NZ238709A - Ring-substituted indole derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £38709 238709 ~Xr\ - .(,.-c\0 • ■ : • , ... • "" f "" -■ \ I u-L-^? ' 1 I /^La\fc-C**• 1^5' I ^ 1 l b.\ j ,ubUcat^ ^ * j r.r-^*«V> • i i ~ '"""^WnT "T> ' *.>♦ •, *** f£ U \i ^5 \ :-'.G. ^-:,J———— i\S| I ^5 t£r-i « ea vc NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NEW, 1.2,3,4,5,6-HEXAHYDROAZEPINO[4,5-B]INDOLES AND 1,2,3,4-TETRAHYDRO -^-CARBOLINES PROCESSES FOR PREPARING THESE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM We, ADIR ET COMPAGNIE, a French body corporate, of 1, rue Carle Hebert, F-92415, Courbevoie, Cedex, France, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement (followed by page la) 23 R wa - ' - V The present invention relates to new 1,2,3,4,5,6-hexahydroazepino [ 4,5-b]indoles and 1,2,3,4-tetrahydro-0-carbolines, to processes for preparing these and to pharmaceutical compositions containing them. 5 The 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles mentioned in the prior art are all different from those claimed by the Applicant, none of them simultaneously possessing a hydroxyl, alkoxy or acetoxy at the 5- position with one or two substituents at the 6-position.

A few 5-hydroxy-l, 2,3,4,5,6-hexahydroazepino- [4,5-b]indoles are described in the literature (FR 1,524,830) as possessing antitussive properties.

More generally, l,2,3,4,5,6-hexahydroazepino[4,5-b]indoles are most often described as neuroleptics, 15 antidepressants, sedatives and tranquillizers, and as a means of treating cerebrovascular disorders (Patents EP 203,902, EP 28,381, EP 64,317, FR 1,524,495).

As regards 1,2,3,4-tetrahydro-p-carbolines, while a large number of compounds have been prepared, only two 20 products containing a carboxyl function at the 3-position and a spiran system at the 1-position are mentioned in the literature, without any pharmacological properties being claimed (Monatsch. Chem. (1985) 116 pp 851-5).

Apart from their good properties in relation to 25 the central nervous system, more especially as anxiolytics, antidepressants and antipsychotics, and in some instances their good activity in the treatment of cerebrovascular disorders and disorders of memory, some of the compounds of the invention possess advantageous analgesic, anti-inflammatory, 30 anticonvulsant and muscle- relaxant properties not possessed by the structurally most closely related compounds of the prior art.

More specifically, the invention relates to the substituted indoles of formula (I): m 23 87 0 9 with A representing either a a bond, the compounds of the invention then being the l,2,3,4-tetrahydro-{i-carbolines of formula (II), or a radical of the formula -CH-, OR7 the compounds of the invention then being the 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles of formula (III): R2 in which: Rl represents hydrogen, halogen, hydroxyl, linear or branched alkoxy having 1 to 4 carbon atoms, linear or branched alkyl having 1 to 6 carbon atoms optionally substituted with up to 3 halogen, oxo, hydroxyl or alkoxy having 1 to 4 carbon atoms, 23 87 0 9 - R2 represents carboxyl, linear or branched alkoxycarbonyl having 1 to 6 carbon atoms and optionally substituted with optionally substituted phenyl, phenyloxycarbonyl, substituted phenyloxycarbonyl, carbamoyl, carbamoyl substituted on the nitrogen with up to 2 linear or branched alkyl having 1 to 6 carbon atoms or cycloalkyl having 4 to 7 carbon atoms, and in the case where A is a radical of the formula -CH-, R2 can also be hydrogen-OR7 - R3 represents hydrogen, linear or branched alkyl 10 having 1 to 6 carbon atoms and optionally substituted with up to 3 halogen, oxo, linear or branched alkoxy having 1 to 4 carbon atoms or optionally substituted phenyl, - R4 and R5 together form a saturated or unsaturated 5-to 12-membered mono- or bicyclic ring-system which can comprise in the ring skeleton from 0 to 3 hetero atoms selected from oxygen, nitrogen and sulfur and which can optionally be substituted with up to 3 oxo, linear or branched alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, phenylcarbonyl, substituted phenylcarbonyl, optionally £^0 substituted phenylalkyl having 7 to 9 carbon atoms, optionally substituted fluorene, with, in the case where R4 and R5 form a bicyclic system, the possibility that one of the rings is an optionally substituted aromatic ring, and in the case where A is a radical of the formula -^H-, R4 and R5 can also represent, OR7 ^25 each independently of one another, hydrogen, optionally substituted phenyl, linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl, with the proviso that, when A is a o bond with Ri = R3 = Rg = H and R2 = COOH then R4 and R5 30 together cannot form a cyclopentyl or a cyclohexyl, and when A is a radical of the formula 238709 o II -CH- with R7 = H or CH3C - ,then R4 and R5 must be other OR7 than H, - R6 represents hydrogen or a linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl, - R7 represents hydrogen or a linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 3 oxo, halogen, alkoxy having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or optionally substituted phenyl, - their isomers, diastereoisomers, enantiomers, - their addition salts with a pharmaceutically-acceptable acid, or, in the case where R2 is a carboxyl, with a pharmaceutically-acceptable base, the term substituted associated in the previous definitions with the expressions phenyl, phenylalkyl, phenyloxycarbonyl and phenylcarbonyl means that the aromatic rings may be substituted with up to 3 linear or branched alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxyl, nitro, trifluoromethyl or halogen.

The invention also encompasses the processes for obtaining the compounds of the general formula (I). The processes for obtaining these compounds depend on the nature of the group A.

- Either a substituted tryptamine of general formula (IV): 23 8 7 R6 in which Ri, R3 and R6 have the same meaning as in the compound of general formula (I), is reacted with an aldehyde of general formula (V): 0 in which R5 and R4 have the same meaning as in the compound of general formula (I), by heating them in an organic acid of general formula (VI): R8 COH (VI) 0 in which Rs is a methyl, ethyl or trifluoromethyl group, so as to obtain the 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole of general formula (VII): in which Ri, R3, R4, R5 and R6 have the same meaning as in the compound of general formula (I) and Rs the same meaning as in the acid (VI), which can be either heated with an alcohol of general formula RgOH, in which Rg is a lower alkyl group, 238709 m branched or otherwise, having 1 to 6 carbon atoms or an aralkyl group, so as to obtain the 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole of general formula (VIII): in which Ri, R3, R4, R5 and R6 have the same meaning as in the compound of general formula (I) and Rg the same meaning as above, or heated in methanol in the presence of 10 equivalents of potassium carbonate so as to obtain the 1,2,3,4,5,6-hexahydroazepino[4,5- b]indole of general formula (IX): H in which Ri, R3, R4, R5 and R6 have the same meaning as in the compound of general formula (I), (VIII) Rg (ix) or a substituted tryptophan of general formula (X): 238709 COOR10 NH2 (x) N R6 in which Ri and R6 have the same meaning as in the compound of general formula (I) and Rio is a lower alkyl, branched or otherwise, having 1 to 6 carbon atoms or an optionally substituted aryl or aralkyl group, is reacted with a ketone of general formula (XI): in which R4 and R5 have the same meaning as in the compound of general formula (I), under a nitrogen atmosphere, either in toluene or benzene under reflux in the presence of para-toluenesulfonic acid, the water formed during the condensation being removed by means of a water-extraction apparatus which can be, for example, a Dean Stark apparatus, or, in some cases, under reflux of methanol or of the ketone itself, so as to obtain, after purification, the JS-carboline of general formula (XII): 0 II (xi) R5 — C — Ri» (xii) in which Ri, R4, R5, R6 and Rio have the same meaning as in the compounds of general formulae (I) and (X), which can be: 238709 m either reacted under reductive amination conditions with an aldehyde of general formula (XIII): in which Rn is a hydrogen atom or a lower alkyl group, branched or otherwise, having 1 to 6 carbon atoms and optionally substituted with one or more halogen atoms, alkoxy groups or aryl groups, substituted or otherwise, so as to obtain the 0-carboline of general formula (XIV): in which Ri, RiOf Rn, R4/ R5 and Re have the same meaning as in the compounds of general formula (XII) and (XIII), - or reacted with an acid chloride, or the corresponding acid anhydride, of general formula (XV): Rl i ~ CH II (xiii) 0 (XIV) R11CC1 (xv) II 0 in which Rn has the same meaning as in the compound of general formula (XIII) so as to obtain the f-carboline of general formula (XVI): 238709 (xvi) in which Ri, Rio, Rn, R6, R5 and R4 have the same meaning as in the compound of general formula (XIV), or reacted, in the case where Rio = CH3, with aqueous barium hydroxide solution so as to obtain the acids of general formula (XVII): in which Ri, R4, R5 and R6 have the same meaning as in the compounds of general formula (I), or reacted, in the case where Rio = CH3, with an amine of general formula (XVIII): COOH (xvii) m 238709 NH 'R12 ■R13 (xviii) in which R12 and R13 represent, each independently of one another, a hydrogen atom or lower alkyl groups, branched or otherwise, having 1 to 6 carbon atoms or cycloalkyl groups having 4 to 7 carbon atoms, so as to obtain the amides of general formula (XIX): in which Ri, R4, R5 and R6 have the same meaning as in the compounds of general formula (I) and R12 and R13 the same meaning as in the amides of general formula (XVIII), it being understood that the compounds of general formula (VII), (VIII), (IX), (XII), (XIV), (XVI), (XVII) and (XIX) form part of the invention and are special cases of the compounds of general formula (I).

The 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles and 1,2,3,4-tetrahydro-p-carbolines of general formula (I), as well as their addition salts with a pharmaceutically-acceptable inorganic or organic acid or, where it is possible, their 2387 09 addition salts with a pharmaceutically-acceptable inorganic or organic base, are very advantageous active principles which may be used, for example, as anxiolytics, antidepressants, antipsychotics and analgesics. Some of these products are also anticonvulsant, muscle-relaxant, anti-inflammatory and effective in the treatment of cerebrovascular disorders and disorders of memory.

The compounds of general formula (I), as well as their addition salts with a pharmaceutically-acceptable inorganic or organic acid such as, for example, hydrochloric, methanesulfonic, citric or maleic acid, or, where it is possible, their addition salts with a pharmaceutically-acceptable inorganic or organic base such as, for example, sodium, potassium or calcium hydroxide, arginine, ethanolamine or diethanolamine, may be made into pharmaceutical preparations according to generally known processes, such as, for example, into tablets, hard gelatin capsules, dragees, solutions for oral administration, injections, suspensions for oral administration, emulsions and suppositories.

Apart from non-toxic and pharmaceutically-acceptable inert excipients such as, for example, distilled water, glucose, lactose, starch, talc, vegetable oils, ethylene glycol, and the like, these preparations can also contain preservatives: stabilizers, wetting agents, emulsifiers, and the like.

The compositions thereby obtained are generally presented in the form of measured doses, and can contain, depending on the conditions being treated and the patient's age and weight, from 0.1 to 500 mg of active principle.

They may, depending on the case, be administered orally, rectally or parenterally at a dose of 0.1 to 500 mg from one to several times a day.

The examples which follow illustrate the invention and in no way limit the latter. 238709 EXAMPLE 1: [(3S)-3-METHOXYCARBONYL-l,2,3,4-TETRAHYDRO~P~CARBOLINE]-1-SPXRO-3'-[2-OXO- 2,3-DIHYDROINDOLE] ^2 2.9 3 g (14.3 mmol) of L(-)-tryptophan methyl ester, 4.2 g (28.6 mmol) of isatin and 2.7 g of para-toluenesulfonic acid (monohydrate) are dissolved in the heated state in the minimum quantity of methanol enabling the reactants to be in solution in the heated state.

The reaction medium is brought to reflux under a nitrogen atmosphere for 48 hours, and the methanol is then removed by distillation under reduced pressure.

The residue obtained is purified by chromatography on a silica column (eluent: chloroform/methanol, 95/5). The product obtained is then recrystallized in methanol. 2.55 g (55%) of [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-0-carboline]-l-spiro-3'-[2-oxo-2,3-dihydroindole] are thereby obtained.

Melting point: 253° C Optical rotation: _ d (MeOH): -151.6° UV (MeOH): Amax at 215, 225, 245, 282 and 285 nm IR (KBr) : vC = 0 at 1715, 1730, 1620 cnrl, other bands 3290 and 3370 cm-1 1H NMR 300 MHz (CDC13) 3,82 ppm s 3H ,05 ppm dd 1H 2,0 ppm broad peak 1H / 238709 13C NMR 75 MHz (CDC13) c 173,3 ppm EXAMPLE 2: [ (3S)-3-METHOXYCARBONYL-l,2,3,4-TETRAHYDRO-P-CARBOLINE]-1-SPIROCYCLOHEXANE 3 g (14.6 mmol) of L(-)-tryptophan methyl ester, 2.86 g (29.2 mmol) of cyclohexanone and 0.28 g of para-toluenesulfonic acid (monohydrate) are dissolved in the heated state in sufficient toluene for the reactants to be in solution 10 under reflux, under a nitrogen atmosphere, in a Dean and Stark apparatus enabling the water formed during the reaction to be removed.

The reaction medium is brought to reflux until the starting materials have disappeared (approximately 20 15 hours), and the toluene is then removed by distillation under reduced pressure.

The crude product obtained is recrystallized in methanol. 3.7 g (89%) of [(3S)-3-methoxycarbonyl-l,2,3,4-20 tetrahydro-|5-carboline]-l-spirocyclohexane are thereby obtained. Melting point: 175° C Optical rotation: ao (MeOH): -70.9° UV (MeOH):Ajmax at 225, 280 and 285 nm -23 87 0 9 XH NMR 300 MHz (CDC13) EXAMPLE 3: [(3S)-3-CARBOXY-l,2,3,4-TETRA- HYDRO-0-CARBOLINE]-1-SPIROCYCLOHEXANE 100 cm3 of saturated aqueous barium hydroxide solution are added to a solution of 1.5 g of [(3S)—3— methoxycarbonyl-1,2,3,4-tetrahydro-P-carboline]-1-spirocyclohexane in 100 cm3 of dioxane. The mixture is brought to reflux for 2 h 30 min and then cooled, and gaseous CO2 is bubbled through until the precipitation of barium carbonate is complete. The precipitate is removed by filtration and the filtrate is taken to dryness. 0.9 g (63%) of [(3S)-3-carboxy-l,2,3,4-tetra-hydro-p-carboline]-1-spirocyclohexane is obtained.

Melting point: 198-201° C Optical rotation: a d = -69.9° (c = 4.81 gl-1 MeOH) UV (MeOH): A max 290, 280 and 220 nm 1H NMR (CDCI3 + CD3OD) 8 : (ppm) 238709 7.45 d(1H); 7.35 d(lH); 7.15 t(lH); 7.05 t(lH); 4.10 dd(lH); 3.35 dd(lH); 3.22 dd(lH); 2.4 to 1.8 unresolved complex (10H) n EXAMPLE 4: [(3S)-3-METHOXYCARBONYL-l,2,3,4-TETRAHYDRO-p-CARBOLINE] - 1-SPIROCYCLOHEPTANE Using the procedure described in Example 2, but replacing eyelohexanone by cycloheptanone, [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-{J-carboline]-l-spiro-cycloheptane is obtained.

Melting point: 130-133° C Optical rotation: cio = -55° (c = 6.00 gl"l MeOH) UV (MeOH): Xmax 288, 280 and 225 nm IR (CHC13 film) bands at 3400, 1730 cirri 1H NMR 300 MHz (CDCI3) 7,32 ppm 7,15 ppm ► h 7,10 ppm 7,48 ppm 7,95 ppm dd 2,76 ppm dd 3,08 ppm CO2CH3 M s 3,83 ppm dd 3,88 ppm 13C NMR 75 MHz (CDCI3) ' 238709 174,2 ppm Other signals (CH2) a 30,0; 29,6; 26,2; 23,1 and 22,4 ppm EXAMPLE 5: [ ( 3S ) - 3 - ( N-PROP YLCARBAMOYL ) - 1,2,3,4-TETRAHYDRO-0-CARBOLINE]-1-SPIROCYCLOHEXANE 2 g of [(3S)-3-methoxycarbonyl-l, 2, 3,4-tetra-hydro-0-carboline]-l-spirocyclohexane and 30 cm3 of N-propylamine are introduced into a sealed tube, and the suspension is then heated at 60° C for 45 hours.

The N-propylamine is removed under reduced pressure and the residue is then purified by chromatography. [(3S)-3-(N-Propylcarbamoyl)-1,2,3,4-tetrahydro--carboline]-l-spirocyclohexane is obtained in a 50% yield.

Melting point: 225-226° C Optical rotation:a d = -101.3° (c = 5.77 gl~l MeOH) UV (MeOH): Amax 290, 283 and 225 nm IR (CHCI3 film): bands at 3200 (broad), 1650 cm-1 1H NMR 300 MHz (CDCI3) 238709 dd 2,63 ppm dd 3,33 ppm d 7,30 ppm t 7,12 ppm —► h t 7,08 ppm d 7,49 ppm s 8,45 ppm CH3«— t 0,99 ppm *4 m 1,62 ppm m 3,30 ppm t 7,39 ppm dd 3,61 ppm 13c NMR 75 MHz (CDC13) 127,1 ppm 118,2 ppm 119,2 ppm 107,6 ppm 53>1 ppm \ 121,5 ppm 110,7 ppm 135,7 ppm 173,6 ppm CH3«— 11,3 ppm H 40,8 et 40,6 ppm (rotamers) 53,5 ppm 141,0 ppm Other signals (CH2) at 38.5, 34.3, 25.8, 25.4, 22.8, 21.6 and 21.2 ppm EXAMPLE 6: [(3S)-3-(N-CYCLOHEXYLCARBAMOYL)- 1,2,3,4-TETRAHYDRO-p-CARBOLINE] -1-SPIROCYCLOHEXANE A suspension under an argon atmosphere of 2 g of [(3S)-3-methoxycarbonyl-l ,2,3,4-tetrahydro-0-carboline]- 1-spirocyclohexane in 35 cm3 of cyclohexylamine is heated to reflux for 20 hours. 238709 The cyclohexylamine is removed by distillation ^ and the residue is then purified by chromatography. [(3S)-3-(N-Cyclohexylcarbamoyl ) -1,2,3 , 4 -tetrahydro-P-carboline]-l-spirocyclohexane is obtained in a 63% 5 yield.

Melting point: 225-230° C Optical rotation: = -60.8° (c = 5.75 gl"l MeOH) UV (MeOH): Amax 289, 280 and 225 nm IR (KBr) 3290, 1660, 1580 cnrl 10 1H NMR 300 MHz (CDC13) I m dd 2,64 ppm dd 3,33 ppm d 3,61 ppm t 7,10 ppm d 7,50 ppm — s'X t .s s 8,65 ppm f n 3,88 ppm 13C NMR 75 MHz (CDCI3) 238709 f ^ 127,1 ppm 110,8 ppm 135,6 ppm 107,7 ppm 172,4 ppm 47,4 ppm 53,1 ppm 53,5 ppm 141,1 ppm Other signals (CH2) at 38.5, 34.1, 33.0, 32.9, 25.8, 25.5, 24.5, 21.7 and 21.2 ppm EXAMPLE 7: [{3S)-3-CARBAMOYL-l,2,3,4-TETRA-HYDRO-p-CARBOLINE]-1-SPIROCYCLO-HEXANE 15 In a sealed tube, 1 g of [ 3-methoxycarbonyl-1,2,3,4-tetrahydro-f}-carboline]-l-spirocyclohexane is dissolved in 12 cm3 of methanol, 3 cm3 of liquid ammonia are then added and the mixture is maintained at room temperature for 36 hours.

The ammonia is allowed to outgas and the product formed, which crystallizes slowly, is isolated by filtration. 0.82 g (82%) of [3-carbamoyl-l,2,3,4-tetrahydro-0-carboline]-l-spirocyclohexane is thereby obtained.

Optical rotation: ao = -117.6° (c = 4.02 gl-l DMSO) Melting point, base: 278-279° C; hydrochloride: 188-189° C UV: Xmax 295 and 220 nm IR (KBr disk): bands at 3500, 3250, 1680, 1560 cnrl 1H NMR (base) (CDCI3 + DMSO-d6) 8 (ppm) 2387 0 #» .3 bs(lH); 7.4 d(lH); 7.3 d(lH), 7.05 t(lH); 6.95 t(lH); 6.8 bs(lH); 4.6 bs(2H); 3.6 m(lH); 3.15 dd(lH); 2.6 dd(lH); 2.15 dt(lH); 1.9-1.3 unresolved complexes (9H) EXAMPLE 8: [( 3S )-3-METHOXYCARBONYL-l, 2 , 3 , 4- TETRAHYDRO-0-CARBOLINE ] -l-SPIRO-4 ' -[1- METHYLPIPERIDINE] 3.7 g (17 mmol) of L(—)-tryptophan methyl ester, 3.85 g (34 mmol) of redistilled N-methyl-4-piperidone and 0.34 g of para-toluenesulfonic acid (monohydrate) are dissolved in the heated state in sufficient toluene for the reactants to be in solution under reflux, under a nitrogen atmosphere, in a Dean and Stark apparatus enabling the water formed during the reaction to be removed.

The reaction medium is brought to reflux until the starting materials have disappeared (approximately 20 hours), and the toluene is then removed by distillation under reduced pressure. The residue obtained is taken up with chloroform and washed copiously with 10% aqueous sodium bicarbonate solution so as to remove as much of the excess N-methyl-4-piperidone as possible.

After its solution in chloroform has been taken to dryness, the crude product is purified by chromatography on a silica column (eluent: CHCI3/CH3OH with a concentration gradient). 3.4 g (64%) of [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-p-carboline]-l-spiro-4'-[1-methylpiperidine ] are thereby obtained in the form of a non-crystalline product.

Optical rotation: ap (MeOH): -19.5° UV (MeOH): Amax at 220, 280 and 296 nm IR (CHCI3 film) vC = 0 at 1725 and 1740 cm-1 1H NMR 300 MHz (CDCI3) 238709 ch3 13C NMR 75 MHz (CDCI3) ch3 m 45,9 ppm EXAMPLE 9: [(3S)-3-CARBOXY-l,2,3,4-TETRA- HYDRO-p-CARBOLINE]-l-SPIRO-4'-[1-METHYLPIPERIDINE] 1 g (31.9 mmol) of [(3S)-3-methoxycarbonyl-1,2,3,4-tetrahydro-JJ-carboline ] -l-spiro-4' - [ 1-methylpiper idine ] is added to a mixture of 20 cm3 of distilled water and 2 cm3 of 38% potassium hydroxide solution.

The quantity of dioxane enabling dissolution to be obtained in the heated state is added, and the reaction medium is maintained for 10 hours under reflux under a nitrogen atmosphere. The reaction medium is then concentrated to 2/3 of its volume and 100 mg of Amberlist 77 cationic resin are added. 238709 The resin is removed by filtration and the reaction medium concentrated under reduced pressure. 0.7 g (67%) of [(3S)-3-carboxy-l,2,3,4-tetra-hydro-p-carboline]-l-spiro-4'-[1-methylpiperidine] is thereby 5 obtained.

UV (MeOH): Xmax at 220, 280 and 290 nm IR (film) broad band at about 1700 cirri EXAMPLE 10: [ (3S)-3-METHOXYCARBONYL-2-METHYL-1,2,3,4-TETRAHYDRO-0-CARBOLINE] -1-10 SPIRO-4'-[1-METHYLPIPERIDINE] 98 mg (0.31 mmol) of [(3S)-3-methoxycarbonyl-1,2,3,4-1etrahydro-p-carboline ]-l-spiro-4 '-[ 1-methylpiper idine] and 39 mg of sodium cyanoborohydride are dissolved in a mixture of 4 cm3 of 40% formaldehyde and 0.5 cm3 of acetic acid. After 15 one hour's stirring at room temperature, the reaction medium is poured into 10% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform phases are washed with water, dried over magnesium sulfate and then taken to dryness under reduced pressure.

Imp 95 mg (93%) of [(3S)-3-methoxycarbonyl-2-methyl- 1,2,3,4-tetrahydro-p-carboline]-l-spiro-4'-[1-methylpiperidine] are thereby obtained in the form of a gum.

Optical rotation: an = (MeOH): -8° ^ UV (MeOH): Amax at 225, 280 and 285 nm 25 IR (CHCI3 film) vC = 0 at 1720 and 1735 cnrl 1H NMR 300 MHz (CDCI3) * 23 8 7 09 23- 13C NMR 75 MHz (CDCI3) f 173,6 ppm CH3 45,6 ppm EXAMPLE 11: [ (3S)-3-CARBOXY-l,2,3, 4-TETRA-HYDRO-P-CARBOLINE ] -l-SPIRO-4 • -PIPERIDINE A mixture of 2.5 g of tryptophan and 1.8 g of 4-piperidone hydrochloride dissolved in a mixture of 70 cm3 of dioxane, 40 cm3 of water and 5 cm3 of 97% sulfuric acid is heated to reflux for 48 hours under an argon atmosphere.

The reaction medium is cooled and the product formed, which precipitates slowly, is isolated by filtration. 2.3 g (62%) of [(3S)-3-carboxy-l,2,3,4-tetra-hydro-p-carboline]-l-spiro-4'-piperidine hydrochloride are thereby obtained.

UV (MeOH): Amax 295 and 222 nm 238709 1H NMR (CDCI3 + CD3OD) 8 (ppm) 7.6 d(lH); 7.4 d(lH); 7.15 t(lH); 7.05 t(lH); 4.2 t(lH); 3.9 multiplet (2-3H); 3.5 multiplet (4H); 2.9 multiplet (3-4H) 13C NMR (CD3OD) 8(ppm) 171.6, 137.5, 130.0, 128.3, 123.5, 120.7, 119.2, 112.4, 105.7, 58.3, 54.5, 43.1, 42.0, 27.2, 25.9 ,-s EXAMPLE 12: [(3S)-3-METHOXYCARBONYL-l,2,3,4-TETRAHYDRO-p-CARBOLINE]-l-SPIRO-4'- PIPERIDINE A suspension of 2.18 g of methyltryptophanate and 10 1.55 g of 4-piper idone hydrate hydrochloride in 160 cm3 of benzene is heated to reflux for 29 hours in a Dean and Stark apparatus.

The benzene is removed by distillation, the residue is dissolved in sufficient methanol and gaseous HC1 is 15 bubbled through to saturation.

The product, which crystallizes slowly, is isolated by filtration. 2.15 g (58%) of [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-Q-carboline ]-l-spiro-4 '-piperidine are thereby <.0 obtained.

Melting point: 182-185° C Optical rotation: an = -46.8° (c = 2.71 gl"l CHC13/CH30H, 3 : 1) UV (MeOH): Amax 295 and 220 nm ** 1H NMR (DMS0-d6) 8(ppm) product in the form of a dihydrochloride 25 H.5 S(1H); 9.8 s(lH); 9.4 s(lH); 7.5 d, J = 7 Hz(lH); 7.45 d, J = 7 Hz(lH); 7.15 t J = 7 Hz(lH); 7.05 t J = 7 Hz(lH); 4.65 m(lH); 3.9 d(3H); 3.4 m(2H); 3.2-2.4 unresolved complexes (8H) 13C NMR (DMSO-d6) 8(ppm) product in the form of a dihydrochloride 238709 EXAMPLE 13: [ 5-ACETOXY-l ,2,3,4,5,6-HEXAHYDRO-AZEPINO[4,5-b]INDOLE]-4-SPIRO-l'-(3'-CYCLOHEXENE) 1.96 g (10.37 mmol) of 4-bromo-4-formylcyclo- hexene are added to a solution of 0.833 g (5.2 mmol) of tryptamine in 50 cm3 of acetic acid, and the reaction medium is then heated to 70° C under a nitrogen atmosphere for 15 hours.

After removal of the acetic acid by distillation ft I under reduced pressure, the residue is taken up with 100 cm3 of methylene chloride. The organic solution is washed with 100 cm3 of 10% aqueous sodium carbonate solution, dried over magnesium sulfate and then taken to dryness, yielding 2.52 g of crude product.

^ A purification by chromatography on a silica column (eluent: CHCI3) enables 1.12 g (70%) of [5-acetoxy-1,2,3,4,5,6-hexahydroazepino[4, 5-b]indole]-4-spiro-l'- ( 3 ' — cyclohexene) to be isolated in the form of a mixture of two diastereoisomers, the proportion, 60:40, of which was determined 20 by NMR.

UV (MeOH): Amax at 220, 280 and 290 nm IR (KBr) vC = O: 1725 cm~l; vC - O - C: 1245, 1235 cm~l 1H NMR 300 MHz (CD3OD) 8(ppm) 238709 * (•—•s 7.1 .85 and 5, .83-5.73 .66-5.5 3.33-3.14 3.14-2.96 2.1 and 2.( JU IF1'™? 7.55 1H d J = 8Hz C(10)H 7.35 1H d J = 8Hz C(7)H 7.18 1H t J = 8Hz C(8)H 1H t J = 8Hz C(9)H 71 1H s (3:2) C(5)-H 1H m C(3')H or C(4')H 1H m C(41)H or C(3')H 2H m C(2)-HH* 2H m C(1)-HH' 2.33-1.63 6H m 3H s (3:2) OCOCH3 13C NMR 75 MHz (CD3OD) 8 (ppm) 171.3 (OCOCH3); 135.0 (C 6a); 131.2 (C 5a); 127.6 (C 10a); 126.5 and 126.0 (C 3'); 123.3 (C 4'); 122.1 and 121.7 (C 8); 119.4 and 119.2 (C 9); 118.3 and 118.0 (C 10); 113.3 (C 10b); 111.3 (C 7); 75.1 and 71.9 (C 5); 55.0 (C 4); 41.9 and 41.8 (C 2); 36.0 and 33.6 (C 2'); 31.7 and 31.4; 26.1; 22.7; 20.7 (OCOCH3) EXAMPLE 14: [5-METHOXY-l,2,3,4,5,6-HEXAHYDRO-AZEPINO[4,5-b]INDOLE]-4-SPIRO-l'-(3'-CYCLOHEXENE) A simple heating in methanol under reflux for 1 hour permits the conversion of [5-acetoxy-l,2,3,4,5,6-hexahydroazepino[ 4, 5-b ] indole ]-4-spiro-l' - ( 3 ' -cyclohexene) to the 5-methoxy compound.

UV (MeOH): Amax at 220, 280 and 290 nm 23 87 0 9 * IR (film) 3380, 3010, 2920, 1460, 1450, 1090 and 900 cnrl 1H NMR 300 MHz (CD3OD) 8 (ppm) 1 8.20 and 8. ,15 1H bs (3 :2) N(6)H 7.52 1H d J = 8Hz C(10)-H 7.34 1H d J = 8Hz C(7)-H 7.22-7.06 2H m C(8)-H + C(9)-H .76-5.47 2H m C(3')H + C(4■)-H 4.18 and 4. 00 1H s (3: 2) C(5)-H 3.34 and 3. 27 3H s (3: 2) OCH3 3.22-2.82 4H m C(1)-HH' + C(2)-HH 2.75-2.48 IH m N(3)H 2.34-1.54 6H m EXAMPLE 15: [ 9-METHOXY-5-ACETOXY-1, 2,3,4,5,6-HEXAHYDROAZEPINO[ 4,5-b]INDOLE]-4-SPIRO-1'-(3'-CYCLOHEXENE) Starting with 5-methoxytryptamine and using the procedure described in Example 6, [9-methoxy-5-acetoxy-1,2,3,4,5,6-hexahydroazepino [ 4,5-b]indole]-4-spiro-l'- ( 3 * — cyclohexene) is obtained in the form of a mixture of diastereoisomers.

UV (MeOH): Amax at 220, 280 and 290 nm IR (film) vC = 0: 1710 cnrl; vC - 0 - C: 1235, 1215 cnrl 1H NMR 300 MHz (CDCI3) 8 (ppm) 238709 CH30 8.46 IH bs N ( 6 ) H 7.16 IH d C(7)-H 6.94 IH s C(10)-H 6.84 IH d C(8)-H .72 IH s C(5)-H .82-5.66 IH m C(3')-H or C( 4' )H .60-5.49 IH m C(4')-H or C(3')-H 3.85 3H s OCH3 3.29- 3.16 2H 3.02-2.87 2H m C(1)HH• 2.67-2.52 IH m N(3)-H 2.33-1.64 6H m 2.07 3H s CH3C m C (2)HH' EXAMPLE 16: [5-ACETOXY-3-METHYL-1,2,3,4,5,6-15 HEXAHYDROAZEPINO[4,5-b]INDOLE]-4- SPIRO-1'-(3'-CYCLOHEXENE) A solution of 0.2 g (1.15 mmol) of N-methyltryptamine and 0.240 mg (1.27 mmol) of 4-bromo-4-formylcyclohexene in 20 cm3 with acetic acid is heated to 70° C 20 for 4 days under a nitrogen atmosphere. After removal of the acetic acid by distillation under reduced pressure, the residue is taken up with 50 cm3 of methylene chloride and washed with 10% aqueous sodium carbonate solution. The organic phase is dried over MgS04, filtered and concentrated under reduced 25 pressure. The crude product obtained is purified by chromatography on silica (eluent: CH2CI2/CH3OH, 97%/3%). 23 8 7 0 [5-Acetoxy-3-methyl-l,2,3,4,5,6-hexahydro-azepino[4,5-b]indole]-4 -spiro-1'-(3'-cyclohexene) is finally obtained in a 42% yield in the form of a mixture of diastereoisomers.

UV (MeOH): Amax at 223, 285 and 292 nm IR (film) 3380, 3000, 2900, 1710, 1450, 1360, 1330, 1230, 1010, 950, 710 cnrl IH NMR 300 MHz (CDCI3) 8(ppm) 8.38 and 8 .35 IH bs ; N(6) - -H 7.53 IH d J = 8Hz C(10)-H 7.27 IH d J = 8Hz C(7)-H 7.19 IH t J = 8Hz C(8)-H 7.10 IH t J = 8Hz C(9)-H .97 and 5 .95 IH s (2:3) C(5)-H .79-5.66 IH m C(3')-H or C(4')-H .64-5.47 IH m C(4')-H or C(31)-H 3.68-3.54 IH m C(2)-H 3.46-3.07 3H m C(2)-H' f C(1)-HH' 2.90-2.72 IH m 2.86 and 2 .82 3H s (3:2) N-CH3 2.45-1.80 5H m 2.08 and 2 .06 3H s (3:2) 0CCH3 EXAMPLE 17: 9-METHOXY-5-ACETOXY-4,4-DIMETHYL-1,2,3,4,5,6-HEXAHYDROAZEPINO[4,5-b]INDOLE #1 238709 A solution of 5.34 g of 5-methoxytryptamine and 4.53 g of 2-bromo-2-formylpropane in 150 cm3 of acetic acid is heated to 60° C under a nitrogen atmosphere for 2 hours. The acetic acid is removed by distillation under reduced pressure 5 and the residue taken up with methylene chloride and washed with % aqueous sodium carbonate solution. The organic phase is . . dried over MgSC>4, filtered and concentrated under reduced pressure. 9-Methoxy-5-acetoxy-4,4-dimethyl-l,2,3,4,5,6-10 hexahydroazepino[4,5-b]indole is obtained in a 66% yield. UV (MeOH): Amax at 215, 285 and 300 nm IR (film) 3380, 2960, 2940, 2840, 1730 (vC = 0), 1480, 1450, 1370, 1250 ( vC - 0 - C), 1020, 960 cnrl XH NMR 300 MHz (CDC13) 8(ppm) To CH3O 8.55 IH bs N(6)-H 7.16 IH d C(7)-H 6.94 IH d C(10)-H 6.82 IH dd C(8)-H 3.85 3H s CH3-O 3.27-3. 17 2H m C(1)-HH 2.96-2. 85 2H m C(2)-HH 2.18 IH bs N(3)-H 2.08 3H s CH3-C-O 1.20 and 1.24 2x3H 2xs -CH3, -CH3 238709 13C NMR 75 MHz (CDCI3) 8(ppm) 171.1(C = 0), 154.0(9), 132.6 (5a), 130.0 (6a), 128.3 (10a), 113.6 (10b), 112.5 (8), 111.9 (7), 100.2 (10), 77.6 (5), 55.8 (CH3O), 53.9 (4), 42.6 (2), 28.8 (CH3), 27.7 (1), 23.7 5 (CH3), 21.0 (CH3 - C) O EXAMPLE 18: 5-HYDROXY-4,4-DIMETHYL-l,2,3,4,5,6 -HEXAHYDROAZEPINO[4,5-b]INDOLE STAGE 1: 5-Acetoxy-4,4-dimethyl-3-trifluoro-acetyl-1,2,3,4,5,6-hexahydroaze-10 pino[4,5-b]indole A solution of 3.2 g of tryptamine and 3 g of 2-bromo-2-formylpropane in 150 cm3 of acetic acid is heated to 60° C under a nitrogen atmosphere for 15 hours. The acetic acid is removed by distillation under reduced pressure and the residue 15 is taken up with methylene chloride and washed with 10% aqueous sodium carbonate solution. After the organic solution has been taken to dryness, the residue is taken up in 10 cm3 of pyridine and 5 cm3 of trifluoroacetic anhydride. The reaction medium is ^^ poured into water and extracted with methylene chloride, then 20 taken to dryness.

The crude product is recrystallized in acetone.

-Acetoxy-4,4-dimethyl-3-trifluoroacetyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole is obtained in a 34% yield.

STAGE 2: 5-Hydroxv-4,4-dimethyl-l,2,3,4,5,6- hexahydroazepinot 4,5-blindole 2 g of 5-acetoxy-4,4-dimethyl-3-trifluoroacetyl-l,2,3,4,5,6-hexahydroazepino[4,5-b]indole and 0.7 g of potassium carbonate in 50 cm3 of methanol are stirred at room temperature 30 under a nitrogen atmosphere for 4 hours. After filtration, the product is extracted with methylene chloride and isolated by r 23 87 0 9 taking to dryness. 5-Hydroxy- 4,4-dimethy1-1,2,3,4,5,6-hexahydroazepinof4,5-b]indole hydrochloride is obtained by dissolving the base in acetone and adding an ethereal solution of hydrochloric acid.

Yield: 95% Analysis of the base: UV (MeOH): Amax at 220, 283 and 290 nm IR (film) 3380, 2960, 2900, 1450 cnrl IH NMR 300 MHz (CDC13) 8(ppm) 1 8.56 IH bs N(6)-H 7.45 IH d C(10)-H 7.20 IH d C(7)-H 7.15 and 7.05 2H t, t C(9)-H and C(8)-H 4.10 IH s C(5)-H 3.10-2.70 6H m C(1)-HH', C(2)-HH' N(3) -H, OH 1.09 3H s ch3 1.01 3H s ch3 EXAMPLE 19: TABLETS CONTAINING 50 MG OF [ ( 3S)-3-METHOXYCARBONYL-l,2,3,4-TETRA-HYDRO-p-CARBOLINE]-1-SPIROCYCLO-HEXANE Preparation formula for 1,000 tablets. [ (3S)-3-Methoxycarbonyl-l,2,3,4-tetrahydro-0-carboline]-1-spiro- cyclohexane 50 g Wheat starch 15 g Corn starch 15 g 2 3 8 7 P ■: & ^ Lactose 50 g Magnesium stearate 1 g Silica 1 g Hydroxypropylcellulose 2 g PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE A: TESTING FOR ANTI-INFLAMMATORY ACTIVITY The anti-inflammatory potential of the compounds was investigated according to a model of acute inflammation 10 induced by the subcutaneous injection of carrageenan into the rat hind foot, according to a technique based on that of WINTER et al. Proc. Soc., Exp. Biol Med, 111, 554 (1962) and WINEGAR et al. J. Pharmacol. Exp. Ther 166, 96 (1969).

Male Sprague-Dawley rats weighing 200 to 300 g 15 are randomized in batches of 10 and receive the test substances by intraperitoneal administration 30 to 60 minutes before the local injection into the left hind foot of 0.1 ml of a 0.5% suspension of carrageenan in sterile physiological saline.

^ * The right hind foot serving as a control receives an injection of physiological saline.

Three hours after the injection of carrageenan, the animals are anesthetized deeply with Narcorem R and the volume of both hind feet is measured by plethysmography.

The results are expressed as a percentage change in volume v%: M 238709 volume left foot - volume right foot v% = volume right foot the anti-inflammatory activity AIA % is defined as / AIA% = 100 - v% (treated) x 100 \ v% (control) Product Dose AIA% [(3S)-3-methoxycarbonyl- 50 mg/Kg 14 % 1,2,3,4-tetrahydro-p- carboline]-l-spiro cyclohexane [(3S)-3-methoxycarbonyl- mg/Kg 14 % 1,2,3,4-tetrahydro-^- carboline]-l-spiro-4'-ti me thy 1 piperidine] V" EXAMPLE B: TESTING FOR ANALGESIC ACTIVITY The analgesic potential of these products was investigated according to the so-called "Acetic Acid Writhing" test, which is based on counting the abdominal cramps induced in mice by the intraperitoneal injection of acetic acid (GAIRIN et 10 al. J. Pharmacol. Exp. Ther 245, 955 (1988)).

The mice, randomized in batches of 10, received the test products intraperitoneally 30 minutes before the intraperitoneal administration of 0.3 cm3 of 1% acetic acid.

The number of cramps is counted between the 5th 15 and 20th minute after the injection of acetic acid. 238709 Products Number of cramps per minute (between the 5th and the 20th minute) - control [(3S)-3-methoxycarbonyl-1,2,3,4-tetrahydro-p-carboline]-l-spiro cyclohexane, 50 mg/Kg 23 ± 14 1 ± 1 The compounds of the literature structurally most closely related to the test products do not evince such analgesic activity.

EXAMPLE C: TESTING FOR ANXIOLYTIC ACTIVITY The anxiolytic potential of these products was , >2 investigated according to the "elevated plus maze" test.

This test enables the behavior of the rat, treated or otherwise, to be studied in a situation of choice between a reassuring enclosed space ("enclosed branch") and an open space creating anxiety ("open branch").

The test consists in counting the number of ■ ■ -i entries into each branch of the maze during 5 minutes, and measuring the time spent in the "open branch".

The rats are randomized in batches of 8 and receive the test products by intraperitoneal administration 60 minutes before the beginning of the test.

Claims (1)

1. 238709 -36- Product Dose total no. of entries % of entries into the open branch % of time spent in the open branch - control 14 ± 2 28 % ± 5% 22 % ±5% - t(3 S)-3-me thoxycarbony1-1,2,3,4-tetrahydro-p* carboline (3S) ]-l-spiro cyclohexane 50 mg/Kg IP 18 ± 2 42 % ± 4% 40 % ±6% - [(3S)—3-methoxycarbonyl-1,2,3,4-tetrahydro-p* carboline]-l-spiro-41 -[1-methyl piperidine] 100 mg/Kg IP 18 ± 1 44 % ± 3% 41 % ±4% 238709 -37- WHffXME CUiivi is:. A compound selected from substituted indole of formula (I): N — R3 (I) R6 R5 Rl| in which: A represents a bond or a radical of the formula -CH-, OR7 Rl represents hydrogen, linear or branched alkoxy having 1 linear or branched alkyl having 1 optionally substituted with up to halogen, hydroxyl, to 4 carbon atoms, to 6 carbon atoms 3 halogen, oxo, hydroxyl or alkoxy having 1 to 4 carbon atoms, R2 represents carboxyl, linear or branched alkoxycarbonyl having 1 to 6 carbon atoms and optionally substituted with optionally substituted phenyl; phenyloxycarbonyl, substituted phenyloxycarbonyl, carbamoyl, carbamoyl substituted on the nitrogen with up to 2 linear or branched alkyl having 1 to 6 carbon atoms or cycloalkyl having 4 to 7 carbon atoms; and in the case where A is a radical of the formula -CH- , OR7 R2 can also be hydrogen, R3 represents hydrogen, linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 3 halogen, oxo, linear or branched alkoxy 238709 -38- having 1 to 4 carbon atoms or optionally substituted phenyl, R4 and R5 together form a saturated or unsaturated 5- to 12-membered mono- or bicyclic ring-system which can comprise in the ring skeleton from 0 to 3 hetero atoms selected from oxygen, nitrogen and sulfur and which can optionally be substituted with up to 3 oxo, linear or branched alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, phenylcarbonyl, substituted phenylcarbonyl, optionally substituted phenylalkyl having 7 to 9 carbon atoms, optionally substituted fluorene, with, in the case where R4 and R5 form a bicyclic system, the possibility that one of the rings is an optionally substituted aromatic ring, and in the case where A is a radical of the formula -CH-, R4 and R5 can also represent, OR7 each independently of one another, hydrogen, optionally substituted phenyl, linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl, with the proviso that, when A is a o bond with Ri = R3 = R6 = H and R2 = COOH then R4 and R5 together cannot form a cyclopentyl or a cyclohexyl, and when A is a radical of the formula O II -CH- with R7 = H or CH3C - ,then R4 and R5 must be OR7 other than H, - Rg represents hydrogen or a linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl, 238709 - 39- - R7 represents hydrogen or a linear or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 3 oxo, halogen, alkoxy having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or optionally substituted phenyl, - its isomers, diastereoisomers, enantiomers, its addition salt with a pharmaceutically-acceptable acid, or, in the case where R2 is a carboxyl, with a pharmaceutically-acceptable base, the term substituted associated in the previous definitions with the expressions phenyl, phenylalkyl, phenyloxycarbonyl and phenylcarbonyl means that the aromatic rings may be substituted with up to 3 linear or branched alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxyl, nitro, trifluoromethyl or halogen. A compound as claimed in claim 1 selected from substituted indole of formula (I) for which A represents a o bond, which corresponds to the 1,2,3,4- tetrahydro-p-carbolines of formula (II): with Ri, R2, R3, R4, R5 and R& having the same meaning as in claim 1, its isomers, diastereoisomers, enantiomers, its addition salt with a pharmaceutically-acceptable acid or, in the case where R2 is a carboxyl, with a pharmaceutically-acceptable base. 23 -40- 3. A compound as claimed in claim 1 selected from substituted indole of formula (I) for which A represents a radical of the formula -CH-, which corresponds to the or7 1,2,3,4,5,6-hexahydroazepino [4,5-b] indoles of formula (III): R2 with Ri, R2, R3, R4, R5, R6 and R7 having the same meaning as in claim 1, its isomers, diastereoisomers, enantiomers, its addition salt with a pharmaceutically-acceptable acid or, in the case where R2 is a carboxyl, with a pharmaceutically-acceptable base. 4. A compound as claimed in claim 1 selected from substituted indole of formula (I) with R6 being hydrogen and R3 being either hydrogen or linear or branched alkyl having 1 to 6 carbon atoms, its isomers, diastereoisomers and enantiomers, its addition salt with a pharmaceutically-acceptable acid or, in the case where R2 is a carboxyl, with a pharmaceutically-acceptable base. 5. A compound as claimed in claim 1, which is [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-0-carboline ] -l-spiro-3'-[2-oxo-2,3-dihydroindole] having the below 238709 -41 - n formula, or its isomers or an addition salt pharmaceutically-acceptable acid. with a / 6. A compound as claimed in claim 1, which is [(3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-p-carboline ] -1-spirocyclohexane, having the below formula, or its isomers or an addition salt with a pharmaceutically-acceptable acid. 10 7. A compound as claimed in claim 1, which is [ (3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-|J- carboline]-1-spirocycloheptane having the below formula, or its isomers or an addition salt with a pharmaceutically-acceptable acid 15 2387 09 -42- 8. A compound as claimed in claim 1 which is [ ( 3S)-3-methoxycarbonyl-l, 2, 3,4-tetrahydro-{}- carboline]-l-spiro-4'-piperidine having the below formula, or its isomers or an addition salt with a pharmaceutically-5 acceptable acid. 10 9. A compound as claimed in claim 1 which is [ (3S)-3-methoxycarbonyl-l,2,3,4-tetrahydro-0- carboline ]-1-spiro-4 1 -[11-methyIpiperidine] having the below formula, or its isomers or an addition salt with a pharmaceutically-aceptable acid. N I CH3 2387 09 -43- 10. A compound as claimed in claim 1 which is [(3S)-3-carboxy-l,2,3,4-tetrahydro-p-carboline]- 1-spiro-4'-cyclohexane having the below formula, or its isomers or an addition salt with a pharmaceutically-acceptable 5 acid or a pharmaceutically-acceptable base. 11. A compound as claimed in claim 1 which is [ (3S)-3-carboxy-lf 2,3,4-tetrahydro-p-carboline]- 1-spiro-41-piperidine having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid or a pharmaceutically-acceptable base. 23 87 0 9 -44- 12. A compound as claimed in claim 1 which is [ ( 3S)-3-carboxy-l, 2, 3,4-tetrahydro-p-carboline ] - 1-spiro-4'-[11-methylpiperidine] having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid or a pharmaceutically-acceptable base. CH3 13. A compound as claimed in claim 1 which is [(3S)-3-methoxycarbony1-2-methy1-1,2,3,4-tetrahydro-J3-carboline]-l-spiro-4'-[1'-methylpiperidine] having the below formula or its isomers or an addition salt with a pharmaceutically-acceptable acid. CH3 -45- 238709 14. A compound as claimed in claim 1 which is I ( 3S)-3-carbamoyl-l,2,3,4-tetrahydro-ji-carboline]-l-spirocyclohexane having the below formula, or its isomers, or an addition salt with a pharmaceutically-5 acceptable acid. r2 o 10 LJ 15. A compound as claimed in claim 1 which is [(3S)-3-(N-propylcarbamoyl)-l,2,3,4-tetrahydro-fJ-carboline]-l-spirocyclohexane having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid. CNH - CH2CH2CH3 238709 -46- 16. A compound as claimed in claim 1 which is [(3S)-3-(N-cyclohexylcarbamoy1)-l,2,3,4-tetrahydro~p-carboline]-l-spirocyclohexane having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid. 17. A compound as claimed in claim 1 which is [5- acetoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole]-4-spiro-1'-(31-cyclohexene) having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid. CH3 23 8 7 -47- 18. A compound as claimed in claim 1 which is [5- methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole]-4-spiro-11-(31-cyclohexene) having the below formula, or its isomers, or an addition salt with a pharmaceutically-5 acceptable acid. 19. A compound as claimed in claim 1 which is [5- acetoxy-9-methoxy-l ,2,3,4, 5,6-hexahydroazepino [ 4, 5-b ] indole]-4-spiro-l'-( 3 '-cyclohexene) having the below 10 formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid. 2!-* 238709 -48- 20. A compound as claimed in claim 1 which is [5- acetoxy-3-methyl-l,2,3,4,5,6-hexahydroazepino[4,5-b] indole] -4- spiro-1'-(3'-cyclohexene) having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid. 21. A compound as claimed in claim 1 which is 5- acetoxy-9-methoxy-4 ,4-dimethyl-l,2,3,4,5,6- hexahydro-azepino [4,5-b] indole having the below formula, or its isomers, or an addition salt with a pharmaceutically-acceptable acid C=0 CH3 23 8 7 0 -49- 22. A compound as claimed in claim 1 which is 5- hydroxy-4,4-dimethyl-l,2,3,4,5,6-hexahydroazepino[4,5-b ] indole having the below formula, or its isomers, or an addition salt with a pharmaceutically-accepable acid. 23. A process for preparing a compound of claim 1, which varies according to the nature of the group A, either a substituted tryptamine of general formula (IV): R6 in which Ri, R3 and R6 have the same meaning as in the compound of general formula (I), is reacted with an aldehyde of general formula (V): 0 II Br c CH /\ R5 R4 (V) 238709 -50- in which R5 and R4 have the same meaning as in the compound of general formula (I)/ by heating them in an organic acid of general formula (VI): in which Rg is a methyl, ethyl or trifluoromethyl group, so as to obtain the 1,2,3,4,5,6-hexahydroazepino[4,5-bjindole of general formula (VII): in which Ri, R3, R4, R5 and Rg have the same meaning as in the compound of general formula (I) and Rs the same meaning as in the acid (VI), which can be either heated with an alcohol of general formula RgOH, in which Rg is a lower alkyl group, branched or otherwise, having 1 to 6 carbon atoms or an aralkyl group, so as to obtain the 1, 2,3,4,5,6-hexahydroazepino[4,5-b]indole of general formula (VIII): R8 COH (VI) II 0 (VII) -51 - 23 8 7 N — R3 (VIII) 1 r~r R6 0 r5 R4 r9 in which Ri, r3, r4, R5 and Rg have the same meaning as in the compound of general formula (I) and Rg the same meaning as above, or heated in methanol in the presence of 10 equivalents of potassium carbonate so as to obtain the l,2,3,4,5,6-hexahydroazepino[4,5- b]indole of general formula (IX): Q 10 w R1 N — R3 (IX) R6 o R5 r4 H in which Ri, R3, R4, R5 and Rg have the same meaning as in the compound of general formula (I), or a substituted tryptophan of general formula (X): R1 COOR10 (X) • » * 2 3 8 7 -52- in which Ri and R6 have the same meaning as in the compound of general formula (I) and Rig is a lower alkyl, branched or otherwise, having 1 to 6 carbon atoms or an optionally substituted aryl or aralkyl group, is reacted with a ketone of general formula (XI): 10 15 R5 — C — Rl| (XI) in which R4 and R5 have the same meaning as in the compound of general formula (I), under a nitrogen atmosphere, either in toluene or benzene under reflux in the presence of para-toluenesulfonic acid, the water formed during the condensation being removed by means of a water-extraction apparatus which can be, for example, a Dean and Stark apparatus, or, in some cases, under reflux of methanol or of the ketone itself, so as to obtain, after purification, the p-carboline of general formula (XII): O 20 Ri COOR10 (XII) R6 R5 in which Ri, R4, R5, Re and Rio have the same meaning as in the compounds of general formulae (I) and (X), which can be: - either reacted under reductive amination conditions with an aldehyde of general formula (XIII): R11 -CH II 0 (XIII) 23 8 7 -53- in which Rn is a hydrogen atom or a lower alkyl group, branched or otherwise, having 1 to 6 carbon atoms and optionally substituted with one or more halogen atoms, lower alkoxy groups having 1 to 4 carbon atoms or aryl groups, substituted or otherwise, so as to obtain the 0-carboline of general formula (XIV): in which Ri, Rio, Rn, R4, R5 and R6 have the same meaning as in the compounds of general formula (XII) and (XIII), or reacted with an acid chloride, or the corresponding acid anhydride, of general formula (XV): R11CC1 II (XV) 0 in which Rn has the same meaning as in the compound of general formula (XIII) so as to obtain the ^-carboline of general formula (XVI): R1 COOR10 C - Ri 1 (XVI) in which Ri, Rio, R11, ^6, R5 and R4 have the same meaning as in the compound of general formula (XIV), - or reacted, in the case where Rio = CH3, with 238709 -54- aqueous barium hydroxide solution so as to obtain the acids of general formula (XVII): R1 COOH (XVII) in which Ri, R4, R5 and R6 have the same meaning as in the compounds of general formula (I), - or reacted, in the case where Rio = CH3, with an amine of general formula (XVIII): NH 'R12 •R13 (XVIII) in which R12 and R13 represent, each independently of one another, a hydrogen atom or lower alkyl groups, branched or otherwise, having 1 to 6 carbon atoms or cycloalkyl groups having 4 to 7 carbon atoms, so as to obtain the amides of general formula (XIX): 0 C - N 'R12 •R13 (XIX) in which Ri, R4, R5 and R6 have the same meaning as in the compounds of general formula (I) and R12 and R13 the same meaning as in the amides of general formula (XVIII), 23 8 7 0 -55- it being understood that the compounds of general formula (VII), (VIII), (IX), (XII), (XIV), (XVI), (XVII) and (XIX) form part of the invention and are special cases of the compounds of general formula (I). 24. A pharmaceutical composition containing as active principle a compound as claimed in claim 1, alone or in combination with one or more pharmaceutical^ acceptable, non-toxic, inert excipients or vehicles. 25. A pharmaceutical composition as claimed in claim 24, presented in a form suitable, in particular, for the treatment of disorders of the central nervous system and of memory, pain, inflammation, stroke and convulsions. 26. A conpound of the general formula XI) as defined in claim 1 substantially as herein described with reference to the examples. 27. A process for the preparation of the compound as defined in claim 1 substantially as herein described with reference to the examples. (j> yi^>■■ ' or.-^ci Agants, A J. PARK Sc SON