acetate. The organic phases are combined, washed with 20 ml of water, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo to give 4.00 g of a solid residue.

This solid residue is recrystallized from 20 ml of dichloromethane to give 3.44 g of the title compound, which is identical to the compound obtained in Example 7. This corresponds to a yield of 65% based on 5.00 g of the perchlorate mixture used as starting material.

Il

Claims (2)

An indoloquinolizine derivative or a salt thereof for use as an intermediate in the preparation of therapeutically useful hydroxyamino-eburnan derivatives of the formula I, wherein R and R represent C 1-6 alkyl, characterized in that the formula of the indoloquinolizine derivative is i HOOC »TJ (VIII) 25. C 1 -C 2 · R 100C 2 R 2 1 In this case, R and R represent C 1-6 alkyl.