FR2720064A1 - New thia-cycloalkyl- and cycloalkyl-b-indole(s) are anti-oxidants - Google Patents

Abstract

(Thia)cycloalkylbindoles of formula (I), their optical isomers and base addn. salts, are new. A = -(CH2)m or a gp. (a); m = 5 or 6; p = 1-4; R1 = OH, SH, O-R4 or -S-R5; R4 = alkyl or acyl; R5 = alkyl, phenyl or benzyl; R2 = H, halo, alkyl, alkoxy or CF3; R3 = alkyl, acyl, carboxyalkyl or alkoxycarbonylalkyl, or H (if A is not pentamethylene); if m = 1, R2 = H and R1 = methoxy, R3 is not methyl; alkyl, alkoxy and acyl are 1-6C gps. Daily dosage is 0.5mg - 2g, pref. 10 - 100mg.

Description

 The present invention relates to thiacycloalkyl [b] indoles, process for their preparation and pharmaceutical compositions containing them.

 It is now established that lipid peroxidation is a major pathological factor. In particular, it is clear that the process of lipid peroxidation and the products it generates can be detrimental to cell viability.

The effects of lipid peroxidation have been implicated in many pathological conditions such as atherosclerosis, hemolytic anemia, and ischemia - reperfusion injury.
Biological and Medical Aspects. 1991 Pergamon Press, page XXi). The possibility of having molecules that make it possible to combat this phenomenon of lipid peroxidation thus proves of great utility for the clinician for the prevention and treatment of pathologies involving such a phenomenon.

 The Applicant has discovered thiacycloalkyl [b] indoles, an original structure, possessing a powerful antioxidant action and allowing protection of lipids, and in particular human LDL (Low Density Lipoproteins), against oxidation.

dans laquelle: - R1 représente un radical choisi parmi:
hydroxy,
-O-R4 avec R4 étant choisi parmi alkyle et acyle;
et -S-R5 avec R5 étant choisi parmi hydrogène, alkyle, phényle et benzyle, - R2 représente un radical choisi parmi hydrogène, halogène, alkyle, alkoxy et
trifluorométhyle, - R3 représente un hydrogène ou un radical choisi parmi alkyle, acyle, carboxyalkyle, alkoxycarbonylaîkyle, - et n représente un entier de 1 à 4, leurs isomères optiques, sous forme pure ou sous forme de mélange, lorsque R1, R2, ou R3 possédent un centre chiral, et leurs sels d'addition à une base pharmaceutiquement acceptable, étant entendu que les termes "alkyle", "alkoxy" et "acyle" représentent des groupements linéaires ou ramifiés contenant de 1 à 6 atomes de carbone.The invention relates more particularly to the compounds of formula (I):

in which: R1 represents a radical chosen from:
hydroxy,
-O-R4 with R4 being selected from alkyl and acyl;
and -S-R5 with R5 being selected from hydrogen, alkyl, phenyl and benzyl, - R2 represents a radical selected from hydrogen, halogen, alkyl, alkoxy and
trifluoromethyl, - R3 represents a hydrogen or a radical chosen from alkyl, acyl, carboxyalkyl, alkoxycarbonylalkyl, and n represents an integer of 1 to 4, their optical isomers, in pure form or in the form of a mixture, when R1, R2, or R3 has a chiral center, and their addition salts with a pharmaceutically acceptable base, it being understood that the terms "alkyl", "alkoxy" and "acyl" represent linear or branched groups containing from 1 to 6 carbon atoms.

Among the pharmaceutically acceptable bases which can be used for salifying the compounds according to the invention, mention may be made, by way of examples and in a nonlimiting manner,
Sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, ethanolamine, arginine, lysine, and diethanolamine.

dans laquelle R2 et n sont tels que définis dans la formule (I), R1' est choisi parmi -0-R4 et -S-Rs avec R4 et R5 tels que définis dans la formule (I) et X représente un atome d'halogène, pour obtenir: - soit un composé de formule (III):

dans laquelle R2, n et R1' sont tels que définis précédemment, - soit, après hydrolyse, un composé de formule (la):

dans laquelle R2, n et R1' sont tels que définis précédemment, composé de formule (III) ou (la) qui est substitué sur l'azote indolique par un radical de formule R3', avec R3' ayant la même signification que R3 tel que défini dans la formule (I) à l'exception de l'hydrogène, afin d'obtenir un composé de formule (la'):

dans laquelle R2, n, R1' et R3' sont tels que définis précédemment, composés de formule (la) ou (la') qui sont, si nécessaire, - soit soumis à une réaction de déalkylation afin d'obtenir un composé de formule (lb):

avec R2, R3 et n tels que définis précédemment et R1" représente un groupement hydroxy ou thiol, - soit soumis à l'action d'un mélange de formule (IV):
Al X'3, R5,SH (IV) dans laquelle X' représente un halogène et R5 représente un alkyle, un phényle ou un ben:yyle, pour obtenir, suivant les conditions d'utilisation du composé de formule (IV): * un composé de formule (lb) tel que défini précédemment, * ou un composé de formule (Ic)

dans laquelle R2, R3, R5' et n sont tels que définis précédemment, composé de formule (Ic) qui peuvent être soumis à une hydrogénation, quand R'5 représente un benzyle, pour obtenir le composé de formule (Id):

dans laquelle R2, R3 et n sont tels que définis précédemment, étant entendu que les termes "alkyle", "alkoxy" et "acyle" représentent des groupements linéaires ou ramifiés contenant de 1 à 6 atomes de carbone, les composés de formule (la), (la'), (Ib), (Ic) et (Id) formant l'ensemble des composés de formule (I), les composés de formule (I) pouvant être, le cas échéant: - purifiés suivant une ou plusieurs méthodes choisies parmi la cristallisation, la
chromatographie sur colonne de silice, I'extraction, la filtration, et le passage sur
charbon ou résine, - séparés, sous forme pure ou sous forme de mélange, en leurs éventuels isomères
optiques, - et salifiées par une base ou un acide pharmaceutiquement acceptable. The invention also relates to the process for the preparation of the compounds of formula (I), characterized in that it is condensed, in the presence of a base such as an alkali metal amide or its combination with an alkaline alkoxide (complex base) and preferentially the complex base NaNH 2 -t.BuONa, the compound of formula (II):

in which R2 and n are as defined in formula (I), R1 'is selected from -O-R4 and -S-Rs with R4 and R5 as defined in formula (I) and X represents an atom of halogen, to obtain: - either a compound of formula (III):

in which R2, n and R1 'are as defined above, or, after hydrolysis, a compound of formula (Ia):

in which R2, n and R1 'are as defined above, compound of formula (III) or (la) which is substituted on indole nitrogen by a radical of formula R3', with R3 'having the same meaning as R3 such as defined in formula (I) with the exception of hydrogen, in order to obtain a compound of formula (la '):

in which R2, n, R1 'and R3' are as defined above, compounds of formula (Ia) or (Ia ') which are, if necessary, - subjected to a dealkylation reaction to obtain a compound of formula (Ib):

with R 2, R 3 and n as defined above and R 1 "represents a hydroxyl or thiol group, or is subjected to the action of a mixture of formula (IV):
Al X'3, R5, SH (IV) wherein X 'is halogen and R5 is alkyl, phenyl or benzyl, to give, depending on the conditions of use of the compound of formula (IV): a compound of formula (Ib) as defined above, * or a compound of formula (Ic)

in which R2, R3, R5 'and n are as defined above, compound of formula (Ic) which can be hydrogenated, when R'5 is benzyl, to obtain the compound of formula (Id):

in which R2, R3 and n are as defined above, it being understood that the terms "alkyl", "alkoxy" and "acyl" represent linear or branched groups containing from 1 to 6 carbon atoms, the compounds of formula (la ), (la '), (Ib), (Ic) and (Id) forming all the compounds of formula (I), the compounds of formula (I) possibly being: - purified according to one or more methods chosen from crystallisation,
silica column chromatography, extraction, filtration, and
coal or resin, - separated, in pure form or as a mixture, into their possible isomers
optics, and salified by a base or a pharmaceutically acceptable acid.

 The substitution of the compound of formula (III) or (la), as defined above, with a radical of formula -R 3, provided for in the above synthesis process, can be carried out by reaction of a compound of formula (III) or (la) with a compound of formula R 3 -X ", Cl COO-R 3, (R 3 -O) 2 SO 2 or (R 3 -O-CO) 2 O wherein R 3 is as defined in formula (la ') and X represents a halogen, optionally followed by a hydrolysis or saponification step for obtaining the acid function from the ester, in the case where R 3 'represents an alkoxycarbonylalkyl.

FOR EXAMPLE THE INVENTION CONCERNED: the preparation of the complex base:
To a suspension of 7 equivalents (eq) of NaNH 2 (including 2 eq for the preparation of the alcoholate and 1 eq for the preparation of the enolate of imine or enamine) in tetrahydrofuran (THF) ( 7 cm3 for 70 mmol of NaNH2), 2 eq.

2-methyl-propan-2-ol at room temperature. After this addition, the mixture is heated at 45 ° C. for 2 hours (the ratio NaNH 2 / t-BuONa is then 2/1 during the cyclization stage).

- the cyclization of imines:
In the basic medium prepared above, there is added at 0 C, 1 eq. imine to be condensed in solution in THF (3 cm3 for 1 mmol). The mixture is stirred magnetically at room temperature or 4095 ° C. The reaction is monitored by gas chromatography.

the preparation of unsubstituted indoles on nitrogen (hydrolysis):
When all the starting material has disappeared, the mixture is hydrolyzed at 0 ° C. After extraction with ether, the organic phase is dried over MgSO 4 and the solvents are evaporated under reduced pressure. The thiacycloalkyl [b] indole is then separated by liquid chromatography.

N-methylation in situ: preparation of N-methylated thiacycloalkyl [b] indoles
When all the starting material has disappeared, the reaction medium is decanted, then the liquid part is transferred into a Mariotte ampoule and then added dropwise at 3 eq. of Me2SO4 in solution in THF at 000. At the end of the addition, the reaction medium is allowed to rise to ambient temperature. After 2 hours, the mixture is hydrolysed with an aqueous solution of NH 4 OH at 32% and then extracted with methylene chloride. The organic phase is then dried over MgSO 4 and the solvents evaporated under reduced pressure. The N-methylated thiacycloalkyl [b] indole is then separated by liquid chromatography.

N-carbethoxymethylation in situ: preparation of thiacycloalkyl [b] indoles N
carbéthoxyméthylés:
The liquid part of the reaction medium is transferred to an addition funnel and added dropwise to a solution of BrCH2COOEt (3 eq) in dimethylformamide (DMF) (6 cm3 for 1 mmol) at room temperature. After 2 hours, the mixture is extracted with ether and the organic phase is washed with water and then dried over MgSO 4 and the solvents evaporated under reduced pressure. The thiacycloalkyl [b] indole thus obtained is then separated by liquid chromatography.

saponification: Formation of N- (carboxymethyl) thiacycloalkyl [b] indoles:
The N- (carbethoxymethyl) thiacycloalkyl [b] indole prepared above is refluxed in a 10% solution of KOH in ethanol. The reaction is followed by thin layer chromatography (TLC).

When all the starting material has disappeared, the reaction is discarded on ice and extracted with ether. The aqueous phase is then acidified and extracted again with ether. The organic phase is dried over MgSO4 and the solvents are evaporated under reduced pressure. The
N- (carboxymethyl) thiacycloalkyl [b] indole is purified by liquid chromatography.

dans laquelle R1 et R2 sont tels que définis dans la formule (I), avec une cétone de formule (V):

dans laquelle n est tel que décrit dans la formule (I).The compounds of formula (II) are readily accessible to those skilled in the art by reaction of an aniline of formula (IIa):

in which R1 and R2 are as defined in formula (I), with a ketone of formula (V):

wherein n is as described in formula (I).

SYNTHESIS OF IMINES AND ENAMINES
More particularly, the imines can be prepared by subjecting the eq.

haloamine and 1 eq. of ketone to azeotropic distillation in benzene. (Depending on the case, the reaction may be catalyzed by an acid (APTS, ZnCl2, ZnBr2, BF3-Et2O)).

After collecting the appropriate amount of water, the imine is distilled under reduced pressure.

 The raw materials used in the preparation processes described above are either commercial or easily accessible to those skilled in the art according to the literature.

 The compounds of the present invention possess very important antioxidant properties. In particular, pharmacological studies have shown that these compounds are endowed with remarkable and specific protective activities with respect to lipid peroxidation and in particular low density lipoprotein (LDL) peroxidation.

 The compounds of the invention therefore have a particularly new and beneficial action in conditions where a peroxidation phenomenon occurs, in particular lipid peroxidation. These new compounds can be used in the treatment or prevention of diseases due to or related to such peroxidation phenomena and in particular ischemic cerebral, renal or cardiac disorders, atherosclerosis, haemolytic anemias, damage due to the reperfusion process, and inflammatory syndromes.

 The present invention also relates to pharmaceutical compositions containing a compound of formula (I), or one of its addition salts with a base or a pharmaceutically acceptable acid, in combination with one or more pharmaceutically acceptable excipients.

 Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, percutaneous, cutaneous, parenteral, nasal, rectal, perlingual, ocular or pulmonary administration and in particular injectable or drinkable preparations, aerosols, eye or nasal drops, single, film-coated or coated tablets, capsules, capsules, creams, ointments, skin gels, pills, packets, sachets, granules and suppositories.

 The dosage varies according to the age, weight and sex of the patient, the route of administration, the nature and intensity of the condition, and any associated treatments. The doses range from 0.5 mg to 2 g per day, particularly from 0.5 mg to 100 mg per day, for example from 10 mg to 100 mg per day.

 The following examples illustrate the invention but do not limit it in any way.

PREPARATION 1: NCMIOPYRAN ILIDEN-3-YL) -3-CH LORO-4-M ETHOXYANILINE
1 eq. 3chloroparaanisidine and 1 eq. thiopyran-3-one are azeotroped in benzene (100 cm3 for 50 mmol). The reaction is monitored by gas chromatography and stopped after 5 hours. The imine is purified by distillation and is obtained with a yield of 40%.

1H NMR: 6.3-7.0 (3H, m, arom H); 3.7 (3H, s, OMe); 3.3 (1H, s, CH); 3.1 (1H, s, CH); 2.0-3.0 (m, 6H, 3 x CH 2)
Mass: 255 - Synthesis of thiopyrano [3,2-b] indoles by cyclization of imines followed by
hydrolysis:
The indole synthesis is described for the compound of Example 1:
EXAMPLE 1: 8-METHOXY-THIOPYRANO [3,2-b] -NODLE

Example 1
STAGE A:
Preparation of the complex base.

 To a suspension of 7 equivalents (hereinafter abbreviated eq.) Of NaNH 2 in tetrahydrofuran (7 cm 3 for 70 mmol of NaNH 2), 2 eq. 2 methyl propan-2-ol at room temperature. After this addition, the mixture is heated at 45 ° C. for 2 hours.

STAGES:
Condensation:
Procedure 1:
To the complex base prepared above, one adds at 00C, 1 eq. N- (thiopyraniliden3-yl) -3-chloro-4-methoxyaniline dissolved in THF (30 cm3 for 10 mmol).

 The mixture is stirred at ambient temperature for 12 hours. The reaction is monitored by gas chromatography. At the end of the reaction, the reaction medium is thrown on ice and extracted with ether.

 After drying over MgSO 4 and evaporation of the solvents under reduced pressure, the title compound is isolated by flash chromatography (Kieselgel 40-6311) with eluent 5% AcOEVether petroleum.

Yield: 53% relative to imine Melting point (Totoli): 123 C lR: 3390 (NH), 2999, 2938, 2922, 2834 (CH)
Analysis (C12H13ONS):
Calculated C 65.72 H 5.97 N 6.38 S 14.62
Found 65.95 6.03 6.53 14.93
Procedure 2:
The crude imine prepared in Preparation 1 from 1 eq. ketone + 1 eq.

of amine, is added at 0 ° C., without purification, to the complex base prepared above. The reaction is carried out as for procedure 1.

Yield: 36.5% compared to ketone.

- Synthesis of N = carbethoxymethyl indoles:
The synthesis will be described for the compound of Example 2:
EXAMPLE 2: 2z (OMETHOXY-THIOPYRANO13,2-BILNDOL + YL) ETHYL ACETATE

Example 2
At the end of the reaction carried out in Example 1 (procedure 1 or 2), the reaction medium is left decanted under a stream of nitrogen. The supernatant is transferred at room temperature into a solution of 4 eq. of BrCH2COOEt in dimethylformamide (DMF) (so as to have a THF / DMF = 1/2 mixture at the end of the addition). When the reaction is complete (followed by thin layer chromatography (TLC)), the reaction medium is thrown on ice, extracted with ether. After drying over MgSO4 and evaporation of the solvents, the title compound is isolated by flash chromatography with eluent 15% acetone / hexane.

Yield: 46% compared to imine
Melting point (Totoli): 98 ° C
IR: 2923 (CH); 1750 (C = O)
Analysis (C1 6H1 9O3NS)
Calc. C 62.92 H 6.27 N 4.58 S 10.49
Tr. 62.58 6.32 4.69 10.36
EXAMPLE 3: 8-METHOXY-IMETHYL-THIOPYRANO [3,2-b] -NODLE
The compound obtained in Example 1 is subjected to the action of 3 eq. of dimethyl sulphate, with stirring, at 0 C. The reaction medium is then stirred for 1 h at room temperature. The mixture is poured onto ice, washed with 32% ammonium hydroxide solution and extracted with ether. The expected compound is purified by liquid chromatography.

Yield: 53% 2nd process:
The compound obtained in Example 1, dissolved in dimethylformamide (DMF) is added dropwise, at 0 ° C., to a suspension of 2 eq. of sodium hydride in DMF (10 cm 3 of DMF for 1 mmole of indole substrate).

The reaction medium is allowed to return to ambient temperature and then 3 eq. dimethyl sulfate.

The medium is then treated in the same manner as in the first method above.

EXAMPLE 4: 8-HYDROXY-5-METHYL-THIOPYRANO [3,2-b] INDOLE
The compound of Example 4 is obtained by dimethylation of the compound obtained in Example 3.

EXAMPLE 5 8-ETHYLTHIO-5-METHYL-THIOPYRANO [3,2-b] INDOLE
To a mixture cooled at 0 ° C. of 380 mg (2.84 mmol) of aluminum chloride and 2.3 g (37.9 mmol) of ethanethiol, 500 mg (1.9 mmol) are added dropwise. of the compound obtained in Example 3, previously dissolved in 5 cm3 of methylene chloride distilled on phosphorus pentoxide. After stirring for 1 hour at 0 ° C., 1.5 eq. of aluminum chloride and 20 eq. ethanethiol. The mixture is stirred for a further 1 h at 0 ° C. and then poured onto ice, treated with 1 N hydrochloric acid and then extracted with dichloromethane.

After treatment of the organic phase and purification of the crude product by chromatography on a silica column, the expected compound is obtained.

EXAMPLE 6: 2 8-METHOXY-THIOPYRANO [3,2-b] -NDOL + YL) ACETIC ACID
By carrying out the hydrolysis of the ester function of the compound obtained in Example 2, the title compound is obtained.

EXAMPLE 7: 5-M EMYL- & BENZYLM IO-THIOPYRANO [3,2-b] IN DOLE
By proceeding as in Example 5, but replacing ethanethiol (CH3CH2SH) with benzylthiol (C6H5-CH2-SH), the title compound is obtained.

EXAMPLES 8 TO 17
By proceeding according to the methods described in the preceding examples and using the appropriate reagents, the compounds can be obtained in the following Table I:
TABLE (I)

<tb> N "<SEP> Example <SEP> R1 <SEP> R2 <SEP> R3 <SEP> | <SEP> n
<tb><SEP> 8 <SEP> -OH <SEP> -H <SEP> -H <SEP> 2
<tb><SEP> 9 <SEP> -O-CH3 <SEP> -H <SEP> -CH2-CH3 <SEP> 2
<tb><SEP> 10 <SEP> -O-CH3 <SEP> -H <SEP> -CH2-CH2-CH3 <SEP> 2
<tb><SEP> 11 <SEP> -O-CH3 <SEP> -H <SEP> - (CH2) 3-CH3 <SEP> 2
<tb><SEP> 12 <SEP> -O-CH3 <SEP> -OCH3 <SEP> -CH3 <SEP> 2
<tb><SEP> 13 <SEP> -OH <SEP> H <SEP> -CH2-CH3 <SEP> 2
<tb><SEP> 14 <SEP> -OH <SEP> H <SEP> -CH2-CH2-COO-CH2-CH3 <SEP> 2
<tb><SEP> 15 <SEP> -OH <SEP> H <SEP> -CH2-CH2-COOH <SEP> 2
<tb><SEP> 16 <SEP> -O-CH3 <SEP> -H <SEP> wCH3 <SEP> 2
<tb><SEP> CH3
<tb><SEP> 17 <SEP> -O-CH3 <SEP> -H <SEP> -CH2COO-CH (CH3) 3 <SEP> 2
<Tb>
PHARMACOLOGICAL STUDY
EXAMPLE A STUDY OF THE PROTECTIVE POWER OF LDL OXIDATION
The ability of the compounds of the invention to reduce the proportions of oxidized LDL was measured in the following manner: a 24 h incubation combining native LDL (Low Density Lipoproteins), a Cu2 + system generating free radicals and the compounds to test.

 The results are obtained after analysis of the medium by a high performance chromatographic technique: FPLC (Fast Protein Liquid Chromatography). The protective power of the test compound is determined after comparison of the chromatogram obtained with that of the reference positive control: probucol. It is clear that the compounds of the invention have a very important protective power. By way of comparison, for a concentration of 10-5 M, the level of protection obtained for the compounds of the invention exceeds that of probucol. This is particularly the case of the compound of Example 1 which allows a very strong protection vis-à-vis an LDL oxidizing system (75% non-oxidized form at 10-5 M).

EXAMPLE B: STUDY OF ANTIPEROXIDIZING ACTIVISTS
The action of the compounds used according to the invention, capable of trapping radicals
HO., Has been studied on the one hand, on the spontaneous peroxidation of lipids and on the other hand, on the peroxidation induced by the Fe2 + - ascorbate system (10 I1M - 250 FM), and this, on homogenates of brains of rats.

a) Study of spontaneous lipid peroxidation
When measuring spontaneous lipid peroxidation, rat brain homogenates are placed in the presence or absence of test compounds for 60 min at 37 ° C. The reaction is stopped at 0 ° C. and the malondialdehyde assay is performed. using thiobarbituric acid. Lipid peroxidation is determined by substances reacting with thiobarbituric acid expressed in nanomoles of malondialdehyde.

b) Study of induced lipid peroxidation
When measuring the lipid peroxidation induced, the methodology is identical to that previously described except for the addition to the homogenate of the radical inducer system: Fe2 + - ascorbate. The reference substances are probucol and vitamin
E. Concentrations of test compounds inhibiting 50% (IC50) peroxidation of the substrate are calculated.

 It has been found that the compounds of formula (I) used according to the invention have a particularly intense antiperoxidant activity since they possess a significantly greater antiperoxidant activity than probucol and vitamin E, which is the body's natural antioxidant. human.

EXAMPLES C AND
The compounds of the invention are also tested on 2 tests for detecting antioxidant activity.

EXAMPLE C INHIBMATION OF CONJUGATED DIENES FORMATION
1 cm3 of linoleic acid emulsion is incubated for 30 min at 37 ° C. in the presence of a solution of FeSO4 (final concentration 4 llmolA) with and without the test compound (final volume 1.55 cm 3).

The dienes are extracted with 8 cm3 of chloroform / methanol (2/1).

After centrifugation, 2 cm3 of the underlying organic phase are removed and stirred for 10 min with an aqueous solution at pH 2.

After centrifugation, 0.250 cm3 of the organic phase are removed and evaporated under nitrogen.

2 cm3 of hexane are then added and the optical density (OD) is measured at 233 nm.

Each assay is performed in triplicate. 4 to 5 hours are necessary to carry out a manipulation comprising 6 determinations (White and reference Fe included).

The percent inhibition of conjugated diene formation is calculated by comparison with the 100% of dienes formed with the Fe2 + control.

The compounds of the invention prove to be very effective in inhibiting the formation of dienes, which confirms their antioxidant character.

EXAMPLE D: PROTECTION OF HEMATIES AGAINST INDUCED HEMOLYSIS
BY AAPH
After centrifugation of a human blood sample, the red blood cells are washed three times with 9% NaCl and 0.250 cm 3 of pellet are suspended in 50 cm 3 of NaCl at 9 × 10.

 75 mM of AAPH under a volume of 0.750 cm 3 are brought into contact with 1 cm 3 of suspension of red blood cells and 10-5 M of the product to be tested in a volume of 0.200 cm 3. A control without AAPH is carried out simultaneously for each product tested, as well as a red cell control and an AAPH control without test product.

 After 30 minutes of incubation with stirring in a water bath at 37 ° C., the suspension of red blood cells is centrifuged for 10 min at + 4 ° C. (3000 rpm) and the optical density at 403 nm of the supernatant is measured relative to witness without AAPH.

The percent inhibition of hemolysis is calculated by comparison with the 100% hemolysis obtained with the AAPH control.

The compounds of the invention very significantly protect red blood cells from haemolysis.

EXAMPLE E PHARMACEUTICAL COMPOSITION COMPRESSES
Preparation formula for 1,000 tablets at 50 mg.

8-methoxy-thiopyrano [3,2-b] indole ...... .... 50 g
Wheat starch ... . .... 15 g
Corn starch .... 15g
Lactose. .. ..... 65 9
Magnesium stearate. .. 2 g Silica ... ... ... lg
Hydroxypropylcellulose .. 2 9

Claims (11)

 and -S-Rs with R5 being selected from hydrogen, alkyl, phenyl and benzyl, - R2 represents a radical selected from hydrogen, halogen, alkyl, alkoxy and trifluoromethyl, - R3 represents a hydrogen or a radical selected from alkyl, acyl, carboxyalkyl , alkoxycarbonylalkyl, - and n represents an integer of 1 to 4, their optical isomers, in pure form or in the form of a mixture, when R1, R2, or R3 have a chiral center, and their addition salts with a pharmaceutically acceptable base it being understood that the terms "alkyl", "Zalkoxy" and "acyl" represent linear or branched groups containing from 1 to 6 carbon atoms.  -R4 with R4 being selected from alkyl and acyl;  hydroxy,  in which: R1 represents a radical chosen from:

 1. Compounds of formula (I): 2. Compounds of formula (I) according to claim 1 wherein n is 2, their optical isomers, in pure form or in the form of a mixture, when R1, R2 or R3 have a chiral center, and their addition salts to a pharmaceutically acceptable base. 3. Compounds of formula (I) according to claim 1 wherein R1 represents a hydroxyl radical or -O-R4 with R4 as defined in claim 1, their optical isomers, in pure form or in the form of a mixture, when R1, R2 or R3 have a chiral center, and their addition salts to a pharmaceutically acceptable base. 4. Compounds of formula (I) according to claim 1 wherein R3 represents a hydrogen atom or an alkyl radical, their optical isomers, in pure form or in the form of a mixture, when R1, R2 or R3 occupy a chiral center, and their addition salts with a pharmaceutically acceptable base. The compound of claim 1 which is 8-methoxy-thiopyrano [3,2-b] indole. The compound of claim 1 which is 2- (8-methoxy-thiopyrano [3,2-b] indol-5-yl) ethyl acetate. 7. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that it is condensed, in the presence of a base such as an alkaline amide or its combination with an alkaline alkoxide (complex base) and preferentially the complex base NaNH 2 -t.BuONa, the compound of formula (II):

 in which R2, n are as defined in formula (I) according to claim 1, R1 'is selected from -O-R4 and -S-Rs with R4 and R5 as defined in formula (I) according to claim 1 and X represents a halogen atom, to obtain: - either a compound of formula (III):

  in which R2, n and R1 are as defined above, or, after hydrolysis, a compound of formula (Ia):

 in which R2, n and R1 'are as defined above, compound of formula (III) or (la) which is substituted on indole nitrogen by a radical of formula R3', with R31 having the same meaning as R3 such that defined in formula (I) with the exception of hydrogen in order to obtain a compound of formula (Ia '):

 in which R2, n, R1 'and R3' are as defined above, compounds of formula (Ia) or (Ia ') which are, if necessary, - subjected to a dealkylation reaction to obtain a compound of formula (Ib):

 optics, and salified by a pharmaceutically acceptable base.  coal or resin, - separated, in pure form or as a mixture, into their possible isomers  silica column chromatography, extraction, filtration, and  in which R2, R3 and n are as defined above, it being understood that the terms "alkyl", "alkoxy" and "acyl" represent linear or branched groups containing from 1 to 6 carbon atoms, the compounds of formula (Ia), (la '), (Ib), (tic) and (Id) forming the set of compounds of formula (I) according to claim 1, the compounds of formula (I) according to claim 1 possibly being: - purified according to one or more methods chosen from crystallisation,

 in which R2, R3 and n are as defined above, a compound of formula (Ic) which can be hydrogenated, when R'5 represents a benzyl, to obtain the compound of formula (Id):

 Al X'3, R5, SH (IV) in which X 'represents a halogen and Rg' represents an alkyl, a phenyl or a benzyl, to obtain, according to the conditions of use of the compound of formula (IV), * a compound of formula (Ib) as defined above: or a compound of formula (Ic):  hydroxy or thiol, - is subjected to the action of a mixture of formula (IV):  with R2, R3 and n as defined previously and R1 "represents a grouping 8. Process according to claim 7, in which the substitution of the compound of formula (III) or (la), as defined in claim 7, with a radical of formula -R3 ,, with R31 having the same meaning as R3 such that defined in claim 1 except for hydrogen, is carried out by reacting a compound of formula (III) or (la) with a compound of formula R3'-X ", Cl-COO-R3 ', ( R3'-O) 2SO2 or (R3'-O-CO) 20 in which R31 is as defined above and X represents a halogen, optionally followed by a hydrolysis step to obtain the acid function from of the ester in the case where R3 'represents an alkoxycarbonylalkyl. 9. Pharmaceutical compositions containing a compound of formula (I) according to claim 1, or a base-addition or pharmaceutically-acceptable addition salt thereof, in combination with one or more pharmaceutically acceptable excipients. 10. Compositions according to claim 9 for the treatment and prevention of conditions involving a peroxidation phenomenon, including lipid peroxidation. Pharmaceutical compositions according to claim 9, for use in the treatment or prevention of conditions due to or related to cerebral, renal or cardiac ischemic disorders, atherosclerosis, haemolytic anemias, reperfusion process damage, and inflammatory syndromes. .