Phenyloxoalkyl piperidines and the pharmaceutical compositions containing them

This invention relates to novel piperidines substituted on the nitrogen atom with a (phenyloxo alkyl) group as well as the processes for their production.

SUMMARY 
The present invention provides the compounds of formula I 
##STR1## 
wherein X.sub.1 and X.sub.2 are substituents K is the residue of a free or 
blocked carbonyl function 
Y is selected from the group consisting of a radical ZR.sub.5 (wherein Z is 
oxygen or sulphur and R.sub.5 is a lower alkyl radical) and an amino group 
n and n' are integers ranging from 0 to 3 
The compounds of formula I and the salts thereof are useful as active 
ingredients of drugs. 
DETAILED EMBODIMENTS OF THE INVENTION 
This invention relates to novel piperidines substituted on the nitrogen 
atom with a phenyloxoalkyl group, the piperidine ring of which further 
bears an alkylguanidine or alkylisourea group. 
Specifically this invention relates to phenyloxoalkyl piperidines of 
formula I 
##STR2## 
wherein X.sub.1 and X.sub.2 the same or different, are hydrogen, a lower 
alkyl radical, a lower alkoxy radical, a halogen, or a trifluoromethyl 
radical or X.sub.1 and X.sub.2 together are an alkylene dioxy group. 
K is the oxygen of a carbonyl function or a group 
##STR3## 
(wherein R.sub.1 and R.sub.2 are lower alkyl radicals or form together a 
lower alkylene chain). 
Y is a radical selected from the group consisting of a radical ZR.sub.5 
(wherein Z is oxygen or sulphur and R.sub.5 is a lower alkyl radical) and 
a radical 
##STR4## 
(wherein R.sub.3 is a lower alkyl, a lower alkenyl, a lower cycloalkyl, or 
a heterocyclanyl radical having 5, 6 or 7 links 
R.sub.4 is hydrogen, a lower alkyl radical or the acyl residue of an 
organic carboxylic acid, 
or R.sub.3 and R.sub.4 together are the alkylene chain of a nitrogenous 
heteroring which may include another hetero atom) 
n is equal to 1, 2 or 3 
and n' is equal to 0 or 1. 
Moreover when Y is an aminogroup of the formula 
##STR5## 
the formula I merely shows one of the optional structures of the 
cyanoguanidines. In acidic medium any of the nitrogen atoms of the 
guanidine group may be protonated. Therefore the compounds according to 
this invention may exist under the two tautomeric forms iminocyanoamine 
and (aminocyano)imine. 
The cyano group may further be located on one or on the other side of the 
plane determined by the double bond --C.dbd.N--. It may exist as an isomer 
of the syn or anti type. 
The tautomeric forms and the isomeric forms are part of this invention. 
This invention also provides the acid addition salts of the compounds of 
formula I with a mineral or organic acid, preferably a 
therapeutically-compatible acid. 
This invention also provides the optically-active isomers of the compounds 
of formula I as well as the diastereoisomers of the compounds of formula 
I. 
Among the acid addition salts of the compounds of formula I may more 
particularly cite the hydrochlorides, the hydrobromides, the sulphates, 
nitrates, phosphates, thiosulphates, formates, acetates, maleates, 
fumarates, benzoates, dichloro 2,6-benzoates, citrates, tartarates, 
(methoxy salicylates), 3,4,5-trimethoxy benzoates, vanillates, the 
O-carbethoxy syringates, the naphthoates, the benzene sulphonates, the 
methane sulphonates, the isothionates, the nicotinates, the isonicotinates 
and the glucose-phosphates. 
When R.sub.3 and R.sub.4 together are the alkylene chain of a nitrogenous 
heteroring, they form with the nitrogen atom to which they are bound, a 
pyrrolidinyl radical, a piperidinyl, a hexamethylene imino, a 
heptamethylene imino or when they include an extra heteroatom, a 
morpholino radical, a tetrahydrothiazinyl, a hexahydropyrimidinyl, a 
hexahydropyrazinyl, a pyrazolidinyl or an imidazolidinyl radical. 
As far as the invention is concerned, a lower alkyl radical is a 
hydrocarbon radical having from 1 to 6 carbon atoms in a straight or 
branched chain, as for example methyl, ethyl, isopropyl, sec butyl, tert 
butyl, pentyl, neo pentyl, and n-hexyl. 
A lower alkoxy radical has from 1 to 6 carbon atom in the alkyl moiety 
which may be straight or branched as for example a methoxy, ethoxy, 
isopropoxy, tert butoxy or pentyloxy. 
An acyl radical derives from an organic carboxylic acid having from 1 to 12 
carbon atoms as for example an alkyl carboxylic acid, an aryl 
alkylcarboxylic acid, a cycloalkyl carboxylic acid, an arylcarboxylic 
acid, and a hetero aryl carboxylic acid. In this respect may be 
specifically cited an acetyl residue, a butyryl residue, a benzoyl 
residue, a 3,4,5-trimethoxy benzoyl residue, a cyclopropylcarbonyl residue 
or a nicotinoyl residue. 
The meanings given to the parameters n and n' play an important role in the 
pharmacological properties of the compounds of formula I. The intensity or 
the duration of action of the compounds according to this invention may be 
modulated by modifying the length of the alkyl chain in one or the other 
part of the molecule. 
Among the compounds of formula I, the following 4 sub-groups may be more 
precisely differentiated which are presently the preferred ones 
(1) The N-cyano N'-(alkyl guanidinyl)piperidines of formula I.sub.A 
##STR6## 
wherein the substituents X.sub.1, X.sub.2, R.sub.3, R.sub.4, n and n' 
have the above-given definitions. 
(2) The N-cyano isoureas and isothioureas of the formula I.sub.B 
##STR7## 
wherein X.sub.1, X.sub.2, R.sub.5, n and n' have the above-given 
definitions. 
and Z is an oxygen or a sulphur atom. 
(3) The ketals of N-cyano ZR.sub.5 -isoureyl piperidines of the formula 
I.sub.C 
##STR8## 
wherein R.sub.1 and R.sub.2 are a lower alkyl radical or together form a 
lower alkylene chain 
and the substituents X.sub.1, X.sub.2, Z, R.sub.5, n and n' have the 
above-given meanings. 
(4) The ketals of cyanoguanidinyl piperidines of the formula I.sub.D 
##STR9## 
wherein the substituents X.sub.1, X.sub.2, R.sub.1, R.sub.2, R.sub.3, 
R.sub.4, n and n' have the above-given definition. 
Among the compounds according to this invention it may be specifically 
cited: 
1-[4-p.fluorophenyl 4-oxobutyl-1)]4-[(N-cyano N'-methyl 
guanidinyl)methyl]piperidine 
1-[4-p.fluorophenyl 4-oxobutyl-1)]4-[(N-cyano N'-allyl 
guanidinyl)methyl]piperidine 
1-[4-p.fluorophenyl 4-oxobutyl-1)]4-[(N-cyano N'cyclopropyl 
guanidinyl)methyl]piperidine 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano N-allyl 
guanidinyl)methyl]piperidine 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methylisothioureido)methyl]piperidine 
The compounds according to this invention are endowed with interesting 
pharmacological properties, namely with antihypertensive and vasodilating 
actions connected with a sedative action on the Central Nervous System. 
Due to their high level of efficiency, the compounds of formula I or the 
acid addition salts thereof have use in human or animal therapy as active 
ingredients of medicines intended to counteract or to decrease the noxious 
effects of the hypertensive condition or to improve conditions in 
peripheric or cerebral vascular diseases. 
For these purposes they are utilized in the form of pharmaceutical 
compositions designed for the administration by parenteral, oral, rectal 
or sublingual ways. 
These pharmaceutical compositions include as active ingredient at least one 
compound of formula I or an acid addition salt thereof, in adjunction or 
admixture with an inert pharmaceutically-acceptable carrier or vehicle. 
As preferred means of administration there may be cited uncoated or coated 
tablets, capsules, soft gelatine capsules, multi-cores tablets, drops, 
drinkable suspensions or solutions, injectable suspensions or solutions 
packed in ampules, multidoses, flasks or in autoinjectable syringes, 
suppositories, sublingual tablets. 
The pharmaceutical compositions according to this invention may also 
include one or several active ingredients having a similar, a 
complementary or synergistic action. In this regard there may be added a 
diuretic agent of thiazidic structure or of triaminopteridine structure or 
a beta-blocking agent such as propranolol, pindolol or atenolol. 
The daily dose may vary within a broad range with respect to the 
therapeutic use, the way of administration, the weight of the patient and 
the duration of the hypertensive condition. Usually in the adult the 
dosology ranges from 0.1 to 50 mg per unit dosage and from 0.1 to 150 mg 
per day. 
In a preferred manner the pharmaceutical compositions, according to this 
invention include from 0.1 mg to 20 mg of active ingredient per unit 
dosage. 
This invention also extends to a process for producing the compounds of 
formula I characterized in that an 4-aminopiperidine of formula II 
##STR10## 
wherein the substituents X.sub.1, X.sub.2, n and n' have the 
previously-given definitions 
R.sub.1 and R.sub.2 are a lower alkyl radical or together are a lower 
alkylene chain, 
are reacted with a cyanoiminating reagent selected from the group 
consisting of 
alkyl cyanoimino isodithiocarbonates of the formula III 
##STR11## 
wherein R.sub.5 and R.sub.6 are a lower alkyl radical and alkyl mixed 
cyanoimino isothiocarbonates of the formula IV 
##STR12## 
wherein R.sub.5 and R.sub.6 have the previously given definitions to 
produce an isothiourea or an isourea of the formula I.sub.C 
##STR13## 
wherein the substituents X.sub.1, X.sub.2, R.sub.1, R.sub.5, n and n' have 
the above given meanings 
and Z is an oxygen or a sulphur atom which may--when desired--be condensed 
with a primary or secondary amine of the formula 
EQU R.sub.3 --NH--R.sub.4 
to obtain the cyanoguanidine of formula I.sub.D 
##STR14## 
wherein the substituents X.sub.1, X.sub.2, R.sub.1, R.sub.2, R.sub.3, 
R.sub.5, n and n' are defined as previously 
and R.sub.4 is a hydrogen or a lower alkyl radical 
or R.sub.3 and R.sub.4 together are the alkylene chain of a nitrogenous 
heteroring 
which may further be hydrolysed in acidic medium to produce the free 
carbonyl derivative of formula I.sub.A 
##STR15## 
in which X.sub.1, X.sub.2, R.sub.3, R.sub.4, n and n' have the previously 
given definitions 
which may, when R.sub.4 is a hydrogen, be acylated by means of a functional 
derivative of a carboxylic acid to produce a N'-acyl N-cyanoguanidine of 
the formula I.sub.A 
##STR16## 
wherein R.sub.3, n and n' have the above-given definitions and R.sub.4 is 
the acyl residue of a carboxylic acid having from 1 to 12 carbon atoms 
or be resolved by means of an optically-active organic acid into its 
optically-active isomers 
or be salified by adding a mineral or organic acid. 
The starting 4-amino piperidines of formula II may be obtained when n' is 
zero according to a process which comprises condensing a reactive ester of 
a phenyl oxo alkyl of formula V 
##STR17## 
wherein X.sub.1, X.sub.2, R.sub.1, R.sub.2 and n have the previously-given 
definitions 
and Z.sub.1 is an easily-split ester 
with a blocked piperidine of the formula VI 
##STR18## 
wherein R.sub.6 and R.sub.7, the same or different, are a lower alkyl 
radical or together form an alkylene chain of 2 to 4 carbon atoms 
to produce a blocked phenyl(oxo alkyl)piperidine, 
the ketonic function of which is selectively freed by functional exchange 
with an .alpha.-ketoacid to obtain a piperidine of formula VII 
##STR19## 
wherein the substituents X.sub.1, X.sub.2, R.sub.1, R.sub.2 and n have the 
same definitions as above, 
condensing the latter with hydroxylamine or a salt thereof to produce the 
corresponding oxime which is further reduced by means of a mixed hydride 
to the corresponding amino derivative. 
The starting 4-aminopiperidines of formula II may also be produced--when n' 
is equal to 1--using a process which comprises condensing a reactive ester 
of phenyl(oxo alkyl) of formula V, with 4-carboxamidopiperidine, reducing 
the (phenyl oxo alkyl)piperidine carboxamide by means of an alkali metal 
mixed hydride and recovering an alkyl piperidyl methylamine of formula III 
##STR20## 
wherein the definitions of the substituents X.sub.1, X.sub.2, R.sub.1, 
R.sub.2 and n remain unaltered. 
The reactive ester of phenyl oxo alkyl is preferably a chloride, a bromide, 
an iodide, a methane sulphonate or a p-toluene sulphonate. 
The condensation with piperidine or with carboxamido piperidine is 
performed in a polar medium preferably in the presence of an alkli metal 
iodide. The polar solvent usually is pyridine, dimethylformamide, methyl 
ethylketone or hexamethyl phosphortriamide. 
The alkali metal mixed hydride is a sodium or lithium aluminumhydride, 
sodium borohydride, potassium borohydride, lithium trimethoxy borohydride 
or lithium cyano borohydride. 
The hydrolysis of the blocked piperidine is performed by functional 
exchange with an .alpha.-keto acid such as pyruvic acid, tartronic acid, 
mesoxalic acid or .alpha.-ketoglutaric acid. The following examples merely 
illustrate the invention. They do not limit it in any manner.

EXAMPLE I 
1-[(4p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methyl)isothioureido methyl]piperidine 
STEP A 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]piperidine 4-carboxamide 
A mixture of 66 g piperidine 4-carboxamide, 130 g 4-p.fluorophenyl 
4,4-ethylenedioxy 1-chlorobutane, 75 g potassium carbonate and 1000 ml 
ethanol is heated to reflux for 18 hours under stirring. After separation, 
the filtrate is concentrated to dryness and the resulting paste is taken 
up with acetonitrile. 
The resulting crystals are extensively washed with water then dried under 
vaccuum. 82 g of the pure title compound are obtained as colourless 
crystals, pure enough to be used for the further steps of the synthesis 
without any other purification. It melts at 145.degree. C. 
STEP B 
1-[(4-p.-fluorophenyl 4-ethylenedioxy)butyl-1]4-aminomethyl piperidine 
25 g of lithium aluminohydride are suspended in 300 ml tetrahydrofuran and 
to this suspension a solution of 80 g of 1-[(4-p.fluorophenyl 
4-ethylenedioxy)butyl-1]piperidine 4-carboxamide in 600 ml tetrahydrofuran 
is added at room temperature. The whole mixture is then heated to reflux 
for one hour. 
After cooling to room temperature, the excess reagent is hydrolysed by 
cautious addition of water and the precipitated alumina is filtered on 
celite. The clear filtrate is concentrated to dryness. The residue is 
taken up in ether, dried on sodium sulphate and evaporated off. 
66 g of the desired amine are thus obtained as a viscous oil which is used 
as such for the next step of the synthesis. 
STEP C 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methylisothioureido)methyl]piperidine 
66 g of 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-aminomethyl 
piperidine and 29 g dimethyl cyanoimino dithiocarbonate are dissolved in 
500 ml ethanol and heated to reflux for 2,5 hours. The reaction medium is 
thereafter concentrated to dryness and the oily residue is taken up with 
isopropyl ether from which it crystallizes. 
After the crystals have been filtered, washed with isopropyl ether and 
dried, 78 g of the desired compound are recovered as colourless crystals 
melting at 124.degree. C. 
EXAMPLE II 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-methyl)guanidinyl methyl]piperidine 
A solution of 10 g 1-[(4-fluorophenyl 4-ethylenedioxy)butyl]4-[(N-cyano 
S-methyl isothioureido)methyl]piperidine in 100 ml methanol is prepared 
into which a stream of methylamine is bubbled while keeping the reaction 
temperature to about 25.degree.. 
After absorption of 25 g methylamine, the mixture is stirred at room 
temperature. 
The progress of the reaction is checked by TLC using as the eluting solvent 
a mixture of chloroform-isopropylamine (1:1). 
After 3 hours, the reaction is complete and the mixture is concentrated to 
dryness to yield a viscous paste which crystallizes on taking up in ether. 
The crystalline mixture is set aside for a night then the crystals are 
separated by filtration, rinsed with ether and dried under vacuum. 8.5 g 
of colourless crystals are thus obtained which may be recrystallized for 
analysis from ethyl acetate. They melt at 152.degree. C. 
EXAMPLE III 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4[(N-cyano N'-methyl)guanidinyl 
methyl]piperidine and its hydrochlorides 
A solution containing 3.5 g of 1-[(4-p.fluorophenyl 
4-ethylenedioxy)butyl-1]4-[(N-cyano N'-methyl)guanidinyl methyl]piperidine 
and 60 ml N-hydrochloric acid is utilized and set aside at room 
temperature. After about 30 mn the mixture begins to crystallize. The 
crystals are separated by filtration, washed with the minimal amount of 
water then with cyclohexane. 
After a further recrystallisation from acetonitrile 2.6 g of colourless 
crystals are obtained. 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'-methyl)guanidinyl 
methyl]piperidine hydrochloride crystallizes with a mole of water. It 
melts at 214.degree. C. 
It may be easily converted into the free base by dissolving it in water, 
alkalinization of the aqueous phase by adding thereto sodium carbonate and 
extraction with ether. The ethereous phase is separated, dried over 
magnesium sulphate, decoloured with charcoal, filtered and evaporated to 
dryness. 
1-[(4-p.fluorophenyl 4oxo)butyl-1]4-[(N-cyano N'-methyl)guanidinyl 
methyl]piperidine appears as an oily product. 
EXAMPLE IV 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano 
N'-propyl)guanidinylmethyl]piperidine 
STEP A 
A mixture of 5 g 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methyl isothioureido)methyl]piperidine, 20 ml piperidine and 40 ml 
n-propylamine is heated to reflux for 17 hours. 
After concentration to dryness and treatment with isopropyl ether, 4.7 g of 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-propyl)guanidinyl methyl]piperidine are recovered as colourless 
crystals melting at 85.degree.. 
STEP B 
The crystals of step A are promptly heated to reflux for 1 minute with 50 
ml N-hydrochloric acid and 50 ml ethanol. The mixture is thereafter 
quickly cooled. Ethanol is expelled, the mixture is cooled in a 
water-bath, the solution is made alkaline with sodium hydroxide and 
extracted with chloroform. An oily product is thus obtained which is taken 
up in isopropyl ether from which it crystallizes. 3.2 g of the desired 
product are obtained as colourless crystals melting at about 84.degree.. 
EXAMPLE V 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4[(N-cyano N'-allyl)guanidinyl 
methyl]piperidine 
STEP A 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-allyl)guanidinyl methyl]piperidine 
A mixture of 5 g 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methylisothioureido)methyl]piperidine, 10 g pyridine and 30 g allylamine 
are heated to reflux for 3 h 30 mn. After concentration an oil is 
recovered which crystallizes by scratching with isopropyl ether. 
After filtration of the ethereous solution, the crystals are washed then 
dried. 4.7 g of the ethylene ketal are obtained as colourless crystals 
melting at 85.degree.. 
STEP B 
5 g of 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-allyl)guanidinyl methyl]piperidine are dissolved in the cold in 250 ml 
of a N-solution of hydrochloric acid. The solution is kept for 17 hours at 
room temperature. One thereafter treats the reaction mixture with sodium 
hydroxide until basic and the aqueous solution is extracted with 
chloroform. The chloroformic solutions are washed with water and 
concentrated. An oily product is obtained which crystallizes from 
isopropyl ether, giving 2.5 g of colourless crystals melting at 90.degree. 
C. 
EXAMPLE VI 
1[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'-cyclopropyl)guanidinyl 
methyl]piperidine 
STEP A 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-cyclopropyl)guanidinyl methyl]piperidine 
A mixture of 6 g 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methylisothioureido)methyl]piperidine, 10 ml pyridine and 20 ml 
cyclopropylamine is prepared, concentrated to dryness and taken up with 
isopropyl ether which gives rise to crystals which are filtered, washed 
with isopropyl ether and dried. Melting point=120.degree. C. 
STEP B 
The selective hydrolysis of the ketal is performed by dissolving it in 150 
ml N-solution of hydrochloric acid and 50 ml water. The mixture is kept 
for 17 hours at room temperature. After having made the medium basic and 
extracted it with ethyl acetate, 3.5 g of the desired 1-[(4-p.fluorophenyl 
4-oxo)butyl-1]4-[(N-cyano N'-cyclopropyl)guanidinyl methyl]piperidine are 
obtained which may be recrystallized from acetonitrile. It melts at 
153.degree.-154.degree. C. 
EXAMPLE VII 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'-morpholino 
guanidinyl)methyl]piperidine 
STEP A 
1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano N'-morpholino 
guanidinyl)methyl]piperidine 
A mixture is made with 6 g 1-[(4-p.fluorophenyl 
4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methylisothioureido)methyl]piperidine, 5 ml dimethylformamide and 30 ml 
morpholine and is heated to 100.degree. for 4 hours. After this, the 
reaction mixture is allowed to cool to normal temperature. The excess 
reagent and solvent are distilled off under reduced pressure. The oily 
residue is taken up in 25 ml isopropyl ether and crystallisation is 
initiated by scratching. After a night in a cool place the crystals are 
separated by filtration, washed with isopropyl ether and dried. 
3.75 g of the (N-cyano N'morpholino guanidine) are thus obtained which melt 
at 107.degree.. 
STEP B 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'-morpholino 
guanidinyl)methyl]piperidine 
3 g of 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-morpholino guanidinyl)methyl]piperidine are dissolved in 100 ml water 
and 0.95 g oxalic acid. The mixture is kept for 12 hours at room 
temperature. 1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'morpholino 
guanidinyl)methyl]piperidine precipitates as the oxalic acid addition 
salt. It is separated by filtration, washed with cool water and dried 
under vacuum. It melts at about 225.degree.-227.degree. C. 
The oxalate is converted to the free base by redissolving it in dioxan, 
alkalizing the solution by adding sodium carbonate and extracting it with 
methylene chloride. The chloromethylenic solution is separated, washed 
with water, dried over sodium sulphate and evaporated to dryness. 
The oily residue is taken up in hot ethanol on cooling it crystallizes. 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano 
N'-morpholinoguanidinyl)methyl]piperidine appears as colourless crystals 
melting at 121.degree.-122.degree.. 
EXAMPLE VIII 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N-cyclohexyl 
guanidinyl)methyl]piperidine and its hydrochloride 
STEP A 
A mixture of 5 g 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
S-methyl isothioureido)methyl]piperidine, 10 g pyridine and 35 ml 
cyclohexylamine is heated to reflux for 6 hours. After having distilled 
off the excess of amine, an oily product is obtained which crystallizes by 
taking it up in few ml of isopropyl ether. 
The mixture is set aside for some hours then the crystals are separated by 
filtration. They are dried, rinsed with a small amount of water then of 
isopropyl ether and finally they are dried under vacuum. 2.85 g of 
1-[(4-fluoro phenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano N'-cyclohexyl 
guanidinyl)methyl]piperidine are thus recovered which are crystallized 
from hot methanol on cooling. The pure compound melts at 
131.degree.-132.degree. C. 
STEP B 
1-[(4-p.fluorophenyl 4-oxo)butyl-1]4-[(N-cyano N'-cyclohexyl 
guanidinyl)methyl]piperidine 
2.4 g 1-[(4-p.fluorophenyl 4-ethylenedioxy)butyl-1]4-[(N-cyano 
N'-cyclohexyl guanidinyl)methyl]piperidine are dissolved in 100 ml water 
and 15 ml acetic acid. The whole mixture is kept at room temperature for 
12 hours, it is then neutralized and extracted with methylene chloride. 
The methylenic phases are separated, washed with water then dried on 
sodium sulphate and evaporated to dryness. 
The dry residue is taken up in hot ethyl acetate and on cooling it 
crystallizes. After drying 1.65 g of 1-[(4-p.fluorophenyl 
4-oxo)butyl-1]4-[(N-cyano N'-cyclohexyl guanidinyl)methyl]piperidine are 
recovered as colourless crystals melting at 145.degree.-146.degree.. 
EXAMPLE IX 
In a similar manner the following compounds have been prepared: 
(a) 1-(4-phenyl 4-oxo butyl-1)4-(N-cyano N'-allyl guanidinyl)piperidine 
which is solvated with one mol of water. MP=110.degree. 
The IR spectrum is in accordance with the structure. 
(b) 1-(4-p.fluorophenyl 4-oxobutyl-1)4-(N-cyano N'-allyl 
guanidinyl)piperidine which melts at 160.degree.. The IR spectrum is in 
accordance with the structure. 
(c) 1-(4-p.fluorophenyl 4-oxobutyl-1)4-(N-cyano N'-methyl 
guanidinyl)piperidine which melts at 215.degree. C. 
The IR spectrum is in accordance with the structure. 
EXAMPLE X 
Tablets containing 5 mg of 1-(4-p.fluorophenyl 4-oxo)butyl-1 4-(N-cyano 
N'-methyl guanidinyl)methyl piperidine 
______________________________________ 
Active ingedient 5 g 
Corn starch 47 g 50 
Lactose 40 g 
Calcium phosphate 35 g 
Ethyl cellulose 5 g 
Talc 10 g 
Magnesium stearate 7 g 50 
for 1000 tablets weighing in average 
.150 g 
______________________________________ 
EXAMPLE XI 
Pharmacological studies on the compounds according to the invention 
(a) Determination of the acute toxicity 
An approximate average lethal dose (LD50) has been determined after oral 
administration of the compounds according to the invention, at increasing 
doses, to batches of 10 female mice EOPS STRAIN (CESAL Breeding) using the 
method of D. E. J. Campbell and W. Richter (Acta Pharmacol and Toxicol 25 
(1967) 345). 
The animals were kept under survey for 5 days. The dead, if any, were 
counted. The average lethal doses range from 600 to 1780 mg/kg depending 
on the tested compounds. 
Search of a possible action on the Central Nervous System 
At high dosages (i.e. 60 mg/kg) the mice show a significant hypothermia, 
ptosis of the lids, a decrease of the motility and a decrease of the 
arousal response. 
Determination of an anti-hypertensive action 
This testing was carried out in batches of awakened male rats made 
hypertensive by ligation of the abdominal aorta. 
The compounds according to this invention were given orally at doses of 2 
mg, 5 mg and 10 mg/kg. They cause a clear and protracted decrease of the 
blood pressure. 
Moreover the said compounds cause a strong hypotension at a dose of 100 and 
500 .mu.g/kg when administered to normotensive rats or normotensive dogs 
previously anaesthetized, intravenously. 
Evidence of a vasodilating action 
The compounds according to the invention induce a peripheral vasodilating 
effect which can be evidenced in the rats namely in the hind limbs which 
show, at the same time, an increase of 3.degree. to 4.degree. C. of the 
cutaneous temperature. 
This effect appears, depending on the product, for doses ranging from 10 to 
20 mg/kg. 
This vasodilating effect is connected to a very marked inhibitory action on 
the diuresis.