3-amino quinuclidine derivatives and the application thereof as accelerators of gastro-intestinal motor function

New derivatives of 3-amino quinuclidine of formula: ##STR1## in which X=sulfur or oxygen; R=H, lower alkyl or benzyl; and Ar=substituted phenyl or substituted pyrimidinyl. These new derivatives have utility in therapeutics as accelerators of the gastro-intestinal motor function and as medicament potentiators.

The present invention relates to new 3-amino quinuclidine derivatives, the 
process for preparing same and the application thereof in therapeutics. 
The new derivatives of the invention correspond more precisely to the 
general formula: 
##STR2## 
in which X represents a sulfur or oxygen atom, R designates a hydrogen 
atom, an alkyl group with 1 to 4 carbon atoms or the benzyl group, and Ar 
designates: 
a phenyl nucleus substituted by a halogen atom or a lower alkyloxy group, 
a phenyl nucleus of structure 
##STR3## 
in which R.sub.1 represents a halogen atom or an alkylcarbonyl group 
whose alkyl residue comprises 1 to 4 carbon atoms, 
the (3-fluoro 2-methoxy)phenyl group, 
the (2-amino 4-methoxy)5-pyrimidinyl group, or 
a phenyl nucleus of structure 
##STR4## 
in which R.sub.2 represents a halogen atom and R.sub.3 represents a 
hydrogen atom or an alkylcarbonyl group whose alkyl residue comprises 1 to 
4 carbon atoms. 
Because of the presence of an asymmetric carbon in their molecule, the 
derivatives of formula (I) exist in the form of racemics, in the form of 
dextrorotatory optical isomers and in the form of levorotatory optical 
isomers. Therefore, the present invention includes the compounds of 
formula (I) under racemic form, under the form of dextrorotatory optical 
isomers and under the form of levorotatory optical isomers. 
The present invention also relates to the acid addition salts of the 
derivatives of formula (I). The acids used in the preparation of these 
salts may be organic acids such as maleic, oxalic or fumaric acid and 
mineral acids such as hydrochloric acid. 
The hydrates of the derivatives of formula (I) and salts thereof also come 
within the scope of the invention. 
The N-oxides of the derivatives of formula (I) further come within the 
scope of the invention. 
The process of the invention for obtaining the derivativee of formula (I) 
consists, when X represents an oxygen atom, in condensing: 
either the acids of formula: 
EQU Ar--COOH (II) 
in which Ar has the same meanings as in formula (I), 
or the acid chlorides of formula: 
EQU Ar--COCl (III) 
in which Ar has the same meanings as in formula (I), respectively with the 
amino quinuclidinic derivatives of formula: 
##STR5## 
in which R has the same meanings as in formula (I). 
When the acids (II) are used, the condensation is effected by the so-called 
"BOISSONAS" technique, preferably in the presence of an alkyl 
chloroformiate and of triethylamine; when the acid chlorides (III) are 
used, the condensation is effected preferably in the presence of a basic 
agent such as triethylamine and in solution in an aprotic solvent. 
Compounds (IV) are obtained by catalytic hydrogenolysis preferably by means 
of palladium on charcoal at 10% in an hydroalcoholic medium and in an 
autoclave, of the compounds of formula: 
##STR6## 
in which R has the same meanings as in formula (I). 
Compounds (V) are obtained by a two stage synthesis which consists in 
condensing the aldehydes of formula: 
EQU R.sub.5 --CHO (VI) 
in which R.sub.5 represents an alkyl group with 1 to 3 carbon atoms or 
formic aldehyde, preferably in an aqueous medium, with 3-benzylamino 
quinuclidine, then in reducing the intermediate compound obtained (non 
isolated) by means of sodium cyanoborohydride (NaBH.sub.3 CN). 
The 3-benzylamino quinuclidine is obtained by condensing benzaldehyde with 
3-amino quinuclidine (condensation effected preferably in toluene) then by 
reducing the Schiff base obtained by means of sodium or potassium 
borohydride (preferably in a methanol medium). 
In the case where, in formula (I), X represents the oxygen atom and Ar 
represents a phenyl group having the particular structure: 
##STR7## 
in which R.sub.2 has the same meanings as before, the corresponding 
derivatives (I) may be obtained also by acid hydrolysis (preferably by 
means of 2N hydrochloric acid) of the derivatives (I) having the 
particular formula: 
##STR8## 
in which R and R.sub.2 have the same meanings as in formula (I) and 
R.sub.4 represents an alkyl group with 1 to 4 carbon atoms, the 
derivatives (Ia), being obtained in accordance with the above-stated 
methods. 
The process of the invention for obtaining the derivatives of formula (I) 
for which X represents a sulfur atom consists in treating the derivatives 
of formula (I) for which X represents the oxygen atom: 
either by the so-called "LAWESSON" reagent of formula: 
##STR9## 
this reaction being carried out in an aprotic medium and preferably in a 
mixture of benzene and dioxane, 
or by means of phosphorous pentasulfide, preferably in H.M.P.T. 
The optical isomers according to the invention are prepared from the 
corresponding racemic mixtures. More precisely, they are obtained by 
salifying the racemic derivatives of formula (I) in base form, by means of 
an optically active organic acid such as L(d)-tartaric acid of 
D(l)-tartaric acid, then by resolving, by the method of successive 
fractionated recrystallizations, the salts resulting from said 
salification, said recrystallizations being advantageously effected in 
methanol. 
The acid addition salts of the derivatives of formula (I) may be prepared 
by simple reaction of the derivatives of formula (I) with an organic or 
mineral acid, according to the usual methods, the derivatives of formula 
(I) and/or the acid being preferably used in solution in appropriate 
solvents. 
Finally, the N-oxides of the derivatives of formula (I) are prepared 
according to the conventional methods described in the literature either 
by means of peracid (preferably M.C.P.B.A.) or hydrogen peroxide. 
The following preparations are given by way of examples to illustrate the 
invention.

EXAMPLE 1 
N-(3-quinuclidinyl)4-amino 5-chloro 2-methoxy benzamide, maleate (I) 
Code number: 2 
To a solution cooled to 0.degree. C. of 12.1 g of 4-amino 5-chloro 
2-methoxy benzoic acid in 300 ml of DMF are added 17.5 ml of triethylamine 
then 4.6 ml of ethyl chloroformiate. The solution obtained is left under 
agitation for 45 minutes at room temperature and to this solution is added 
a suspension of 12 g of 3-aminoquinuclidine dichlorhydrate and 13.2 ml of 
triethylamine (which has been stirred at 50.degree. C. for an hour), at 
0.degree. C. and within 30 minutes. Then the mixture is left for 12 hours 
at room temperature, the DMF is evaporated, the residue is taken up in 
chloroform, washed with a solution of sodium carbonate, then with water, 
dried on sodium sulfate, filtered, the filtrate is evaporated and the 
residue is chromatographed on an alumina column (Eluent: 
chloroform-methanol 99%-1%). The compound obtained (4.3 g) is dissolved in 
ethyl acetate and a solution of 1.57 g of maleic acid in 30 ml of ethyl 
acetate is added and the precipitate obtained (3.8 g) is filtered. 
Yield: 15% 
Melting point: 194.degree. C. 
By the same process, but from the corresponding reagents, the compounds of 
formula (I) are obtained, appearing under code numbers 1, 3 to 8, 12, 15 
to 18, 20, 21, 23 and 24 in the following table I. 
EXAMPLE 2 
N-(3-quinuclidinyl)3-fluoro benzamide, oxalate (I) 
Code number: 5 
A suspension of 12 g of 3-amino quinuclidine dichlorhydrate and 33.6 ml of 
triethylamine in 100 ml of DMF is heated at 50.degree. C. for an hour. 
Then it is cooled to 0.degree. C. and a solution of 9.5 g of 3-fluoro 
benzoic acid chloride in 30 ml of dimethylformamide is added within one 
hour. Then the mixture is left under agitation for 12 hours at room 
temperature, filtered, the filtrate is evaporated, the residue is taken up 
in methylene chloride, washed with a sodium carbonate solution, with 
water, dried on sodium sulfate and the solvent is evaporated. The residue 
is dissolved in acetone and a solution of 5.4 g of oxalic acid in acetone 
is added, the precipitate obtained is filtered and recrystallized in 88% 
ethanol. 7.4 g (yield=38%) of the expected compound are obtained. 
By the same process, but from the corresponding reagents, the compounds of 
formula (I) are obtained shown under code numbers 1 to 4, 6 to 8, 12, 15 
to 18, 20, 21, 23 and 24 in table I below. 
EXAMPLE 3 
Hydrated chlorhydrate of (4-amino 5-chloro 2-methoxy 1-phenyl 
N-(3-quinuclidinyl)-thioformamide (I) 
Code number: 22 
A mixture of 14.5 g of (4-amino 5-chloro 2-methoxy) 3-benzoylamino 
quinuclidine [(I); code number 2] and 27.1 g of LAWESSON's reagent in 500 
ml of benzene and 500 ml of dioxane is heated at reflux for 3 hours. Then 
it is washed with concentrated NaOH, with water, the washing waters are 
extracted by means of ethyl acetate, the organic phases are brought 
together, dried on sodium sulfate and filtered and the filtrate is 
evaporated. The residue is chromatographed on an alumina column (eluent: 
ethyl acetate 90%-methanol 10%). The purified product obtained is 
dissolved in ethanol, hydrochloric ethanol is added to the solution 
obtained, the mixture is cooled and the precipitate formed is filtered and 
recrystallized in a methanol-water mixture (98%-2%). Thus 1.8 g of the 
expected product are obtained (Yield=12%). 
EXAMPLE 4 
Hemi-fumarate of (4-amino 5-chloro 2-methoxy)N-(3-quinuclidinyl)N-methyl 
benzamide (I) 
Code number: 24 
A solution of 45.4 g of (4-acetamido 5-chloro 
2-methoxy)N-(3-quinuclidinyl)N-methyl benzamide [(I), code number 23--in 
base form and prepared according to anyone of the preceding examples 1 of 
2] in 450 ml of 2N HCl is brought to reflux for 15 minutes. Then it is 
washed with ethyl acetate, basified with concentrated NaOH, extracted with 
chloroform, dried on sodium (or magnesium) sulfate, filtered and the 
filtrate is evaporated. The residue is dissolved in ethanol and an ethanol 
solution of fumaric acid is added and the precipitate obtained is 
filtered. 29.4 g (Yield=62%) of the expected product are obtained. 
EXAMPLE 5 
Hemi-fumarate of (4-amino 5-chloro 2-methoxy)N-(3-quinuclidinyl)N-methyl 
thiobenzamide (I) 
Code number: 25 
A solution of 12 g of sodium pentasulfide and 14.6 g of the compound (I) 
obtained in the preceding example (in base form) in 150 ml of H.M.P.T. is 
brought to 110.degree. C. for 2 hours. Then the solution is thrown into 
iced water, the mixture obtained is filtered, the precipitate is taken up 
in basic water (aqueous NaOH) and extracted with chloroform. The 
chloroformic phase is dried on sodium (or magnesium) sulfate, filtered and 
the filtrate is evaporated; the residue is chromatographed on an alumina 
column (eluent: chloroform 99%-methanol 1%), then on a silica column 
(medium pressure liquid chromatography; eluent: chloroform 95%-methanol 
4.75%-ammonia 0.25%), these chromatographies being required for 
eliminating the H.M.P.T. Thus 3.2 g (yield=21%) of pure product is 
obtained which is dissolved in ethanol, an ethanol solution of fumaric 
acid is added and the precipitate obtained is filtered, which corresponds 
to the expected product. 
EXAMPLE 6 
3-methylamino quinuclidine (IV) 
1st step: 3-benzylamino quinuclidine 
A mixture of 50 g of 3-amino quinuclidine and 40 ml of benzaldehyde in 1000 
ml of toluene is brought to reflux for 45 minutes, while eliminating the 
water formed. Then the solvent is evaporated, the residue is dissolved in 
800 ml of methanol and 15 g of potassium borohydride are added within 3 
hours while maintaining the temperature at 0.degree. C. Then the solvent 
is evaporated, the residue is taken up in water, the mixture obtained is 
extracted with ethyl acetate (or with chloroform), dried on sodium (or 
magnesium) sulfate, filtered and the filtrate is evaporated. Thus 85 g 
(yield .perspectiveto.100%) of the pure expected product are obtained (one 
spot in TLC) which is in liquid form. 
2nd step: 3-(N-methyl N-benzylamino)quinuclidine (V) 
To a solution of 73.7 g of 3-benzylamino quinuclidine in water 
(.perspectiveto.300 to 400 ml) are added, while cooling to 5.degree. C., 
51 ml of a 40% aqueous formaldehyde solution. Then after the addition, the 
mixture is left for 30 minutes at 5.degree. C., then 32 g of sodium 
cyanoborohydride are added within 1 to 2 hours. Then it is left at room 
temperature for 12 hours, extracted with ethyl acetate, the mixture 
obtained is dried on sodium (or magnesium) sulfate, filtered, the filtrate 
is evaporated and the residue is distilled (Boiling point [0.04 
mm/Hg]=125.degree. C.). Thus the expected product is obtained practically 
quantitatively. 
3rd step: 
A mixture of 33.3 g of 3-(N-methyl N-benzylamino)quinuclidine and 16 g of 
palladium on charcoal at 10% (50% humidity) in 500 ml of ethanol is heated 
in an autoclave at 80.degree. C. for 6 hours 30 minutes and under a 
hydrogen pressure of 6 bars. Then it is filtered, the solvent is 
evaporated (under a good vacuum and when cold) and the residue is 
distilled (Boiling point [24 mm/Hg]=110.degree. C.). Thus the expected 
product is obtained with a yield of 43%. 
EXAMPLE 7 
chlorhydrate of dextrorotatory (26) and levorotatory (27) meta-chloro 
(3-N-quinuclidinyl)benzamides 
To 52.5 g of racemic meta-chloro (3-N-quinuclidinyl)benzamide [(I), code 
number 20], in base form, is added a solution of 29.7 g of dextrorotatory 
L tartaric acid in 500 ml of methanol, the mixture obtained is brought to 
reflux, filtered when hot and left to cool. 47 g of precipitate (melting 
point .perspectiveto.178.degree. C.) are obtained after filtration, which 
are redissolved in 500 ml of boiling methanol. After cooling and 
filtration, 28 g of precipitate (melting point .perspectiveto.188.degree. 
C.) are obtained, which are dissolved in 250 ml of boiling methanol. After 
cooling and filtration, 20 g of compound (melting point 
.perspectiveto.192.degree. C.) are obtained which are dissolved in water, 
the aqueous solution obtained is basified by means of sodium carbonate, 
extracted with chloroform, dried on sodium sulfate, filtered and the 
filtrate is evaporated. The product obtained is dissolved in acetone and 
hydrochloric ethanol (.perspectiveto.6N) is added, the precipitate 
obtained is filtered and recrystallized in ethanol. Thus, 9.4 g of 
dextrorotatory isomer (27) are obtained: .perspectiveto..sub.D.sup.20 
(methanol), C.perspectiveto.2.5)=+15.1.degree., melting point=240.degree. 
C. [the corresponding base has a .alpha..sub.D.sup.20 (methanol, 
C.perspectiveto.2.5)=+33.3.degree. and a melting point=125.degree. C.]. 
The mother waters (filtrates) of the first three recrystallizations in 
methanol are brought together, evaporated, the residue is taken in water, 
the mixture obtained is basified by means of sodium carbonate, extracted 
with chloroform, the extract is dried on sodium (or magnesium) sulfate, 
filtered and the filtrate is evaporated. 42 g of product are obtained to 
which is added a solution of 23.8 g of levorotatory D tartaric acid in 500 
ml of methanol; the mixture is brought to reflux, filtered when hot, then 
after cooling of the filtrate, the precipitate obtained is filtered 
(melting point=186.degree. C.). This precipitate is dissolved in 350 ml of 
boiling methanol, the solution is filtered when hot, then after cooling of 
the filtrate, the precipitate obtained is filtered. Thus 25 g of a 
precipitate are obtained (melting point=192.degree. C.) which is dissolved 
in water. The solution is basified by means of sodium carbonate, extracted 
with chloroform, the extract is dried on sodium (or magnesium) sulfate, 
filtered and the filtrate evaporated, the residue is dissolved in acetone 
and hydrochloric ethanol (.perspectiveto.6N) is added. The precipitate 
obtained is filtered and recrystallized in ethanol (.perspectiveto.100 
ml). Thus 10.9 g of levorotatory isomer (27) are obtained: 
.alpha..sub.D.sup.20 (methanol, C.perspectiveto.2.5)=-15.4.degree., 
melting point=240.degree. C. [the corresponding base has a 
.alpha..sub.D.sup.20 (methanol, C.perspectiveto.2.5)=-34.3.degree. and 
melting point=125.degree. C.]. 
TABLE I 
__________________________________________________________________________ 
##STR10## (I) 
numberCode 
##STR11## R Form Empirical formula 
weightMolecular 
(.degree.C.)pointMelting 
ANALYSISELEMENTARY%CHN 
__________________________________________________________________________ 
##STR12## H Hydrated Base 
C.sub.13 H.sub.19 N.sub.5 O.sub.2 +0.5% 
H.sub.2 O 
277.32 
198 Cal. Obt. 
55.97 55.61 
6.82 6.70 
25.12 25.43 
2 
##STR13## " Maleate 
C.sub.19 H.sub.24 ClN.sub.3 O.sub.6 
425.86 
194 Cal. Obt. 
53.58 53.32 
5.68 5.78 
9.87 9.97 
3 
##STR14## " Oxalate 
C.sub.17 H.sub.22 N.sub.2 O.sub.6 
350.36 
188 Cal. Obt. 
58.27 58.15 
6.33 6.47 
8.00 7.89 
4 
##STR15## " " C.sub.16 H.sub.19 FN.sub.2 O.sub.5 
338.33 
232 Cal. Obt. 
56.80 56.52 
5.66 5.66 
8.28 8.27 
5 
##STR16## " " C.sub.16 H.sub.19 FN.sub.2 O.sub.5 
338.33 
223 Cal. Obt. 
56.80 56.73 
5.66 5.72 
8.28 8.27 
6 
##STR17## " HCl C.sub.14 H.sub.18 FClN.sub.2 O 
284.76 
238 Cal. Obt. 
59.05 58.97 
6.37 6.35 
9.84 9.84 
7 
##STR18## " Oxalate 
C.sub.17 H.sub.22 N.sub.2 O.sub.6 
350.36 
188 Cal. Obt. 
58.27 58.29 
6.33 6.55 
8.00 8.12 
8 
##STR19## " Hydrated HCl 
C.sub.15 H.sub.21 ClN.sub.2 O.sub.2 
+H.sub.2 O 
314.84 
190 Cal. Obt. 
57.23 57.47 
7.36 6.92 
8.90 8.83 
12 
##STR20## " HCl C.sub.15 H.sub.21 BrClN.sub.3 O.sub.2 
389.70 
&gt;260 Cal. Obt. 
46.11 45.69 
5.42 5.35 
10.76 10.51 
15 
##STR21## " " C.sub.15 H.sub.20 Cl.sub.2 N.sub.2 
331.242 
215 Cal. Obt. 
54.39 54.07 
6.09 6.25 
8.46 8.33 
16 
##STR22## " " C.sub.17 H.sub.23 ClN.sub.2 O.sub.3 
338.83 
245 Cal. Obt. 
60.26 60.03 
6.84 6.91 
8.27 8.20 
17 
##STR23## " " C.sub.15 H.sub.20 ClFN.sub.2 O.sub.2 
314.78 
246 Cal. Obt. 
57.23 57.36 
6.40 6.31 
8.90 8.92 
18 
##STR24## " " C.sub.15 H.sub.20 ClBrN.sub.2 O.sub.2 
375.69 
220 Cal. Obt. 
47.95 47.80 
5.37 5.58 
7.46 7.48 
20 
##STR25## " " C.sub.14 H.sub.18 Cl.sub.2 N.sub.2 
301.21 
242 Cal. Obt. 
55.82 55.53 
6.02 6.08 
9.30 9.35 
21 
##STR26## " Base C.sub.15 H.sub.19 FN.sub.2 O.sub.2 
278.32 
125 Cal. Obt. 
64.73 64.47 
6.88 7.00 
10.07 10.00 
22 
##STR27## " 1.05 HCl +0.5% H.sub.2 O 
C.sub.15 H.sub.21 Cl.sub.2 N.sub.3 OS 
+0.5% H.sub.2 O +0.05 HCl 
365.97 
&gt;260 Cal. Obt. 
49.22 48.26 
5.86 5.54 
11.48 11.51 
23 
##STR28## CH.sub.3 
Maleate 
C.sub.22 H.sub.28 ClN.sub.3 O.sub.7 
481.92 
237 Cal. Obt. 
54.82 54.96 
5.85 6.07 
8.72 8.43 
24 
##STR29## " 1/2 fumarate +1.35% H.sub.2 O 
C.sub.18 H.sub.24 ClN.sub.3 O.sub.4 +1.35% 
H.sub.2 O 
387.08 
&gt;260 Cal. Obt. 
55.85 55.79 
6.40 6.29 
10.86 10.50 
25 
##STR30## " 1/2 fumarate +11.7% H.sub.2 O 
C.sub.18 H.sub.24 ClN.sub.3 O.sub.3 S 
+11.7% H.sub.2 O 
444.32 
194 Cal. Obt. 
48.00 47.83 
6.67 6.00 
9.33 9.35 
26 
##STR31## H HCl dextroro- tatory Base dextroro- tatory 
C.sub.14 H.sub.18 Cl.sub.2 N.sub.2 O 
C.sub.14 H.sub.17 ClN.sub.2 O 
301.21 264.75 
240 125 
Cal. Obt. Cal. 
55.82 55.70 -- 
6.02 6.18 -- 
9.30 9.39 -- 
-- 
27 
##STR32## H HCl levoro- tatory Base levoro- tatory 
C.sub.14 H.sub.18 Cl.sub.2 N.sub.2 O 
C.sub.14 H.sub.17 ClN.sub.2 O 
301.21 264.75 
240 125 
Cal. Obt. -- 
55.82 55.71 
6.02 6.20 
9.30 9.27 
-- 
Cal. 
Obt. 
__________________________________________________________________________ 
The compounds of the invention have been tested on laboratory animals and 
showed activity on the digestive system (particularly as accelerators of 
the gastro-intestinal motor function). This activity was shown: 
by the gastric evacuation test on rats, carried out with the following 
method: The compounds of the invention are administered orally together 
with 20 steel balls to wakeful rats having eaten nothing for 20 hours. The 
action on the gastric evacuation of the tested compounds was evaluated 90 
minutes after administration thereof by the percentage of animals whose 
stomach contained no balls, these balls being counted by radiological 
examination. To illustrate the invention, some results obtained with the 
compounds of the invention are given in table II below; 
by the total transit test in rats, carried out according to the following 
method: The compounds of the invention were administered orally 
simultaneously with 20 steel balls to wakeful rats having eaten nothing 
for 20 hours. The fast was broken immediately after the administration and 
the compounds of the invention were administered a second time at the same 
dose after a period of 7 hours. The total transit was evaluated 24 hours 
after the first administration of the compounds to be tested by the 
percentage of the animals having evacuated all the balls in the faeces, 
the balls being counted by radiological examination. To illustrate the 
invention, some results obtained with the compounds of the invention are 
shown in table III below. 
In addition, the acute toxicity in mice was evaluated according to the 
method of MILLER and TAINTER described in Proc. Soc. Exp. Biol. Med. 57 
261 (1944). 
TABLE II 
______________________________________ 
Code number % animals 
of the LD.sub.50 toxicity - 
Dose whose stomach 
compounds 
mice administered 
contained no ball 
tested (mg/kg/i.p.) 
(mg/kg/p.o.) 
after 90 minutes 
______________________________________ 
2 105 5 75 
10 100 
3 110 2.5 100 
5 140 2.5 100 
______________________________________ 
TABLE III 
______________________________________ 
Code number 
LD.sub.50 % animals 
of the toxicity - Dose having completely 
compounds 
mice administered 
evacuated the 
tested (mg/kg/i.p.) 
(mg/kg/p.o.) 
balls after 24 hours 
______________________________________ 
2 105 1 64 
7 150 10 50 
6 150 10 55 
17 140 1 57 
18 160 1 38 
22 300 1 63 
1 300 10 50 
20 145 1 50 
23 50 1 38 
24 70 1 38 
25 80 1 44 
______________________________________ 
As the above tables show, the difference between the toxic doses and the 
active doses allows use to be made in therapeutics of the compounds of the 
invention in the field of the digestive system and more particularly as 
accelerator of the gastro-intestinal motor function and as a medicament 
potentiator, particularly of analgesic medicaments such as aspirin or 
paracetamol for example. 
The present invention also relates therefore, as medicaments, and more 
especially as medicaments useful in the field of the digestive system, to 
the derivatives of formula (I), the pharmaceutically acceptable acid 
addition salts thereof, the hydrates of these derivatives and salts and 
the N-oxides of these derivatives. 
The invention extends finally to the pharmaceutic compositions containing, 
as active ingredient, at least one of the above-defined medicaments, in 
association with an appropriate vehicle. These compositions may be 
administered orally, in the form of capsules, tablets, pills etc. . . at 
doses which may reach 500 mg of active ingredient per day (taken in one or 
several doses per day) or parenterally in the form of an injectable solute 
at doses which may reach 200 mg of active principle per day (in 1 or 2 
daily injections).