FR2494692A1 - NEW 4,5,6,7-TETRAHYDROISOXAZOLO (5,4-C) 3-SUBSTITUTED PYRIDINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

3-Substituted 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine compounds, having the general formula in which R represents a branched or unbranched alkyl group having 1 to 17 carbon atoms inclusive, a phenyl group optionally substituted by one or two lower alkyl groups, lower alkoxy groups or halogen atoms, a phenylalkyl group, a lower alkoxy group or a group -NR<1>R<2> in which R<1> and R<2> are each hydrogen, or a lower alkyl, phenyl or cyclohexyl group, and pharmaceutically acceptable acid addition salts of these compounds have an activity connected to gamma -aminobutyric acid (GABA) and are indicated for use in the treatment of diseases which are connected with defective function of the GABA system, such as epilepsy, Parkinsonism, schizophrenia, Huntington's Chorea (chronic progressive hereditary chorea), diseases in which a deficient function of the pituitary hormones plays a role and cerebral arteriosclerosis. In addition, the compounds exhibit strong analgesic and myotonic action. They are prepared by acylation of compounds of the general formula in which R<3> represents an amino group-protecting group, which can be easily removed after the acylation without adversely affecting the acylated hydroxyl group. The invention also relates to medicaments which contain a compound of the formula I as active substance.

Description

News 4,5,6,7-tetrahydroisoxazolo
3-substituted i'5,4-cgpyridines, process
for their preparation and compositions
pharmaceutical products containing them.

The present invention relates to novel 4,5,6,7-tetrahydroisoxazolo / S, 4-c2, 3-substituted pyridines useful in particular as medicaments, a process for the preparation of these derivatives and pharmaceutical compositions containing them.

où R représente un radical alcoyle, ramifié ou non ramifié, ayant 1 à 17 atomes de carbone inclusivement, un radical phényle éventuellement substitué par un ou deux radicaux choisis parmi les radicaux alcoyle inférieurs, alcoxy inférieurs et halogéno, un radical phénylalcoyle, un radical alcoxy inférieur ou un radical -NRR ou R et R représentent chacun un atome d'hydrogène ou un radical alcoyle inférieur, phényle ou cyclohexyle, ainsi que leurs sels d'addition avec des acides pharmaceutiquement acceptables, qui se sont révélés avoir une activité liée à l'acide Y-aminobutyrique (GABA) et dont l'emploi est indiqué pour le traitement des maladies liées à un mauvais fonctionnement du système GABA, telles que l'épilepsie, la maladie de Parkinson, la schizophrénie, la chorée de Huntington, les maladies impliquant un mauvais fonctionnement des hormones hypophysaires et l'artériosclérose cérébrale. The invention relates to novel compounds corresponding to the formula

where R represents an alkyl radical, branched or unbranched, having 1 to 17 carbon atoms inclusive, a phenyl radical optionally substituted by one or two radicals chosen from lower alkyl, lower alkoxy and halo radicals, a phenylalkyl radical, an alkoxy radical lower or a radical -NRR or R and R each represent a hydrogen atom or a lower alkyl, phenyl or cyclohexyl radical, as well as their addition salts with pharmaceutically acceptable acids, which have been found to have an activity related to the 'Y-aminobutyric acid (GABA) and whose use is indicated for the treatment of diseases linked to a malfunction of the GABA system, such as epilepsy, Parkinson's disease, schizophrenia, Huntington's chorea, diseases involving a malfunction of pituitary hormones and cerebral arteriosclerosis.

In addition, they have significant analgesic and myotonolytic effects.

The compounds of formula I have been described generally, for example in patent application EP No. 78 100 191.2 where it is indicated that they serve as intermediates for the preparation of THIP (4,5,6,7-tetrahydro isoxazoloS , 4-cSpyridinol-3) which has been shown to have GABA related activity. However, we do not know of real examples of these intermediaries.

The Applicant has discovered that, surprisingly, the compounds of formula I as well as their addition salts with pharmaceutically acceptable acids have an activity linked to GABA as important as that of THIP and that some of the new compounds of the invention also have a prolonged effect compared to THIP. In addition, these compounds have pronounced analgesic and myotonolytic effects.

The invention further relates to their application as medicaments and to novel pharmaceutical compositions containing as active ingredient a compound of formula I or an addition salt thereof with pharmaceutically acceptable acids.

The properties of the products of the invention make them particularly suitable for the treatment of diseases linked to a malfunction of the system.
GABA, for the relief of pain of various origins and for the treatment of myotonic conditions (for example to induce muscle relaxation or to treat muscle spasm or muscle spasticity).

The terms "lower alkyl" and "lower alkoxy" refer to such radicals having 1 to 6 carbon atoms inclusive.

As examples of pharmaceutically acceptable salts of the compounds of formula I, mention may be made of the salts formed with mineral acids, for example hydrochlorides, hydrobromides, nitrates, sulphates, phosphates and the like, or with organic acids, for example acetates, propionates , glycolates, malonates, maleates, succinates, fumarates, tartrates, citrates, oxalates, benzoates, pamoates, methanesulphonates, ethanesulphonates, benzenesulphonates, toluenesulphonates and the like, these salts possibly being prepared according to methods known per se, for example by addition of acid indicated at the base, preferably in a solvent.

où R3 représente un groupe protecteur du radical amino facilement éliminable, avec un dérivé réactif d'un acide de formule R.COOH où R a la même définition que ci-dessus, puis on élimine le groupe protecteur R3 et on isole le composé de formule I sous forme de la base libre ou d'un de ses sels d'addition avec des acides pharmaceutiquement acceptables.According to the process of the invention, a compound of formula

where R3 represents an easily removable protective group for the amino radical, with a reactive derivative of an acid of formula R.COOH where R has the same definition as above, then the protective group R3 is removed and the compound of formula is isolated I in the form of the free base or one of its addition salts with pharmaceutically acceptable acids.

As protecting groups R3, there are preferably used groups which can then be removed very easily, such as alkoxycarbonyl groups. Preferably, substitution is carried out with a tert-butoxycarbonyl (tert-BOC) group according to the method described by Tarbell et al., Proc. Nat. Acad. Sci. 69 (3), p.

730, 1972.

O-acylation is carried out according to the process of the invention in a conventional manner in an organic solvent, preferably in the presence of a tertiary amine, at low temperature.

Some of the starting compounds of formula II are readily prepared by reacting 3-hydroxy 4,5,6,7-tetrahydroisoxazolo / S, 4-cgpyridine (hereinafter to simplify THIP), with a dialkyl dicarbonate, of preferably di-tert-butyl dicarbonate.

After acylation according to the process of the invention, the protecting group R3 can be removed under mild conditions such as controlled hydrolysis.

When R3 represents a tert-butoxycarbonyl group, it can be easily removed by reaction with anhydrous trifluoroacetic acid at about OOC.

The process of the invention is illustrated by the following practical examples which are not limiting.

Example 1. 3-hydroxy 6- (tert-butoxycarbonyl) 4,5,6,7 tetrahydroisoxazolé5,4-cJpyridine.

11.1 g of hydrobromide are suspended.
THIP in 50 ml of dioxane and 25 ml of water. By adding 4.0 g of sodium hydroxide in 25 ml of water while cooling with ice, a clear solution is obtained. 11.0 g of di-tertbutyl dicarbonate are added and the temperature is raised to 250C. The mixture is vigorously stirred for a further 1.5 hours. 300 ml of ethyl acetate and 100 ml of water are added and the pH of the aqueous solution is adjusted to about 3.0 with a solution of monopotassium sulfate. The ethyl acetate phase was separated and washed with two 25 ml portions of water, dried over anhydrous magnesium sulfate and the solvent evaporated to give 11.8 g (98%) of product. Pf 134-1360C, IR (KBr): vOH 2400-3200 (wide complex bands), vc = o 1690 cm
Example 2. 3-Acetoxy 4,5,6,7-tetrahydroiso xazolo / 5,4-cgpyridine oxalate.

4.8 g of THIP protected by the tert-butoxy-carbonyl radical are dissolved in 100 ml of anhydrous tetrahydrofuran, 2.1 g of triethylamine are added and the solution is cooled to OOC. A solution of 1.8 g of acetyl chloride in 20 ml of anhydrous tetrahydrofuran is added dropwise at a temperature below 5 ° C. Finally, the solution is stirred for 15 minutes at room temperature, the triethylammonium hydrochloride is filtered off and the tetrahydrofuran is evaporated off. Yield: 4.2 g (75 X) of 3acetoxy 6- (tert-butoxy-carbonyl) 4,5,6,7-tetrahydroiso xazoloz5,4-cSpyridine. P.f. 93-970C.

3.0 g of this product is added to 10 ml of ice-cold anhydrous trifluoroacetic acid. The mixture is stirred until there is no more evolution of carbon dioxide. The excess trifluoroacetic acid is evaporated off and the oil obtained is dissolved in a few milliliters of anhydrous acetone. 2.5 g of anhydrous oxalic acid in 10 ml of anhydrous acetone are added.
The oxalate precipitates with stirring and cooling.

Yield: 2.2 g (76%). P.f. 217-2190C (decomp.).

(Found: C 44.43; H 4.59; N 10.07; calcd for C10H12N2O7: C 44.12; H 4.45; N 10.29%).

Example 3. 3-Benzyloxy 4,5,6,7-tetrahydroiso xazolog5,4-cSpyridine oxalate.

Intermediate 3-benzoyloxy 6- (tert-butoxycarbonyl) 4,5,6,7-tetrahydroisoxazolog5,4-cSpyridine is prepared in the form of an oil with a yield of 74% according to the procedure of Example 2.. eliminates the tert-butoxycarbonyl group as described above to obtain the oxalate with a yield of 71%.

Pf 195-1970C (decomp.). (Found: C 53.51; H 4.35
N 8.64; C15H14N207 requires: C 53.89; H 4.23
N 8.38X).

Example 4. 3- (2,6-Dimethylbenzyloxy) 4,5,6,7 tetrahydroisoxazolo /, 4-c2pyridine oxalate.

3- (2,6-Dimethylbenzyloxy) 6- (tertbutoxycarbonyl) 4,5,6,7-tetrahydroisoxazoloz5,4-cgpyridine is prepared in an 80% yield according to the procedure of Example 2. M.p. 147-1490C.

The tert-butoxycarbonyl group is removed as described above to obtain the oxalate with a yield of 84%. Mp 188-1900C (dec.) (Found: C 55.51;
H 5.16; N 7.62; C17Hl8N207 requires: C 56.34
H 5.02; N 7.73%).

Example 5. Ethyl 3- (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridyl) carbonate oxalate.

Intermediate ethyl 6- (tert-butoxycarbonyl) 3® (4,5,6,7-tetrahydroisoxazoloz5,4-cSpyridyl) carbonate is prepared in 68% yield from tert-BOC THIP and chloroformate. ethyl according to the procedure of Example 2. Pf 95-970C. The tert-butoxycarbonyl group is removed as described above to obtain the oxalate in a yield of 97%.

Mp 154-1570C (decomp.). (Found: C 43.76; H 4.84;
N 9.27; C11H14N2O8 requires: C 43.71; H 4.68
N 9.27%).

Example 6. 3- (4,5, 6, 7-tetrahydroisoxazolo [5,4-c] pyridyl) N, N-dimethylcarbamate oxalate.

4.8 g of tert-BOC THIP are dissolved in 100 ml of anhydrous tetrahydrofuran and 2.1 g of triethylamine are added. While cooling with ice, 2.2 g of N, N-dimethylcarbamoyl chloride in 20 ml of anhydrous tetrahydrofuran are added. The mixture is refluxed for 2 hours and finally the tetrahydrofuran is evaporated. The residue is dissolved in 200 ml of methylene chloride and washed with two 250 ml portions of an ice-cold 0.1 M solution of potassium carbonate. The methylene chloride phase is dried with magnesium sulfate and the solvent is evaporated off.

The remaining oil is subjected to column chromatography (Silica gel 60 "Merck"). 6- (tert-Butoxycarbonyl) 3- (4, 5,6,7-tetrahydroisoxazolo [5,4-c] pyridyl) N, N-dimethylcarbamate is eluted with ether.

Yield 2.4 g (39%). P.f. 68-720C.

The tert-butoxycarbonyl group was removed as described above to give the oxalate in a yield of 9470. Mp 240-2420C (decomp.). (Find
C 43.79; H 5.35; N 13.35; C1lHl5N307 requires
C 43.85; H 5.03; N 13.95).

Example 7.

As described in Example 6, replacing N, N-dimethylcarbamoyl chloride with
N, N-diethylcarbamoyl and N-methyl N-phenylcarbamoyl chloride, respectively the oxalate of
3- (4,5,6,7-tetrahydroisoxazolo 5,4-cgpyridyl) N, N-diethylcarbamate, melting at 216-2180C, and
3- (4,5,6,7-tetrahydroiso-xazolo / 5,4-cgpyridyl) N-methyl N-phenylcarbamate, melting at 183-1840C.

The analgesic activities of the compounds of Example 7 were studied according to the hot plate technique on the mouse described by Chen and Beckmann,
Science, vol. 13, p. 631, 1951, and ED50s of 16 and 18 mg / kg per os were obtained, respectively, as well as activity against arthritis pain in rats according to the method of AW Pircio et al., Eur. J. Pharmacol. flight. 31, p. 207-215, 1975, and ED50s of approximately 56 (one hour), 42 (3 hours), 42 (5 hours) and 25 (1 hour), and 25 (3 hours) were obtained by oral administration, respectively. and 15 (5 hours).

The following were prepared in a similar fashion: 3-butanoyloxy 4,5,6,7-tetrahydroisoxazolo / 5, 4-cJpyridine citrate, 3-octyloxy 4,5,6,7-tetrahydroisoxazolo g5,4-cvpyridine succinate, 3-palmitoyloxy 4,5,6,7-tetrahydroisoxazo lo / 5, 4-cipyridine maleate, and 3- (4,5,6,7-tetrahydroisoxazoloz5,4- N-methyl N-cyclohexylcarbamate acetate cSpyridyl).

The compounds of formula I were studied according to reliable standard test methods described herein after Antaaonism to isoniazid.

Mice, males, 20-25 g.

Isoniazid 300 mg / kg s.c.

Macrolon type II cages.

Dose and procedure.

The compound to be studied is injected intraperitoneally at doses of 0, 1/2, 1/8 and 1/32 of the
LD50 iv determined. In the case of insoluble substances, doses of 0, 1/4, 1/16 and 1/64 of the determined ip LD50 are used.

5 mice are used for each dose.

Immediately after administration of the test substance, 300 mg / kg of isoniazid is injected subcutaneously. This dose of isoniazid causes intermittent tonic and clonic convulsions within 60 minutes.

The calculations are carried out by direct operation on the electronic data processing terminal. The results are recorded in the form of the percentage increase in the time to onset of seizures and furthermore, according to the Van der Waerden test, the minimum effective dose, i.e. the lowest dose, is calculated. having a significant effect.

The ED50 is the dose expressed in mg / kg which increases the time to onset of seizures by 50%.

Electric shock with an arillaaé floor on the mouse.

Male mice 20-23 g.

A Perspex cage is used, the bottom of which is screened with a Perspex cover, in which a microphone sensitive to the frequency of a mouse cry is placed. A stimulator with a mechanically driven potentiometer applies to the grid a series of square pulses of continuously increasing intensity on the order of milliamps. The pulses have a frequency of 20 cycles / second and a duration of 5 ms. The intensity is recorded on a digital milli-ammeter connected to the stimulator. Activation of the microphone by a mouse cry cuts the current and the final milli-amperage appears on the meter.

Dose and procedure.

The test substance is administered intraperitoneally in doses of 1/2, 1/4 and 1/8 of the
Intravenous LD50 determined. For insoluble substances, doses of 1/4, 1/8 and 1/16 of the intraperitoneal LD50 are used. Five mice are used for each dose. Each mouse constitutes its own control.

Before administration of the test substance, the animals are placed on the grid one at a time and the pain threshold is determined by increasing the intensity of the current until the mouse cries out. You can read the pain threshold on the milliammeter.

Fifteen minutes and thirty minutes after administration of the test substance, the mice are studied again and the pain thresholds are recorded. In addition, the test substance can be tested after oral administration at doses of 1/1, 1/2 and 1/4 of the
Intravenous LD50 and determine the pain threshold before and 30 minutes after administration. Oral insoluble substances are studied at doses of 1/2, 1/4 and 1/8 of the intraperitoneal LD50.

there is an analgesic effect when the pain threshold increases compared to the value before administration (control value). The results are indicated in percentages of elevation of the pain threshold calculated from the control value. You can also perform direct recording. In this case, the punched instructions and punched cards are used automatically and the results are recorded as the minimum effective dose determined from the van der Waerden X test.

Binding of 3H-GABA to rat brain membranes.

Rats 125-200 g.

Sucrose 0.32 M (solution prepared frankly every day).

10% Triton X-10O.

0.05 N Tris-citrate buffer (pH N 6.8).

Trisma (base) 6.05 g.

Citric acid monohydrate 3.502.

for 1 liter of water.

3H-GABA = aminobutyric acid, -2.3-H (N) about 35 Ci / mmol, from New England Nuclear (diluted daily to 1 µM in water).

Operating mode.

A. Preparation of membranes.

We kill rats with a blow to the head, we bleed them and we remove the brains that are cooled in ice-cold saline solution. After rinsing and weighing, two brains are brought together which are homogenized in 40 ml of ice-cold 0.32 M sucrose with a mechanical homogenizer having a Teflon pestle (6 back-and-forth movements, slow rotation speeds).

Samples were centrifuged for 10 minutes at 100g and then the supernatants were centrifuged for 20 minutes at 17,000g (4CC). To each pellet, 20 ml of water are added and the samples are homogenized (Ultra
Turrax) for 30 seconds. After adding 10 ml of water again, the samples were centrifuged for 20 minutes at 8500g (40C). Two-thirds of the supernatant is discarded and the light brown upper part of the pellets is rotated by hand.

This supernatant is centrifuged for 30 minutes at 37,500 g (40C). The pellet is homogenized (Ultra Turrax) for 1 minute in 10 ml of water. The sample is divided into two glass containers and 25 ml of water are added to each of them (each glass container then contains the membranes of a brain in 30 ml of water). These samples are centrifuged for 30 minutes at 37,500 g (40C), the pellets are frozen in an acetone / carbon dioxide snow mixture placed in a capped flask and stored frozen until use (at least overnight).

B. Pretreatment of membranes.

On the day of the measurements, the pellet is frozen in acetone and carbon dioxide snow for 20 minutes and 25 ml of water are added before homogenization (Ultra Turrax) for one minute. 25 ml of 0.05 N citrate-tris buffer and 250 ml of
10% Triton X-loO, then the sample is incubated for 30 minutes at 370C and centrifuged at 37,500g for 20 minutes (40C). The supernatant is discarded and the pellet is suspended in a citrate-0.05 N tris buffer (Ultra Turrax, 75 sec.) To a concentration of 30 mg of the original wet weight per ml. The suspension is left at room temperature for 20 minutes and then stored on ice.

C. Binding test.

Into each incubation tube, in duplicate, operating on ice, pour 780 microliters of water, 200 microliters of drug dissolved in water, 20 microliters of 3H-GABA, micromolar (the final concentration in 3H-GABA in the tubes is 10 nM) and 1000 microliters of the membrane suspension. After incubation on ice for 5 minutes, the samples are centrifuged at 31,000 xg for 18 minutes. The supernatant is discarded and the pellet is washed carefully with three times 5 ml of water. icy. 1 ml of Soluene 350 is added and the samples are incubated for 30 minutes at 370C. 10 ml of Instagel or Lumagel containing 10 ml of acetic acid per liter are added and the radioactivity is determined by counting the scintillations of the liquid. The non-specific binding of 3H-GABA is determined by incubating the samples with 1 nM GABA.

Each series consists of 8 duplicates (one control, one containing 1 nM of GABA and one to two series of test compounds being in concentrations of 3 to 6.

The means of controls and samples at 1 mM GABA are calculated. The counts per minute as a function of the drug concentration are recorded on semilogarithmic paper and the S-curve corresponding to the best fit is plotted. The values of the IC50 are determined, which are expressed by the concentrations for which the binding is equal to 50% of the total binding minus the non-specific binding.

The results obtained are shown in the following table where the substances studied are indicated by the number of the example describing their preparation.

The corresponding experimental results obtained with THIP are provided for reference.

BOARD

<tb> Substance <SEP> Antagonism <SEP> Shock <SEP> elec- <SEP> CI50 <SEP><SEP> of <SEP> fixed
<tb> studied <SEP> vis-à-vis <SEP> of <SEP> cross <SEP> on <SEP> tion <SEP> of <SEP> 3H-GABA
<tb><SEP> isoniazid <SEP><SEP> mouse
<tb> Example <SEP> 2 <SEP> 2.9 <SEP> + <SEP> 2.8 <SEP>. <SEP> 10 <SEP>
<tb> Example <SEP> 3 <SEP> 3.2 <SEP> + <SEP> 3.3 <SEP>.
<tb>

Example <SEP> 4 <SEP> 8.6 <SEP> + <SEP> 5.3 <SEP>. <SEP> 1-6 <SEP>
<tb> Example <SEP> 5 <SEP> 10.8 <SEP> + <SEP> 8.2 <SEP>.
<tb>

Example <SEP> 6 <SEP> 1.2 <SEP> + <SEP> 5.5 <SEP>.
<tb>

THIP <SEP> 1.3 <SEP> + <SEP> 1.7 <SEP>
The compounds of formula I and their addition salts with non-toxic acids can be administered to animals such as dogs, cats, horses, sheep or the like and to man, orally or parenterally, and either. can, for example, be used in the form of tablets, capsules, powders, syrups or ordinary sterile injectable solutions. The results of administration to humans have been very satisfactory.

Particularly suitably, the compounds of formula I are administered orally in the form of unit doses such as tablets or capsules, each unit dose containing an addition salt with a non-toxic acid of one of said compounds in an amount of 'approximately 5 to approximately 100 mg and, most preferably however, approximately 10 to 50 mg calculated as free amine, the total daily dose generally being between approximately 20 and approximately 200 mg. The individual doses as well as the exact daily dosages should of course be determined in each particular case according to medical principles under the guidance of a physician.

To prepare tablets, the active ingredient is usually mixed with ordinary tablet adjuvants such as male starch, potato starch, talc, magnesium stearate, gelatin, lactose. , gums or the like.

When the compound of formula I is a free amine, preferably R represents a lower alkyl radical having 8 to 17 carbon atoms inclusive and the composition can advantageously be an injectable oily solution, such a solution often having a very prolonged effect by ratio to that obtained with the corresponding unesterified compound.

Typical examples of formulations of compositions containing 3-acetoxy 4,5,6,7-tetrahydroisoxazolo gS, 4-cgpyridine (referred to for simplicity as Lu 18-013) as an active ingredient are shown below.

1. Tablets containing 10 mg of Lu 18-013 calculated as free base in the form of the oxalate
Lu 18-013 10 mg
Lactose 37 mg
Potato starch 74 mg
Gelatin 2 mg
Talc 8 mg 2. Capsules each containing
Read 18-13 25 mg
Lactose 40 mg
Magnesium stearate 0.5 mg
Any other pharmaceutical tablet adjuvant compatible with the active ingredient can be used and additional compositions and dosage forms can be similar to those currently used for neuroleptics such as thiothixene, clopenthixol and flupenthixol. Also a combination of the compounds of formula I as well as their salts with non-toxic acids with other active ingredients in particular other neuroleptics, thymoleptics, tranquilizers or the like are within the scope of the invention.

As previously indicated, when isolating the compounds of formula I as an acid addition salt, the acid is preferably selected so as to have an ion which is non-toxic and pharmacologically acceptable, at least. less at the usual therapeutic doses. As examples of characteristic salts forming part of this preferred group, mention may be made of the hydrochlorides, hydrobromides, sulphates, acetates, phosphates, nitrates, methanesulphonates, ethanesulphonates, lactates, citrates, tartrates, or bitartrates, pamoates and maleates of amines of formula I.

Other acids are also suitable and if desired they can be used. For example, it is also possible to use, as acids forming an addition salt with an acid, fumaric, benzolic, ascorbic, succinic, salicylic, bismethylenesalicylic, propionic, gluconic, malic, malonic, mandelic, cinnamic, citraconic, stearic, palmitic, itaconic, glycolic, benzenesulfonic, and sulfamic.

When it is desired to isolate a compound of the invention in the form of a free base, the operation is carried out according to a conventional technique such as dissolving the isolated or non-isolated salt in water, treatment with an appropriate alkaline material, extraction of the salt. liberated free base with a suitable organic solvent, drying the extract and evaporating to dryness or fractional distillation to isolate the free basic amine.

The medicaments of the invention, taking into account the above properties, are particularly suitable in the following therapeutic applications, namely to relieve, attenuate, soften or inhibit the manifestations of certain physiological-psychological abnormalities of animals as well as of man. A suitable amount of a compound of formula I or an addition salt thereof with non-toxic acids is administered for this purpose. A suitable amount is between about 0.5 mg and about 20 mg per kg of body weight and per day and between about 20 mg and about 200 mg per day for oral administration.

Claims (5)

1. New compounds characterized in that they correspond to the formula

where R represents an alkyl radical, branched or unbranched, having 1 to 17 carbon atoms inclusive, a phenyl radical optionally substituted by one or two radicals chosen from lower alkyl radicals lower alkoxy and halo, a phenylalkyl radical, a lower alkoxy radical or a radical -NRR or R and R each represent a hydrogen atom or a lower alkyl, phenyl or cyclohexyl radical, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for preparing a compound according to claim 1, characterized in that it comprises the reaction of a compound of formula

where R3 represents an easily removable amino protecting group, with a reactive derivative of an acid of the formula R.COOH, where R has the same definition as in the desired compound, then the elimination of the protecting group R3 and the isolating the compound of formula I as the free base or as an addition salt with a pharmaceutically acceptable acid. 3. New medicaments characterized in that they contain an effective amount of at least one compound according to claim 1. 4. Pharmaceutical composition characterized in that it contains as active ingredient at least one of the medicaments according to claim 3. 5. Pharmaceutical composition according to claim 4, characterized in that it further contains a minor tranquilizer or a neuroleptic.