FR2528850A1 - NEW AMINOCYCLOLS - Google Patents

Abstract

THE INVENTION CONCERNS 5-S- (2R-BUTYL) -AMINO-CYCLOLS. THESE COMPOUNDS MAY BE USED TO PREPARE PHARMACOLOGICALLY ACTIVE SUBSTANCES.

Description

 The subject of the present invention is new ergopeptide alkaloids, a process for their preparation and their use in therapy as active principles of medicaments.

 The invention relates in particular to 5'S- (2R-butyl) -ergopeptide alkaloids, and their acid addition salts.

 These alkaloses 5'S- (2R-butyl) -ergopeptidi: ques, designated in the present description as compounds of the invention, are epimers completely unknown until now of ergopeptide alkaloids obtained by chemical synthesis or, in certain cases, d 'ergopeptide alkaloids existing in nature or prepared by fermentation. They can carry the usual substitutes in the chemistry of alkaloids of ergopeptides.

They can also exist in the form of isomers, for example in the form of 8R or 8S isomers.

The chemistry of ergopeptide alkaloids has recently been developed by
J. Rutschmann and P. Stadler in the book by B. Berde and HO Schild "Ergot alkaloids and related compounds" 1978, Springer Verlag, Berlin, pages 29 to 85. It is assumed that the known derivatives 5'S- (2-butyl), like for example ss-ergocryptine, have the configuration S in the secondary butyl side chain (see page 37 of the work mentioned above and also page 2468 of the Dictionary of Organic Compounds, 5th edition, volume 3, Chapman and Hall, New York, 1982). In the 8th Collective Index of Chemical Abstracts, the carbon atom in position 2 of the secondary butyl residue having the configuration S, is numbered 13 '.

dans laquelle R1 signifie un groupe méthyle, éthyle ou isopropyle, et leurs sels d'addition d'acides.More particularly, the present invention relates to the compounds of formula I

wherein R1 signifies methyl, ethyl or isopropyl, and their acid addition salts.

 In accordance with the process of the invention, to prepare the 5'S- (2R-butyl) ergopeptide alkaloids of the invention, and their acid addition salts, an acid addition salt of a 5'S- is condensed Corresponding (2R-butyl) aminocyclol, or one of its precursors, with a reactive derivative of a corresponding lysergic acid, or one of its precursors, and the compounds thus obtained are obtained in the form of the free base or in the form of 'an acid addition salt.

 By "aminocyclol" is meant characteristic tripeptides which comprise a hydroxy group and which are used in the synthesis of ergopeptide alkalofdes. They are in particular cyclic tripeptides comprising an amino group in position 2 'and a hydroxy group in position 12'.

dans laquelle R1 a la signification donnee précédemment, ou un précurseur d'un tel composé, avec un dérive reactif d'un acide de formule III

ou un precurseur d'un tel composé, et on récupère le composé de formule I ainsi obtenu, a l'état de base libre ou sous forme d'un-sel d'addition d'acide. One can in particular prepare a compound of formula I as defined above, or an acid addition salt of this compound, by a process which is characterized in that an acid addition salt is condensed of a compound of formula II

in which R1 has the meaning given above, or a precursor of such a compound, with a reactive derivative of an acid of formula III

or a precursor of such a compound, and the compound of formula I thus obtained is recovered, in the free base state or in the form of an acid addition salt.

 The condensation process according to the invention can be carried out according to known methods for the preparation of similar ergopeptide alkaloids.

 As the acid addition salt of 5'S- (2R-butyl) - aminocyclol, there may be mentioned for example the hydrochloride. As the reactive derivative of lysergic acid, use is made, for example, of acid chloride or the mixed anhydride with sulfuric acid or trifluoroacetic acid. The adduct of lysergic acid can also be used with (i) dimethylformamide or acetamide and (ii) thionyl chloride, phosgene or oxalyl chloride. The condensation is preferably carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile. The reaction can be carried out at temperatures of, for example, between about -300 and +20.

 As stated above, a precursor of lysergic acid or aminocyclol can be used. Such a precursor can consist of a compound which can be converted into the starting material according to known methods. When the condensation has been carried out, the product obtained can be converted according to known methods to the desired compound of the invention.

Thus, for example, the derivative of lysergic acid and / or amino cyclol can be temporarily protected.

 The free bases of the invention can be converted into acid addition salts according to known methods, and vice versa. Acids suitable for salt formation include, for example, hydrochloric acid and methanesulfonic acid.

dans laquelle R1 a la signification donnée précédemmgnt. The starting materials are known or can be prepared according to known methods from known compounds. Thus the compounds of formula II can be prepared according to known methods from the compounds of formula IV

in which R1 has the meaning given above.

dans laquelle R1 a la signification donnée précédemment, avec un composé de formule VI

et hydrogénation subséquente du produit obtenu.for example by passing through the hydrazide and the benzyl ester as described in the examples
The compounds of formula IV can be prepared by reaction of the compounds of formula V

in which R1 has the meaning given above, with a compound of formula VI

and subsequent hydrogenation of the product obtained.

The compound of formula VI can be prepared for example according to the following reaction scheme from optically active compounds:

 The compounds of formula II, IV, VI, VII, VIII and IX are new and form part of the present invention.

 The aminocyclols are preferably prepared in an optically pure form from optically active compounds, as described above.

It is also possible to use certain starting materials such as isoleucine in racemic or diastereoisomeric form and, after reaction with an optically active starting material such as L-proline, to separate the diastereoisomers according to known methods, for example by chromatography. Thus, for example, the compound of formula VI can be separated from its diastereoisomers obtained for example from isoleucine containing the compound of formula X.

 The compounds of the invention can be isolated according to known methods and be purified by. example by high pressure liquid chromatography or any other chromatographic method, or by crystallization.

 According to another aspect, the invention relates to a 5'5- (2R-butyl) -ergopeptide alkaloid, having less than 5%, or less than 2%, or less than 1% of 5'S- (2S-butyl) epimer corresponding, such as dihydro-B-ergocryptine.

 The presence of an epimer can be detected according to the usual analytical methods, for example by high pressure liquid chromatography or by nuclear magnetic resonance.

The compound of formula I where R signifies an isopropyl group [compound 5'S- (2R-butyl)] can be distinguished from the corresponding epimer, dihydro-P- ergocryptine compound 5'S- (2S-butyl) 3, by the displacement of peaks rmn In the proton NMR spectrum (360 MHz; solvent: CDC13), the two compounds exhibit the following displacements
Compound 5'S- (2R-butyl) Compound 5'S- (2S-butyl)
C-5'-H d = 4.53 ppm f = 4.50 ppm
C-13'-H d = 1.30 ppm K = 1.50 ppm
In the 13 C NMR spectrum (360 MHz, 30 mg / 1.5 ml; pD = 3.4) the compounds have the following displacements:
Compound 5'S- (2R-butyl) Compound 5'S- (2S-butyl)
CH3 on C-13 '# = 17.5 ppm = 16.4 ppm
CH2 on C-13 '# = 27.4 ppm f = 28.6 ppm
Thus it is possible to detect the presence of 1% or more of the 5'S- (2S-butyl) epimer in the compounds of the invention.

 A suitable system for high pressure liquid chromatography comprises a) 1 of triethylamine in water mixed with b) 1% of triethylamine in acetonitrile. The solvent system initially comprises 15% of b) and is increased to 50 s, 0 of b) in the space of 20 minutes.

The system circulates at a speed of 2 ml / minute through a RP 18 column (Knauer) with a length of 25 cm and a diameter of 4.6 mm. Compound 5'S- (2R-butyl) of Example 1 below has a retention time of 19 minutes. Ss-dihydroergocryptine has a retention time of 20 minutes.

 Another suitable solvent system is a water / acetonitrile / tetramethyl ammonium chloride / trimethylamine mixture (755 g: 240 g: 4 g: 1 g); solid phase: Lichromosorb R 18 from Merck (particle size 10, μm; column 16 mm in diameter and 25 cm in length).

 When the preparation of a particular starting product is not specifically described, it will be a known compound or one which can be prepared in a known manner from known products, or in a manner analogous to that described herein. request.

 The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and are not corrected.

Example 1 (5R, 8R, 10R) -N - {(2R, 5S, 11S, 12S) -5- (2R-butyl) -octahydro- 12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazoloU3 , 2-aapyrrolo (2lcipyraZine-2-yl-6-iethyl -ergol i ne-8-carboxamide or (5'a, 10a) -9,10-dihydro-12'-hydroxy-2 methylethyl) - 5 ' - [(R) -1-methylpropyl] ergotamane-3 ', 6', 18-trione
To a mixture of 5.36 g (20 mM) of anhydrous (5R, 8R, 1OR) - 9,10-dihydrolysergic acid, 40 ml of anhydrous dimethylformamide and 20 ml of anhydrous acetonitrile, 1.8 are added. ml (22.5 mM) of trifluoro acetic acid then, with stirring and at -10 ", 2.8 ml (20 mM) of trifluoroacetic anhydride and 20 ml of pyridine.

The reaction mixture is stirred for a further 5 minutes at -100, 3.62 g (10 mM) of (2R, 5S, 11S, 12S) -2-amino-5- (2R-butyl) -octahydro- hydrochloride are added. 12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazoloU3,2-a] pyrrolot2,1-c] pyrazine and, with stirring, the temperature is allowed to rise to 22 for 2 hours. The mixture is distributed between methylene chloride and water, the organic phase is dried over sodium sulphate, filtered and evaporated. The residue is recrystallized from a mixture of ethyl acetate and ether.

F = 190910; [α] 20 = -43.5 "Ic = 0.5 in
D pyridine).

 NMR spectrum (360 MHz, CDCl3): f0.98 ppm (6H, t), 1.09 - 1.17 (6H, q), 1.3 (1H, m, C-13-H).

 13C NMR spectrum (360 MHz, 30 mg / 1.5 ml, pD = 3.4): No visible signal at 16.4 or 28.6 ppm which can be attributed to the dihydro-ss-ergocryptine epimer , which indicates that the product contains no epimer or contains less than 1% epimer.

(2R, 5S, llS, 12S) -2amino-5- (2R-butyl) -octahydro-12-hydroxy-2-isopropyl3,6-dioxo-8H-oxazolo [3,2-a] -pyrrolo hydrochloride 2,1-c] pyrazine, used as starting material, can be prepared as follows a) (3S, 8aS) -3- (2R-butyl) -hexahydro-pyrrolo [1,2-a] pipe-
raz1ne-1,4-dione (compound of formula VI)
i) (2S, 3R) -L-allo-isoleucine methyl ester
30 g (229 mM) of (2S, 3R) -L-allo 20 are dissolved
isoleucine ([α] 546 = + 45 2, [c = 5 in HCl 6M])
in 300 ml of 6.8N hydrochloric acid in the
methanol and stirred for 18 hours on time
ambient rature. The solvent is evaporated and
divides the evaporation residue between 300 ml
a saturated aqueous solution of carbonate
of potassium and 600 ml of ether.
aqueous phase 3 times with each time
600 ml of ether. We combine the organic phases,
the overall phase is dried over sodium sulfate,
it is filtered, it is evaporated and the residue is dried
up to constant weight under high vacuum, which
gives the methyl ester of (2S, 3R) -L-allo
isoleucine as a clear, yellow oil
clear. By extraction of the aqueous phase with
methylene chloride, you can get
additional quantities of product 20 = + 450 (c = 3 in chloride
Ea30
methylene).

NMR spectrum (100 MHz, CDCl3): # 0.81-1.01 ppm
(6H, 4 peaks, CH3-C-3, CH3 -CH2-C-3), 3.46 (1H, d, J =
4Hz, C-2-H), 3.71 (3H, s, COOCH3).

ii) Condensation with CBO-L-Proline
40.35 g (161.5 mM) of 2S-benzyloxycarbonyl
L-proline in 600 ml of tetrahydrofuran, we
added with stirring 26.15 g (161.5 mM) of N, N
solid carbonyldiimidazole. After 5 minutes, the
C02 release is complete and mixing is
colored in pale yellow. The mixture is stirred for
another 1 hour at room temperature and
add a solution of 22.95 g drop by drop
(158.3 mM) methyl ester of (2S, 3R) -L-allo
isoleucine in 155 ml of tetrahydrofuran.

The mixture is stirred for 2 hours at
room temperature and extracted with one liter
ether. The organic phase is washed twice
with water, and the aqueous phases are extracted
washing with ether. We bring together the phases
organic, the overall phase is dried over sulfate
of sodium, it is filtered, it is evaporated and it is dried
the residue at 30 under high vacuum, which gives
the compound of formula VIII in the form of an oil
clear, light yellow.

iii) Elimination of the CB0 protective group
Has a pre-hydrogenated mixture consisting of
12.0 g of 10% palladium on carbon in 500 ml
of methanol, a 64 g solution is added
(170 mM) of the compound of formula VIII in 800 ml
methanol. The mixture is hydrogenated for
2.5 hours at room temperature and
at 757 mm Hg; the absorption of hydrogen is
2.9 liters. Then filter the reaction mixture
tional on Hyflo, we wash it with a mixture
in equal parts of methylene chloride and
methanol and dried. After evaporation,
the compound of formula VII is obtained in the form
of a yellow oil.

iv) Cyclization to diceto-piperazine (composed of
formula VI)
The compound of formula VII is heated for
two and a half hours at 1200 under high vacuum.

The mixture is partially stirred in ether
crystallized thus obtained and then added
1 hexane, which gives a crystallized compound
(8.669) and an oily compound (27.4 g). The
oily compound is subjected to cycli again
station.

The crystallized compound, which is the compound
of the title, is recrystallized from a mixture
ether and hexane. Needles are thus obtained
colorless melting at 132-135; [a] D = 1560
D
(c = 1 in methylene chloride).

NMR spectrum (360 MHz, CDCl3): f0.80 ppm
(3H, d, J = 6.5 Hz, CH3 -C-9), 3.98 (3H, t, J =
7 Hz, CH3-CH2-C-9), 1.42 (2H, m), 1.92 (1H, m),
2.45 (2H, m), 2.38 (2H, m), 3.52 to 3.59
(2H, m), 4.08 (2H, m).

b) (2R, 5S, 11S, 12S) -5- (2R-butyl) -octahydro-12-hydroxy-2-
isopropyl-3,6-dioxo-8H-oxazolo [3,2-a] -pyrrolo [2,1-c] - ethyl eyrazine-2-carboxylate
i) Under a nitrogen atmosphere, 21 g (100 mM) are mixed
of (3S, 8aS) -3- (2R-butyl) -hexahydro-pyrrolo [1,2-a] -
piperazine-1,4-dione with 200 ml of dioxane
anhydrous, 57.3 ml (334 mM) of N-ethyl-N, N-diiso
propylamine and 53.32 g (178.6 mM) of S - (+) - 2-
benzyloxy-2-chloroformyl-3-methyl-butyrate
of ethyl and heated to reflux for 3
hours. After cooling the reaction mixture
nel, we distribute it between 1 liter of ether and
1N cold hydrochloric acid. We wash the
organic phase twice with solution
saturated aqueous potassium bicarbonate and
the aqueous phase is re-extracted with ether.

The organic phases are combined, the
overall phase on sodium sulfate, it is filtered
and we concentrate it, which gives an oil
Yellow.

ii) This product is treated by a mixture
10 g pre-hydrogenated 10% palladium on
coal in 2.6 liters of absolute ethanol. We
hydrogen the mixture for 18 hours under
normal pressure, we filter it on Hyflo and we
evaporates it. The residue is dried under high vacuum,
which gives a yellow oil that we make
crystallize in a mixture of ether and ether
of oil. The title compound is thus obtained; F = 95-96; [α] 20 = +9 (c = 1 in
D
1 ethanol).

c) Acid ~ (2R, 5S, llS, 12S) -Z- (~ R-butyl-octahydro-12-
hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo [3,2-a] -
pyrrolo [2,1-c] pyrazine-2-carboxylic
28.64 g of the ester obtained in step b)
suspended in 20 ml of methanol, add
172 ml of sodium hydroxide N.

The resulting colorless solution is stirred
for 19 hours at room temperature and
it is then washed twice with 500 ml
ether. We combine the organic extracts of
washing and they are extracted with water. We bring together
aqueous phases and the phase is made alkaline at 0
overall aqueous with 103.2 ml of hydrochloric acid
2N, which precipitates the desired compound under
form of an oil. We obtain a crystallized product
after treatment in an ultrasonic bath. We
then dries the product at 500 for 24 hours,
which gives the title compound as
colorless crystals.

F = 114-115; second form of crystalli
station: F = 172-173; [α] 20 = 11.70 (c = 1.5 in
D
pyridine).

d) (2R, 5S, 11S, 12S) -5- (2R-butyl) -octahydro-12-hydroxy-2-
isopropyl-3,6-dioxo-8H-oxazolo [3,2-a] -pyrrolo [2,1-c] - eyrazine-2-carbohydrazide
To a solution of 9.04 ml of dimethyl
formamide in 132 ml of methylene chloride,
a solution of 8.37 ml of chloride is added to -10
of oxalyl in 33 ml of methylene chloride,
which gives a white suspension which is stirred
for another 15 minutes at -10.

Then added 23.36 g (65.8 mM) of
the acid obtained in step c) in solid form, this
which raises the temperature of the mixture to
-60. The resulting bright yellow solution is
stirred for another 30 minutes at -10 is added
then in the space of 4 minutes a solution of
42.9 g of sodium azide in 204 ml of water. The
temperature of the mixture is +5 and the mixture
becomes reddish. The mixture is stirred for
another 15 minutes at -10 and we extract it with
900 ml of methylene chloride. We shake it
organic phase with 420 ml of a solution
saturated aqueous potassium bicarbonate cooled
with ice and the aqueous phase is extracted at
twice with 800 ml of methylene chloride.

The organic phases are combined, the
overall solution over sodium sulfate, filtered, Gn, evaporated and the residue is dried under high vacuum.

After recrystallization of the residue in a mixture
of ether and methylene chloride, the
title compound in the form of colorless crystals;
the product melts above 1750 (with decomposition
tion).

e) Benzyl ester of acid (2R, 5S, llS, 12S) -5-
(2R-butyl) -octahydro-12-hydroxy-2-isopropyl-3,6-
dioxo-8H-oxazolo [3,2-a] pyrrolo [2,1-c] -pyrazine-2- carbamic
16.54 g (43.6 mM) of the carbohydrazide obtained
under d) dissolved in 110 ml of chloro
form, add 13.52 ml (130.8 mM) of alcohol
anhydrous benzyl and heated to reflux for
35 minutes. This gives a clear solution
yellowish. The easily volatile parts are
distilled and excess alcohol
benzyl is removed at 1200 under high vacuum.

The yellow crystalline residue is triturated in
ether to purify it and we recrystallize it
in a mixture of methylene chloride and 20
ether. F = 197-1990; [20] D = +400 (c = 0.6 in
methanol).

f) (2R, 5S, llS, 12Si-2-amino-5- monohydrochloride
(2R-butyl) -octahydro-12-hydroxy-2-isopropyl-3,6-
dioxo-8H-oxazolo [3,2-a] pyrrolo [2,1c -] - pyrazine
(composed of formula II)
16 g (34.8 mM) of the carbamate are mixed
obtained under e), 8 g of palladium a 10; on coal,
1.12 liters of methanol and 112 mM of chlorhy acid
drique and hydrogen at 190 under normal pressure.

Filter the mixture, concentrate the filtrate
at 30 until it starts to crystallize, we
the mixture with 500 ml of ether and stirred. We
filter the product, wash it with ether and wash it
constant weight dries under vacuum.

F = greater than 145 (with decomposition);
20
[α] D = +55 (c = 0.15 in dimethylformamide).

 The compounds of the invention and their pharmaceutically acceptable acid addition salts have not so far been described in the literature. In animal tests, they have interesting pharmacological properties and can therefore be used as medicines.

 In particular, the compounds of the invention exert an inhibitory action on the secretion of prolactin, as appears from the standard tests carried out on animals. Thus, for example, in the test carried out according to the method described by E. Flückiger et al. in Experienta 34, 1330-1332, (1978), the subcutaneous administration of the compounds of the invention at a dose of between approximately 0.1 mg / kg to approximately 10 mg / kg, causes inhibition of implantations in the rat.

 In this test, the compound of Example 1 has an OD 50 of about 1.84 mg / kg subcutaneously. The compound is therefore 5 times more active than co-dergocrine in this test.

 Thanks to this property, the compounds of the invention can be used in therapy as an inhibitor of prolactin secretion, for example for the treatment of lactation, galactorrhea, hyperprolactinic hypogonadism, acromegaly or prolactinomas.

 The compounds of the invention also exerts a serotoninergic action as appears from conventional tests carried out on animals. Thus, for example, in the sleep / wake cycle test carried out on the chronically implanted rat according to the principle described by J.M Vigouret et al.

in Pharmacology, 16, (1), 156-173 (1978), the compounds of the invention cause an inhibition of the REM sleep phase and a prolongation of the waking phase after intraperitoneal administration at doses of between approximately 0 , 3 and about 10 mg / kg or orally at doses between about 1 and about 10 mg / kg.

 The serotoninergic activity of the compounds of the invention has been confirmed by the inhibition which they exert on the reserpinic syndrome in the model of the EEG PGO potentials in cats implanted according to the method described by J.M. Vigouret et al.

in the article mentioned above, after administration intravenously at doses of between about 0.01 and about 1 mg / kg. In this test, the compound of Example 1 has an LD50 of 0.11 mg / kg after administration by intravenous route and can therefore be considered to be three times more active than co-dergocrine in this test.

In addition, the compounds of the invention increase the use of local cerebral glucose in the sensomotor cortex, the hippocampus and the Nucleus habenula, as appears from the autoradiographic technique with carbon-labeled 2-deoxyglucose on the rat brain. after intraperitoneal administration at doses between about 0.01 and about 3 mg / kg [for the procedure, see for example L. Solokoff, Journal of Cerebral
Blood Flow and Metabolism, 1981, (1), 7-36;
HE Savaki et al., Brain Research 1982, 233, 347-358 and J. Mc Cul loch et al!., Journal of Cerebral
Blood Flow and Metabolism, 1981, 1, 133-136].

 Thanks to these properties, the compounds of the invention can be used in therapy also for the treatment of cerebral insufficiencies, for example of senile dementia, in particular in its early stages, and to increase alertness.

 Furthermore, the compounds of the invention exert an α-sympatholytic action as is apparent from conventional tests. Thus, for example in cats, the compounds of the invention exert an α-sympatholytic action by intravenous infusion at doses of between approximately 0.01 and approximately I mg / kg.

The compounds also exert an antihypertensive effect as appears from tests carried out in normotensive dogs under anesthesia according to the method described by D. Chu., Et al. In Naunyn-Schmiedeberg's
Arch.Pharmacol. (1975), Suppl. 287, R 18, after intravenous administration at doses between about 0.001 mg / kg and about 10 mg / kg.

The antihypertensive action was also observed in the spontaneously hypertensive rat, after subcutaneous administration of the compounds of the invention at doses of between approximately 0.01 and approximately 10 mg / kg.

 In general, the compound of Example 1 is approximately 1 to 3 times more active than co-dergocrine in these tests.

 Thanks to these properties, the compounds of the invention can be used in therapy as antihypertensive agents, especially in geriatrics.

 The invention therefore also includes the therapeutic use of the compounds of the invention as medicaments, in particular as inhibitors of prolactin secretion, as vigilance-enhancing agents, as agents for the treatment of senile dementia and as anti -hypertensives. The preferred indications are the treatment of senile dementia and the treatment of hypertension. The compound of Example 1 is the preferred compound.

 For each of the therapeutic uses indicated above, the daily dose of compound of the invention to be administered is between approximately 0.3 and approximately 30 mg, in particular between 2 and 4 mg, advantageously administered in divided doses 2 to 4 times daily as unit doses, or as a delayed-release form.

 In general, the unit doses contain at least 0.01 mg or at least 0.1 mg of compound of the invention or one of its pharmaceutically acceptable acid addition salts, and at least 0 , 7 by weight, for example up to 90% by weight, in particular from 1 to 10t by weight of compound of the invention or one of its pharmaceutically acceptable acid addition salts.

 Unit doses suitable, for example for oral or rectal administration, contain between approximately 0.1 and 15 mg, in particular 0.1 to 9 mg of a compound of the invention or one of its salts. pharmaceutically acceptable acid addition. The unit doses can for example be in the form of tablets, capsules, dragees or suppositories.

 Liquid solutions, for example solutions for oral administration, can contain at least 0.1 mg / ml, in particular from 0.5 to 2 mg / ml of compound of the invention.

 Unit doses suitable for example for parenteral administration, such as for example sterile injectable suspensions, contain between approximately 0.01 and approximately 3 mg, in particular 0.03 to 1 mg of compound of the invention or the one of its pharmaceutically acceptable acid addition salts.

 The compounds of the invention may, if desired, be administered in the form of a pharmaceutically acceptable acid addition salt. Such salts have an activity of the same order as that of the free bases. The compounds of the invention are preferably administered in the form of a free base.

 The invention also includes medicaments containing, as active principle, a compound according to the invention in the free base state or in the form of an acid addition salt.

The invention also includes the
pharmaceutical compositions containing, while
active substance, a compound according to the invention to
the free base or pharmaceutically acceptable acid addition salt state, in combination with pharmaceutically acceptable carriers or diluents. Such compositions can be prepared according to known methods.

 To prepare the pharmaceutical compositions intended for rectal or parenteral oral administration, the active substance is mixed with the pharmaceutically acceptable vehicles and diluents and, if appropriate, with other excipients. Thus it is possible to prepare tablets, granules, dispersible powders, dragees, capsules, syrups, suspensions, solutions and elixirs intended for oral administration. Suppositories for rectal administration and solutions and suspensions for parenteral administration can also be prepared. Pharmaceutical compositions for oral administration may contain one or more excipients, such as, for example, sweetening agents, flavorings, colors and preservatives to produce acceptable and palatable compositions.

 The tablets may contain the active substance in mixture with diluents, such as for example calcium carbonate or lactose, dispersing agents such as talc and alginic acid, binders such as starch, polyvinylpyrrolidone or gelatin, lubricants such as magnesium stearate, steric acid or talc. The tablets can be coated according to the usual techniques in order to delay disintegration and absorption in the gastrointestinal tract and thus produce a long duration of action.

 The capsules can contain the active substance in mixture with a solid diluent such as lactose or starch, and a lubricant such as for example magnesium stearate.

 The suspensions, syrups and elixirs may contain the active substance in admixture with usual excipients for such compositions such as, for example, suspending agents such as methylcellulose, gum tragacanth and sodium alginate, surfactants -actives such as lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan mono-oleate, and preservatives such as methyl, ethyl or propyl para-hydroxybenzoate.

 The injectable compositions, suppositories and other pharmaceutical compositions can, as indicated above, be prepared according to the usual methods.

 Due to their ease of preparation and administration, solid forms are preferred, such as, for example, tablets or capsules.

Examples of pharmaceutical compositions which can be prepared according to the usual methods are given below:
Tablets
Constituent Weight
Compound of the invention, for example the compound of Example 1 0.1 mg
Tartaric acid 0.1 mg
Lactose 85.9 mg
Mat starch 10 mg
Gelatin 0.3 mg
Magnesium stearate. 0.3 mg
Talc 2 mg
Capsules
Compound of the invention, for example the compound of Example 1 0.1 mg
Thinners and lubricants (lactose, starch, magnesium stearate) 299.9 mg
Liquid compositions Weight in mg
sterile suspension suspension
injectable liquid for 1 admini stra-
tion by channel
Compound of the invention, for example oral the compound of Example 1 0.05 0.1
Sodium salt of carboxymethylcellulose 1.25 12.5
Methylcellulose 0.4 - Po.lyvinylpyrrolidone 5 -
Lecithin 3 -
Benzyl alcohol 0.01 -
Aluminum and magnesium silicate - 47.5
Flavoring - qs

Colorant - q.s.

Weight in mg
Sterile suspension Liquid suspension
injectable administrable
ear flies oral iWlethylparabene - 4.5 Propylparaben - 1.0
Polysorbate 80 (e.g.
Tween 80) - 5
Sorbitol solution at 70, * - 2,500
Stabilizing buffer qsqs

Water qspl ml qsp 5 ml
The above composition can be administered, for example, once a day for the treatment of senile dementia.

The compounds of the invention, in the free base state or in the form of a pharmaceutically acceptable acid addition salt, show good general tolerance in dogs at a dose between approximately 1 and 30 mg / kg administered daily for 4 weeks. For exemple,
the compound of Example 1 when administered for 4 weeks orally at a daily dose of 10 mg / kg causes only very weak side effects characteristic of ergopeptide alkaloids, for example an emetic effect, salivation, weight loss and a reduction in food consumption only low.

 At a dose of 30 mg / kg by oral vote, no cardiotoxic effect is observed. The compound of Example 1 can therefore be considered to have good tolerance.

Claims (2)

CLAIM 1.- A compound, characterized in that it is chosen from  i) a 5'S- (2R-butyl) aminocyclol,  ii) a compound of formula

 and iii) a compound of formula  addition of acid,  in the free base state or in the form of a salt  or one of its precursors,  ethyl or isopropyl,  in which R1 represents a methyl group,