FR2478639A1 - Antiinflammatory indolizino indole(s) - having cerebral vaso:regulating and oxygenating properties - Google Patents

Abstract

Indolizino (8,7-b) indoles of formula (I) their isomers, mixts. of isomers, and acid addition salts are new. In(I) R1-R2 are H, or 1-4C alkyl; R3 is H, halogen, 1-6C alkyl, 1-6C alkoxy, OH, or CF3; R4 is H or acyl. (I) are used as cerebral vasoregulators and oxygenators, and antiinflammatories. (I) are prepd. by reducing a cpd. of formula (II) (where R is lower alkyl) and acylating the reduced cpd.

Description

 The present invention relates to novel indolizino (8,7-b) indole derivatives, to their process of preparation and to their applications in human and veterinary medicine.

dans laquelle
R1 et R2 représentent, indépendamment l'un de l'autre, l'hydro
gène ou un groupe alcoyle en C1 à C4 ;
R représente l'hydrogène, un halogène, notamment un fluor,
un groupe alcoyle ou alcoxy en C1 à C6, un groupe hydro
xy ou trifluorométhyle ,
R4 représente l'hydrogène ou un groupe acyle, notamment
alcanoyle en C1 à C6.The derivatives of the invention correspond to the formula

in which
R1 and R2 represent, independently of one another, the hydro
gene or a C1-C4 alkyl group;
R represents hydrogen, a halogen, especially a fluorine,
a C1-C6 alkyl or alkoxy group, a hydro group
xy or trifluoromethyl,
R4 represents hydrogen or an acyl group, in particular
C1 to C6 alkanoyl.

 The compounds of the invention have two asymmetric carbon atoms (Cl and Cl) and formula (I) above represents the four possible stereoisomers: cis-d, cis-1, trans-d and trans-1.

 Accordingly, the invention relates to each stereoisomer as mixtures d-1 of the same diastereoisomer.

 The invention also relates to addition salts with pharmaceutically acceptable inorganic or organic acids.

The subject of the invention is also a process for the preparation of the claimed compounds, characterized by the following reaction sequence
Stage 1.

 A tryptamine of formula (II) (R = H) is condensed in which R 3 has the above meanings with 4-bromo-ethyl butyrate thus obtaining the lactam (III) (R 2 = H) (K. Nagarajan, Ch. Weissmann , H. Schmid and P. Parrer, Helv.- Chim.

Acta., 1963, 46, 1212).

 The condensation is carried out by heating under reflux in an inert solvent such as toluene, dimethylformamide, a lower alkanol, especially amyl alcohol or, preferably, methoxyethanol, in the presence of an alkali metal carbonate, such as sodium carbonate or potassium carbonate.

The lactam (III) (R = H) can be condensed with an alkoxylating agent of formula R2X (IV) in which R2 (96H) has the above meanings and X is a halogen, a methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, alkylsulphonyloxyoxy group. of formula -OSO2R, or alkyloxycarbonyloxy of formula -OCOOR, thus obtaining a lactam of formula (III) in which R2 is different from hydrogen.

 The condensation is carried out by heating under reflux in an inert solvent, such as dimethylformamide, dimethylsulfoxide or a lower alkanol, especially ethanol, in the presence of a base, such as an alkali metal hydride, especially hydride. sodium hydroxide, an alkali metal alcoholate, especially sodium methoxide or sodium ethoxide or potassium tert-butoxide, an alkali metal carbonate, such as sodium or potassium carbonate or an alkali metal hydroxide, such as sodium hydroxide, sodium or potassium hydroxide.

Stage 2

ou
- les composés (VIb) à partir des lactames (III) pour lesquels R2 est différent de l'hydrogène

The lactam (III) is treated with a strong base, such as lithium diisopropylamide, and then condensed with a chloroformate of formula ClCOOR (V), in which R is a lower alkyl group (C1 to C12) thus obtaining
a separable mixture of compounds (VIa) and (VIIa) from lactams (III) for which R is hydrogen

or
compounds (VIb) from lactams (III) for which R2 is different from hydrogen

 Lithium diisopropylamide is formed "in situ" by addition at -780C, of a hexane solution of butyllithium to a solution of diisopropylamine in tetrahydrofuran. The lactam (III) and the chloroformate (V) are successively added to the medium at the same temperature.

Compound (VIa) can be selectively obtained from the corresponding lactam (III) (R2 = H) using a variant of replacing the chloroformate (V) with carbon dioxide. The acid (VIII) thus obtained can then be esterified by simple treatment at room temperature with a hydrochloric or sulfuric solution of the alcohol ROH. Ester (VIa) (R = CH 3) can also be obtained directly by treating the dianion from (III) (R 2 = H) by the stoichiometric amount of dimethyl carbonate.

The introduction of a substituent R 1 other than hydrogen may be carried out at this stage of the condensation synthesis of compounds (VIIa) and (VIb) with a halide of formula
R1X wherein R1 has the above meanings and X is halogen, thereby obtaining derivatives (VIIb) and (VIc) respectively.

(VIc) (R1 = R2). Finally, the direct alkylation of (VIa) under the same conditions leads to the derivative (VIc) in which R1 = R2

(VIc) (R1 = R2).

 The reaction is carried out in an inert solvent, such as dimethylformamide, tetrahydrofuran or a lower alkanol, especially tert-butanol, in the presence of a base, such as an alkali metal hydride, especially sodium hydride, an alkoxide alkali metal, especially sodium methylate and ethoxide and potassium tertiobutylate, or an alkali metal carbonate, especially sodium and potassium carbonates. The reaction temperature is between 100C and the boiling temperature of the chosen solvent.

The compound (VIIb) can be converted into a derivative (VIc) (R2 = H) by saponification by heating with a hydroalcoholic solution of sodium hydroxide followed by re-esterification, at room temperature, in a hydrochloric or sulfuric solution of the alcohol ROH

Stage 3.

The compounds (VIa, b, c) grouped under the general formula (VI) lead to the cyclized derivatives (X) by treatment with phosphorus oxychloride.

 The reaction is carried out either in an inert solvent such as methylene chloride, chloroform or acetonitrile with an excess of phosphorus oxychloride, or using the latter as a solvent. The reaction temperature is between 150C and the boiling temperature of the mixture.

The compound (X) or the corresponding perchlorates can be directly used in the next step, but those for which R1 is hydrogen can be substantially converted to enamine (XI) by treatment with ammonia or a hydroxide. of alkali metal, such as soda or potash.

Stage 4.

The reduction of immonium (X) leads to a mixture of cis and trans esters (XII).

 Similarly, the reduction of enamine (XI) leads to cis and trans (XII) (R1 = H).

The stereoselectivity of the reaction strongly depends on the experimental conditions used
The reduction of (X) or (XI) is by hydrogen in acetic acid in the presence of palladium on carbon, or by sodium borohydride in acetic acid, or in methanol mixed with small amounts of 12N hydrochloric acid, preferably leads to the isomer (XII) cis.

 On the other hand, the reduction of these same compounds (X) and (XI) by powdered zinc in acetic acid preferentially provides the trans isomer (XII).

 These cis (XII) and trans (XII) diastereoisomers can be easily separated by silica column chromatography.

It is also possible to benefit from the insolubility in the ethyl ether of the cis isomer in order to rid it of its isomer.

 It is also possible to convert all the cis isomer (XII) into trans isomer (XII) by epimerization, at room temperature, in a solution of the RONa + alcoholate in ROH alcohol.

Stage 5.

The reduction of the esters (XII) with lithium aluminum hydride in tetrahydrofuran at room temperature leads to the claimed alcohols (I) (cis) and (I) (trans).

 These alcohols (XII) can be acylated by treatment with acid anhydrides of formula (R4CO) 2 or acid chlorides of formula R4COC1.

The cis structure of one of the diastereoisomers was determined by X-ray spectrography. The enantiomers d and 1 of each diastereoisomer can be separated by conventional resolution techniques, for example by fractional crystallization of tartrates, dibenzoyl-tartrates or diparatolyl-tartrates or more conveniently, by separation of the diastereoisomeric esters obtained by treatment of the mixtures dl with the chloride of one of the enantiomers of Mosher's acid, (JA Dale,
DL Dull and HS Mosher, J. Org. Chem., 1969, 34, 2543), for example, (-) - (-) - methoxy-α-trifluoromethyl phenylacetic acid, followed by regeneration of the optically active alcohols by basic hydrolysis.

The following experiments and examples illustrate the invention
EXPERIMENT 1 [(indolyl-3) -2-ethyl-1-pyrrolidinone-2
Derivative (III) (R2 = R3 = H).

 A mixture of 100 grams (0.64 moles) of tryptamine, 34 grams (0.32 moles) of sodium carbonate and 1250 cm3 of 2-methoxy ethanol is refluxed. 21.7 grams (0.624 mole) of ethyl bromo-4-butyrate are added dropwise to the reaction medium.

 Reflux is maintained for 24 hours. After cooling, the reaction mixture is concentrated to dryness, taken up in water and extracted with methylene chloride. The decanted organic extracts are washed with 2N hydrochloric acid, dried over sodium sulfate and concentrated in vacuo.

 91 grams (yield: 65%) of cream crystals are collected, F. = 138 C.

EXPERIMENT 2 E (1-methyl-3-indolyl) -2-etahyl] -1-pyrrolidinone-2
Derivative (III) (R2 = Me, R3 = H).

Procedure a.

 5.76 grams (0.12 moles) of sodium hydride (d 50% in oil) are washed several times with anhydrous tetrahydrofuran. The suspension is suspended in 20 cm3 of anhydrous dimethylformamide and a solution of 25 grams (0.11 mol) of [(indolyl-3) -2-ethyl] -1-pyrrolidinone-2 derivative (III) (experiment 1) is added. in 40 cm3 of anhydrous dimethylformamide. Stirring is carried out at room temperature for 1 hour. A solution of 16.7 grams (0.12 mole) of methyl iodide in 20 cm3 of anhydrous dimethylformamide is then added dropwise. After stirring for three hours at room temperature, the reaction medium is evaporated to dryness. The residue is taken up in water and extracted with methylene chloride.

 The organic extracts are dried over sodium sulfate and concentrated in vacuo. 13.4 grams (yield 50%) of cream crystals are obtained, mp = 86-880 ° C.

Procedure b.

 Anhydrous tetrahydrofuran (2.65 grams, 53 mmol) of 50% sodium hydride was washed several times with anhydrous tetrahydrofuran in the oil.

The suspension is suspended in 30 cm3 of anhydrous tetrahydrofuran and a solution of 10 grams (44 mmol) of [(indolyl-3) -2-ethyl-1-pyrrolidone-2 (experiment 1) is added dropwise to 90 cm3 of anhydrous tetrahydrofuran. Stirring at room temperature for 1 hour, 4.5 cm3 (53 mmol) of dimethylcarbonate dissolved in 10 cm3 of anhydrous tetrahydrofuran and refluxed for 6 hours.

 The reaction medium is evaporated to dryness, the residue is taken up in water and extracted with methylene chloride.

 The organic extracts are dried over sodium sulfate and concentrated in vacuo.

 9.26 grams (yield: 87%) of cream crystals are recovered, mp = 86-880 ° C.

EXPERIMENT 3 [k (indolyl-3) -2-ethyl] -1-oxo-2-pyrrolidin-3-methyl carboxylate
Derivative (VIa) (R = H, R = CH3) and methyl [(methoxycarbonyl-1-indolyl-3) -2-ethyl-1-oxo-2-pyrrolidin-3-carboxylate
Derivative (VIIa) (R = H, R = CH3).

 A solution of 13.8 cm3 (0.092 mole) of anhydrous diisopropylamine in 50 cm3 of dry tetrahydrofuran was cooled to -780C.

45.3 cm3 (0.092 mole) of a solution of 13% n-butyl lithium in hexane are added dropwise. After stirring for 15 minutes, a solution of 10 grams (0.044 mol) of derivative (III) (R 2 = R 3 = H) (experiment 1) in 300 cm 3 of tetrahydrofuran is added and then, after 30 minutes of stirring, 6, 23 grams (0.092 moles) of methyl chloroformate. It is further stirred at -7 ° C. for one hour, the cooling is stopped and 250 ml of water and 250 cm 3 of methylene chloride are added to the reaction mixture.

 The aqueous phase is decanted and extracted with methylene chloride. The organic fractions are combined, dried over sodium sulphate and concentrated in vacuo.

10.2 grams of a brown oil are obtained, a mixture of four separable compounds by chromatography on a silica column.
derivative (VIa) (R3 = H, R = CH3)
derivative (VIIa) (R3 = H, R = CH3)
- derivative (III) (R3 = H, R2 = COOCH3)
derivative (III) (R 2 = R 3 = H) starting product.

 The mixture of the derivatives (VIa) and (VIIa) is suitable for the following operations and obtaining the final derivatives XII (R1 = R2 = R3 = H).

 EXPERIMENT 4 Methyl [1-methylindol-3-yl] -2-ethyloxo-2-pyrrolidin-3-carboxylate.

Derivative (VIb) (R = R2 = CH3, R3 = H).

 Prepared according to the procedure of Example 3 from the derivative (III) (R 2 = Me, R 3 = H) (experiment 2) this compound was obtained in the form of an oil (yield: 52%) after column chromatography of silica.

EXPERIENCE 5
[(3-Indolyl) -2-ethyl] -1-oxo-2-pyrrolidinecarboxylic acid.

Derivative (VIII) (R = H).

 A solution of 22.3 grams (0.22 moles) of anhydrous diisopropylamine in 100 cm3 of dry tetrahydrofuran is cooled to -780C. 117 cm 3 (0.22 moles) of 12% solution in hexane of n-butyl lithium are added dropwise and then, after 15 minutes of stirring, 20.1 grams (0.088 mole) of derivative (III ) (R2 = R3 = H) (experiment 1) in solution in 600 cm3 of tetrahydrofuran. The medium is stirred for 30 minutes, then dry carbon gas is bubbled for 3 hours.

 The cooling is stopped and 500 cm 3 of 2N hydrochloric acid and 500 cm 3 of methylene chloride are added to the medium. The aqueous phase is decanted and extracted with methylene chloride. Concentrated organic extracts provide an oil which is left standing for 24 hours. This oily residue is then taken up in sodium hydroxide and extracted with methylene chloride. The aqueous phase is acidified with 6N hydrochloric acid and then extracted with methylene chloride. These latter organic extracts are dried over sodium sulfate and concentrated in vacuo.

 20 grams (yield: 83%) of a brown oil directly usable in the following operations are obtained.

EXPERIENCE 6
L-acid (5-methoxy-3-indolyl) ethyl-1-oxo-2-pyrrolidinecarboxylic acid.

Derivative (VIII) (R = OCH3).

 Prepared according to the procedure of the experiment 4.

 Brown oil, yield: 48%.

EXPERIENCE 7
[(5-Fluoro-3-indolyl) -2-ethyl-2-oxo-3-pyrrolidinecarboxylic acid.

Derivative (VIII) (R = F).

 Prepared according to the procedure of the experiment 4.

 Clear gum, yield: 55%.

 EXPERIMENT 8 [(indolyl-3) -2-ethyl-1-oxo-2-pyrrolidin-3-carboxylic acid methyl ester.

Derivative (VIa) (R3 = H, R = CH3).

Procedure A.

 A solution of 17.4 grams (0.064 mol) of derivative (VIII) (R3 = H) (experiment 5) in 60 cm3 of 3.5N hydrochloric methanol is stirred at room temperature for 16 hours under nitrogen. After concentration in vacuo the oily residue is taken up in chloroform and filtered through a bed of silica.

 The concentrated filtrate provides 14 grams of oil, yield: 77%.

Oerative mode B
A solution of 14.7 grams (0.145 mole) of anhydrous diisopropylamine in 60 cm 3 of dry tetrahydrofuran is cooled to -7 ° C. 78.5 cm (0.145 mole) of 12% solution in hexane of n-butyllithium are added dropwise and then, after stirring for 15 minutes, 15 grams (0.066 mole) of derivative (III) (R. = R = H) (experiment 1) dissolved in 400 cm of dry tetrahydrofuran. The mixture is stirred at -7 ° C. for 30 minutes and then 5.9 cm.sup.3 (0.07 mol) of dimethyl carbonate are added.

 Stirring is maintained at -780C for 2 hours, allowed to return to room temperature, 200 cm3 of 1N hydrochloric acid are added and the reaction medium is extracted with methylene chloride. The organic extracts, washed with water and dried over sodium sulfate, are concentrated in vacuo. 15.3 grams of oil are collected (yield: 80%).

 EXPERIMENT 9 Methyl [5-methoxy-5-indolyl] -2-ethyl] -1-oxo-pyrrolidin-3-carboxylate.

Derivative (VIa) (R3 = OCH3, R = CH3).

 Prepared according to the procedure of experiment 7 from derivative (VIII) (R3 = OCH3) (experiment 6).

 Cream crystals, mp = 112-1140 ° C (methanol), yield: 67%.

 EXPERIMENT 10 L (5-Fluoro-indol-3-yl) -2-ethyl-1-oxo-2-pyrrolidin-3-carboxylic acid methyl ester.

Derivative (VIa) (R3 = F, R = CH3).

 Prepared according to the procedure of experiment 7 from derivative (VIII) (R3 = F) (experiment 7).

 Cream crystals, mp = 140-1420C, (methylene chloride), yield: 75%.

 EXPERIMENT 11 [1-Methoxycarbonyl-1-indol-1-yl) -2-ethyl-1-ethyl-3-oxo-2-pyrrolidinecarboxyl carboxylate.

Derivative (VIIb) (R1 = C2H5, R3 = H, R = CH3).

 A solution of 12.5 grams (0.0364 mole) of derivative (VIIa) (R3 = H, R = CH3) (experiment 3) and 4.50 grams (0.040 mole) of potassium tertiobutylate in 120 cm 3 of anhydrous tetrahydrofuran. 8.5 grams (0.055 mole) of ethyl iodide are then added dropwise. After stirring for 2 hours at room temperature, the reaction medium is diluted with methylene chloride, washed with 2N hydrochloric acid and then with water. The organic phase is then dried over sodium sulfate and concentrated.

 9 grams of an oil containing, in equivalent proportions, the derivatives (VIIb) (R = C 2 H 5, R = H, R = CH 3) and (VIc) are obtained (R = C 2 H 5, R = R = H, R = CH 3) it can be separated by chromatography on a silica column (eluent: toluene 7, ethyl acetate 3).

Derivative (VIIb) 4.70 grams of oil (molar yield: 35%).

Derivative (VIc) 3.95 grams of oil (molar yield: 35%).

 The mixture can also be used in the following operation.

EXPERIENCE 12
L-acid (3-indolyl) -2-ethyl-1-ethyl-3-oxo-3-pyrrolidinecarboxylic acid.

Derivative (IX) (R1 = C2H5, R3 = H).

A solution of 9.4 grams (0.0252 mol) of derivative (VIIb) (R1 = C2H5, R3 = H) is heated at 600 ° C. for 6 hours.
R = CH) (experiment 11) and 5.65 grams of 85% potassium hydroxide in 100 cm 3 of absolute ethanol. The reaction medium is evaporated to dryness and taken up in water. The resulting solution is acidified with 2N hydrochloric acid and extracted with methylene chloride. The organic extracts are dried over sodium sulphate and concentrated.

 Recrystallization of the residue gives white crystals, mp = 1500 ° C (isopropyl ether-methanol), yield 72%.

 EXPERIMENT 13 L (3-indolyl) -2-ethyl] -1-ethyl-3-oxo-2-pyrrolidin-3-carboxylic acid methyl ester.

Derivative (VIc) (R1 = C2H5, R2 = R3 = H, R = CH3).

 Prepared according to the procedure of experiment 8 from the derivative (IX) (R1 = C2H5, R3 = H) (experiment 12) oily compound, yield: 85%.

 EXPERIMENT 14 (Methyl-1-ethyl-3-indolyl) -2-ethyl-1-ethyl-3-oxo-3-pyrrolidinecarboxyl carboxylate.

Derivative (VIc) (R1 = R2 = C2H51 R3 = H, R = CH3).

 Prepared according to the procedure of Experiment 2 from the derivative (VIa) (R3 = H, R = CH3) (experiment 8) using two equivalents of sodium hydride and ethyl iodide.

 Oily compound, yield: 61%.

 EXPERIMENT -15 methyl tetrahydro-2,3,5,6 llH-indolizino (8,7-b) indole-1 carboxylate.

2 3
Derivative (XI) (R = R = H, R = CH3).

 A solution of 11.6 grams (0.040 mol) of derivative (VIa) (R = H, R = CH 3) (experiment 8) in 30 cm 3 of phosphorus oxychloride is heated at 50 ° C. for 2 hours. Evaporation to dryness of the reaction medium leaves an oily residue consisting of the immonium salt (X) (R 1 = R 2 = R 3 = H, R = CH 3) which is treated with 6N ammonia and extracted with sodium chloride. methylene. The organic extracts are dried over sodium sulfate and concentrated in vacuo.

 9.1 g (yield: 83%) of light yellow crystals, mp = 1160 ° C., are obtained.

 EXPERIMENT 16 Methyl cis-hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole-1 carboxylate.

Derivative (XII) cis (R1 = R2 = R3 = H, R = CH3).

 A solution of 34.1 grams (0.13 mole) of derivative (XI) (R2 = R3 = -H, R = CH3) (experiment 15) is stirred in 600 cm3 of pure acetic acid. 9.83 grams (0.26 moles) of sodium borohydride are added in small portions. After stirring for 1 hour, the solution is concentrated to a quarter of its initial volume and poured over ice-cold ammonia. It is extracted with methylene chloride. The organic extracts are dried over sodium sulphate and then concentrated. The light yellow crystals collected are triturated twice in hot ethyl ether to remove the highly soluble minority isomer.

 The cis isomer crystals are filtered and dried 22 grams, mp = 1680C, yield: 62 t.

 EXPERIMENT 17 cis methyl hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole-1 carboxylate.

Derivative (XII) cis (R 1, R 2 = R 3 = H, R = CH 3).

 At room temperature, at atmospheric pressure, a mixture of 1 gram (0.0037 mol) of derivative (XI) (R 2 = R 3 = H, R = CH 3) (experiment 15) is hydrogenated until the absorption is stopped. 0.1 gram of palladium carbon and 50 cm of pure acetic acid. After filtration of the catalyst, the acetic acid is evaporated under vacuum. The residue taken up in ammonia is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo. We obtain a mixture of trans (XII) cis and (XII) trans in an 80/20 ratio whose treatment, similar to that of experiment 16, allows to isolate the pure cis isomer with a yield of 60%.

 EXPERIMENT 18 methyl trans hexahydro-2,3,5,6,11,11b 1H-indolizine (8,7-b) indole-1 carboxylate.

Derivative (XII) trans (R1 = R2 = R3 = H, R = CH3)
Procedure a.

 A solution of 1 gram (0.00372 mol) of stamen (XI) (R 2 = R 3 = H, R = CH 3) (experiment 15) in 5 cm 3 of stirring is stirred under nitrogen at room temperature. pure acetic acid and 1 gram of zinc powder is added in small portions. It is stirred for 2 hours until! discoloration of the solution.

 The reaction medium is filtered through Celite and then evaporated under vacuum. The residue is taken up in an aqueous solution containing 5% sodium bicarbonate and extracted with chloroform. The organic extracts are dried over sodium sulfate and concentrated in vacuo.

 1 gram (yield: 99 t) of a clear oil containing 87% of derivative (XII) trans and 13% of derivative (XII) cis are collected and separated by chromatography on a column of silica (eluent: methylene chloride -methanol).

 The trans derivative (XII) is obtained in the form of a clear gum (yield: 70%).

Procedure b.

 A solution of sodium methoxide (2 mmol) is prepared by adding 50 mg of sodium in 10 cm of anhydrous methanol under a dry nitrogen atmosphere. A solution of 2.7 grams (10 mmol) of derivative (XII) cis (R1 = R2 = R3 = H, R = CH3) (experiment 16) in 15 cm3 of anhydrous methanol is introduced into the medium. It is stirred for 12 hours at room temperature, 22 cm3 (2.2 mmol) of 0.1 N hydrochloric acid are added, concentrated in vacuo to remove methanol and extracted.

The residual aqueous phase is extracted with methylene chloride. The organic extracts are dried over sodium sulphate and evaporated to dryness. 2.6 g (yield: 96%) of trans isomer (XII) are collected in the form of a light gum.

 EXPERIMENT 19 Methoxy-8-methyl-2,3,5,6-tetrahydro-11H-indolizino (8,7-b) indole-1-carboxylate.

Derivative (XI) (R2 = H, R3 = OCH3, R = CH3).

 Prepared according to the procedure of the experiment from derivative (IVa) (R3 = OCH3, R = CH3) (experiment 9).

 Crystals light yellow, m.p. 121-126 ° C, yield 97%.

 EXPERIMENT Cis-Methoxy-8-hexahydro-2 -, -3-5-, 6, 11,11b 1H-indolizino (8,7-b) -indole-1-carbox-ylate-methyl.

Derivative (XII) cis (R1 = R2 = H, R3 = OCH31 R = CH3).

 Prepared according to the procedure of experiment 16 from the derivative (XI) (R3 = OCH3, R = CH3) (experiment 19).

 Light yellow crystals, F. = 2020C, yield: 62%.

 EXPERIMENT 21 Methyl 8-fluoro-2,3,5,6-tetrahydro-1H-indolizino (8,7-b) indole-1-carboxylate.

Derivative (XI) (R = H, R = F, R = CH 3).

 Prepared according to the procedure of the experiment from derivative (VIa) (R3 = F, R = CH3) (experiment 10).

 Crystals light yellow, F. = 1560C, yield: 75%.

 EXAMPLE 22 Methyl cis and trans-fluoro-8-hexahydro-2,3,5,6,11,11b 1a-indolizino (8,7-b) indole carboxylate.

Derivative (XII) cis and trans (R = H, R = F, R = CH3)
Prepared according to the procedure of experiment 16 from the derivative (XI) (R2 = H, R3 = F, R = CH3) (experiment 21).

 Separated by chromatography on silica (eluent methylene chloride 95 methanol 5).

Derivative (XII) cis: light yellow crystals, F. = 1350C,
yield: 47%.

Derivative (XII) trans: brown oil.

Picrate: yellow crystals, mp = 200-202 ° C (ethanol), (yield 30%).

 EXPERIMENT 23 methyl-11 methyl tetrahydro-2,3,5,6 1H-indolizino (8,7-b) indole-1 carboxylate.

Derivative (XI) (R2 = R = CH3, R3 = H).

 Prepared according to the procedure of experiment 15 from the derivative (VIb) (R = R2 = CH31 R3 = H) (experiment 4), light yellow oil, yield: 90%.

 EXPERIMENT 24 Methyl cis-methyl-11 hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole-1 carboxylate.

Derivative (XII) cis (R1 = R3 = H, R2 = R = CH3).

 Prepared according to the procedure of experiment 16 from the derivative (XI) (R2 = R = CH3, R3 = H) (experiment 23).

 Cream crystals, mp = 106 ° C., yield: 45%.

 EXPERIMENT 1 Methyl cis-ethyl-1 hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole-1 carboxylate.

Derivative (XII) cis (R1 = C2H5, R2 = R3 = H, R = CH3).

 Immonium (X) (R 1 = C 2 H 5, R 2 = R 3 = H, R = CH 3) is prepared according to the procedure of experiment 15 from the derivative (VIc) (R 1 = C 2 H 5, R 2 = R 3 = H, R = CH3) (experiment 13) but, after evaporation of the reaction medium, the residue is treated with an aqueous solution of lithium perchlorate. The resulting solution is extracted with methylene chloride.

The organic extracts are dried over sodium sulfate and concentrated in vacuo. The residue is concretized in ethyl ether. The yellow crystals obtained are filtered and dried.

F. = 1700C, yield: 90%.

 Immonium perchlorate X isolated is then reduced according to the procedure of Example 16. The derivative (XII) cis (R = C 2 H 5, R = R = H, R = CH 3) isolated in base form is converted into hydrochloride .

 Cream crystals, mp = 25 ° C., overall yield of the hydrochloride derivative of the cis derivative (XII) = 57%.

 EXPERIMENT 26 Methyl cis-diethyl-1,11-hexahydro-2,3,5,6,11,11b 1H-inolizino (8,7-b) indole-1 carboxylate.

 Prepared according to the procedure of experiment 25 from derivative (VIc) (R1 = R2 = C2H5, R3 = H, R = CH3) (experiment 14). Isolated as a clear oil, yield = 44%.

 EXAMPLE 1 cis-1H-hydroxymethylhexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole

Derivative (I) cis (R1 = R2 = R3 = R4 = H).

 A suspension of 2.5 grams (0.0656 mol) of lithium aluminum hydride in 150 cm3 of anhydrous tetrahydrofuran is stirred under a nitrogen atmosphere. A solution of 17.7 grams (0.0656 mol) of derivative (XII) cis (R 1 = R 2 = R 3 = H, R = CH 3) (experiment 17) in 250 cm 3 of tetrahydrofuran is added dropwise. After stirring for 30 minutes, 100 cm 3 of tetrahydrofuran containing 5% of water are added slowly, followed by 10 grams of sodium sulfate. The insoluble mineral salts are filtered, washed with 200 cm3 of hot tetrahydrofuran. The combined filtrates are evaporated under vacuum, and the residue obtained is taken up in N sodium hydroxide. The crystals are filtered from the solution, washed with water, drained, dried (15.7 g, mp = 2340 ° C.) and recrystallized. in 900 cm3 of methanol).

 12.7 grams of pale yellow crystals are obtained, yield: 80%, mp = 2440 ° C.

 EXAMPLE 2 trans-hydroxymethyl-1 hexahydro-2, 3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) trans (R1 = R2 = R3 = R4 = H).

 Prepared according to the procedure of Example 1 from the derivative (XII) trans (R1 = R2 = R3 = H, R = CH3) (experiment 18).

 Beige crystals, yield: 75%, F. = 1970C (methanol).

 EXAMPLE 3 1-cis-1-hydroxymethyl-8-hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) cis (R = R = R4 = H, R = OCH3).

 Prepared according to the procedure of Example 1 from the derivative (XII) cis (R = R2 = H, R3 = OCH3, R = CH3) (experiment 20).

Light green crystals, F. = 2450C (ethanol), yield: 72%
EXAMPLE 4 8-cis-fluoro-1-hydroxymethylhexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) cis (R1 = R2 = R4 = H R3 = F).

 Prepared according to the procedure of Example 1 from the derivative (XII) cis (R1 = R2 = H, R3 = F, R = CH3) (experiment 22). Isolated as hydrochloride.

 Pale green crystals, mp = 2420C (ethanol), yield: 50%.

 EXAMPLE 5 cis-1-hydroxymethyl-11-hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) cis (R1 = R3 = R4 = H, R2 = CH3).

 Prepared according to the procedure of Example 1 from the derivative (XII) cis (R1 = R3 = H, R2 = R = CH3) (experiment 24).

Isolated as hydrochloride.

 Beige crystals, F. = 1660C (ethanol), yield 77%.

 EXAMPLE 6 cis-ethyl-1-hydroxymethyl-1, hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) cis) (R1 = C2H5, R = R3 = R4 = H).

 Prepared according to the procedure of Example 1 from the derivative (XII) cis (R1 = C2H5, R2 = R3 = H, R = CH3) (experiment 25).

 White crystals: mp = 220 ° C (methanol), yield: 72%.

 EXAMPLE 7 cis-diethyl-1,11-hydroxymethyl-1, hexahydro-2,3,5,6,11,11b 1Hindolizino (8,7-b) indole.

Derivative (I) cis (R1 = R2 = C2H51 R3 = R4 = H).

 Prepared according to the procedure of Example 1 from the derivative (XII) cis (R1 = R2 = C2H5, R3 = H, R = CH3) (experiment 26. Isolated as picrate, F. = 2180C (ethanol- water), yield: 67%.

 EXAMPLE 8 cis-acetyloxymethyl-1 hexahydro-2,3,5,6,11,11b 1H-indolizino (8,7-b) indole.

Derivative (I) cis (R1 = R2 = R3 = H R4
= CH3COO-).

 A solution of 14.5 grams (0.060 mol) of derivative (I) cis (R = R = R = R4 = H) (Example 1) in a mixture of 60 cm3 of acetic anhydride and 100 cm3 of dry pyridine.

 The reaction medium is evaporated under vacuum and the residue is taken up in a 5% solution of sodium bicarbonate in water. The aqueous phase obtained is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo. The crystals collected are recrystallized from 95% methanol.

 12.7 grams of white crystals are obtained, yield 74%, mp.

EXAMPLE 9
Separation of the constituents of cis-hydroxymethyl-1 hexahydro 2.3.56,11,11b 1H-indolizino (8,7-b) indole
a) To a solution of 6.5 grams (0.026 mol) of (-) -alpha-methoxy-trifluoromethylphenacetyl chloride in 40 cm3 of tetrahydrofuran is added dropwise at room temperature, 2.63 grams (0.026 mol). ) of triethylamine, then 5.98 grams (0.0247 mol) of the derivative (I) cis (R = R = R = R4 = H) (Example 1) in solution in 800 cm3 of tretrahydrofuran.

 After stirring for 48 hours at room temperature, the triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in a mixture of methylene chloride and methanol and the solution is filtered through a bed of silica. After concentrating, 9.7 grams of an oil consisting of the mixture of diastereoisomeric esters are obtained. Their separation is carried out by liquid chromatography under pressure (support: silica, eluent: 9/1 methylene chloride methanol).

Each ester is obtained in the form of an oil.

b) Saponification of the esters.

 A solution of 1.6 grams of ester in a mixture of 3.5 cm 2N sodium hydroxide and 40 cm3 of ethanol is stirred for 16 hours at room temperature. The precipitate is filtered, rinsed with water, drained, dried under vacuum and recrystallized from methanol.

Enantiomeric alcohol from the higher Rf ester:
F = 258 C [α]; 436 = -0.069 (C = 3.32, MeOH)
Enantiomeric alcohol from the lower Rf ester:
F = 256 [+ alpha] 436 = + 0.060 (C = 2.94, NeOH).

 The results of the toxicological and pharmacological tests, which are recalled below, highlight the properties of the derivatives of the invention which render them valuable in therapeutics.

I - Toxicological looper.

 This study, which focused on acute, chronic, delayed toxicities, local and general tolerance and possible teratogenic effects, found that the compounds of the invention are perfectly tolerated both by the oral and parenteral routes without causing any local or general reaction.

By way of example, the LD 50 / kg / 24h determined by the oral route in mice, according to the method of Mille et al.
Tainter, is greater than 300 mg for all derivatives.

 In addition, examination of rabbits in the third generation showed no teratogenic effect.

II - Pharmacological study.

 This study focused on different actions.

1) Voltage effects.

This experiment is carried out on rabbits grouped by 5 in different batches. A carotid catheterization is performed and the animals are prepared for the recording of blood pressure and electrocardiogram. The animal is left for a few moments, then injected into the marginal vein of the ear substance test. The results are grouped in the following table which indicates the average values determined within each lot.

<Tb>

<SEP> Product <SEP> Dose <SEP> Hypotension <SEP> Duration <SEP> Number <SEP> of <SEP> Rabbits
<tb> derivative <SEP> of <SEP> Maximum <SEP> Dose <SEP> in <SEP> of <SEP><SEP><SEP> phase presenting <SEP> of
<tb> Example <SEP> No. <SEP> in <SEP> mg / kg <SEP> percentage <SEP> hypotensive <SEP> disorders <SEP> cardiac
<tb><SEP> 1 <SEP> 2 <SEP> 26.2 <SEP>8'25"<SEP> 0
<tb><SEP> 2 <SEP> 2 <SEP> 26.8 <SEP>6'12"<SEP> 0
<tb><SEP> 3 <SEP> 2 <SEP> 24.5 <SEP>4'30"<SEP>
<tb><SEP> 4 <SEP> 2 <SEP> 25.8 <SE>7'22"<SEP> o <SEP>
<tb><SEP> 5 <SEP> 2 <SEP> 25.6 <SEP> 5 <SEP> r <SEP> 37t <SEP> 1 <SEP>
<tb><SEP> 6 <SEP> 2 <SEP> 26.1 <SEP>5'40"
<tb><SEP> 7 <SEP> 2 <SEP> 25.4 <SEP> 7 '<SEP> 15 "<SEP> 0
<tb><SEP> 8 <SEP> 2 <SEP> 25.6 <SEP>6'28"<SEP> 0
<Tb>
It is found that the derivatives of the invention produce a net hypotensive effect with excellent cardiac tolerance since the frequency of heart disorders is very low (only 3 out of 35 animals).

 These results demonstrate the good hypotensive activity of the derivatives of the invention and excellent cardiac tolerance.

20) Cerebral vasodilator action in rabbits.

 The measurement of the arterial perfusion pressure in the anesthetized rabbit makes it possible to measure the qualitative variations of cerebrovascular resistance to flow, that is to say in its hemorheological and non-parietal sense.

 The technique used consists in interposing, on the heparinized animal, between the common carotid and the right internal carotid, a peristatic pump on a silicone polyethylene catheter and ligating the other arterial afferents, namely the contralateral carotid and the two vertebral ones. . This pump is set to ensure immediately after ligation of the disconnected carotid segment, a flow such that the perfusion pressure in the catheter remains the same as the previous carotid pressure. This flow rate is kept constant. A brief rest period is provided to which, the flow remaining always constant, the perfusion pressure stabilizes definitively, the vascular adaptations having been achieved and determining a certain degree of resistance to the flow of blood perfused.Conjoint, an electrocardiograph is connected to each animal.

 The vasodilator action of the derivatives of the invention decreases this resistance and results in a lowering of the perfusion pressure (PP).

 Different batches of 5 rabbits thus receive, for one minute in the marginal vein of an ear, the test products in solution in physiological saline at the dose of 2 mg / kg.

 The results are collated in the following table.

All animals saw the infusion pressure decrease significantly while maintaining a normal electrocardiographic pattern.

<Tb>

<SEP> Derived <SEP> from <SEP> Decreased <SEP> from <SEP><SEP><SEP> Pressure from <SEP> Infusion
<tb> Example <SEP> No. <SEP> Average <SEP> Value <SEP> Max <SEP> Total <SEP> Duration
<tb> (mm <SEP> Hg)
<tb><SEP> 1 <SEP> 35 <SEP> 10 <SEP> mn
<tb><SEP> 2 <SEP> 38 <SEP> 7 <SEP> mn
<tb><SEP> 3 <SEP> 44 <SEP> 8 <SEP> mn
<tb><SEP> 4 <SEP> 41 <SEP> 8 <SEP> mn
<tb><SEP> 5 <SEP> 50 <SEP> 7 <SEP> mn
<tb><SEP> 6 <SEP> 45 <SEP> 9 <SEP> mn
<tb><SEP> 7 <SEP> 38 <SEP> 10 <SEP> mn
<tb><SEP> 8 <SEP> 40 <SEP> 8 <SEP> mn
<tb> 3) Curaric anoxia in mice.

 This study is carried out in the mouse which receives at time 0, by intraperitoneal injection, 20 mg / kg of gallamine triiodo ethoxide. The products to be tested are administered, at the dose of 25 mg / kg, by the same route, five minutes earlier (time -5 minutes) to batches of 5 animals, the control group receiving no treatment.

 The onset time of convulsive seizure, respiratory arrest and cardiac arrest are timed from time 0.

The results, representing the averages obtained inside each batch, are collated in the following table.

<Tb>

<SEP> Derived <SEP> from <SEP><SEP> Separation Time <SEP> in <SEP> seconds
<tb><SEP> Example <SEP> No. <SEP> Crisis <SEP> Shutdown <SEP> Shutdown
<tb><SEP> convulsive <SEP> respiratory <SEP> cardiac
<tb> Lot <SEP> control <SEP> 84 <SEP> 145 <SEP> 361
<tb><SEP> 1 <SEP> 121 <SEP> 254 <SEP> 582
<tb><SEP> 2 <SEP> 2 <SEP><SEP> 134 <SEP> 212 <SEP> 565
<tb><SEP> 3 <SEP> 148 <SEP> 238 <SEP> 540
<tb><SEP> 4 <SEP> 137 <SEP> 225 <SEP> 578
<tb><SEP> 5 <SEP> 152 <SEP> 236 <SEP> 529
<tb><SEP> 6 <SEP> 128 <SEP> 240 <SEP> 533
<tb><SEP> 7 <SEP> 130 <SEP> 215 <SEP> 575
<tb><SEP> 8 <SEP> 8 <SEP> 136 <SEP> 235 <SEP> 513
<Tb>
It can be seen that the onset times for the various symptoms are considerably longer and that the derivatives of the invention provide effective protection against the effects of anoxia.

 The results of these studies demonstrate the excellent general cardiac tolerance as well as the low toxicity of the derivatives of the invention. Their interesting vasoregulatory properties of micro-circulation and oxygenating brain tissue make them very useful in human and veterinary medicine.

 The drug of the invention may be presented for oral administration in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented for rectal administration in the form of suppositories and, for parenteral administration, in the form of injectable solution.

 Each unit dose of 0.05 to 2 grams advantageously contains from 0.001 gram to 0.050 gram of active principle, the doses administered daily may vary from 0.001 gram to 0.200 gram of active principle depending on the age of the patient and the condition being treated.

 Some pharmaceutical formulations of the drug of the invention will be given hereinafter as non-limiting examples.

1. Tablets.

Derived from Example 1 0.010 gram.

Excipient: magnesium stearate, telc, glucose, polyvinyl.

 pyrrolidone.

2. Sugared tablets.

Derived from Example 2 0.005 gram.

Excipient: lactose, starch, talc, gelatin, titanium oxide,
sugar, gum arabic, shellac, beeswax,
yellow orange.

3. Capsules.

Derived from Example 4 0.025 gram.

Excipient: talc, malus starch, magnesium stearate.

4. Injectable ampoules.

Derived from Example 7 0.005 gram.

Excipient: isotonic solvent q.s. 2 ml.

5. Suppositories.

Derived from Example 5 0.020 gram.

Excipient: semi-synthetic triglycerides.

 The toxicological and pharmacological studies which have just been reported have demonstrated the good tolerance of the derivatives of the invention, as well as their oxygenating and vaso-regulating cerebral activities.

 The drug of the invention can thus be administered to humans with advantage in the treatment of all inflammatory and painful conditions, regardless of their etiology inflammatory rheumatism, chronic rheumatism, degenerative rheumatism, ab-articular diseases; acute gout / inflammatory diseases of the otorhinolaryngological sphere, trauma, odonto-stomatology, postoperative surgery, gynecology, urology and proctology.

 Thus, by increasing the cerebral circulatory flow and facilitating the use of oxygen by the nerve cell, the drug of the invention can be administered to humans with profit in the treatment of disorders of acute cerebral circulatory insufficiency. or chronic, disorders of consciousness, cranial trauma and their sequelae and diseases of vascular or traumatic origin in ophthalmology and otolaryngology.

Claims (9)

1. Indolizino (8,7-b) indoles of formula

 in which : R and R are, independently of each other, hydrogen or  an alkyl group having up to! 4 carbon atoms R3 is hydrogen, a halogen, an alkyl group having  up to 6 carbon atoms, an alkoxy group having  up to 6 carbon atoms, a hydroxy group or a  trifluoromethyl group; and R4 is hydrogen or an acyl group, their radicals are  with acids and their isomers and mixtures  isomers.  2. Indolizino (8,7-b) indoles according to claim 1, characterized in that R4 is an alkyl group having up to 6 carbon atoms.  3. Indolizino (8,7-b) indoles according to claim 1, which are a) cis-hydroxymethyl-1 hexahydro-2,3,5,6,11,11b 1H-indoli  zino (8,7-b) indole g (b) 1-trans-1H-hydroxymethylhexahydro-2,3,5,6,11,11b lHindo  lizino (8,7-b) indole; c) 1-cis-1-hydroxymethyl-8-hexoxy-2,3,5,6-hexahydro, 11, 11b 1H  indolizino (8,7-b) indole; d) 8-cis-fluoro-1-hydroxymethylhexahydro-2,3,5,6,11,11b 1H  indolizino (8,7-b) indole; e) 1-cis-1-hydroxymethyl-11-hexahydro-2,3,5,6,11,11b 1H  indolizino (8,7-b) indole; f) cis-ethyl-1-hydroxymethyl-hexahydro-2,3,5,6,11,11b 1H indolizino (8,7-b) indole; g) cis-diethyl-1,1,1-hydroxymethyl-1, hexahydro-2,3,5,6,11,11b  1H-indolizino (8,7-b) indole.  indolizino (8,7-b) indole. h) 1-cis-1-ethylacetyloxymethylhexylhydro-2,3,5,6,11,11b 1H  4. Process for preparing an indolizino (8,7-b) indole of formula

 in which R1 and R2 are, independently of one another, hydrogen or  an alkyl group having up to 4 carbon atoms R3 is hydrogen, a halogen, an alkyl group having  up to 6 carbon atoms, an alkoxy group having  up to 6 carbon atoms, a hydroxy group or a  trifluoromethyl group; and R4 is hydrogen or an acyl group and their addition salts with acids, characterized in that it consists in reducing an ester of formula

R4 is hydrogen, and to obtain the acid addition salt, to salify with an acid. R being lower alkyl, to obtain indolizinoindole, in which R4 is hydrogen of the same configuration (cis or trans) as in the starting ester, then to obtain the indolizinoindole in which R4 is acyl, to acylate indolizinoindole in which  5. Method according to claim 4, characterized in that it consists in carrying out the reduction with lithium hydride and aluminum.  6. Esters useful for the preparation of the compounds of claim 1, of the formula

 wherein R, R1, R2 and R3 have the meanings and positions defined in claim 4.  7. Intermediates useful for the synthesis of the compounds of claim 1, of the formula

 wherein R4, which is hydrogen or -COOR and R, R1, R2 and R3 have the meanings and positions defined in claim 4.  8. Intermediates useful for the synthesis of the compounds of claim 1, of the formula

  wherein R2 and R3 have the meanings given in claim 4.  9. A medicament with oxygenating and vaso-regulating cerebral activities, characterized in that it comprises an indolizinoindole according to one of claims 1 to 3.