FI72319C - FOERFARANDE FOER FRAMSTAELLNING AV HYDROXIAMINOEBURNANDERIVAT. - Google Patents

Description

7231 9

Process for the preparation of hydroxyamino-eburnan derivatives

Divided separated from application 801757 5

The invention relates to a new process for the preparation of hydroxyamino-eburnan derivatives of the formula I and their pharmaceutically acceptable acid addition salts and optically active isomers.

OuCi - 15 R1OOC-v.

1 R2

NH R

0B

In the formula 2, R and R are C 1-6 alkyl.

The compounds of the formula I are biologically active and can be used in particular as vasodilators. The compounds of formula I may also be used as intermediates in the preparation of other therapeutically useful compounds.

The process according to the invention is characterized in that the monoester derivative of octahydroindoloquinolizine of the formula "ΓΊγίΟ (VII)

H I

HOOC S

35 1/2 R2

R 00C R

2 7231 9 1 2 wherein R and R are as defined above are reacted with a nitroso-forming agent in an acidic medium, and if desired the obtained compound of formula (I) is partitioned into its optical isomers and / or the resulting compound 5 is converted into a pharmaceutically acceptable acid addition salt.

In the process, a compound of formula (VII) is nitrosated in an acidic medium. This reaction can be carried out, for example, with an alkali nitrile such as potassium or sodium nitrite in glacial acetic acid. Alternatively, a compound of general formula (VII) may be nitrosated with a C 1-8 alkyl nitrite, preferably tert-butyl nitrite or amyl nitrite, in an inert organic solvent, preferably a halogenated C 1-6 aliphatic hydrocarbon (such as dichloromethane), to a few in the presence of an acid dissolved in a drop of C 1-6 aliphatic alcohol, preferably in the presence of ethanolic hydrochloric acid.

Hungarian Patent Application No. 634 (corresponding JP Kokai 78/147100 is referenced in Chemical Abstracts, 20 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 starting material used in the process of the invention. The pentacyclic starting material of the known method is prepared tetracyclically from an indoloquinolizine derivative by a multi-step synthesis. According to the invention, the pentacyclic compound of formula (I) can instead be prepared directly from a simple tetracyclic indoloquinolizine derivative (formula VII). The method according to the invention contains fewer process steps than the known method and is thus much simpler.

The compounds of formula (I) may be converted into pharmaceutically acceptable acid addition salts by reacting them with the appropriate acids.

tl 3 7231 9

Suitable acids are, for example, mineral acids such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid), sulfuric acid, phosphoric acid, nitric acid, perchloric acid and the like, organic carboxylic acids such as formic acid, acetic acid, acetic acid, propionic acid, propionic acid, glycolic acid, glycolic acid cinnamic acid, benzoic acid, phenylacetic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, p-aminosalicylic acid, etc., alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, sulfonic acid, arylsulfonic acid, etc. sulfonic acid, sulfanilic acid, etc., amino acids such as aspartic acid, glutamic acid, etc.

The novel compounds of formula (VII) used as starting materials are obtained by reacting a hexahydroindoloquinolizinium derivative of the formula 20 * - as »xj 4 2 7231 9 in which R is as defined above and X is an acid residue, optionally in the presence of a basic catalyst, with a diester derivative of methylenemalonic acid having the formula COOR1 CH, = cf (ΠΙ) XCOOR1 10 wherein R1 is as defined above, and a hexahydroindroloquinolizine ester derivative of the formula 15r -CH 2 ^ 2 RX00C ^ or 25 L! 5 7231 9 N \ (ivb) 5 έ R100C2C - CH2 2

R100C ^ I R

CH0 I 2

10 CH

1/1 l rlooc coor1 1 2 where R, R and X have the same meaning as above, Hydrogenated from catalytic. The octahydroindoloquinolines-25 sinium ester derivative of the formula thus obtained

20 T H

R100C ^ A

CH-CIip η ____ ** 2 R ^

R 10 ° C or 25 k

30 R100C \ A

C - CH2 (Vb)

R OOC ^ I

CH0 I 2

CH

35 i ^ I

R ^ OOC GOOR1 6 7231 9 1. 2 wherein R and R are as defined above is treated with a base to give an octahydroindoloquinolizine monoester derivative of formula VII.

2

Compounds of formula II wherein R is a g-5 alkyl group and X is an acid residue can be prepared as described in 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 paraform-10 aldehyde.

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, an aceto-nitrile and the like solvents 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 also 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 excess of a compound of the formula III is used, in addition to the compounds of the formulas IVa and IVb, a small amount of the compound of the formula li 7 7231 9 i- v. / S is formed. If * "X" "

5 A

R1OOC ^ ./ 1 A - CH2 r2 R ^ OOCT I (IVc) ^ ¾. / C00R1

ln C - CH? - CH

10 ./ \. ^ COOR1 RJ-OOC 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 a compound of general formula III.

The compounds of formulas IVa, IVb and IVc are novel and are also biologically active. 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 salt-2o with a base. Although the next step of the synthesis can also be carried out with free bases, it is preferable to use acid addition salts of the general 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-transferring metals such as palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum or tungsten, as well as their oxides and sulfides, can equally be used as hydrating ka-3q talts. Catalysts on supports can also be used in the hydrogenation step. Examples of carriers which may be mentioned are carbon (primarily activated carbon), silica, alkaline earth metal sulphates and alkaline earth metal carbonates. Most often, 35 palladium on activated carbon or Raney nickel is used as the catalyst, but the 8 7231 9 catalyst should always be selected based on 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, C 3-8 aliphatic alcohol, halogenated C 1-6 aliphatic hydrocarbon, ethyl acetate, dioxane, glacial acetic acid or a mixture thereof. If platinum oxide is used as the 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 or 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, kAjAp, is also obtained as a reaction product.

R ^ OOC ^ i I (Vc) 30 a - ch, ^ ooc ^ l r2 fn2 / C00R1 C - CHp - CH / \ i XC00R1 35 irooc cooir 9 7231 9 wherein R ^ and R ^ have the same meaning as above.

The intermediates of formulas Va, Vb and Vc are new and biologically active. If desired, these compounds can be converted into acid addition salts using, for example, the acids listed above in connection with the preparation of salts of the final products, or, if desired, the racemic compounds can be divided into optical isomers in a manner known per se.

When the mother liquor obtained from the catalytic hydrogenation is neutralized and subjected to preparative plate chromatography, small amounts of a compound of the formula

15 I h N

i ^ R1 200Cv H I J (VI) R100C '/ 20 2 where R and R have the same meaning as above.

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

35 In the next step of the synthesis, the formula Va and / or 10 7231 9

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 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 or a mixture thereof with a base gives a half ester of formula VII. 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 20 Va obtained is identical to the compound obtained by hydrogenation of a compound of formula IVa or a mixture of compounds of formula IVa and IVb.

The compounds of formula VII are novel and biologically active. If desired, these compounds can be converted into their acid addition salts or the racemic compounds can be divided into optical isomers in a known manner.

The compounds of formula I are valuable intermediates for the synthesis of compounds with excellent pharmaceutical properties. Thus, for example, when a compound of formula I is treated with a dilute aqueous acid solution, a mixture of the corresponding vincamic acid ester and apovincaminic acid ester is formed. These compounds can be separated by fractional crystallization and, if desired, converted to other esters. Thus, according to formula I

II

11 7231 9 can be converted to either vincamine, a compound with valuable pharmaceutical properties, or apovincamic acid ethyl ester (Caviton), a compound even more potent than vincamine, or both pharmaceutically active compounds can be prepared simultaneously from a suitable compound of formula I. (see HU Patent Application No. RI-634).

The compounds of formula I have a vasodilating effect and primarily affect the blood circulation in the limbs.

Pharmacological tests were performed on dogs anesthetized with chloralosurethane. The test substance was administered intravenously as an aqueous solution at a dose of 1 mg / kg body weight, and arterial blood pressure, pulse, and state-15 mover flow were measured. The latter measurement was performed in the femoral artery and the internal carotid artery. The resistance of these vascular systems was calculated from the values obtained according to the following formula 20 blood pressure

Vascular resistance = -------- blood flow in the vessel examined

The results are shown in Tables 1 and 2.

25 Abbreviations mean: MABP = mean arterial blood pressure PR = pulse CBF = blood flow in the internal carotid CVR = vascular resistance in the carotid 30 FBR = blood flow in the femoral artery FVR = femoral vascular resistance 7231 9 12

O I

(N φ

: rö -P

,> 1 (O -P

+ I i — I Ό -rl

Φ CO

O <ö> 1 -P m Md

> -H -P -P - Cί C

P to -P h n φ I (0 M Φ CO - (0 φ

O -H 3 -P: <tJ rH -H M

G X -p · Η X -P r-c

• H CO 3 p (CJ -P MU

6 Φ Π3 (J -n 3 -n 3 λ; g: r0 φ d

• P 'p. 3 - e C

CO 3 d o h N

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\ ΚΛ (N OJ

N tri rP rH

e s o X rH cOfHCNrHOO ID OJ 00 CN 00 p I «k- ·> ·» · »

c0 C CO 2 (N 2 CO O 'O H (M IT \ OCN

r * O rH r-1 + | (M +1 H -HO U "\ + | I + | + +1 + CO +1+ rHl C0-P LO LO LP \ · * IN · *

O, * P OJC-TNIA OJ (N OJ

X 0 1) r-l r-l

P * -p -H

3 Φ X

p S3 OJCOlAtNcOCOiX) fHUOvC

2 I Φ «· * -» fr * »· *» M (\ j ** * 9 * i ° LO LA LT \ LO C "» CO O r — I UO CT O ΜΛ

^? § rH iH +1 I OJ + | rH

'> + | I +1 + +1 + CO + 1 + 01 J ΚΛ CO LT \ <"Ή * - 'pp ojltnca ooco oj V 8 rP ^ + Ί 3

3. ' jj (T OJ CO tN OJ LO LT \ rH OJ

^ fri · * fr * ► <r ^ · · * »^ LT \ · * ·»

r-3 IN o LO (N O O O OI CO «H O IA

3 5 rH r-l OJOJ + llOJtN + 14-

4j φ +1 I +1 + + | + -r +1 4 · oj I

φ> rH CO rH rP * -CN *

rH LO CjO OJ rH rP

(0-—. Rp i — I rH

• H -P

g H LD CN

i — I MO CO O · - CO »~

<0 O r- · - v O O

> LO CT O MO +1 CO +1

rp rH rH r — I r — I iA

e - O + | + | +1 · +1 * -

<0 K OJ CO CT ΜΛ OJ OJ

(0 - ro, cf · tN

X "rp rH i — I rH

3 G φ I I

S ^ -f · W rH rPrP rp

^ »P r— I SI S

M 'p.h0 d · d · 5> βχ · η ö'p ö

• S e Tl -H Ή a -H S.-H

^ § p £ i * ö · a. ^ S.

.¾ 2, 2 -h 'a ω a to • p 3 φ r * m K ® £ «g * *%« ^ äi j 5 s e g si £ Si il 13 7231 9

Table 2 Maximum percentage effects of (+) - cis-14-methoxycarbonyl-14-hydroxyamino-eburnan (3α £ Η, 16o <Et) in separate tests 5 .... , ------------—-— ....—- Number of dogs used Average - 247 256 259 263 standard error BABP -11 -15 0-5 -10.2 + 2.31 10 PR 0 + 9 +14 +8 + 7.7 + 3.0 CBF +38 +25 +14 + 5 +20.5 + 7.3 CVR -34 -32 -22 -13 -25 + 5.5 * FBF + 116 +57 +67 +44 +71 + 15.9 * 15 * F VR -58 -43 -46 -32 -4 ^, 7 + 5.3 x) Statistically significant mean (P <0.05)

The data in the tables show that the compound, when administered intravenously at a dose of 1 mg / kg body weight, causes a temporary and slight increase in blood pressure and an increase in pulse. The main effect of the compound is an increase in blood flow in the two vascular systems studied. This effect is particularly marked in the limb vessels (71%), resulting from an enlargement of about 45% in the blood vessels in question. At the same time, a 25% dilation can be observed in the carotid artery, resulting in a 20% increase in blood flow.

The following examples illustrate the invention.

Preparation of starting materials 30 Example I

(+) - 1-ethyl-1- (2,2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-b] quinolizine and ( +) - 10C-ethyl-1,6- (2 ', 2', 4 ', 4'-tetraethoxycarbonylbutyl) -1,2,3,4,6,7,12,12b ^ -35 octahydroindolo72,3-a "/ quinolizine 14 7231 9

A solution of 8.0 mL (8.8 g, 48.8 mmol) of methylenemalonic acid diethyl ester in 10 mL of dichloromethane is added to a stirred suspension of 10.00 g (28.4 mmol) of 1-ethyl-1 , 2,3,4,6,7-hexahydro-5 12 H-indolo, [2,3-a] n-quinolizine-5-ion perchlorate in 60 ml of dichloromethane and 3.6 ml (2.6 g, 25, 7 moles) of triethylamine. The reaction mixture is allowed to stand at room temperature for 2 days.

The solvent is evaporated off under vacuum and the orange-red oily residue is triturated 3 times with 30 ml of ether and 3 times with 30 ml of petroleum ether.

18 g of oil are obtained, which is 1-ethyl-1- (2 ', 21-diethoxycarbonylethyl) -1,2,3,4,6,7-hexahydro-12K-indolo [2,3-a] quinolizine-5-ion perchlorate and 1-ethyl-1- (2- [2,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5- ion-perchlorate mixture. This mixture is used directly, i.e. without purification, in the following synthetic step: IR (KBr): 3260 (indole NH), 1735, 1715 (CO), 1615 and 2020 (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 8 g of a pre-hydrogenated 10% palladium-on-carbon catalyst. 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 (+) - 1-ethyl-1H-3- (2,2,2,4,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12, 12b were obtained. ° C-octahydroindolo [2,3-a] quinolizine perchlorate, corresponding to 45.3% calculated from 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5 yield of ionic perchlorate 35. The product sp. after crystallization from ethanol: il 15 7231 9

Analysis for C 18 H 18 N 2 O-HCl 2 (molecular weight 699.18) Calculated: C 56.68, H 6.63, N 4.01% Found: C 57.00, H 6.55, N 4 , 10% (+) - 10-ethyl-1β- (2 ', 2', N'-tetraethoxycarbon-5-ylbutyl) -1,2,3,4,6,7,12,12b oC-octahydroindole / 2,3-α7-quinolizine hydrochloride m.p. is 211-212 ° C (from ethanol). Mass spectrum (m / e,%): 426 (M + -172; 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), 156 (6), 144 (5), 127 (10), 99 (10 ).

10 (+) - N, N-ethyl-1- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12,12bcs <6 -octahydro- The indolo 2,2,3-α-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, drying over anhydrous magnesium sulfate, filtering and evaporating the filtrate.

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 (+) - 10 H -ethyl-1H-(2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4 After removal of the perchlorate of c7-octahydro-indolo [2,3-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 ml of ethanol and the solution is acidified to pH 5 with ethanolic hydrochloric acid. The hydrochloride is precipitated from solution with 10 ml of ether, the solid is filtered off, washed with ether and dried.

4.0 g of (+) - 1H-ethyl-1H- (21,2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12br7-octa-35 hydroindole are obtained. , 1,3-α7-quinolizine hydrochloride, corresponding to a calculated calculation of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5- yield of ionic perchlorate.

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

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

Mass spectrum (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), 184 (8), 184 (7), 170 (10), 169 (12), 156 (5), 145 (0.6), 144 (5), 143 (3), 10 127 (1), 124 (3).

(+) - 10 C-ethyl-1H - (2,2,2-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-a] quinolites the sine base is prepared by dissolving the hydrochloride in dichloromethane, shaking the solution with 5% aqueous sodium carbonate, separating the organic phase, drying over anhydrous magnesium sulphate, filtering and evaporating the filtrate to dryness.

1 H-NMR (CDCl 3 # S): 7.82 (1H, indole NH), 7.2-6.85 (4H, m, aromatic protons), 3.90 (4H, q, J = 7.3, cps , 20 O-CH 2), 1.2-0.8 (9H, m, -CH 2) ppm.

(+) - [4-ethyl-ethyl] - (2 ', 2'-dimethoxycarbonylethyl) -1,2,3,4,6,7,12,12b o6-octahydro-indolo [1,2] 3- The α7-quinolizine base prepared as described above is subjected to thin-layer chromatography on KG-60 PF254 + 366 silica gel 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 (+) - 10 - (, -ethyl-1H- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo? -octahydro-indolo, [2,3-a] quinolizine, corresponding to a calculated yield of 2% of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine- 5-a perchlorate ion.

35 mp: 127-128 ° C (from ethanol).

IR (KBr): 3280 (indole NH), 1730, 1705 (CO) cm -1.

Il 17 7231 9

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 II

5 (+) - 10 C-ethyl-1β- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bb-octahydro-indolo / 2,3- N-quinolizine and (+) - 10 (, - ethyl-1β- (2 ', 2', 4 ', 4'-tetraethoxycarbonylbutyl) -1,2,3,4,6,7,12,12b- o <C-octahydro-indolo [2,3-a] quinolizine A solution of 3.03 ml (3.12 g, 18.4 mmol) of methylenemalonic acid diethyl ester in 5 ml of dichloromethane is added to the stirred suspension. containing 5.00 g (14.2 mmol) of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ion perchlorate in 30 ml of di -15 chloromethane 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 20 g of petroleum ether.

9 g of oily substance 1-ethyl-1- (21,2'-diethoxycarbonylethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5- ion perchlorate and 1-ethyl-1- (2 ', 21,4', 4'-tetraethoxycarbon-25-butyl-butyl) -1,2,3,4,6,7-hexahydro-12H-indolo [4 Mixture of 2,3-α-7-quinolizine-5-ion perchlorate. 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, 3020 (C = N) cm oily residue obtained as above is dissolved in a mixture of 10 ml of ethanol and 25 ml dichloromethane, and the solution is hydrogenated in the presence of 6 g of prehydrated 10% palladium-on-carbon catalyst. When 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.

5 The separated material is filtered off, washed with ethanol and dried. 8.0 g of a mixture of (+) - 1qC-ethyl-18- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7 are obtained. , 12,12b-octahydro-indolo [2,3-a] quinolizine perchlorate and (+) - 10-ethyl-1H-ethyl (2 ', 2'-diethoxy-10-carbonylethyl) -1,2,3 , 4,6,7,12,12b o-octahydro-indolo- (2,3-a7-quinolizine perchlorate; mp 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. vacuum. The residue is subjected to preparative thin-layer chromatography (adsorbent: alumina type T, solvent: 3: 1 mixture of dichloromethane and benzene, eluent: 20: 1 mixture of dichloromethane and 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 ethanolic hydrochloric acid. The hydrochloride is precipitated with 1.2 ml of ether, filtered, washed with ether and dried.

0.46 g of (+) - 1 H -ethyl-1R is obtained. -30 (21,21-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b octahydro-indolo, [2,3-a] quinolizine hydrochloride, corresponding to a yield of 70.5%. Sp. 202-204 ° C (from ethanol and ether).

The substance with a lower R

The result is 0.26 g of (+) - 10 (.-Ethyl-1- [3- (2- [2,4-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12,12b] o-octahydroindolo [2,3-a] quinolizine perchlorate-5, corresponding to a yield of 26%, mp 216-218 ° C (from ethanol) Example III

(+) - 10C-ethyl-1β- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo (-octahydro-indolo / 2,3-a7-quinolizine) 10,600 mg (1 mmol) of (+) - 10-ethyl-1 H 3- (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7 , 12,12bo-octa-hydro-indolo, [1,3-a] quinolizine prepared as in Example I or II is dissolved in 8 ml of ethanol and a solution of 120 mg of potassium hydroxide in 1 ml is added: in water and 1 ml of ethanol.

Using thin layer chromatography using alumina (type T) as the adsorbent and a 3: 1 mixture of dichloromethane and benzene as the solvent, the reaction time is determined to be 20 minutes at room temperature. In this sys-20 system, (+) - 1 H -ethyl-1β- (2,2,2-diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12bo-octahydro-indolo / The R 1 value of γ, 3-α "7-quinolizine is higher than that of (+) - 1 H -ethyl-1R - (2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1.2 , 3,4, 6,7,12,12bo R-ar-25 vol of? -Octahydro-indolo [2,3-a] quinolizine The reaction mixture is neutralized to pH 6 with acetic acid and the solvent is distilled off in vacuo. to 1 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. The result is 0.25 g of (+) - 10-ethyl-1 / 5- (2 ', 20,731,921-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo (, - octa-hydro-indolo [2,3-a] quinolizine hydrochloride, corresponding to a yield of 53%, mp 201-204 ° C (from ether).

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

5 Example IV

(+) - [1-ethyl-1 / 8- (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12b o (, - octahydroindo) -Lo / 2,3-aTkinolitsiini

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 (+) - 1 o N-ethyl-per- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-a] quinolizine prepared as in Example I or 2.3 rally 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 (+) - 10H-ethyl-1 H} - (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo (N-octahydro) is obtained. -indolo [2,3-a] quinolizine, corresponding to a yield of 74%, mp 113-116 ° C (from water).

For thin-layer chromatography on a KG-6 silica gel plate using 15 ml of benzene, 5 ml of methanol and 2 drops of concentrated aqueous ammonia as solvent, 10-ethyl-1- [3- (2 ', 2'-diethoxycarbonylethyl) -1,2,3, The R 1 value of 4,6,7,12,12b N-C-octahydro-indolo [5,3-a] quinolizine-30 is higher than that of (+) - IryL-ethyl-ββ- (2 1 -carboxy- 2'-ethoxycarbonyl) -1,2,3,4,6,7,12,12b octahydro-indolo </ 2,3-α7-quinolizine Rf value.

IR (KBr): 3360 (indole NH), 1715 (CO), 1600 (COO-) -1 cm 3 Mass spectrum (m / e,%): 354 (M + -44: 53), 353 (58), 339 ( 8), 325 (0.3), 309 (12), 281 (2), 267 (100), ... 44 (1000).

Il · 7231 9 21

Example V

(+) -1ο6-ethyl-1 / β- (2'-carboxy-2'-ethoxycarbonyl) -1,2,3,4,6,7,12,12b'5 (/ - octahydro- indolo / 2,3-α7-quinolizine 5 Solution containing 0,092 g (1,64 nmol) of potassium

hydroxide in 0.3 ml of water and 0.9 ml of ethanol are added to a solution of 0.428 g (0.715 mmol) of (+) - 1 <* i-ethyl-1 / 3- (2T, 2 ', 4', 4 * -Tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12,12bo6-octahydro-indolo [2,3-a] quinolith-10-zine prepared as in Example I or II

In 3 ml of ethanol. The reaction mixture is boiled in a steam bath for 0.75 hours. The solvent is then evaporated off under vacuum, the oily residue is dissolved in 3 ml of water and the resulting solution is 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 (+) - N-ethyl-1 / 3- (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12,12bo (. 20 octahydroindolo [2,3-a] quinolizine, corresponding to a yield of 74%, mp 112-114 ° C.

Example VI

(+) - 10 - (, -ethyl-1β- (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,5,6,7,12,12b 06-octahydro-25 indolo / 2 The 3-α7-quinolizine The filtrate obtained in Example II is used as a starting material when the reaction mixture which is (+) - 1-O-ethyl-1 / β- (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,6, 7,12,12bo {-octahydro-indolo [2,3-a] quinolizine perchlorate and 30 '(+) - 10-ethyl-1β- (2', 2 ', 4', 4'-tetraethoxycarbonylbutyl) - A solution of 1,2,3,4,6,7,12,12bo-1-octahydro-indolo [3,3-a] quinolizine perchlorate in ethanol-dichloromethane and containing these two salts in a weight ratio of about 3: 1, the catalyst has been removed.

35 The solvent is evaporated off under vacuum 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 which is 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 (4.28 mmol) of potassium hydroxide dissolved in 2 ml are added. of water. The reaction mixture is boiled for 1-1.5 hours in 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 a mixture of starting materials. The pH of the aqueous phase is adjusted to 6 with acetic acid and the separated organic matter is extracted four times with 15 ml of dichloromethane. 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 is filtered off, washed with 5 ml of ether and dried.

0.76 g of (+) - 10E-ethyl-1- (2 * - 25 carboxy-2 * -ethoxycarbonylethyl) -1,2,3,4,6,7,12,12boC "octahydro-indolo / 2 , 3-α7-quinolizine, corresponding to a yield of 59%. Sp. 108-111 ° C (decomposes).

Preparation of final products Example 1 3Q (+) - cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (30 ° H, 16 ° <5Et)

A solution of 0.39 g (5.65 mmol) of sodium nitrite in 5 ml of water is added to a solution of 0.75 g (1.885 mmol) of (+) - 10-ethyl-1 / 8- (21- carboxy-21-ethoxy-35-cyccarbonylethyl) -1,2,3,4,6,7,12,12bo (, - octahydro-indolo)

II

23 7231 9 / 2,3- a/k.nolizine prepared as in Example in 6.15 ml of 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 dichloromethane 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-ethoxycarbon-15-yl-14-hydroxyamino-eburnan (3aC H, 16 oi Et) are obtained, corresponding to a yield of 72%. Mp 156-158 ° C (from dichloromethane).

When thin layer chromatography on a silica gel KG-6 plate using a 14: 3 mixture of benzene and methanol (+) - cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan-20n (30 ° H, 16c <Et) has an Rf value of higher than the (+) - 1-ethyl-1 / 3- (2'-carboxy-2'-ethoxycarbonylethyl) -β, 2,3,4,6,7,12,12b-octahydro the R 2 value of indolo-1,3-α7-quinolizine.

The title compound did not cause melting point-25 earth as a mixture with (+) - cis-14-ethoxycarbonyl-14-hydroxyamino-eburnan (30 (, H, 16 «CEt) prepared according to HU Patent Application No. RI-634, and it was identical to the latter in all its physical and chemical properties.

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 35 (8.5), 267 (40), 253 (92), 237 (15), 211 (18).

24 7231 9

Example 2 (-) - 3?, 16-ού S-14-ethoxycarbonyl-14-hydroxyamino-eburnan

To give the title compound, (+) - cis-14-ethoxycarbon-5-yl-14-hydroxyamino-eburnan (3 o H, 16 o (Et) is dissolved in dibenzoyl-D-tartaric acid. Mp 169-171 ° C (from dichloro-20 methane)). = -56.1 ° (c = 1.05, in dimethylformamide).

Example 3 10 (+) - cis-14-methoxycarbonyl-14-hydroxyaminoeburnan (3 ° C H, 16 ° C Et)

Proceed according to Examples II, VI and 1, with the difference that 8 ml of methylenemalonic acid diester are replaced by a corresponding amount of methylenemalonic acid di-15 methyl ester. The title compound mp 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, CH 2 CH 3) ppm. Mass spectrum: m / e 70 eV, M + = 369.

Analysis for C 21 H 27 N 3 O 3 (weight 369.14):

Calculated: C 68.27, H 7.36, N 11.38% Found: C 68.58, H 7.29, N 11.28%

Example 4 (+) - cis-14-ethoxycarbonyl-14-hydroxyamino-25 eburnane (3o (H, 16c, Et) 8.00 g of (+) - 10 H -ethyl-γ- (21.2 ' -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12bcK, -octahydro-indolo [2,3-a] quinolizine and (+) - 10-ethyl-1 / 3- ( 2 ', 2', 4 ', 4'-tetraethoxycarbonyl-butyl) -1,2,3,4,6,7,12,12b oö “A mixture of octahyd-30-ro-indolo / 2,3-a7-quinolizine perchlorates , prepared according to Example II, 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. 19 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.

5 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 2.0 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 vigorously cooling on ice. The resulting mixture 15 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.

Claims (1)

A process for the preparation of hydroxyamino-eburan derivatives of the formula I and their pharmaceutically acceptable acid addition salts and optically active isomers, in which R and R represents C 1-6 alkyl, characterized in that the monoester derivative of octahydroindoloquinolizine of the formula 20 above, is reacted with a nitroso group-forming agent in an acidic mass medium, and, if desired, the resulting compound of formula I is partitioned into its optical isomers and / or the resulting compound is converted into a pharmaceutically acceptable acid addition salt.