FR2543954A1 - 4-Acylamino-1-azaadamantanes, process for their preparation and application in therapeutics - Google Patents

Abstract

The invention relates to 4-acylamino-1-azaadamantanes represented by the general formula I: in which R represents a phenyl group, a substituted phenyl group, a pyridyl group, a naphthyl group, a tetrahydronaphthyl group or a coumarinyl group, and X represents a single bond or a saturated or unsaturated divalent group containing 1 to 3 carbon atoms, if appropriate substituted by a methyl or phenyl group, X not being a single bond when R is a phenyl group. Application in therapeutics, especially for the treatment of cardiovascular diseases.

Description

The present invention, carried out in the laboratories of CERES - Center
European Scientific Research - relates to new derivatives of adamantane, and more particularly derivatives of the 4-acylamino-adamantane series, their application in therapy, and a process for their preparation.

Various compounds are known comprising in their molecule an adamantyl type nucleus, whose hexagonal condensed four-ring structure can cause various particular physical and chemical properties due to its steric rigidity. Aza-adamantane derivatives, or aza-tricyclo 3,3,1-decane, having an adamantyl group in which a nitrogen atom is substituted for a carbon atom in a bridge, at the junction of three of the condensed rings of the adamantyl tetracyclic nucleus, have been studied very little. An example of a method for preparing such derivatives of the aza-adamantane type is described in French Patent 2,358,404.

French patent application 81.18682, in the name of the Applicant, describes 4-acylamino-4,8,8-trimethylazadanantamines, in which the carbonyl group of the acylamino group is substituted by an alkyl, phenyl, benzyl or phenethyl group, having pharmacological properties useful for their application in the treatment of cardiovascular diseases.

The subject of the invention is new 4-acylamino-4,4,8-trimethylazadiamine which can be used therapeutically for the treatment of cardiovascular diseases.

The subject of the invention is also a process for the preparation of novel derivatives of the 4-acylamino-trimethyl-4,8,8-aza-1 adamantane type.

The object of the present invention also extends to new drugs consisting of derivatives of the 4-acylamino-trimethyl-4,8,8-aza-1-adamantane type, as well as pharmaceutical compositions containing them, for the treatment of cardiovascular diseases. .

dans laquelle R représente un groupe phényle, un groupe phényle substitué, un groupe pyridyle, un groupe naphtyle, un groupe tétrahydronaphtyle ou un groupe coumarinyle, et X représente une liaison simple ou un groupe divalent saturé ou insaturé de 1 à 3 atomes de carbone, substitué le cas échéant par un groupe méthyle ou phényle, X n'étant pas une liaison simple lorsque R est un groupe phényle.The novel 4-acylamino-4-adamantanes according to the present invention may be represented by the general formula (I) below:

wherein R represents a phenyl group, a substituted phenyl group, a pyridyl group, a naphthyl group, a tetrahydronaphthyl group or a coumarinyl group, and X represents a single bond or a divalent saturated or unsaturated group of 1 to 3 carbon atoms, optionally substituted with methyl or phenyl, X not being a single bond when R is phenyl.

When R is phenyl, this group may have one or more substituents selected from one or more halogen atoms or one or more alkyl (eg, methyl, ethyl, propyl, butyl, etc.), hydroxy, alkoxy (by methoxy, ethoxy, isopropoxy, etc.), amino, alkylamino (for example isopropylamino), dialkylamino (for example dimethylamino, diethylamino, etc.), nitro, cyano, acylamino (for example acetylamino), haloalkyl (for example trifluoromethyl, trichloromethyl, etc. to form, for example, p-nitrophenyl, p-aminophenyl, p-dimethylaminophenyl, p-acetylaminophenyl, p-methoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, p-hydroxyphenyl, dihydroxy -3,4 phenyl, p-chlorophenyl, m-chlorophenyl, 3,4-dichlorophenyl, p-trichloromethylphenyl, m-trifluoromethylphenyl, p-cyanophenyl,
As indicated above, X may be a single bond, except when R is a phenyl group, or a divalent group. This divalent group has 1 to 3 carbon atoms and can be saturated or unsaturated. It can be constituted, for example, by a methylene, ethylene, trimethylene or a carbon chain comprising an ethylenic or acetylenic bond, and for example a vinylene or ethynylene group. This divalent group may be substituted with a methyl or phenyl group to form, for example, a divalent propylene or phenyl-ethylene group.

The invention preferably relates to the compounds of general formula (I) wherein R is a 4-pyridyl, 3-pyridyl, or substituted phenyl group and
X is a single bond or a divalent group -CH2-, -CH2CH2- or CH-CH- and compounds where X is a single laison and R is a naphthyl, tetrahydronaphthyl or coumarinyl group.

The invention also relates to the salts of the 4-acylamino-4-adamantane derivatives, represented by the general formula (I) above, and in particular the pharmaceutically acceptable salts, obtained by reacting a mineral or organic acid on the derivative of formula (I) as a base. This salification reaction can be carried out according to the usual methods of the technique, by reacting the acid and the 4-acylamino-4-aza-1-adamantane derivative of formula (I) in substantially stoichiometric proportions, in a suitable solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, methylene chloride, ethyl ether, ethyl acetate, etc. The acid may be, for example, hydrochloric acid, lactic acid, tartaric acid, phosphoric acid, oxalic acid, formic acid, sulfuric acid, maleic acid, hydrobromic acid, hydroiodic acid, and the like.

par réaction d'acylation, dans un solvant approprié, au moyen d'un acide, un chlorure d'acide, un ester ou un anhydride de structure appropriée.The novel 4-acylamino-4-trimethyl-4,8,8-adamantanes according to the invention can be obtained from 4-amino-4-aza-trimethyl-4,8,8-adamantane of general formula (II) above. below:

by acylation reaction, in an appropriate solvent, by means of an acid, an acid chloride, an ester or an anhydride of appropriate structure.

In the acylation reaction of the amine of general formula (II), it is possible to use in particular isonicotinic acid, p-chlorocinnamic acid, m-trifluoromethylcinnamic acid, naphthalene carboxylic acid and coumarin acid. carboxylic acid, phenylpropionic anhydride, p-chlorophenylpropionic anhydride, cinnamic acid chloride.

All the solvents commonly used in the acylation reactions may be suitable for the preparation of the derivatives in accordance with the invention, in particular an ether such as diethyl ether, the tetrahydrofuran, dioxane, a chlorinated solvent such as carbon tetrachloride, chloroform, methylene chloride, or an ester such as ethyl acetate. According to the invention, methylene chloride and chloroform are preferably used.

The acylation reaction of 4-amino-4-trimethyl-4,8,8-adamantane of formula (II) is carried out in the cold, and it may be advantageous to dissolve the starting products in a bath-cooled solvent. ice or cold water bath, and allow the temperature to rise slowly during the reaction.

In order to facilitate the acylation reaction, especially when the acylating agent is an acid such as p-chlorocinnamic acid, naphthalene carboxylic acid, etc., it is advantageous to add N-reactive medium to the reaction medium. hydroxysuccinimide and dicyclohexylcarbodiimide. The quantities used can be for example of the order of 1 to 2 moles of
N-hydroxysuccinimide and from 1 to 3 moles of dicyclohexylcarbodiimide to 1 to 2 moles of acid and 1 mole of 4-amino-4-aza-trimethyl-4,8,8 adamantane of formula (-Il).

If necessary, the base obtained can be salified, as indicated above, or transformed by modification of a substituent. For example, the compound of formula (I) in which R is a pyridyl group and X is -CH = CH-, obtained by the action of pyridyl acrylic acid on the amine of formula (II), may be reduced by catalytic hydrogenation for convert it into a corresponding derivative where R is a pyridyl group and X is -CH2-CH2-.

The 4-amino-1-aza-trimethyl-4,8,8-adamantane of general formula (II) is a known product, described in French Patent 2,358,404, which can be prepared from a pinene treated with a mercuric salt and a nitrile in an anhydrous medium to obtain a bicyclic imine which is reduced to amine and then cyclized by the action of an aldehyde to provide azaadamantane of formula (II).

The examples given below illustrate the invention in more detail without limiting its scope.

EXAMPLE 1
N-cinnamoylamino-4-trimethyl-4,8,8 aza-1 adamantane.

4,09 amino-4-trimethyl-4,8,8-aza-1-adamantane is dissolved in 40 ml of methylene chloride, and 3.49 and then 0.59 of cinnamic acid chloride are successively added, the reaction mixture being kept under agitation on an ice bath.

After filtration of the precipitate formed, redissolved in water, then alkanization, filtered, dried, according to the usual techniques, and the precipitate is purified by recrystallization from a mixture of ethanol and water.

N-cinnamoylamino-4-trimethyl-4,8,8-aza-1-adamantane crystals are thus obtained whose melting point is F = 153-1540 ° C.

IR spectrum (Nujol) v = 3290, 1660, 1620, 1540, 1345, 1215, 985 cm
EXAMPLE 2
N- (p-hydroxyphenyl-3-propionyl) amino-4-trimethyl-4,8,8
aza-l adamantane.

To a solution of 7,09 of p-hydroxyphenyl-3 propionic acid in 70 ml of ethanol at 950, 12 ml of potassium hydroxide solution are added dropwise, followed by 12 ml of benzyl chloride, with stirring. The mixture is refluxed for one hour, then 30 ml of water and 4.5 ml of potassium hydroxide solution are added and reflux is maintained for 30 minutes.

Ethanol is removed by evaporation in vacuo, flooded with water, acidified and extracted with a mixture of methylene chloride and methanol. After crystallization from acetone, 9.89 p-benzyloxyphenyl-3-propionic acid (yield: 90 g) is obtained, the melting point being F = 123-125 C.

7.99 of the acid obtained above are reacted with 5.09 of 4-amino-trimethyl-4,8,8-azadadamantane in the presence of 3.69 of N-hydroxysuccinimide and 8.09 of dicycloxylcarbodilmide, added gradually in 90ml of methylene chloride. The reaction is carried out on an ice bath.

After reaction; 50 ml of dilute sodium hydroxide solution are added, decanted and washed with water. The basic fraction is crystallized from ethyl acetate to afford 9.29 of N- (p-benzyloxyphenyl-3-propionyl) amino-4-trimethyl-4,8,8 aza-1 adamantane (yield 82 Q), the point of which is melting point is F = 130-135C.

Catalytic hydrogenation of 8.59 of the above compound in 100 ml of methanol in the presence of 850 mg of palladium on carbon (10: 0) gives, after crystallization in ethanol, 5.79 of N- (p-hydroxyphenyl) 3-propionyl) amino-4-trimethyl-4,8,8 aza-1 adamantane.

Melting point F = 242-2440C.

The above product is converted into its hydrochloride by the usual techniques, by the action of concentrated hydrochloric acid in ethanol.

Melting point F = 254-25 ° C.

IR spectrum (Nujol) v = 3290, 2730, 2660, 2570, 1830, 1640, 1615, 1590, 1530, 1515, 1275, 1265, 990, 965, 825,
790, 705 and 650cm-1.

EXAMPLE 3
Np-chlorocinnamoylamino-trimethyl-4,8,8
-aza-l adamantane.

9.09 of 4-amino-trimethyl-4,8,8-aza-1-adamantane are reacted with 11.9 g of p-chlorocinnamic acid, while stirring, on an ice-bath, in the presence of 8.29 g. of N-hydroxysuccinimide and 16.59 of dicyclohexylcarbodiimide in 150 ml of methylene chloride for about 48 hours.

12.99 crystals of N-p-chlorocinnamoylamino-4-trimethyl-4,8,8 aza-1 adamantane (yield 780 °) are thus obtained, recrystallized from ethyl acetate.

Melting point F = 176-1790C.

IR spectrum (Nujol) v = 3310, 3120, 3040, 1660, 1620, 1590, 1570,
1530, 1515, 1490cm-1
EXAMPLE 4
N- (p-chlorophenyl-3-propionyl) amino-4
trimethyl-4,8,8 aza-1 adamantane
The procedure is as in Example 3 by reacting 4,59-amino-4-trimethyl-4,8,8-aza-1 adamantane with 6.29 3-p-chlorophenylpropionic acid in the presence of dicyclohexylcarbodiimide and N -hydroxysuccinimide in methylene chloride.

There is thus obtained 7.19 pure crystals of the above product (yield 85%) recrystallized from ethyl acetate.

Melting point F = 172-1740C.

The corresponding tartrate is prepared by the action of tartaric acid in ethanol and crystallization in water.

Melting point F = 152-1620C (pasty melting).

IR spectrum (Nujol) v = 3290, 1635, 1550, 1490cm 1. (base)
EXAMPLE 5
Chloromethylate
N- (3-phenylpropionyl) amino-4-trimethyl-4,8,8
aza-l adamantane.

The procedure is as in Example 1 by reacting 4-amino-trimethyl-4,8,8 aza-1 adamantane with propionic acid chloride in ethanol.

The product obtained is converted into its iodomethylate by the action of methyl iodide in ethanol. The iodomethylate is converted to chloro methylate by dissolving in a type ion exchange resin
Amberlite IRA 400-C1 (Prolabo), in methanol. Chloromethylate crystallizes in ethanol.

Melting point: F> 2600C.

IR spectrum (Nujol) v = 3400, 3250, 3080, 1655, 1635, 1570, 740 and 695cm-1.

EXAMPLE 6
N-isonicotinoylamino-4-trimethyl-4,8,8
aza-l adamantane
The procedure is as in Example 3 by reacting 5,19-amino-4-trimethyl-4,8,8-aza-1 adamantane with 4,89 of isonicotinic acid in the presence of N-hydroxysuccinimide and dicyclohexylcarbodiimide.

The desired product is obtained with a yield of 76 Q.

By the action of hydrochloric acid in methanol, the dihydrochloride which precipitates is obtained.

Melting point F> 2600C.

IR spectrum (Nujol) v = 3450, 3250, 1640, 1600, 1550, 1500cl 1.

EXAMPLE 7
N- (3-ss-pyridyl-3'-acryloyl) amino-4-trimethyl-4,8,8
aza-l adamantane.

The procedure is as in Example 1 starting from 9.99 of aminoazaadamantane and 10.79 of 3'-acrylidyl acrylate in the presence of dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The desired product is obtained with a yield of 65%, after crystallization in isopropyl ether.

Melting point F = -1370C.

The dimaleate is prepared in ethanol by the action of maleic acid, evaporation to dryness, trituration of the powder with isopropyl ether and crystallization in ethanol.

IR spectrum (Nujol) v = 3390, 3250, 3050, 1660, 1620, 1590, 1550cm-1.

EXAMPLE 8
N- (6-pyridyl-3'-propionyl) amino-4-trimethyl-4,8,8
aza-l adamantane
The above product is obtained by catalytic hydrogenation of the product of Example 7 by means of a palladium on carbon catalyst (10%) according to the usual techniques.

Melting point F = 1650C (benzene).

The corresponding maleate is prepared in ethanol from which it is precipitated.

Melting point F = 1290C (decomposition).

IR spectrum (Nujol) v = 3240, 3200, 3050, 1660, 1550cl 1.

EXAMPLE 9
N- (4'-naphthalenecarboxamino) -4,8-trimethylamino
aza-l adamantane.

The reaction is carried out as in Example 3 by reacting 3,59 of mantane aminoaza with 7.59 of naphthalene carboxylic acid-2 in the presence of 2.59 of
N-hydroxysuccinimide and 13.6 g of dicyclohexylcarbodiimide in 100 ml of methylene chloride.

The desired product crystallizes in ethyl acetate (yield: 70La).

Melting point F = 173-1750 ° C.

Thin layer chromatography Rf = 0.35.

(eluent: CH2Cl2-MeOH-NH4OH, 85-15-2).

EXAMPLE 10
N- (tetrahydro-1 ', 2', 3 ', 4' naphthalene carboxyl-2 ')
amino-4-trimethyl-4,8,8 aza-1 adamantane.

The procedure is as in Example 3 by reacting 3.59 of aminoazaadamantane with 4.8 g of 1,2,3,4-tetrahydro-naphthalene carboxylic acid in the presence of 16.99 of dicyclohexylcarbodiimide and 3.29 of N -hydroxy succinimide in 120 ml of methylene chloride.

The isolated product is purified by chromatography on a silica column
Merk 60H using as solvent methylene chloride-methanol-ammonia (86-14-1) to provide 1.99 of residue which, after crystallization from ethyl acetate, provides 1.79 of the desired product .

Melting point F = 207-2090C.

The corresponding hydrochloride is prepared by the action of cold concentrated hydrochloric acid in ethanol.

Melting point F> 2600C.

IR spectrum (Nujol) v = 3320, 3060, 1645, 1535, 740cl ~ 1. (based)
EXAMPLE 11
N- (coumarin carboxyl-3 ') amino-4-trimethyl-4,8,8
aza-l adamantane.

The procedure is as in Example 3 by reacting 3,59 aminoazaadamantane with 4,29 coumarin-3-carboxylic acid in the presence of 2.59 of
N-hydroxysuccinimide and 5.29 dicyclohexylcarbodiimide in 100ml of methylene chloride.

5.79 of the desired product are obtained after crystallization from absolute ethanol (yield: 86%).

Mp 230-2340C.

The hydrochloride is prepared by precipitation in ethanol by the action of concentrated hydrochloric acid.

Melting point F> 2600C.

IR spectrum (Nujol) v = 3330, 3310, 3035, 2995, 1700, 1650, 1605, 1560,
1525, 795, 755cm. (based)
EXAMPLE 12
N- (m-trifluoromethylphenyl-3'-propionyl) amino-4
trimethyl-4,8,8 aza-1 adamantane
4.09 of aminoazaadamantane is reacted with 6.59 m-trifluoromethylcinnamic acid in the presence of 3.59 of N-hydroxysuccinimide and 9.29 of dicyclohexylcarbodiimide in 80 ml of methylene chloride.

7.39 (yield 90 Ω) of crystals of N- (m-trifluoromethyl cinnamoyl) amino-4-trimethyl-4,8,8 aza-1-adamantane are thus obtained, recrystallized from ethyl acetate.

The catalytic hydrogenation of the product obtained as indicated above, in the presence of palladium on carbon (10%), provides, in quantitative yield, N- (m-trifluoromethylphenyl-3'-propionyl) amino-4-trimethyl-4,8, 8 aza-1 adamantane as a colorless oily product which is purified and precipitates in isopropyl ether.

Melting point F = 60-660C.

The corresponding tartrate is prepared by the action of tartaric acid in ethanol, followed by precipitation in ethyl acetate.

Melting point F = 146-1500C.

IR spectrum (Nujol) v = 3290, 3230, 3180, 1640, 1570, 1120cm libase)
EXAMPLE 13
N- (m-chlorophenyl-3'-propionyl) amino-4
trimethyl-4,8,8 aza-1 adamantane.

The procedure is as in Example 12 starting from dichlorocinnamic acid which is reacted with aminoazaadamantane in the presence of N-hydroxysuccinimide and dicyclohexylcarbodiimide then catalytic hydrogenation is carried out to obtain the desired product which crystallizes in the aqueous phase. 'ethyl acetate.

Melting point F = 124-1260C.

IR spectrum (Nujol) v = 3290, 1635, 1545cl 1.

EXAMPLE 14
N- (p-dimethylaminophenyl-3'-propionyl) amino-4
trimethyl-4,8,8, aza-1 adamantane
The procedure is as in Example 12 starting from p-dimethylaminocinnamic acid which is reacted with aminoazaadamantane in the presence of
N-hydroxysuccinimide and dicyclohexylcarbodiimide followed by catalytic hydrogenation to obtain the desired product which crystallizes from ethyl acetate.

Melting point F = 170-1740C.

IR spectrum (Nujol) v = 3300, 3180, 3050, 1640, 1615, 1565, 1520, 1380cm1.

EXAMPLE 15
N- (dichloro-3 ", 4"phenyl-3'-propionyl) amino-4
trimethyl-4,8,8 aza-1 adamantane.

4.59 of aminoazaadamantane is reacted with 7.49 of 3'-dichloro-4'-phenylpropionic acid in the presence of 3.89 N-hydroxysuccinimide and
18.59 dicyclohexylcarbodiimide in 120ml of methylene chloride.

This gives the desired product, which crystallizes in acetate
ethyl.

 Melting point F = 86-920C.

 IR spectrum (Nujol) v = 3300, 3220, 3180, 3040, 1640, 1560cl ~ 1.

EXAMPLE 16
N- (trimethoxy-2 ", 3", 4 "phenyl-3'-propionyl) onino-4
trimethyl-4,8,8 aza-1 adamantane
The procedure is as in Example 2 starting from trimethoxy-2 ', 3', 4 ', 3-phenylpropionic acid and the desired product is obtained in the form of crystals crystallizing in ethyl acetate.

Melting point F = 98-1000C.

IR spectrum (Nujol) v = 3580, 3300, 3280, 3160, 1660, 1600, 1550,
1490, 1095, 1085cm-1.

EXAMPLE 17
N- (3-phenylbutyryl) amino-4-trimethyl-4,8,8
aza-l adamantane
The procedure is as in Example 15 starting from 3-phenyl butyric acid to obtain the desired product which crystallizes in ethyl acetate.

Melting point F = 136-1380C.

IR spectrum (Nujol) v = 3300, 1640, 1570, 154 cm -1
EXAMPLE 18
N- (2,6-diphenyl-2 'acetyl) amino-4-trimethyl-4,8,8
aza-l adamantane
The procedure is as in Example 15 from diphenylacetic acid to obtain the desired product which crystallizes in ethanol.

Melting point F = 219-2230C.

IR spectrum (Nujol), v = 3290, 3050, 2990, 1665, 1645, 1545, 1490,
725,: 5Ucm
The experiments carried out on 4-acylamino adamantanes according to the present invention have revealed interesting toxicological and pharmacological properties, which demonstrate their possible application in human and veterinary therapy.

Toxicological study
Acute toxicity of the derivatives of the invention was studied by intraperitoneal (IP) administration to the mouse (10 animals, 5 males and 5 females per dose) and calculation of the 50 lethal dose (LD 50) according to the Litchfield method and Wilcoxon (J. Pharmacol 1949, 96, 99-113). Table 1 shows the LD 50 values of derivatives whose preparation is described in the examples.

TABLE 1
Example DL 50 IP

n0 (mg / kg)
2,300
4,250
6,400
10,150
12,200
14-365
16,300
18,300
Pharmacological properties
A. Hemodynamic tolerance
The hemodynamic tolerance of the derivatives of the invention has been studied in the dog anesthetized with pentobarbital sodium. The endocavity pressures are measured using catheters connected to Statham sensors while the recording of the external electrocardiogram (ECG) allows measurement of the heart rate. The cardiac output is measured using an electromagnetic sensor placed on the aorta at its origin. The total peripheral resistances R are calculated from the value of the mean aortic pressure (P) and the cardiac output (Q) according to the relation R = P / Q.

After measuring the parameters in the control period, the derivatives are injected intravenously in cumulative doses (30 minutes apart between
doses). Parameter variations with respect to the period
control are measured between 20 and 30 minutes after each injection and expressed as a percentage of variation from the control.

This hemodynamic safety study shows that:
the systolic blood pressure generally decreases from 10 to 30 °;
- the heart rate decreases moderately;
- the cardiac output is decreased constantly but these variations remain
limited from 20 to 30 0;
- the ratio of the first derivative of left ventricular pressure to
Instant left ventricular pressure decreases at high doses
from 10 to 40la;
- the total peripheral resistances vary little.

We therefore note that cardiovascular tolerance in anesthetized dogs
sié is satisfactory since the effects are limited to a moderate fall
cardiac output, contractility index and arterial pressure
systolic heart rate while heart rate and resistance
total peripherals vary differently.

B. Experimental antiarrhythmic properties
a) Electrophysiological studies in anesthetized dogs
The study is carried out in the dog anesthetized with pentobarbital, thorax
closed, using bipolar catheter-electrodes introduced into the
heart cavities by transcutaneous veins and arteries. The elec
surface trocardiogram (standard derivation D2) is recorded in
permanently.

During the electrophysiological study, the derivatives are injected
intravenous? minutes for each dose, and 30 minutes apart
between each dose. The measurement of the different parameters is carried out before
the injection of the first dose (control period) and 10 to 28 minutes
after the injection of each dose of the substance.

The results obtained show that the derivatives of the invention have
moderate (or inconsistent) effects on sinus automaticity as they
produce a constant prolongation of intracardiac conduction times
at all levels, as well as longer refractory periods. Of
by these characters, the derivatives of the invention produce in dogs
anesthetized effects typical of group I of the classification of
Vaughan-Williams (quinidine group and derivatives).

b) ANTI-MYTHIC TESTS
Antiarrhythmic activity was observed in mice using the Lawson test following the method described by JW Lawson, J. Pharmacol. Exp.

Ther. 1968, 160, 22-31, and Cr. Narcisse et al., Ann. Pharma. Fr. 1979, 37,
325-330, in the rat by the test of aconitine poisoning according to S.

Witchitz et al., Med. Heart. Int. 1971, X (2), 281-286 and on the dog by
the Harris test described in Circulation, 1950, 1, 1318, and by the test in
-Adrenaline after experimental infarction according to IJ Steffe et al., J.

 Pharmacol. Exp. Ther. 1980, 214, 50-57.

Aconitine poisoning
The results obtained show that the percentage of extension of the delay
appearance of ventricular arrhythmias (ventricular extrasystoles and
ventricular tachycardias), and death, induced by aconitine
after intravenous injection of several derivatives consistent with the
vention, compared to a group of untreated control animals, is in
the majority of cases exceed 50%, and generally between 50 and
150 for injected doses of between 5 and 20 mg / kg.

These results show that the derivatives according to the invention exercise a
protective effect against arrhythmias since they significantly lengthen the
delay in onset of ventricular arrhythmias and death.

Lawson's test
The Lawson test is a test of the study of antifibrillatory power because
dia derivatives. The mice (20 per dose) receive an injection
intraperitoneal derivative 10 minutes before being placed in the atmosphere
saturated with chloroform. As soon as the respiratory arrest is obtained, the thorax is
open (5 to 10 seconds) and check whether the heart is ventricular fibrillation or not. The effective dose 50 (DE 50) of the derivative studied is the
dose that protects half of the mice against ventricular fibrillation
anoxic.

It is found that the DE 50 of the derivatives of the invention is between 25 and 200 mg / kg while the maximum tolerated dose is generally 100 to 30 mg / kg.

It is observed, for example, that in the case of the derivatives described in Examples 4, 10, 13, 14 and 17, the values of DE 50 are 80, 40, 50, 125 and 75 mg / kg - respectively, whereas the values of the maximum tolerated dose are 200, 110, 150, 300 and 200 mg / kg, respectively.

These results show that the derivatives according to the invention have a satisfactory antifibrillatory activity, comparable to that of a known compound such as quinidine.

Harris test
Ligation of the anterior interventricular artery in the anesthetized dog leads to the appearance of an experimental myocardial infarction followed by significant ventricular arrhythmias.

Dogs are studied 24 to 48 hours after the procedure. The electrocardiogram (ECG) is then recorded continuously, the conscious dog being at rest in an isolated laboratory. After a period of 3 hours of ECG recording for measuring the dog's heart rate and the frequency of ventricular extrasystoles (VAS) - pre-treatment control period - the derivative to be studied is injected intravenously in 1 minute. The continuous recording of the ECG allows, in the hours following the injection, to measure the frequency of the ESV / mn over successive periods of 30 to 60 minutes. The number of ESV per minute measured over 3 hours of control period varies from 66 to 172 / min with an average to lil / min. It is found that the derivatives according to the invention cause a significant decrease in the number of ESV per minute, of the order of 60 to 100 depending on the derivatives and the administered dose (1 to 14 mg / kg). The duration of this antiarrhythmic effect observed varies according to the derivatives from 1h to more than 5h. For example, the percentage decrease in ESV / min in the case of the derivative of Example 10 (cumulative dose 6.6 mg / kg) is 98S (0 to eh), 91S (at 1h) and 77 (1 to 2h).

Ventricular arrhythmias with adrenaline after experimental infarction
The results obtained with the adrenaline test, carried out according to the technique described in the reference indicated above, show that the antiarrhythmic effects can be maintained for more than one hour and can go to almost complete disappearance of the arrhythmias triggered by the 'adrenaline.

It is therefore found that the 4-acylamino-4-adamantane type derivatives which are the subject of the present invention have interesting antiarrhythmic properties on different experimental models, whether it be aconitine poisoning, or acute myocardial ischemia.

Their cardiovascular tolerance is good because the harmful hemodynamic effects remain limited. The study of their cardiac electrophysiological properties shows that these derivatives possess "quinidine-like" group I antiarrhythmic characteristics, and that they act as well on the supraventricular as on the ventricular level itself, which makes it possible to envisage potentialities. extended antiarrhythmics.

These properties show that the derivatives according to the invention can be used in human and veterinary therapy, in particular for the treatment of cardiovascular diseases, and more particularly for the treatment of various forms of cardiac, supraventricular and ventricular arrhythmias.

The acylamino-4-aza-1-adamantane derivatives according to the invention and their pharmaceutically acceptable salts can be administered in the usual forms, the active principle being diluted in a pharmaceutically acceptable carrier suitably selected, for example in tablet form, capsule, dragee, suppository, injectable solution or syrup.

By way of example, the tablets may be prepared by mixing the derivative of general formula (I) or a salt thereof with one or more solid diluents such as lactose, mannitol, starch, polyvinylpyrrolidone, stearate - magnesium, talc, etc. If necessary, the tablets may comprise several layers superimposed around a core, according to the usual techniques, to ensure a gradual release or a delayed effect of the active ingredient. The coating may for example consist of one or more layers of polyvinyl acetate, carboxymethylcellulose or cellulose acetate phthalate.

The derivative according to the invention may also be administered in the form of a syrup or an oral solution obtained by dissolving the derivative of formula (I) or a pharmaceutically acceptable salt thereof, in water or glycerol, by for example, and optionally adding a usual additive such as a sweetener and an antioxidant.

Injectable solutions may be prepared according to well-known techniques and consist for example of a solute containing a derivative of formula (I) or a pharmaceutically acceptable salt thereof, dissolved in bidistilled water, an aqueous-alcoholic solution, propylene glycol, etc., or a mixture of these solvents. If appropriate, a suitable additive such as a preservative can be added.

The dosage may vary depending on the nature of the condition being treated, and the subject concerned. The doses administered daily are generally of the order of 1 to 40 mg / kg, and preferably 5 to 30 mg / kg orally in humans, but may be adjusted by the practitioner depending on the circumstances.

Claims (10)

1. Acylamino-4-aza-1 adamantanes characterized in that they are represented.  wherein R represents a phenyl group, a substituted phenyl group, a pyridyl group, a naphthyl group, a tetrahydronaphthyl group or a coumarinyl group, and X represents a single bond or a divalent saturated or unsaturated group of 1 to 3 carbon atoms, optionally substituted with methyl or phenyl, X not being a single bond when R is phenyl, and their acid salts.

with the general formula (I): 2. 4-Acylanaza-adamantane according to claim 1, characterized in that X is a single bond. 3. 4-Acylamino-4-adamantane according to claim 1, characterized in that X is a divalent group of formula -CH2-, -CH2CH2-, or -CH = CH-, optionally substituted by a methyl or phenyl group. . 4. 4-Acylamino-4-adamantane according to claim 2, characterized in that R is a naphthyl, tetrahydronaphthyl or coumarinyl group. 5. Acylamino-4-aza-1-adamantane according to any one of claims 1 to 3, characterized in that R is a pyridyl4 group, a 3-pyridyl group, a phenyl group or a substituted phenyl group. 6. Acylamino4 aza-1 adamantane according to claim 5, characterized in that R is a phenyl group substituted with one or more halogen atoms or with one or more alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino or nitro groups, cyano, acylamino, or haloalkyl. 7. Process for the preparation of 4-acylamino-adamantanes according to claim 1, characterized in that the 4-amino-4-aza-1-trimethyl-4, A, 8, adamantane of general formula (II) is treated. :

 by acylation reaction, in an appropriate solvent, by means of an acid, an acid chloride, an ester or an anhydride of appropriate structure. 8. Process according to claim 7, characterized in that the acylation reaction is carried out using an acid in the presence of N-hydroxysuccinimide and dicyclohexylcarbodiimide. 9. Process according to any one of claims 7 and 8, characterized in that the solvent is an ether, tetrahydrofuran, dioxane, carbon tetrachloride, chloroform, methylene chloride, or an ester. 10. Pharmaceutical compositions characterized in that they contain acylamino-r, aza-1 adamantane according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, as active ingredient, associated where appropriate with a suitable support.