4-acylamino-1-azaadamantanes, and compositions for use thereof in medicine

The invention relates to 4-acylamino-1-azaadamantanes represented by general formula (I): ##STR1## wherein R represents an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group, useful in particular, for the treatment of cardiovascular diseases.

FIELD OF THE INVENTION 
The present invention relates to new adamantane derivatives, and more 
particularly to derivatives of the 4-acylamino-1-azaadamantane series, the 
use thereof in medicine and a process for the preparation thereof. 
BACKGROUND OF THE INVENTION 
Various compounds are known which comprise in their molecule a nucleus of 
the adamantyl type, whose structure with four condensed hexagonal rings 
produces various particular physical and chemical properties due to its 
steric rigidity. Derivatives of the azaadamantane or 
[3,3,1]azatricyclodecane types, with an adamantyl group wherein a nitrogen 
atom is substituted for a bridgehead carbon atom, at the junction of three 
of the condensed rings of the tetracyclic adamantyl nucleus, have been 
studied very little. An example of a method of preparation of such 
derivatives of the azaadamantane type is described in French Pat. No. 
2,358,404. 
SUMMARY OF THE INVENTION 
An object of the invention is new 
4-acylamino-4,8,8-trimethyl-1-azaadamantanes useful in medicine for the 
treatment of cardiovascular diseases. 
An object of the invention is also a process for the preparation of new 
derivatives of the 4-acylamino-4,8,8-trimethyl-1-azaadamantane type. 
A further object of the invention is new medications composed of the 
derivatives of the 4-acylamino-4,8,8-trimethyl-1-azaadamantane type, as 
well as pharmaceutical compositions containing the same, for the treatment 
of cardiovascular diseases. 
The new 4-acylamino-1-azaadamantanes of the present invention can be 
represented by general formula (I) below: 
##STR2## 
wherein R represents an alkyl group, a substituted alkyl group, an aryl 
group, or a substituted aryl group. 
DETAILED DESCRIPTION OF THE INVENTION 
The alkyl group represented by R in formula (I) above can be a lower alkyl 
group with 1 to 4 carbon atoms such as a methyl, ethyl, n-propyl, 
isopropyl, butyl group, etc.; this alkyl group can be substituted, in 
particular by an amino, alkoxy or cyano group, to form, for example, a 
2-aminoethyl or dimethylaminomethyl group, etc. 
When R represents an aryl group, this group can in particular be a phenyl 
group, a naphthyl group, a tolyl group, a phenethyl group, a benzyl group, 
a phenylpropyl group, a 2,2-diphenyl ethyl group or a 3,3-diphenylpropyl 
group. 
The aryl group represented by R may bear one or more substituents selected 
from among a halogen atom or an alkyl (for example, methyl, ethyl, propyl, 
butyl, etc.), hydroxy, methylenedioxy, alkoxy (for example methoxy, 
ethoxy, isopropoxy, etc,), amino, alkylamino (for example, 
isopropylamino), dialkylamino (for example, dimethylamino, diethylamino, 
etc.), nitro, cyano, acylamino (for example, acetylamino), acyl (for 
example, formyl, acetyl, etc.), or haloalkyl (for example, 
trifluoromethyl, trichloromethyl, etc.) group, to form, for example, a 
p-nitrophenyl, p-aminophenyl, p-acetylaminophenyl, p-methoxyphenyl, 
p-methoxyphenethyl, 3,4-dimethoxyphenyl, 3,4-dimethoxyphenethyl, 
3,4-dimethoxybenzyl, 3,4-dihydroxyphenyl, p-chlorophenyl, 
3,4-dichlorobenzyl, 3,4-methylenedioxyphenyl, 3,4-methylenedioxybenzyl, 
p-trichloromethylphenyl, p-trifluoromethylbenzyl, p-cyanophenyl, 
p-cyanophenethyl, 2-cyano-2,2-diphenylethyl, 3-cyano-3,3-diphenylpropyl, 
group etc. 
The invention preferably relates to compounds of general formula (I) 
wherein R represents an aryl group such as a phenyl, benzyl, phenethyl, 
phenylpropyl, 2,2-diphenyl ethyl and 3,3-diphenyl propyl group, or a 
substituted aryl group such as a p-nitrophenyl, p-aminophenyl, 
p-acetylaminophenyl, p-methoxyphenyl, 3,4-dimethoxyphenyl, 
3,4-dimethoxybenzyl, p-methoxybenzyl, p-methoxyphenethyl and 
3,4-methylenedioxy phenyl group. 
The invention also relates to the salts of derivatives of the 
4-acylamino-1-azaadamantane type, represented by general formula (I) 
above, and in particular to the pharmaceutically acceptable salts, 
obtained by reacting a mineral or organic acid with the derivative of 
formula (I) as a base. This salt forming reaction can be carried out using 
methods which are conventional in the art, by reacting the acid and the 
derivative of the 4-acylamino-1-azaadamantane type of formula (I) in 
substantially stoichiometric proportions, in an appropriate solvent such 
as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, methylene 
chloride, diethyl ether, ethyl acetate, etc. The acid can, for example, be 
hydrochloric acid, lactic acid, tartaric acid, phosphoric acid, oxalic 
acid, formic acid, sulfuric acid, maleic acid, hydrobromic acid, hydriodic 
acid, etc. 
The new 4-acylamino-4,8,8-trimethyl-1-azaadamantanes of the invention can 
be obtained from the 4-amino-4,8,8-trimethyl-1-azaadamantane of general 
formula (II) below: 
##STR3## 
by action of an acylation agent, in an appropriate solvent. 
The acylation reaction can be carried out using conventional techniques, 
for example, by means of an acid, an acid chloride, an ester or an 
anhydride. In particular an acylation agent can be selected from acetic 
anhydride, propionic anhydride, N-diethylaminoacetic (or diethylglycine) 
acid, N-dimethylaminoacetic acid, benzoyl chloride, p-nitrobenzoic acid 
chloride, p-methoxybenzoic acid chloride, phenylacetic acid, 3-phenyl 
propionic acid, 3,3-diphenyl propionic acid, phenylbutyric acid, etc. The 
acylation agent is preferably used in slight excess. 
All the solvents currently used in acylation reactions are suitable for the 
preparation of the derivatives of the invention, in particular an ether 
such as diethyl ether, tetrahydrofuran, dioxane, a chlorinated solvent 
such as carbon tetrachloride, chloroform, methylene chloride, or an ester 
such as ethyl acetate. In accordance with the invention, methylene 
chloride and chloroform are preferably used. 
The acylation reaction of 4-amino-4,8,8-trimethyl-1-azaadamantane of 
formula (II) is carried out cold, and it may be advantageous to dissolve 
the starting materials in a solvent cooled on an ice bath or on a cold 
water bath and to allow the temperature to increase slowly during the 
reaction. 
So as to facilitate the acylation reaction, in particular when the 
acylation agent is an acid such as phenylacetic acid, phenylbutyric acid, 
etc., it is advantageous to add N-hydroxysuccinimide and 
dicyclohexylcarbodiimide to the reactive medium. The quantities used can, 
for example, be on the order of 1 to 2 moles of N-hydroxysuccinimide and 1 
to 3 moles of dicyclohexylcarbodiimide for 1 to 2 moles of acid and 1 mole 
of 4-amino-4,8,8-trimethyl-1-azaadamantane of formula (II). 
As necessary, the base obtained may be converted to the salt, as indicated 
above, or transformed by modification of a substituent. For example, the 
derivative of formula (I), where R is a p-nitrobenzyl group, obtained by 
action of p-nitrobenzoic acid chloride on the derivative of formula (II), 
can be reduced by hydrogenation with a catalyst to transform it into the 
corresponding derivative where R is a p-aminobenzoyl group which itself 
can be acetylated to form a p-acetylaminobenzoyl group using conventional 
techniques, for example, by action of acetyl chloride in tetrahydrofuran. 
The 4-amino-4,8,8-trimethyl-1-azaadamantane of general formula (II) is a 
known product, described in French Pat. No. 2,358,404, which can be 
prepared from a pinene treated with a mercuric salt and a nitrile in an 
anhydrous medium in order to obtain a bicyclic imine which is reduced to 
an amine, then cyclized by the action of an aldehyde to yield the 
azaadamantane of formula (II). 
The examples given below illustrate the invention in greater detail, 
without limiting the scope thereof.

EXAMPLE 1 
4-N-Propionylamino-4,8,8-trimethyl-1-azaadamantane 
5 ml of propionic anhydride were added to a solution of 7 g of 
4-amino-4,8,8-trimethyl-1-azaadamantane in 50 ml of methylene chloride, 
placed in a flask on an ice bath, while maintaining the mixture under 
agitation. 
When the reaction was completed, 50 ml of water containing 5 ml of sodium 
hydroxide solution was poured therein, then decanted and washed with 
water. This was extracted with methylene chloride, washed, dried and the 
organic phases were distilled to obtain 9.2 g of a reddish oily residue 
which, after crystallization in a mixture of ethyl acetate and isopropyl 
ether, yielded 5.2 g of 4-N-propionylamino-4,8,8-trimethyl-1-azaadamantane 
(yield 60%). 
Melting point=110.degree.-112.degree. C. (ethyl acetate/isopropyl ether). 
I.R. Spectrum (Nujol): .nu.=3000 to 3400 (3300,3050), 1630, 1540 cm.sup.-1. 
N.M.R. Spectrum (CDCl.sub.3): .delta.=1.11 (3H, t, J=8), 1.27 (6H, s), 1.52 
(3H, s), 1 to 1.4 (1H), 1.6 to 2.3 (6H), 2.15 (2H, Q, J=8), 2.98 (2H, d, 
J=14), 3.42 (2H, d, J=14), 5.53 (1H mobile) ppm. 
T.L.C. (Thin layer chromatography). 
(CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH: 84/16/3) RF=0.5. 
The above product (5 g) was dissolved in 40 ml of heated tetrahydrofuran, 
and to this solution was added a solution of 20 ml of tetrahydrofuran 
containing 2.3 g of maleic acid. After filtration and washing with 
isopropyl ether, 7.2 g of 
4-N-propionylamino-4,8,8-trimethyl-1-azaadamantane maleate was collected. 
Melting Point=190.degree.-192.degree. C. (tetrahydrofuran). 
EXAMPLE 2 
N-(diethylaminoacetyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
10 g of diethylglycine hydrochloride was dissolved in 70 ml of methanol to 
which 5 g of sodium bicarbonate was added. The mixture was maintained 
under agitation for 2 hours, evaporated until dry, dissolved in methylene 
chloride and, after filtration, washing and evaporation of the solvent, 
7.9 g of diethylglycine in the base form was obtained. 
7 g of 4-amino-4,8,8-trimethyl-1-azaadamantane was reacted with the 7.9 g 
of diethylglycine obtained as indicated above, in the presence of 7.4 g of 
N-hydroxy succinimide and 15.4 g of dicyclohexylcarbodiimide, in 120 ml of 
methylene chloride, for 48 hours. 
7.9 g (yield 72%) of 
N-(diethylaminoacetyl)-4-amino-4,8,8-trimethyl-1-azaadamantane was 
obtained which was purified by conversion to the dihydrochloride, then by 
crystallization in ethanol. The product was in the form of a colorless 
oil. 
TLC (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH: 85/15/2) Rf=0.5. 
I.R. Spectrum (film): .nu.=3000 to 3600 (3320), 1670, 1510 cm.sup.-1. 
N.M.R. Spectrum (CDCl.sub.3): .delta.=1.05 (6H, t, J=7), 1.30 (6H, s), 1.56 
(3H, s), 1.0 to 2.3 (7H), 2.60 (4H, q, J=7), 2.98 (2H, s), 3.08 (2H, d, 
J=15), 3.55 (2H, d, J=15), 7.50 (1H mobile) ppm. 
EXAMPLE 3 
N-(p-aminobenzoyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
6.8 g of 4-amino-4,8,8-trimethyl 1-azaadamantane was dissolved in 100 ml of 
chloroform, by cooling the solution on an ice bath, and 7.3 g of 
p-nitrobenzoic acid chloride dissolved in 70 ml of chloroform was added 
dropwise. 
After reaction, the precipitate formed was collected by filtration and 
dissolved in ammonia. The aqueous phase was extracted with methylene 
chloride to yield 5.5 g of 
N-(p-nitrobenzoyl)-4-amino-4,8,8-trimethyl-1-azaadamantane, in the form of 
white crystals with a melting point of 206.degree. C. 
I.R. Spectrum (Nujol): .nu.=3420, 3200, 1650, 1600, 1570, 1520 cm.sup.-1. 
TLC (CH.sub.2 Cl.sub.2, MeOH, NH.sub.4 OH, 80-20-1): Rf=0.60. 
By reduction of the above product with hydrogen in the presence of platinum 
in a 10% methanol solution, followed by filtration and recrystallization 
in isopropanol, N-(p-aminobenzoyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
was obtained in the form of white crystals. 
Melting Point: 218.degree. C. 
I.R. Spectrum (Nujol): .nu.=3440, 3320, 1640, 1610 cm.sup.-1. 
TLC (CH.sub.2 Cl.sub.2 -MeOH-NH.sub.4 OH, 80-20-1) Rf=0.40. 
If desired, the above product can be acetylated by dissolving it in 
tetrahydrofuran, and dropwise adding a solution of acetyl chloride in 
tetrahydrofuran; after recrystallization in ethanol, 
N-(p-acetylaminobenzoyl)-4-amino-4,8,8-trimethyl-1-azaadamantane was 
obtained in the hydrochloride form. 
Hydrochloride: Melting Point: 230.degree. C. (ethanol). 
I.R. Spectrum (Nujol): .nu.=3650 to 2000, 1670, 1630, 1610, 1600, 1530, 
1510 cm.sup.-1. 
Base: I.R. Spectrum (Nujol): .nu.=3600 to 2000, 1670, 1640, 1600, 1535, 
1505 cm.sup.-1. 
T.L.C. (AcOEt+20% HNEt.sub.2) Rf=0.20. 
EXAMPLE 4 
N-(3-phenylpropionyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
15.6 g of 3-phenylpropionic acid was reacted on 12.5 g of 
4-amino-4,8,8-trimethyl-1-azaadamantane in the presence of 8.2 g of 
N-hydroxysuccinimide and 24.0 g of dicyclohexylcarbodiimide in 130 ml of 
methylene chloride for 72 hours. 
After filtration, treatment and separation of the dicyclohexylurea formed, 
purification by conventional techniques and crystallization in ethyl 
acetate, 13.7 g of 
N-(3-phenylpropionyl)-4-amino-4,8,8-trimethyl-1-azaadamantane was obtained 
(yield 65%). 
Melting point: 134.degree.-136.degree. C. (ethyl acetate). 
I.R. Spectrum (Nujol): .nu.=2800 to 3500 (3230 and 3050), 1645, 1600, 1565, 
1490, 755 and 700 cm.sup.-1. 
NMR Spectrum (CDCl.sub.3): .delta.=1.25 (6H, s), 1.49 (3H, s), 1.0 to 2.3 
(7H), 2.5 (2H, m), 2.9 (2H, m), 3.0 (2H, d, J=15), 3.45 (2H, d, J=15), 
5.35 (1H mobile), 7.35 (5H) ppm. 
TLC (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH 84/16/3): Rf=0.55. 
4.5 g of the above base was dissolved in 30 ml of tetrahydrofuran, the 
viscous precipitate was decanted, dissolved in 15 ml of absolute ethanol 
and the solution was poured into 100 ml of isopropyl ether under agitation 
on an ice bath. After filtration, 5.9 g of 
N-azaadamantyl-phenylpropionamide tartrate was obtained (yield 89%). 
Melting Point: 95.degree.-110.degree. C. (viscous melting) 
(ethanol/isopropyl ether). 
EXAMPLE 5 
N-[3-(p-methoxy-phenyl)propionyl]-4-amino-4,8,8-trimethyl-1-azaadamantane 
8.4 g of 3-p-methoxyphenylpropionic acid was reacted with 6.0 g of 
4-amino-4,8,8-trimethyl-1-azaadamantane, in the presence of 4.3 g of 
N-hydroxysuccinimide and 13.6 g of dicyclohexylcarbodiimide, in 80 ml of 
methylene chloride for 40 hours. 
The basic fraction was extracted using conventional techniques and the 
residue was crystallized in ethyl acetate. In this manner 5.6 g of 
N-[3-(p-methoxyphenyl)propionyl]-4-amino-4,8,8-trimethyl-1-azaadamantane 
was obtained with a yield of 51%. 
Melting Point: 149.degree.-151.degree. C. (ethyl acetate). 
T.L.C. (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH 85/15/2) Rf=0.55. 
I.R. Spectrum (Nujol): .nu.=3000 to 3600 (maximum about 3290), 1635, 1610, 
1550, 1510 cm.sup.-1. 
N.M.R. Spectrum (CDCl.sub.3): .delta.=1.23 (6H, s), 1.48 (3H, s), 1.0 to 
2.3 (7H), 2.50 (2H, m), 2.90 (2H, m), 2.98 (2H, d, J=15), 3.45 (2H, d, 
J=15), 3.75 (3H, s), 5.60 (1H mobile), 6.77 (2H, d, J=9), 7.13 (2H, d, 
J=9) ppm. 
The above base was transformed into the corresponding hydrochloride by 
conventional techniques, by the action of concentrated hydrochloric acid 
in ethanol. 
Melting Point: &gt;260.degree. C. (ethanol). 
EXAMPLE 6 
N-(3,3-diphenylpropionyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
8.4 g of 3,3-diphenylpropionic acid in two fractions of 6.4 g and 2 g were 
reacted on 4.5 g of 4-amino-4,8,8-trimethyl-1-azaadamantane in the 
presence of 3.3 g of N-hydroxy succinimide and 9.5 g of 
dicyclohexylcarbodiimide in 75 ml of methylene chloride for 48 hours. 
After treatment and elimination of the dicyclohexylurea formed, using 
conventional techniques, 6.4 g of a crystalline residue was obtained, 
which was purified by crystallization in a mixture of ethyl acetate and 
ethanol. 
Melting Point: 222.degree.-224.degree. C. (ethanol/ethyl acetate). 
I.R. Spectrum (Nujol): .nu.=3285, 1660, 1635, 1595, 1550, 1540, 700 and 690 
cm.sup.-1. 
N.M.R. Spectrum (CDCl.sub.3): .delta.=1.23 (6H, s), 1.38 (3H, s), 0.9 to 
2.3 (7H), 2.90 (2H, d, J=8), 2.93 (2H, d, J=15), 3.35 (2H, d, J=15), 4.50 
(1H, t, J=8), 5.35 (1H mobile), 7.20 (10H, s) ppm. 
T.L.C. (CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH 85/15/2) Rf=0.4 
6.4 g of the crude base obtained as indicated above were dissolved in 100 
ml of boiling tetrahydrofuran. 2.5 g of L(+)tartaric acid dissolved in 25 
ml of hot tetrahydrofuran was added. This was left to cool, filtered and 
the precipitate obtained (8.4 g) was recrystallized in absolute ethanol to 
yield 7.0 g of 
N-(3,3-diphenylpropionyl)-4-amino-4,8,8-trimethyl-1-azaadamantane tartrate 
(yield 80%). 
Melting point: 224.degree.-228.degree. C. (ethanol). 
EXAMPLES 7 TO 11 
The process of Example 1 was repeated, replacing the propionic anhydride 
with benzoyl chloride or with p-methoxybenzoic acid chloride, and 
4-N-benzoylamino-4,8,8-trimethyl-1-azaadamantane (Example 7) or 
N-(p-methoxybenzoyl)-4-amino 4,8,8-trimethyl-1-azaadamantane (Example 8), 
respectively, were obtained. 
Likewise, using the process of Example 4, but replacing the 
3-phenylpropionic acid with 2-phenylacetic acid or with 
3,4-dimethoxyphenylacetic acid or with 4-phenylbutyric acid, 
N-phenylacetyl-4-amino-4,8,8-trimethyl-1-azaadamantane (Example 9), or 
N-(3',4'-dimethoxy-phenyl-acetyl)-4-amino-4,8,8-trimethyl-1-azaadamantane 
(Example 10), or 
N-(4-phenylbutyryl)-4-amino-4,8,8-trimethyl-1-azaadamantane (Example 11), 
respectively, were obtained, the characteristics of which are given in the 
following table. 
______________________________________ 
Example 
MP (.degree.C.) 
I.R. Spectrum 
No. (Solvent) (cm.sup.-1) (Nujol) 
Salt MP (.degree.C.) 
______________________________________ 
7 130-132 -- hydrochlor. 
&gt;260 
(H.sub.2 O) 
8 110-120 2500-3500,1630 
hydrochlor. 
&gt;260 
(AcOEt) 1600,1555,1500 
1245 
9 169-171 3300,1655,1635 
tartrate 
100-110 
(AcOEt) 1545,725 
10 169-171 3290,1640,1610 
hydrochlor. 
&gt;260 
(AcOEt) 1595,1545,1515 
1265,1235,1160 
1030,790 
11 62-64 3000-3500,1640 
hydrochlor. 
&gt;260 
(AcOEt + 1565,1490,740 
(i-C.sub.3 H.sub.7).sub.2 O) 
695 
______________________________________ 
The 4-acylamino-1-azaadamantanes of the present invention have interesting 
toxicological and pharmacological properties, which demonstrate their use 
in human and veterinarian medicine. 
Toxicological Study 
The acute toxicity of the derivatives of the invention were studied by 
intraperitoneal administration (I.P.) on the mouse (10 animals, 5 males 
and 5 females per dose) and calculation of the lethal dose 50 (LD 50) in 
accordance with the method of Litchfield and Wilcoxon (J. Pharmacol. 96, 
99-113 (1949)). Table 1 gives the LD 50 values for the derivatives whose 
preparation is described in Examples 1 to 11. 
In certain cases (derivatives of Examples 4, 6, 9), the LD 50 was also 
calculated after oral administration (P.O.) of the derivatives. 
TABLE 1 
______________________________________ 
LD 50 by Intraperitoneal and Oral Administration 
Example LD 50 I.P. 
LD 50 P.O. 
No. (mg/kg) (mg/kg) 
______________________________________ 
3 95 
4 375 2400 
5 250 
6 51 380 
7 230 
8 250 
9 430 2400 
______________________________________ 
Pharmacological Properties 
A. Hemodynamic Tolerance 
The hemodynamic tolerance of the derivatives of the invention was studied 
on dogs anesthesized with sodium pentobarbital. Endocavitary pressures 
were measured by means of catheters connected to Statham sensors while 
external recording of the electrocardiogram (E.C.G.) provided the 
measurement of cardiac frequency. Cardiac flow was measured by means of an 
electromagnetic sensor placed on the beginning of the aorta. The total 
peripheral resistances R were calculated from the value of the average 
aortic pressure (P) and the cardiac flow (Q) in accordance with the 
formula R=P/Q. 
After measurement of the parameters during a control period, the 
derivatives were injected intravenously in cumulative doses (30 minute 
interval between doses). The variations of the parameters in relation to 
the control period were measured within 20 and 30 minutes after each 
injection and are expressed as a percentage of variation in relation to 
the control. 
Table 2 summarizes the variations in hemodynamic parameters observed 
between the first and last injections. 
TABLE 2 
__________________________________________________________________________ 
Cardiovascular Tolerance in the Anesthetized Dog 
(percentages of variation in relation to the control period) 
Cumulative 
Systolic dp/dt/p Total 
Example 
Doses Arterial 
Cardiac 
Cardiac 
Left Peripheral 
No. mg/kg Pressure 
Frequency 
Flow Ventricular 
Resistances 
__________________________________________________________________________ 
3 0.1 to 3 
-3 to -33% 
0 to -14% 
+7 to -32% 
+14 to -50% 
-10 to +7% 
4 0.3 to 10 
-7 to -28% 
-7% -7 to -23% 
0 to -40% 
0 to -13% 
5 1 to 10 
0 to +3% 
0 +4 to -8% 
+2 to -15% 
-6 to +11% 
6 0.1 to 1 
-8 to -16% 
-3 to +10% 
-3 to -18% 
-6 to -13% 
0 
8 0.3 to 10 
-6 to -21% 
-7 to -15% 
-7 to -22% 
0 to -28% 
0 
9 1 to 10 
- 5 to -28% 
0 to -12% 
0 to -30% 
0 to -33% 
-5 to +15% 
__________________________________________________________________________ 
These hemodynamic tolerance results show that: 
Systolic arterial pressure decreases by 16 to 35% with all the derivatives 
except the derivative of Example 5 which produces no significant 
modification of this parameter (0 to +3%). 
Cardiac frequency decreases moderately (maximum -15% with the derivative of 
Example 8) with the majority of the derivatives of the series except for 
the derivative of Example 5 where the frequency does not change and that 
of Example 6 where it increases slightly (+10%). 
Cardiac flow is constantly decreased but these variations remain limited 
from -8 to -32%. 
The ratio of the first differential quotient of the left ventricular 
pressure to the instantaneous left ventricular pressure decreases with 
strong doses by -13 to -50%. 
The total peripheral resistances vary little. 
In conclusion, cardiovascular tolerance in the anesthetized dog is 
satisfactory since the effects are limited to a moderate drop in cardiac 
flow, in contractility index and in systolic arterial pressure while the 
cardiac frequency and the total peripheral resistances vary diversely. 
B. Experimental Atiarrhythmic Properties 
(a) Electrophysiological Studies on the Anesthetized Dog 
This study was carried out on dogs anesthetized with pentobarbital, with a 
closed thorax, by means of bipolar catheter-electrodes introduced into the 
cardiac cavities by transcutaneous venous and arterial means. The surface 
electrocardiogram (standard derivation D.sub.2) is recorded permanently. 
By means of a programmable JANSEN (R) stimulator, the following parameters 
may be measured: 
spontaneous cardiac frequency (FC); 
sinus recuperation time (SRT.sub.c) after auricular stimulation imposed at 
160 b/mn for 1 mn; 
intracardiac conduction times (auriculohisien at a constant frequency, 
His-Purkinje, intraventricular); 
the effective and functional refractory periods measured at an imposed 
constant frequency, with the extrastimulus method. 
During the electrophysiological study, the derivatives were injected 
intravenously for 2 minutes for each dose and at 30 minute intervals 
between each dose. The doses are expressed as a cumulative value and as a 
base term. 
The measurement of the various parameters was carried out before the 
injection of the first dose (control period) and from 10 to 28 minutes 
after the injection of each dose of the substance. The results are 
expressed as a percentage of variation in relation to the control period. 
The electrophysiological effects of four examples of derivatives of the 
invention are given in Table 3. 
The results obtained show that the derivatives of the invention have 
moderate (or inconstant) effects on sinusal automaticity whereas they 
produce a constant lengthening of the intracardiac conduction times at all 
levels, as well as a lengthening of the refractory periods. From these 
characteristics, the derivatives of the invention on the anesthetized dog 
produce effects typical of Group I of the Vaughan-Williams classification 
(the group of quinidine and its derivatives). 
(b) Antiarrhythmic Tests 
Antiarrhythmic activity was observed in the mouse by means of the Lawson 
test using the method described by J. W. Lawson, J. Pharmacol. Exp. Ther., 
160, 22-31, (1968) and C. Narcisse et al, Ann. Pharma. Fr., 37, 325-330 
(1979), in the rat by the aconitine intoxication test of S. Witchitz et 
al, Coeur Med. Int., X(2), 281-286, (1971) and in the dog by the Harris 
test described in Circulation, 1, 1318, (1950) and by the test with 
adrenalin after experimental infarct of I. J. Steffe et al, J. Pharmacol. 
Exp. Ther., 214, 50-57 (1980). 
Aconitine Intoxication 
The anesthetized rat was intoxicated with an intravenous perfusion of 
aconitine while its electrocardiogram (ECG) was permanently recorded. 
During the perfusion at constant rate, the time necessary for the 
appearance of ventricular arrhythmias, successive extrasystoles (ESV), 
then stable ventricular tachycardium (TV) and the time within which the 
animal died were measured. 
TABLE 3 
__________________________________________________________________________ 
Electrophysiological Effects 
Deriva- 
No. of 
tives 
Evalua- 
Doses VARIATION (%) 
No. tions 
(mg/kg) 
F.C. St-H HV QRS PREA PREV 
__________________________________________________________________________ 
3 3 0.5 to 5 
0 to -24 
+2 to +76 
+13 to +98 
+8 to +39 
+2 to +50 
0 to +20 
4 2 0.3 to 14.3 
0 +7 to +10 
0 to +80 
0 to +15 
+10 to +35 
0 to +10 
6 1 0.1 to 1.4 
0 to +32 
0 to +25 
0 to +92 
0 to +50 
+18 to +50 
+10 to +20 
9 2 1 to 19 
0 0 to +30 
+18 to +100 
0 to +23 
+6 to +45 
+2 to +15 
__________________________________________________________________________ 
F.C.: Cardiac frequency 
StH: Time of auriculohisien conduction 
HV: Time of HisPurkinje conduction 
QRS: Time of intraventricular conduction 
PREA: Effective auricular refractory period 
PREV: Effective ventricular refractory period 
The animals were divided into a control group (untreated) and treated 
groups (different doses). The results are expressed as a percentage of 
prolonging the time of appearance of the arrhythmias and of death of the 
treated groups in reaction to the control group. 
The results obtained are shown in Table 4 below and express the percentage 
of prolongation of the time of appearance of ventricular arrhythmias 
(ventricular extrasystoles and ventricular tachycardiums), and of the 
death, induced by the aconitine after an intravenous injection (I.V.) of 
several derivatives of the invention, in relation to a group of untreated 
control animals. 
TABLE 4 
______________________________________ 
Derivative 
Injected Dose 
Ventricular Arrhythmias 
No. mg/kg ESV (%) TV (%) Death (%) 
______________________________________ 
8 5 +45 +43 +46 
10 +71 +84 +215 
20 +98 +107 +112 
6 1 +52 +93 +69 
2 +67 +139 +97 
9 10 +31 +79 +44 
20 +100 +79 +84 
40 +171 +147 +88 
4 5 +37 +50 +25 
10 +60 +86 +39 
20 +103 +89 +65 
5 5 +41 +20 +21 
10 +51 +48 +36 
20 +65 +54 +50 
7 5 +59 +53 +29 
10 +35 +35 +45 
20 +111 +105 +89 
______________________________________ 
The results given in Table 4 show that the derivatives of the invention 
exert a protective effect against arrhythmias since they considerably 
prolong the time of appearance of ventricular arrhythmias and of death. 
Lawson Test 
The Lawson test is a test for the study of the cardiac antifibrillatory 
power of the derivatives. The mice (20 per group) received an 
intraperitoneal injection of the derivative 10 minutes before being placed 
in a chloroform-saturated atmosphere. Upon respiratory arrest, the thorax 
was opened (5 to 10 seconds) and whether or not the heart was in 
ventricular fibrillation was checked. The efficacy dose 50 (ED 50) of the 
derivative being studied is the dose which protects half the mice against 
anoxic ventricular fibrillation. 
Table 5 summarizes the results of the Lawson test obtained with certain 
derivatives of the present invention. 
TABLE 5 
______________________________________ 
Derivative ED 50 Maximum Dose Tolerated 
No. (mg/kg) (mg/kg) 
______________________________________ 
3 37 50 
4 72 200 
5 61 200 
7 76 150 
8 49 100 
9 90 200 
______________________________________ 
These results show that the derivatives of the invention possess 
satisfactory antifibrillatory activity, comparable to that of a known 
compound such as quinidine. 
Harris Test 
The ligature of the anterior interventricular artery in the anesthetized 
dog causes the appearance of an experimental infarct of the myocardium 
followed by considerable ventricular arrhythmias. 
The dogs were studied 24 to 48 hours after the intervention. The 
electrocardiogram (ECG) was then recorded permanently, the conscious dog 
being at rest in an isolated laboratory. After a period of 3 hours of ECG 
recording, allowing for the measurement of the cardiac frequency of the 
dog the frequency of ventricular extrasystoles (ESV)--pre-treatment 
control period--the derivative to be studied was injected intravenously 
for 1 minute. Continuous recording of the ECG enabled, in the hours 
following the injection, measurement of the frequency of the ESV/mn for 
successive periods from 30 to 60 min. The number of ESV per minute 
measured for 3 hours during the control period varied from 66 to 172/min 
with an average of 111/min. It was noticed that the derivatives of the 
invention caused a considerable decrease in the number of ESV per minute, 
on the order of 35% to 95% depending upon the derivative and the dose 
administered (1 to 14 mg/kg). The length of this antiarrhythmic effect 
observed varied depending on the derivatives from 1 hour to more than 5 
hours. For example, the percentage decrease of the ESV/min in the case of 
the derivative of Example 11 (cumulative dose 14 mg/kg) was 96% (0 to 1/2 
hour), 50% (1/2 to 1 hour) and 68% (1 to 2 hour). The corresponding values 
for the derivative of Example 4 (3 mg/kg) were 44%, 55% and 45%, 
respectively. 
Ventricular Arrhythmias with Adrenalin after Experimental Infarct 
2 to 5 days after an experimental infarct, the effects of discontinuous 
injections (in intravenous bolus of 4 g/kg of basic adrenalin) of 
adrenalin were observed on the electrocardioagram of the conscious dog. 
During a first phase (control) of the experiment, three successive 
injections of adrenalin were given and, in the 2 minutes following each 
injection, the frequency of the ventricular extrasystoles was measured. In 
this manner, by increasing the dose of adrenalin as necessary, it was 
possible to determine the dose which caused the appearance of ventricular 
extrasystoles at a higher frequency than or equal to half the total number 
of ventricular systoles. 
After injection of the derivative to be tested, the same dose of adrenalin 
was reinjected after 5 minutes, then 30 minutes, 60 minutes, 90 minutes, 
etc., and its effects were compared to those observed during the control 
period. 
Table 6 summarizes the results obtained with the adrenalin test. The 
results therein are expressed as a percentage of extrasystoles (on the 
total number of systoles) measured during the 2 minutes following the 
injection of adrenalin before and after the administration of the 
derivative to be tested. The results in this table show that the 
antiarrhythmic effects can be maintained for more than one hour and can 
continue until the almost total disappearance of the arrhythmias caused by 
the adrenalin. 
TABLE 6 
______________________________________ 
Test with Adrenalin after Experimental Infarct 
Control Injected 
Example Period Dose ESV Percentage at 
No. (% of ESV) (mg/kg) 5 min 30 min 
60 min 
______________________________________ 
3 94% 4.3 63% 77% 90% 
4 74% 14.3 36% 59% 60% 
5 40% 10 9% 14% 16% 
6 85% 1.3 29% 17% 17% 
8 71% 4 35% 36% 53% 
9 48% 1 11% 27% 45% 
______________________________________ 
It can therefore be noted that the derivatives of the 4-acylamino 
1-azaadamantane type of the present invention possess important 
antiarrhythmic properties on various experimental models, whether 
intoxication with aconitine or acute myocardiac ischaemia. Their 
cardiovascular tolerance is good since negative hemodynamic effects remain 
limited. A study of their electrophysiological cardiac properties shows 
that these derivatives possess "quinidine-like" characteristics of Group 
I of antiarrhythmics, and that they act well at both the supraventricular 
and ventricular levels, which enables extended antiarrhythmic 
potentiality. 
These properties show that the derivatives of the invention can be used in 
human and veterinarian medicine, in particular for the treatment of 
cardiovascular diseases, and more particularly for the treatments of 
various forms of cardiac arrhythmias, both supraventricular and 
ventricular. 
The derivatives of the 4-acylamino-1-azaadamantane type of the invention 
and their pharmaceutically acceptable salts can be administered in 
conventional forms, the active constituent being employed with an 
appropriately selected pharmaceutically acceptable carrier, for example, 
in the form of tablets, capsules, lozenges, suppositories, injectable 
solutions or syrups. 
By way of example, tablets can be prepared by mixing the derivative of 
general formula (I) or one of its salts with one or several solid diluents 
such as lactose, mannitol, starch, polyvinylpyrrolidone, magnesium 
stearate, talc, etc. Where necessary, the tablets may comprise several 
layers superposed around a nucleus, in accordance with conventional 
techniques, in order to ensure progressive liberation or a delayed effect 
of the active ingredient. The coating may, for example, be composed of one 
or several layers of polyvinyl acetate, carboxymethylcellulose or 
cellulose acetophthalate. 
The derivative of the invention may also be administered in the form of a 
syrup or drinkable solution obtained by dissolving the derivative of 
formula (I) or one of its pharmaceutically acceptable salts, in water or 
glycerol, for example, and adding as necessary a conventional additive 
such as a sweetener and an antioxidant. 
Injectable solutions can be prepared using well-known techniques and can be 
composed, for example, of a solution containing a derivative of formula 
(I) or one of its pharmaceutically acceptable salts, dissolved in 
bidistilled water, a hydroalcoholic solution, propyleneglycol, etc., or a 
mixture of such solvents. Where necessary, an appropriate additive such as 
a preservative may be added. 
Dosages may vary in accordance with the type of condition and the subject 
being treated. Doses administered daily are generally comparable to those 
of quinidinic treatments, (e.g. 5 to 50 mg-leg.sup.31 1 orally) but can be 
adjusted by the practitioner depending upon the circumstances. 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.