IE47518B1 - Indolo (2,3-a) quinolizidines,preparation and therapeutic use - Google Patents

Abstract

The invention relates to a multistep preparation process of new indolo(2,3-a)quinolizidines of the general formulae (I) and (II): (I) (II) wherein R stands for -COOC2H5, -COOH, -CN, a primary or secondary methylenamino group, a methylenamido group, or wherein R, together with the ring nitrogen of the indolo ring, represents one of the groupings N-CO-NH-CH2 or N-CO. These compounds of the invention are useful in the field of blood circulation in the brain.

Description

The invention relates to indolo (2,3-a)-quinolidines, to methods for their preparation and to therapeutic compositions containing them.

The new indolo (2,3-a) quinolidines according to the 5 invention have the general formulae (I) and (II) where R stands for -COOC^Hg, -COOH, -CN, a primary or ·. .secondary anji nomethyl group, ' an amidomethyl group or an amido group, or wherein R, together with the ring nitrogen of the indolo ring, represents one of the groupings -N-CO-NH-CH2- or -N-CO-; the latter derivatives are D homo azaeburnamonines or D eburnamonines.

The invention also provides acid addition salts of the above compounds, when applicable.

R may be, for example, an N-alkoxycarbonyl-aminomethyl, N-aryloxycarbonyl-aminomethyl, N-alkanoyl-aminomethyl, N-alkyl-aminomethyl, substituted ureido-methyl, substituted piperazido, piperonyl-substituted amido group.

Preferred identities of R according to this invention are -COOH, -NH2, N-ethoxycarbonyl-ami nomethyl, N- (3,4,5-tri methoxybenzoyl)-ami nomethyl, N-phenoxycarbonyl-aminomethyl, diethylaminoethyl-ureidomethyl, N-pentanoyl-aminomethyl, N-pentyl-aminomethyl and piperonyl-substituted piperazido.

The compounds according to this invention are especially interesting for their activity in the field of blood circulation in the brain. The invention accordingly provides therapeutic compositions comprising one or more such compounds in admixture with a therapeutically acceptable diluent or carrier. 7 518 The above compounds may be prepared according to the invention by condensing together 2-aminoraethyl--3-indole and l-chloro-4-(Aj-4chlorocarbonyl-hexane, wherein A stands for -COOCgH- or ~CN, to form the corresponding amide ; subjecting the amide to strongly basic conditions to eliminate HCl and effect ring formation at the nitrogen atom on the 3-indole substituent ; effecting quinolizidine ring formation of the product by treating it with a dehydrating agent followed by a perchlorate salt ; hydrogenating the resulting quinolizidinium perchlorate to produce the corresponding indolo (2,3-a) quinolizidine isomer mixture and separating the isomers ; the corresponding reaction schemes are represented hereafter under the heading Initial Common Routes and lead only to the compounds wherein R is -COCCgHg or -CN ( 2 isomer forms in each case, i.e., 4 compounds).

All the other derivatives derive from these compounds :either directly, e.g. the acids, from the esters, by saponification (see the schemes Specific Routes A = -COOCgHc), or the aminomethyi from the nitriles, by reduction with lithium aluminium hydride (see same schemes when A = -CN), or from the acids or aminomethyi derivatives, by well known reactions.

In the following schemes :1 is a reference to cis-isomers II a reference to trans-isomers 1(a) to 1 (i).references of 'the various steps of Example 1 wherein the starting material is the 4-ethoxycarbonyl derivative and the final products, acids or derivatives thereof and (a) to 2 (g).references to the various steps of Example 2 wherein the starting material is the 4-cyano derivative and the final products aminomethyi compounds or derivatives thereof.

Initial Common routes Specific routes (Π) A = -CN The compound? according to the invention in which k is a secondary amino or amido group, or E homo azaeburnamonines according to the invention, may be prepared from the above products in which R is -COOH or -NHg by methods known per se for the interconversion substituent groups.

Typical reaction conditions for each reaction step sequence are as illustrated :n the following Examples. Other conditions for effecting tne cam-; conversions will be readily apparent to those skilled in the art.

The invention is illustrated by the following Examples.

Example 1 - (a) Preparation of 3- |2l-(2-ethoxycarbonyl-2-ethyl-5'l-chloro-valeroylamino) -ethy 13. -indole To a suspension of 2.5 g (0.0184 mole) of 3-(2‘-aminoethyl)-indole (tryptamine) in 50 ml dry chloroform containing 2 g (0.02 mole) of triethylamine cooled in an ice bath there were added drop by drop 4.7 g (0.0184 mole) of 2-ethyl-2-ethoxycarbonyl-5-chloro-valeroyl chloride. After stirring for 2 hours at room temperature, the solution was washed with diluted aqueous hydrochloric acid. After drying the organic phase and evaporating it under reduced pressure there was obtained 6.6 g of the above product which, recrystaliized from petroleum ether/isopropyl ether melted at 76^ and had a yield of 95%. The results of analysis were as follows : IR (KBr) 3350 and 3300 cm-1 NH 1735 cm~l CO ester 1640 cm'* CO amide.

Calculated for C^H^OjCl : C=63.40% ; H=7.18% ; N=7.40% Found : C=C3.39% ; H=7.05% ; N=7.51%. (b) Preparation of l-[~(2indol-3 -yl ethyl)-3-ethyl-3-ethoxycarbonyi].-2pi peridone.

To a suspension of 34.4 g (0.0908 mole) of the above compound in 150 ml of a 1:1 mixture of dry benzene and hexamethylphosphoric/triamide cooled in an ice bath there was added, in small quantities and in a nitrogen atmosphere, 10.6 g (0.0946 mole) of potassium t-butoxide. After stirring for 8 hours at room temperature, the solution was poured into a cold dilute aqueous solution of hydrochloric acid. The aqueous phase, after decantation, was extracted two times with benzene. The resulting organic phase was washed twice with water and dried. After evaporating under reduced pressure there was obtained 30 g of the desired product which, recrystaliized from isopropyl ether, melted at 84°F and had a yield of 96%, the results of analysis were as follows : IR (KBr) 3250 cm'1 1730 cm-1 1620 cm-1 NH indole CO ester CO amide Calculated for Found :C20H26N2°3 ' 0=70.15% ; H=7.65% ; N=8.13% C=69.97% ; H=7.65% ; N=8.20%. (c) Preparation of 1-ethyl-1-ethoxycarbonyl-5,12b-didehydro-indolo(2,3-a) quinolizidinium perchlorate Into a solution of 30 g (0.0876 mole) of the above compound in 480 ml of dry toluene there were poured 240 ml of distilled phosphoryl chloride. This solution was heated under reflux for 9 hours with a moisture guard. Excess phosphoryl chloride and toluene were then removed by evaporation under reduced pressure. The residue was taken up with methylene dichloride and the solution was washed with water, dried over sodium sulphate and evaporated under reduced pressure. A part of the solution was agitated with a 1M aqueous solution of lithium perchlorate. After decanting the aqueous phase, washing with water, drying over sodium sulphate and •evaporating the solvent under reduced pressure there was obtained a yellow powder which was recrystallized from ethanol. The resulting product melted at 191°F. The results of analysis were as follows : 3340 cm-1 NH 1740 cm’1 CO ester 1625 cm’1 C=N<® (d) Preparation of 1-ethyl-1-ethoxycarbonyl-indolo (2,3-a)- guinolizidine (12b-H ; l-CgHg Trans and Cis isomers).

A solution of 5.25 g (0.0147 mole) of the above perchlorate salt in 80 mis ethanol was hydrogenated for 12 hours in the presence of 0.3 g of platinum oxide. After filtration, the ethanol was evaporated under reduced pressure and the residue taken up with methylene dichloride and agitated with 5% sodium hydroxide. The organic phase was decanted and washed with distilled water.

On chromatography of a solution of the product with methylene dichloride over 100 grams of silica, and elution with the same solvent, there was separated 1.12 g of a first fraction (yield 2555) which was the 12b-H ; l-CpHg trans isomer of the product and melted at 112°C (recrystallized from petroleum ether/isopropyl ether).

The results of analysis were as follows : JR (KEr) 3410 cm1 770, ?B05, 1710 cm'1 NMR (CDCl, 90 (¾) : among other signals : 8.5 4 4.356 3.856 1.355 0.755 Calculated for C2OH26fl2°2 : Found : The later fractions of v/as the 12b-H ; 1-CgHg cis ' Ni! 2825 cm-1 Bohlmann bands CO ester OH (s) (NH indole) 2H (q) (o-ch2-ch3) IH (s) (h ort9a) 3H (t) (ch3-ch2~o-) 3H (t) (CTI^-CH2) 0=73.59% *T H=8.03% ; N=8.58% 0=73.47% ; H=8.12% ; N=8.33%. chromatography gave 1.8 g of an oil which somers of the desired product.

The results of analysis were as IR (KBr) 3420 cm'1 3750, 3800 cm'1 1705 cm'1 NMR (CC1. 90 MH,) follows : NH Bohlmann bands CO ester. amung other signals : 7.785 IH (s) (NH indole) 20 4.156 2Η (q) (-och2-ch3) 3.936 IH (s) (H on~C9a) 1.096 3!! (t) (CH3-CH2-O) 0.3 6 3H (t) (ch3-ck2-) The hydrochloride, recrystallized from isopropanui, melted at 25 above 260°C.

Calculated fur C.^H^Og.HCl ,1.5 H2C : C=61.57% ; H=7.75% ; N=7.18% Found : C=61.51% ; H=7.33% ; N=7.35%. (ώ) Preparation of l-ethyl-l-carboxy-indolo (2,3-a) Quinolizi dine 20 (12b-H ; lC^H^ Trans Isomer), Hydrochloride.

To a solution of 8.8 g of the ester obtained in step (d) above, in 100 nil cf ethanol are added 8.8 g of KOH and the mixture is refluxed for 12 hours. The solvent is evacuated under reduced pressure and the residue retreated by iced water, acidified by concentrated hydrochloric acid until acid pH is reached ; hydrochloride precipitates, is separated, washed and dried. Yield 9.5 g (100%) of the product crystallized with 1 mole of H20. H.P. : > 260°C.

Analysis Formula CjgH22N202,HCl,H20 M.W. : 353.

Calculated Found : IP. (KBr) 61.01% 61.20% 3340 cm', 1705 cm_i 6.75% 7.08% 7.72% 7.93% (f) Preparation of l-ethyl-l-piperonylpiperazidocarbonyl-indolo(2,3-a)quinolizidine (12b-H ; 1-CgHg Trans Isomer) Dihydrochloride. g of hydrochloride of step (e) above are suspended in 50 ml of benzene and there are added, while cooling, 40 ml of oxalyle chloride.

After stirring for 24 hours at 40°C, excess of oxalyle chloride is evacuated by distillation under reduced pressure and the residue is retreated four times by dry benzene. The dry residue is thus suspended in 50 ml of methylene chloride and cooled at 0’C. A solution of 3.6 g of piperonyl piperazine and 3.4 g of triethylamine in 20 ml of methylene chloride are added and the mixture is stirred for 6 hours at room temperature. After filtration of the insolubles and evacuation of methylene chloride, the residue is treated on a silica gel column (eluent CHgClg). 4.9 g (yield : 60%) of an oily product are obtained.

IR (film) 3360 cm1 (NH) ; 1640 cm1 (CO).

NMR (C0Cl3, internal TMS) sin 106 9.2 Is (IH) NH indole 5.9 Is (2H) o-ch2-o 4.05 ls (IH) “ (¾.) 0.3 lt (3H) ch3-ch2 Dihydrochloride is obtained by treatment -/ith aqueous HCl, ethanol ; crystallization witn 3HgO. Melting point 242°C. * Analysis ,3H20 M.W. : 627.6 in Calculated Founo : C 57.40 57.82 H 7.01 6.55 N 8.92 8.64 (g) Preparation cF 1-ethyl-l Qtrimethoxybenzami do-4)pi perazi nocarbonyfl indolo (2,3-a) Quinolizidine-(12b-H ; 1-C,H5 .Trans Isomer) Hydrochloride.

CH,0 g of hydrochloride of step (e) above are treated by oxalyle chloride as described in step (f) above. 5.3 g of dry residue are obtained, to which there are added 50 ml of methylene chloride and the mixture is cooled at 0°C. A solution of 3 g of triethylamine and 3 g of trimethoxy benzoyl-4amino-1 piperazine in 20 ml of methylene chloride. The mixture is stirred for 24 hours at room temperature, then washed with a 10% aqueous soda solution, then with water, dried and the excess solvent is evacuated. 7.2 g of an oily product are obtained.

IR (film) 3380 cm-1 and 3240 cm-1 (Nil) 1650 cm'1 and 1620 cm'1 (CO) Hydrochloride is obtained M.P. : 225°C.

Analysis C^H^jH^Ojj.HCl C Calculated 62.87, Found 62.24by treatment with aqueous HCl, in ethanol.

M.W. : 611 Η N 6.92 11.46 6.95 11.18 (h) Preparation of 1-ethyl-1-carboxy-indolo-(2,3-a)-quino! izidine Into a solution of 5.8 g of l-ethyl-l-ethoxycarbonyl-indolo(2,?-s) quinolizidine (12b-H ; l-C^dg cis isomer) obtained in the preceding example (d), m 100 ml of ethanol at 95%, there are added 5.S g of potassium hydroxide. The mixture is refluxed for 12 hours, the solvent evaporated under reduced pressure and the residue retreated with iced water and acidified with HCl up to pH = 4.5. The product crystallizes, is separated, washed and dried. 4.1 g of acid are thus obtained.

Analysis ^13^22^2 (4=298.37 C H N Calculated 72.45 7.43 9.37 Found 72.61 7.49 9.20 IR 1620 cm'3 v CO, OH associated. (i) Preparation of + D Nor Eburnamonine There are added, dropwise, to a suspension of 6 g (0.0179 mole) of l-ethyl-l-carboxy-indolo(2,3-a) quinolizidine (12b-H ; cis isomer) of previous step (h), in 60 ml of dry benzene, 30 ml of oxalyle chloride.

The suspension is stirred for 2 hours at room temperature, then refluxed for 9 hours. The solvents are evacuated under reduced pressure and the residue retreated with methylene chloride, is stirred in the presence of diluted soda. The organic solution, washed with water, dried on sodium sulphate, evaporated under reduced vacuum, gives 4.25 g of the researched product.

Yield 83%.

After washing on alumina column, 3.25 g of beige crystalline product are obtained. M.P. = 136°C (diisopropylic oxide).

IR (KBr) 2805, 2845, 1735, 1660 cm’1C18H20N2° = 2θθ·96· Calculated % : C 77,11 H =7.19 Found : 77.54 7.78 N 9.99 .09 H|RMN (COClj) reference 7.5-7.05 (m) 3H aromatic int. TMS = 0 7.9-7.7 (m) aromatic ; ; 4.3 (m) IH ; 1.1 (t) CH--CH, Hydrochloride The necessary amount of aqueous HCl 7fl is added to a solution of 3.25 g of base in 30 ml of absolute alcohol. The solvents are evaporated under reduced vacuum, at 30°C and the residue, retreated with acetone, gives 3.32 g of a white crystalline product. M.P. : 264°C.

IR (KBr) : 3400, 2470, 2320, 1740, 1680 cm1 C13RMN (DgO) reference dioxan 6 ppm 107.426 C = 0 ; -13.712 CH ; -82.162 CH3 Example 2 (a) Preparation of 3-El-(2-cyano-2-5thy1-5-chloro-valeroylaniino)ethyfj-indole.

In a 1 litre flask there were placed 3) g (0.194 mole) of tryptamine 500 ml of diehloromethane and 20 g (0.198 mole) of triethylamine. The mixture was cooled to 0°C over ice and there were added 40 g (0.192 mole) of 2-cyano-2-ethyl-5-chloro-valeroyl chloride dissolved in 150 ml of methyl dichloride. After 2 hours at room temperature the mixture was washed with water, then with 10% hydrochloric acid, then with 10% sodium hydroxide. It was then dried and the solvent removed by evaporation. The product, recrystaliized from isopropyl ether/petroleum ether, melted at 120°C (yield 40 g). The results of analysis are as follows : 3400 cm1 NH indole 3340 cm-1 NH amide 2860 cm1 CN. 1660 cm-1 C-N Calculated for C.gH^NgClO : C = 65.0 % ; H = 6.64% ; N = 12.65% Found : C = 64.03% ; H = 6.73% ; N = 12.60%. (b) Preparation of 1-[/21-indol-3-yl-ethyl)-3-ethyl-3-cyano]-2-piperidone In a 1 litre round-bottomed flask there were placed 22 g (0.0655 mole) of the product of step (a) above, 200 ml of tetrahydrofuran, and 300 ml of V-butanol. The mixture was cooled to 0°C over ice and there were added, in small quantities, 8.5 g (0.076 mole) of potassium tert, butoxide. After 2 hours at room temperature, the mixture was reduced in volume and hydrolysed. The organic phase was extracted with methylene dichloride, washed with water, dried and the solvent removed by evaporation. The desired product, recrystaliized from ethanol/ether 50/50 melted at 180°C (yield 15 g, 80%). The results of analysis are as follows: IR 3400 cm1 NH indole 2260 cm1 CN 1635 cm1 C-N Calculated for C^H^O : C = 73.2 % ; H « 7.1 % ; N = 14.2 % Found : ' C = 72.46% ; H = 7.15% ; N = 14.01%. il 7 518 (c) Preparation of 1-ethyl-l-cyano-5,12b-didehydro-indolo(2,3-a)qui noli zi di ni um Perchlorate.

In a 1 litre flask there were placed, with stirring, 50 g (0.169 mole) of the product of step (b) above and 700 rol of phosphoryl chloride. After heating under reflux for 20 hours the reaction mixture was concentrated and extracted 2 or 3 times with 500 ml of methylene dichloride which was then removed by evaporation. The product was then taken up with 300 ml of methylene dichloride and cooled over ice, and 300 ml of a solution of lithium perchlorate (1 mole) was added with vigorous stirring. There was produced a yellcw precipitate which, recrystallized from methanol melted at 260°C (yield 44 g, 70%). The results of analysis are as follows : IR 3400 cm1 NH indole 2260 cm1 1620 cm'1 (d) Preparation of l-ethyl-l-cyano-indolo(2i3-a)-quinolizidine (12b-H ; 1-CgHg Trans Isomer), In a 1-litre round-bottomed flask there were placed 200 ml methanol, 100 ml methylene dichloride and 13.5 g (0.036 mole) of the perchlorate product of step (c) above. The flask was cooled to about 5°C and 5 g of sodium bcrohydratc were added in small quantities. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted 'with methylene dichloride. After drying and.removing the solvent, there were obtained 8 g of yellow crystals, recrystallized from isopropyl et'ner melting at 160°C (yield 80%). The results of analysis are as follows : IR 3420 cm1 ) NH and Bohlmann bands CN NMR (dimethylsulphoxide dg, 80 ΜΗχ) 0.86« , 3H (t) (CH3) 3.77 6, IH (s) (Jfat C9a) 9.66 6 , IH (s) (NH) Calculated for ClgHzlN3 : C = 77.7% ; H = 7.2% : N = 15.2% Found : C = 77.55%; H = 7.32%; N « 15.10%. (e) Preparation of 1-ethyl-1-cyano-inriolo(2,3-a)quiriolizidine (12h-H ; 1-C,H5 Cis Isomer).

In a 1-litre tinsK tnere were placed 19 g of the perchlorate product of step (c) above, 300 cc of 95% ethanol and 49 g zinc powder. There was added in an ampoule 100 mis concentrated hydrochloric acid. Mild reflux could be observed during the addition of the acid. The mixture was allowed to stand at room temperature for 10 hours. It was then concentrated, washed with water and extracted with methylene dichloride. It was made alkaline with sodium hydroxide and filtered through Celite (Trade Mark). After decanting, drying and evaporating off the solvents there were obtained 6 g of a product, insoluble in ether, melting at 25O°C. The results of analysis are as follows : IR 3410 cm1 (NH) 2260 cm1 (CN) Calculated for c18H2lN3-1/4H2° : C = 76.5% ; H = 7.60% ; N = 14.85% Found : C = 76.59%; H = 7.80% ; N = 14.55%.

The ether extracts were concentrated ro provide 4 g (total yield 71.5%) of the cis isomer of the same product as step (ci) above.

NMR (dimethylsulphoxide dg, 80 MHZ) 1.056 3H (t) (CHg) 3.455 IH (s) (rfat Cga) .326 IH (S) (NH) (f) Preparation of 1-ethyl-1-aminomethyl-indolo(2,3-a)quinoiizidine (12b-H ; Ι-CgHg Trans Isomer II).

In a 1-litre flask there were placed 4 g of lithium aluminium hydride and 400 ml of dry ether. The flask was cooled to frcm 0 to 5°C, and there were added, in small quantities, 8,9 g of the product of step (d) above. After leaving the flask to stand for 1 hour at room temperature, there were added 60 ml dry tetrahydrofuran. The mixture was heated for 2 hours under reflux. After cooling there were added, drop by drop, 40 ml water, followed by 200 ml of methylene dichloride.

The mixture v;as stirred for 15 minutes. On filtering over celite. drying and concentrating the filtrate there was obtained 7.2 g of white crystals which, recrystallized from ether, melted at 175°C (80% yield).

The results of analysis are as follows : IR 3280, 3190 cm'1 NH2 3350 cm1 NH indole The CN peak at about 2250 cm1 was absent.

Calculated for Ο1θΗ25Ν3 : C = 76.4 % ; H = 8.85% ; N = 14.8 % Found : C = 75.85% 5 H = 8.90% ; N = 15.52%. (g) Preparation of l-ethyl-l-anrinomethyl-indolg^S-a) Quinolizidine (12b-H ; 1-C,K5 Cis Isomer I).

To a 500 ml flask there were added 3.4 g of lithium aluminium hydride, 200 ml of ether and 100 ml of tetrahyJrofuran. While cooling over ice there were added, in small quantities, 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 was. isolated as in step (f) above. On recrystallization from diethyl ether/petroleum ether 50/50 there was obtained 5 g of a product melting at 125SF (yield 71%).

Calculated for 01θΗ25Ν3 ; C = 76.4 % ; H = 8.85% ; N = 14.8 % Found : C = 76.25% ; H = 8.61% ; ti =14.43 %.

Example 3 1-ethoxycarbonylaminomethyl-1-ethyl-ihdolo (2,3-a) Quinolizidine Hydrochloride (12b-H ; 1-CgHg Trans Isomer II).

To a solution of 2 g (0.00705 mol) of the trans product II of Example 2(f) in 20 ml in dimethoxyethane, cooled to 0°C, there were alternately added, so as to maintain the pH basic, portions of ; 800 mg of ethyl chloroformate in solution in 5 ml of dimethoxy· 25 ethane ; and 750 mg of sodium carbonate in solution in 5 ml cf water.

After allowing the reaction mixture to stand for 3 hours at 47S18 ambient temperature, the product was extracted with dichloromexhanc, the dichloromethane extract was washed with water, dried and evaporated to dryness. The product was recrystallized from ethanol.

Height : 2 g Yield : 80%. M.P. : 140°C. IR 3210 cm1 amide NH 3400 cm1 inucle NH 2760 and 2800 cm3 Echlmann bands 1690 cm3 carbamate C = 0.

The results of microanalysis are as follows : Calculated for C21H2gN302 : C = 71.0 % ; li = 8.17% ; M = 11.8 % Found : C = 70.94% ; H = 8.18% ; N = 11.54%.

The hydrochloride salt was formed from the above 2 g of product by adding 4N HCl in 20 nil of ethanol.

Height : 2 g Yield : 90% M.P. : 260C.

Example 4 E Homo Azaepieburnamonine Hydrochloride First 1-phenoxycarbonyl ami nomethyl-1-ethyl- indolo (2,3~a) quinolizidine (12b-H ; l-CgHg trans isomer) was prepared by repeating the procedure of Example 3, but replacing the ethyl chloroformate with phenyl chloroformate.

To a solution of 8 g (0.02 mol) of the product in 250 ml of tetrahydrofuran there were added 2 g of sodium hydride to 5i'%. After stirring for 90 minutes, the reaction product was extracted with diethyl ether, washed with water and dried. The diethyl ether 'was removed by evaporation to leave 5 g of an oil, analysis of which gave the following data : IR 3200 cm3 amide NH 1670 cm-3 anride C = 0 NMR (CC14 ; internal TMS) 0.65 3 (3H,t, CH3-CH2) to 3.2 C (solid 15 protons) 3.3 δ (IH, s, angular proton 12Js H) 7.2 δ (solid 3H aromatics) 8.1 6 (solid IH aromatic) The hydrocnloride salt was prepared by treating the above oil with 4N hydrochloric acid in 20 ml of ethanol, followed by centrifuging. The yield was 60%, calculated on the starting amine (II). M.P. : 260°C. The product crystallized with 1/2 mol of water of crystallization.

The results of microanalysis are as follows : Calculated for CjgH^O.BCl.O.S HgO : C = 64.5% ; H = 7.05%; N = 11.8% Found : C = 64.38%; H = 7.112; N = 11.622 Example 5 1-(31,4',51-trimethoxybenzoylami nomethyl)-1-ethyl-indolo (2,3-a) Quinolizidine Hydrochloride (12bpH ; l-C?Hg Trans Isomer II).

Into a threc-r.ecked bottle of 250 ml capacity fitted with a stirrer, a CaClg guard, a thermometer and a dropping funnel there were added 2.85 of the trans proouct II of Example 2(f), 1.1 g of triethylamine and 50 ml of dichloromethane.

The mixture was stirred and cooled to 0.2°C. At this temperature there were slowly' added 2.31 g of 3,4,5-trimethoxybenzoyl chloride in 15 ml of dichloromethane. The addition took place over a period of 15 to 20 minutes, after which time the reaction mixture was stirred for 1 hour at 0°C then for 15 hours at ambient temperature.

The reaction mixture was then washed several times with water, then with 102 aqueous sodium hydroxide and then again with water. It was dried over sodium sulphate and concentrated to form a non-crystalline mass, having the texture of meringue and melting towards 100°C, CCM : 90/10 8/10 IR <230 cm'1 NH 3190 cm1 NH 2750 and 2800 cm Bohlmann bands 1640 cm-1 C = 0 amide dosage of the base with HC104 : 97%.

To prepare the hydrochloride salt, the above product was dissolved in a 1:1 mixture of di-isopropyl ether and isopropanol, and 4N hydrochloric acid was added, he hydrochloride salt crystallized when hot, and was filtered while hot and washed with ethanol.to produce 4.5 g (88% yield) of the product.

COM : 90/10 8/10 M.P. : 210°C bond on the plate dosage of hydrochloride : 100% (1 function).

Microanalysis gave the following results : Calculated fcr CjgHggN^.HCl : C = 65.45% ; H = 7.00% ; N = 8.18% Found : C = 64.34% ; H = 7.17% ; N = 8.11% C = 64.15% ; K = 7.16% ; N = 7.96%. 1-(N' [diethylaminoethyl^] -N-ureidomethyl)-1-ethyl-indolo (2,3-a) Quinolizidine (12b-H ; l-CgHq Trans Isomer II).

There was first prepared the corresponding 1-phenoxycarbonylaminomethyl-I-ethy! derivative, 7 g of the trans product II of Example 2(f) and 100 ml of tetrahydrofuran were placed in a three-necked flask of 500 ml capacity, having a stirrer and two dropping funnels The flask was cooled to between G°C and 5°C and at this temperature, there were simultaneously added 4.25 g of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium carbonate in 50 ml of water. The rates of addition were such as to maintain the pH at from 6 to 7. The flask was then allowed to warm to ambient temperature and stirring was continued for 3 hours. The reaction product was extracted with 100 ml cf dichloromethane and the extract was washed several times with water before being dried with sodium sulphate, and concentrated by evaporation, 'here were obtained il g of the product, which was an oil, IR 3270 cm'1 NH 1710 cm'1 C = 0 The 1-ureidomethyl product was prepared es follows : into a 500 ml flask provided with a cooler,'there were placed 11 g of the above oil 3.5 g of dimethylaminoethyl c-nine and 180 ml of methanol. The amount of dimethylaminoethyl amine used corresponded to a 20% excess. The mixture was heated under reflux for 2.5 hours and then the methanol was removed by evaporation. The residue vzas taken up in dichloromethane and washed with 10% aqueous sodium hydroxide then with water. After drying over sodium sulphate it w&s concentrated to provide a yellowish crystalline product. The product was taken up in two stages in diethyl ether and centrifuged. The first stage yielded 4.6 g of crystalline product melting at 202°C, and the second stage yielded 0.8 g of crystalline product melting at 198°C. The combined products were then recrystallized from benzene to provide 4.65 g of the final product.

M.P. : 204°C. amine (II).

COM : 90/10 Yield : 45% based on the /10 IR : 3360 cm'1 NH 3250 cm'1 NH 1620 cm 1 C = 0 urea Microanalysis gave the following results : Calculated for C^HggNgO : C = 70.6 % ; H = 9.17% ; N = 16.45% Found : C = 70.58% ; H - 9.20% ; N = 16.67%.

Example 7 1-pentanoylami nomethyl-1-ethyl-indolo (2,3-aj-quinolizidi ne (12b-H ; l~C2Hg Trans Isomer II) Using reaction conditions and techniques identical to those of Example 5, there were reacted a solution of 5.7 g of the trans product II of Example 2(f) and 2.1 g ot triethyiamine in 220 ml of dichloromethane and a solution of 2.45 g pentanoyl chloride in 20 ml £ of dichloromethane.

There were thus obtained 7.8 g of an oil containing a little residual triethylamine.

IR : 3180-3380 cm-1 NH 1630-1650 cm1 C = 0 From the oil it was possible to obtain crystals of the product, melting at 11O°C.

Example 8 1-pentylaminomethyl-1-ethyl-indolo (2,3-a)-quinolizidine (12ti-H ; 1-C?HR Trans Isomer II) In a three-necked flask of 500 ml capacity having a stirrer, a condenser, a thermometer, and a dropping funnel there were placed 100 ml of anhydrous diethyl ether. When this had been cooled over an ice bath there added 4 g of lithium hydride, and the contents of the flask were stirred for 15 minutes. There was then added very slowly a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous diethyl ether. The mixture was then heated under reflux for 2 hours and stirred for a further 15 hours at ambient temperature. It was then cooled over an ice bath and there were added dropwise 20 ml of water followed by 150 ml of dichloromethane. The reaction mixture was then filtered over celite, dried over sodium sulphate and concentrated by evaporation. There were obtained 7 g of an oil which could be crystallized to a product melting at 80°C.

Recrystallization from the minimum amount of isopropanol gave 4.3 g of a crystalline product melting at 97CC.

Dosage of the base with HC10a : 100* (2 functions).

Microanalysis gave the following results : Calcualted for C23H35«3 : C = 78.20% ; H - 9.92% ; if = 11.90% Found : C = 78.18% ; H =· 9.81% ; N = 12.00%.

IR basic : 3310 cm-1 NH 1620 cm1 C = 0 Dimaleate An acid addition salt with maleic acid was prepared, working in solution in a mixture of isopropanol and di-isopropyl ether. Initially the salt formed as an oil, but was recrystallized from ethyl acetate to give 6.7 g of the dimaleate, melting at 105°C.

Dosage of the dimaleate with HCIO^ : 99.6% (2 functions).

Rf : 90/10 9/10.

Example 9 : 1-guanidinocarbonylaminomethyl-1-ethyl-indolo (2,3-a)-quinolizidine Dimaleate (12bH ; l-CgHg Trans Isomer) . dimaleate Into a 250 ml flask, 9 g of the compound prepared in Example 3, 2.2 g of base guanidine (liberated from 3 g of chlorohydrate by the couple ethylate-ethanol) are put into 120 ml of ethanol. The mixture is refluxed for 48 hours and the solvent evaporated to dryness. The residue is retreated by a water-methylene chloride mixture, filtered on celite and decanted, the organic phase washed again with water. The methylene chloride phase is then washed twice by a 5% acetic acid solution and the acid waters are alkslinized with sodium bicarbonate in the presence of ether ; the ethereal phases are dried and evaporated. 6.4 g of a porous mass are obtained and chromatographed on silica (60 g of silica : eluent CH2C12- MeOH 80-20).

After separating 0.7 g of a first product, a second one is isolated and crystallized in ether. Yield : 3.5 g. M.H. = 150°C.

IR (KBr) : 3200-3400 cm’1 strong and broad bands (v NH) 1600 cm1 broad band (v C = 0) The dimaleate is prepared in isoHropanol.

CCM (Merck plate ΜΓ 254 : eluent acetone, CHC1,, n butanol 30 30 30 Rf = 0.4 1 spot MicroanalysisC20H28N6° - We M: = 600 Calculated % C 56.00 H 6.00 N 14.00 Found : 56.07 6.46 12.59 Example 10 EHomo 14 Azaeburnamonine (12t>-H ; 1-0?Ης Cis Isomer I).

Example 4 was repeated except that the cis product (I) of Example 15 2(g) was used in place of the trans product (II) of Example 2(f). There was obtained 5.7 g of product (yield 69%). M.P. : 190°C.

IR : 3260 cm1 NH 1690 cm1 0 = 0 Microanalysis gave the following results : Calculated for O^Hg^O : C = 73.8 % ; H = 7.45% ; N = 13.6 % Found : C = 73.48% ; H = 7.35% ; N = 12.99%.

The hydrochloride was obtained by adding 4 N HCl to a solution of the base in a 1:1 mixture of ethanol and diethyl ether.

Example 11 1-ethoxycarbonylamiliomethyl-1-ethy1 -indolo (2,3-a)-quinolizidine Hydrochloride (i2b-H ; l-CpH^ cis Isomer I).

The procedure of Example 3 was repeated except that the cis product (I) of Example 2(g) was used instead of the trans product (II) of Example 2(f). There was obtained 2.1 g of the free base (842 yield) M.P. : 210°C.

IR 3400 cm1 3210 cm1 2790 and 2810 cm1 indole NH amide NH Bohlmann bands 1690 cm1 carbamate C=0 Microanalysis gave the following results : Calculated for Cg^NgOg : C = 71.0 2 ; H = 8.172' ; N = 11.822 Found : C = 70.852 ; H = 8.222 ; N = 11.942.

NMR (CDClg ; internal TMS) l.lfi (6 H, t, CHg ethyl and ethyl ester) 1.5 to 3.5δ (15H, solid) 3.9 fi(2H, q, CHgO) .655 (IH, m, NH-amide) 7.25 fi(4H, solid, aromatics) 7.9 6(1H, s, NI! - indole) The hydrochloride salt was prepared using 4N hydrochloric acid in acetone.

Yield : 902. M.P. : 250°C. 4751s Example 12 χ- (Ν'- |cli ethyl ami noethyl] —·-N-ureidomethvl)-l-6thyl-indolo(2,3-3) quinolizidine (12b-H ; l-Cphg Isomer I) The first part of Example 6 was repeated using the cis product I of Example 2(g) instead of the trans product II of Example 2(f). The second part of Example 6 was then repeated on a smaller scale, using 3 g of the 1-phenoxycarbonylami nomethyl derivative, 1.2 g of diethylaminoethyl amine and 50 ml of methanol. There was thus produced 2.8 g of the above product which was an oil.

The di-hydrochloride salt was obtained by treatment with 4N hydrochloric acid in acetone. The salt was isolated by concentrating the acetone solution and recrystallizing from a 1:1 mixture of ethyl acetate and ethanol.

There were obtained 1-8 a of product, melting at ?50°C. Yield : 48.5% based on the weight of amine base.

IR 3300 cm-1 1640 cm'1 Microanalysis gave the following results assuming i mole of water of crystallization.

Calculated for CggH^gtlgO. 2HC1. HgO : C = 58.30% ; H = 8.35% ; N = 13.74% Found : C = 58.56% ; H = 8.25% ; N - 13.60%.

Toxicity LD 50 has been determined per os on mice. The compounds of the invention present a toxicity comparable to that of vincamine or a lower one. The more toxic (LD 50 : 400 mg/kg ; vincamine 450 mg/kg) are those of Examples 2 (f), 3 and 4; the less toxic are those of Examples 5, 10 and 12 whereas the remaining compounds present an intermediate toxicity.

Pharmacology The activity of the compounds of the invention has been researched in the field cf femoral and vertebral flows, arterial pressure and cardiac rhythm. Comparison was made with vincamine and with compounds described in French Patent Publications Nos. 2 285 377 and 2 292 475. The experimentation conducted as still known for vincamine, has shown that the compounds of the invention, and more particularly these of examples 3 and 5: a) induce an increase of the femoral flow ; French patent publications compounds present a similar action but vincamine reduces this flow ; b) induce a strong increase of the vertebral flow ; French patent publications compounds do not act at all or induce a moderate increase whereas vincamine reduces this flow ; c) do not affect significantly arterial blood pressure whereas the comparison compounds lower it ; d) induce a slight increase of cardiac rhythm whereas French patent publications compounds generally induce a more important increase and vincamine lowers this factor.

From these results the compounds of the invention appear to have a very favourable action in the field of cerebral irrigation, which was confirmed clinically.

Posology The compounds of the invention may be administered i.v. or per os, at doses comparable to those used for vincamine, (dosage units for 5 to mg). ^7318

Claims (5)

1. An indolo (2,3-a) quinolizidine of the general formula (I) or (II) 5 (I) (II) wherein R stands for -COOCgHg, -COOH, -CN, a primary or secondary aminomethyl group, an amidomethyl group or an amido group, or wherein R, together with the ring nitrogen of the indolo ring, represents one of the groupings 10 -N-C0-NH-CH 2 - or -N-CO-; or a therapeutically acceptable acid addition salt thereof.

2. A compound according to claim 1, substantially as disclosed in any of the Examples herein.

3. A process for the preparation of a compound according to 15 claim 1, comprising condensing together 2-aminoethyl-3-indole and l-chloro-4-(A)-4-chlorocarbonyl-hexane, wherein A stands for -COOCgHg or -CN, to form the corresponding amide; subjecting the amide to strongly basic conditions to eliminate HCl and effect ring formation at the nitrogen atom 20 on the 3-indole substituent; effecting quinolizidine ring formation of the product by treating it with a dehydrating agent followed by a perchlorate salt; hydrogenating the resulting quinolizidinium perchlorate to produce the corresponding l'ndolo (2,3-^) quinolizidine isomer mixture and separating the isomers.

4. A process for the preparation of a compound according to claim 1, substantially as disclosed in any of the Examples herein.

5. 5. A therapeutic composition comprising one or more compounds according to claim 1 or claim 2 in admixture with a therapeutically acceptable diluent or carrier. Dated this 24th day of November 1978