New piperidine tetrahydropyridine and pyrrolidine compounds

The invention relates to compounds of formula I: ##STR1## in which R.sub.1 represents a naphthyl radical, a dihydronaphthyl radical, a tetrahydronaphthyl radical, a quinolyl radical or a 1,4-benzodioxanyl radical, A represents a single bond, a double bond, a methylene radical, a radical of formula z.sub.1 : EQU --CH.dbd. (z.sub.1) or a radical of formula z.sub.2 : EQU .dbd.CH-- (z.sub.2) the ring B represents a piperidyl radical, a pyrrolidinyl radical, or a 1,2,3,6-tetrahydropyridyl radical, and R.sub.2 represents: a hydrogen atom, a benzyl radical, or an alkyl radical having 1 to 6 carbon atoms, on condition that in one of these cases R.sub.1 is other than a naphthyl (y.sub.1), dihydronaphthyl (y.sub.2) or tetrahydronaphthyl (y.sub.3) radical and B is other than a piperidinyl radical, or an aminoalkyl radical having 1 to 6 carbon atoms, a cyanoalkyl radical having 1 to 6 carbon atoms, or a radical of formula w.sub.1 : ##STR2## in which n is 1-6 and R.sub.4 represents a hydrogen atom, a halogen atom, an alkyl radical having 1 to 6 carbon atoms, or an alkoxy radical having 1 to 6 carbon atoms , and their addition salts with a pharmaceutically-acceptable inorganic or organic acid, and medicaments containing the same.

The present invention relates to new piperidine, tetrahydropyridine and 
pyrrolidine compounds. 
Some 4-naphth-1-yl-1,2,3,6-tetrahydropyridine compounds having antiviral 
properties are described in the literature (EP 156,433). 
4-(3,4-Dihydro-2-phenyl-1-napth-1-yl)piperidine compounds having 
contraceptive or sedative properties are also known (J. Med. Chem. (1967), 
10(1), pp 78-84 Arzneim. Forsch., (1970), 20(9), pp 1235-1238 ; Int. J. 
Neuropharmacol. (1969), 8(2) pp 153-160) Acta. Pol. Pharm. (1967), Vol 
24(5), pp 489-96 ; J.Chem. Soc. C. (1969) 2 pp 217-22). 
Trifluoromethylphenyltetrahydropyridines are also used for the preparation 
of medicaments intended to control anxiety-depression disorders. 
The compounds of the invention are distinguished from other piperidine, 
tetrahydropyridine and pyrrolidine compounds described in the literature 
and mentioned above by their original structures and by their 
pharmacological properties. 
On the cardiovascular level, the compounds of the invention reduce the 
arterial pressure and the heart rate. This action results from a central 
inhibition of the sympathetic tonus and is associated with their 
5-HT.sub.1A agonist properties. 
At the level of the central nervous system, the compounds Of the invention 
have demonstrated 5-HT.sub.1A agonist properties. 
They may therefore be useful in the treatment of hypertension, migraine, 
depression, anxiety, schizophrenia, stress and pain.

The present invention relates more particularly to the compounds of general 
formula I: 
##STR3## 
in which R.sub.1 represents a naphthyl radical, of formula y.sub.1 : a 
dihydronaphthyl radical, of formula y.sub.2 : 
##STR4## 
a tetrahydronaphthyl radical of formula y.sub.3 : 
##STR5## 
in which formulae R.sub.3 represents a hydrogen atom, a halogen atom, an 
alkyl radical having 1 to 6 carbon atoms, a hydroxyl radical or an alkoxy 
radical having 1 to 6 carbon atoms), a quinol-3-yl radical (optionally 
substituted on the benzene ring by one or more halogen atoms, alkyl 
radicals having 1 to 6 carbon atoms, hydroxyl radicals or alkoxy radicals 
having 1 to 6 carbon atoms) or a 1,4-benzodioxan-5-yl radical, 
A represents a single bond, a double bond (on condition, however, that 
R.sub.1 represents a tetrahydronaphthyl radical), a methylene radical, a 
radical of formula z.sub.1 : 
EQU --CH.dbd. (z.sub.1) 
or a radical of formula z.sub.2 : (on condition, however, that in this 
case R.sub.1 represents a tetrahydronaphthyl radical), 
EQU .dbd.CH-- (z.sub.2) 
the ring B represents a piperidyl radical (on condition, however, that in 
this case A represents a single or a double bond), a pyrrolidinyl radical 
(on condition, however, that in this case A represents a methylene 
radical, a radical z.sub.1 or a radical z.sub.2) or a 
1,2,3,6-tetrahydropyridyl radical (on condition, however, that in this 
case A represents a single bond), and 
R.sub.2 represents: 
a hydrogen atom, a benzyl radical or an alkyl radical having 1 to 6 carbon 
atoms, on condition that in one of these cases R.sub.1 is other than a 
naphthyl (y.sub.1), dihydronaphthyl (y.sub.2) or tetrahydronaphthyl 
(y.sub.3) radical and B is other than a piperidinyl radical, or 
an aminoalkyl radical having 1 to 6 carbon atoms, a cyanoalkyl radical 
having 1 to 6 carbon atoms or a radical of formula w.sub.1 : 
##STR6## 
(in which: n is 1-6 and 
R.sub.4 represents a hydrogen atom, a halogen atom, an alkyl radical having 
1 to 6 carbon atoms or an alkoxy radical having 1 to 6 carbon atoms), 
on condition, however, that 
when R.sub.1 is a radical y.sub.2, R.sub.3 represents a hydrogen atom, A a 
single bond and B a piperidyl radical, R.sub.2 does not at the same time 
represent a methyl radical, and 
when R.sub.2 is a radical y.sub.1, R.sub.3 represents a hydrogen atom, A a 
single bond and B a 1,2,3,6-tetrahydropyridyl radical, R.sub.2 does not at 
the same time represent a hydrogen atom, and 
when R.sub.1 is a radical y.sub.3, R.sub.3 represents a hydrogen atom, A a 
double bond and B a piperidyl radical, R.sub.2 does not at the same time 
represent a methyl radical, 
its possible stereoisomers, 
and its addition salts with a pharmaceutically acceptable inorganic or 
organic acid. 
The present invention also relates to a process for preparing compounds of 
general formula I, wherein: either 
a compound of formula II: 
##STR7## 
in which R.sub.2' represents an alkyl radical having 1 to 6 carbon atoms 
or a benzyl radical, is reacted with a compound of formula III: 
EQU R.sub.1 --X (III) 
in which R.sub.1 has the same meaning as for the formula I and X 
represents a bromine or lithium atom or an MgBr group, to form the 
compounds of formula IV: 
##STR8## 
in which R.sub.1 has the meaning indicated above and R.sub.2' represents 
an alkyl radical having 1 to 6 carbon atoms or a benzyl radical, 
which is subjected to the action of hydrobromic acid to form the compounds 
of formula I.sub.a : 
##STR9## 
in which R.sub.1 has the same meaning as for the formula I and R.sub.2' 
represents an alkyl radical having 1 to 6 carbon atoms or a benzyl 
radical, and then 
either 
the compounds of formula I.sub.a are subjected to the action of ethyl 
chloroformate in the presence of an alkali metal inorganic salt to form 
the compounds of formula V: 
##STR10## 
in which R.sub.1 has the same meaning as for the formula I, A is a single 
bond and B represents a 1,2,3,6-tetrahydropyridyl radical, 
or 
the compounds of formula Ia are first subjected to a catalytic 
hydrogenation to form the compounds of formula I.sub.b : 
##STR11## 
in which R.sub.1 has the same meaning as for the formula I and R.sub.2' 
represents an alkyl radical having 1 to 6 carbon atoms or a benzyl 
radical, 
then to the action of ethyl chloroformate in the presence of an alkali 
metal inorganic salt to form the compounds of formula V, 
in which R.sub.1 has the same meaning as for the formula I and B represents 
a piperidyl radical, or 
a compound of formula VI: 
##STR12## 
in which R.sub.3 has the same meaning as for the formula I, is reacted 
either 
with a compound of formula VII, 
##STR13## 
to form the compounds of formula V in which R.sub.1 represents a 
tetrahydronaphthyl radical of formula y.sub.3, A is a double bond and B 
represents a piperidyl radical, 
or 
with a compound of formula VIII: 
##STR14## 
in which R.sub.2' has the same meaning as for the formula II, to form the 
compounds of formula IX: 
##STR15## 
in which the meaning of R.sub.3 and R.sub.2' remains identical to that 
given above, 
which are subjected to the action of paratoluenesulfonic acid to form the 
compounds of formulae I.sub.c and I.sub.d : 
##STR16## 
in which formulae R.sub.3 has the same meaning as for the formula I and 
the meaning of R.sub.2' is identical to that given for the formula II, 
which compounds are then separated 
then subjected to the action of ethyl chloroformate in the presence of an 
alkali metal inorganic salt to form the compounds of formula V, in which 
R.sub.1 represents a dihydronaphthyl radical of formula y.sub.2 or a 
tetrahydronaphthyl radical of formula y.sub.3, A is, respectively, a 
methylene radical or a radical of formula z.sub.2 and B represents a 
pyrrolidinyl radical, or 
with a compound of formula X: 
##STR17## 
in which R.sub.2' has the same meaning as for the formula II, to form the 
compounds of formula XI: 
##STR18## 
in which the meaning of R.sub.3 remains identical to that given for the 
formula I and R.sub.2' represents a benzyl radical or an alkyl radical 
having 1 to 6 carbon atoms, 
which compounds are then subjected to the action of para-toluenesulfonic 
acid to form the compounds of formula I.sub.e : 
##STR19## 
in which R.sub.3 has the same meaning as for the formula I and R.sub.2' 
represents an alkyl radical having 1 to 6 carbon atoms or a benzyl 
radical, which compounds are then 
either 
reacted with ethyl chloroformate to form the compounds of formula V in 
which R.sub.1 represents a dihydronaphthyl radical of formula y.sub.2, A 
is a single bond and B represents a piperidyl radical, 
or 
subjected to the action of tetrachloro-1,2-benzoquinone to form the 
compounds of formula I.sub.f : 
##STR20## 
in which R.sub.3 has the same meaning as for the formula I and R.sub.2' 
represents an alkyl radical having 1 to 6 carbon atoms or a benzyl 
radical, 
which compounds are then 
reacted with ethyl chloroformate to form the compounds of formula V in 
which R.sub.1 represents a naphthyl radical of formula y.sub.1, A is a 
single bond and B represents a piperidyl radical, 
and then 
the compounds of formula V are subjected either to the action of 
hydrobromic acid or to the action of potassium hydroxide, to form the 
compounds of formula Ig: 
##STR21## 
in which the meaning of R.sub.1, A and B remains identical to that given 
for the formula I, 
which compounds are then reacted with a compound of formula XII: 
EQU Br--(CH.sub.2).sub.n -1--CN (XII) 
in which n has the same meaning as for the formula I, to form the 
compounds of formula I.sub.h : 
##STR22## 
in which R.sub.1, A, B and n have the same meaning as for the formula I, 
which compounds are then subjected to the action of lithium aluminum 
hydride to form the compounds of formula I.sub.i : 
##STR23## 
in which the meaning of R.sub.1, A, B and n remains identical to that 
given for the formula I, which compounds are reacted with a compound of 
formula XIII: 
##STR24## 
in which the meaning of R.sub.4 remains identical to that given for the 
formula I, to form the compounds of formula I.sub.j : 
##STR25## 
in which R.sub.1, A, B, n and R.sub.4 have the same meaning as for the 
formula I, and then 
the compounds of formula I.sub.a -I.sub.j (which make up all of the 
compounds of formula I) are separated into their possible stereoisomers, 
and/or the said compounds are converted to a salt with a pharmaceutically 
acceptable organic or inorganic acid, to form the corresponding addition 
salts. 
The reaction of the compounds of formula II with the compounds of formula 
III is carried out in the presence of butyllithium, in tetrahydrofuran or 
some other chemically equivalent solvent, and at a temperature of between 
-60.degree. C. and -78.degree. C. 
Preferentially, the catalyst used during the hydrogenation of the compounds 
of formula I.sub.a to form the compounds of formula I.sub.b is 
palladium-on-charcoal. 
During the reaction of the compounds of formulae Ia, I.sub.b, I.sub.c, 
I.sub.d, I.sub.e and I.sub.f with ethyl chloroformate, the alkali metal 
inorganic salt used is sodium bicarbonate. 
The reaction of the compounds of formula VI with the compounds of formula 
VII is carried out in the presence of the titanium 
trichloride/dimethoxyethane complex and the zinc-copper system (prepared 
by the process described in J.Org.Chem. (1989), 54, p. 3749). 
The reaction of the compounds of formula IX and XI with 
para-toluenesulfonic acid is carried out at elevated temperature, in 
dichloromethane or in some other halogenated aliphatic solvent of low 
molecular weight (C.sub.1 -C.sub.3). 
In order to form the compounds of formula I.sub.f, the oxidation of the 
compounds of formula Ie is carried out using tetrachloro-1,2-benzoquinone, 
at elevated temperature, in an anhydrous alcoholic solvent. 
In order to form the compounds of formula I.sub.g, the compounds of formula 
V are subjected at elevated temperature either to the action of potassium 
hydroxide in solution in ethanol or to the action of 48% hydrobromic acid. 
The reaction of the compounds of formula I.sub.i with the compounds of 
formula XIII is carried out at ambient temperature. 
Amongst the pharmaceutically acceptable acids for the preparation of the 
addition salts with compounds of general formula I, the following may be 
mentioned: hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric, 
ascorbic, tartaric, maleic, mandelic and methanesulfonic acids, etc. 
The compounds of the present invention have very valuable pharmacological 
properties. On the cardiovascular level, the compounds of the invention 
lower the arterial pressure and the heart rate in rats and in dogs. This 
action results from a central inhibition of the sympathetic tonus. In 
fact, pharmacological studies have shown that the lowering in pressure 
caused by the i.v. administration of the compounds of the invention to 
dogs is accompanied by a significant reduction in the electrical activity 
of the renal sympathetic nerve. 
This central reduction in the sympathetic tonus results from an activation 
Of the central 5-HT.sub.1A receptors at the level of the retrofacial 
nucleus (Eur. Journal of Pharm., (1989,160,p.385-294). Pharmacological 
studies have also proved that the compounds of the invention are more 
active than flesinoxan, a reference compound having antihypertensive 
properties owing to its agonist activity on the 5-HT.sub.1A receptors 
(European Journal of Pharmacology, (1988),149,p.213-223). On the other 
hand, the compounds of the invention have a beneficial activity at the 
renal level (T.I.P.S., (1989), 10, p.469-471). 
Binding studies have confirmed that the compounds of the invention also 
behave as very powerful ligands for 5-HT.sub.1A receptors, with an agonist 
or antagonist activity on the central nervous system. 
The compounds of the invention therefore find their application in the 
treatment of stress (Neuropharmac.,(1989), Vol.25, No.5, p.471-476), 
migraine (T.I.P.S., (1989), Vol.10, pp.200-204) anxiety, depression, 
schizophrenia and pain (Pharmacology and Toxicology, (1989), 64, p.3-5), 
(Drugs of the Future, (1988), 13, No.5, p.429-437), (J. Neural. Transm., 
(1988), 74, p.195-198). 
The compounds which are active at the level of the 5-HT.sub.1A receptors 
may also modify the alimentary and sexual behavior (Jour. of Receptor 
Research, (1988), 8, p.59-81). 
The invention also extends to the pharmaceutical compositions containing, 
as active principle, at least one compound of general formula I, or one of 
its salts with a pharmaceutically compatible inorganic or organic acid, in 
combination with one or more inert and suitable excipients. 
The pharmaceutical compositions thus obtained are advantageously presented 
in diverse forms, such as, for example, tablets, coated tablets, capsules, 
suppositories, injectable solutions or drinkable solutions. 
The dosage may vary widely depending on the age and the weight of the 
patient, on the nature and the severity of the illness and on the 
administration route. In general, the unit dose will range between 0.1 and 
100 mg and the daily dose, usable in human medicine, between 0.1 and 500 
mg. The preferred administration route is the oral or parenteral route. 
The following examples, given without any limitation being implied, 
illustrate the invention. 
The melting points were measured using the Micro-Kofler technique. 
The proton nuclear magnetic resonance (1H NMR) spectra of the compounds of 
general formula I were recorded, depending on the case, at 200 and 400 MHz 
and are indicated in Table I. 
EXAMPLE 1 
1-Methyl-4 (naphth-1-yl) 1,2,3,6 tetrahydropyridine hydrobromide 
Stage A 
4-Hydroxy-1 methyl-4-(naphth 1-yl)piperidine 
A solution of 51.75 g of 1-bromonaphthalene in 250 ml of tetrahydrofuran is 
added dropwise, at -78.degree. C. and under a stream of nitrogen, to a 
solution of 175 ml of butyllithium (1.6 M in hexane) in 500 ml of 
tetrahydrofuran. 
After stirring for 1 hour, a solution of 28.29 g of 1-methylpiperid-4-one 
in 250 ml of tetrahydrofuran is added dropwise. 
The reaction mixture is stirred for 1 hour at -78.degree. C. and then for 5 
hours at 20.degree. C. and is then hydrolyzed with 100 ml of a saturated 
ammonium chloride solution. 
Extraction with dichloromethane followed by evaporation of the solvent 
leaves an oily residue which, taken up in ethyl ether, crystallizes in the 
form of a white solid. 
Yield: 73 % 
Melting point : 160.degree. C. 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 2.2 ppm 
s+m 3H+4H; 2.65 ppm m 4H; 7.35 ppm m 4H; 7.75 ppm d 1H; 7.85 ppm m 1H; 8.9 
ppm m 1H. 
Stage B 
49 g of the compound obtained in the preceding stage, in suspension in 1 
liter of a 48% hydrobromic acid solution, are refluxed for 24 hours. The 
residue obtained after evaporation is taken up 3 times with ethanol and 
then with acetone to yield, after filtration and drying, 47.94 g of 
1-methyl-4-naphth-1-yl-1,2,3,6-tetrahydropyridine hydrobromide. 
Yield : 86.65% 
Melting point : &gt;260.degree. C. 
EXAMPLE 2 
1 Methyl-4-naphth-1-ylpiperidine hydrobromide 
20 g of the compound from Example 1 are reduced with 1680 ml of hydrogen 
under atmospheric pressure and at ambient temperature, in the presence of 
1 g of 10% palladium-on-charcoal, in 1 liter of ethanol and 100 ml of 
dimethylformamide. 
After filtering off the catalyst and evaporation of the solvents, a crude 
product is obtained which when taken up in acetone yields 19 g of the 
expected hydrobromide. 
Yield : 95.5% 
Melting point : &gt;260.degree. C. 
EXAMPLE 3 
4-Naphth-1-ylpiperidine hydrobromide 
Stage A 
Ethyl [4-(naphth-1 Yl)piperid-1-yl]carbamate 
19 g of the salt obtained in Example 2 are converted to 
1-methyl-4-naphth-1-ylpiperidine using sodium hydroxide in 
dichloromethane. 
The base thus obtained is immediately brought into contact with 10 g of 
sodium bicarbonate in 500 ml of toluene, under a stream of nitrogen. 100 
ml of ethyl chloroformate are added in fractions to the reaction mixture 
and the whole is then refluxed for 24 hours. Filtration followed by 
evaporation leads to 10.7 g of an oil. 
Yield: 61.14% 
Stage B 
10.5 g of the compound obtained in Stage A in 300 ml of a 48% hydrobromic 
acid solution, are refluxed for 20 hours. After evaporation and washing 
twice with ethanol, the residue is taken up in acetone and the mixture 
then filtered to give 4-(naphth-1-yl)pyperidine hydrobromide. 
Yield: 86.64% 
Melting point: &gt;260.degree. C. 
EXAMPLE 4 
(4-Naphth-1-ylpiperid-1-yl)acetonitrile hydrochloride 
5 g of the compound from Example 3, 7.088 g of potassium carbonate and 
2.259 g of bromoacetonitrile in 200 ml of acetone are stirred for 10 hours 
under reflux and a stream of nitrogen. After filtering and evaporation of 
the filtrate, the residue obtained is treated with an ethanolic solution 
of hydrogen chloride to give 4.5 g of the expected hydrochloride. 
Yield: 91.83% 
Melting point: 172.degree. C. 
EXAMPLE 5 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-naphth-1-ylpiperidine hydrochloride 
Stage A 
1-(2-Aminoeth-1-yl)-4-naphth-1-ylpiperidine 
1.75 g of lithium aluminum hydride are added in fractions under a stream of 
nitrogen to a solution of 4.4 g of the compound from Example 4 in 150 ml 
of tetrahydrofuran. After stirring for 1 hour, the mixture is hydrolyzed 
with 1.75 ml of water, 3.5 ml of a 10% (wt/wt) sodium hydroxide solution 
and 7 ml of water. Filtration through celite, followed by evaporation of 
the solvent, yields an oily product which is used as it is in the 
following stage. 
Yield: quantitative 
Stage B 
A solution of 1.81 g of triethylamine in 40 ml of tetrahydrofuran is added 
dropwise at -5.degree. C., under a stream of nitrogen, to a solution of 
3.8 g of the compound obtained in the preceding stage, in 180 ml of 
tetrahydrofuran. Under the same conditions, a solution of 2.84 g of 
4-fluorobenzoyl chloride in 40 ml of tetrahydrofuran is added to the 
reaction mixture. After having stirred for 1 hour at ambient temperature, 
the mixture is hydrolyzed using a saturated sodium bicarbonate solution. 
Phase separation, followed by drying of the organic phase over sodium 
sulfate and the evaporation of the solvent leads to a product which, when 
taken up in ethyl ether, crystallizes in the form of a white solid. 
3.3 g of the corresponding hydrochloride are obtained after addition of an 
ethanolic solution of hydrogen chloride. 
Yield: 64% 
Melting point: 260.degree. C. 
EXAMPLE 6 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-naphth-1-yl-1,2,3,6-tetrahydropyridine 
hydrochloride 
Stage A 
Ethyl (4-naphth-1-yl-1,2,3,6-tetrahydropyrid-1-yl)carbamate 
22.3 g of the compound from Example 1 are treated with 50 ml of ethyl 
chloroformate and 30 g of sodium bicarbonate, in accordance with the 
procedure described in Stage A of Example 3, to give the expected product. 
Yield: 53.88% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 1.3 ppm t 
3H; 2.55 ppm m 2H 3.8 ppm m 2H 4.1-4.3 ppm g+m+m 2H+1H+1H; 5.8 ppm m 1H; 
7.25 ppm dd 1H; 7.35-7.55 ppm m 3H; 7.7-8 ppm 2H+1H. 
Stage B 
4-Naphth-1-yl-1,2,3,6-tetrahydropyridine hydrobromide 
The treatment of 11 g of the carbamate obtained in the preceding stage with 
a 48% hydrobromic acid solution yields 9.02 g of 
4-naphth-1-yl-1,2,3,6-tetrahydropyridine hydro bromide. 
Yield: 80% 
Melting point: &gt;260.degree. C. 
Stage C 
(4-Naphth-1-yl-1,2,3,6 tetrahydropyrid-1-yl)acetonitrile hydrochloride 
This salt was obtained from the compound obtained in Stage B using the 
process described in Example 4. 
Yield: 80% 
Stage D 1-(2-Aminoeth-1-yl)-4-naphth-1-yl-1,2,3,6-tetrahydropyridine 
6.25 g of the hydrochloride prepared previously are reduced using 2.5 g of 
lithium aluminum hydride and yield the expected amino compound, which is 
used immediately in the following stage. 
Yield: quantitative 
Stage E 
The treatment of 5.5 g of the amine prepared in the preceding stage with 
2.66 g of triethylamine and 4.18 g of 4-fluorobenzoyl chloride leads to a 
crude product which is purified by chromatography on a silica gel column 
(70-230 mesh) using a 97: 3: 0.3 (V/V/V) mixture of dichloromethane, 
methanol and aqueous ammonia as the elution solvent. 
The product thus obtained is converted to the hydrochloride. 
Yield: 37% 
Melting point: 233.degree. C. 
EXAMPLE 7 
3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)quinoline dihydrobromide 
Stage A 
3-(4-Hydroxy 1-methylpiperid 4-yl)quinoline 
95.01 g of 3-bromoquinoline were treated with 200 ml of a 2.5 M solution of 
butyllithium in hexane and 51.62 g of 1-methylpiperid-4-one in accordance 
with the procedure described in Stage A of Example 1, in order to obtain 
the expected product. 
Yield: 53.84% 
Melting point: 175.degree. C. 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 2.3 ppm 
t+d 2H; 2.4 ppm s 3H; 2.55 pp t+d 2H; 2.85 ppm d 2H; 7.7 and 7.55 ppm m+m 
2H; 7.8 ppm d 1H; 8.10 ppm d 1H; 8.25 ppm d 1H; 9.1 ppm d 1H. 
Stage B 
The 3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)quinoline dihydrobromide was 
obtained by treating 53 g of the compound obtained in Stage A with a 48% 
hydrobromic acid solution. 
Yield: 72.80% 
Melting point: &gt;260.degree. C. 
EXAMPLE 8 
3-(1,2,3,6-Tetrahydropyrid-4-yl)quinoline hydrochloride 
This product was prepared from the compound of Example 7 and using the 
procedure described in Stages A and B of Example 6. The compound obtained 
was converted to a salt using an alcoholic solution of hydrogen chloride. 
Yield: 65% 
Melting point: &gt;260.degree. C. 
EXAMPLE 9 
3-(1-Methylpiperid-4-yl)quinoline dihydrobromide 
Hydrogenation of the compound of Example 7, in accordance with the 
procedure described in Example 2, yields the expected compound. 
Yield: 95.4% 
Melting point: &gt;260.degree. C. 
EXAMPLE 10 
3-Piperid-4-ylquinoline dihydrobromide 
This product was prepared from the compound of Example 9 using the 
procedure described in Example 3. 
Yield: 74% 
Melting point: &gt;260.degree. C. 
EXAMPLE 11 
[4-(Quinol-3-yl)piperid-1-yl]acetonitrile dihydrochloride 
The treatment of 10.90 g of the compound from Example 10 with 2.3 ml of 
bromoacetonitrile and 16 g of potassium carbonate yields 9.08 g of the 
expected product, in the form of the base. An ethanolic solution of 
hydrogen chloride is used for conversion to the salt. 
Yield: 85.77% 
Melting point: 210.degree.-214.degree. C. 
EXAMPLE 12 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-quinol-3-ylpiperidine dihydrochloride 
This product was prepared from the compound of Example 11 and in accordance 
with the procedure described in Example 5. 
Yield: 50% 
Melting point: 229.degree. C. 
EXAMPLE 13 
1-Benzyl-3-[3,4-dihydro-7-methoxynaphth-1-yl)methylenyl]pyrrolidine 
Stage A 
1-Benzyl-3-[(1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)methylenyl]p 
yrrolidine 
40 g of 3-chloromethyl-1-benzyl pyrrolidine are added under nitrogen to a 
suspension of 4.63 g of magnesium in 100 ml of anhydrous ethyl ether. 
The reaction mixture is diluted little by little with 300 ml of benzene at 
the rate at which the magnesium disappears. The mixture is refluxed for 1 
hour and then cooled to 0.degree. C. and a solution of 37 g of 
7-methoxy-1,2,3,4-tetrahydronaphth-1-one in 120 ml of benzene is added. 
The temperature is allowed to rise to 20.degree. C. and after 36 hours the 
mixture is hydrolyzed with 200 ml of a saturated ammonium chloride 
solution. 
After drying and concentrating the organic phase, the oil obtained is 
purified by chromatography on silica using a 100 3 (V/V) mixture of 
dichloromethane and methanol as eluent. 
Yield: 48% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 1.65 to 
2.1 ppm m+m+m+d+dd 1H+2H+2H+2H+1H; 2.15 to 2.5 ppm m+m+m 1H+1H+1H; 2.6 to 
2.85 ppm m+m+dd 2H+1H+1H; 3.55 ppm dd 2H; 3.75 ppm s 3H; 6.7 ppm dd 1H; 
7.0 ppm d 1H; 7.05 ppm d 1H; 7.1 to 7.4 ppm m 5H. 
Stage B 
A solution of 20 g of the product obtained in Stage A and 11.9 g of 
para-toluenesulfonic acid monohydrate in 600 ml of dichloromethane is 
refluxed for 30 minutes. 
The amine is then salted out using a sodium hydroxide solution and the 
organic phase is concentrated. The oil obtained is purified by 
chromatography on silica (70-230 mesh) using a 3:100 (V/V) mixture of 
methanol and dichloromethane as eluent. 
12 g of 1-benzyl-3-[3,4-dihydro-7-methoxynaphth-1-yl) 
methylenyl]pyrrolidine are thus obtained. 
EXAMPLE 14 
1-Benzyl-3-[(7 methoxy-1,2,3,4-tetrahydronaphth-1-yl) 
methylidyn]pyrrolidine 
3 g of this compound were obtained on purification, by chromatography, of 
the oil obtained in Stage B of Example 13. 
EXAMPLE 15 
4-(3,4-Dihydro-7-methoxynaphth-1-yl)-1 methylpiperidine 
Stage A 
4-(1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)-1-methylpiperidine 
A solution of 40 g of 4-chloro-1-methylpiperidine in 150 ml of 
tetrahydrofuran is added to a suspension of 6.9 g of magnesium in 50 ml of 
tetrahydrofuran. 
The formation of the magnesium compound is completed by refluxing for 2 
hours. 
A solution of 32.2 g of 7-methoxy-1,2,3,4-tetrahydronaphth-1-one in 150 ml 
of tetrahydrofuran is then added at 10.degree. C. 
Stirring of the reaction mixture is continued at ambient temperature for 15 
hours and the mixture is then hydrolyzed at 0.degree. C. using 15 g of 
ammonium chloride in solution in 80 ml of water. 
After evaporation of the solvent under vacuum, the residue is taken up in 
water, the mixture is acidified and washed with ethyl ether, the aqueous 
phase is then rendered alkaline and the product extracted with 400 ml of 
toluene is washed with 200 ml of water. 
After concentration under vacuum, the oil obtained crystallizes. 
Melting point: &gt;60.degree. C. 
Stage B 
A solution of 15 g of the oil obtained in Stage A, in 400 ml of anhydrous 
dichloromethane, is refluxed for 20 minutes in the presence of 11.4 g of 
para-toluenesulfonic acid. 
After cooling, the reaction mixture is washed with 20 ml of a saturated 
sodium bicarbonate solution. The organic phase is dried over sodium 
sulfate and then concentrated under vacuum. An oil is obtained. 
Yield: 40% 
EXAMPLE 16 
4-(7-Methoxynaphth-1-yl)-1-methylpiperidine 
A mixture of 11.5 g of the product from Example 15 and 23.1 g of 
tetrachloro-1,2-benzoquinone in solution in 600 ml of anhydrous ethyl 
alcohol is refluxed for 30 hours. 
After concentration under vacuum, the residue is taken up in water and then 
extracted with dichloromethane and the extract is dried over anhydrous 
sodium sulfate and concentrated under vacuum. 
The product obtained is purified on a neutral alumina column using a 
99.5:0.5 (V/V) mixture of dichloromethane and methanol. 
Yield: 82% 
EXAMPLE 17 
4-(7-Methoxynaphth-1-yl)piperidine hydrochloride 
Stage A 
Ethyl 4-(7-methoxynaphth-1-yl)piperid-1-yl]carbamate 
The compound of Example 16 is dissolved in 200 ml of anhydrous xylene in 
the presence of 3.9 g of sodium carbonate and 17.6 ml of ethyl 
chloroformate are added at 20.degree. C. The mixture is refluxed for 24 
hours. 
The reaction mixture is cooled and then hydrolyzed using a 2 N hydrochloric 
acid solution. 
The organic phase is washed with a dilute sodium hydroxide solution, dried 
over sodium sulfate and concentrated under vacuum. 
Yield: 88% 
Stage B 
A mixture of 8.9 g of the carbamate obtained in Stage A, 12.7 g of 
potassium hydroxide, 30 ml of water and 200 ml of ethyl alcohol is 
refluxed for 40 hours. 
After evaporation under vacuum, the residue is taken up in water and the 
mixture is extracted with dichloromethane. 
The organic phase is dried over sodium sulfate and concentrated under 
vacuum. 
The oil obtained is converted to the salt using 3.12 ml of a 7.6 N 
ethanolic solution of hydrogen chloride. 
Yield: 55% 
Melting point: 240.degree. C. 
EXAMPLE 18 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-(7-methoxynaphth-1-yl) piperidine 
hydrochloride 
This product was prepared from the compound of Example 17 and using 
successively the procedures described in Examples 4 and 5. 
Yield: 25% 
Melting point: 215.degree. C. 
EXAMPLE 19 
4-(7-Methoxy-1,2,3,4 tetrahydronaphth-1-yl)piperid-4-ylidene 
Stage A 
Ethyl 
[4-(7-methoxy-1,2,3,4-tetrahydronaphth-1-y1)piperid-4-ylidene]carbamate 
921 g of the 1 M 1.5 M titanium trichloride/dimethoxyethane complex and 
then 888 g of the zinc/copper system (prepared by the process described by 
J. McMurry. J. Org. Chem. (1989), 54, p. 3749) are poured successively, 
under a stream of argon, into 8 liters of dimethoxyethane. The mixture is 
refluxed for 13 hours and then cooled to 20.degree. C. 
A solution consisting of 31 g of 7-methoxy-1,2,3,4-tetrahydronaphth-1-one, 
60.3 g of ethyl (4-oxopiperid-1-yl)carbamate and 400 ml of dimethoxyethane 
is added dropwise in the course of 5 hours to the reaction mixture. The 
latter is then refluxed again for 15 hours, then cooled and diluted with 3 
liters of dichloromethane. 
After filtering through celite and concentrating the filtrate under vacuum, 
the residue obtained is taken up in 800 ml of dichloromethane. 
The insoluble matter is removed by filtering off and the organic phase is 
evaporated under vacuum. 
The oil obtained is purified by chromatography on a silica column using 
dichloromethane as eluent. 
Yield: 55% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 1.25 ppm t 
3H; 1.75 ppm q 2H; 2.45 ppm m 4H; 2.6 ppm t 2H; 2.65 ppm t 2H; 3.4 ppm t 
2H; 3.55 ppm t 2H; 3.8 ppm s 3H; 4.2 ppm q 2H; 6.7 ppm m 2H; 7.0 ppm d 1H. 
Stage B 
2.6 g of the compound obtained in Stage A were treated by the procedure 
described in Stage B of Example 17 in order to obtain the expected salt. 
Yield: 63% 
Melting point: &gt;260.degree. C. 
EXAMPLE 20 
[4-(7 Methoxy-1,2,3,4-tetrahydronaphth-1-yl)piperid-4-ylidene]acetonitrile 
This compound was prepared from the compound of Example 19 using the 
procedure described in Example 4. 
Yield: 94% 
EXAMPLE 21 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-(7-methoxy-1,2,3,4-tetrahydronaphth-1-y 
l)piperid-4-ylidene hydrochloride 
This compound was prepared from the compound of Example 20 using the 
procedure described in Example 5. 
Yield: 80% 
Melting point: 120.degree. C. 
EXAMPLE 22 
1-Benzyl-4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine 
Stage A 
1-Benzyl-4-hydroxy-4-(1,4-benzodioxan-5-yl)piperidine 
23.3 ml of a 1.6 M solution of butyllithium in hexane are added dropwise to 
a solution, previously cooled to -60.degree. C., of 8 g of 
5-bromo-1,4-benzodioxane in 400 ml of tetrahydrofuran. When the addition 
is complete, the mixture is stirred at -60.degree. C. for 5 minutes and a 
solution of 8 g of 1-benzylpiperid-4-one in 100 ml of tetrahydrofuran is 
then added dropwise. The mixture is stirred for 2 hours at -40.degree. C. 
and then for 2 hours at ambient temperature before hydrolyzing using 80 ml 
of water. 
The organic phase is separated off and the aqueous phase is extracted with 
twice 100 ml of dichloromethane. The combined organic phases are washed 
once using 20 ml of water and dried over magnesium sulfate. 
The solvents are evaporated under vacuum and the product obtained in the 
crude stage is chromatographed on 520 of silica (70-230 mesh), eluting 
using a 98:2 (V/V) dichloromethane/methanol mixture. 
Yield: 72% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 2.05 ppm m 
2H; 2.1 ppm m 2H; 2.55 ppm m 2H; 2.75 ppm m 2H; 3.6 ppm s 2H; 4.25 ppm m 
4H; 6.8 ppm m 3H; 7.1-7.4 ppm m 5H 
Stage B 
A solution of 8 g of the product obtained in the preceding stage, in 100 ml 
of glacial acetic acid and 8 ml of concentrated hydrochloric acid, is 
refluxed for 14 hours. 
After returning to ambient temperature, the mixture is concentrated and the 
residue is taken up using 250 ml of dichloromethane. 
The separated organic phase is washed once using 80 ml of 1 N sodium 
hydroxide and then once using 80 ml of water. 
After drying over magnesium sulfate and concentrating under vacuum, an oil 
is obtained. 
Yield: 74% 
EXAMPLE 23 
4-[5-(1,4-Benzodioxan-5-yl)]-1-[2-(4-fluorobenzamido)eth-1-yl]-1,2,3,6-tetr 
ahydropyridine hydrochloride 
Stage A 
Ethyl [4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyrid-1-yl]carbamate 
8 g of ethyl chloroformate are added at ambient temperature, with stirring, 
to a solution containing 5.5 g of the product from Example 22 in 50 ml of 
toluene. When the addition is complete, the mixture is refluxed for 2 
hours. 
The cooled solution is filtered, the filtrate is concentrated under vacuum 
and the residue is taken up in 250 ml of a 50:50 (V/V) mixture of ethyl 
ether and diisopropyl ether. The precipitate is filtered off and the 
filtrate is concentrated in order to obtain an oil. 
Yield: 63% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 
1.3 ppm t 3H; 2.5 ppm m 2H; 3.65 m 2H; 4-4.30 ppm m 2H; 4.10 ppm s 4H; 4.35 
ppm q 2H; 5.8 ppm m 1H; 6.6-6.8 ppm m 3H 
Stage B 
4-[(1,4-Benzodioxan-5-yl)]-1,2,3,6-tetrahydropyridine hydrochloride 
1.7 ml of trimethylsilane iodide are added dropwise to a solution of 3 g of 
the carbamate obtained in the preceding stage, in 4.2 ml of chloroform. 
When the addition is complete, the mixture is stirred for 1 hour under 
reflux and then for 2 hours at ambient temperature. 
The mixture is filtered rapidly, the filtrate is diluted using 20 ml of 
chloroform, 10 ml of a methanolic solution of hydrogen chloride are then 
added dropwise and the mixture is diluted using 30 ml of ethyl ether. The 
precipitate formed is the expected product. 
Yield: 77% 
Melting point: 184.degree. C. (decomposition) 
Stage C 
[4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyrid-1-yl]acetonitrile 
2.5 g of potassium carbonate and, dropwise, a solution of 1.08 g of 
bromoacetonitrile in 10 ml of acetone are added to a solution of 1.9 g of 
the amine hydrochloride obtained in Stage B in 40 ml of acetone. 
The mixture is stirred for 2 hours at ambient temperature and filtered and 
the filtrate is concentrated under vacuum. The residue, taken up in 20 ml 
of dichloromethane, is washed using 10 ml of water and the organic phase 
is then dried over magnesium sulfate. 
After evaporation of the solvent, an oil is obtained. 
Yield: 99% 
Proton nuclear magnetic resonance spectrum (solvent CDCl.sub.3): 2.6 ppm m 
2H; 2.8 ppm t 2H; 3.3 ppm m 2H; 3.65 ppm s 2H; 4.2 ppm s 4H; 5.8 ppm m 1H; 
6.75 ppm m 3H 
Stage D 
1-(2-Aminoethyl)-4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine 
A solution containing 1.9 g of the compound obtained in Stage C, in 20 ml 
of anhydrous tetrahydrofuran, is added dropwise to a suspension of 0.56 g 
of lithium aluminum hydride in 30 ml of anhydrous tetrahydrofuran. 
After 4 hours' contact at ambient temperature, the mixture is hydrolyzed 
using 0.6 ml of a saturated ammonium chloride solution. 
The mixture is filtered and the filtrate is dried over magnesium sulfate. 
After concentration of the solvent, an oil is obtained which is used as 
such in the following step. 
Stage E 
All of the compound obtained in Stage D is dissolved in 20 ml of 
chloroform. A solution of 0.64 g of triethylamine in 5 ml of chloroform 
and then, dropwise, a solution of 0.94 g of para-fluorobenzoyl chloride in 
30 ml of chloroform are added thereto. 
After 3 hours' contact, the mixture is washed once using 10 ml of water and 
the organic phase is dried over magnesium sulfate and then concentrated 
under vacuum. 
The crude oil is dissolved in 50 ml of ether and the product is 
precipitated by adding an ethereal solution of hydrogen chloride. 
The precipitate filtered off is taken up in 20 ml of ether. A solid is thus 
obtained which is the expected salt. 
Yield: 68% 
Melting point: 214.degree. C. 
EXAMPLE 24 
[4-(3,4-Dihydro-7-methoxynaphth-1-yl)piperid-1-yl]acetonitrile 
Stage A 
Ethyl[4-(3,4-dihydro-7-methoxynaphth-1-yl)piperid-1-yl]carbamate 
The expected product is obtained using the compound from Example 15 and 
treating it in accordance with the procedure described in Stage A of 
Example 3. 
Yield: 93% 
Stage B 
4-(3,4-Dihydro-7-methoxynaphth-1-yl)piperidine 
The expected product is obtained using the compound described in Stage A 
and treating it in accordance with the procedure described in Stage B of 
Example 17. 
Yield: 77% 
Stage C 
[4-(3,4-Dihydro-7-methoxynaphth-1-yl]piperid-1yl]acetonitrile 
The expected product is obtained using the compound described in Stage B 
and treating it in accordance with the procedure described in Example 4. 
Yield: 92% 
______________________________________ 
Elementary microanalysis: 
C % H % N % 
______________________________________ 
Calculated 76.56 7.85 7.79 
Found 75.50 9.92 9.57 
______________________________________ 
EXAMPLE 25 
1-(2-Aminoeth-1-yl)-4-(3,4-dihydro-7-methoxynaphth-1-yl) piperidine 
The expected product is obtained using the compound from Example 24 and 
treating it in accordance with the process described in Stage A of Example 
5. 
Yield: 81% 
EXAMPLE 26 
1-(2-Aminoeth 1-yl) 4-(1,2,3,4-tetrahydro-7-methoxynaphth-1-yl)piperidine 
900 mg of the compound described in Example 25 are reduced by catalytic 
hydrogenation at ambient temperature in the presence of 0.1 g of platinum 
oxide in 10 ml of acetic acid. The expected product is obtained after 
filtering off the catalyst, neutralizing the filtrate with sodium 
hydroxide solution and extracting with dichloromethane. 
Yield: =100% 
______________________________________ 
Elementary microanalysis: 
C % H % N % 
______________________________________ 
Calculated 74.96 9.78 9.71 
Found 74.99 9.83 9.27 
______________________________________ 
EXAMPLE 27 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-(3,4-dihydro-7-methoxynaphth-1-yl)piper 
idine hydrochloride 
The expected product is obtained in the form of the base using the compound 
from Example 25 and treating it in accordance with the procedure described 
in Stage B of Example 5. The base is converted to the corresponding 
hydrochloride by treatment with an alcoholic solution of hydrogen 
chloride. 
Yield: 65% 
Melting point: 250.degree. C. 
______________________________________ 
Elementary microanalysis: 
C % H % N % Cl % 
______________________________________ 
Calculated 67.48 6.80 6.30 7.97 
Found 67.36 6.78 6.23 7.95 
______________________________________ 
EXAMPLE 28 
1-[2-(4-Fluorobenzamido)eth-1-yl]-4-(1,2,3,4-tetrahydro-7-methoxynaphth-1-y 
l)piperidine hydrochloride 
The expected product is obtained in the form of the base using the compound 
from Example 26 and treating it in accordance with the procedure described 
in Stage B of Example 5. The base is converted to the corresponding 
hydrochloride by treatment with an alcoholic solution of hydrogen 
chloride. 
Yield: 42% 
Melting point: 204.degree. C. 
______________________________________ 
Elementary microanalysis: 
C % H % N % Cl % 
______________________________________ 
Calculated 67.18 7.22 6.27 7.93 
Found 67.36 7.24 6.42 7.87 
______________________________________ 
EXAMPLE 29 
1-Benzyl-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine 
64 mmoles of the compound obtained in Stage B of Example 13 are refluxed in 
220 ml of anhydrous ethanol in the presence of 19 g of o-chloranil and 8.5 
ml of a 7.6 N ethanolic hydrochloric acid solution. 
After evaporation, the residue is taken up in water, the whole is brought 
to pH 10 and filtered through celite and the filtrate is extracted with 
dichloromethane. 
The expected product is obtained after drying and evaporating off the 
solvents and is purified by chromatography on silica (elution solvent: 
dichloromethane/ methanol/aqueous ammonia 99:1:0.1). 
Yield: 70% 
EXAMPLE 30 
3-[7-Methoxynaphth-1-yl)methyl]pyrrolidine 
The expected product is obtained by catalytic hydrogenation of the compound 
from Example 29.degree. at 60.degree. C. in ethanol in the presence of 1.5 
g of palladium-on-charcoal. 
Yield: 85% 
EXAMPLE 31 
1-Cyanomethyl-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine 
The expected product is obtained using the compound from Example 30 and 
treating it in accordance with the procedure described in Example 4 
without conversion to the hydrochloride. 
Yield: 95% 
EXAMPLE 32 
1-(2-Aminoeth-1-yl)-3-[(7-methoxynaphth-1-yl)methyl]pyrrolidine 
The expected product is obtained using the compound from Example 31 and 
treating it in accordance with the procedure described in Stage A of 
Example 5. 
Yield: 65% 
EXAMPLE 33 
1-[2-(4-Fluorobenzamido)eth-1-yl]-3-[(7-methoxynaphth-1-yl) 
methyl]pyrrolidine 
The expected product is obtained using the compound from Example 32 and 
treating it in accordance with the procedure described in Stage B of 
Example 5. 
Yield: 80% 
Melting point: &gt;260.degree. C. 
______________________________________ 
Elementary microanalysis: 
C % H % N % 
______________________________________ 
Calculated 65.31 5.89 5.64 
Found 64.99 5.72 5.99 
______________________________________ 
TABLE I 
__________________________________________________________________________ 
##STR26## 
NMR SPECTRUM 
EX- (Solvent) 
AMPLE s = salt 
No. R.sub.1 A B R.sub.2 b = base 
__________________________________________________________________________ 
1 
##STR27## 
##STR28## 
CH.sub.3 .sup.1 H NMR 
(DMSO-d.sub.6) s 
2.75ppm m 2H; 2.95ppm 
s 3H; 3.5ppm m 2H; 
3.95 ppm m 2H; 5.75ppm 
m 1H; 7.35ppm dd 1H; 
7.55 ppm m 3H; 7.9ppm 
d 1H; 8ppm m 1H; 8.05 
ppm m 1H; 9.5-10.5ppm 
1H (exchangeable) 
2 
##STR29## 
##STR30## 
CH.sub.3 .sup.1 H NMR 
(DMSO-d.sub.6 ) s 
2-2.2ppm m 4H; 2.8ppm 
s 3H; 3.3ppm m 2H; 3.6 
pm m 2H; 3.7ppm m 1H; 
7.3-7.7ppm m +d 3H+1H; 
7.85ppm d 1H; 7.95ppm 
dd 1H; 8.2ppm dd 1H; 
9.2-10.2 ppm 1H 
exchangeable 
3 
##STR31## 
##STR32## 
H .sup.1 H NMR 
(DMSO-d.sub.6) s 
1.9-2.15ppm m 4H; 3.1- 
.6ppm m 4H; 3.8ppm m 
1H; 7.3-7.65ppm m+t+d 
2H+1H+1H; 7.8ppm d 1H; 
7.95ppm m 1H; 8.3ppm m 
1H; 8.4-9 ppm 1H 
exchangeable 
4 
##STR33## 
##STR34## 
CH.sub.2 CN .sup.1 H NMR 
(DMSO-d.sub.6) s 
2-2.4ppm m 4H; 3.2-3.9 
pm m+m+m 1H+2H+2H; 
4.6ppm s 2H; 
7.25-7.65ppm m+d 
3H+1H; 7.8ppm d 1H; 
7.9ppm dd 1H; 8.25ppm 
dd 1H 
5 
##STR35## 
##STR36## 
##STR37## .sup.1 H NMR 
(DMSO-d.sub.6) s 
1.8-2.4ppm m 4H; 3-3.5 
pm m 4H; 3.5-4ppm m 
5H; 7.2-7.7ppm m+m+t 
3H+1H+2H; 7.8ppm d 1H; 
7.85-8.15 ppm dd+m 
2H+1H; 8.2 ppm d 1H; 
8.8-9.3ppm 1H 
exchangeable; 10.4- 
10.7ppm 
1H exchangeable 
6 
##STR38## 
##STR39## 
##STR40## .sup.1 H NMR 
(DMSO-d.sub.6) s 
2.5-2.7ppm m 1H; 2.9- 
3.2ppm m 1H; 3.3-3.6 
ppm m+m 2H; 3.7-4.05 
ppm m+t 2H+2H; 4.2 ppm 
m 1H; 5.75ppm m 1H; 
7.25-7.40ppm m 3H; 
7.45-7.60ppm m 3H; 
7.8- 8.0ppm m+m 1H+1H; 
.05-8.3ppm m+dd 1H+2H; 
9.15ppm 
1H exchangeable; 
11-11.4 ppm 1H 
exchangeable 
7 
##STR41## 
##STR42## 
CH.sub.3 .sup.1 H NMR 
(DMSO-d.sub.6) s 
3.0ppm m+s 5H; 3.4- 
3.75ppm m 2H; 4.0-4.2 
ppm m 2H; 6.8ppm m 1H; 
7.9ppm m 1H; 8.05 ppm 
m 1H; 8.25ppm d 1H 
8.3ppm m 1H; 9.1 ppm d 
1H; 9.5ppm d 1H; 5.5-7 
1H exchangeable; 
9.5-10.5ppm 1H 
exchangeable 
8 
##STR43## 
##STR44## 
H .sup.1 H NMR 
(DMSO-d.sub.6) s 
2.9ppm m 2H; 3.4-3.75 
ppm m 2H; 4.0-4.2ppm m 
2H; 6.8ppm m 1H; 7.9 
ppm m 1H; 8.05ppm m 
1H; 8.25ppm d 1H; 8.3 
ppm m 1H; 9.1ppm d 1H; 
9.5ppm d 1H; 5.5- 7 1H 
exchangeable; 9.5- 
10.5ppm 1H 
exchangeable 
9 
##STR45## 
##STR46## 
CH.sub.3 .sup.1 H NMR 
(DMSO-d.sub.6) s 
2.10ppm m 2H; 2.25ppm 
2H; 2.85ppm s 3H; 
3.20ppm m 2H; 3.30ppm 
1H; 3.60ppm m 2H; 
7.95ppm m 1H; 8.10ppm 
m 1H; 8.25ppm d 1H; 
8.35ppm d 1H; 9.00ppm 
d 1H; 9.30ppm d 1H; 
1.7-4ppm 1H ex- 
changeable; 9-10.2ppm 
1H exchangeable 
10 
##STR47## 
##STR48## 
H .sup.1 H NMR 
(DMSO-d.sub.6) s 
2.05ppm m 2H; 2.25ppm 
m 2H; 3.15ppm m 2H; 
3.35ppm m 1H; 3.50ppm 
m 2H; 7.95ppm m 1H; 
8.10ppm m 1H; 8.25ppm 
d 1H; 8.35ppm d 1H; 
9.15ppm d 1H; 9.30ppm 
d 1H; 5.5-9ppm 2H 
exchangeable 
11 
##STR49## 
##STR50## 
CH.sub.2 CN .sup.1 H NMR (D.sub.2 
O) s 2.1- 2.4ppm m 2H; 
2.45ppm m 2H; 
3.35-3.6ppm m 1H; 
3.45ppm m 2H; 3.85 ppm 
m 2H; 4.55ppm s 2H; 
7.85-8.3ppm d+d+t+t 
1H+1H+1H+1H; 9.10 ppm 
d 1H; 9.15ppm d 1H 
12 
##STR51## 
##STR52## 
##STR53## .sup.1 H NMR 
(DMSO-d.sub.6) s 2.1- 
2.4ppm m 4H; 3.05-3.50 
pm m 5H; 3.6-3.9ppm m 
4H; 7.3ppm t 2H; 7.90 
ppm td 1H; 7.95-8.15 
ppm m 3H; 8.3ppm m 
2H; 8.85ppm d 1H; 9.1 
ppm 1H exchangeable; 
9.2ppm d 1H; 10.7-11.0 
pm 1H exchangeable 
13 
##STR54## CH.sub.2 
##STR55## 
##STR56## .sup.1 H NMR 
(CDCl.sub.3) b 1.55 
ppm m 1H; 2.0ppm m 2H; 
2.25ppm m 2H; 2.6- 
2.3ppm m 5H; 2.7 ppm t 
2H; 2.8ppm m 1H; 
3.7-3.5ppm 2d 2H; 3.8 
ppm s 3H; 5.85ppm t 
1H; 6.6ppm dd 1H; 
6.8ppm d 1H; 7.05ppm d 
1H; 7.4- 7.2m 5H 
14 
##STR57## CH 
##STR58## 
##STR59## .sup.1 H NMR 
(CDCl.sub.3) b 1.55ppm 
m 1H; 1.8ppm m 1H; 
2ppm m 1H; 2.6- 2.3ppm 
m+t+m 2H+2H+2H; 2.9ppm 
t 2H; 3.2ppm m 1H; 
3.7- 3.5ppm 2d 2H; 
3.8ppm s 3H; 5.95ppm 
dd 1H; 6.75 ppm dd 1H; 
6.95ppm d 1H; 7.15ppm 
d 1H; 7.4- 7.2ppm m 
5H 
15 
##STR60## 
##STR61## 
CH.sub.3 .sup.1 H NMR 
(CDCl.sub.3) b 1.6 ppm 
m 2H; 1.85ppm m 2H; 
2.1-2.2ppm m 4H; 
2.3ppm s 3H; 2.45ppm m 
H; 2.65ppm m 2H; 3.00 
ppm m 2H; 3.8ppm s 3H; 
.9ppm m 1H; 6.7ppm dd 
1H; 6.8ppm d 1H; 7.1 
ppm d 1H 
16 
##STR62## 
##STR63## 
CH.sub.3 .sup.1 H NMR 
(CDCl.sub.3) b 
1.8-2.1ppm m 4H; 2.2 
ppm m 2H; 2.4ppm s 3H; 
-3.3ppm m 3H; 3.95ppm 
s 3H; 7.15ppm dd 1H; 
7.2-7.45ppm m 3H; 7.9 
ppm d 1H; 7.8ppm d 1H 
17 
##STR64## 
##STR65## 
H .sup.1 H NMR 
(DMSO-d.sub.6) s 
1.8-2.1ppm m 4H; 3.1- 
3.5ppm m 4H; 3.5-3.8 
ppm m 1H; 3.9ppm s 3H; 
.2ppm dd 1H; 7.3 ppm m 
2H; 7.45ppm d 1H; 
7.75ppm m 1H; 7.85 ppm 
d 1H; 9-9.5ppm 2H 
exchangeable 
18 
##STR66## 
##STR67## 
##STR68## .sup.1 H NMR 
(DMSO-d.sub.6) s 
1.9-2.4ppm m 4H; 3.1- 
3.9ppm m 9H; 3.9ppm s 
3H; 7.1-7.4ppm 
m+t+d+dd 2H+1H+1H+1H; 
7.45 ppm d 1H; 7.7ppm 
m 1H; 7.85ppm d 1H; 
8.05 ppm dd 2H; 
9-10.7ppm 2H 
exchangeable 
19 
##STR69## 
##STR70## 
H .sup.1 H NMR 
(DMSO-d.sub.6) s 
1.7ppm m 2H; 2.3-2.6 
ppm t+t 2H+2H; 2.6 ppm 
t 2H; 2.75ppm t 2H; 
3.1ppm m 2H; 3.4ppm m 
2H; 3.75ppm s 3H; 6.65 
pm d 1H; 6.7ppm dd 1H; 
7.05ppm d 1H; 9.3 ppm 
1H exchangeable 
20 
##STR71## 
##STR72## 
CH.sub.2 CN .sup.1 H NMR 
(CDCl.sub.3) b 1.85ppm 
q 2H; 2.5ppm t 2H; 
2.5-2.7ppm m 8H; 
2.75ppm t 2H; 3.55ppm 
d 2H; 3.8ppm s 3H; 
6.7m 2H; 7.05ppm d 1H 
21 
##STR73## 
##STR74## 
##STR75## .sup.1 H NMR 
(CDCl.sub.3) b 1.2 ppm 
q 2H; 2.3-2.8 ppm m 
14H; 3.55ppm q 2H; 
3.8ppm s 3H; 6.75 ppm 
m 2H; 7.0-7.3ppm m 3H; 
7.85ppm dd 2H 
22 
##STR76## 
##STR77## 
##STR78## .sup.1 H NMR 
(CDCl.sub.3) b 
2.8-2.4ppm m 4H; 3.1 
ppm m 2H; 3.6ppm s 2H; 
.2ppm s 4H; 5.8ppm m 
1H; 6.75ppm m 3H; 7.3 
ppm m 5H 
23 
##STR79## 
##STR80## 
##STR81## .sup.1 H NMR 
(CDCl.sub.3) b 
2.7-3.8ppm m 6H; 3.8- 
4.25ppm m 4H; 4.25ppm 
m 4H; 5.8ppm m 1H; 
6.65-6.9ppm m 3H; 7.15 
pm t 2H; 8.2ppm dd 2H; 
9 and 12.2 ppm 2H 
exchangeable 
__________________________________________________________________________ 
PHARMACOLOGICAL STUDY 
EXAMPLE 34 
Evaluation of the Antihypertensive activity of the Compounds of the 
Invention 
Mongrel dogs (males and females) were anesthetized with phenobarbital (30 
mg/kg i.v.) and then placed under artificial respiration (Bird Mark VII 
respirator). The arterial pressure was measured using a catheter placed in 
the abdominal aorta via the femoral artery. This catheter is connected to 
a pressure cell (Statham.RTM. R.sub.23 D.sub.6) connected to a recorder. 
The heart rate was measured using a Gould Biotach.RTM.. 
The sympathetic nervous activity was recorded at the level of the renal 
nerve using a silver electrode. The amplified signal was displayed on an 
oscilloscope (Tektronix 5115.RTM.) and then measured in UV using a Gould 
integrator. The compounds to be examined were administered intravenously. 
The results of this study, indicated in Table II, have demonstrated that 
the compounds of the invention are more active than, or at least 
comparable with, the reference product flesinoaxan, in racemic form or in 
the form of an isomer (+). This isomer is the most active isomer of 
flesinoxan. 
TABLE II 
__________________________________________________________________________ 
EFFECT ON THE EFFECT ON THE 
ARTERIAL PRESSURE 
CARDIAC RHYTHM 
DOSES 
COMPOUNDS (mmHg) (B/min) .mu.g/kg 
__________________________________________________________________________ 
Flesinoxan (+) Isomer 
##STR82## 
##STR83## 10 30 100 
Flesinoxan racemic 
##STR84## 
##STR85## 10 30 100 300 
Compounds of the invention 
##STR86## 
##STR87## 3-10 10-30 30-100 
__________________________________________________________________________ 
With regard to the sympathetic nervous activity, the results obtained with 
the compound of Example 18 after i.v. administration of a dose of 30 
.mu.g/kg are given in FIG. 1. 
EXAMPLE 35 
Evaluation of the Affinity for 5-HT.sub.1A Receptors 
Hippocampus tissue obtained from decapitated Wistar rats was used for the 
studies. The animals were sacrificed 48 hours before the experiment and 
the isolated tissues were stored at -86.degree. C. For preparation of the 
membranes, the tissues were then homogenized using 20 volumes of a 50 mM 
Tris HCl buffer solution (pH =7.7, adjusted using NH.sub.4 Cl at 
25.degree. C.) for one volume of tissue, at a temperature close to 
0.degree. C., using a Polytron.RTM. homogenizer, and the whole was then 
centrifuged. (35,000 g.times.20 min at 4.degree. C.). The pellet thus 
obtained was suspended in 100 volumes of an incubation buffer solution. 
(60 mM Tris, 10 .mu.M pargyline, 4 mM CaCl.sub.2 and 0.1% (wt/v) ascorbic 
acid; pH adjusted to 7.7 with 5N HCl). The compounds to be examined were 
also diluted in the incubation buffer and the solutions were then prepared 
by adding 100 .mu.l of a solution of the compound to be examined and 100 
.mu.l of a solution of [3H] 8-OH-DPAT C =0.4 nM (specific radioactivity 
=205 Ci/mmol) to 12.times.75 mm glass tubes. The non-specific binding was 
determined using a 10 .mu.M 5-hydroxytryptamine solution and corresponds 
to 5-10% of the total binding. 
The tubes were incubated for 30 min at 37.degree. C. and the solutions were 
then filtered through GF/B glass fiber filters treated with 0.1% of 
polyethyleneimine (Whatman.RTM.). The filters were rinsed twice with 5 ml 
of the incubation buffer solution and were then placed in ampoules to 
which 4.5 ml of "Picofluor scintillation fluid".RTM. (Packard) had been 
added. The radioactivity was determined using external standards. 
The pKi were evaluated using the Cheung-Prusoff equation: 
EQU -log (IC.sub.50 /[1+[3H]8-OH-DPAT]/Kd). 
The compounds of the invention have a high affinity for the 5-HT.sub.1A 
sites. The pKi of the compounds of the invention are of the order of 9.02 
moles/liter. 
______________________________________ 
PHARMACEUTICAL PREATION 
EXAMPLE 36 
Capsules containing 1 mg of 1-[2-(4-fluorobenzamido)eth-1-yl]- 
4-(7-methoxynaphth-1-yl)piperidine hydrochloride [F.A.E.M.N.P] 
______________________________________ 
F.A.E.M.N.P. 1 mg 
Corn starch 15 mg 
Lactose 25 mg 
Talc 5 mg 
______________________________________