SE431650B - INDOLO (2,3-A) QUINOLIZIDIN AND SET TO MAKE IT - Google Patents

Description

790628? -3 then with a perchlorate; hydration of the resulting the quinolizidine perchlorate is carried out to give the corresponding indole- (2; 3-a) -quinolizidine isomer mixture and the isomers separated. Corresponding reaction schemes are shown below under the heading "original common sequence" and leads only to compounds where R represents -COOC 2 HS or -CN (2 isomer- forms in each case, i.e. H compounds).

All other derivatives are derived from these compounds, namely ligen - either directly, e.g. the acids, from the esters by saponification (see scheme "specific reactions" A = -COOC2H5) 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 refer to cisëisomers - II relates to trans isomers, 1 (a) -1 (h) relates to different steps according to Example 1, wherein the starting material is the H-ethoxycarbonyl derivative and the end product acids or derivatives thereof and 2 (a) -2 (g) relates to the various steps of Example 2, where the starting material is the H-cyano derivative and the end products are methylamino derivatives. 79Ü6287 ~ 3 u: Original common sequence 1 (a) or 2 (a) cH cH m! 'A'.

I / 2 2 2 I I / n + czns - 'c - (cn2) 3_c1 ___> _ (KC / NH m hrs cocz | \\ J \ J _ Ä 1 (b) or 2 (b) t ßut_Q K ¶ 7906287-3 eigçifíka reíajgëioneg A = COOC2H 5 (I) ¶ _ - (11) (I) O fl '(11) 7906287 ~ 3 The invention is illustrated by the following examples. _ExemEé1 1 (a) Preparation of 3- [E '- (2 "-ethoxycarbonyl-2" -ethyl-5 "-chloro- -valeroylamino) -ethyl7-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 4.7 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 organ- ka phase and evaporation thereof under reduced pressure was obtained 6.6 g of the above product, which after recrystallization 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 results: 1 IR (Kßr) 3350 and 3300 cm -1 NH 1735 cm_1 CO ester 1640 cm'1 co amia.

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- [X2'-indol-3 "-ylethyl) -3-ethyl-3-ethoxy- carbonyl7-2-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 hexamene tylphosphoric 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, the solution was poured to a cold, dilute aqueous solution of hydrochloric acid.

After decantation, the aqueous phase was extracted twice with benzene.

The resulting organic phase was washed twice with water and dried. After evaporation under reduced pressure, 30 were obtained g of the desired product, which after recrystallization from iso- propyl ether had a melting point of 84 ° C and was obtained in a yield of 96%. Analysis gave the following results: 1 IR (Kur) 3250 cm -1 NH inaol 1730 cm_1 CO ester 1620 cm'1 co amia.

Calculated for C 20 H 26 N 2 O 3: C = 70.15%; H = 7.65%; N = 8.1j% | Found: C = 69.97%; H = 7.65%; N = 8.20% J 7906287-3 (c) Preparation of 1-ethyl-1-ethoxycarbonyl-5,12b-didehydro- _-indel- (2,3-a) -quinolizidinium perchlorate.

To a solution of 30 g (0.0876 mol) of the above In 480 ml of dry toluene was poured 240 ml of distilled phosphoryl chloride. rid. The solution was heated under reflux for 9 hours under moisture exclusion. ning. 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. Part of the solution is stirred was treated with a 1M aqueous solution of lithium perchlorate. After decanting of the aqueous phase, washing of the organic phase with water, drying over sodium sulphate and evaporation of the solvent at reduced pressure, a yellow powder was obtained, which was recrystallized ur ethanol. The resulting product melted at 191 ° C. Analysis- the results were as follows: I IR çxsr) 3340 cm -1 NH 1740 cm_1 CO ester 1625 cm * c = N <Q (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.

In chromatography of a solution of the product with methyl lendichloride over 100 g of silicon and eluting with the same solution means 1.12 g of a first fraction were separated (yield 25%), which was 12b-H; The 1-C2H5 trans isomer of the product and had one melting point of 112 ° C (recrystallized from petroleum ether / isopropyl ether).

Analysis gave the following results: IR (xßr) 3410 cm -1 1 NH 2770, zsos, 2825 cm'1 Bohlmann band 1 1710 cm-CO ester 7906287-3 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 δ 1H (s) (H on C9a) 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 = 8.33%.

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

The analysis results were as follows: 1 IR (mar) 3420 cm -1 NH 3750, 3800 cm_1 Bohlmann band 1705 cm_1 CO ester.

NMR (OCl 4 90 MHz) among other signals: 7.78 δ 1H (s) (NH indole) 4.15 δ 2H (q) (-OCH 2 -CH 3) 3.93 δ 1H (s) (H on Cga) 1.09 6 3H (t) (CH 3 -CH 2 -O) 0.9 a; sn (t) (cH3-cH2-) The hydrochlorides melted - after recrystallization from iso- propanol - at over 260oC.

Calculated for C20H26N2O2.HCl.1,5H2O: C = 61.57%; H = 7.75%; N = 7.18% Found: C = 61.51%; H = 7.33%; N = 7.35%. (e) Preparation of 1-ethyl-1-carboxy-indole- (2,3-a) -quinolizine din (12b-H; 1-C2H5 trans isomer), hydrochloride.

To a solution of 8.8 g of the substance of step (d) above obtained 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 rust was treated with ice water, acidified 790628? -3 by means of concentrated hydrochloric acid to acidic pH range, after which the hydrochloride was precipitated and separated, washed and dried.

The yield was 9.5 g (100%) of the product after recrystallization 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: 61.20% 7.08% 7.93% Obtained = 61, o1% 6.75% 7.72% IR (Cure) 3340 cm -1 NH 1705 cm'1 (-c-ou). in Il f O (f) Preparation of 1-ethyl-1-piperonylpiperazidocarbonyl- -indole- (2,3-a) -quinolizidine (12b-H; 1-C2HS-trans isomer) dihydro- chloride. o-Q-1 CHZ-Inl- .c / \ \ \ c_o / 8 _ 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 is suspended was then dissolved 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 1 10'6 9.2 1s (1H) NH indole 5.9 1s (ZH) 0-CH 2 -O 4.05 1s (1H) H (C12b) I 0.3 1t (3H) CH 3 -CH 2 7906287-3 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-trimethoxybenzamido-4) -piperazine nokarbonyl7-indole- (2,3-a) -quinolizidine- (12b-H; 1-C2H5-trans isomer) hydrochloride 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 trimethoxybenzoyl-4-amino-1-piperazine in 20 ml of methylene chloride added thesis. The mixture was stirred for 24 hours at room temperature and washed. was then diluted with a 10% aqueous soda solution, then with water, was then dried and the excess solvent was evaporated. after. 7.2 g of an oily product were obtained.

IR (film) 3380 cm -1 and 3240 cm -1 (NH) 1650 cm * and 1620 cm * (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) -quinolizine din (12b-H; 1-CZHS-cis-isomer). 79o62a? -3 10 To a solution of 6.8 g of 1-ethyl-1-ethoxycarbonyl-indole - (2,3-a) -quinolizidine (12b-H; 1-C 2 H 5 -cis-isomer) obtained according to Example (d) in 100 ml of ethanol (95%), 6.8 g of potassium hydroxide were added.

The mixture was boiled under reflux for 12 hours each time. after the solvent was evaporated under reduced pressure and the residue was treated with ice water and acidified with hydrochloric acid to pH = 4.5. The product which crystallized, separated, washed and dried. 4.1 g of the acid were obtained.

Analysis C 18 H 22 N 2 O 2 M = 298.37 C H N Calculated: 7z, ¿s% 7.43% 9.37% Obtained 72.61% 7.49% 9.20% IR 161620 cm-1 in CO, H associated Example 2 4 (a) Preparation of 3- [2- (2 "-cyano-2" -ethyl-5 "-chloro-vale- roylamino) -ethyl] -indole. .

In a 1 liter bottle was placed 31 g (0.0194 mol) of tryptamine, 1500 ml of dichloromethane and 20 g (0.0198 mol) of triethylamine. The mixture was cooled to 0 ° C over ice and then 40 g (0.192 mol) were added 2-cyano-2-ethyl-5-chloro-valeroyl chloride, dissolved in 150 ml of 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 removed. by evaporation. After recrystallization from isopropyl ether / petroleum ether, the product had a melting point of 120 ° C and was obtained with a yield of 40 g. The analysis results were as follows: 1 IR (xßr) 3400 cm -1 NH indole 0 3340 cm -1 NH amia 2860 cm -1 cN 1660 cm -1 c-N ä Calculated for c§8H22N3c1o = c = 6s, o%; n = 6.64%; N = 12.6s% Obtained = c = 64.03%; n = 6.7s%; N = 12.6o%. 7906287-3 11 (b) Preparation of 1 - [(2'-indol-3 "-yl-ethyl) -3-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 t-butanol. The mixture was cooled to 0 ° C over ice and then added. in small portions 8.5 g (0.076 mol) of potassium tert-butoxide. After 2 hours at room temperature, the volume of the mixture and the was lysed. The organic phase was extracted with methylene chloride, washed with was taken with water and dried and the solvent was removed by evaporation. After recrystallization, the desired product was removed ethanol / ether 50/50 a melting point of 180 ° C and obtained in a yield of 15 g corresponding to 80% of theory. The analysis results were 1 janae = IR 3400 cm "NH inaoi 2260 cm -1 cN 1635 cm-1 C-N å Calculated for C 18 H 23 N 3 O: C = 73.2%; H = 7.1%, N = 14.2% Obtained = c = 72.46%; H = 7.15%; N = 14.01%. (c) Preparation of 1-ethyl-1-cyano-5,12b-didehydro-indole - (2,3-a) -quinolizidinium perchlorate. ' 50 g (0.169 mol) were introduced into a 1 liter flask with stirring. of the product from step (b) above and 700 ml of phosphoryl chloride. After heating for 20 hours with reflux cooling, the reaction was concentrated. mixture and extracted two or three times with 500 ml methylene dichloride, which was then removed by evaporation. 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) were added below vigorous stirring. A yellow precipitate was obtained which, after recrystallization, methanol had a melting point of 260 ° C (yield 44 g, corresponding to 70% of the theoretical).

The analysis results were as follows: 1 IR 3400 cm -1 NH inaoi -1 2260 cm C-N -1 -GD 1620 cm C-N (d) Preparation of 1-ethyl-1-cyano-indole- (2,3-a) -quinolizidine (12b-H; 1-CZH5-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 the perchlorate product from step (c) above. The bottle was cooled to about 5 ° C and 5 g of sodium borohydride. rat was added in small portions. The solution was then stirred for 2 hours ? 90628? -3 12 at room temperature, concentrated, washed with water and extruded. was reacted with methylene dichloride. After drying and disposal of the solvent was obtained 8 g of yellow crystals, which after isopropyl ether had a melting point of 160 ° C (yield: 80%).

The analysis result was as follows: I IR 3420 cm / h 3440 cm_1 - 2760 cm_1 NH and Bohlmann band 2800 cm 2250 cm ~ 1 CN NMR (dimethyl sulfoxide die, 80 MHz) 0.86 6.3H (t) (CH3) 3.77 6.1H (S) (H at C 9.66 6.1H (s) (NH) Calculated for C 18 H 21 N 3: C = 77.7%; H = 7.2%; N = 15.2% Obtained: - C = 77.55%, H = 7.32%; N = 15.10%. (e) Preparation of 1-ethyl-1-cyano-indole- (2,3-a) -quinolizidine (12b-H; 1-C2HS-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 an 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. Thereafter, the it was washed, washed with water and extracted with methylene dichloride. rid. The product was made alkaline with sodium hydroxide and filtered through Celite®. After decantation, drying and evaporation of the solution 6 g of a product which was insoluble in ether and melted at 250 ° C. The analysis results were as follows: IR 3410 cm -1 (NH) 2260 cm'1 (cm) Calculated for C 18 H 21 N 3 .1 / 4H 2 O: C = 76.5%; H = 7.60%; N = 14.85% Obtained: C = 76.59%; H = 7.80%; N = 14.55%.

The ether extracts were concentrated to give 4 g (total yield) 71.5%) of the cis isomer of the same product as in step (d) above.

NMR (dimethylsulfoxide d6, 80 MHz) 1.05 6.3H (t) (CH 3) 3.45 δ 1H (s) (H at C 10.32 6.1H (s) (NH) 790628? -3 13 (f) Preparation of 1-ethyl-1-aminomethyl-indole- (2,3-a) -quino- lizidine (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 0-5 ° C 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 then 200 ml of methylene chloride. The mixture was stirred for 15 minutes. In the case of felt Celite® drying, drying and concentration of the filtrate 7.2 g of white crystals were kept, which after recrystallization from ether melted at 175 ° C. The yield was 80% of the theoretical, analytical results. was as follows: IR 3280, 3190 cm -1 NH 3350 cm "1 The CN top at about 2250 cm_1 was missing. 2 NH indole Calculated for C 18 H 25 N 3: C = 76.4%; H = 8.85%; N = 14.8% Found: C = 75.85%; H = 8.90%; N = 15.52%. (g) Preparation of 1-ethyl-1-aminomethyl-inhalo- (2,3-a) -quino- lizidine (12b-H; 1-C2H5-cis-isomer 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 of step (e) above.

After allowing the mixture to stand for 15 hours at room temperature, the product according to step (f) above. After recrystallization of di- ethyl ether / petroleum ether 50/50 5 g of a product with a molten point 125 ° C (yield 71%).

Calculated for C 18 H 25 N 3: C = 76.4%; H = 8.85%; N = 14.8% Found: C = 76.25%; H = 8.61%; N = 14.43%.

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

.HCl / ' C2H5O.CO.NH 7906287-3 14 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 added alternately. and, 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 temperature, the product was extracted with dichloromethane, after which the methane extract was washed with water, dried and evaporated Dryness. The product was recrystallized from ethanol. weight: 2 g. yield = 80%. mp = 140 ° C. » IR 3210 cm amide NH 3400 cm -1 indole NH 2760 och zßoo cm'1 Bonimann-bana 1690 cm_1 carbamate c = o.

The results of microanalysis were as follows: Calculated for C 21 H 29 N 3 O 2: C = 71.0%; H = 8.17%; N = 11.8% Found: C = 7Q94%; H = 8.16%; N = 11.54%.

The hydrochloride salt was formed from the above 2 g of product. by adding 4N HCl in 20 ml of ethanol. 'Weight: 2 g.-Yield; 90%. »m.p. = 20 ° C.

Example 4 1- (3 ', 4§5'-trimethoxybenzoylaminomethyl) -indole- (2,3-a) -quino- lizidine hydrochloride (12b-H; 1-c2H5-trans-isomer II) CH 0 '.HCl C530 -CO-NH-CH2 / '/ CH3 In a three-necked bottle of 250 ml volume, equipped with a stirrer. caCl2 drying tube, thermometer and dropping funnel, 2.85 g of trans- product II according to Example 2 (f), 1.1 g of triethylamine and 50 ml of dichloro- methane.

The mixture was stirred and cooled to 0-2 ° C. At this temperature In turn, 2.31 g of 3,4,5-trimethoxybenzoyl chloride in 15 ml were slowly added dichloromethane. The addition took place over a period of 15-20 minutes, after which the reaction mixture was stirred for 1 hour at 0 ° C and thereafter 15 hours at ambient temperature. , 1 7906287-3 15 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. com: 90/10 8/10 IR 3230 cm -1 1 NH 3190 cm -1 NH 2750 and 2800 cm_1 Bohlmann tape 16Ä0 cm_1 C = 0 amide dosage of the base with HClOu: 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 was heated and filtered while still hot and was then washed with ethanol to give H, 5 g (88% yield) of the product. ccM = 90/10 8/10 mp = 21000 dosage of hydrochloride: 100% (1 function).

Microanalysis gave the following results: Calculated for o28H35N5ou.Hc1 = c = 65, H5%; H = 7.00 1; N = 8.18% Obtained: C = 6U,} U%; H = 7.17%; N = 8.11% C = 6A, 15%; H = 7.16%; N = 7.96% Example 5 1- (N'-Diethylaminoethyl-7-N-ureidomethyl) -1-ethyl-indole- (2,3-a) -quinolizidine (120-H; 1-CQH5-trans-isomer II). (c2H5) 2N-cH2cH2-NH-coNHcH2 ' Initially, the corresponding 1-phenoxycarbonyl- aminomethyl-1-ethyl derivative, 7 g of the trans product II from Example 2 (f) and 100 ml of tetrahydrofuran were introduced into a 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 500 and at this temperature, H, 25 g of phenyl chloroformate in 50 ml were added simultaneously tetrahydrofuran and 2.9 g of sodium bicarbonate in veøezsv-3 16 50 ml of water. The addition rates were regulated so that maintained a pH of 6-7. The bottle was then allowed to assume giving fi 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.

IR 3270 cm -1 NH 1710 cm -1 c = 0 The 1-ureidomethyl product was prepared as follows: In a 500 ml bottle, equipped with a cooler, 11 g of the above standing oil, 3.5 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 H, 6 g of a crystalline product, m.p. 202 ° C and the other the step gave 0.8 g of crystalline product, m.p.

The combined products were recrystallized from benzene and gave 4.65 g of the final product.

M.p. : 20Ä ° C Yield: H5% calculated on -amine (II).

CCM 2 90/10 5/10 dosing of base with HCl0u: 100% (2 functions).

1H; 3360 cm -1 1 NH to 3250 cm -1 NH 31620 6m'1 c = o urea.

Microanalysis gave the following results: Calculated for c 25 H 39 N 5 O; c = 70.6 1; H = 9.17%; N = 16.45 1 Found: C = 70.58%; H = 9.20%; N = 16.67%.

Example 6 l 1-pentanoylaminomethyl-1-ethyl-indole- (2,3-a) -quinolizidine (12b-H; 1-C2H5-trans-isomer II) ? 906287 ~ 3 17 hrs l | N 'N IN hrs . '. _., * '\\\ g cH3- (c§I2) 3-co_-1IH-c§12 Using the same reaction conditions and technique as in Example 4 obtained 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 dichloromethane and a solution of 2.45 g of pentanoyl chloride in 20 ml of dichloromethane.

There was thus obtained 7.8 g of an oil containing a small residual amount of triethylamine.

IR: 3180-3380 cm -1 NH 1630-1650 cm'1 c = o.

Crystals of the product could be obtained from the oil 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).

CH3- (cH2) 4-NH-cH In a three-necked bottle with a volume of 500 ml, equipped with a stirrer. re, cooler, thermometer and dropping funnel, 100 ml of anhydrous were introduced diethyl ether. After cooling over an ice bath, 4 g of lithium was added. umhydride and the contents of the bottle were stirred for 15 minutes. Then add a solution of 7.4 g of the product from Example 6 was slowly added in 50 ml of anhydrous diethyl ether. The mixture was then heated for 2 hours. under reflux and stirred for an additional 15 hours. when re- rewarding 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 veoszefz-z 18 The mixture was then filtered over Celite (:% was dried over) sodium sulfate and concentrated by evaporation. You are- held 7 g ”of an oil, which could be crystallized into a product with melting point 80 ° C.

Recrystallization from a small amount of isopropanol gave 1.3 g of a crystalline product, m.p. 9700.

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

Microanalysis gave the following results: Calculated for c 23 H 35 N 5: c = 78.20 z; H = 9.92 z; N = 11.90%; Rear = c = 78.18 z; H = .81%; N = 12.00 z. I IR basic = 3310 @ m'1 NH -, = 1620 cm "1 c = o É Dimaleat. V 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 with melting point 10590.

Dosage of dimaleate with HCl0u: 99.6% (2 functions).

Rf: 90/10 9/10 Example 8 1-Guanidinocarbonylaminomethyl-1-ethyl-indole- (2,3-a) - quinolizidine dimaleate (12bH; 1C2H5 trans isomer). dimaleat NH C-NHCONH --- ' H2N 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 by means (fi-ethanol) in 120 ml of ethanol. Among- The mixture was heated to reflux for 48 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. 790628? -3 19 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 3.5 g and melting point 15000.

IR (KBr): 3200-BHOO cm-1 strong and broad bands (V NH) 1600 cm "1 wide band (9 c = o) The dimaleate was prepared in isopropanol.

CCM (Merck plate MP 25k: eluent: acetone, CHCl 3, n-butanol, 30 BO. 30 NHOH 25% 10, Rf = o, u 1 spot microanalysis C20H28N6O + C8H8O8 M = 600 Calculated: C 56.00 H 6.00 N 1Ä, O0 Obtained 56.07 6, H6 12.59 Example 9 1-Ethoxycarbonylaminomethyl-1-ethyl-indole- (2,5-a) -quinolizidine- hydrochloride (12b-H; 1-CZH5-cis-isomer-I).

N 'N .2HCl IN hrs C2H5Q-CO-NH-CH2 ~ 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 (BH% yield). melting point = 21 ° C.

IR 3400 cm -1 indo NH 3210 cm -1 1 amide NH 2790 and 2810 cm_1 Bohlmann tape 1690 cm_1 carbamate C = O Microanalysis gave the following results: Calculated for c 21 H 29 N 3 O 2 = c = 71.0%; H = 8.17%; N = 11.82% Obtained = C = 70.85%; H = 8.22%; N = 11.9h%.

NMR (CDCl 3; internal TMS) 1.1 6 (6H, t, CH ethyl and ethyl ester) 5 _ '79C1628? -3 20 1.5 to 3.5 ~ 6 (15H, solid) 3.9 δ (2H = Q »CH 2 O) 5.65 δ (1H, m, NH-amide) 7.25 6 (UH, solid, aromatic groups) 7.9 δ (1H, S, NH- inaol) The hydrochloride salt was prepared using HN chloride. hydrogen in acetone.

Exchange; 90%. smäitpunkt; 25 ° C.

Toxicity r 'I LD 50 was determined per os in mice. The compounds according to the invention showed a toxicity comparable to that of Ûincamine or lower toxicity. The more toxic compounds.

(LD 50: Ä00 mg / kg; Vincamine 450 mg / kg) are those according to the examples 2 (f) and 3. A less toxic compound is that of Example 11, while other compounds show an average toxicity.

Pharmacology The activity of the compounds of the invention was examined with respect to the femoral (in the thigh) and vertebral (in the vertebrae) flow, arterial pressure and heart rate. A comparison was made with Vincamine and with chemically related compounds, as described in French Patents 2,285,877 and 2,292,475. carried out in French Pat. No. 2,285,877 (= DOS) 2 541 48U) described in more detail, i.e. by means of dogs, which anesthetized with mebubarbital and treated with 3.5 mg / kg "Vincamine" and partly with an equivalent amount (moles) of the others tested compounds, showed that the compounds of the invention and especially the compounds of Examples 5 and U 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 Vincamine_reduced this flow; c) does not significantly affect arterial blood pressure while the comparations 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 7906287'3 21 The invention appears to have a very beneficial effect on the brain. flushing, which was clinically confirmed.

Poso1ogi '(dosage) The compounds of the invention may be administered i.v. or per os in dosages comparable to those of Víncamine (dosage units 5 to NO mg).

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

NO NCCHZCH2 H2NCH2CH2CH2 (I) (II) known through french known through french pat.skriften 2 285 877 pat.skriften 2 292 H75 (= DOS 2 5U1 UBH) 22 79Û6287 ~ 3 R nßnnæ +. & + R ßnßß fl + R + u.% QQ.5 . .Ham Q .gm w mfm fl + R: .N - & @ .w @ fi + § fi.:> +. @@ Q = .Ham w .xm R m.m + w z 1 R ~ «om« + R mqmz + .mmas . .Hem> .xm R 13 + x É + w mä? “W mä + nä? .Ham w .xm R ßnâ + R was + fi R + »QS-QS .Hmm m .gm w: am + & fl + w æ .: m «+ x> .fl> + .wßßs .Hmm = .xm R m.w + w m. Fi 1 x æ ~ m fi m + w ww + .mans .Hmm n .xm w nlw fl + w o.mm | w fi + & m. fl on + HH R QS + R m: | R ämm + R fi šm + H w æ.m ~ 1 .w ~ «mw | x w «wm 1 w m.m fl | mc fi Emoc fi> mcw> xwnm »nmwm nm» fi m¶.xo> nß fi o fi m mum fi m »fl mnnw» nw> møm fl u ß fi ænoëmm umuasmwhmw fl mnmmäww

Claims (2)

9G6287-3 Patent claims Indole- (2,3-a) -quinolizidines, characterized in that they correspond to the general formulas (I) (II) wherein R represents -COOCÉHS, -COOH, -CN, a primary methyleneamino group, a methyleneaminoalkyl- or methylenamidoalkyl group, a methyleneamidoalkoxy group, a methylenamido-substituted phenyl group, a dialkylaminoalkylureidoomethyl group or guanidino-carbonylaminomethylmethyl group, the alkyl and alkoxy groups containing up to 5 carbon atoms, and therapeutically acceptable acid addition salts. A process for the preparation of novel indole- (2,3-a) -quinolizidines according to claim 1 having the general formulas HN 'NIHR i | \ (I) \ (II) wherein R represents -COOC H -COOH, -CN, a primary methyleneamino group,> a methyleneaminoalkyl-Eessler methylenamidoalkyl group, a methyleneamidoalkoxy group, a methylenamido-substituted phenyl group, a dialkylaminoalkylureido-methyl group or guanidino-carbonylaminomethylmethyl group, wherein the alkyl group and acid addition salts of these compounds, characterized in that 2-amino-ethyl-Bindol is condensed together with 1-chloro-- (A) -N- -chloro-carbonyl-hexane, where A represents -COCO 2 H 5 or -CN , whereby the corresponding amide is formed, which is then subjected to treatment under strong basic conditions to eliminate HCl and effect ring formation at the nitrogen atom in the 3-position of the indole, after which quinolizidine ring formation of the product is effected by treating the same with first a dehydrating agent and then with a perchlorate, after which the resulting quinolizidine dihydrochlorate is hydrogenated to the corresponding indole- (2,3-a) -quinolizidine-isomer mixture and the isomers are then separated. Summary New indole- (2,3-a) -quinolizidines of the general formulas (I) (II) wherein R represents one of the groups -COOCQHE, -COOH, -CN, a primary or secondary methyleneamino group, a methylenamido group or together with the nitrogen atom of the indole ring represent the group N-CO-NH-CH 2 or N-CO-, as well as therapeutically acceptable acid addition salts of these compounds. Also ways to present the new associations.