HU192897B - Process for production of new derivatives of methanoazecino /5,4-b/ indole - Google Patents

Abstract

Octahydro-indolo(2,3a) quinolizine deriv. (II), where R1 is 1-6C atom alkyl gp. and R2 is 1-6C atom alkyl sulphonyl or 6-4C atom aryl sulphonyl gp., is heated in a neutral organic solvent to 50-90 deg.C to obtain a quat. sulphonate (III), which is then reacted with an alkaline metal cyanide to obtain the norquebrachamine deriv. (I). A reaction with acid produces its salt.

Description

This invention concerns a process (I) methano-azecino (5,4-b) indole-azármazákok formula - wherein R ^l represents

A C 1 -C 4 alkyl group by reacting an octahydroindolo (2,3-a) quinolizine B compound of formula II wherein R ¹ is as defined for formula I and R * is optionally substituted The C 1-6 alkylsulfonyl or phenyl azulfonyl group is heated at 50-90 ° C in an inert organic solvent, preferably C 1-6 aliphatic alcohol, acetonitrile, dimethylsulfoxide. quaternary sulfonate of the formula wherein R ¹ and R ^J are as defined above optionally without isolation, with an alkali metal cyanide.

The novel compounds of the present invention have valuable therapeutic effects, namely antihypoxic, anticonvulsant, antidepressant and analgesic effects.

In the above formulas, R ¹ and R alkylsulfonyl group in ^one szuszbtituensben cBoportja alkyl straight or branched chain groups such as methyl, ethyl, n-propyl, i-propyl, η-butyl, sec- butyl, tert-butyl, ß-butyl, η-pentyl, i-pentyl, η-hexyl, i-hexyl.

Both the alkyl group and the phenyl group may optionally contain one or more identical or different substituents, such as C 1 -C 4 alkyl, alkylthio, alkoxy, halogen et al.

The starting materials of formula (II) may be prepared, for example, by reacting the corresponding hydroxymethyl-octahydroindolo (2,3-ay substituted phenylsulfonic acid, or a reactive derivative thereof, such as halides.

The alkali metal cyanide used in the process of the invention may be any cyanide of any alkali metal such as potassium, sodium, etc.

In the reaction of the present invention, the compound of formula (III) obtained in the first step may be isolated from the reaction mixture by any suitable method and the isolated compound of formula (II) may be reacted with an alkali The compound of formula I is not isolated from the reaction mixture, but is reacted with the alkali metal cyanide in the reaction mixture itself.

The compound of formula (III) is reacted with an alkali metal cyanide, preferably in an inert organic solvent, preferably in a solvent used in the preparation of compounds of formula (III), such as a C1-C6 aliphatic alcohol, acetonitrile, dimethylsulfoxide, etc., preferably methanol. , preferably at elevated temperatures, for example 50-90 ° C.

If desired, the crude product obtained by the process of this invention may be recrystallized or otherwise purified. The quality of the solvent used for recrystallization is determined by the solubility conditions of the material to be recrystallized.

The structure of the compounds of the present invention is clearly evidenced by the location of the elemental analysis results and the bands of the infrared mass and the characteristic groups measured by ¹ C NMR.

To test the effect of the compounds of formula (I) prepared according to the method of the present invention, the substances were added in a dose of 30 mg / kg in ¹ dose, 2% Tween 80, one hour before the experiments. CFLP (LATI) mice and Hannover-Wistar (LATI) rats were used in the experiments.

Our testing methods were as follows.

Maximum electroshock (mouse)

Shock was applied via a corneal electrode (20 mA, 0.2 ms HSE SchockgerSt typ. 207). Male animals of 22-24 g were used for the experiments. Animals considered to have a tonic extensor seizure after treatment are considered protected.

Metrazole cramps

Mice weighing 18-22 g were used. The animals were pre-treated with 125 mg / kg pentylene tetrazole subcutaneously. We have classified animals that have

a) clone b) b) tonic extensor seizure is omitted and the animals are survivors.

Observation time is 1.5 hours.

Strichnine spasm

In animals (18-22 g), tonic extensor convulsions were induced by intraperitoneal administration of 2.5 mg / kg strychnine nitrate. Animals that have a seizure response after treatment are considered protected.

Reezerpin hypothermia reversible effect

Test substances were administered 16 hours after an intraperitoneal dose of 5 mg / kg reserpine. Tracheal temperature of animals before administration of reezerpin (To), 16 hours after administration of reserpine (Tis) and administration of the substance

After 192397, it was recorded every 5 hours (Tn-Tiii) on an ELAB thermometer (typ. TE-3).

Hexobarbital sleep time measurement in rat

Female rats (50-60 g) were pretreated with (a) 1 hour, (b) 24 hours, 60 mg / kg hexobarbital Na (Evipan Bayer). The sleep criterion is “loss of rathing reflex. The criterion for awakening is the return of the reflex, that is, the spontaneous correction of the posture. The mean of the sleep times and the standard deviation of the mean were calculated.

Asphyxial anoxia

The animals were treated after 16 hours of fasting and then placed in 100 ml well-sealed vials, and the time from closure to last respiratory movement was recorded as survival time. Animals that lived 30% longer than the mean survival time of the control group were considered protected.

Hypobaric hypoxia were treated with the substances for one hour and then placed in a desiccator. In the desiccator, the pressure was reduced to 170 mmHg in 20 seconds, and from this time until the last respiratory movement, survival time was recorded. Animals that were 100% longer than the mean survival time of the control group were considered protected.

Measurement of analgesic effect

One hour after pretreatment, male mice (18-22 g) were administered intraperitoneally 0.6% acetic acid in a volume of 0.3 ml. “Frequency of Writhing Syndrome was recorded every 10 minutes for 30 minutes. The change in response to treatment was compared to the mean values of the "Writhing syndrome" in the control group.

Antipyretic effect

In male rats weighing 160-180 g, hypothermia was induced subcutaneously with a beer yeast suspension (0.5% brewer's yeast 1% gum arabic in 0.3 ml volume). After 4 hours, the animals were treated with the test substances and the animals' tracheal temperature was recorded with an ELAB thermometer (typ. TE-3) for 4 hours. The antipyretic activity is expressed as the percentage of animals at which the treatment temperature is 1 C below the mean temperature of the solvent-treated control group.

The active ingredient of formula (I) may be formulated in pharmaceutical compositions with non-toxic, inert, solid or liquid carriers and / or excipients suitable for parenteral or enteral administration in the pharmaceutical field. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, for example solid (round or lozenge pills, tablets, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, soft gelatin capsule, injectable ). The amount of solid carrier can vary within wide limits, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffering agents, flavoring agents, perfumes and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic effects. Preferably, the composition is formulated in dosage units which include, for example, sifting, mixing, granulating, and pressing or dissolving the ingredients to form appropriate compositions. The compositions may be subjected to other conventional pharmaceutical operations (e.g., etherification).

The invention is further illustrated by the following non-limiting examples.

Example 1 1,2,4,5,6,7,8,9-octahydro-7α-ethyl-3,7-methano-3H-azecino (5,4-b) indole-8β-carbonitrile

12.40 g (34.21 mmol) of 1cc-ethyl-11b-mesyloxymethyl-1,2,3,4,6,7,12,12bcc-octahydroindole (2,3-a) quinolizine 500 Dissolve in anhydrous maethanol (ml) and reflux for 25 minutes. Sodium cyanide (12.40 g, 252.98 mmol) was then added and the reaction mixture was refluxed for a further 27 hours.

After completion of the reaction, the resulting solution was evaporated to dryness in vacuo, the residue was suspended in water (600 mL) and extracted with dichloromethane (3 x 100 mL). The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The evaporation mara-37 strain was treated with 50 mL of hot methanol and filtered. The crude product was recrystallized from methanol.

7.30 g of the title compound are thus obtained in the form of white crystals.

Yield: 72.73%.

Melting point: 218-220 ° C.

Analysis calculated for C 19 H 23 N 3 (m.p. 293.39): C, 77.77; H, 7.90; N, 14.32.

Found: C, 77.73; H, 7.91; N, 14.60.

Infrared (potassium bromide) λmax: 3380 cm ^-1 (ind-NH), 2320 cm ^-1 (CN).

¹³ C-NMR spectrum (in pyridine-ds): δ 7.85 (C5-CH3-CH5), 18.90 (C7), 26.46 (Cl1),

29.51 <C6), 31.69 (C6-CH1-CH5), 35.86 <C3), 41.49 (C5), 51.61 (C10), 52.07 (C8), 111.69 ( C17), 112.58 (C12), 118.60 (C14), 119.39 (-CN), 119.68 (315), 122.12 (C16), 127.48 (C13), 128.93 < C2), 136.68 (C18) ppm.

Example 2 1,2,4,5,6,7,8,9-octahydro-7oc-ethyl-3,7-methano-3H-azecino (5,4-b) indole-8oc-carbonitrile

12.40 g (34.21 mmol) of loc-ethyl-10- (mesyloxymethyl) -1,2,3,4,6,7,12b-octahydroindole (2,3-a) quinolizine in 500 ml dissolved in anhydrous methanol and refluxed for 25 minutes.

The reaction solution was then evaporated to dryness and the residual oil was triturated with ether (3 x 20 mL) and decanted. The crystals thus obtained are dried.

12.2 g of 1cc-ethyl-1,5-methano-1,2,3,4,6,7,12,12boc-octahydro-indolo (2,3-a) quinolizine-5-lumium methanesulfonate are thus obtained. .

Yield: 98.4%.

Mp 155-157 ° C.

MS (m / z): 254 (11), 157 (21), 144 (15), 125 (5), 124 (6), 110 (100), 96 (10), 79 (11).

12.2 g of lcc-ethyl-1,5-methano-1,2,3,4,6,12,12boc-octahydroindole (2,3-a) quinolizine-5-luminescansulfonate are dissolved in 500 ml of methanol. , to the solution was added 12.4 g (252.98 mmol) of sodium nitrum cyanide and the reaction mixture was refluxed for 27 hours.

The reaction mixture was worked up as described in Example 1.

All the title product obtained has the same physical properties as described in Example 1.

Claims (2)

PATENT CLAIMS A process for the preparation of a novel methanoazecino (5,4-b) indole derivative of formula (I) wherein R ¹ is C 1 -C 4 alkyl, characterized in that an octahydroindolo of formula (II) (-a) a quinolizine derivative wherein R ¹ is as defined for formula (I) and R ² is optionally substituted C 1-6 alkylsulfonyl or phenylsulfonyl in an inert organic solvent, preferably 1-6; aliphatic alcohol, acetonitrile, dimethyl sulfoxide, 50-90 ° C, heated, and then the thus obtained (111) quaternary formula sulfonate - wherein R ¹ Pedigree R ² are as defined above -, optionally without isolation, with an alkali metal cyanide. Process for the preparation of a pharmaceutical composition characterized in that the novel methanoazecino (5,4-b) indole derivative of the formula I according to claim ^1, wherein R ¹ represents a C 1 -C 4 alkyl group - in medicine mixed with customary excipients and / or excipients and converted to a pharmaceutical composition.