CA1211441A - Preparation of novel substituted piperidinoguanidines, and pharmaceuticals enclosing said products - Google Patents

Abstract

. PROCESS FOR THE PREPARATION OF NOVEL SUBSTITUTED PIPERIDINOGUANIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM It relates to a process for the preparation of phenyloxoalkyl piperididoguanidines of general formula I. <IMG> in which X1, X2, R3 and R4 are substituents n is equal to 1, 2 or 3 and n 'is equal to 0 or 1 which consists in subjecting the cyan derivative corresponding to a hydrolysis. The invention also relates to the preparation of these compounds or of their salts as active principle of medicament in particular for the treatment of vascular diseases.

Description

The object of the invention is new piperidino-guanidin ~ s substituted ~ es, their process of preparation as well as the pharmaceutical compositions containing it.

The object of the invention is more particularly to new piperidinoguanidines substituted ~ es ~ azo ~ e imi ~ ique with a carboxamide radical.

Its specific purpose is a process of preparation of the (phenyl oxoalkyl) piperidinoguanidines of formula general I
, / ~~~~ ~~~~~ ~ N ~ CON. ~ 2 X1 ~ C (CH2) n_ N) ~ (CH2) n 'NH ~ C ~ N R3 ~ I) in which X1 and X2, identi ~ ues or di ~ férents, represent ~
hydrosene, an alkyl radical in ~ er, an alkoxy radiccl in ~ érieur, a h ~ logene or a trifluoromethyl radical au together form a dioxy alkylene residue, ). . .
R3 represents an alkyl radica1 in ~ & rleur, a lower alkenyl radical, a cycloolco radical ~ the lower or a ra ~ ical l1eterocyclanyl ayan-t 5, 6 or 7 chalnons.

~ 4 repreàence de l'h ~ drogan ~, ~ n radical alco ~ le Inner or the acyl residue of an orsanic carboxylic acid or R3 and R4 ~ together form the alkyl residue of a nitrogenous heterocycle that can make up another heteroatom.

n is 1, 2 or 3 and n 'is equal to O or 1 which consists of submitting a ketal of (4- ph ~ nvloxoalcoyl) pip ~ curtain of for ~ ule g ~ néralc It -`:? , ~
~ t ~

X ~ C ~ l2) n ~ (CH2) D, - N ~ l C \ ~ R2 (Il) in which the substituents Xl, X2, R3, RL ;, n and n 'have the meanings previously provided.
, Rl and R2 are lower alkyl radicals or form together a lower alkyl chain 3 the action of a strong acid in an aqueous medium to obtain.
carboxamidoguanidine of general formula I which we can if desired, when R is hydrogen, acylate by the action of a Dri ~ e functional carboxylic acid to form.A N'- acyl N-carboxamido-guanidine de. General formula I

Xl ~ C - (CH2 ~ n - N ~ N ~

in which Xl, X2, R3, n and n have the previous definitions and R4 ~ the acyl r0ste of a carboxylic acid having 1 3 12 carbon atoms or even split by the action of an organic acid optically active in its optical somers or else to salify by adding a mineral acid or organic.
,.

. .. -.
Lp ~

12 ~

...
In a preferred way, the strong acid is an acido minérQl and note ~ nent a hydrohalic acid - ~ omme liacide hydrochloric or hydrobromic - or sulfuric acid.

... . .
The react ~ on hydrolys ~ se ~ octu ~ of pr2férenco by heating and by ~ refluxing the reaction medium ~
lou ~; sometimes, lower reaction temperatures ~ esalcment possible, Only the 1Q reaction time is changed.

~ ette hydrolysis reaction simu1tan ~ e of the function c ~ t ~ l in ketone and nitrile function in carboxamide demand a short heating time and generally heating times ~ age between 1 minute and 60 minutes ~ are perfect.

It is however possible to ef ~ ectucr these two reactions in two): time. We can thus release the ketone anointing in a first time by exchange of function with a liquid ketonic or an aldellyd aide then hydrolyze then the ~ anointing ni ~ rile in carboxcJmide by the action of a strong ccide.

Liberation of the cotton function is not very co ~ mod ~ ment by aclion of glyoxyliquo acid or aci ~ e p ~ Jruvique.
.
The hydrolysc of the nitrile function is ~ .ec.ue by action of ~ 'acidc sulfuriquo or hydrochloric acid.

~ 2 ~

Salification of the compounds of formula general I is conveniently done by the action of a mineral acid or organic preferably th ~ rapeutically compatible in an aqueous, or ethanolic, or acetonic medium. The salts thus obtained are generally sufficient ~ soluble in water and in particular the hydrochlorides.

The sparingly soluble salts in water serve as means of identification or purification.

The splitting of the compounds of formula general I is carried out by salification b using an acid optically active, for example d-tartaric acid, di 0-benzoyltartric acid, di 0-toluyltartric acid, d-camphosulfonic acid, d-camphoric acid, acid abietic or pimaric acid. The split salts thus formed are then converted into an optically active base per action of a mineral or organic base.

The starting compounds of general formula II
are obtained by a process which consists in what we do react a 4-aminc-piperidine of general formula III

C ~ (CH2 ~ _ t ~ h2 ~ - N; ~ 2 (III3 X2 ~ 1 2 in which the substituents X19 X2, R ~, R2, n and n 'have the meanings provided previously.
with a r ~ actiF of cyano imination chosen from the group consisting of cyanoimino isodithiocarbonates of alkyl of general formula IV
R5 5> C _ N - CN (~ V) i ~ 6 S
in which Rs and Rs are lower alkyl radicals and the mixed cyanoimino isothiocarbonates of alkyl of formula general V
R5 s > ~ _ N _ CN ~ V) ., ... /

`" ~ z ~

in which Rs ~ and R6 represent lower alkyl radicals to form an isothiourea or an isourea of general formula VI

Xl ~ C ~ N _ CN (VI) X2 ~ 1 R2 ~ ~ C ~) r_NH _C

in which Xl, X2, Rl, R2, Rs ~ ~, n and n 'are defined like before that we react with a primary or secondary amine of formula HN ~ 3 in which R3 has the previous meanings and R4 represents hydrogen, an alkyl radical lower, a lower alkenyl radical or a radical lower arylalkyl to form a cyanoguanidine of general formula II
: / ~~~ \ ~ N .CN
X1 y C _ (CH2) - ~ (CH2), _ NHL ~ C ~ SN ~ R3 tII ~
X ~ R1 R2 in which Xl, X2, Rl, R2, R3, n and n are defined as previously ~ and R4 is hydrogen, a lower alkyl rzste, a radical : lower alkenyl or a lower arylalkyl radical.

The following examples illustrate the invention without however limiting it.
: Example I
1- ~ (4- p. FluoroDhenyl 4-oxo) -1 butyll 4 - [(N-carboxamido N'-methyl) quanidinvlm ~ thyll piperidine and _n fumarate /.

~ ' ~ Z'l ~

9.5 hours are brought to the boil of [(4 fluoroph ~ nyl 4- ethylenedioxy) -1 butyl] -l [(N- cyano N'- methyl) guanidinylm ~ thyl] -4 piperidine and 100 ml of hydrochloric acid in normal solution.

ûn cools, makes alkaline by soda, extract with ethyl acetate, concentrate and concentrate for 3 sec.
organic solution.

3.3 grams of a viscous product are obtained semi-solid which is transformed into crystallized fumarate by adding a solution of 1.1 grams of fumaric acid in ethanol. The fumarate quickly precipitates. We separate it by filtration and spinning. 3.4 grams of crystals Fi = 220.

1- (p.fluorophenyl 4-oxobutyl-1) fumarate 4 - [(N-carboxamido N '- methyl) guanidinyl methyl] piperidine is soluble in water but sparingly soluble in solvents organic.

Example II
1 - [(4- p. Fluorophenyl 4-oxo) - lbutyll 4 [(N- carboxamido N'- cYclopropyl) quanidinylmethyll piperidine and its fumarate We wear a suspension of 5 grams of 1 - [(4- p.fluorophenyl 4- ethylenedioxy) - 1 butyl]
4 [(N- cyano N'-cyclopropyl) guanidinyl methyl] pip ~ ridine

2 minutes at boiling point with 100 ml of an acid solution ~ normal hydrochloric.

After cooling, it is made alkaline with soda and exhausts the aqueous solution with chloroform.
After dry evaporation of the solvent, 3.7 grams are obtained of a thick oil which is transformed into fumarate by boil 5 minutes with a solution of 1 gram of acid fumaric in 50 ml of ethanol.
r ................................................. .... ......

~ z ~

3.5 grams of the fumarate sought are obtained in the form of white crystals of Fi = 19u.

Example III
1- ~ (4- p. Fluorophenyl 4-oxo) - 1 butyll 4- ~ N-carbDxamido N '- allyl) quanidinylmethyll - piperidine and its fumarate 6 grams of 1 - [(4- p.fluorophenyl 4,4-ethylenedioxy) butyl] 4 {(N- cyano N'-allyl) guanidinylmethyl]
piperidine are dissolved in 300 ml of sulfuric acid normal.

After a week's rest ~ temperature ambient, the solution is made alkaline by addition of soda and extracted with chloroform. The chloroform phases are separated, washed with acid water and then with water, dried and dry concentrated. 5.7 9 are obtained from an oily product which it is converted to fumarate using 1.6 grams of acid fumaric in ethanol.

The crystals formed are separated by filtration9 washed and dried. nn gets 6.1 9 fumarate of the sought product, which crystallizes with half a molecule of water Fi = 190-19Z.

Example IV
1- ~ (4- p.fluorophenyl 4- oxo) butyl - 1 ~ 4- ~ (N-carboxamido N-cvclohexyl) quanidinylmethYll-eieeridine - Stage A
1 - [(4- p. Fluorophenyl 4-oxo) butyl - 1] 4- ~ (N-cyano N '- cyclohexyl) quanidinylmethyll pieéri_ine 5 grams del - [(4- p.
fluorophenyl 4,4-ethylenedioxy) butyl] 4 - [(N-cyano S- methyl-isothioureido) - methyl] piperidine, 20 ml of pyridine and 30 ml of cyclohexylamine. The reaction is followed by chromatography.
written in a thin layer and after 5 hours the reaction is total.
~:. . ./. . .

4 ~ l - The reaction medium is then concentrated for 3 sec and the oil obtained is treated with isopropyl ether. The solid formed is filtered, washed and dried ~ to dryness then recrystallized in acetonitrile.

3.6 9 of 1 - [(4- p.fluorophenyl 4,4-ethylenedioxy) butyl] 4 ~ (N-cyano N'-cyclohexyl) guanidinomethyl]
piperidine of PF = 131-132.
To hydrolyze the ketal, we put this product dissolved in 150 ml hydrochloric acid and 100 ml ethanol. After a few hours of rest at room temperature ambient, it deposits beautiful colorless crystals. Hydrochloride of the sought product thus formed is separated by filtration, washed and dried. 3 grams of product of Fi = 170 are collected.

The base is released by treatment with soda and extraction with ethyl acetate.

A viscous product is thus obtained which crystallizes on recovery with ac ~ tonitrile. The derivative cyclohexylated is separated by filtration, washed with acetonitrile and dried under vacuum.

We retrieve the sought product in this way in the form of white crystals melting at 145-146.

Stage B
1-¦ (4- p.fluorophenyl 4-oxo) but ~ l - 11 4- [N- carboxamido N'-cyclohexyl) _quanidinylmethyll piperidine and son_fumarate 25 ~ 2910 is suspended from 1 - [(4- p.fluorophenyl 4- oxo) butyl -1] 4 - [(N-cyano N '- cyclohexyl guanidinyl) methyl ~ piperidine in 50 ml of a normal acid solution hydrochloric.
/ - -The mixture is brought to reflux for 30 minutes, then let return to 3 ordinary temperature.

Add sodium hydroxide until reaction frankly alkaline in the middle. We then exhaust with methylene three times. The organic phases are brought together, they are washed with water, dried and filtered. We bring then dry by distillation under reduced pressure.

An oily residue weighing 1921 is thus recovered.
It is transformed into fumarate by recovery in the minimum hot ethanol and addition of 191 acid solution fumaric in 25 ml of ethanol. We begin crystallization by scraping and then leaves for 12 hours in a cold room.
The crystals are then separated by filtration, wrung out, rinse them with a few ml of ethanol then vacuum dry them.

The fumarate recovered is in the form colorless crystals melting at 136-137.

Example V
lL (4- p.fluorophenyl 4-oxo) butyl -11 4 - [(N-carboxamido N '- mo ~ eholyl) quanidinylmethyll pieeridine Stage A
_______ 1-¦ (4- e._fluorophenyl 4-oxo) butyll 4 - [(N- cyano N '_-morpholyl) guanidinylmethyl¦ piperidine It is brought to the boil for 16 hours, a mixture from 1 - [(4- p. fluorophenyl 4,4 - ethylenedioxy) butyl] -4 - [(N-cyano S- methylisothioureido) - methyl] piperidine and 100 ml of morpholine.

After concentration ~ dry, we obtain 9 grams of uncrystallizable oil, which are dissolved in 250 ml normal hydrochloric acid and this mixture is left to stand 17 hours at room temperature.
. / -'~

10.
`` lZ ~

After alkalinization of the medium by addition of soda then extraction with ~ acetate of the aqueous phase, we get after brought to dry, 4 grams of oil ~ which is purified by chromatography on silica H. (Mercken employing the CHCl 3 - isopropylamine mixture (9: 1) as eluent.

ûn obtains 3 grams of product in the form of oil which then crystallizes by taking up in isopropyl ether.
La 1 - [(4- p.fluorophenyl 4-oxo) butyl -1] 4 - [(N-cyano N'- morpholyl) guanidinylmethyl] piperidine occurs as form of colorless crystals melting at 121-122.

Stage B
1 - [(4- p.fluorophenyl 4-oxo) butyl] - 1] 4 [(N - carboxamido N '- morpholyl) guanidinylmethyl] piperidine.

294 of 1 - [(4- p.fluorophenyl 4-oxo) are dissolved butyl] 4- [(N- cyano N'- morpholyl) guanidinyl methyl]
piperidine obtained in stage A of the present example, in 35 ml of Dioxane and 15 ml of 5N hydrochloric acid are added thereto.
The mixture is brought to reflux of the solvent for 45 min. We then allow to cool to room temperature, frankly the reaction medium by progressive addition of sodium hydroxide solution, then the aqueous phase is exhausted methylene chloride. The methylene phases are combined, washed with water, dried and evaporated to dryness.

The viscous residue is taken up in ether isopropyl hot. By cooling the carboxamido-guanidine precipitates.

We separate the crystals which we wring, wash with isopropyl ether then dried under vacuum.

12 ~ L41 1905 carboxamido-guanidine is thus obtained in the form of colorless crystals melting at 105-106. The fumarate melts at 170.

Example VI
By operating in the same way from 1- (4 p.fluorophenyl 4,4 ~ thylenedioxy butyl-l) 4-amino piperidine we obtain:
- 1- (4-p.fluorophenyl 4-oxobutyl-1) 4- (N-carboxamido N'-allylguanidinyl) piperidine in the form of fumarate F = 186 (the infrared spectrum and micro-analysis conform to the advertised structure).
- 1- (4-p.fluorophenyl 4-oxobutyl-1) 4-(N-carboxamido N'-methyl guanidinyl) piperidine in the form of fumarate crystallized with a water molecule F = 195 approximately.
Microanalysis and the Infra-Red spectrum are consistent with the structure announced ~
From l- (l-phenyl 4,4-ethylenedioxy butyl-1) 4-aminopiperidine was prepared 1- (4-phenyl 4-oxobutyl-1) 4- (N-carboxamido N'-cyclopropylguanidinylj piperidine isolated as hydrochloride F = 210-211.

Example VII
Production of tablets containing 5 mg of active ingredient.

- 4-¦ (N-carboxamido N'-methyl) quanidinyl methyll piperidine 65, ~ _ ~
(corresponding to 50 9 basic) Wheat starch ..................... 625 9 Corn starch .................... 545 9 Micro-crystalline cellulose ....... 46 9 Carboxymethyl starch .............. 17 9 5 Methylcellulose ................... 4 9 5 Magnesium stearate ............. 22 9 5 Talc .............................. 22 9 5 per 10,000 finished tablets at an average weight of 09150 , ;; ~
, ",.... /.. -12.
1; 2 ~ L ~ L4 ~

Example VIII

E. pharmacological study ~ es compounds according to the invention, a) Da'termination de_la toxici.e ai ~ u ~ -Unc dose l ~ thale ~ oy ~ nnc (~ Lso) approached summer determined after oral administration of the compounds sclon the invention, in increasing doses to batches of 10 50uris fem ~ lles CE5AL elevaga EOPS, by the method of DEJ Campbell and W. Richter (ActG Pharmacol. And Toxicol ~ 25 (1967) 345).

The animals were kept under observation for ~
5 days. The dead when there are ~ are enumerated. The doses medium lethal are of the order of 1200 mg ~ kg ~

b) Finding an effect on At high doses (60 mg / kg) we find in Mouse hypo, hermia i ~ bearing, ptosis of the eyelids, ~ ne di ~ inution of motor skills and arousal reactions ~
c) nëtenmination of 1 anti-hypertensive effect The test was carried out on batches of male rats - vigils rendered hypert ~ ndus by li3ature of the abdominal aorta.
'.
The products, according to the invention, have been administered ~ o orally at doses of 2.5 or 10 mg / k ~. They make one net and prolonged pressure drop.

In addition, c ~ s same compounds entralnent in besides a very clear hypotension for doses of 100 and 500 ~ g / kg when ~ are administered; intravenously streaked, normotensive rats ~ or normotensive dogs unaesthetized.

d) Search for an effect. vascdilator The compounds according to the invention do not cause no peripheral vasodilate effect. We do not find in rat, particularly on the hind legs, none vasodilatat ~ on ni augmenta ~ ion of lq .empera.ure cutaneous, This ~ ffet does not appear even for doses up to ~
'10 mg / kg.

Claims (8)

The realizations of the invention on the subject of-what an exclusive property right or lien is claimed, are defined as follows:
l. A process for obtaining carboxamido-guanidines of general formula I:

(I) in which X1 and X2, identical or different, represent try hydrogen or halogen;
R3 represents a lower alkyl radical, a lower alkenyl radical or lower cycloalkyl radical;
R4 represents hydrogen or a radical lower alkyl where R3 and R4 together form a morpho- cycle line, - n is 1, 2 or 3 and n 'is 0 or 1 characterized in that a ketal of (4-phenyl-oxoalkyl) piperidine of general formula II:

(II) in which the substituents X1, X2, R3, R4, n and n 'have the meanings previously provided;
R1 and R2 are lower alkyl radicals or together form a dioxy alkylene chain to the action of a strong acid in aqueous media to obtain the carboxamido-guanidine of general formula I in which R4 represents hydrogen or a lower alkyl radical or forms with R3 a morpholine ring and the substituents X1, X2, R3, n and do not keep the previous meanings. 2. A method according to claim 1 in which is carried out the additional salification step by addition of a mineral or organic acid. 3. The (phenyloxoalkyl) piperidinoguanidines of general formula I:

in which X1 and X2, identical or different, represent hydrogen or halogen;
R3 represents a lower alkyl radical, a lower alkenyl radical or lower cycloalkyl radical;
R4, represents hydrogen or a radical lower alkyl where R3 and R4 together form a morpholine ring, n is 1, 2 or 3 and n 'is 0 or 1 each time they are obtained according to the process of the claim cation 1 or one of its obvious chemical equivalents. 4. The salts of (phenyloxoalkyl) piperidino-guanidines of general formula I:

in which X1 and X2, identical or different, represent smell of hydrogen or halogen;
R3 represents a lower alkyl radical, a lower alkenyl radical or a cycloalkyl radical inferior ;
R4 represents hydrogen or a radical lower alkyl where R3 and R4 together form a morpholine ring, n is 1, 2 or 3 and n 'is 0 or 1 each time they are obtained by the method of claim 2 or one of its obvious chemical equivalents. 5. A method according to claim 1 in which to prepare l- (p.fluorophenyl 4-oxobutyl-1) 4 - [(N-carboxamido N'-methyl) guanidinyl methyl] piperidine submit l- [1- (4-fluorophenyl 4-ethylenedioxy) butyl]
4 - [(N-cyano N'-methyl) guanidinyl methyl] piperidine in action of a strong aqueous acid when hot, then neutralizes the medium reaction by addition of a sodium hydroxide solution.
. 6. A method, according to claim 5, for obtain the fumarate of 1- (p.fluorophenyl 4-oxobutyl-1) 4 - [(N-carboxamido N'-methyl) guanidinyl methyl] piperidine, in which the 1- (p.fluorophenyl 4-oxobutyl-1) is reacted 4- [(N-carboxamido N-methyl) guanidinyl methyl] piperidine with fumaric acid in solution in a solvent organic. 7. 1- (p.fluorophenyl 4-oxobutyl-1) 4- [(N-carboxamido N'-methyl) guanidinyl methyl] piperidine, each once obtained by the process of claim 5 or one of its obvious chemical equivalents. 8. 1- (p.fluorophenyl 4-oxobutyl-1) fumarate 4- [(N-carboxamido N'-methyl) guanidinyl methyl] piperidine, each time it is obtained according to the process of the claim cation 6 or one of its obvious chemical equivalents.