CH660735A5 - NEW E-HOMO-EBURNAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The invention relates to new racemic and optically active E-homoeburnan derivatives, their physiologically tolerable acid addition salts, a process for their preparation and the pharmaceutical preparations containing these compounds. The new compounds correspond to the general formula (I)

40

45

(i)

50

55

wherein R1 and R2 are the same or different and represent alkyl groups with 1-6 carbon atoms.

According to the invention, these compounds or their acid addition salts are prepared by using racemic or optically active octahydroindolo [2,3-a] quinolisin derivatives of the general formula (II)

(n)

c — CH2 '

60

where A is hydrogen or the groupings of the general formulas -CH2CH (C02R1) 2 or -CHj-CXCOzRVC ^ -CH (C02R ') 2, the meaning of R1 and R2 is the same as above and R3 is identical to R1 or if A is hydrogen

65

(II)

R%? C-

660 735

where A is hydrogen or the groupings of the general formulas -CHj-CHfCOjR ^ or -CH2-C (C02R1) 2-CH2-CHfCC ^ R1 ^, the meaning of R1 and R2 is the same as above and R3 and R1 are identical or - if A is hydrogen - R3 can also be hydrogen, or cyclize their acid addition salts, if desired the racemic compound of the general formula (I) obtained broken down into its optical antipodes and / or from racemic or optically active compounds of the general formula (I ) forms physiologically acceptable acid addition salts.

The compounds of general formula (I) have valuable pharmaceutical effects. Some of them, especially those belonging to the cis series, have a significant antidepressant effect, while others, especially those belonging to the trans series, have an antihypoxic effect. The invention therefore also relates to the pharmaceutical preparations containing the compounds of the general formula (I) or their physiologically tolerable acid addition salts and their preparation.

In the formulas, R1 and R2 represent alkyl groups with 1-6 carbon atoms. The groups can be straight or branched. Examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, terc.-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl.

The physiologically acceptable acid addition salts can be formed with any inorganic or organic acid suitable for this purpose. Of the inorganic acids, for example, the hydrogen halides, such as hydrochloric acid, hydrogen bromide, also sulfuric acid, phosphoric acid and perhalic acids are suitable; Examples of organic acids are formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, cinnamic acid, and also the alkylsulfonic acids such as methanesulfonic acid and arylsulfonic acid for example p-toluenesulfonic acid and also the cyclohexylsulfonic acids, finally aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutamic acid etc. called.

The compounds of the general formula (II) used as starting materials in the process according to the invention can be prepared in accordance with an earlier proprietary right (Hungarian patent application No. RI-713) by electrophilizing the corresponding hexahydroindolo [2,3-a] quinolisium salts with dialkyl methylene malonate and the product obtained is catalytically hydrogenated and then optionally partially hydrolyzed.

Those of the compounds of the general formula (II) in which the meaning of R1 and R3 are identical can be cyclized with bases which are correspondingly strong. Examples of strong bases are the alkali metal hydrides, e.g. As sodium hydride, potassium hydride, the alkali alcoholates, such as potassium or sodium ethylate, particularly preferably potassium tert-butoxide, in aprotic organic solvents, for example xylene, toluene, advantageously benzene, mentioned. The ring closure is expediently carried out at the boiling point of the reaction mixture. The reaction proceeds within a short time, within 10-40 minutes, in advantageous cases within 15-30 minutes.

For the cyclization of those compounds of the general formula (II) in which A and R3 are hydrogen, a dehydrating agent, advantageously phosphorus oxychloride or phosphorus pentoxide, is used. The reaction is expediently carried out in an inert organic solvent, such as aromatics, expediently benzene, or chlorinated hydrocarbons, for example chloroform or carbon tetrachloride.

If the starting compounds are used in the form of their acid addition salts, for example as hydrohalides, perchlorates or other salts, the compound of the general formula (II) is expediently released from its salt before the cyclization. The base can be released with the aqueous solution of an inorganic base, for example with an alkali carbonate such as sodium carbonate or potassium carbonate or an alkali hydroxide, for example sodium hydroxide or potassium hydroxide, in a water-immiscible inert organic solvent, for example a halogenated hydrocarbon such as dichloromethane or Chloroform.

With the process according to the invention, compounds of the general formula (I) can be prepared both in the trans and cis positions. It depends on whether the starting compound of the general formula (II) was in the trans or cis position.

15 With the method according to the invention, racemic and optically active compounds of the general formula (I) can be obtained. If the starting compound was in the form of a racemate, the end product is also racemic. However, it can be separated into its optical antipodes in a manner known per se. Optically active compounds can also be used as starting materials; in this case, optically active compounds of the general formula (I) are obtained directly.

The racemes or optically active compounds of the general formula (I) obtained according to the invention can, if desired, be converted into their physiologically tolerable acid addition salts. Salt formation is preferably carried out in an inert organic solvent, advantageously in an alkanol having 1-6 carbon atoms, for example in methanol, by dissolving the base of the general formula (I) in this solvent and then adding the corresponding acid as long as until a weakly acidic pH is reached (about pH to 6). Then the acid addition salt of the compound of the general formula (I) is separated from the reaction mixture, expediently by precipitation with an water-immiscible organic solvent, for example diethyl ether.

If desired, the optically active compounds of the general formula (I) or their racemates or acid addition salts obtained by the process according to the invention can be further purified, for example by recrystallization. The solvent suitable for recrystallization is determined by the solubility and crystallization properties of the substance to be recrystallized.

The antihypoxic effect of the compounds of the general formula (I), which is particularly pronounced in the 3β, 17a-trans compounds, is demonstrated in the survival time of mice in the test of normobaric hypoxia. For this purpose, 5 male mice are placed in a glass cylinder with a volume of 3 liters. A gas mixture containing 96% nitrogen and 4% 50 oxygen is flowed through the cylinder. The time between the onset of the mice and their death is measured. The animals that were still alive after twice the time that the untreated control animals died were considered protected. The substances to be examined 55 were administered intraperitoneally at a dose of 50 mg / kg to 10 animals 30 minutes before introduction into the glass cylinder. The results are summarized in the following table.

Table 1

60

65

connection

Survival time, min

average

%

protection

%

(±) -trans-14-oxo-15-

8.3 ± 1.1

+32

20th

ethoxycarbonyl-E-ho-

moeburnan (3ß, 17a)

control

6.3 ± 1.45

-

0

Vinkamin

7.1 ± 1.30

+ 13

0

660 735

In particular, the 3a, 17a-cis compounds of the general formula (I) have a valuable antidepressant effect.

The active compounds of the general formula (I) can be formulated into the customary pharmaceutical preparations which can be administered parenterally or enterally. The usual, non-toxic, solid and liquid carriers, extenders and auxiliaries are used. Possible carriers are, for example: water, gelatin, lactose, milk sugar, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil etc. The dosage forms can be different, for example solid, rounded or square tablets, Dragees, capsules such as hard gelatin capsules, pills, sup-positorien; liquid pharmaceutical preparations such as aqueous or oily solutions, suspensions or emulsions, syrups, injection solutions. The amount of solid carrier can vary within wide limits, for example between 25 mg and one gram. The preparations can optionally contain the auxiliaries customary in pharmacy, such as preservatives, wetting agents, emulsifiers, salts for adjusting the osmotic pressure, buffers, flavors, fragrances, etc. The pharmaceutical preparations can also contain other pharmaceutically active compounds without a synergistic effect. The preparations are expediently formulated in the dosage units corresponding to the chosen administration form. The pharmaceutical preparations are prepared using methods known per se, for example by sieving, mixing, granulating and pressing or dissolving. The preparations can also be subjected to the usual measures in the pharmaceutical industry (e.g. sterilization).

The invention is illustrated by the following examples, but is not limited to the examples.

example 1

(±) -cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) From 880 mg (1.90 mmol) (±) -la-ethyl-lß (2 ', 2'-diethoxycar -bonyl-ethyl) -l, 2,3,4,6,7,12ba-octahydroindolo [2,3-a] quinolisin hydrochloride, the base is released in 25 ml dichloromethane with 10 ml 10% aqueous sodium carbonate solution. After the organic phase has been separated off, the aqueous phase is extracted with a further 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo.

The remaining oil is dissolved in 15 ml of absolute benzene, the solution is mixed with 258 mg (2.3 mmol) of potassium tert-butoxide and the mixture is refluxed under a nitrogen atmosphere for 20 min. After cooling, the pH of the mixture is adjusted to 6 with ice cooling with acetic acid. Then the solvent is distilled off in vacuo. The evaporation residue is dissolved in 20 ml dichloromethane, the solution is adjusted to pH 9 with 10 ml 5% aqueous sodium carbonate solution, and the phases are separated from one another. The aqueous phase is extracted with a further 5 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtration, freed from the solvent in vacuo. 560 mg of oil are obtained. The oil is recrystallized from 1.5 ml of methanol,

whereby 480 mg of product are obtained. Yield 66.5%. Melting point: 143-144 ° C (ethanol)

IR (KBr): 1738 (ester), 1690 cm "1 (lactam)

Ms / m / e,% /: 380 / M +, 100 /, 379/35 /, 363/20 /, 352/17 /, 351/26 /, 335/12 /, 323 / 9.1 /, 307 / 55 /, 252/35 /, 237/17 /.

'H NMR (CDC13): Ô = 8.52-7.35 (4H, m, aromatic), 4.31 (2H, q, J = 7.2Hz, OCH2), 4.08 (1H, s, 3-H), 3.75 (1H, d, J = 11 Hz, 15-H), 1.34 (3H, t, J = 7.6 Hz, OCH2CH3), 0.91 (3H, t, J = 8.1 Hz, CH2CH3)

Example 2

(±) -trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3ß, 17a)

400 mg (0.94 mmol) (±) -cc-ethyl-lß- (2 ', 2'-diethoxycarbonyl-ethyl) -l, 2,3,4,6,7,12,12bß-octahydroindolo [ 2,3-a] quinolisin 5 (to be obtained as a by-product of Example 1 of Hungarian Patent Application No. RI-713) are dissolved in 10 ml of anhydrous benzene, and 125 mg (1.11 mmol) of potassium tert are added to the solution. -butylate. The reaction mixture is refluxed for 20 minutes under a nitrogen atmosphere. 10 The pH of the cooled reaction mixture is adjusted to 6 with ice cooling with acetic acid and the solvent is distilled off in vacuo. The remaining substance is dissolved in 10 ml dichloromethane.

The solution is made alkaline with 5% aqueous sodium carbonate solution 15 pH 9. After the phases have been separated, the organic phase is extracted with 5 ml of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtering, freed from the solvent in vacuo. The oil obtained (300 mg) 20 is crystallized from 2 ml of ethanol. 260 mg (73.0%) of product are obtained, which melts at 173-175 ° C (ethanol).

IR (KBr): 2750-2700 (Bohlmann), 1735 (ester), 1680 cm "1 (lactam);

Ms / m / e,% /: 380 / M +, 100 /, 378/38 /, 363/14 /, 352/11 /, 351/16 /, 25335/11 /, 323 / 5.5 /, 307 / 34 / ...

'H NMR (CDCI3): Ô = 8.56-7.24 (4H, m, aromatic protons), 4.32 (2H, q, J = 7.6 Hz, OCH2), 4.08 (1H, dd, ^ = 13.6 Hz, J2 = 2.7H6.15-H), 3.41 (H, s, 3-H), 1.35 (3H, t, J = 7.6Hz, OCH2CH3), 0.74 (3H, t, J = 6 Hz, CH2CH3).

30 -

Example 3

(±) -cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) 35 From 634.5 mg (±) -la-ethyl-lß- (2 ', 2', 4 ', 4'-tetraethoxycar-bonyl-butyl) -l, 2,3,4,6,7,12,12ba) -octahydroindolo [2,3-a] quino-lisine hydrochloride or from 698.0 mg (1 mmol) of the corresponding hydroperchlorate, the base is released in 25 ml of dichloromethane with 10 ml of 10% aqueous sodium carbonate solution. 40 The base is extracted with dichloromethane. The combined extracts are dried over anhydrous magnesium sulfate, the solvent is distilled off in vacuo.

The remaining oil is dissolved in 15 ml of anhydrous benzene, 145 mg (1.3 mmol) of potassium tert-45 butoxide are added to the solution and the reaction mixture is refluxed under a nitrogen atmosphere for half an hour. The pH of the cooled mixture is adjusted to 6 with acetic acid and the solvent is distilled off in vacuo. The residue is dissolved in 10 ml of dichloromethane and the solution 50 made alkaline to pH 9 with 10 ml of 5% aqueous sodium carbonate solution. After the phases have been separated, the aqueous phase is extracted with 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate and, after filtering, the solvent is removed in vacuo. The remaining oil is crystallized from 1 ml of ethanol. 307 mg (80.8%) of product are obtained, which melts at 143-144 ° C (ethanol).

Example 4

(±) -cis-14-Oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) 870 mg (1 mmol) (±) -la-ethanol-lß (2 ', 2', 4 ', 4', 6 ', 6'-hexaäthoxycarbonyl-hexyI-65l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] quinolisin hydro-perchlorate and works on the im Example 3 described way, 264 mg (69.5%) of product are obtained which melts at 142-143 ° C. (ethanol).

660 735

Example 5

(±) -cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3al7a) hydrochloride

200 mg (±) -cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) prepared according to Example 1 are dissolved in a mixture of 3 ml dichloroethane and 2 ml ethyl alcohol. The pH of the solution is adjusted to 2 using hydrochloric acid ethanol. Then the reaction mixture is evaporated to dryness and the evaporation residue is crystallized from 1.5 ml of ethanol. 165 mg (75.2%) of product are obtained. Melting point: 204-207 ° C (ethanol).

Example 6

(+) - cis-14-Oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) 300 mg (0.755 mmol) (±) -la-ethyl-lß- (2'-carboxyethoxy-carbonyl-ethyl) -l, 2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] chi-

nolisin are suspended in 2 ml of anhydrous benzene and 2 ml of phosphorus oxychloride are added to the suspension with ice cooling. The reaction mixture is refluxed with stirring for 8-9 hours.

s After cooling, the reaction mixture is evaporated to dryness in vacuo. The residue is triturated with 2 ml of ice water. The pH is adjusted to 9 with 10% aqueous sodium carbonate solution and the mixture is extracted with 3x2 ml dichloromethane. The combined organic phases are dried over anhydrous magnesium sulfate and, after filtering, are freed from the solvent in vacuo. The remaining oil (226 mg) is crystallized from 0.5 ml of ethanol. 156 mg of product are obtained. Yield: 54.3%.

15 melting point: 142-144 ° C (ethanol),

IR (KBr): 1725 (ester-CO), 1680 cm1 (lactam-CO).

M

Claims (8)

660 735 PATENT CLAIMS. 1. Racemic and optically active E-homo-eburnan derivatives of the general formula (I) (I) ° 2 | i, wherein R1 and R2 are the same or different and represent an alkyl group having 1 to 6 carbon atoms, and their physiologically tolerated acid addition salts. 2. (±) -cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan- (3a, 17a) and its hydrochloride as compounds according to claim 1. 3. (±) -trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3a, 17a) as a compound according to claim 1. 4. Process for the preparation of racemic and optically active E-homo-eburnan derivatives of the general formula I stands, R3 can also stand for hydrogen, or cyclize their acid addition salts and, if desired, form physiologically compatible acid addition salts from racemic or optically active compounds of general formula I. 5. The method according to claim 4, characterized in that a strong base is used to cyclize compounds of the general formula II in which R3 and R1 are identical. 6. The method according to claim 5, characterized in that an alkali metal hydride or alkali metal alkoxide is used as the strong base. 7. The method according to claim 4, characterized in that for the cyclization of compounds of general formula II in which A and R3 are hydrogen, phosphorus oxychloride is used. 15 8. The method according to any one of claims 4 to 7, characterized in that one carries out the cyclization in an inert organic aprotic apolar solvent. 9. A process for the preparation of pharmaceutical preparations, characterized in that one is racemic or optical 20 active E-homo-eburnan derivatives of the general formula I, in which the meaning of R1 and R2 is the same as in claim 1, or their physiologically tolerable acid addition salts mixed with carriers and / or auxiliaries and formulated into pharmaceutical preparations. 10. Medicament preparations, characterized by a content of racemic or optically active E-homo-eburnan derivatives of the general formula I or their physiologically tolerable acid addition salts. 30th (I) in which R1 and R2 are the same or different and represent an alkyl group having 1 to 6 carbon atoms, and the physiologically tolerable acid addition salts of these compounds, characterized in that racemic or optically active octahydroindolo [2,3-a] quinolisin derivatives of the general formula II 25th