FR2674752A1 - Use of 4-amino-1-(2-pyridyl)piperidines for the preparation of medicaments for the treatment and prophylaxis of conditions resulting from a dysfunction of the serotoninergic system - Google Patents

Abstract

The invention relates to the use of 4-amino-1-(2-pyridyl)piperidines of general formula (I) in which R represents hydrogen, a halogen atom, a methyl, trifluoromethyl, (C1-C3) alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C1-C3) alkylthio or trifluoromethylthio group, or a phenoxy or phenylthio group optionally substituted with a halogen, a (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) alkylthio or cyano group, or one of their pharmaceutically acceptable salts, for the preparation of medicaments for the treatment and prophylaxis of conditions resulting from a dysfunction of the serotoninergic system in which a selective serotoninergic action via the 5-HT3 receptors is required.

Description

 The present invention relates to a new therapeutic use of certain 4-amino-1- (2-pyridyl) piperidines.

dans laquelle R peut représenter l'hydrogène, un atome d'halogène, un groupe méthyle, trifluorométhyle, (C1-C4) alcoxy, trifiuorométhoxy, 2, 2, 2-trifluoroéthoxy, (C1-C3 )alkylthio, trifiuorométhylthio, ou phénoxy ou phénylthio éventuellement substitués par un halogène, un groupe (C1-C3)alkyle, (Cl-C3)alcoxy, (C1-C3)alkylthio, ou cyano, et leurs sels pharmaceutiquement acceptables, ainsi qu'un procédé pour leur préparation.EP-B-0021973 describes the class of 4-aiiino-1- (2-pyridyl) piperidines of general formula (I)

in which R can represent hydrogen, a halogen atom, a methyl group, trifluoromethyl, (C1-C4) alkoxy, trifiuoromethoxy, 2, 2, 2-trifluoroethoxy, (C1-C3) alkylthio, trifiuoromethylthio, or phenoxy or phenylthio optionally substituted by a halogen, a group (C1-C3) alkyl, (Cl-C3) alkoxy, (C1-C3) alkylthio, or cyano, and their pharmaceutically acceptable salts, as well as a process for their preparation.

 The compounds of formula (I) were described there as anorectic agents essentially devoid of major side effects such as sedative or exciting activity, action inhibiting locomotor activity and undesirable cardiovascular effects.

 Among the products of formula (I), 4-amino-1- (6-chloro-2-pyridyl) piperidine hydrochloride, described in Example 1 of EP-B-0021913 and named CM 57227, was subjected to all the tests necessary for passage to the human clinic. Tested in humans at a dose of 10 mg, the product was well tolerated and showed good anorectic activity.

We have now found that the compounds of formula (I) where R has the
meaning given above, as well as their pharmaceutically acceptable salts, show a very interesting psychotropic activity, at doses much lower than those causing the appetite suppressing activity.

où R représente l'hydrogène, un atome d'halogène, un groupe méthyle, trifluorométhyle, (C1-C3)alcoxy, trifluorométhoxy, 2,2,2-trifluoroéthoxy, (C1-C3)alkythio, trifluorométhylthio, ou phénoxy ou phénylthio éventuellement substitués par un halogène, un groupe (C1,C3)alkyle, (C1
C3)alcoxy, (C1-C3)alkylthio, ou cyano, ou un de ses sels pharmaceutiquement acceptables, pour la préparation d'un médicament à activité psychotrope.A first object of the present invention is therefore the use of at least one compound of formula (I)

where R represents hydrogen, a halogen atom, a methyl, trifluoromethyl, (C1-C3) alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C1-C3) alkythio, trifluoromethylthio, or phenoxy or phenylthio group substituted by halogen, (C1, C3) alkyl, (C1
C3) alkoxy, (C1-C3) alkylthio, or cyano, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament with psychotropic activity.

 It has also been found, biochemically, that the compounds of formula (I) described as inhibitors of uptake (called "uptake" in English) of serotonin in EP-B-0021973, have an agonist activity selective towards S-HT3 receptors both at peripheral and central level.

 A second subject of the invention is therefore the use of at least one compound of formula (I) in which R is as defined above or one of its pharmaceutically acceptable salts, for the preparation of medicaments for the treatment and prophylaxis of all conditions resulting from a dysfunction of the serotonergic system and in which a selective serotonergic action via the 5-ffF3 receptors is reputed to have beneficial effects.

 In the text of this patent application, the term "halogen" identifies one of the four common halogens, fluorine, chlorine and bromine being particularly preferred.

 The terms "(C1-Cj) alkyl", "(C1-C3) alkoxy", and "(C1-C3) alkylthio" refer to groups containing the residue of a saturated aliphathic hydrocarbon containing 1, 2, or 3 atoms of carbon, namely methyl, ethyl, propyl, and isopropyl.

 The pharmaceutically acceptable salts of the compounds of formula (r) include the non-toxic salts derived from mineral or organic acids which salify one or both of the basic functions present in the molecules of the compounds of formula (r) above, such as the hydrochlorides , hydrobromides, sulfates, phosphates, succinates, tartrates, fumarates, maleates, pamoates, napsylates, mesylates, tosylates, etc.

 A preferred class of compounds of formula (I) includes compounds (r) where R is in the 6- position of the 2-pyridyl radical.

 An even more advantageous class comprises the compounds of formula (I) where R is hydrogen, a halogen atom, a methyl group or a (C-C3) alkoxy group in position 6.

 4-smino-1- (6-chloro-2-pyridyl) piperidine and its pharmaceutically acceptable salts, 4-amino-1- (6-bromo-2-pyridyl) -piperidine and its pharmaceutically acceptable salts, 4- smino- (6-methyl-2-pyridyl) piperidine and its pharmaceutically acceptable salts, and 4-amino - (6-methoxy-2-pyridyl) piperidine and its pharmaceutically acceptable salts are particularly preferred compounds.

dans laquelle R a la signification donnée ci-dessus et Hal représente un atome d'halogène, avec une 4-sminopipéridine bloquée de formule (III)

dans laquelle X représente un atome dthydrogène, ou un groupe (C1
C4)alkyle, et en hydrolysant ensuite la 4-amino-1-(2-pyridyl)pipéridine
N-acylée ainsi obtenue de formule (W)

dans des conditions acides ou basiques.These compounds are easily prepared according to the general method described in EP-B-0021913, by reacting the corresponding 2-halopyridine of formula (II)

in which R has the meaning given above and Hal represents a halogen atom, with a blocked 4-sminopiperidine of formula (III)

in which X represents a hydrogen atom, or a group (C1
C4) alkyl, and then hydrolyzing 4-amino-1- (2-pyridyl) piperidine
N-acylated thus obtained of formula (W)

under acidic or basic conditions.

 A more detailed description of the general method for preparing the compounds (I) as well as some specific examples are contained in the aforementioned European patent EP-B-0021973.

 The new psychotropic activity of the compounds of formula (I), was demonstrated by testing these compounds in conventional animal models usually used in pharmacology laboratories and considered as predictive, for example antidepressant, antipsychotic, antiaggressive, and / or anxiolytic properties in the man.

 In the "forced swimming test" we use, for example, rats forced to swim in a very limited place which then develop a characteristic immobile behavior; in this animal model, the reduction in immobility by products having antidepressant activity is evaluated; (R.D. PORSOLT et al., Nature, 1977, 226, 730-732).

 In another animal model, mice are used which are subjected to negative stimulation which causes the inhibition of a certain behavior in order to avoid the undesired situation; by administering substances endowed with psychotropic activity, this inhibition is prevented to a certain extent (J.R. BOISIER et al., European J. Pharmacol., 1968, 4, 145-151).

 The selective agonist activity of the 5-HT3 receptors has been demonstrated by administering the compounds of formula (I) intravenously in the anesthetized rat. This administration causes a fleeting decrease in the heart rate (Bezold-Jarish effect), the intensity of which varies according to the dose, comparable to that obtained by administering serotonin or methylserotonin.

 This effect is inhibited by selective 5-HT3 receptor antagonists (eg ICS 205930 and zacopride), while it is not inhibited by serotonin D receptor antagonists (eg methysergide).

More particularly, the Bezold-Jarish effect caused by the compounds of formula (I) was evaluated using Sprague rats
Dawley weighing between 200 and 300 g, anesthetized with a dose of 1.25 g / kg intraperitoneally of urethane. The blood pressure is recorded at the level of a carotid artery and the heart rate evaluated by the frequency of the pulsations using a cardiotachymeter.

A catheter is placed in the jugular vein for delivery of the substances.

 Different doses of the test compounds are administered intravenously in a volume of 0.5 Tnl / kg.

 The bradycardia caused by each dose is expressed as a percentage inhibition of the basal frequency. It is thus possible to calculate the Dol50, that is to say the dose which inhibits the heart rate by 50% in the animals treated.

 By way of example, in this test, 4-mino-1- (6-chloro-2-pyridyl) piperidine (the compound of formula (I) where R = 6-Cl) shows an LD50 lower than that of serotonin and that of 2-methylserotonin.

 On the basis of the properties thus discovered, the compounds of formula (I) are indicated for the treatment of certain pathologies relating to CNS disorders and in particular of the serotonergic system.

 In addition, the compounds of formula (I) are not very toxic, their toxicity being well compatible with use in therapy.

 For use as psychotropics, the compounds of formula (I) as well as their pharmaceutically acceptable salts, can be suitably administered by oral, parenteral, sublingual, rectal or transdermal route, prepared in the form of pharmaceutical compositions.

 The amount of active ingredient to be administered per day depends on the particularity of the therapeutic indication, the severity of the conditions to be treated, as well as the patient's weight and the route of administration.

 In any case, the overall dose in humans generally varies between 0.05 and 100 mg per day, for example from 0.1 to 50 mg, and more suitably from 0.5 to 20 mg per day.

 The pharmaceutical compositions for the use of the compounds of formula (I) as psychotropic agents contain at least one product chosen from the compounds of formula (I) and their pharmaceutically acceptable addition salts in association with a pharmaceutically inert vehicle.

 They can be prepared according to usual methods well known in the field of galenics.

 The active principle can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, aqueous vehicles or not, fatty substances of animal origin or vegetable, paraffinic derivatives, glycols, the various wetting agents, dispersants, or emulsifiers, preservatives, etc.

 For oral administration, which is in any case the preferred administration route, suitable pharmaceutical forms include tablets, delayed-release tablets, dragees, capsules, suspensions, solutions, or also liposomes.

 In the case of intravenous, subcutaneous or intramuscular administration, sterile or sterilizable solutions are used, while conventional suppositories, or capsules or microcysters can be produced for rectal administration.

 For transdermal administration, conventional patches prepared using techniques well known to those skilled in the art can be used.

 The unit dosage forms for the new therapeutic use will generally comprise from 0.05 to 20 mg, preferably combining from 0.1 to 10 mg, including for example the dosage from 0.5 to 5 mg (in particular 0.5 , 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 mg of product).

These unit doses are normally administered one or more times a day, preferably one to three times a day.

 If desired, the pharmaceutical compositions of the present invention may also contain one or more other known and commonly used drugs for the same therapeutic indications.

Claims (5)

1. Use of at least one compound of formula (I)

 where R represents hydrogen, a halogen atom, a methyl group, trifluoromethyl, (Cl-C3) alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (Cl-C3) alkythio, trifluoromethylthio, or phenoxy or phenylthio optionally substituted by a halogen, a group (Cl ~ C3) alkyl, (C1 C3) alkoxy, (C1-C3) alkylthio, or cyano, or a pharmaceutically acceptable salt thereof, for the preparation of medicaments for the treatment and prophylaxis of conditions resulting from a dysfunction of the serotonergic system in which a selective serotonergic action by 5-H13 receptors are requested. 2. Use according to claim 1 wherein R is in position 6- of the 2-pyridyle radical. 3. Use according to claim 2 wherein R represents a hydrogen atom, a halogen atom, a methyl group, or a group (C1 C3) alkoxy in position 6-. 4. Use according to claim 3 in which the compound of formula (I) is chosen from the group consisting of 4-amino-1- (6-chloro-2-pyridyl) piperidine, 4-amino-1- (6-bromo -2-pyridyl) piperidine, 4-amino-1- (6-methyl-2-pyridyl) piperidine, 4-amino- (6-methoxy-2-pyridyl) piperidine and their pharmaceutically acceptable salts. 5. Use according to claim 4 in which the compound of formula (I) is chosen from 4-amino-1- (6-chloro-2-pyridyl) piperidine and its pharmaceutically acceptable salts.