FR2494114A1 - Cyclo:heptindolol hypotensive and antihypertensive derivs. - are 5-trans-amino-1-opt. substd. 3,4,5,6-tetra:hydro-1H-cyclo:hept (c,d)- indol-6-ols and their salts - Google Patents

Abstract

New cycloheptindolol derivs. of formula (I) are 5-trans-R1-NH-1-R-3,4,5,6 tetrahydro 1H-cyclohept-(c,d) indol-6-ol and their acid addn. salts (where R is H, 1-5C alkyl or opt. substd. 7-12C aralkyl and R1 is H, 1-5C alkyl, 4-7C cycloalkylalkyl or opt. substd., 7-12C aralkyl). Cpds. are hypotensives and antihypertensives which may be administered orally e.g. 5-200 mg daily) or parenterally. The cpds. have low toxicity (e.g. oral LDO in mice is 200 mg/kg for (I) (R1, R is H and its acetate; R is H, R1 is methyl as HCl and R is methyl; R1 is H as acetate and 100 mg/kg R is H, R1 is isopropyl. Activity tests are described.

Description

 The present invention relates to the application, as medicaments, of cycloheptindolol derivatives and their salts and the pharmaceutical compositions containing them.

dans laquelle R représente un atome d'hydrogène, un radical alcoyle renfermant de I à 5 atomes de carbone ou un radical aralcoyle renfermant de 7 à 12 atomes de carbone, éventuellement substitué, et R1 représente un atome d'hydrogène, un radical alcoyle renfermant de 1 à 5 atomes de carbone, cycloalcoylalcoyle renfermant de 4 à 7 atomes de carbone, ou aralcoyle renfermant de 7 à 12 atomes de carbone, éventuellement substitué ainsi que par les sels d'addition avec les acides pharmaceutiquement acceptables desdits dérivés.The subject of the invention is new medicaments characterized in that they consist of cycloheptindolol derivatives, corresponding to the general formula

in which R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, which is optionally substituted, and R1 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, cycloalkylalkyl containing from 4 to 7 carbon atoms, or aralkyl containing from 7 to 12 carbon atoms, optionally substituted as well as by addition salts with pharmaceutically acceptable acids of said derivatives.

 In the general formula I and in the following, the term "alkyl radical" containing 1 to 5 carbon atoms means, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl radical; the term "aralkyl radical" containing from 7 to 12 carbon atoms, optionally substituted, denotes, for example, a benzyl or phenethyl radical, the substituents of which may be, for example, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl or methylthio radicals; the term cycloalkylcarlyoyl radical containing from 4 to 7 carbon atoms means, for example, a cyclopropylmethyl radical.

The addition salts with pharmaceutically acceptable acids may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric acids.
citric, oxalic, glyoxylic, aspartic, alkanesulfo
such as benzene sulphonic acid.

Among the medicaments, object of the invention, it is possible
mention, in particular, the cycloheptindolol
in formula (I) above wherein R and R1 represent
a hydrogen atom or an alkyl radical containing I
to 5 carbon atoms and their addition salts with
pharmaceutically acceptable acids
Among the medicaments which are the subject of the invention,
more particularly:
5-R, S-trans amino 3,4,5,6-tetrahydro 1H-cyclohept
/ c, d / indol-6-ol
5-R, S-trans 5-methylamino 3,4,5,6-tetrahydro 1H-cyclo
hept / c, d / indol-6-ol
as well as their addition salts with pharmaceutic acids
acceptable.

Cycloheptindolol derivatives of formula (I) and their salts
possess very interesting pharmacological properties they are endowed, in particular, of remarkable properties hypotensive and antihypertensives.

 Because of these properties, the drugs, object of the present invention, can be used in the treatment of essential arterial hypernsai, hypertension of the fifties, menopause, diabetic, obese and plethoric, as well as in the treatment of arterial hypertension of the elderly, atherosclerosis and in the treatment of renal hypertension.

 The usual dose, variable depending on the product used, the subject treated and the condition in question, can be for example, from 5 mg to 200 mg per day, orally, in man, the product of Example 1.

 The invention finally relates to pharmaceutical compositions which contain at least one aforementioned derivative, or one of its addition salts with pharmaceutically acceptable acids, as active principle.

 As medicaments, the derivatives corresponding to formula (I) and their addition salts with pharmaceutically acceptable acids may be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

 These pharmaceutical compositions can be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, single or coated tablets, capsules, capsules, granules, suppositories, injectable preparations. ; they are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various dispersing or emulsifying wetting agents, preservatives.

dans laquelle R a la signification déjà indiquée, que l'on fait réagir, en présence d'un agent basique tel qu'un carbonate ou un hydroxyde alcalin, ou une amine tertiaire, avec un halogénure de formule tII ::
Hal-R'1 (III) dans laquelle Hal représente un atome de chlore, de brome ou de préférence d'iode et R'1 a la signification de R1 déjà indiquée à l'exception de lthydrogène pour obtenir un produit de formule IV

dans laquelle R et R'î ont la signification déjà indiquée, que lton soumet à un agent capable d'hydrolyser l'amide trifluoroacétique pour obtenir le produit de formule (I) cherché.The products of formula I in which R 1 has the meaning already indicated with the exception of hydrogen, and R has the meaning already indicated, may be prepared generally by reacting a product of formula I in which R 1 represents a hydrogen atom, and R has the indicated meaning with trifluoroacetic anhydride, preferably in the presence of a base, to obtain a product of formula II

in which R has the meaning already indicated, which is reacted, in the presence of a basic agent such as an alkali metal carbonate or hydroxide, or a tertiary amine, with a halide of formula III:
Hal-R'1 (III) wherein Hal represents a chlorine, bromine or preferably iodine atom and R'1 has the meaning of R1 already indicated with the exception of hydrogen to obtain a product of formula IV

wherein R and R 'have the meaning already indicated, that it subject to an agent capable of hydrolyzing the trifluoroacetic amide to obtain the product of formula (I) sought.

 For the preparation of the products of formula (I), it may be preferable in certain cases to operate in a particular manner. To obtain a product of formula (I) in which R 1 represents a methyl radical, it is possible to prepare a carbamate. alkyl, preferably ethyl, on the nonindole nitrogen atom of the product of formula (I) wherein R1 represents a hydrogen atom and R has the meaning already indicated, then reduce said carbamate; the carbamate may be prepared by action on the product of formula (I) in which R 1 represents a hydrogen atom; an alkyl haloformate in the presence of a base such as an alkali carbonate; the reduction is for example carried out using lithium aluminum hydride under reflux of tetrahydrofuran.

 An example of such a preparation is given below in the experimental part.

In order to prepare a product of formula (I) in which R 1 represents an ethyl radical, the corresponding Nacetyl derivative can be prepared and then reduced.

In order to prepare a product of formula (I) in which R 1 represents an isopropyl radical, a product of formula (I) in which R 1 represents a hydrogen atom can be reacted with acetone in the presence of a reducing agent such as than sodium cyanoborohydride. An example of such a preparation is given below in the experimental part.

The product of formula (I) in which R and R 1 represent a hydrogen atom can be prepared by treating 3,4-dihydro-1H-cyclohept / c, d / indol-6-one described in
Chem. Pharm. Bull. 25 (11), p. 3023, 1977, by or tert-butyl nitrite in the presence of hydrochloric acid, then reducing the keto-oxime obtained for example by catalytic hydrogenation followed by the action of sodium borohydride. An example of such a preparation is given below in the experimental part.

The products of formula (I) in which R 1 represents a hydrogen atom and R has the meaning already indicated, with the exception of hydrogen may be prepared by reacting a halide of formula (V)
Hal-R '(v) in which Hal has the meaning already indicated and R' has the meaning of R already indicated, with the exception of hydrogen, on 3,4-dihydro 1H-cyclohept / c, d / indol-6-one, by phase transfer, according to the technique of A. Bosco et al, described in Synthesis 2, 124 (1976), for example in the presence of a quaternary ammonium salt, such as tetrabutyl chloride;
ammonium, benzyltriphenylphosphonium chloride, or preferably tetrabutyl ammonium hydrogen sulphate, aqueous sodium hydroxide and benzene, and then oxime preparation and reduction as indicated above. An example of such a preparation is shown below in the experimental part.

 The salts of the cycloheptindolol derivatives corresponding to the general formula (I) can be prepared by reacting, in substantially stoichiometric proportions, a mineral or organic acid with said derivatives.

 The following examples illustrate, but not limit, the invention.

 Example 1: 5-R, S-trans amino 3,4,5,6-tetrahydro 1H-eclohept / c, d / indol-6-ol.

Stage A: ~ 5 = 3,4-dihydro oxime ~ 1H = cyclohept] cd / indol 5,6dione.

18.5 g of 3,4-dihydro-1Hcyclohept / c, d / indi-6-one, described in Chem, are dissolved with stirring and nitrogen. Pharm. Bill. 25 (11) p. 3023, 1977, in 185 cm3 of tetrahydrofuran, cooled in an ice bath, added 22 cm3 of 5 mol / l hydrochloric ethanol, then 13.5 cm3 of tert-butyl nitrite, stirred for a further 30 minutes in an ice-bath, drained , washed with ether, dried under reduced pressure at 800C and 16.2 g and 3.16 g of melting crystals with decomposition at 2350C.

Stage B, 5-R, S-trans amino 3,4,5,6-tetrahydro 1H-cyclohept
LC12 Indol-6-ol.

 5 g of the product obtained in the preceding stage are suspended in 100 cm 3 of methanol, 2.5 g of palladium on active charcoal are added to 10 SS, stirred for 40 minutes at room temperature under hydrogen, filtered, rinsed with methanol, cooled in an ice-bath, 2.5 g of sodium borohydride are added over 10 minutes, allowed to come to ambient temperature under an inert atmosphere, stirred for 1 hour, evaporated to dryness, taken up in refluxing methylene chloride, filtered, dried to dryness redissolved at 500 ° C. in 7 cm 3 of methanol, 70 cm 3 of ethyl acetate are added, filter, rinsed with ethyl acetate and concentrated to 50 cm 3, then 25 g of acetic acid solution are added to the mixture. 1.1N ethyl acetate, left to stand at room temperature for 1 hour, ice for 30 mites, drained, washed, dried under reduced pressure at 700 ° C., and 4.9 g of the acetate of the expected product, melting at 1500 ° C., are recovered. .

 Recrystallization from methanol-ethyl acetate 1-1 gives the acetate as a white crystalline solid, mp 1650 ° C.

Analysis of the acetate: C12H14N2O, C2H402 = 262.30
Calculated: C% 64.10 H% 6.92 N0 / o 10.68
Found: C% 64.2 H% 7.1 N% 10.4
Release of the base
10.8 g of acetate, as obtained above, are suspended in 300 cm 3 of ethyl acetate, 100 cm 3 of concentrated ammonia, saturated with sodium chloride, stirred under nitrogen for 15 minutes while stirring. minutes, decanted, washed with salt water, dried, brought to dryness and obtained 9.8 g of the expected product in the form of gum.

Example 2: R, S-trans-5-methylamino-3,4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol hydrochloride.

Stage AR * S = trans N = (6-hydroxy-2,4,5,6-tetrahydro-1H-cyclohexyl, Jdindol = 5 = yl) Q-methyl carbamate
2.62 g of 5-R-trans-amino-acetate 3,4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol and 52 cm 3 of ethyl acetate were dissolved with stirring. cm 3 of water and 2.62 g of potassium carbonate, added during 10 minutes at room temperature 2.6 cm3 of ethyl chloroformate, stirred for 1 hour, distilled under reduced pressure, diluted with a little ice water, triturated for 30 minutes at room temperature, drained, washed, dried under reduced pressure at 60-700C, purified with methanol, filtered, concentrated, crystallization initiated, ice for 3 hours and recovered 1.45 g of gray crystals very melting at 190 C.

Step B: R, S-trans 5-methylamino 3,4,5,6-tetrahydro-1H-cyclohept Lc, dLindol-6-ol hydrochloride
3.6 g of aluminum hydride are suspended at room temperature under an inert atmosphere under stirring in 50 cm3 of tetrahydrofuran, and a solution of 1.83 g of carbamate as obtained above is added over 20 minutes. in 75 cc of dioxane; refluxed for 2 hours, cooled and added in 30 minutes 50 cm3 of 10% hydrated tetrahydrofuran, diluted with 50 cm3 of water, filtered, rinsed with ethyl acetate, added sodium chloride powder, decanted extracted twice with ethyl acetate, washed twice with water, once with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, distilled to dryness, and recovered. 2 g of an orange resin.

Preparation of the hydrochloride
The resin obtained is dissolved in 3 cm 3 of ethanol, 1.5 ml of 5N hydrochloric ethanol are added dropwise, ice for 1 hour, filtered, washed and dried under reduced pressure at 700 ° C. and 1.24 g is obtained. beige crystals melting at 2240C with decomposition.

Analysis: C13H16N2OCl HCl = 252.7
Calculated: C% 61.78 H% 6.78 N% 11.08 Cl% 14.03
Found: C% 63.8 H% 6.7 N% 11.1 C1% 13.9
Example 3: S-trans 5- (1-methylethyl) amino-4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol
10.5 g of R, S-trans-5-amino-3,4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol acetate are suspended under stirring and inert atmosphere in 105 cm 3 of methanol and 52.5 cm3 of acetone, cooled to OOC, added in 15 minutes 10.5 g of sodium cyanoborohydride, stirred for 3 hours 30 minutes to OOC, filtered, rinsed with ethyl acetate, evaporated to dryness chromatography on a silica column under pressure (benzene-ethyl acetate-triethylamine eluent 7-2-1) and recovers 6.32 g of crystals. The crystals are redissolved in 6 cm3 of ethyl acetate while hot, this temperature is left for 1 hour 30 minutes, filtered off, dried under reduced pressure at room temperature and 4.03 g of white crystals are obtained, melting at 100 ° C. .

Analysis: C15H20N2O = 244.338
Calculated: C% 73.74 N 8.25 NSS 11.46
Found: C% 73.5 H% 8.3 N5 / o 11.4
Example 4: 54-trans 5-amino-1-methyl-3,4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol acetate
Stage A 1-methyl: 1-methyl-1,3,4,5-tetrahydro-6H-cyclohept] c, d] indol-6-one
The mixture is stirred for 30 minutes at 40-450C under an inert atmosphere, 5 g of 3,4-dihydro-1H-cyclohept / c, d / indol-6-one with 50 cm3 of benzene, 2.5 cm3 of methyl iodide, 25 cm3 of 5N sodium hydroxide and 9.2 g of tetra-n-butylammonium hydrogen sulphate, diluted with water, decanted, extracted with ethyl acetate, washed with hydrochloric acid N, with water, dried the organic phase, brought to dryness, purified the residue by chromatography on silica (eluent: chloroform-ethyl acetate 95-5), recovered 6.3 g of the expected product which is crystallized in isopropanol and obtained 5, 15 g of the expected product (mp 70 ° C.).

Stage B: 5-oxime of 1-methyl 3,4-dihydro 1H-ccIohept LcXdL indol 5,6-dione.

 10.41 g of product as obtained above is dissolved under an inert atmosphere, in 20 cm 3 of tetrahydrofuran, 85 cm 3 of ethyl ether are added, cooled to -50 ° C., 16.4 cm 3 of 3.5 hydrochloric ethanol are added. N, stirred for 5 minutes, introduced in 30 minutes 7 cm3 of tert-butyl nitrite, stirred for 30 minutes while maintaining the temperature below OOC, filtered, washed with ethyl ether, dried under reduced pressure and obtained 10, 5 g of the expected product (mp = 190 ° C. and then 2000 ° C.).

Stage C: 5 R Acetate, 5-amino-1-Methyl S-trans 34.5.

 6-tetrahydrofc, [c, d] 1H-cyclohept [c, d] indol-6-ol.

 For 1 hour 45 minutes the 10.5 g obtained above is hydrogenated in 210 cm 3 of methanol, with 5.25 g of 10% palladium on carbon, filtered, cooled in an ice bath, 5.25 g of borohydride added. of sodium in 10 minutes, under an inert atmosphere, stirred for another 10 minutes, then 40 minutes at room temperature, distilled the methanol under reduced pressure, 30 cm3 of water added, extracted with ethyl acetate, washed with water dry, dry distil under reduced pressure, purify by chromatography on silica (eluent: ethyl acetate-methanol-ammonia 90-5-5) and obtain 9.1 g of base of the expected product.

Acetate preparation
The above base is dissolved in 10 cm 3 of ethanol, ethyl acetate is slowly added in a slight excess, the mixture is left standing for 48 hours, filtered, washed with ethanol, at room temperature. ethyl acetate, with ethyl ether, dries and gives 4.12 g of acetate (mp-yi400C).

After recrystallization from isopropanol (mp: ~ 1400C then 1600C).

Analysis: C15H20N2O3 = 276.336
Calculated: C% 65.19 H% 7.29 N% 10.13
Found: C% 65.2 H% 7.4 N% 10.2
Example 5
Tablets having the formula - Acetate 5-R, S-trans amino 3,4,5,6-tetrahydro were repaired
1H-cyclohept / c, d / indol-6-ol 0 10 mg - Excipient qs for a tablet finished at .... 100 mg.

(Detail of excipient: lactose, starch, talc, magnesium stearate).

Example 6
Tablets having the formula - Hydrochloride R, S-trans 5-methylamino 3,4,5,6 were prepared.
tetrahydro-1H-cyclohept / c, d / indol-6-ol ...... 15 mg - Excipient qs for a tablet finished at .... 100 mg.

(Detail of the excipient: lactose, starch, talc, magnesium stearate.

Pharmacological study:
A) Antihypertensive action in the awake dog.

The study of the antihypertensive action of the product of Example 1 was carried out on the Beagle dog weighing 12 kg to 14 kg made hypertensive by wrapping 2 kidneys with cellWhane according to the technique described by Irvine
H. Page in Science (1939) 89 p. 273-274.

 The product was administered orally at doses of 1 mg / kg and 10 mg / kg.

 Blood pressure was measured at the dog's tail by means of a pneumatic sleeve and using a piezoelectric pressure transducer. The pressure was measured before and 1 hour, 3 hours, 6 hours and 24 hours after administration of the product.

The table below shows the percentage changes in blood pressure, after administration of the product, compared to the initial control pressure.

<Tb>

Product <SEP> Dose <SEP> Variation <SEP>% <SEP> of <SEP><SEP> Pressure
<tb><SEP> of <SEP>'<SEP> Arterial
<tb> the example <SEP> mg / kg
<tb><SEP> 1st <SEP> day
<tb><SEP> 1 <SEP> hour <SEP> 3 <SEP> hours <SEP> 6 <SEP> hours <SEP> 24 <SEP> hours
<tb><SEP> after <SEP> 1 '<SEP> after <SEP>1'<SEP> after <SEP> 1 '<SEP> after <SEP> ad
<tb><SEP> adminis- <SEP> adminis- <SEP> adminis- <SEP> ministratior <SEP>
<tb><SEP> tration <SEP> tration <SEP> tration
<tb><SEP> 1 <SEP> 1 <SEP> - <SEP> 16 <SEP> - <SEP> 17 <SEP> - <SEP> 13 <SEP> - <SEP> 10
<tb><SEP> 10 <SEP> - <SEP> It <SEP> - <SEP> 27 <SEP> - <SEP> 10 <SEP> - <SEP> 32
<Tb>
B) Determination of antihypeftensive activity.

 The antihypertensive action was studied in male spontaneously hypertensive rats (OKAMOTO strain) aged 20 weeks weighing 300 to 320 g.

 The product was orally administered 48 hours after intracarterid catheter placement.

 Blood pressure was measured at the tail of the rat by means of a pneumatic sleeve and using a piezoelectric pressure transducer. The pressure was measured before and 1 hour, 4 hours and 24 hours after the administration of the product.

The table below shows the percentage changes in blood pressure, after administration of the product, compared to the initial control pressure.

<Tb>

Product <SEP> Dose <SEP> Variation, '<SEP> of <SEP><SEP> Pressure
<tb><SEP> of <SEP> Arterial
<tb> the example <SEP> mg / kg
<tb><SEP> 1 <SEP> hour <SEP> 4 <SEP> hours <SEP> 24 <SEP> hours
<tb><SEP> after <SEP> ad- <SEP> after <SEP> ad- <SEP> after <SEP> ad
<tb><SEP> ministration <SEP> ministration <SEP> ministration
<tb><SEP> 1 <SEP> 1 <SEP> 24 <SEP> -21 <SEP> - <SEP> 12
<Tb>
C) Determination of hypotensive activity.

 Hypotensive activity was studied in male Wistar rats weighing approximately 300 g and anesthetized with nembutal (50 mg / kg intravenously).

 The test product was administered intravenously into the jugular vein.

 Carotid arterial pressure was measured before and after administration of the tested product.

The table below indicates the variations expressed as a percentage of the blood pressure after administration of the tested product relative to the initial control blood pressure.

<tb> Products <SEP> Dose <SEP> Variation <SEP>% <SEP> of <SEP><SEP> Pressure
<tb><SEP> of <SEP> Arterial
<tb> the example <SEP> mg / kg
<tb><SEP> 1 <SEP> minute <SEP> 5 <SEP> minutes <SEP> 10 <SEP> minutes <SEP> 30 <SEP> minutes
<tb><SEP> after <SEP> 1 '<SEP> after <SEP> li <SEP> after <SEP>1'<SEP> after <SEP><SEP>
<tb><SEP> adminis- <SEP> adminis- <SEP> adminis- <SEP> adminis
<tb><SEP> tration <SEP> tration <SEP> tration <SEP> tration
<tb><SEP> 0.1 <SEP> - <SEP> 3 <SEP> - <SEP> 15 <SEP> - <SEP> 28 <SEP> - <SEP> 34
<tb><SEP> 0.01 <SEP> 0 <SEP> - <SEP> 7 <SEP> - <SEP> 16 <SEP> - <SEP> 16
<tb><SEP> 2 <SEP> 1 <SEP> - <SEP> it <SEP><SEP> - <SEP><SEP> 28 <SEP> - <SEP> 34 <SEP> - <SEP> 30
<tb><SEP> 0.1 <SEP> - <SEP> 1 <SEP> - <SEP> 12 <SEP> - <SEP> 17 <SEP> - <SEP> 10
<tb><SEP> 3 <SEP> 10 <SEP> - <SEP> 34 <SEP> - <SEP> 31 <SEP> - <SEP> 26 <SEP> - <SEP> 29
<tb><SEP> 1 <SEP> - <SEP> 15 <SEP> - <SEP> 18 <SEP> - <SEP> 18 <SEP> - <SEP> 21
<tb><SEP> 4 <SEP> 10 <SEP> - <SEP> 31 <SEP> - <SEP> 21 <SEP> - <SEP> 15 <SEP><SEP> O <SEP>
<Tb>

D) Study of the toxicity alguë.

 DLo lethal doses of the various compounds tested after oral administration were evaluated in mice.

 DLo is the maximum dose causing no mortality in 8 days.

The results obtained are as follows

<tb> Products <SEP> of <SEP>
<tb> 1 '<SEP> example <SEP>
<tb><SEP> in <SEP> mg / kg
<tb><SEP> 1 <SEP> 200
<tb><SEP> 2 <SEP> 200
<tb><SEP> 3 <SEP> 100
<tb><SEP> 4 <SEP> 200
<Tb>

Claims (6)

 in which R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, which is optionally substituted, and R1 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, cycloalkylalkyl containing from 4 to 7 carbon atoms, or aralkyl containing from 7 to 12 carbon atoms, optionally substituted, and also by addition salts with pharmaceutically acceptable acids of said derivatives.

 1) - Medicines, characterized in that they consist of cycloheptindolol derivatives corresponding to the general formula 2) - Medicaments, characterized in that they consist of the cycloheptindolol derivatives corresponding to the formula (I) of claim 1, in which R and R1 represent a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, as well as the addition salts with the pharmaceutically acceptable acids of said derivatives. 3) - Medicaments, characterized in that they consist of 5-R, S-trans amino 3,4,5,6-tetrahydro 7H-cyclohept / c, d / indol-6-ol as well as its salts addition with pharmaceutically acceptable acids. 4) - Medicaments, characterized in that they consist of 5-R, S-trans-5-methylamino-3,4,5,6-tetrahydro-1H-cyclohept / c, d / indol-6-ol and only by its addition salts with pharmaceutically acceptable acids. 5) - Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs defined in one of claims 1 or 2. 6) - Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs defined in claim 3 or 4.