FR2755013A1 - NOVEL THERAPEUTIC APPLICATION OF ANTAGONISTS OF SUBSTANCE P - Google Patents

Abstract

The invention concerns the use of active principles having an activity antagonist of the substance P, capable of passing through the hematoencephalic barrier, for preparing a medicine for the treatment of diskinesia linked with diseases of the central nervous system.

Description

NOVEL THERAPEUTIC APPLICATION OF ANTAGONISTS OF SUBSTANCE P
The present invention relates to the application of active ingredients endowed with a substance P antagonist activity and capable of passing the blood-brain barrier, for the preparation of a medicament for the treatment of dyskinesias.

Dyskinesias is a syndrome that causes impaired movement such as involuntary movements of limbs, tongue, pupils or neck [Baldessarini, The Pharmacological Basis of Therapeutics, 8th edition (1990), section 3 [Drugs and the
Treatment of Psychiatric Disorders], Chap 18, 383-435, Goodman and
Gilman's, Pergamon Press].

The causes of dyskinesias in humans are many and varied.

An example is dyskinesia due to the use of most neuroleptic drugs which shows neurological side effects which have been described in more detail by Baldessarini et al., Am. J. Psychiatry, 137, 1163-1172 (1980). ) and by Latimer, Can.

J. Psychiatry 40, 2suppl, 49S-54S (1995).

Among these side effects, tardive dyskinesia is a syndrome that appears after prolonged treatment, lasting several months or years, by neuroleptics and leading to impaired movement. These effects disappear by re-administration of the neuroleptic agent. There is currently no other form of treatment for these conditions
Substance P antagonists are described for their activity in many diseases, including CNS disorders, but it has never been demonstrated that these active substances may have an effect on the treatment of dyskinesias and nothing could let it be assumed.

It has now been found, and this is the subject of the present invention, that the substance P antagonists that cross the blood-brain barrier are capable of treating dyskinesias.

The present invention relates to the application of these products to the preparation of a medicament for the treatment of these conditions as well as compositions which contain these active principles.

Substance P-substance antagonists that cross the blood-brain barrier may be exemplified by products of the 1,2-diaminoethane or 2-acylamino-2-aminoethane derivatives class, which are receptor antagonists. nonpeptidyl tachykinins, of the class of perhydroisoindoles, of the class of 3-amino-quinuclidine-2-substituted, of the class of 2,3-disubstituted piperidines, of the class of 3-amino-2-substituted-piperidines, from the class of trisubstituted derivatives of morpholine, the class of substituted aromatic derivatives, the class of quaternary salts of substituted piperidines, or basic quaternary amides.

dans laquelle m est 0, 1, 2 ou 3 ; n est 0 ou 1 ; o est 0, 1 ou 2 ; p est 0 ou 1,
R est phényle, indolyle-2 ou -3 ou indolinyle-2 ou -3, benzothiényle, benzofuranyle ou naphtyle, éventuellement substitués par un ou deux atomes d'halogène ou radicaux alcoyloxy (1 à 3C), trifluorométhyle, alcoyle (1 à 4C), phénylalcoyloxy (1 à 3C) ou alcanoyle (1 à 4C)
R1 est trityle, phényle, diphénylméthyle, phénoxy, phénylthio, pipérazinyle, pipéridinyle, pyrrolidinyle, morpholinyle, indolinyle, indolyle, benzothiényle, hexaméthylèneiminyle, benzofuranyle, tétrahydropyridinyle, quinolyle, isoquinolyle, quinolyle saturé, isoquinolyle saturé, phénylalcoyle (1 à 4C), phénylalcoyloxy (1 à 4C), quinolylalcoyle (1 à 4C), isoquinolylalcoyle (1 à 4C), quinolylalcoyle saturé (1 à 4C), isoquinolylalcoyle saturé (1 à 4C), benzoylalcoyle (1 à 3C), alcoyle (1 à 4C) ou -NH-CH2-R5, les radicaux
R1 ci-dessus pouvant être substitués par un atome d'halogène ou un radical alcoyle (1 à 4C), alcoyloxy (1 à 4C), trifluorométhyle, amino, alcoylamino (1 à 4C), dialcoylamino (1 à 4C) ou alcanoylamino (2 à 4C), ou substitués par un radical phényle, pipérazinyle, cycloalcoyle (3 à 8C), benzyle, alcoyle (1 à 4C), pipéridinyle, pyridinyle, pyrimidinyle, alcanoylamino (2 à 6C), pyrrolidinyle, alcanoyle (2 à 6C) ou alcoyloxycarbonyle (alcoyle : 1 à 4C), pouvant être lui-même substitué par halogène, alcoyle (1 à 4C), alcoyloxy (1 à 4C), trifluorométhyle, amino, alcoylamino (1 à 4C), dialcoylamino (1 à 4C) ou alcanoylamino (2 à 4C) ; ou bien
R1 est amino, un groupe partant, un atome d'hydrogène, alcoylamino (1 à 4C) ou dialcoylamino (alcoyle : 1 à 4C)
R5 est pyridyle, anilinoalcoyle (1 à 3C) ou anilinocarbonyle
R2 est hydrogène, alcoyle (1 à 4C), alcoylesulfonyle (1 à 4C), carboxyalcoyle (alcoyle : 1 à 3C), alcoyloxycarbonyle alcoyle (alcoyle 1 à 3C) ou -CO-R6
R6 est hydrogène, alcoyle (1 à 4C), haloalcoyle (1 à 3C), phényle, alcoyloxy (1 à 3C), hydroxyalcoyle (1 à 3C), amino, alcoylamino (1 à 4C), dialcoylamino (1 à 4C) ou -(CH2) R7 ; q est 0 à 3
R7 est carboxy, alcoyloxycarbonyle (alcoyle : 1 à 4C), alcoylcarbonyloxy (alcoyle : 1 à 4C), amino, alcoylamino (1 à 4C), dialcoylamino (alcoyle : 1 à 4C), alcoyloxycarbonylamino (alcoyle : 1 à 6C) ou phénoxy, phénylthio, pipérazinyle, pipéridinyle, pyrrolidinyle, morpholinyle, indolinyle, indolyle, benzothiényle, benzofuranyle, quinolyle, isoquinolyle, quinolyle saturé, isoquinolyle saturé, phénylalcoyle (1 à 4C), quinolylalcoyle (1 à 4C), isoquinolylalcoyle (1 à 4C), quinolylalcoyle saturé (1 à 4C), isoquinolylalcoyle saturé (1 à 4C), benzoylalcoyle (1 à 3C) étant entendu que tous les R7 aryle ou hétérocyclyle pouvent être substitués par un atome d'halogène ou par un groupe trifluorométhyle, alcoyloxy (1 à 4C), alcoyle (1 à 4C), amino, alcoylamino (1 à 4C), dialcoylamino (1 à 4C) ou alcanoylamino (2 à 4C) et étant entendu que les groupes R7 pouvent être substitués par phényle, pipérazinyle, cycloalcoyle (3 à 8C), benzyle, pipéridinyle, pyridinyle, pyrimidinyle, pyrrolidinyle, alcanoyle (2 à 6C) ou alcoyloxycarbonyle (1 à 4C) pouvant être à leur tour substitués par halogène, trifluorométhyle, amino, alcoyloxy (1 à 4C), alcoyle (1 à 4C), alcoylamino (1 à 4C), dialcoylamino (alcoyle : 1 à 4C) ou alcanoylamino (2 à 4C)
R8 est hydrogène ou alcoyle (1 à 6C)
R3 est hydrogène, phényle, phénylalcoyle (1 à 6C), cycloalcoyle (3 à 8C), cycloalcényle (5 à 8C), alcoyle (1 à 8C), naphtyle ou alcoyle (2 à 8C) pouvant être substitués par un ou deux halogène, alcoyloxy (1 à 3C), alcoylthio (1 à 3C), nitro, trifluorométhyle ou alcoyle (1 à 3C) et
R4 est hydrogène ou alcoyle (1 à 3C) sous réserve que si R1 est hydrogène ou halogène, R3 est phényle, phénylalcoyle (1 à 6C), cycloalcoyle (3 à 8C), cycloalcoylène (5 à 8C) ou naphtyle. More particularly, the products of the 1,2-diaminoethane or 1-acylamino-2-aminoethane derivatives, non-peptide tachykinin receptor antagonists, of the general formula

wherein m is 0, 1, 2 or 3; n is 0 or 1; o is 0, 1 or 2; p is 0 or 1,
R is phenyl, indolyl-2 or -3 or indolinyl-2 or -3, benzothienyl, benzofuranyl or naphthyl, optionally substituted by one or two halogen atoms or alkoyloxy (1 to 3C), trifluoromethyl, alkyl (1 to 4C) ), phenylalkyloxy (1 to 3C) or alkanoyl (1 to 4C)
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolyl, isoquinolyl, saturated quinolyl, saturated isoquinolyl, phenylalkyl (1-4C), phenylalkoxy (1 to 4C), quinolylalkyl (1 to 4C), isoquinolylalkyl (1 to 4C), saturated quinolylalkyl (1 to 4C), saturated isoquinolylalkyl (1 to 4C), benzoylalkyl (1 to 3C), alkyl (1 to 4C) or -NH-CH2-R5, the radicals
R1 above may be substituted by a halogen atom or an alkyl radical (1 to 4C), alkyloxy (1 to 4C), trifluoromethyl, amino, alkylamino (1 to 4C), dialkylamino (1 to 4C) or alkanoylamino ( 2-4C), or substituted by phenyl, piperazinyl, cycloalkyl (3-8C), benzyl, (1-4C) alkyl, piperidinyl, pyridinyl, pyrimidinyl, (2-6C) alkanoylamino, pyrrolidinyl, alkanoyl (2-6C). ) or alkyloxycarbonyl (alkyl: 1 to 4C), which may itself be substituted by halogen, alkyl (1 to 4C), alkyloxy (1 to 4C), trifluoromethyl, amino, alkylamino (1 to 4C), dialkylamino (1 to 4C) ) or alkanoylamino (2 to 4C); or
R1 is amino, a leaving group, a hydrogen atom, alkylamino (1 to 4C) or dialkylamino (alkyl: 1 to 4C)
R5 is pyridyl, anilinoalkyl (1-3C) or anilinocarbonyl
R2 is hydrogen, (1-4C) alkyl, (1-4C) alkylsulfonyl, (C1-3C) alkyl (C1-3alkoxy) alkyl, (C1-3C) alkyloxycarbonyl or -CO-R6
R6 is hydrogen, (1-4C) alkyl, haloalkyl (1-3C), phenyl, (1-3C) alkyloxy, hydroxyalkyl (1-3C), amino, (1-4C) alkylamino, (1-4C) dialkylamino, or - (CH2) R7; q is 0 to 3
R7 is carboxy, alkyloxycarbonyl (1-4C alkyl), alkylcarbonyloxy (1-4C alkyl), amino, (1-4C) alkylamino, dialkylamino (1-4C alkyl), alkyloxycarbonylamino (1-6C alkyl) or phenoxy , phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, saturated quinolyl, saturated isoquinolyl, phenylalkyl (1 to 4C), quinolylalkyl (1 to 4C), isoquinolylalkyl (1 to 4C), saturated quinolylalkyl (1 to 4C), saturated isoquinolylalkyl (1 to 4C), benzoylalkyl (1 to 3C) with the proviso that all R7 aryl or heterocyclyl may be substituted with a halogen atom or with a trifluoromethyl, alkyloxy (1 to 4C), alkyl (1-4C), amino, alkylamino (1-4C), dialkylamino (1-4C) or alkanoylamino (2-4C) and it being understood that the R7 groups may be substituted by phenyl, piperazinyl, cycloalkyl (3 at 8C), benzyl, piperidinyl, pyridinyl pyrimidinyl, pyrrolidinyl, (2-6C) alkanoyl or (1-4C) alkyloxycarbonyl which in turn may be substituted by halogen, trifluoromethyl, amino, (1-4C) alkyloxy, (1-4C) alkyl, (1-4C) alkylamino. 4C), dialkylamino (alkyl: 1 to 4C) or alkanoylamino (2 to 4C)
R8 is hydrogen or alkyl (1-6C)
R 3 is hydrogen, phenyl, phenylalkyl (1 to 6C), cycloalkyl (3 to 8C), cycloalkenyl (5 to 8C), alkyl (1 to 8C), naphthyl or alkyl (2 to 8C) which may be substituted with one or two halogens. , alkyloxy (1 to 3C), alkylthio (1 to 3C), nitro, trifluoromethyl or alkyl (1 to 3C) and
R4 is hydrogen or (1-3C) alkyl with the proviso that if R1 is hydrogen or halogen, R3 is phenyl, phenylalkyl (1-6C), cycloalkyl (3-8C), cycloalkylene (5-8C) or naphthyl.

- le symbole R1 représente un radical phényle éventuellement substitué par un ou plusieurs atomes d'halogène ou radicaux hydroxy, alcoyle pouvant être éventuellement substitués (par des atomes d'halogène ou des radicaux amino, alcoylamino ou dialcoylamino) alcoyloxy ou alcoylthio pouvant être éventuellement substitués [par des radicaux hydroxy, amino, alcoylamino ou dialcoylamino éventuellement substitués (par des radicaux phényle, hydroxy ou amino), ou dialcoylamino dont les parties alcoyle forment avec l'atome d'azote auquel elles sont rattachées, un hétérocycle à 5 à 6 chaînons pouvant contenir un autre hétéroatome choisi parmi l'oxygène, le soufre ou l'azote, éventuellement substitué par un radical alcoyle, hydroxy, hydroxyalcoyle)], ou substitué par des radicaux amino, alcoylamino, dialcoylamino dont les parties alcoyle peuvent former avec l'atome d'azote auquel elles sont rattachées, un hétérocycle tel que défini ci-dessus, ou représente un radical cyclohexadiènyle, naphtyle ou hétérocyclyle mono ou polycyclique, saturé ou insaturé (5 à 9 atomes de carbone) et un ou plusieurs hétéroatomes choisis parmi l'oxygène, l'azote ou le soufre, et éventuellement substitué par un atome d'halogène ou par un radical alcoyle ou alcoyloxy, - le symbole R2 représente un atome d'hydrogène ou halogène ou un radical hydroxy, alcoyle, aminoalcoyle, alcoylaminoalcoyle, dialcoylaminoalcoyle, alcoyloxy, alcoylthio, acyloxy, carboxy, alcoyloxycarbonyle, dialcoylaminoalcoyloxycarbonyle, benzyloxycarbonyle, amino ou acylamino, - le bicycle

représente un cycle perhydroisoindole ou thiapyranopyrrole de formule générale

et le symbole X représente un atome d'oxygène ou de soufre ou un radical NR6 pour lequel R6 est un atome d'hydrogène, un radical alcoyle contenant 1 à 12 atomes de carbone et éventuellement substitué [par un ou plusieurs radicaux carboxy, dialcoylamino, acylamino, alcoyloxycarbonyle, alcoyloxycarbonylamino, carbamoyle, alcoylcarbamoyle, dialcoylcarbamoyle (les portions alcoyle de ces substituants pouvant être elles même substituées par dialcoylamino ou phényle) ou substitué par des radicaux phényle, phényle substitué (par halogène, alcoyle, alcoyloxy, ou dialcoylamino), naphtyle, thiènyle, furyle, pyridyle ou imidazolyle] ou un radical dialcoylamino, ou bien si le cycle est de formule (IIb) ou (IIc) le symbole X représente un atome d'oxygène, ou un radical NH, ou bien - le bicycle

représente un cycle perhydroisoindole ou thiapyranopyrrole de formule générale

et le symbole X représente un atome d'oxygène.By way of example, products of the class of perhydroisoindoles of general formula

the symbol R 1 represents a phenyl radical optionally substituted by one or more halogen atoms or hydroxyl, alkyl radicals which may be optionally substituted (with halogen atoms or amino, alkylamino or dialkylamino) alkyloxy or alkylthio radicals which may be optionally substituted; [by optionally substituted hydroxy, amino, alkylamino or dialkylamino radicals (with phenyl, hydroxy or amino radicals), or dialkylamino whose alkyl parts form, with the nitrogen atom to which they are attached, a 5- to 6-membered heterocycle; which may contain another heteroatom selected from oxygen, sulfur or nitrogen, optionally substituted by an alkyl, hydroxy, hydroxyalkyl) radical, or substituted by amino, alkylamino, dialkylamino radicals, the alkyl moieties of which may form with nitrogen atom to which they are attached, a heterocycle as defined above, or represents a radical mono or polycyclic cyclohexadienyl, naphthyl or heterocyclyl, saturated or unsaturated (5 to 9 carbon atoms) and one or more heteroatoms selected from oxygen, nitrogen or sulfur, and optionally substituted by a halogen atom or by a alkyl or alkyloxy radical, the symbol R2 represents a hydrogen or halogen atom or a hydroxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, alkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino radical; bicycle

represents a perhydroisoindole or thiapyranopyrrole ring of general formula

and the symbol X represents an oxygen or sulfur atom or an NR6 radical for which R6 is a hydrogen atom, an alkyl radical containing 1 to 12 carbon atoms and optionally substituted [with one or more carboxyl, dialkylamino radicals, acylamino, alkyloxycarbonyl, alkyloxycarbonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl (the alkyl portions of these substituents may themselves be substituted by dialkylamino or phenyl) or substituted by phenyl, substituted phenyl (by halogen, alkyl, alkyloxy, or dialkylamino), naphthyl , thienyl, furyl, pyridyl or imidazolyl] or a dialkylamino radical, or if the ring is of formula (IIb) or (IIc) the symbol X represents an oxygen atom, or an NH radical, or else - the bicycle

represents a perhydroisoindole or thiapyranopyrrole ring of general formula

and the symbol X represents an oxygen atom.

In general formulas (IIa) to (IIe) - the symbols R are identical and represent phenyl radicals optionally substituted by a halogen atom or by a methyl radical in position 2 or 3, - the symbols R "are identical and represent hydrogen atoms or together form a bond, - the symbol R3 represents a halogen atom or a hydroxyl radical and the symbol R4 represents a hydrogen atom or simultaneously with
R3 represents a halogen atom.

the symbol R'3 represents a phenyl radical optionally substituted in the -2-position by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the R'4 symbol represents a fluorine atom or a hydroxyl radical, and the symbol R5 represents a hydrogen atom or the symbols R'4 and R5 represent hydroxyl radicals, or the symbol R'4 forms with R5 a bond.

the symbol R "3 represents a hydrogen atom and the symbol R" 4 represents a fluorine atom or a hydroxyl radical, or the symbol R "3 represents a phenyl radical optionally substituted in the -2 position by an alkyl radical or alkyloxy (1 or 2 carbon atoms), and the symbol R "4 is hydroxy, or the symbols R" 3 and R "4 together form an oxo radical.

the symbol n is an integer from 0 to 2, it being understood that the products of general formula (IIa), (IIb) and (IIc) may have stereoisomeric forms which are described in more detail in European patent applications EP 429 366
EP 514 273 and EP 514 275; that the products of general formula (IId) are in the form (3aS, 4S, 7aS) or (3aRS, 4RS, 7aRS) or mixtures of these forms, if R4 is hydroxy or fluorine and R5 is hydrogen, or are in the form (3aS, 4S, 5S, 7aS) or (3aRS, 4RS, 5RS, 7aRS) or mixtures of these forms, if R4 and R5 are hydroxy, or are in the form (3aS, 7aR) or (3aRS , 7aSR) or mixtures of these forms, if R4 forms a bond with R5; and that the products of general formula (IIe) are in the form (3aS, 7R, 7aR), (3aR, 7S, 7aS) or (3aRS, 7SR, 7aSR), if R4 is hydroxy and
R 3 is a phenyl radical, or is in the form (3aR, 7S, 7aS), (3aS, 7R, 7aR) or (3aRS, 7SR, 7aSR) or mixtures thereof, if
R3 is hydrogen and R4 is hydroxy, or is in the form (3aR, 7R, 7aS), (3aS, 7S, 7aR) or (3aRS, 7RS, 7aSR) or mixtures thereof, if
R3 is hydrogen and R4 is fluorine, or are in the form (3aS, 7aR), (3aR, 7aS) or (3aRS, 7aSR) or mixtures thereof, if R3 together with R4 form an oxo radical.

sous ses formes (R) ou (S) sur la chaîne -CHR1R2, ou sous forme du mélange de plusieurs de ces formes.In the formula (IIf) - the symbol R3 represents a phenyl radical optionally substituted in the -2 position by an alkyl or alkyloxy radical containing 1 or 2 carbon atoms or by a fluorine atom, or disubstituted by trifluoromethyl radicals and - the symbols R5 and R'5 are the same or different and represent a hydrogen atom or a hydroxy or alkyl radical and the other a hydrogen atom or an alkyl radical, and - the R4 symbol represents a hydroxyl radical, or well - the symbol R4 represents a fluorine atom if the symbols R5 and
R'5 represents a hydrogen atom or an alkyl radical, or - the symbol R4 forms a bond with R5 and - the symbol R6 represents a hydrogen atom or an alkyl, hydroxy or hydroxyalkyl radical, and - the symbols R represent a hydrogen atom, an alkyl radical, a hydroxy or hydroxyalkyl radical and the other a hydrogen atom, an alkyl, phenyl or hydroxyalkyl radical, the alkyl and acyl radicals mentioned are straight or branched and contain 1 to 4C (except special mention), in racemic form, in the stereoisomeric forms of structure

in its forms (R) or (S) on the chain -CHR1R2, or in the form of a mixture of several of these forms.

sous leurs formes stéréoisomères ou leurs mélanges, dans laquelle
A) le cycle

représente une 3-amino-quinuclidine-2-substituée de structure

dans laquelle
R1 est un radical -NH-CH2-R, =N-CH2-R ou -N=CH-R, pour lequel
R est cycloalcoyle (5 à 7 atomes de carbone), norbornyle, pyrrolyle, thiényle, pyridyle, indolyle, biphényle ou phényle pouvant être substitués par 1 ou 2 substituants choisis parmi cyano, nitro, amino,
N-monoalkylamino (1 à 3 atomes de carbone), fluor, chlore, brome, trifluorométhyle, alcoyle ou alcoyloxy (1 à 3 atomes de carbone), allyloxy, hydroxy, carboxy, alcoyloxycarbonyle dont la partie alcoyle contient 1 à 3 atomes de carbone ou benzyloxycarbonyle, carboxybenzyloxy, alcoyloxycarbonylbenzyloxy dont la partie alcoyle contient 1 à 3 atomes de carbone, carboxamido ou N,N-dialcoylcarboxamido dont les parties alcoyle contiennent 1 à 3 atomes de carbone, ou R représente 2,3-dihydrobenzofuranyle, alcoyloxythiényle dont la partie alcoyle contient 1 à 3 atomes de carbone, hydroxypyridyle, quinolyle, naphtyle, alcoyloxynaphtyle dont la partie alcoyle contient 1 à 3 atomes de carbone, ou 2,3-méthylènedioxyphényle,
R2 est un radical Ar-CHR'- pour lequel
R' est un radical alcoyle ramifié (3 ou 4 atomes de carbone), un radical alcoylène ramifié (5 ou 6 atomes de carbone), un radical cycloalcoyle (3 à 7 atomes de carbone), furyle, thiényle, pyridyle, indolyle, biphényle ou phényle pouvant être substitués par 1 ou 2 substituants choisis parmi fluor, chlore, brome, trifluorométhyle, alcoyle ou alcoyloxy (1 à 3 atomes de carbone), carboxy, alcoyloxycarbonyle dont la partie alcoyle contient 1 à 3 atomes de carbone ou benzyloxycarbonyle ou représente phényle substitué par 1 ou 2 radicaux choisis parmi les radicaux cités précedemment ou phénylalcoyle dont la partie alcoyle contient 1 à 3 atomes de carbone, allyloxy ou hydroxy, et Ar est un radical phényle pouvant être substitués par 1 ou 2 substituants choisis parmi fluor, chlore, brome, trifluorométhyle, alcoyle ou alcoyloxy (1 à 3 atomes de carbone), et
R3 est un atome d'hydrogène ou un radical alcoyle (1 à 4 atomes de carbone) situé en position 5
B) le cycle

représente une pipéridine 2,3-disubstituée de structure

1) dans laquelle
R1 est un radical -X-CH2-R pour lequel X est un atome d'oxygène ou de soufre, et R est un radical phényle éventuellement substitué par 1 à 3 radicaux identiques ou différents choisis parmi alcoyle, alcényle ou alcynyle (2 à 6 atomes de carbone), halogène, cyano, nitro, trifluorométhyle, triméthylsilyle, -OR', -SCH3, -SOCH3, -SO2CH3, -NR'R", -NR'COR", -NR'CO2R", -CO2R' ou -CONR'R" pour lesquels R' et R" identiques ou différents représentent hydrogène, alcoyle, phényle ou trifluorométhyle, étant entendu que R dans -X-CH2-R peut aussi porter un substituant SR', SOR' ou SO2R',
R2 est un radical phényle, naphtyle, indazolyle, thiényle, furyle, pyridyle, thiazolyle, tétrazolyle ou quinolyle pouvant être substitués par alcoyle, alcoyloxy, halogène ou trifluorométhyle, ou un radical benzhydryle ou benzyle, ces radicaux pouvant être substitués par alcoyle ou alcoyloxy (1 à 6 carbones), halogène ou
CF3,
Y est -(CH2)n- pour lequel n égale 1 à 3,
R3 et R5 sont H, halogène, -CH2ORO, alcoyle, oxo, COORO ou CONRORO pour lesquels RO est H, CF3, alcoyle ou phényle, et
R4 est H, alcoyle éventuellement substitué [par COOR00, eONROOR00,
OH, CN, CORS, -NR00R00, C(NOH)NROOR001 CONHphénylalcoyle, COCOOR00, COCONROOR00, phényle éventuellement substitué (par 1 ou plusieurs substituants alcoyle, alcoyloxy, halogène ou CF3), ou par un hétérocycle aromatique lui-même pouvant être substitué], RO est défini comme précédemment et ROO est H ou alcoyle; étant entendu que sauf mention spéciale, les radicaux et parties alcoyle cités ci-dessus contiennent de 1 à 6 atomes de carbone) ; ou bien 2) dans laquelle
Y est (CH2)n pour lequel n égale 1 à 6 et peut représenter une chaîne insaturée, a) R1 est un radical -NH-CH2-R pour lequel R représente un radical phényle trisubstitué par des radicaux X1 à X3 pour lesquels X1 est H, alcoyle ou alcoyloxy (1 à 10C) éventuellement substitués par 1 à 3 atomes de fluor et, X2 et X3 sont H, halogène NO2, alcoyle ou alcoyloxy (1 à 10C) éventuellement substitués par 1 à 3 atomes de fluor, OH, CN, phényle, NH2, alcoylamino, dialcoylamino, alcoylcarbamoyle, alcoylcarbamoylalcoyle ou acylamino (dont les parties alcoyle ou acyle contiennent 1 à 6C), ou alcoyloxyalcoyle (dont les parties alcoyle contiennent 1 à 4C), ou b) R1 est un radical -NR'-CH2-R pour lequel R est aryle choisi parmi phényle, naphtyle, indanyle, thiényle, pyridyle, furyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, triazolyle, tétrazolyle et quinolyle éventuellement substitués par 1 ou plusieurs substituants choisis parmi halo, nitro, alcoyle, alcoyloxy, trifluorométhyle, amino, phényle, alcoylamino, formamido, acylamido, acylamidoalcoyle, alcoylcarbamoyle ou cycloalcoyle (3 à 7C) éventuellement substitué par 1 ou 2 substituants tels que cités ci-dessus et dans lequel l'un des atomes de carbone peut être remplacé par N, O ou S, et R' est un atome d'hydrogène ou un radical alcoyle,
R2 est un atome d'hydrogène, un radical alcoyle droit ou ramifié, phénylalcoyle, benzhydryle ou un radical aryle ou cycloalcoyle tel que définis précédemment pour R ou aryle tel que thiazolyle, isothiazolyle, oxazolyle, isoxazolyle triazolyle ou tétrazolyle, ces différents cycles pouvant être substitués par 1 ou plusieurs substituants choisis parmi les substituants cités précédemment pour R, ou choisis parmi dialcoylamino, alcoyloxycarbonyle, alcoyloxycarbonylalcoyle, acyloxy, acylalcoyloxy, acyle ou acylalcoyle,
R6 est un atome d'hydrogène ou lorsque R1 est défini comme en a) peut être un radical phényle ou alcoyle (1 à 6 carbones), ou bien R2 et R6 forment ensemble avec le carbone auquel ils sont attachés un carbocycle saturé de 3 à 7 chaînons dans lequel les atomes de carbone peuvent être éventuellement remplacés par O, N ou S,
R4 est un radical -(CHR")m-R"' pour lequel m est un entier de 0 à 6, chacun des motifs CHR" pouvant former avec le motif adjacent une double liaison, et tous les R" n'étant pas nécessairement identiques,
R3 et R5 peuvent être des atomes d'hydrogène ou des radicaux hydroxy, halo, amino, alcoylamino, dialcoylamino, alcoyloxy, alcoyloxycarbonyle, alcoyloxycarbonylalcoyle, acyloxy, acylalcoyloxy, acyle ou acylalcoyle ou des radicaux tels que cités précédemment pour la définition de R2, sous réserve de ne pas pouvoir former de cycle avec R5, ou si R1 est défini comme en a) R3 et R5 peuvent aussi être oxo, hydroxyalcoyle ou alcoyloxyalcoyle, et
R" et R"' sont définis comme R3 et R5, ou si R1 est un radical défini comme en a), R" peut aussi être =N-OH et R"' un radical -NHCORd,
NHCH2Rd, SO2Rd ou NHSO2Rd, et Rd est H, alcoyle, phénylalcoyle ou phényl substitué par alcoyle (les parties alcoyle ayant 1 à 6C), ou bien 3) dans laquelle
Y est (CH2)n pour lequel n égale 1 à 4 et peut représenter une chaîne insaturée,
R1 est un radical -NR'-CH2-R pour lequel R représente aryle choisi parmi phényle, naphtyle, indanyle, thiényle, pyridyle, furyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, triazolyle, tétrazolyle et quinolyle éventuellement substitués par 1 ou plusieurs substituants choisis parmi halo, nitro, alcoyle, alcoyloxy, trifluorométhyle, amino, alcoylamino, acylamino, acylaminoalcoyle, formamido, alcoylcarbamoyle ou cycloalcoyle (3 à 7C) éventuellement substitué par 1 ou 2 substituants tels que cités ci-dessus et dans lequel l'un des atomes de carbone peut être remplacé par N, O ou S, et R' est H ou alcoyle (1 à 8C) éventuellement substitué par OH, alcoyloxy (1 à 4C) ou fluoro,
R2 est un atome d'hydrogène, un radical alcoyle droit ou ramifié, phénylalcoyle, benzhydryle ou un radical aryle ou cycloalcoyle tel que définis précédemment pour R, phénylalcoyle (1 à 6C), ou benzhydryle, ces différents cycles pouvant être substitués par 1 ou plusieurs substituants choisis parmi les substituants cités précédemment pour R, ou choisis parmi dialcoylamino, alcoyloxycarbonyle, alcoyloxycarbonylalcoyle, acyloxy, acylalcoyloxy, acyle, acylalcoyle ou alcoylcarbamoylalcoyle,
R4 est un radical -(CHR")m-R"' pour lequel m est un entier de 0 à 6, chacun des motifs CHR" pouvant former avec le motif adjacent une double liaison, et tous les R" n'étant pas nécessairement identiques,
R6 est H, phényle ou alcoyle ou bien R2 et R6 forment ensemble avec le carbone auquel ils sont attachés un carbocycle saturé de 3 à 7 chaînons dans lequel les atomes de carbone peuvent être éventuellement remplacés par O, N ou S,
R3 et R5 sont définis comme en 2) ou peuvent aussi être cyano ou halométhyle
R" peut aussi être =N-OH ou l'un des radicaux définis pour R2, R3 ou
R5 et R"' un radical -NHCORd, -NHCH2Rd, SO2Rd ou l'un des radicaux définis pour R2, R3 ou R5 et Rd est H, alcoyle, phénylalcoyle ou phényl (les parties alcoyle citées ci-dessus ayant 1 à 6C), ou bien
C) le cycle :

représente une 3-amino-pipéridine-2-substituée ou un dérivé trisubstitué de la morpholine de structure

1) dans laquelle
X est un groupement - CH2-, R3 est un atome d'hydrogène,
R1 est -NH-CH2-R pour lequel R est aryle choisi parmi indanyle, phényle et naphtyle ; hétéroaryle choisi parmi thiényle, furyle, pyridyle et quinolyle ; cycloalcoyle (3 à 7C) dans lequel l'un des atomes de carbone peut être remplacé par N, O ou S et ou les groupes zaryle et hétéroaryle peuvent éventuellement être substitués par 1 ou plusieurs substituants et cycloalcoyle par 1 ou 2 substituants choisis indépendemment parmi chlore, fluor, brome, iode, nitro, alcoyle ou alcoyloxy (1 à 10C) eux-mêmes éventuellement substitués par 1 à 3 fluors, amino, alcoylthio (1 à 10C), alcoylsulfinyle (1 à 10C), alcoylsulfonyle (1 à 10C), phényle, phénoxy, alcoyl(1 à 10C)sulfonylamino, dialcoyl(1 à 10C)aminoalcoyle(1 à 10C), cyano, hydroxy, cycloalcoyloxy (3 à 7C), alcoyl(1 à 6C)amino, dialcoyl(1 à 6C)amino, H-CO-NH- et alcoyl(1 à 6C)-CO-NH-, et
R2 représente thiènyle, benzhydryle, naphtyle ou phényle éventuellement substitué par 1 à 3 substituants choisis parmi chlore, fluor, brome, iode, cycloalcoyloxy(3 à 7C), alcoyle ou alcoyloxy (1 à 10C) éventuellement substitués par 1 à 3 atomes de fluor ; ou bien 2) dans laquelle
X est un atome d'oxygène, R1 est bis trifluorométhylbenzyloxy, R2 est phényle et R3 est 5-oxo-1H,4H-1,2,4-triazolométhyle.By way of example of the class of 3-amino-quinuclidine-2substituted, of the class of 2,3-disubstituted piperidines, of the class of 3-amino-2-piperidines-substituted, may be products of general formula

in their stereoisomeric forms or mixtures thereof, wherein
A) the cycle

represents a 3-amino-quinuclidine-2-substituted structure

in which
R1 is a radical -NH-CH2-R1 = N-CH2-R or -N = CH-R, for which
R is cycloalkyl (5 to 7 carbon atoms), norbornyl, pyrrolyl, thienyl, pyridyl, indolyl, biphenyl or phenyl which may be substituted with 1 or 2 substituents selected from cyano, nitro, amino,
N-monoalkylamino (1 to 3 carbon atoms), fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), allyloxy, hydroxy, carboxy, alkyloxycarbonyl, the alkyl part of which contains 1 to 3 carbon atoms or benzyloxycarbonyl, carboxybenzyloxy, alkyloxycarbonylbenzyloxy wherein the alkyl portion contains 1 to 3 carbon atoms, carboxamido or N, N-dialkylcarboxamido wherein the alkyl portions contain 1 to 3 carbon atoms, or R is 2,3-dihydrobenzofuranyl, alkyloyloxythienyl, the portion of which alkyl contains 1 to 3 carbon atoms, hydroxypyridyl, quinolyl, naphthyl, alkyloxynaphthyl, the alkyl part of which contains 1 to 3 carbon atoms, or 2,3-methylenedioxyphenyl,
R2 is a radical Ar-CHR'- for which
R 'is a branched alkyl radical (3 or 4 carbon atoms), a branched alkylene radical (5 or 6 carbon atoms), a cycloalkyl radical (3 to 7 carbon atoms), furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl may be substituted with 1 or 2 substituents selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), carboxy, alkyloxycarbonyl wherein the alkyl portion contains 1 to 3 carbon atoms or benzyloxycarbonyl or represents phenyl substituted with 1 or 2 radicals chosen from the radicals mentioned above or phenylalkyl whose alkyl part contains 1 to 3 carbon atoms, allyloxy or hydroxy, and Ar is a phenyl radical which may be substituted with 1 or 2 substituents chosen from fluorine, chlorine bromine, trifluoromethyl, alkyl or alkyloxy (1 to 3 carbon atoms), and
R3 is a hydrogen atom or an alkyl radical (1 to 4 carbon atoms) located in the 5-position
B) the cycle

represents a 2,3-disubstituted piperidine of structure

1) in which
R 1 is a radical -X-CH 2 -R for which X is an oxygen or sulfur atom, and R is a phenyl radical optionally substituted with 1 to 3 identical or different radicals chosen from alkyl, alkenyl or alkynyl (2 to 6 carbon atoms), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR ', -SCH3, -SOCH3, -SO2CH3, -NR'R ", -NR'COR", -NR'CO2R ", -CO2R' or -CONR'R "for which R 'and R", which are identical or different, represent hydrogen, alkyl, phenyl or trifluoromethyl, it being understood that R in -X-CH2-R may also carry a substituent SR', SOR 'or SO2R',
R2 is a phenyl, naphthyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl or quinolyl radical which may be substituted by alkyl, alkyloxy, halogen or trifluoromethyl, or a benzhydryl or benzyl radical, these radicals may be substituted by alkyl or alkyloxy ( 1 to 6 carbons), halogen or
CF3,
Y is - (CH2) n- for which n is 1 to 3,
R3 and R5 are H, halogen, -CH2ORO, alkyl, oxo, COORO or CONRORO for which RO is H, CF3, alkyl or phenyl, and
R4 is H, optionally substituted alkyl [by COOR00, eONROOR00,
OH, CN, CORS, -NR00R00, C (NOH) NROOR001 CONHphenylalkyl, COCOOR00, COCONROOR00, phenyl optionally substituted (with 1 or more alkyl, alkyloxy, halogen or CF3 substituents), or with an aromatic heterocycle which may itself be substituted] , RO is defined as above and ROO is H or alkyl; it being understood that, except where otherwise stated, the radicals and alkyl portions mentioned above contain from 1 to 6 carbon atoms); or 2) in which
Y is (CH2) n for which n is 1 to 6 and may represent an unsaturated chain, a) R1 is a radical -NH-CH2-R for which R represents a phenyl radical trisubstituted by radicals X1 to X3 for which X1 is H, alkyl or alkyloxy (1 to 10C) optionally substituted with 1 to 3 fluorine atoms and, X2 and X3 are H, halogen NO2, alkyl or alkyloxy (1 to 10C) optionally substituted with 1 to 3 fluorine atoms, OH, CN, phenyl, NH 2, alkylamino, dialkylamino, alkylcarbamoyl, alkylcarbamoylalkyl or acylamino (the alkyl or acyl parts of which contain 1 to 6C), or alkyloxyalkyl (of which the alkyl parts contain 1 to 4C), or b) R1 is a radical -NR -CH2-R wherein R is aryl selected from phenyl, naphthyl, indanyl, thienyl, pyridyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl optionally substituted with 1 or more substituents selected from halo, nitro, alkyl, alkyloxy, trifl uoromethyl, amino, phenyl, alkylamino, formamido, acylamido, acylamidoalkyl, alkylcarbamoyl or cycloalkyl (3-7C) optionally substituted with 1 or 2 substituents as mentioned above and wherein one of the carbon atoms may be replaced by N , O or S, and R 'is a hydrogen atom or an alkyl radical,
R2 is a hydrogen atom, a straight or branched alkyl radical, phenylalkyl, benzhydryl or an aryl or cycloalkyl radical as defined above for R or aryl such as thiazolyl, isothiazolyl, oxazolyl, isoxazolyl triazolyl or tetrazolyl, these various rings being substituted with 1 or more substituents selected from the substituents mentioned above for R, or selected from dialkylamino, alkyloxycarbonyl, alkyloxycarbonylalkyl, acyloxy, acylalkyloxy, acyl or acylalkyl,
R 6 is a hydrogen atom or when R 1 is defined as a) may be phenyl or alkyl (1 to 6 carbons), or R 2 and R 6 together with the carbon to which they are attached a saturated carbocycle of 3 to 7-membered ring in which the carbon atoms can optionally be replaced by O, N or S,
R4 is a radical - (CHR ") mR"'for which m is an integer of 0 to 6, each of the CHR "units being able to form with the adjacent unit a double bond, and not all the R"'s being necessarily identical,
R3 and R5 may be hydrogen atoms or hydroxy, halo, amino, alkylamino, dialkylamino, alkyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, acyloxy, acylalkyloxy, acyl or acylalkyl radicals or radicals as previously mentioned for the definition of R2, reserve not to be able to form a ring with R5, or if R1 is defined as in a) R3 and R5 may also be oxo, hydroxyalkyl or alkyloxyalkyl, and
R "and R"'are defined as R3 and R5, or if R1 is a radical defined as in a), R "may also be = N-OH and R"' a radical -NHCORd,
NHCH2Rd, SO2Rd or NHSO2Rd, and Rd is H, alkyl, phenylalkyl or alkyl-substituted phenyl (the alkyl portions having 1 to 6C), or 3) wherein
Y is (CH2) n for which n is 1 to 4 and may represent an unsaturated chain,
R1 is a radical -NR'-CH2-R for which R represents aryl selected from phenyl, naphthyl, indanyl, thienyl, pyridyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl optionally substituted with 1 or more substituents selected from halo, nitro, alkyl, alkyloxy, trifluoromethyl, amino, alkylamino, acylamino, acylaminoalkyl, formamido, alkylcarbamoyl or cycloalkyl (3 to 7C) optionally substituted with 1 or 2 substituents as mentioned above and in which one of carbon atoms may be replaced by N, O or S, and R 'is H or alkyl (1-8C) optionally substituted with OH, alkyloxy (1-4C) or fluoro,
R2 is a hydrogen atom, a straight or branched alkyl radical, phenylalkyl, benzhydryl or an aryl or cycloalkyl radical as defined above for R, phenylalkyl (1 to 6C), or benzhydryl, these different rings may be substituted with 1 or a plurality of substituents selected from the substituents mentioned above for R, or selected from dialkylamino, alkyloxycarbonyl, alkyloxycarbonylalkyl, acyloxy, acylalkyloxy, acyl, acylalkyl or alkylcarbamoylalkyl,
R4 is a radical - (CHR ") mR"'for which m is an integer of 0 to 6, each of the CHR "units being able to form with the adjacent unit a double bond, and not all the R"'s being necessarily identical,
R6 is H, phenyl or alkyl or R2 and R6 together with the carbon to which they are attached form a saturated 3 to 7-membered carbocycle in which the carbon atoms may be optionally replaced by O, N or S,
R3 and R5 are defined as in 2) or may also be cyano or halomethyl
R "can also be = N-OH or one of the radicals defined for R2, R3 or
R5 and R "a radical -NHCORd, -NHCH2Rd, SO2Rd or one of the radicals defined for R2, R3 or R5 and Rd is H, alkyl, phenylalkyl or phenyl (the alkyl portions mentioned above having 1 to 6C); , or
C) the cycle:

represents a 3-amino-piperidine-2-substituted or a trisubstituted derivative of morpholine structure

1) in which
X is a group - CH2-, R3 is a hydrogen atom,
R1 is -NH-CH2-R wherein R is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; cycloalkyl (3 to 7C) in which one of the carbon atoms can be replaced by N, O or S and where the zaryl and heteroaryl groups can optionally be substituted by 1 or more substituents and cycloalkyl by 1 or 2 substituents independently selected from chlorine, fluorine, bromine, iodine, nitro, alkyl or alkyloxy (1 to 10C), themselves optionally substituted with 1 to 3 fluors, amino, alkylthio (1 to 10C), alkylsulfinyl (1 to 10C), alkylsulphonyl (1 to 10C) ), phenyl, phenoxy, (1-10C) alkylsulfonylamino, dialkyl (1-10C) aminoalkyl (1-10C), cyano, hydroxy, cycloalkoxy (3-7C), alkyl (1-6C) amino, dialkoyl (1- 6C) amino, H-CO-NH- and alkyl (1-6C) -CO-NH-, and
R 2 represents thienyl, benzhydryl, naphthyl or phenyl optionally substituted with 1 to 3 substituents selected from chlorine, fluorine, bromine, iodine, cycloalkoxy (3 to 7C), alkyl or alkyloxy (1 to 10C) optionally substituted with 1 to 3 fluorine atoms; ; or 2) in which
X is oxygen, R 1 is bis trifluoromethylbenzyloxy, R 2 is phenyl and R 3 is 5-oxo-1H, 4H-1,2,4-triazolomethyl.

1) dans laquelle
R1 et R2 sont indépendemment H, alcoyle pouvant être substitué (par
OH, CN, CORa, COORa, CONRaRb, ou NRaRb), CORa, COORa ou CONRaRb dans laquelle Ra et Rb peuvent être H, alcoyle, phényle ou phénylalcoyle (1 à 4 carbones) (éventuellement substitués sur le cycle par alcoyle, alcoyloxy, halogène ou trifluorométhyle),
R3 est H ou alcoyle,
X et Y sont H ou forment ensemble =0,
Z est O, S ou NR" pour lequel R" est H ou alcoyle,
R' est un radical -CHR R pour lequel RO est -(CH2)n-phényle pouvant être substitué sur le cycle par 1 ou plusieurs alcoyle, alcényle ou alcynyle (2 à 6 carbones), halogène, CN, NO2, CF3, triméthylsilyle,
ORa, SRa, SORa, SO2Ra, NRaRb, NRaCORb, NRaCOORb, COORa ou CONRaRb dans lesquels Ra et Rb sont définis comme ci-dessus à l'exception d'être phényle substitué, a) ou bien R1 et R2 peuvent aussi être CONRaCOORb ou SO2Ra, ROO est H, alcoyle, phényle éventuellement substitué comme défini pour RO, et n dans RO égale 0, et
R est Q-CH2- pour lequel Q est phényle, naphtyle, benzothiophényle, benzofuranyle, benzyle ou indazolyle éventuellement substitués; b) ou bien R1 et R2 peuvent aussi être CO-alcoyl-NRaRb, CONRaCOORb ou S02Ra,
R3 est défini comme ci-dessus pour la formule générale (V) ou représente alcényle,
X et Y sont définis comme pour la formule générale (IV) ou Y est OH, alcoyloxy, ou X et Y forment ensemble =NOR",
Z est un radical -CH2- ou -CH=, ROO est H ou forme avec Z une double liaison et n dans RO égale 0, et
R est Q-CH2- pour lequel Q est phényle substitué par 1 ou plusieurs halogènes, ou naphtyle, indolyle, benzothiophényle, benzofuranyle benzyle ou fluorényle éventuellement substitués; ou bien 2) dans laquelle
R1 est H ou alcoyle, R3 et R sont définis comme en lb) et a) X et Y sont définis comme en lb) et -Z-R' représente

dans laquelle

est une éventuelle liaison covalente et
R' est phényle pouvant être substitué sur le cycle par 1 à 3 groupes alcoyle, alcényle ou alcynyle (2 à 6C), halogène, CN, NO2, CF3, triméthylsilyle, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCOORb, COORa ou
CONRaRb dans lesquels Ra et Rb sont Ra et Rb peuvent être H, alcoyle, phényle ou trifluorométhyle et
R2 est un groupe -CO-W-R6 pour lequel W est une liaison ou une chaîne hydrocarbonée saturée ou insaturée ayant 1 à 6 atomes de carbone et
R6 est un groupe azacyclique ou azabicyclique, aromatique ou non aromatique, ou un groupe -CO-Z-W-R6 pour lequel Z est O,S ou NR" dans lequel R" est H ou alcoyle, W est défini comme ci-dessus et R6 est
NR7R8 ou R7 et R8 sont H, alcoyle, phényle ou phénylalcoyle éventuellement substitués sur le phényle par 1 ou plusieurs alcoyles, alcoyloxy, halo, trifluorométhyle, ou bien un groupe azacyclique ou azabicyclique, aromatique ou non aromatique, ou un groupe -CO-Z' pour lequel Z' est -alcoyl-COOH, phényle, phénylalcoyle où chaque groupe phényle est substitué par carboxy ; ou bien b) X et Y forment ensemble un radical oxo et -Z-R' représente un radical -NR4-CH2R' pour lequel R' est défini comme en a) ci-dessus et
R4 est H ou alcoyle et
R2 est un groupe -CO-Z' pour lequel Z' est défini comme ci-dessus en a).By way of example, derivatives of the class of substituted aromatic derivatives may be products of general formula

1) in which
R1 and R2 are independently H, alkyl may be substituted (by
OH, CN, COR, COORa, CONRaRb, or NRaRb), CORa, COORa or CONRaRb in which Ra and Rb may be H, alkyl, phenyl or phenylalkyl (1 to 4 carbons) (optionally substituted on the ring by alkyl, alkyloxy, halogen or trifluoromethyl),
R3 is H or alkyl,
X and Y are H or together = 0,
Z is O, S or NR "for which R" is H or alkyl,
R 'is a radical -CHR R for which RO is - (CH2) n-phenyl which may be substituted on the ring by 1 or more alkyl, alkenyl or alkynyl (2 to 6 carbons), halogen, CN, NO2, CF3, trimethylsilyl ,
ORa, SRa, Sora, SO2Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb wherein Ra and Rb are defined as above except for being substituted phenyl, a) or R1 and R2 may also be CONRaCOORb or SO2Ra, ROO is H, alkyl, optionally substituted phenyl as defined for RO, and n in RO equals 0, and
R is Q-CH2- for which Q is phenyl, naphthyl, benzothiophenyl, benzofuranyl, benzyl or indazolyl, optionally substituted; b) or R1 and R2 may also be CO-alkyl-NRaRb, CONRaCOORb or SO2Ra,
R3 is defined as above for the general formula (V) or is alkenyl,
X and Y are defined as for general formula (IV) where Y is OH, alkyloxy, or X and Y together form = NOR ",
Z is a radical -CH2- or -CH =, ROO is H or forms with Z a double bond and n in RO equals 0, and
R is Q-CH2- for which Q is phenyl substituted with 1 or more halogens, or naphthyl, indolyl, benzothiophenyl, benzofuranyl benzyl or optionally substituted fluorenyl; or 2) in which
R1 is H or alkyl, R3 and R are defined as in lb) and a) X and Y are defined as in lb) and -ZR 'represents

in which

is a possible covalent bond and
R 'is phenyl which may be substituted on the ring by 1 to 3 alkyl, alkenyl or alkynyl (2-6C), halogen, CN, NO2, CF3, trimethylsilyl, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCOORb, COORa or
CONRaRb in which Ra and Rb are Ra and Rb may be H, alkyl, phenyl or trifluoromethyl and
R2 is a -CO-W-R6 group for which W is a bond or a saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms and
R6 is an aromatic or nonaromatic azacyclic or azabicyclic group, or a -CO-ZW-R6 group for which Z is O, S or NR "wherein R" is H or alkyl, W is defined as above and R6 is
NR7R8 or R7 and R8 are H, alkyl, phenyl or phenylalkyl optionally substituted on the phenyl by 1 or more alkyls, alkyloxy, halo, trifluoromethyl, or an azacyclic or azabicyclic, aromatic or nonaromatic group, or a group -CO-Z wherein Z 'is -alkyl-COOH, phenyl, phenylalkyl wherein each phenyl group is substituted with carboxy; or b) X and Y together form an oxo radical and -ZR 'represents a radical -NR4-CH2R' for which R 'is defined as in a) above and
R4 is H or alkyl and
R2 is a group -CO-Z 'for which Z' is defined as above in a).

1) dans laquelle
Am+ représente un radical

By way of example, derivatives of the class of quaternary salts of substituted piperidines, or basic quaternary amides, may especially be products of general formula

1) in which
Am + represents a radical

pour lequel X1, X2, X3 forment ensemble avec l'atome d'azote auquel ils sont liés, un système azabicyclique ou azatricyclique éventuellement substitué par phényle ou benzyle, A est un anion,
Ar est phényle éventuellement mono ou poly substitué (par halogène, alcoyle ou alcoyloxy (1 à 3C), ou trifluorométhyle), thiényle, benzothiényle, naphtyle ou indolyle et
T' représente une liaison directe, un groupe hydroxyméthylène, alcoyloxyméthylène (alcoyle 1 à 4C ou alcoylène (2 à 5 C),
Z est un groupe aromatique ou hétéroaromatique mono, di, ou tricyclique éventuellement substitué,
R est et H, alcoyle (1 à 4C), -alcoyloxy(1 à 4C)alcoyle(2 à 4C), c > - alcanoyloxy(2 à 4C)alcoyle(2 à 4C), et R' est H ou bien R et R' forment un groupe 1,2-éthylène, 1,3-propylène ou 1,4-butylène et
T représente > C=O et m=2.Y is Y'-CXX'-CX "or Y '- (CH2) x-CX where Y' is phenyl which may be substituted (by 1 or more H, halogen, OH, alkyloxy, alkyl or CF3), cycloalkyl, pyridyl or thienyl, X is
If X 'forms a bond with X ", or X and X' form oxo and X" is H, x is 0 and XO is H or x is 0 or 1 and XO is OH, alkyloxy, acyloxy, carboxy, carbalcoyloxy, CN, -NH-CO-alkyl, mercapto or alkylthio, or XO forms a bond with the carbon atom of piperidine, and
Q is alkyl or benzyl, R 'is H and R is H or alkyl, or
Y is Y'-CXO for which Y 'is defined as above, XO forms with Q an ethylenyl radical and, R' and R together with the atoms to which they are attached, a piperidino radical, A is a Cl-, Ber anion I, acetate, methanesulfonate, e.g. toluenesulfonate, </ R
Am + represents a radical:

for which X1, X2, X3 together with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system optionally substituted by phenyl or benzyl, A is an anion,
Ar is phenyl optionally mono or poly substituted (by halogen, alkyl or alkyloxy (1 to 3C), or trifluoromethyl), thienyl, benzothienyl, naphthyl or indolyl and
T 'represents a direct bond, a hydroxymethylene group, alkyloxymethylene (alkyl 1 to 4C or alkylene (2 to 5 C),
Z is an optionally substituted mono-, di-, or tricyclic aromatic or heteroaromatic group,
R is and H, (1-4C) alkyl, -alkyl (1-4C) alkyl (2-4C), alkanoyloxy (2-4C) alkyl (2-4C), and R 'is H or R and R 'form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group and
T represents> C = O and m = 2.

The products of the general formulas (I), (II), (III), (IV) and (V) can be prepared according to, by application or by analogy with the methods described in the patent applications
EP 429,366, EP 514,273; EP 514,275; EP 635,003; EP 711,280;
EP436334; EP693489; WO 90/05729; WO 91/09844; WO 92/12152
WO 92/17449; WO 93/00331; WO 93/01169; WO 93/01170; WO 93/18023
WO 93/21181; WO 94/04022; WO 94/10167; WO 94/19320; WO 95/14017
EP 528,495; EP 559,538; EP 591,040; US 5457107.

The activity of substance P antagonists, which cross the blood-brain barrier, in the treatment of dyskinesias has been demonstrated in the haloperidol-induced dyskinesia model in rats:
PRINCIPLE:
The model of haloperidol-induced dyskinesias (a classical neuroleptic) is characterized by involuntary movements of the mouth, face, tongue known as the Vacuous Chewing Movement Syndrome (VCM) [Jergensen et al. Psychopharmacology, 116: 89-92 (1994); Waddington
Psychopharmacology, 101: 431-447 (1990)].

The decanoate form of haloperidol is capable of inducing in the rat as early as the 4th week after injection, a large number of buccolingual movements (very similar to the dyskinetic movements occurring in humans following a chronic administration of neuroleptics).

TECHNICAL:
Male Sprague-Dawley rats weighing 200-220 g are kept for at least 5 days before use. The rats are grouped by 3, with free access to food and water. In the morning of the experiment the food and the water are suppressed for the duration of the experiment.

40 mg / kg of haloperidol decanoate (0.8 ml / kg) are injected intramuscularly to induce orofacial dyskinesia. (Jrgensen et al., Psychopharmacol., 116, 89 (1994) Control animals receive an equivalent volume of vehicle used for haloperidol.

Six weeks after the injection of haloperidol decanoate, the animals receive the substance P antagonist, intraperitoneally, or its excipient. The dyskinetic behavior characterized by abnormal oral-buccal movements is measured by counting the number of cheeses during 2 periods of 30 minutes of observation each: one preceding the administration of the molecule to be tested and the other 30 minutes after the administration of this molecule. The measurements are compared. An active product is a product that significantly reduces the number of involuntary movements assessed after its administration compared to the number of involuntary movements evaluated prior to its administration.

RESULTS
The following products have been studied
Product 1: 2-Imino-2- (2-methoxyphenyl) ethyl] -2,7-diphenyl perhydroisoindolone-4- (3aR, 7aR)

Product 2: (R) -1- [N- (2-methoxybenzyl) acetylamino] -3- (1H-indol-3-yl) -2- [N- (2- (4- (piperidin-1-yl) piperidin-1-yl) acetylamino] -propane:

Product 3: (2S, 3S) -3- (2-Methoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine dihydrochloride

Table I

<tb><SEP> Product <SEP> dose <SEP>% <SEP> Inhibition <SEP> of
<tb><SEP> Oral Movements
<tb><SEP> (mg / kg <SEP> ip) <SEP> of <SEP> chewing
<tb> product <SEP> 1 <SEP> 30 <SEP> 69 <SEP>%
<tb> product <SEP> 2 <SEP> 10 <SEP> 47 <SEP>%
<tb> product <SEP> 3 <SEP> 30 <SEP> 54 <SEP>%
<Tb>
At doses of 10 to 30 mg / kg ip the studied products inhibit from 47 to 69% of abnormal oral movements of chewing.

The present invention also relates to the preparation of pharmaceutical compositions comprising a substance P antagonist capable of passing the blood-brain barrier, in pure form or in the form of an association with one or more compatible and pharmaceutically acceptable diluents and / or adjuvants and / or optionally in combination with any other physiologically active pharmaceutically compatible product for the treatment of dyskinesias.

The compositions prepared according to the invention can be used parenterally, orally, rectally, transdermally and aerosols.

Sterile compositions for parenteral administration which may especially be used in the form of infusions are preferably aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents may be used. suitable. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules, which contain in addition to the active product excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

Solid compositions for oral administration may be capsules, tablets, pills, powders or granules.

In these compositions, the active ingredient (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions may also comprise substances other than diluents, for example a lubricant such as magnesium stearate.

Liquid compositions for oral administration may be pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products.

The compositions for topical administration may be, for example, creams, ointments, or lotions.

The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, serum or any other pharmaceutically acceptable carrier. For use in the form of dry aerosols intended to be directly inhaled, the active ingredient is finely divided and combined with a water-soluble solid diluent or carrier with a particle size of 30 to 80 m, for example dextran, mannitol or lactose.

In general, the doctor will determine the dosage he considers the most appropriate based on age, weight and all other factors specific to the subject to be treated. The doses depend on the desired effect and the duration of the treatment. For an adult, they are generally between 0.25 and 2500 mg per day in staggered doses.

The following example, given as a non-limiting example, illustrates a composition prepared according to the invention and intended for the treatment of dyskinesias.

Example
The active compound tablets are prepared according to the usual technique and have the following composition: - [imino-1- (2-methoxy-phenyl) -2-ethyl] -2,7-diphenyl
perhydroisoindolone-4- (3aR, 7aR) 25 mg - starch ..................................... ... 83 mg - silica ........................................ 30 mg - magnesium stearate .......................... 3 mg

Claims (6)

1. Application of active ingredients endowed with a substance P antagonist activity and capable of passing the blood brain barrier, for the preparation of a medicament for the treatment of dyskinesias. 2- Application according to claim 1, for the preparation of a  drug for the treatment of tardive dyskinesia. 3- Application according to claim 1 or 2, characterized in that  active ingredients endowed with an antagonistic activity of the  Substance P, able to pass the blood brain barrier  are selected from the class of 1,2-diaminoethane derivatives or  of 1-acylamino-2-aminoethane receptor antagonists to  non-peptide tachykinins, the class of perhydroisoindoles,  the class of 3-amino-quinuclidines-2-substituted, the class of  2,3-disubstituted piperidines, the class of 3-amino-piperidines  2-substituted, the class of trisubstituted derivatives of the  morpholine, the class of substituted aromatic derivatives, the  class of quaternary salts of substituted piperidines, or  basic quaternary amides. 4- Application according to one of claims 1 to 3 characterized in  what active ingredients endowed with an antagonistic activity of  Substance P, able to pass the blood brain barrier  are chosen from [imino-1 (2-methoxy-phenyl) ethyl]  2-diphenyl-7,7-perhydroisoindolone-4- (3aR, 7aR), C (R) -1- [N- (2-methoxybenzyl) acetylamino] -3- (1H-indol-3-yl) -2- [N- (2- (4- (piperine  din-1-yl) piperidin-1-yl) acetylamino] -propane}, the dihydrochloride  (2S, 3S) -3- (2-methoxy-5-trifluoromethoxybenzyl) amino-2-phenyl-  piperidine. 5- Pharmaceutical composition for application according to one  Claims 1 to 4. 6- Preparation of a pharmaceutical composition intended for  the application according to one of claims 1 to 4.