SE435622B - THERAPEUTIC COMPOSITION CONTAINING INDOLO (2,3-A) QUINOLIZIDINES - Google Patents

Description

8997M54: a perchlorate; hydrogenation of the resulting quinolizidine The chlorate is carried out to give the corresponding indole (2,5-a) ~ quinolizidine isomer mixture and the isomers are separated. The corresponding the reaction sohemans are shown below under the heading "originating common sequence "and leads only to compounds, where R denotes -COOCZH5 or -CN (2 isomeric forms in each case, i.e.

H compounds).

All other derivatives are derived from these compounds, namely -either directly, e.g. the acids, from the esters by saponification (see scheme "specific reactions" A = -COOCZH5) or methyleneamino from nitriles by reduction with lithium aluminum ~ hydride (see the same schemes when A = -CN), or from acids or methylamino derivatives according to well known reactions.

In the following schedules ~ I refers to cis isomers - II relates to trans isomers, - 1 (a) -1 (h) refers to different steps according to fi 'example 1, where at the starting material is the 4-ethoxycarbonyl derivative and the final product the products acids or derivatives thereof and 2 (a) -2 (g) relates to the various steps of Example 2, where the starting material is the 4-cyano derivative and the end products are methylamino derivatives. 5 aooveus-4 Original joint sequence 1 (a) or 2 (a) cH cH m! A ' //, __j / 2 2 2 I L- J '+ c¿n5 - f - (cazb _c1__¿_ I (KC / NH im hrs \ 'cou IJ J å k? 1 (b) or 2 (b) t But _O K -aoovsas-u _ ¶ ~ Specific reactions 5 <1) 'UU 30078454: 5 The invention is illustrated by the following examples.

Example 1 (a) Preparation of 3-15 '- (2 "-ethoxycarbonyl-2" -ethyl-5 "~ -chloro-valeroylamino) -ethyl-indole.

To a suspension of 2.5 g (0.0184 mol) of 3- (2'-aminoethyl) - -indole (tryptamine) in 50 ml of dry chloroform, containing 2 g (0.02 mol) of triethylamine, cooled in an ice bath, was added dropwise 4,? g (0.0184 mol) 2-ethyl-2-ethoxycarbonyl-5-chloro-valeroyl chloride. After stirring for 2 hours at room temperature, the solution was washed with dilute aqueous hydrochloric acid. After drying the or- the mechanical phase and its evaporation under reduced pressure 6.6 g of the above product were kept, which after recrystallization ring from petroleum ether / isopropyl ether had a melting point of 76 ° C and was obtained with a yield of 95%. Analysis of the product gave the following ~ the results: 1 IR (rar) 3350 and 3300 cm -1 NH 1735 cm_1 CO ester 1640 cm_1 CO amide.

Calculated for C 20 H 27 N 2 O 3 Cl: C = 63.40%; H = 7.18%; N = 7.40%.

Found: C = 63.39%; H = 7.05%; N = 7.51%. (b) Preparation of 1-(1'-indol-3 "-ylethyl) -3-ethyl-3-ethoxy- carbonyl-2-piperidone.

To a suspension of 34.4 g (0.0908 mol) of the above compound in 150 ml of a 1: 1 mixture of dry benzene and hexane methylphosphoric acid triamide, cooled in an ice bath, was added in small portions and under a nitrogen atmosphere 10.6 g (0.0946 mol) of potassium t-butoxide.

After stirring for 8 hours at room temperature, poured loose to a cold, dilute aqueous solution of hydrogen chloride ~ acid. After decanting, the aqueous phase was extracted twice benzene. The resulting organic phase was washed twice with water and dried. After evaporation under reduced pressure 30 g of the desired product were obtained, which after recrystallization isopropyl ether had a melting point of 84 ° C and was obtained with a yield of 96%. Analysis gave the following results: 1 IR (rar) 3250 cm -1 NH inaol 1730 cm_1 CO ester 1620 cm_1 CO amide.

Calculated for C 20 H 22 N 2 3: C = 70.15%; H = 7.65%; N = 8.13% Found: C = 69.97%; H = 7.65%; N = 8.20%. 800784544 (c) Preparation of 1-ethyl-1-ethoxycarbonyl-5,12b-didehydro- -indole- (2,3-a) -quinolizidinium perchlorate.

To a solution of 30 g (0.0876 mol) of the above compound in 480 ml of dry toluene was poured 240 ml of distilled phosphoryl chloride.

The solution was heated under reflux for 9 hours with moisture exclusion. Excess phosphoryl chloride and toluene were removed by evaporation under reduced pressure. The residue was taken up in methylene dichloride and the solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Some of the solution was stirred with a 1M aqueous solution of lithium perchlorate. After decanting of the aqueous phase, washing of the organic phase with water, drying over sodium sulfate and evaporation of the solvent under reduced pressure a yellow powder was obtained, which was recrystallized. rades ur ethanol. The resulting product melted at 191 ° C.

The analysis results were as follows: 1 IR (KBr) 3340 cm -1 NH 1740 cm_1 CO ester 1625 cm -1 1 c = N <; (] (d) Preparation of 1-ethyl-1-ethoxycarbonyl-indole- (2,3-a) - quinolizidine (12b-H; 1-C2H5 trans and cis isomers).

A solution of 6.25 g (0.0147 mol) of the above perchlorate rat salt in 80 ml of ethanol was hydrogenated for 12 hours in the presence of 0.3 g platinum oxide. After filtration, the ethanol was evaporated reduced pressure and the residue was taken up in methylene dichloride and stirred with 5% sodium hydroxide. The organic phase was decanted and washed with distilled water.

By chromatography on a solution of the product with methyl lendichloride over 100 g of silicon and eluting with the same solvent part was separated 1.12 g of a first fraction (yield 25%), which was 12b-H; 1-CZ point 112 ° C (recrystallized from petroleum ether / isopropyl ether).

The H5 trans isomer of the product and had a melt Analysis gave the following results: 1 IR (KBr) 3410 cm -1 NH 2770, 2805, 2825 cm_1 Bohlmann band 1 1710 cm-CO ester 8007M54: NMR (CDCl 3 90 MHz: among other signals: 8.5 6 OH (s) (NH indole) 4.35 δ 2H (q) (O-CH 2 -CH 3) 3.85 ß m (s) m on cga) 1.35 δ 3H (t) (CH 3 -CH 2 -O-) 0.75 δ 3H (t) (CH 3 -CH 2) Calculated for C 20 H 26 N 2 O 2: C = 73.59%; H = 8.03%; N = 8.58% Found: C = 73.47%; H = 8.12%; N = B, 33%.

The latter chromatography fractions gave 1.8 g of an oil, which was 12b-H; The 1-C H -cis isomer of the desired product.

Analysis resultsâeâ were as follows: IR (xßr) 3420 cm -1 NH 3750, 3800 cm_1 ~ Bohmnann band 1705 cm_1 CO ester NMR (OCl 4 90 MHz) among other signals: 7.78 δ 1H (s) (NH indole) 4.15 δ 2: 1 (q) (-oca2-cH3) 3.93 a m (s) (n on cga) 1.09 6 3H (t) (CH 3 -CH 2 -O) 0.9 6 3H (t) (CH 3 -CH 2 -) The hydrochlorides melted - after recrystallization from iso- propanol - at over 260OC.

Calculated for C20H26N2O2.HCl1.5 H2O: C = 61.57%; H = 7.75%; N = 7.18% Found: C = 61.51%; H = 7.33%; N = 7.35%. (c) Preparation of 1-ethyl-1H-carboxy-indole- (2,3-a) -quinoline lizidine (12b-H; 1-C2H5-trans isomer), hydrochloride. l | H Hcl / 'D32 Z Hooc ”I To a solution of 8.8 g of that obtained in step (b) above, ~ The ester in 100 ml of ethanol was added 8.8 g of KOH and the mixture was boiled. was refluxed for 12 hours. The solution was evaporated reduced pressure and the rest was treated with ice water, acidified by means of concentrated hydrochloric acid to an acidic pH range, each 80078ß5-4 8 after the hydrochloride was precipitated and separated, washed and dried. The yield was 9.5 g (100%) of the product after thinning with 1 mole of water. Melting point: above 260 ° C.

Analysis Formula C 18 H 22 N 2 O 2, HCl, H 2 O Molecular weight: 353. c. H N Calculated: 51.20% 7.08% 7.93% Revenue = 61.01% 6.75% 7.72% IR (xßr) 3340 cm -1 NH '1705 cm "1 (-E-on) O (f) Preparation of 1-ethyl-1-piperonylpiperazidocarbonyl -indole- (2,3-a) -quinolizidine (12b-H; 1-C2H5-trans-isomer) dihydro- chloride. 2 HC] f '\ f o cH2-N - cf LB \ ___ / N 5 6 g of hydrochloride from step (e) above were suspended in 50 ml benzene and then 40 ml of oxalyl chloride were added under cooling.

After stirring for 24 hours at 40 ° C, excess was evaporated off oxalyl chloride by distillation under reduced pressure and the residue traded for 4 hours with dry benzene. The dry residue sus- was then suspended in 50 ml of methylene chloride and the mixture was cooled to OOC. A solution of 3.6 g of piperonylpiperazine and 3.4 g of tri- ethylamine in 20 ml of methylene chloride was added and the mixture was stirred. 6 hours at room temperature. After filtration of insoluble constituents and evaporation of the methylene chloride were treated over a silica gel column (eluent CH 2 Cl 2).

Yield 4.9 g (60%) of an oily product.

IR (film) 3360 cm -1 (NH); 1640 cm -1 (co).

NMR (coc13, internal TMS) δ and 10'6 9.2 1s (1H) NH indole 5.9 1s (2H) O-CH 2 -O 4.05 1s (1H) H (C12b) 0.3 1t (3H) CH 3 -CH 2 800781154 » 9 The hydrochloride was obtained by treatment with aqueous hydrochloric acid in ethanol. Recrystallization gave product with 3H 2 O.

The melting point was 242 ° C.

Analysis C 30 H 36 N 4 O 3, 2HCl, 3H 2 O Molecular weight: 627.6 C H N Calculated: 57.40 7.01 8.92 Obtained: 57.82 6.55 8.64 (g) Preparation of 1-ethyl-1-trimethoxybenzamide (4) -pipe azinocarbonyl] -indole- (2,3-a) -quinolizidine- (12b-H; 1-C2H5-trans ~ isomer) hydrochloride.

HCl CH 0 CH O - CH3O 5 g of hydrochloride from step (e) above were treated with oxalyl chloride as described in step (f) above. 5.3 g of one were obtained dry residue, to which was added 50 ml of methylene chloride, after which the mixture was cooled to 0 ° C. A solution of 3 g of triethylamine and 3 g of trimethoxybenzoyl-4-amino-1-piperazine in 20 ml of methylene chloride to sat. The mixture was stirred for 24 hours at room temperature and washed. was then taken with a 10% aqueous soda solution, then with water, was then dried and the excess solvent was evaporated. after. 7.7 g of an oily product were obtained.

Imfilm) 3380 cm ”and 3240 cm- (NH) 1650 om ”and 1620 01151 (co) The hydrochloride was obtained by treatment with aqueous hydrochloric acid in ethanol. Melting point: 225 ° C.

Analysis: C 32 H 41 N 5 O 5, HCl Molecular weight: 611 C H N Calculated: 62.87 6.92 11.46 Obtained: 62.24 6.95 11.18 (h) Preparation of 1-ethyl-1-carboxy-indole- (2,3-a) -kilonizine din (12b-H; 1-CZHS-cis-isomer). 800 '? 8l @ 5 ~ læ 10 To a solution of 6.8 g of 1-ethyl-1-ethoxycarbonyl-indole (2,3-a) -quinolizidine (12b-H; 1-C2H5-cis-isomer) obtained according to Example (d), in 100 ml of ethanol (95%) was added 6.8 g of potassium hydroxide.

The mixture was boiled under reflux for 12 hours each time. after the solvent was evaporated under reduced pressure and the residue treated with ice water and acidified with hydrochloric acid pH = H, 5. The product which crystallized, separated, was washed and dried. 4.1 g of the acid were obtained. Analysis C18H N O M = 298.57 22 2 2 C H N Calculated: 72, ü5 7, U3 9.37 Obtained fi: 72.61 7, u9 9.20 IR 1620 cm U l U CO, OH associated Example 2 (a) Preparation of 5 - [- 2 '- (2 "-cyano-2" -ethyl-5 "-chloro- -valeroylamino) -ethyl_7-indole. ' In a 1 liter flask was placed 31 g (0.019 U mol) of trypt amine, 500 ml of dichloromethane and 20 g (0.0198 mol) of triethylamine.

The mixture was cooled to 0 ° C over ice and then HO g was added (0.192 mol) 2-cyano-2-ethyl-5-chloro-valeroyl chloride, dissolved in 150 ml methylene chloride. After 2 hours at room temperature, the mixture was washed. with water and then with 10% hydrochloric acid and finally with 10% sodium hydroxide. The product was then dried and the solvent was removed by evaporation. After recrystallization from isopropyl ether / petroleum ether, the product had a melting point of 12,000 and was obtained with a yield of H0 g. The analysis results was as follows: IR (xßr) šhoo Gm'1 NH inaol 33uo cm "1 NH amia 2860 cm_1 CN 1660 cm -1 c-N 101. 65.0%; H = 6.6n%; N = 12.65% 64.03%; H = 6.78 z; N = 12.6o%.

Calculated for C 18 H 22 N 3 ClO: C Obtained: C 8007845-'4 11 (b) Preparation of 1- (2'-indol-3 "-yl-ethyl) -5-ethyl-3- -cyano-2-piperidone.

In a 1 liter round bottom flask was placed 22 g (0.0665 mol) of the product from step (a) above, 200 ml of tetrahydrofuran and 300 ml of t-butanol. The mixture was cooled to 000 over ice and after 8.5 g (0.076 mol) of potassium tert ~ were added in small portions -butoxide. After 2 hours at room temperature, the mixture was reduced. volume and was hydrolyzed. The organic phase extra- cured with methylene chloride, washed with water and dried and the solvent was removed by evaporation. The desired pro- after recrystallization from ethanol / ether, the product had 50/50 g melting point of 18000 and was obtained in a yield of 15 g 80% of the theoretical. The analysis results were as follows: IR suoo cm'1 NH inaoi 2260 cm'1 CN ' 1635 cm -1 1 c-N 5 Calculated for C 18 H 23 N 3 O: C = 75.2%; H = 7.1%; N = 13.2% Increased: = 72, u6%; H = 7.15%; N = 1h, o1%. (c) Preparation of 1-ethyl-1-cyano-5,12b-didehydro-indo- - (2,3-a) -quinolizidinium perchlorate.

50 g (0.169) were introduced into a 1 liter bottle with stirring mol) of the product from step (b) above and 700 ml of phosphoryl chloride.

After heating for 20 hours with reflux condenser the reaction mixture was extracted and extracted two or three times with 500 ml of methylene dichloride, which was then removed by evaporation ning. The product was then taken up in 300 ml of methylene dichloride and cooled over ice and 300 ml of a solution of lithium perchlorate (1 mol) was added with vigorous stirring. A yellow trap was obtained ~ which after recrystallization from methanol had a melting point of 26000 (yield UH g, corresponding to 70% of theory).

The analysis results were as follows: IR zuoo cm'1 NH inaoi 2260 cm -1 CEN 1260 cm_1 C = N () (d) Preparation of 1-ethyl-1-cyano-indole- (2,3-a) -quinoline zidine (12b-H; 1-C2H5 trans isomer).

200 ml of methanol were introduced into a 1 liter round bottom flask. 100 ml of methylene dichloride and 13.5 g (0.036 mol) of perchlorate the product from step (c) above. The bottle was cooled to about 500 and 5 g 8007815 -k 12 sodium borohydrate was added in small portions.The solution was stirred then 2 hours at room temperature, concentrated, washed with water and extracted with methylene dichloride. After drying and disposal of the solvent, 8 g of yellow crystals were obtained which, after recrystallization from isopropyl ether, had a molten point 160 ° C (yield: 80%).

The analysis results were as follows: IR 5u2o cm "1) BHÄO cm_1) 2760 cm-1) NH and Bohlman bands 2800 cm'1) 2250 cm -1 CN 1 H NMR (α-methylsulfoxy, δ, 80 MHz) 0.86 6, BH (t) (cH 3) § 3.77 ', 1H (S) (H at Cga) 9.66 6.1H (S) (NH) Calculated for C 18 H 21 N 3: C at 77.7%; H = 7.2%; N = 15.2% Ernålietz c 77.55%; H = 7.32%; N 15.10 z. (e) Preparation of 1-ethyl-1-cyano-indole- (2,5-a) -quino- lysidine (12b-H; 1-C2H5-cis-isomer).

19 g of the perchlorate product were introduced into a 1 liter bottle according to step (c) above, 300 cm 3 of 95% ethanol and 40 g of zinc powder.

100 ml of concentrated hydrochloric acid were then added to one ampoule. A slight reflux could be observed during the addition of the acid. The mixture was allowed to stand for 10 hours at room temperature.

It was then concentrated, washed with water and extracted. cured with methylene dichloride. The product was made alkaline with sodium hydroxide and filtered through Celite. After decant- drying, drying and evaporation of the solvent, 6 g were obtained of a product which was insoluble in ether and melted at 25,000.

The analysis results were as follows: Ia 3410 cm -1 (NH) 2260 cm -1 (CN) Calculated for c18H21N3.1 / 4H2O: 0 76.5%; hrs Obtained = c -76.59%; H The ether extracts were concentrated to give N g (total yield) 71.5%) of the cis isomer of the same product as in step (d) above.

NMR (dimethyl sulfoxide d6, 80 MHz) 1.05 6.3H (t) (CH 3) 3, H5 6, 1H (S) (H at C 10.32 δ (1H (s) (NH) 7.60%; N = 1Ä, 85% II Il 9a) 7.80%; N- = 1H, 5ß z. aoovsus-4 13 ' (f) Preparation of 1-ethyl-1-aminomethyl-indole- (2,3-a) - quinolizidine (12b-H; 1-C2H5-trans isomer II).

4 g of lithium aluminum hydride were introduced into a 1 liter bottle and 400 ml of dry ether. The bottle was cooled to 0-500 and then was added in small portions 8.9 g of the product from step (d) above.

After allowing the bottle to stand for one hour at room temperature, 60 was added ml dry tetrahydrofuran. The mixture was heated for 2 hours under reflux. flow. After cooling, 40 ml of water were added dropwise and thereafter to 200 ml of methylene chloride. The mixture was stirred for 15 minutes. at filtration over Celite R, drying and concentration of filters 7.2 g of white crystals were obtained, which after recrystallization from ether melted at 175 ° C. The yield was 80% of theory.

The analysis results were as follows: IR 3280, 3190 cm -1 NH 2 3350 cm -1 NH indole The CN peak at about 2250 cm -1 was missing. 14.8% 15.52%.

Calculated for C 18 H 25 N 3 = c = 7s, 4%; H = 8.85%; N Found: C 75.85%; H = 8.90%; N II ll (g) Preparation of 1-ethyl-1-aminomethyl-indole- (2,3-a) - quinolizidine (12b-H; 1-C2H5-cis-isomers I).

In a 500 ml bottle was introduced 3.4 g of lithium aluminum hydride, 200 ml of ether and 100 ml of tetrahydrofuran. During cooling with ice add was added in small portions 6.9 g of the cis isomer according to step (e) above. After allowing the mixture to stand for 15 hours at room temperature, the product was isolated according to step (f) above. After recrystallization ring from diethyl ether / petroleum ether 50/50 5 g of a product were obtained with a melting point of 125 ° C (yield 71%).

Calculated for C 18 H 25 N 3: C = 76.4%; H = 8.85%; N = 14.8% Obtained: = 76.25%; H = 8.61%; N = 14,432.

Example 3 1-Ethoxycarbonylaminomethyl-1-ethyl-indole- (2,3-a) -quinolizine din hydrochloride (12b-H; 1-C2H5-trans isomer II).

.HCl 800784541 lü To a solution of 2 g (0.00705 mol) of the trans product II from Example 2 (f) in 20 ml of dimethoxyethane, cooled to 0 ° C, was set alternately, in order to maintain basic pH, portions of: 800 mg of ethyl chloroformate dissolved in 5 ml of dimethoxyethane and 750 mg sodium bicarbonate dissolved in 5 ml water.

After allowing the reaction mixture to stand for 3 hours at ambient at that temperature the product was extracted with dichloromethane, after which The dichloromethane extract was washed with water, dried and evaporated. was taken to dryness. The product was recrystallized from ethanol. weight; 2 g Usbyce = 80% mp = 1uo ° c 1 1 1 I IR 3210 cm -1 amide NH znoo cm'1 indoi NH 2760 and 2800 cm "1 Bonimann band 1690 cm_1 carbamate C = O 5 The results of microanalysis were as follows: Calculated for c21H29N5o2; c = 71.0 1; H = 8.17%; N 11.8% Found: C = 70.9H%; H = 8.16%; N 11.5Ä%.

The hydrochloride salt was formed from the above 2 g of by adding ANY HCl in 20 ml of ethanol. weight; 2 g. Yield: 90%. mp = 26 ° C.

Example Ut 1- (3'-H'-5'-trimethoxybenzoylaminomethyl) -indole- (2,3-a) - quinolizidine hydrochloride (12b-H; 1-CZH5-trans isomer II) .H01 CH O 3 o _ _ _ CH5. co NH cH2 CHBO In a three-necked bottle of 250 ml volume, equipped with a stirrer, CaCl 2 drying tube, thermometer and dropping funnel, were introduced 2.85 g of the trans product II of Example 2 (few, 1.1 g of tri- ethylamine and 50 ml of dichloromethane.

The mixture was stirred and cooled to 0-2 ° C. At this temperature was slowly added 2.31 g of 3,5,5-trimethoxybenzoyl chloride in 15 ml of dichloromethane. The addition took place over a period of time of 15-20 minutes, after which the reaction mixture was stirred for 1 hour 800781454: 15 at 0 ° C and then 15 hours at ambient temperature. * " The reaction mixture was then washed several times water and then with 10% aqueous sodium hydroxide and then again with water. The product was then dried over sodium sulfate and concentrated to a non-crystalline mass, which exhibited meringue structure and melted at about 10,000. ccM = 90/10 8/10 : R 3250 cm-1 NH 3190 @ m'1 NH 2750 and 2800 cm_1 Bohlmann tape 16uo cm'1 c = 0 amide dosage of the base with HClOH: 97%.

To prepare the hydrochloride salt, the above was dissolved product in a 1: 1 mixture of diisopropyl ether and isopropanol and UN hydrochloric acid was added. The hydrochloride salt crystallizes they were heated and filtered while still hot and then washed with ethanol to give 4.5 g (88% yield) of the product.

CCM: 90/10 8/10 mp: 210 ° C dosage of hydrochloride: 100% (1 function).

Microanalysis gave the following results: Calculated for C 28 H 35 N 3 O 3.HCl: C = 65, U5%; H = 7.00%; N = 8.18 Obtained = c = 6u, 3u%; H = 7.17%; N = 8.11 c = 64.15%; H = 7.16%; N = 7.96 BQE-QBQ .

Example 5 1- (N'-Diethylaminoethyl) N-ureidomethyl) -1-ethyl-indel- (2,3-a) -quinolizidine (12b-H; 1-C2H5-trans-isomer II). H I I, N I N I _ I H I _ _ '5 (C2H5) 2N cH2cH2 NH-conncase,, Initially, the corresponding 1-phenoxy- carbonylaminomethyl-1-ethyl derivative, 7 g of the trans product II from Example 2 (f) and 100 ml of tetrahydrofuran were introduced into one three-necked bottle with a volume of 500 ml, which was equipped with a stirrer and two dropping funnels. The bottle was cooled to between 0 and SCC and at this temperature, 0.25 g of phenylchlorine was added simultaneously. formed in 50 ml of tetrahydrofuran and 2.9 g of sodium bicarbonate in 80 078 45 - l: - 16 50 ml of water. Addition rates regulated; so that one maintained a pH of 6-7. The bottle was then allowed to assume temperature and stirring was continued for 3 hours.

The reaction product was extracted with 100 ml of dichloromethane and the extract was washed several times with water before drying by sodium sulfate and concentrated by evaporation.

11 g of the product were obtained, which was in the form of an oil.

: R 3270 cm -1 1 NH 1710 cm -1 1 c = o The 1-ureidomethyl product was prepared as follows: Into a 500 ml bottle, equipped with a condenser, was introduced.11 g of the above standing oil, 5.5 g of dimethylaminoethylamine and 180 ml of methanol.

The amount of dimethylaminoethylamine used corresponded to about 20% excess. The mixture was heated for 2.5 hours under reflux and then the methanol was removed by evaporation. The residue was taken up in dichloromethane and washed with 10% aqueous containing sodium hydroxide and then with water. After drying over sodium sulfate was evaporated to dryness to give a yellowish crystalline product. The product was incorporated in two steps in diethyl ether and centrifuged. The first step gave 4.6 g of a crystalline product, m.p. 20,200 and the other the step gave 0.8 g of crystalline product, m.p.

The combined products were recrystallized from benzene and gave Ä, 65 g of the final product. sm.p. ; 2o4 ° c Yield: 45% calculated on -amine (II). V ~ CCM: 90/10 5/10 dosing of base with HCl0u: 100% (2 functions).

IR; 5360 cm -1 NH c 3250 cm -1 1 NH 1620 cm_1 C = O urea.

Microanalysis gave the following results: _ Calculated for C 25 H 39 N 5 O: C = 70.6%; H = 9.17%; N = 16.5% Ernålietz 'c = 70.58 z; H = 9.20%; N = 16.67%.

Example 6 I 1-pentanoylaminomethyl-1-ethyl-indole- (2,3-a) -quinolizidine (12b-H; 1-C2H5-trans-isomer II) 800781154: 17 CH3- (oH2) 3-co-NH-cH2 Using the same reaction conditions and technique which in Example 4 was given a solution of 5.7 g of the trans product II from Example 2 (f) react with 2.1 g of triethylamine in 120 ml of di- chloromethane and a solution of 2.45 g of pentanoyl chloride in 20 ml of di- chloromethane.

7.8 g of an oil containing one were thus obtained small residual amount of triethylamine. 1R = 3180 - 3380 cm " 1630 - 1650 cm 1 1 From the oil kundáman obtain crystals of the product with melting point 110 ° C. Analysis showed compliance with the formula.

Example 7 1-pentylaminomethyl-1-ethyl-indole- (2,3-a) -quinolizidine (12b-H; 1-C2H5-trans-isomer II).

H J / CH3- (CH2) 4-NH-CH2 In a three-necked bottle with a volume of 500 ml, equipped with a stirrer, cooler, thermometer and dropping funnel, 100 ml of anhydrous ethyl ether. After cooling over an ice base, 4 g of lithium ~ was added hydride and the contents of the bottle were stirred for 15 minutes.

Then a solution of 7.4 g of protein was slowly added. the product from Example 6 in 50 ml of anhydrous diethyl ether. Among- The mixture was then heated for 2 hours under reflux and stirred for an additional 15 hours at ambient temperature.

The mixture was then cooled in an ice bath and added dropwise 20 ml of water and then 150 ml of dichloromethane. Reaction mixture $ 007845'Å w The mixture was then filtered over Celite (: z) dried over sodium sulfate and concentrated by evaporation. You are- held 7 grave an oil, which could be crystallized into a product with melting point 80 ° c.

Recrystallization from a small amount of isopropanol gave H, 3 g of a crystalline product, m.p. 97 ° C.

I Dosage of base with HClOu: 100% (2 functions).

Microanalysis gave the following results: Calculated for c23H5N3 = c = 78.20%; H = 9.92%, = 11.90% Rear = c = 78.18 z; H = 9.81 z, N = 12.00 z.

IR basic = 3510 cm -1 NH - N 1620 cm "1 c = o '' Dimaleat.

An acid addition salt with maleic acid was prepared thereby worked in solution in a mixture of isopropanol and di- -isopropyl ether. Initially, the salt formed as an oil which was then recrystallized from ethyl acetate to give 6.7 g of the dimaleate, m.p. 1 ° C.

Dosage of dimaleate with HClOu: 99; 6% (2 functions).

Rf: 90/10 9/10 Example 8 1 1-guanidinocarbonylaminomethyl-1-ethyl-indole- (2,3-a) - quinolizidine dimaleate (12bH; 1 C2H5 trans isomer). dimaleat NH C-NHCONH - - ' HZN In a 250 ml bottle, 9 g of it according to Example 3 were introduced prepared compound, 2.2 g of base in the form of guanidine (liberated ' from 3 g of chlorohydrate (methyl thyrethanol) in 120 ml of ethanol. Among- The mixture was heated to reflux for H8 hours and the solvent completely stripped. The residue was treated with a water-methylene- chloride mixture and filtered over Celite®® and decanted, after which the organic phase was washed again with water.

The methylene chloride phase was then washed twice with 5% acetic acid. acid solution and the acidic waters were alkalized with sodium bicarbonate ~ settled in the presence of ether. The ether phases were then dried and concentrated. 19 I 30078054, fumes. 6, H g of a porous mass was obtained and chromatographed over silica gel: (60 g of silica eluent CH 2 Cl 2 -MeOH 80-20).

After separating 0.7 g of a first product, it was isolated a second product which was recrystallized from ether. The yield was 5.5 g and melting point 15000.

IR (KBr): 3200-5000 cm-1 strong and broad bands (\) NH) 1600 cm'1 wide web (0 c = 0) The dimethylate was prepared in isopropanol.

CCM (Merck plate MP 254: eluent: acetone, CHCl 3, n-butanol, 50 30 _. 30 Nnuon 25% 10 Rf = 0.0 1 spot microanalysis C20H28N6O + C8H8O8 M = 600 Calculated: C 56.00 H 6.00 N 1Ü, O0 Obtained 56.07 6.06 12.59 Eäe fl rleli 1-Ethoxycarbonylaminomethyl-1-ethyl-indole- (2,3-a) -quinolizidine- hydrochloride (12b-H; 1-C2H-cis-isomer-I). 5. 3 N 'N .2Hc1 å _ _ _ I c2H5o co NH CH,, _ \ _ The procedure of Example 3 was repeated, except that the product (I) from Example 2 (g) was used instead of the product (II) from Example 2 (f). 2.1 g of it were obtained free base (80% yield). melting point 21 ° C.

IR zuoo cm'1 indole NH 3210 cm_1 amide NH ' 2790 and 2810 cm'1 Bohlmann tape 1690 cm_1 carbamate C = 0 Microanalysis gave the following results: Calculated for C 21 H 29 N 3 O 2: C = 71.0 Z; H = 8.17%; N = 11.82% Retention C = 70.85%; H = 8.22%; N = 11.9H%.

NMR (CDCl 3; internal TMS) 1.1 6 (6H, t, CH5 ethyl and ethyl ester) soovaus-4 20 1.5 to 3.5 δ (15H, solid) 3.9 δ (an, q, cH 2 O) - 5.65 δ (1H, m, NH-amia) 7.25 δ (HH, solid, aromatic groups) 7.9 δ (1H, s, NH- inaoi) The hydrochloride salt was prepared using HN chloride. hydrochloric acid in acetone.

Yield: 90%. melting point = 25 ° C.

Toxicity LD 50 was determined per os in mice. The compounds according to the finding showed a toxicity comparable to that of Vincamine or lower toxicity. The more toxic compounds (LD 50: Ä00 mg / kg; Vincamine H50 mg / kg) are those according to examples 2 (f) and 5. A less toxic compound is that of Example H, while other compounds show an average toxicity.

Pharmacology g The activity of the compounds included in the compositions according to the invention have been examined with respect to the femoral and vertebral flow, arterial pressure and heart rhythm. An equal was made with Vincamine and with chemically close relatives compounds described in French Patents 2,285,877 and 2,292 H75. The experiments, which were conducted on it in French U.S. Pat. No. 2,285,877 (= DOS 2,551 HBH) the way, ie. by means of dogs anesthetized with mebubarbital and treated with 3.5 mg / kg "Vincamíne" and equivalent amount (moles) of other tested compounds, showed that the compounds of the invention and in particular the compounds of examples 3 and 4 a) caused an increase in the femoral flow (flow rate ningen). The compounds according to the French patents showed a similar effect but Vincamine reduced this flow; b) caused a sharp increase in vertebral flow.

The associations according to the French patents had none effect or caused a moderate increase while Víncamine decreased this flow; c) does not significantly affect arterial blood pressure while the comparative associations decreased the same; d) induced a slight increase in heart rate while the French patents provided a increase and Vincamine decreased the heart rate.

From the above results it appears that the compounds according to 80078454: El The invention appears to have a very beneficial effect on the brain. flushing, which was clinically confirmed.

Posology '(dosage) The compounds of the invention may be administered i.v. or per os in dosages comparable to those of Vincamine (dosage units 5 to H0 mg).

The formulas for the known comparative compounds tested are given below. and a summary of the experimental results in the form.

L N? \ / H NCH CH CH NCCH2CH2 2 2 2 2 (I) (II) known through french known through french pat.skriften 2 285 877 pat.skriften 2 292 N75 (= DOS 2 SH1 USM) 8007845-k 22 w M fl w + .. R mnm + R mnm> fi + w fifi ow + .MQQS .HCG m .Nm § m. 3 + ä im - R QS? “À ii + .äxï .acw æ .xm w m w + w 3 | x Anyone? w reach: +. rob .H50 N .MM w fi no fi + x: .m + w m.mæ fi + w æ fl wm + .mans .acw m .xm Q n Q .ß N m + & wa: + R HON ... x + .Mnmnw fi .HGW m .NM n A q § I w + R fl + x æ ^: @ fi + ä> _fi> +. @@ Q = .acw = .XW ß n q n n \ N w + k m fi I w w m fi m + w> m¶ + .mans .HEM M .Nm & + å I. & H + $ m-un fi awßæ. x wn fl r + & N: I & Hnwm + WN. .warm + H § w.mm 1 w m.mm | m m fl mm | x m “n fi 1 wc fi Emo: fl> 1 wßü> åwhävhm fi m .HWu-.HM »UAOPHPGOHQ QUDHM ä fl dâßwß fi wkw 0Ü.O.H.H QHNQOEQrA pmu fl zmwnmm fi mmæwämw

Claims (1)

23 'Patent claims Therapeutic composition, characterized in that it contains, as an active ingredient in admixture with binders or carriers suitable per se for the administration form in question, indole- (2,5-a) -quinolizidines with the general formulas (I) (II) wherein R represents -COOC 2 H 5, -COOH, -CN, a primary methyleneamino group, a methyleneaminoalkyl or methylenamidoalkyl group, a methyleneamidoalkoxy group, a methyleneamic substituted phenyl group, a dialkylamino group carbonyl aminomethyl group, the alkyl and alkoxy groups containing up to 5 carbon atoms, or therapeutically acceptable acid addition salts of these compounds. 8067845 'in Abstract Therapeutic composition, which as active ingredient in admixture with the binders or carriers suitable per se for the administration form in question contains novel indole- (2,3-a) -quinolizidines of the general formulas (I) (II wherein R represents one of the groups -COOC 2 HS, -COOH, -CN, a primary methyleneamino group, a methylenaminoalkyl or methylenamidoalkyl group, a methylenamidoalkoxy group, a methylenamido-substituted phenyl group, and a dialkylamino-alkylureido-methyl group or guanidino-carbonylaminomethyl group, wherein the alkyl and alkoxy groups contain up to 5 carbon atoms, or therapeutically acceptable acid addition salts of these compounds.