CH641181A5 - INDOLO-QUINOLIZIDINES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS CONTAINING THEM. - Google Patents

Description

The present invention relates to indoloquinolizidines, their preparation process and the therapeutic compositions containing them.

Among the nitrogenous polycyclic compounds, tetracyclic aldehydes, such as those described in "Helvetica Chimica Acta", 60,1801-10, 1977, as well as indolo (2,3-a) qui-nolizines, are especially known. in patent application FR-A No. 2197873, the latter being usable for example for the synthesis of vincamine. On the other hand, indolo (2,3-a) quinolizidines have so far never been described in the literature.

The new indolo (2,3-a) quinolizidines according to the present in-

where R represents - COOC2H5, —COOH, —CN, a primary or secondary methylenamino group, a methylenamido group, or in which R, with the nitrogen of the indolo ring, represents one of the groups N — CO — NH — CH 2 or N — CO; the latter derivatives are D-homoazaéburnamonines or D-éburnamonines.

The present invention also relates, where appropriate, to the acid addition salts of the above compounds.

R 5 can be, for example, methylenaminocarbalcoxy, methylaminoaryloxycarbonyl, methylaminoalkanoyl, methylaminoalkyl or a substituted methylenureido group.

Preferably, R can represent COOH, NH2, methylenami-nocarbethoxy, methylenamino (trimethoxy-3,4,5) -benzoyl, methylenaminophenoxycarbonyl, methylenureidodiethylaminoethyl, methylenaminopentanoyl, methylenaminopentyl and amidopipyr.

The compounds according to the present invention are particularly interesting for their activity in the field of san-guinean circulation in the brain. Accordingly, the present invention provides therapeutic compositions comprising one or more of these compounds mixed with a therapeutically acceptable diluent or reaction carrier.

The above compounds can be prepared according to the present invention, by condensing together Faminoethyl-2-indole-3 and chloro-1-chlorocarbonyl-4- (A) -4-hexane, where A represents —COOC2H5 or - CN , to form the corresponding amide; by subjecting the amide to a strongly basic agent to remove HCl and effect the formation of a cycle with the nitrogen atom on the indol-killing agent 3; by carrying out the formation of a quinolizidine cycle of the product by the action of a dehydrating agent, then of a perchlorate; by hydrogenating the quinolizidinium perchlorate obtained to produce the indolo (2,3-a) quinolizidine isomer mixture and separating the isomers; the corresponding reaction schemes are presented below under the title "Common initial sequence" and lead only to compounds where R is - COOC2Hs or - CN (2 isomeric forms in each case, ie 4 compounds).

All the other derivatives come from these compounds:

- either directly, for example, acids, from esters, by saponification (cf. the diagrams "Specific reactions"

A = - COOCjH5), or methylenamino from nitriles, by reduction with aluminum / lithium hydride (cf. the same diagrams with A = —CN),

- either from acids or methylamino derivatives, by 40 well known reactions.

In the following diagrams:

- I is a reference to cisisomers,

- It is a reference to the transisomers,

- 1 a to 1 i are references to the different stages of Example 45 pie 1 where the starting material is the derivative of ethoxycarbonyl-4 and the final products, of acids or derivatives thereof, and

- 2 a to 2 g are references to the different stages of Example 2, where the starting product is the cyano-4 derivative and the final products of the methylamino derivatives.

50

Common initial sequence

3

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H2 / Fe

Specific reactions

A - -COOCjHJ

A - -CN

HC:

2 (g)

jl.iAlH4

(XI)

H2N • '

(XI)

The present invention is illustrated by the following examples: Example 1:

a) Preparation of [(2-ethoxycarbonyl-2-ethyl-2 "-ethyl-2" -5-chloro-5 "-valeroylaminoethyl-2) -2] -3-indole.

To a suspension of 2.5 g (0.0184 mol) of (aminoethyl-2 ') - 3-indole (tryptamine) in 50 ml of dry chloroform containing 2 g

(0.02 mol) of triethylamine cooled in an ice bath, 4.7 g (0.0184 mol) of ethyl-2-ethoxycarbonyl-2-chloro-5-valeroyl chloride are added dropwise. After stirring for 2 h at room temperature, the solution is washed with dilute aqueous hydrochloric acid. After drying the organic phase and removing under reduced pressure, 6.6 g of the above product are obtained which, recrystallized from a petroleum ether / isopropyl ether mixture, melts at 76 ° C. Yield 95%. The results of the analysis are as follows:

IR (KBr): 3350 and 3300 cm "1 1735 cm" 1 1640 cm-1

Analysis for C20H27N2O3CI: Calculated: C 63.40 H 7.18 Found: C 63.39 H 7.05

NH

CO ester CO amide

N 7.40% N 7.51%

20

25

30

b) Preparation of [(indol-2'-ylethyl-3 ") - l-ethyl-3-ethoxy-carbonyl-3] -piperidone-2

To a suspension of 34.4 g (0.0908 mol) of the compound of the preceding step in 150 ml of a 1: 1 mixture of dry benzene and hexamethylphosphoric / triamide cooled in an ice bath, the following is added, in small quantities, and under a nitrogen atmosphere, 10.6 g (0.0946 mol) of potassium t-butoxide. After stirring for 8 h at room temperature, the solution is poured into a cold solution of dilute hydrochloric acid. After decantation, the aqueous phase is extracted twice with benzene. The organic phase obtained is washed twice with water and dried. After evaporating under reduced pressure, 30 g of the desired product are obtained which, recrystallized from isopropyl ether, melts at 84 ° C. Yield 96%. The results of the analysis are as follows:

IR (KBr): 3250 cm -1 NH indole 1730 cm-1 CO ester 35 1620 cm-1 CO amide

Analysis for C2oH26N203:

Calculated: C 70.15 H 7.65 N 8.13%

Found: C 69.97 H 7.65 N 8.20%

40

c) Preparation of ethyl-I-ethoxycarbonyl-1-didehydro-5,12b-indolo (2,3-a) Quinolizidinium perchlorate

240 ml of distilled phosphoryl chloride 45 are poured into a solution of 30 g (0.0876 mol) of the compound from the preceding step, in 480 ml of dry toluene. This solution is heated at reflux for 9 h with a guard against humidity. The excess phosphoryl chloride and toluene is then removed under reduced pressure. The residue is taken up in methylene dichloride and the solution, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Part of the solution is stirred with an aqueous IM solution of lithium perchlorate. After decanting the aqueous phase, the organic phase is washed with water, dried over sodium sulfate and the solvent evaporated under reduced pressure; a yellow powder is obtained which is recrystallized from ethanol. The product obtained melts at 55,191 ° C. The results of the analysis are as follows:

IR (KBr): 3340 cm-1 NH

1740 cm -1 CO ester 1625 cm-1 C = N <©

60

d) Preparation of ethyl-1-ethoxycarbonyl-1-indolo (2,3-a) -quinolizidine (12b-H; 1-QHS trans- and cisisomers)

A solution of 6.25 g (0.0147 mol) of the perchlorate salt of the previous step in 80 ml of ethanol is hydrogenated for 12 h 65 in the presence of 0.3 g of platinum oxide. After filtration, the ethanol is evaporated under reduced pressure and the residue taken up with methylene dichloride and stirred with 5% sodium hydroxide. The organic phase is decanted and washed with distilled water.

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4

After chromatography of a solution of the product with methylene dichloride on 100 g of silica, and elution with the same solvent, 1.12 g are separated from a first fraction (yield 25%) which is the 12b-H transisomer; 1-C2H5 of the product and which melts at 112 ° C (recrystallized from petroleum ether / isopropyl ether).

The results of the analysis are as follows:

IR (KBr): 3410 cm "1

2770.2805, 2825 cm "1 1710 cm" 1

NMR (CDC13 90 MHz):

Among other signals:

NH

Bohlmann CO ester bands

8.5 8 OH (s) (NH indole)

4.35 5 2H (q) (O - CH ^ - CH3)

3.85 5 1H (s) (H on C9a)

1.35 8 3H (t) (CHa-CH;, - O—)

0.75 5 3H (t) (CHj — CH2)

Analysis for C20H26N2O2:

Calculated: C 73.59 H 8.03 N 8.58%

Found: C 73.47 H 8.12 N8.33%

The last chromatography fractions give 1.8 g of an oil which is the 12b-H cisomer; 1-C2HS of the desired product. The results of the analysis are as follows:

IR (KBr): 3420 cm "1

3750, 3800 cm "1705 cm" 1

NMR (CC14 90 MHz): Among other signals:

NH

Bohlmann CO ester bands

7.78 8 IH (s) 4.15 8 2H (q) 3.93 8 1H (s) 1.09 5 3H (t) 0.9 8 3H (t)

(NH indole) (—OCHi — CH3) (H on C9a) (CH3-CH2-0) (CH3 — CH2—)

The hydrochlorides, recrystallized from isopropanol, melt at more than 260 ° C.

Analysis for C20H26N2O2-HCl- I, 5H2C:

Calculated: C 61.57 H 7.75 N 7.18%

Found: C 61.51 H 7.33 N 7.35%

e) Preparation of ethyl-I-carboxy-1-indolo (2,3-a) quinolizidine (12b-H; 1-QHS transisomer), hydrochloride

HCl f) Preparation of ethyl-1-piperonylpiperazidocarbonyl-1-indolo (2,3-a) -quinolizidine (12b-H; 1-C ^ Hs transisomer) dichlorhydrate

2 HC t

0 - <^> - ch2- / S? - /

6 g of the hydrochloride from step e above are suspended in 50 ml of benzene and 40 ml of oxalyl chloride are added while cooling. After stirring for 24 h at 40 ° C, the excess oxalyl chloride is removed by distillation under reduced pressure and the residue is taken up four times in dry benzene. The dry residue is then suspended in 50 ml of methylene chloride and cooled to 0 ° C. A solution of 3.6 g of piperonylpiperazine and 3.4 g of triethylamine in 20 ml of methylene chloride is added and the mixture is stirred for 6 h at room temperature. After filtration of the insoluble matters and evacuation of the methylene chloride, the residue 25 is taken up on a column of colloidal silica (eluent CH2Cl2). 4.9 g of an oily product are obtained (yield: 60%).

IR (film) 3360 cm "1 (NH); 1640 cm" 1 (CO).

NMR (COCl3), int. TMS in 10 "6 9.2 8 ls (IH) NH indole 5.9 8 ls (2H) O-CHi-O 4.05 8 ls (1H) H (CI2b)

0.3 8 lt (3H) CHi-CH2

The hydrochloride is obtained by treatment with HCl in aqueous-alcoholic solution; crystallization with 3H20. Mp 242 ° C.

30

Analysis for C30H36N4O3 • 2HC1 • 3H20 P.M.: 627.6:

Calculated: C 57.40 H 7.01 N8.92%

Found: C 57.82 H 6.55 N 8.64%

g) Preparation of ethyl-1 [(trimethoxybenzamido-4) piperazi-nocarbonyl] -! - indolo (2,3-a) quinolizidine- (12b-H; 1-QHS transisomer) hydrochloride

HOOC

To a solution of 8.8 g of the ester obtained in step d above, in 100 ml of ethanol, 8.8 g of KOH are added and the mixture is brought to reflux for 12 h. The solvent is removed under reduced pressure and the residue taken up in ice water, acidified with concentrated hydrochloric acid until an acid pH is reached; the hydrochloride precipitates, it is separated, washed and dried. Yield 9.5 g (100%) of the product crystallized with 1 mol of H2O. M> 260 ° C.

Analysis for C18H22N202- HCl-H20 P.M .: 353:

Calculated: C 61.20 H 7.08 N 7.93%

Found: C 61.01 H 6.75 N 7.72%

IR (KBr): 3340 cm "1 NH

1705 cm "1 (-C-OH)

II

O

-NH-N

55 5 g of hydrochloride from step e above are taken up in oxalyl chloride as described in step f above. 5.3 g of dry residue are obtained, to which 50 ml of methylene chloride are added and the mixture is cooled to 0 ° C. and a solution of 3 g of triethylamine and 3 g of trimethoxybenzoyl-4-amino-1-piperazine 60 in 20 ml of methylene chloride. The mixture is stirred for 24 h at room temperature, then washed with a 10% aqueous sodium hydroxide solution, then with water, dried and the excess solvent is removed. 7.2 g of an oily product are obtained.

IR (film): 3380 cm 1 and 3240 cm 1 1650 cm "1 and 1620 cm-1

(NH) (CO)

The hydrochloride is obtained by treatment with HCl in hydroalcoholic solution. F = 225 C.

5

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Analysis for C ^ H ^ NsOs • HCl P.M.: 611:

Calculated: C 62.87 H 6.92 N 11.46%

Found: C 62.24 H 6.95 N 11.18%

h) Preparation of ethyl-1-carboxy-1-indolo (2,3-a) -quinolizi-

dine (12b-H; 1-Q> HS cisisomèré)

In a solution of 6.8 g of ethyl-1-ethoxycarbonyl-1-indole (2,3-a) quinolizidine (12b-H; 1-C2H5 cisisomerized) obtained in Example d, in 100 ml of ethanol at 95%, 6.8 g of potassium hydrate are added. The mixture is brought to reflux for 12 h, the solvent evaporated under reduced pressure, and the residue taken up in ice water and acidified with HCl until a pH = 4.5 is reached. The product precipitates, is separated, washed and dried. 4.1 g of acid are thus obtained.

Analysis for C18H22N202 P.M. = 298.37:

Calculated: C 72.45 H 7.43 N9.37%

Found: C 72.61 H 7.49 N 9.20%

IR 1620 cm-1 v CO, OH associated.

i) Preparation of ± D-noreburnamonin

1) (C0C)

2) NaOH aq.

HOOi

Was added dropwise to a suspension of 6 g (0.0179 mol) of ethyl-1-carboxy-1-indolo (2,3-a) quinolizidine (12b-H; 1-C2HS cisisomerized) of 1 step h above in 60 ml of dry benzene, 30 ml of oxalyl chloride. The suspension is stirred for 2 h at room temperature, then brought to reflux for 9 h. The solvents are removed under reduced pressure and the residue is taken up in methylene chloride with stirring, in the presence of dilute sodium hydroxide. The organic solution, washed with water, dried over sodium sulfate, evaporated under reduced vacuum, gives 4.25 g of the desired product. Yield 83%.

After washing on an alumina column, 3.25 g of beige crystals are obtained. M = 136 ° C. (Diisopropyl oxide.)

IR (KBr): 2805, 2845, 1735, 1660 cm- '.

Analysis for CI8H20N20 = 280.96:

Calculated: C 77.11 H 7.19 N 9.99%

Found: C 77.54 H 7.78 N 10.09%

H, NMR (CDC13) int reference. TMS 8 XMS = Û 7.9-7.7 (m) aromatic; 7.5-7.05 (m) 3H aromatic; 4.3 (m) 1H; 1.1 (t) CH, -CH „

Hydrochloride

To a solution of 3.25 g of base in 30 ml of absolute alcohol, the necessary quantity of 7N aqueous HCl is added. Solvents are

evaporated under reduced pressure at 30 ° C and the residue, taken up in acetone, gives 3.32 g of white crystals. Mp 264 ° C.

IR (KBr): 3400, 2470, 2320, 1740, 1680 cm -> C13 NMR (D20) dioxane reference 8 ppm 107.426 C = 0; —13.712 CH; -82.162 CH.

Example 2:

a) Preparation of [(2-cyano-2-ethyl-2 "-5-chloro-5-valeroyl-amino) -2" -ethyl] -3-indole

In a 11 flask, 31 g (0.0194 mol) of tryptamine, 500 ml of dichloromethane and 20 g (0.0198 mol) of triethylamine are placed. The mixture is cooled to 0 ° C. on ice and 40 g (0.192 mol) of cyano-2-ethyl-2-chloro-5-valeroyl chloride dissolved in 150 ml of methylene chloride are added. After 2 h at room temperature, the mixture is washed with water, then with 10% hydrochloric acid, then with 10% sodium hydroxide. It is then dried and the solvent is removed. The product, recrystallized from an isopropyl ether / petroleum ether mixture, melts at 120 ° C. (yield 40g). The results of the analysis are as follows:

IR (KBr): 3400 cm "1 NH indole

3340 cm ~ 1 NH amide

2860 cm-1 CN

1660 cm-1 C-N

II

O

Analysis for Ci8H22N3C10:

Calculated: C 65.00 H 6.64 N 12.65%

Found: C 64.03 H 6.78 N 12.60%

b) Preparation of [(indole-2 '~ yl-3 "-ethyl) ethyl-3-cyano-3] -l-piperidone-2

22 g (0.0665 mol) of the product from step a above, 200 ml of tetrahydrofuran, and 300 ml of t-butanol are placed in an 11 round flask. The mixture is cooled to 0 ° C. on ice and 8.5 g (0.076 mol) of potassium tert-butoxide are added in small amounts. After 2 hours of stirring at room temperature, the mixture is concentrated and hydrolyzed. The organic phase is extracted with methylene chloride, washed with water, dried and the solvent removed. The desired product, recrystallized from ethanol / ether 50/50, melts at 180 ° C (yield 15 g, 80%). The results of the analysis are as follows:

IR: 3400 cm ~ 1 NH indole 2260 cm-1 CN 1635 cm-1 C-N

II

O

Analysis for CI8H23N30:

Calculated: C 73.20 H 7.10 N 14.20%

Found: C 72.46 H 7.15 N 14.01%

c) Preparation of ethyl-1-cyano-1-didehydro-5, I2b-indolo (2,3-a) - quinolizidinium perchlorate

In a 11-flask, 50 g (0.169 mol) of the product from step b above and 700 ml of phosphoryl chloride are placed, with stirring. After having heated under reflux for 20 h, the mixture is concentrated and extracted 2 or 3 times with 500 ml of methylene chloride which is then removed. The product is then taken up in 300 ml of methylene chloride and cooled on ice, and 300 ml of a solution of lithium perchlorate (1 mol) are added with vigorous stirring. A yellow precipitate forms which, recrystallized from methanol, melts at 260 ° C. Yield 44 g, 70%. The results of the analysis are as follows:

IR: 3400 cm "1 NH indole 2260 cm-1 C = N 1620 cm" 1 C = N ©

5

10

15

20

25

30

35

.40

45

50

55

60

65

641181

6

NH and Bohlmann bands d) Preparation of ethyl-1-cyano-1-indolo (2,3-a) -quinolizidine (12b-H; 1-QHs transisomer)

In a 11 round flask, 200 ml of methanol, 100 ml of methylene chloride and 13.5 g (0.036 mol) of the perchlorate from step c above are placed. The flask is cooled to about 5 ° C and 5 g of sodium borohydride are added in small amounts. The solution is then stirred for 2 h at room temperature, concentrated, washed with water, and extracted with methylene chloride. After having dried and removed the solvent, 8 g of yellow crystals are obtained which, recrystallized from isopropyl ether, melt at 160 ° C. (yield 80%). The results of the analysis are as follows:

IR: 3420 cm-1 3440 cm-1 2760 cm-1 2800 cm-1 2250 cm-1 CN

NMR (dimethyl sulfoxide d6, 80 MHz):

0.86 S 3H (t) (CHa)

3.77 8 1H (s) (H in C9a)

9.66 6 1H (s) (NH)

Analysis for C18H2iN3:

Calculated: C 77.70 H 7.20 N 15.20%

Found: C 77.55 H 7.32 N 15.10%

e) Preparation of ethyl-1-cyano-1-indolo (2,3-a) quinolizidine (12b-H; 1-QH5 cisisomerized)

19 g of the perchlorate from step c above, 300 ml of 95% ethanol and 40 g of zinc powder are placed in a 11-flask. 100 ml of concentrated hydrochloric acid are added to an ampoule. A slight reflux can be observed during the addition of the acid. The mixture is left to stand at room temperature for 10 h. It is then concentrated, washed with water and extracted with methylene chloride. It is alkalized with soda and filtered through celite. After decanting, drying and evaporating the solvents, 6 g of a product, insoluble in ether, melting at 250 ° C. are obtained. The results of the analysis are as follows:

IR: 3410 cm "1 2260 cm" 1

The CN peak at about 2250 cm 1 is absent.

Analysis for C1SH25N3:

Calculated: C 76.40 H 8.85 N 14.80%

s Found: C 75.85 H 8.90 N 15.52%

g) Preparation of ethyl-1-aminoethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-QHS cisisomèré I)

3.4 g of aluminum / lithium hydride, 200 ml of ether and 100 ml of tetrahydrofuran are poured into a 500 ml flask. By re-cooling on ice, 6.9 g of the cisisomer of step e above is added in small amounts. After having left the product to stand for 15 h at room temperature, the product is isolated, as in step f above. After recrystallization from a 50/50 ethyl ether / petroleum ether mixture, 5 g of a melting product 15 at 125 ° C. are obtained (yield 71%).

Analysis for C, sH2sN3:

Calculated: C 76.40 H 8.85 N 14.80%

Found: C 76.25 H 8.61 N 14.43%

20 Example 3:

Preparation of ethoxycarbonylaminoethyl-1-ethyl-1-indolo (2,3-a) quinolizidine hydrochloride (12b-H; 1-QHs transisomer II)

• HCt

30

(NH)

(CN)

Analysis for C18H21N • l / 4H20:

Calculated: C 76.50 H 7.60 N 14.85%

Found: C 76.59 H 7.80 N 14.55%

The ether extracts are concentrated to give 4 g (total yield: 71.5%) of the cisomer of the same product as that of step d above.

NMR (dimethyl sulfoxide d6, 80 MHz):

1.05 8 3H (t) (CHa)

3.45 8 1H (s) (H in C%)

10.32 8 1H (NH)

0 Preparation of ethyl-1-aminoethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-Qß5 transisomer II)

In a 11-flask, 4 g of aluminum / lithium hydride and 400 ml of dry ether are placed. The flask is cooled to 0-5 ° C, and 8.9 g of the product from step d above is added in small quantities. After allowing the flask to stand for 1 h at room temperature, 60 ml of dry tetrahydrofuran are added. The mixture is heated at reflux for 2 h. After having cooled it, 40 ml of water are added dropwise, then 200 ml of methylene chloride. The mixture is stirred for 15 min. After filtering through celite, drying and concentrating the filtrate, 7.2 g of white crystals are obtained which, recrystallized from ether, melt at 175 ° C (yield 80%).

The results of the analysis are as follows:

C2H5O.CO.NH '

To a solution of 2 g (0.00705 mol) of the trans II derivative of example 35 p 2 f in 20 ml of dimethoxyethane, cooled to 0 ° C., parts are added alternately, in order to maintain the basic pH. of:

800 mg of ethyl chloroformate dissolved in 5 ml of dimethoxyethane, and

750 mg of baking soda in solution in 5 ml of water. After allowing the mixture to stand for 3 h at room temperature, the product is extracted with methylene chloride, the extract, washed with water, dried, is evaporated to dryness. The product is recrystallized from ethanol.

Weight: 2 g Yield: 80% F .: 140 ° C 45 3210 cm "1 NH amide

3400 cm "1 indole NH

2760 and 2800 cm-1 Bohlmann strips 1690 cm-1 carbamateC = 0

50

55

The results of the microanalysis are as follows:

Analysis for C21H29N30:

Calculated: C 71.00 H 8.17 N 11.80%

Found: C 70.94 H 8.16 N 11.54%

The hydrochloride is formed from 2 g of the above product, by adding 4N HCl in 20 ml of ethanol. Weight: 2 g; Yid: 90%. Mp 260 ° C.

Example 4:

Preparation of D-homoazaëburnamonine hydrochloride

.Hce

IR: 3280, 3190 cm "1 3350 cm" 1

NH2

NH indole

7

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First, phenoxycarbonylaminomethyl-1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-C2H5 transisomer) is prepared according to the method of Example 3, but replacing the chloroformate ethyl with phenyl chloroformate.

To a solution of 8 g (0.02 mol) of the product, thus obtained in 250 ml of tetrahydrofuran, 2 g of 50% sodium hydroxide are added. After stirring for 90 min, the product is extracted with ethyl ether, washed with water and dried. The ethyl ether is evaporated to leave. 5 g of an oil, the analysis of which gives the following results:

3200 cm ~ 1 amide NH 1670 cm-1 amide C = O

NMR (CC14; int. Reference TMS):

0.65 S (3H, t, CH3 — CH2)

1 to 3.2 8 (15 solid protons)

3.3 8 (1H, s, angular proton 12b-H) 7.2 5 (solid 3H aromatics)

8.1 8 (aromatic 1H solid)

The hydrochloride is prepared by treating the above oil with hydrochloric acid in 20 ml of ethanol, then centrifuging. The yield is 60%, calculated on the starting amine (II). Mp 260 ° C. The product precipitates with lA mol of water of crystallization.

The results of the microanalysis are as follows:

Analysis for C19H23N30 • HCl • 0.5H20:

Calculated: C 64.50 H 7.05 N 11.80%

Found: C 64.38 H 7.11 N 11.62%

Example 5:

Preparation of (trimethoxy-3 ', 4', 5'-benzoylamino-methyl) -! - indolo (2,3-a) quinolizidine (12b-H; 1-QHS trans-isomer II), hydrochloride

CH, 0

■ CO-NH-CH

CH-0

2.85 g of the trans II derivative of Example 2 f, 1 are added to a 250 ml three-necked flask, fitted with an agitator, a CaCl 2 guard, a thermometer and a dropping funnel. 1 g of triethylamine and 50 ml of methylene chloride.

The mixture is well stirred and then cooled to 0-2 ° C. At this temperature, 2.31 g of trimethoxy-3,4,5-benzoyl chloride are slowly added in 15 ml of methylene chloride. The addition takes place in 15 to 20 min, after which the mixture is stirred for 1 h at 0 ° C, then for 15 h at room temperature.

The mixture is then washed several times with water, then with 10% aqueous sodium hydroxide and again with water. It is dried over sodium sulphate and concentrated to form a non-crystalline mass, having the texture of a meringue and melting at approximately 100 ° C.

CCM: 90/10 8/10

IR: 3230 cm-1 NH

3190 cm-1 NH

2750 and 2800 cm -1 Bohlmann bands 1640 cm-1 C = O amide

Base dosage with HC104: 97%

To prepare the hydrochloride, the above product is dissolved in a 1: 1 mixture of diisopropyl ether and isopropanol, then 4N hydrochloric acid is added. The hydrochloride precipitates hot, filtered hot and washed with ethanol; 4.5 g (88% yield) of the desired product are obtained.

CCM: 90/10 8/10 F: 210 ° C

Hydrochloride dosage: 100% (1 function).

Microanalysis gives the following results:

Analysis for C28H35N304- HCl:

Calculated: C 65.45 H 7.00 N 8.18%

C 64.34 H 7.17 N8, ll%

C 64.15 H 7.16 N 7.96%

Example 6:

Preparation of [(N'-diethylaminoethyl) -N-ureidomethyl / -

1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-QHS trans isomer II)

(C „H,) 0N-CH-CH0-NH-CONHCH

First, the corresponding derivative of phenoxy-

carbonylaminomethyl-1-ethyl-1, 7 g of the trans II derivative of Example 2 f and 100 ml of tetrahydrofuran are placed in a 500 ml three-necked flask fitted with an agitator and two dropping funnels. The flask is cooled to 0-5 ° C. and, at this temperature, 4.25 g of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium bicarbonate in 50 ml of water are simultaneously added (the amounts added were calculated to maintain pH 6-7). The mixture is then allowed to warm to room temperature, and the mixture is continued to stir for 3 h.

The product is extracted with 100 ml of methylene chloride, and the extract is washed several times with water before being dried with sodium sulfate and concentrated by evaporation. 11 g of the product, which is an oil, are obtained.

IR: 3270 cm-1 NH 1710cm-1 C = 0

The ureidomethyl-1 product is prepared as follows:

11g of the above oil, 3.5 g of dimethylaminoethylamine and 180 ml of methanol are placed in a 500 ml flask fitted with a condenser. The amount of dimethylaminoethyl used corresponds to an excess of 20%. The mixture is heated at reflux for 2.5 h, then the methanol is removed by evaporation. The residue is taken up in methylene chloride, washed with 10% sodium hydroxide, then with water. After drying over sodium sulfate, it is concentrated, which gives yellowish crystals. The product is then taken up in two times with ethyl ether and centrifuged. The first step gave 4.6 g of crystals melting at 202 ° C, and the second step gave 0.8 g of crystals melting at 198 ° C. The combined products are then recrystallized from benzene to give 4.65 g of the final product.

M: 204 ° C Yield 45% based on amine (II).

CCM: 90/10 5/10

Dosage of the base with HC104: 100% (2 functions).

IR: 3360 cm-1 NH 3250 cm-1 NH 1620 cm-1 C = Urea

Microanalysis gives the following results:

Analysis for C25H39N50:

Calculated: C 70.60 H 9.17 N 16.45%

Found: C 70.58 H 9.20 N 16.67%

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Example 7;

Preparation of pentanoylaminomethyl-1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-QHs transisomer II)

ch, - (ch0), - co-nh-ch;

Using conditions and techniques identical to those of Example 5, a solution of 5.7 g of the trans derivative of Example 2 f and 2.1 g of triethylamine in 120 ml of methylene chloride is reacted, and a solution of 2.45 g of pentanoyl chloride in 20 ml of methylene chloride.

7.8 g of an oil are thus obtained which contains a little triethylamine residue.

IR: 3180-3380 cm-1 NH 1630-1650 cm "1 C = 0

From the oil, it was possible to obtain crystals of the product, melting at 110 ° C., the analysis of which showed the correspondence with the formula.

Example 8:

Preparation of pentylaminomethyl-1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-QHS transisomer II)

ch, - (ch.,). -nh-ch ',

100 ml of anhydrous ethyl ether are placed in a 500 ml three-necked flask, fitted with an agitator, an ascending cooler, a thermometer and a dropping funnel. After cooling on an ice bath, 4 g of lithium hydride are added, and the contents of the flask are stirred for 15 min. Then a solution of 7.4 g of the product of Example 7 in 50 ml of anhydrous ethyl ether is added very slowly. The mixture is then heated at reflux for 2 h and stirred for a further 15 h at room temperature. It is then cooled on an ice bath and 20 ml of water are added dropwise, followed by 150 ml of methylene chloride. The mixture is filtered through celite, dried over sodium sulfate and concentrated by evaporation. 7 g of an oil are obtained, which can be crystallized to form a product which melts at 80 ° C.

Recrystallization from the minimum amount of isopropanol gives 4.3 g of a crystallized product, melting at 91 ° C.

Dosage of the base with HC104: 100% (2 functions). Microanalysis gives the following results:

Analysis for C23H3SN3:

Calculated: C 78.20 H 9.92 N 11.90%

Found: C 78.18 H 9.81 N 12.00%

Basic IR: 3310 cm ~ 1 NH 1620 cm "1 C = 0

Dimaleate

The acid addition salt is prepared with maleic acid in solution in a mixture of isopropanol and diisopropyl ether. Initially, the salt appears as an oil, but can be recrystallized from ethyl acetate to give 6.7 g of dimaleate, melting at 105 ° C.

Determination of dimaleate with HC104: 99.6% (2 functions).

Rf: 90/10 9/10

Example 9:

Preparation of guanidinocarbonylaminomethyl-1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-Ç, H5 transisomer), dimaleate nh l-nhconh— '

9 g of the compound prepared in Example 3, 2.2 g of guanidine base (released from 3 g of hydrochloride by the ethylate / ethanol pair) are placed in 120 ml of ethanol in a 250 ml flask. heated at reflux for 48 h.

The solvent is evaporated to dryness and the residue taken up in a water / methylene chloride mixture. Filtered through celite and decanted, then the organic phase is washed, first with water, then twice with a 5% acetic acid solution. Acidic waters are alkalized with sodium bicarbonate in the presence of ether. The ethereal phases are dried and evaporated. 6.4 g of meringue are obtained which is chromatographed on silica (60 g of silica: eluent CH2Cl2 / MeOH 80/20).

After separating 0.7 g of a first product, a second product is isolated and crystallized from ether.

3.5 g F: 150 ° C

IR (KBr): 3200-3400 cm ~ 1 wide and strong bands (v NH) 1600 cm ~ 1 broad band (v C = O)

The dimaleate is prepared in isopropanol. TLC (Merck F 254 plate: eluent acetone: 30, CHC1: 30, n butanol: 30,

NH4OH: 10) 25%

Rf = 0.4 1 spot

Microanalysis for C20H28N6O + C8H8O8 M = 600:

Calculated: C 56.00 H 6.00 N 14.00%

Found: C 56.07 H 6.46 N 12.59%

Example 10:

Preparation of D-homo-14-azaéburnamonine (12b-H;

1-CJI5 cisisomèré I)

'nh.

"

The same process is used as in Example 4, except that one starts from the eis I derivative of Example 2 g instead of the trans II derivative of Example 2 f. 5.7 g of product are obtained (yield 69%). Mp 190 ° C.

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IR: 3260 cm-1 NH 1690 cm "1 C = 0

Microanalysis gives the following results:

Analysis for C19H23N30:

Calculated: C 73.80 H 7.45 N 13.60%

Found: C 73.48 H 7.35 N 12.99%

The hydrochloride is obtained by adding 4N HCl to a solution of the base in a 1/1 mixture of ethanol and ethyl ether.

Example 11:

Preparation of ethoxycarbonylaminomethyl- 1-ethyl-1-indolo (2,3-a) quinolizidine (12b-H; 1-Ç> HS cisisomèré I), hydrochloride

HCt

C-HçC-CO-NH-CH '{

The process of example 3 is repeated, except that the derivative eis I

of example 2 g is used instead of the trans derivative II of example 2 f. 2.1 g of free base are obtained. (Yield 84%.) M = 210 ° C.

3400 cm "1 indole NH

3210 cm "NH amide

2790 and 2810 cm "1 strip by Bohlmann

1690 cm "1 carbamate C = O

Microanalysis gives the following results:

Analysis for C21H29N302:

Calculated: C 71.00 H 8.17 N 11.82%

Found: C 70.85 H 8.22 NI 1.94%

NMR (CDC13; int. Ref. TMS):

1.15 (6H, t, CH3 ethyl and ethyl ester)

1.5 to 3.5 S (15H, solid)

3.9 8 (2H, q, CH, Q)

5.65 6 (1H, m, NH-amide)

7.25 8 (4H, solid, aromatic)

7.9 5 (1H, s, NH-indole)

The hydrochloride is obtained by the action of 4N hydrochloric acid in acetone. Yield: 90%; Mp 250 ° C.

Example 12:

Preparation of [N '- (diethylaminoethylated) N-ureidomethyl] -1 ethyl-1-indolo (2,3-a) quinolizidine (12b-H; I-C2HS cisisomerized I)

<c2H5) 2NCH2CH2NH-CO-NH-CH

The procedure is first as in the first part of Example 6, using the eis I derivative of Example 2 g instead of the trans II derivative of Example 2 f.

The procedure is then carried out as in the second part of Example 6, but on a smaller scale, using 3 g of the phenoxycarbonylaminomethyl derivative-1.1.2 g of diethylaminoethyl amine, and 50 ml of methanol. 2.8 g of the desired product, which is an oil, are thus obtained.

Its dihydrochloride is obtained by the action of 4N hydrochloric acid in acetone. The salt is isolated by concentrating the acetone solution and recrystallizing the latter from a 1/1 mixture of ethyl acetate and ethanol.

1.8 g of a product are obtained which melts at 250 ° C. Yield: 48.5% relative to the starting amine.

IR: 3300 cm "1 1640 cm-1

Microanalysis gives the following results (with 1 mol of water of crystallization):

Analysis for C25H39NS0-2HC1-H20:

Calculated: C 58.30 H 8.35 N 13.74%

Found: C 58.56 H 8.25 N 13.60%

Toxicity:

The LD 50 was determined per os on mice. The compounds of the invention have a toxicity comparable to that of vincamine, or lower. The most toxic (LD 50: 400 mg / kg: vincamine 450 mg / kg) are those of Examples 2 f, 3 and 4; the least toxic are those of Examples 5, 10 and 12, while the remaining compounds exhibit intermediate toxicity.

Pharmacology:

The activity of the compounds of the invention has been sought in the field of action on the femoral and vertebral flow rates, the blood pressure and the heart rate. A comparison was made with vincamine and with the compounds described in the French patent publications Nos 2285377 and 2292475. The experiment carried out according to the same techniques as vincamine has shown that the compounds of the invention, and more particularly those of examples 3 and 5:

a) cause a large increase in femoral flow; the compounds described in French patent publications have a similar action, but vincamine reduces this flow rate;

b) cause a large increase in vertebral flow; the compounds described in French patent publications do not act at all or cause a moderate increase, while vincamine reduces this flow rate;

c) do not significantly affect arterial blood pressure, while the comparison compounds reduce it;

d) cause a slight increase in the heart rate, while the compounds described in French patent publications generally cause a greater increase and vincamine reduces this factor.

From these results, the compounds of the present invention appeared to have a very favorable action in the field of cerebral irrigation, which has been confirmed clinically.

Dosage:

The compounds of the present invention can be administered i.v. or per os in doses comparable to those used for vincamine (dosage units containing from 5 to 40 mg).

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Claims (3)

641181 2 1. Indolo (2,3-a) quinolizidines corresponding to the following formulas (I) and (II): in which R represents a —COOC2H5, - COOH, —CN radical, a primary or secondary methylenamino radical, a methylenamido group or, with the nitrogen of the indolo nucleus, an N-CO-NH-CH2 orN-CO- group, as well as the therapeutically acceptable acid addition salts of these bodies. 2. Process for the preparation of the compounds according to claim 1, comprising: - the condensation of amino-2 ethyl indole-3 on chloro-1 (A) -4 chlorocarbonyl-4 hexane, in which A represents a radical —C00C2H5 or - CN, to form the corresponding amide; - the treatment of this amide under strongly basic conditions in order to eliminate HCl and to carry out the formation of the cycle on the nitrogen atom in position -3 of the indole; The formation of the quinolizidine cycle of the above product, by treating it first with a dehydrating agent, then with a perchlorate; The hydrogenation of quinolizidinium perchlorate to obtain the mixture of indomers of indolo (2,3-a) quinolizidine, and - separation of isomers. 3. Therapeutic composition in which at least one of the active ingredients consists of one of the compounds according to claim 1, combined with any excipient suitable for the chosen mode of administration.