WO1998018465A1

WO1998018465A1 - Use of antagonists of substance p for treating tardive diskinesia

Info

Publication number: WO1998018465A1
Application number: PCT/FR1997/001914
Authority: WO
Inventors: Assunta Imperato; Saliha Moussaoui; Carmen Obinu; Olivier Gobbo
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1996-10-29
Filing date: 1997-10-24
Publication date: 1998-05-07
Also published as: FR2755013A1; AU4951497A; FR2755013B1

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

USE OF ANTAGONISTS OF SUBSTANCE P FOR THE TREATMENT OF LATE DYSKINESIA

The present invention relates to the application of active principles endowed with an antagonistic activity of substance P and capable of crossing the blood-brain barrier, for the preparation of a medicament intended for the treatment of dyskines and related to diseases of the nervous system central and in particular late dyskinesias.

Dyskinesias are a syndrome that results in impaired movement such as involuntary movements of the limbs, tongue, lips or neck [Baldessarim, The Pharmacological bas s 10 of Therapeutics, 8th edition (1990), section 3 [Drugs and the Treatment of Psychiatry Disorders], Chap 18, 383-435, Goodman and Gilman's, Pergamon press].

The causes of dyskinesias in humans are many and diverse. An example is that of dyskinesias due to the use of most of the neuroleptic drugs which appear neurological side effects which have been described in more detail by Baldessarim et al., Ara. J. Psychiatry, 137, 1163-1172 (1980) and by Latimer, Can. J. Psychiatry 40, 2suppl, 49S-54S (1995).

Among these side effects, tardive dyskmesis is a syndrome which appears after prolonged treatment, of several months or several years, by neuroleptics and which results in impaired movements. These effects disappear by re-administration of the neuroleptic agent. There is currently no other form of treatment for these conditions.

25 Substance P antagonists are described for their activity in many conditions, including central nervous system conditions, but these active substances have never been shown to have an effect on the treatment of disease-related dyskinesias of the central nervous system and nothing

30 could suggest. It has now been found, and this is the subject of the present invention, that substance P antagonists which cross the blood brain barrier are capable of treating dyskinesias linked to diseases of the central nervous system.

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

Among the antagonists of substance P which cross the blood-brain barrier may be mentioned by way of example the products of the class of derivatives of 1,2-diamino ethane or of 1-acylamino-2-amino ethane, receptor antagonists. non-peptidic tachykinins, of the perhydroisoindole class, of the 3-amino-quinuclidin-2-substituted class, of the 2,3-disubstituted piperidin class, of the 3-amino-piperidin-2-substituted class , from the class of trisubstituted morpholine derivatives, from the class of substituted aromatic derivatives, from the class of quaternary salts of substituted piperidines, or of quaternary basic amides.

More particularly, among the products of the class of derivatives of 1,2-diamino ethane or 1-acylamino-2 amino-2 ethane, antagonists of substance P (non-tachykinin receptor antagonists), mention may be made of those of formula general:

R ⁸ _R 4

I ι

R— (CH ₂ ) _n —C-CH ₂ —N— (CH ^ -R- * (D

NH _R 2

R ¹

where 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, indolinyl-2 or -3, benzothienyl, benzofuranyl or naphthyl, these rings being optionally substituted by one or two halogen, (1-3C) alkyl, trifluoromethyl, (1-4C) alkyl , phenylalkoyl (1 -3C) oxy or alkanoyl (1-4.C);

R ¹ is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahy- dropyridinyl, quinolyl, isoquinolyl, isoquinolyl, isoquinolyl , phenylalkyl (1-4C), phenylalkyloxy (1-4C), quinolylalkyl (1-4C), isoquinolylalkyl (1-4C), quinolylalkyl (1-4C) saturated, isoquinolylalkyl (1-4C) saturated, benzoylalkyl -3C), (1-4C) alkyl or -NH-CH2 ~ R ^, the radicals R ¹ above can be substituted by halogen, alkyl (1-4C), alkyloxy (1-4C), trifluoromethyl, amino, alkyllamino (1-4C), dialcoylamino (alkyl: 1-4C) or alkanoylamino (2-4C), or the radicals R ^{1 which} may be substituted by phenyl, piperazinyl, cycloalkyl (3-8C), benzyl, alkyl (1- 4C), piperidinyl, pyridinyl, pyrimidinyl, alkanoylamino (2-6C), pyrrolidinyl, alkanoyl (2-6C) or alkyloxycarbonyl (alkyl: 1-4C ), which themselves can be substituted by halogen, alkyl (1-4C), alkyloxy (1- 4C), trifluoromethyl, amino, alkylamino (1-4C), dialcoylamino (alkyl: 1-4C) or alkanoylamino (2-4C) ; or

R 'is also amino, a leaving group (group of atoms which is displaced from the carbon atom by attack by a nucleophile in a nucleophilic substitution reaction), a hydrogen atom, alkylamino (1 -4C) or dialkoylamino (alkyl: 1 -4C);

R- ^> is pyridyl, anilinoalkyl (1 -3C) or anilinocarbonyl;

R ² is hydrogen, alkyl (1-4C), alkylsulfonyl (1-4C), carboxyalkyl (alkyl: 1-3C), alkyloxycarbonylalkyl (alkyl: 1-3C) or -CO-R ⁶ ;

R ° is hydrogen, alkyl (1-4C), haloalkyl (1-3C), phenyl, alkyloxy (1-3C), hydroxyalkyl (1-3C), amino, alkyllamino (1-4C), dialkoylamino (alkyl: 1 - 4C) or - (CH ₂ ) qR ⁷ ; q is 0 to 3;

R ⁷ is carboxy, alkyloxycarbonyl (alkyl: 1-4C), alkylcarbonyloxy (alkyl: 1-4C), amino, alkylamino (1-4C), dialcoylamino (alkyl: 1-4C), alkyloycarbonylamino (alkyl: 1-6C ), phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolyl, iso-quinolyl, saturated quinolyl, saturated isoquinolyl, phenylalkyl (1-4C), quinolylalkyl (1-4C) 1-4C), quinolylalkyl (1-4C) saturated, isoquinolylalkyl (1-4C) saturated, benzoylalkoyl (1-3C);

it being understood that all of the R ⁷ aryl or heterocyclyl can be substituted by halogen, trifluoromethyl, alkyloxy (1-4C), alkyl (1-4C), amino, alkylamino (1-4C), dialkoylamino (alkyl: 1-4C) or alkanoylamino (2-4C) and

it being understood that the R ⁷ groups may be substituted by phenyl, piperazinyl, c / cloalkyl (3-8C), benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, alkanoyl (2-6C) or alkoxycarbonyl (1-4C) - which can in turn be substituted by halogen, trifluoromethyl, amino, alkyloxy (1-4C), alkyl (1-4C), alkylamino (1-4C), dialcoylamino (alkyl: 1-4C) or alkanoylamino (2-4C) );

R ° is hydrogen or alkyl (1-6C);

R- is hydrogen, phenyl, phenylalkyl (1-6C), cycloalkyl (3-8C), cycloalkenyl (5-8C), alkyl (1-8C), naphthyl or alkenyl (2-8C) by one or two halogen, alkyl (1-3C), alkylthio (1-3C), nitro, trifluoromethyl or alkyl (1-3C) and

R ⁴ is hydrogen or alkyl (1-3C);

provided that if R ¹ is hydrogen or halogen, R ^ is phenyl, phenylalkyl (1-6C), cycloalkyl (3-8C), cycloalkenyl (5-8C) or naphthyl, the alkyl radicals being straight or branched chain.

By way of example, among the products of the perhydroisomedols class, mention may be made of those of general formula:

the symbol R represents a phenyl radical optionally substituted by one or more halogen atoms or hydroxy, alkyl radicals which can be optionally substituted (by halogen atoms or amino, alkylamino or dialkoylamino radicals) alkyloxy or alkylthio which can be optionally substituted [by hydroxy, amino, alkylamino or dialkoylamino radicals optionally substituted (by phenyl, hydroxy or amino radicals), or dialkoylamino, the alkyl parts of which form, with the nitrogen atom to which they are attached, a heterocycle at 5 to 6 links which may contain another heteroatom chosen from oxygen, sulfur (or nitrogen, optionally substituted by an alkyl, hydroxy or hydroxyalkyl radical), or substituted by amino, alkylamino or dialkylamino radicals, the parts of which alkyl can form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a saturated or msaturated cyclohexadienyl, naphthyl or heterocyclyl radical, mono or polycycllyl (5 to 9 carbon atoms) and one or more heteroatoms chosen from oxygen, nitrogen or sulfur, and optionally substituted by a halogen atom or by an alkyl or alkyloxy radical,

the symbol R ₂ represents a hydrogen or halogen atom or a hydroxy radical, alkyl, ammoalkyl, alkylammoalkyl, alkylammoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, alkyloxycarbonyl, dialkylammoalkylcarbonylcarbonylammoyalkylcarbonyl

the bicycle:

represents a perhydroisomdole or thiapyranopyrrole cycle of general formula:

and the symbol X represents an oxygen or sulfur atom or a NRg radical for which Rg is a hydrogen atom, an alkyl radical containing 1 to 12 carbon atoms and optionally substituted [by one or more carboxy, dialkoylamino radicals, acylammo, alkyloxycarbonyl, alkyloxycarbonylammo, carbamoyl, alkylcarbamoyl, dialcoylcarbamoyl (the alkyl portions of these substituents can themselves be substituted by dialkoylamino or phenyl) or substituted by phenyl, substituted phenyl, alkyloyl, alkyl, alkyl, alkyl , thienyl, furyl, pyridyl or imidazolyl] or a dialkoylamino radical, or else if the ring has the formula (Ilb) or (Ile) the symbol X represents an oxygen atom, or an NH radical, or else

the bicycle

represents a perhydroisomdole or thiapyranopyrrole cycle of general formula:

and the symbol X represents an oxygen atom.

In the general formulas (lia) to (Ile):

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 hydroxy 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 position -2 by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the symbol R ' ₄ represents a fluorine atom or a hydroxy radical, and the symbol R5 represents a hydrogen atom or the symbols R'4 and R5 represent hydroxy 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 hydroxy radical, or else the symbol R "3 represents a phenyl radical optionally substituted in position -2 by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the symbol R "4 is a hydroxy radical, or else the symbols R" 3 and R "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), (Ilb) and (Ile) can 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 (Ild) 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 present in the form (3aS, 4S, 5S, 7aS) or (3aRS, 4RS, 5RS, 7aRS) or mixtures of these forms, if R4 and R 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 (Ile) are in the form (3aS, 7R, 7aR), (3aR, 7S, 7aS) or (3aRS, 7SR, 7aSR), if R ₄ is hydroxy and R3 is a phenyl radical , or are in the form (3aR, 7S, 7aS), (3aS, 7R, 7aR) or (3aRS, 7SR, 7aSR) or their mixtures, if R3 is hydrogen and R4 is hydroxy, or are in the form ( 3aR, 7R, 7aS), (3aS, 7S, 7aR) or (3aRS, 7RS, 7aSR) or their mixtures, if R3 is hydrogen and R is fluorine, or are in the form (3aS, 7aR), (3aR, 7aS) or (3aRS, 7aSR) or their mixtures, if R3 forms with R4 an oxo radical.

In the formula (Ilf)

the symbol R3 represents a phenyl radical optionally substituted in position -2 by an alkyl or alkyloxy radical containing 1 or 2 carbon atoms or by a fluorine atom, or disubst killed by trifluoromethyl radicals and the symbols R and R'5 are identical or different and one represents a hydrogen atom or a hydroxy or alkyl radical and the other a hydrogen atom or an alkyl radical, and

the symbol R4 represents a hydroxy radical, or else the symbol R4 represents a fluorine atom if the symbols R5 and R'5 represent a hydrogen atom or an alkyl radical, or else the symbol R4 forms with R a bond and,

the symbol Rg represents a hydrogen atom or an alkyl, hydroxy or hydroxyalkyl radical, and

the symbols R represent one 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 (unless special mention), in racemic form, in stereoisomeric forms of structure:

in its forms (R) or (S) on the chain -CHR- _] R2, or in the form of a mixture of several of these forms.

By way of example, among the products of the class of 3-ammo-quιnu- clιdιnes-2-substituted, of the class of piperidines 2, 3-desubstituted, of the class of 3-ammo-pιpérιdmes-2- substituted, we can cite those of general formula:

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

represents a 3-ammo-quιnuclιdιne-2-substituted structure

in which

Rl is -NH-CH ₂ -R, = N-CH ₂ -R or -N = CH-R, for which

R is cycloalkyl (5-7C), norbornyle, pyrrolyle, thienyle, pyridyle, dolyle, biphenyle, 2, 3-dιhydrobenzofuranyl, alcoyloxythienyl of which the alkyl part contains 1 to 3 carbon atoms, hydroxypyridyle, quinolyle, naphthyle / alaphyl / the alkyl part contains 1 to 3 carbon atoms, 2, 3-methylenedιoxyphenyl or phenyl which may be substituted by 1 or 2 substituents chosen from cyano, nitro, amino, N-monoalkylammo, fluorine, chlorine, bromine, trifluoromethyl, alkyl, alkyloxy, allyloxy, hydroxy, carboxy, alkyloxycarbonyl, benzyloxycarbonyl, carboxybenzyloxy, alkyloxycarbonylbenzyloxy, carboxamido or N, N-dιalcoylcarboxamιdo,

R ₂ is an Ar-CHR'- radical for which

R 'is branched alkyl (3-4C), branched alkenyl (5-6C), cycloalkyl (5-7C), furyl, thienyl, pyridyl, mdolyle, biphenyl or phenyl which can be substituted by 1 or 2 substituents chosen from fluorine, chlorine , bromine, trifluoromethyl, alkyl, alkyloxy, carboxy, alkyloxycarbonyl, benzyloxycarbonyl, phenylalkyl, allyloxy or hydroxy,

Ar is a thienyl or phenyl radical which can be substituted with 1 or 2 substituents chosen from fluorine, chlorine, bromine, trifluoromethyl, alkyl or alkyloxy, and R3 is a hydrogen atom or an alkyl radical (1-4C) located in position 5,

Unless otherwise stated, the radicals and alkyl portions are in a straight or branched chain and contain 1 to 3 carbon atoms.

B) the cycle

represents a 2, 3-disubstituted piperidine

in which

R- _| is -X-CH ₂ -R for which X is an oxygen or sulfur atom, and R is phenyl optionally substituted by 1 to 3 identical or different radicals chosen from alkyl, (2-6C) alkenyl, (2- 6C), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR ', -SR', -SOR ', -S0 ₂ R', -NR'R ", -NR'COR", -NR'C0 ₂ R " , -C0 ₂ R 'or -CONR'R "for which R' and R" identical or different represent hydrogen, alkyl, phenyl or trifluoromethyl,

R is phenyl, naphthyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl, benzhydryl or benzyl all these radicals which may also be substituted by alkyl, alkyloxy, halogen or trifluoromethyl,

Y is - (CH ₂ ) _n - for which n equals 1 to 3, each carbon in this chain being able to be substituted by R3 and / or R R ₃ and R ₅ are independently H, halogen, -CH ₂ OR °, alkyl, oxo, COOR °° or CONR ^ R ⁰⁰⁰ for which R ° is H, alkyl or phenyl, R °° is hydrogen or alkyl and R ⁰⁰⁰ is hydrogen or alkyl,

R ₄ is H, COR °, COOR ⁰⁰ , COCONR ^∞ R ⁰⁰⁰ , COCOOR ⁰⁰ or alkyl optionally substituted by [COOR ^c C0NR ^o O ^o OR- OOO OH, CN, COR °, -NR ⁰⁰ R ⁰⁰⁰ , C (N0H) NR ^oo R ⁰⁰⁰ , CONHphenylalkyl (alkyl 1 -4C), COCOOR ⁰⁰ ,

C0C0NR ^oo R ^oo ° or phenyl optionally substituted (by 1 or more alkyl, alkyloxy, halogen or CF3 substituents], R ° R °° and R °°° are defined as above,

it being understood that, unless otherwise indicated, the radicals and alkyl parts mentioned above are in straight or branched or cyclic chain and contain from 1 to 6 carbon atoms;

c) the cycle:

is a cycle of formula

R ₁₁ - (CH ₂ ) mR _l0

in which

X is (CH ₂ ) _n in which n is an integer from 1 to 6 and in which each of the CC single bonds can be replaced by a double bond and in which each carbon can be optionally substituted by R ₈ ,

R ₆ is hydrogen, straight or branched chain alkyl, cycloalkyl (3-7C) in which one of the carbons can be replaced by an atom nitrogen, sulfur or oxygen, R ₆ may also be an aryl chosen from biphenyl, phenyl, phenylalkyl, benzhydryl, benzyl, indanyl and naphthyl or a heteroaryl chosen from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, quinolyl, these aryls and heteroaryls being optionally substituted by one or more halogen, nitro, alkyl (1-1 OC), mono or di or trifluoroalkyl (1-1 OC), alkyloxy (1 -1 OC), mono or di or trifluoroalkyloxy (1-1 OC), amino, hydroxyalkyl, alkyloxyalkyl, alkyllamino, alkyloxycarbonyl, alkylcarbonylalkyl, alkyoycarbonyl, alkylcarbonylalkyl, alkylcarbonyl, alkylcarbonyl , alkyl-CO-NH-alkyl, NHCHO and NH-CO-alkyl, in which the phenyls of the benzhydryls can be optionally replaced by naphthyl, thienyl, furyl or pyridyl,

R ₇ represents hydrogen, phenyl or alkyl,

or else R ₆ and R ₇ form together with the carbon atom to which they are attached a saturated carbocyclic having 3 to 7 carbon atoms and in which one of the carbon atoms can be optionally replaced by oxygen, sulfur or nitrogen,

R _a and R ₉ independently represent hydrogen, hydroxy, halogen, amino, oxo, nitrile, hydroxyalkyl, alkyloxyalkyl, dialkoylamino, haloalkyl, alkyloxy, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylalkylcarbonyloxyalkyl mentioned for R ₆ ,

Rio is NHCOR12, NHCH2R12, NHSO ₂ R ₁₂ or one of the radicals mentioned for R ₆ , R ₈ and R ₉ ,

R11 is oxi ino or one of the radicals mentioned for R ₆ , R _e and R ₉ ,

Ri2 is alkyl, hydrogen, phenylalkyl or phenyl optionally substituted by alkyl, m is an integer from 0 to 8, in which each of the CC single bonds can be replaced by a double bond or a triple bond and the carbons are optionally substituted by R,

and let R- _| is a radical -NH-CH ₂ -R for which R represents a phenyl radical trisubstituted by radicals X- \ to X3 for which X- _| is H, alkyl (1-1 OC) optionally substituted with 1 to 3 fluorine atoms or alkyloxy (1-1 OC) optionally substituted with 1 to 3 fluorine atoms and, X ₂ and X3 are independently H, halogen NO ₂ , alkyl (1-1 OC) optionally substituted with 1 to 3 fluorine atoms, alkyloxy (1-1 OC) optionally substituted with 1 to 3 fluorine atoms, OH, CF ₃ , CN, phenyl, NH ₂ , alkylamino, dialcoylamino, alkylcarbamoyl, alkylcarba oylalkoyl, hydroxyalkyl, NHCHO, NHCOalkyl (1-6C alkyl) or alkyloxyalkyl (in which the alkyl parts contain 1- 4C),

either R represents -N (R °) CH ₂ -R ⁰⁰ , R ° is hydrogen or alkyl (1-8C) optionally substituted with hydroxy, alkyloxy or fluorine and R ⁰⁰ is cycloalkyl (3-7C) in which one of the carbons may be replaced by a nitrogen, sulfur or oxygen atom and optionally substituted by 1 or 2 substituents, an aryl chosen from phenyl, naphthyl, mdanyl or a heteroaryl chosen from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl , oxazolyle, isoxazolyle, triazolyle, tétrazolyle and quinolyle, the aryls and heteroaryl being optionally substituted by one or more substituents, the substituents of the cycloalkyl, aryls and heteroaryl being chosen among halogen, nitro, alkyl, alkyloxy, trifluoromethyle, alkylamino, phenyl, CO-NH-alkyl, alkyl-CO-NH-alkyl, NHCHO and NH-CO-alkyl,

it being understood that (a) if m is zero, R is absent, (b) nor R ₈ , R ₉ , R ₁₀ and Rπ cannot form with the carbon atom to which l is attached a cycle with R ₇ , (c) if R ₈ and R ₉ are attached to the same carbon atom, the latter are independently hydrogen, fluoro, alkyl, hydroxyalkyl and alkyloxyalkyl, or together form with the carbon atom to which they are attached a saturated carbocycle which forms a spiro with the nitrogen cycle to which ls are attached, (d) if n is equal to 2 and one of R ₈ or R ₉ is 5-hydroxyalkyl or 5-alkyloxyalkyl, the other is hydrogen or (1-3C) alkyl, (e) if n is equal to 2, nor R8 and R9 do not represent 4-hydroxyalkyl or 4-alkyloxyalkyl, (f) if none of i, X ₂ and X ₃ is a fluorinated alkyloxy, at least one of Rj, R ₆ , R ₇ is an aryl substituted by a fluorinated alkyloxy,

it being understood that, unless otherwise stated, the radicals and alkyl parts mentioned above are in a straight or branched or cyclic chain and contain from 1 to 6 carbon atoms);

d) the cycle

represents a 3-amιno-pιpérιdme-2-substιturée or a trisubstituted derivative < ^~ X the structure morpholme:

R,

in which

R- _| is -NH-CH ₂ -R for which R is aryl chosen from mdanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; cycloalkyl (3-7C) in which one of the carbon atoms can be replaced by N, 0 or S and where the aryl and heteroaryl groups can optionally be substituted by 1 or more substituents and the cycloalkyl radical can be optionally substituted with 1 or 2 substituents, these substituents being independently chosen from chlorine, fluorine, bromine, iodine, nitro, amino, alkylthio (1 to 10C), alkylsulfmyl (1-10C), alkylsulfonyl (1-10C), phenyl, phenoxy , 10C alkyl) suifonylammo, alkyl (1- 1 OC) sulfonylam oalkyl (1 -1 OC), dialcoyl (1 -1 OC) aminoalkyl (1-1 OC), cyano, hydroxy, cycloalkyloxy (3-7C), alkyl (1 -6C) amino, dialcoyl (1 - 6C) amιno, H-CO-NH-, alkyl (1 -6C) -CO-NH-, alkyl (1-10C) optionally substituted with 1 to 3 fluorine or alkyloxy (1-1 OC) optionally substituted with 1 to 3 fluorine and

R ₂ represents thienyl, benzhydryl, naphthyl or phenyl optionally substituted with 1 to 3 substituents chosen from chlorine, fluorine, bromine, iodine, cycloalkyloxy (3-7C), alkyl (1-10C) optionally substituted with 1 to 3 fluorine atoms or alkyloxy (1-1 OC) optionally substituted with 1 to 3 fluorine atoms;

and either X is a group -CH ₂ -, R3 is a hydrogen atom,

let X be an oxygen atom, R- _| is 3,5- bis (trifluoromethyl) benzyloxy, R ₂ is phenyl and R3 is (5-oxo-1H, 4H-1,2, 4-trιazolo) methyl.

By way of example, among the products of the class of substituted aromatic derivatives, mention may be made of those of formula:

R ^ ₂

in which

1) or R is Q-CH ₂ - for which Q is phenyl, naphthyl, mdolyl, benzothiophenyl, benzofuranyl, benzyl or dazolyl, these different rings being optionally substituted by one or more alkyl, alkenyl (2-6C), alkynyl (2 -6C), halogen, cyano, nitro, trifluoromethyl, trifluorosilyl, ORa ', SRa', SORa ', S0 ₂ Ra', NRa'Rb ', NRa'CORb', NRa'COORb ', COORa' or CONRa'Rb ' and the mdolyl which may be optionally substituted on nitrogen by alkyl, phenylalkyl, COORa 'or CONRa' Rb ',

Z is 0, S or NR "for which R" is H or alkyl, X and Y are H or together form = 0,

R- _| and R ₂ are independently H, alkyl which can be substituted (by OH, CN, CORa, COORa, CONRaRb, or NRaRb), CORa, COORa, CONRaRb, CONRaCOORb, SO ₂ Ra or phenylalkyl (1 -4C) optionally substituted on phenyl by one or more alkyl, alkyloxy, halogen or trifluoromethyl,

Ra and Rb are independently H, (1-12C) alkyl, trifluoromethyl or phenyl optionally substituted by one or more alkyl, alkyloxy, halogen or trifluoromethyl,

R is H or alkyl,

R 'is CH (R ₄ ) R ₅ ,

R ₄ is hydrogen, alkyl or phenyl optionally substituted by 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C), halogen, cyano, N0 ₂ , CF3, trimethylsilyl, ORa ', SRa', SORa ', NRa'Rb ', NRa'CORb', NRa'COORb ', COORa' or CONRa'Rb '

R ₅ is phenyl optionally substituted with 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C), halogen, cyano, NO ₂ , CF3, trimethylsilyl, ORa ', SRa', SORa ', NRa'Rb' , NRa'CORb ', NRa'COORb', COORa 'or CONRa'Rb',

Ra 'and Rb' are independently H, alkyl, trifluoromethyl or phenyl

unless otherwise stated, the radicals and alkyl portions are in a straight or branched or cyclic chain and contain 1 to 6C.

2) either R is Q-CH - for which Q is phenyl substituted by one or more halogens, naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or 9-fluorenyl, these rings being optionally substituted by alkyl, (2-6C) alkenyl, alkynyl (2-6C), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa ', SRa', SORa ', S0 ₂ Ra', NRa'Rb ', NRa'CORb', NRa'COORb ', COORa' or CONRa 'Rb' and indolyl which may be optionally substituted on nitrogen by alkyl, optionally substituted phenylalkyl, COORa 'or CONRa'Rb',

R- _| and R ₂ are independently H, alkyl which can be substituted (by OH, CN, CORa, COORa, CONRaRb, or NRaRb), CORa, COORa, CONRaRb, CONRaCOORb, COalcoylNRaRb, S0Ra or phenylalkyl (1 -4C) optionally substituted on phenyl by one or more alkyl, alkyloxy, halogen or trifluoromethyl,

Ra and Rb are independently H, alkyl (1 -12C), phenyl optionally substituted by alkyl, alkyloxy, halogen or trifluoromethyl or phenylalkyl (1 -4C) optionally substituted on phenyl by alkyl, alkyloxy, halogen or trifluoromethyl

one of X and Y is hydrogen and the other is hydroxy or alkyloxy; or else X and Y together form = 0, = N0H or = N0alkyl,

R ₃ is hydrogen, alkyl, alkenyl (2-6C),

-Z-R 'represents X ^ R' in which is a possible covalent bond,

R 'is phenyl optionally substituted by 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C), halogen, cyano, NO ₂ , CF3, trimethylsilyl, ORa', SRa ', SORa', NRa'Rb ' , NRa'CORb ', NRa'COORb', COORa 'or CONRa'Rb'

Ra 'and Rb' are independently H, alkyl, trifluoromethyl or phenyl,

unless otherwise stated, the radicals and alkyl portions are in a straight or branched or cyclic chain and contain 1 to 6C

3) either R is Q-CH ₂ - for which Q is phenyl substituted by one or more halogen, naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or 9-fluorenyl, these rings being optionally substituted by alkyl, alkenyl (2-6C) , (2-6C) alkynyl, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa ', SRa', SORa ', S0 ₂ Ra', NRa'Rb ', NRa'CORb', NRa'COORb ', COORa' or CONRa'Rb 'and 1 dolyle which may be optionally substituted on nitrogen by alkyl, optionally substituted phenylalkyl, COORa 'or CONRa'Rb',

Ri is hydrogen or alkyl

R ₂ is a group -CO-W-Rg for which W is a bond or a saturated or unsaturated hydrocarbon chain having 1 to 6 carbon atoms and Rg is an aromatic or non-aromatic azacyclic group or an aromatic or non-aromatic azabicyclic group, the latter optionally containing one or more additional heteroatoms chosen from N, S, 0, NH or Nalcoyl and which can be optionally substituted by alkyl, alkyloxy, oxo, SH, = S, halogen, trifluoromethyle, NRaRb, NRaCORb, CONRaRb, COORa and CH ₂ 0Ra,

R3 is hydrogen, alkyl or alkenyl (2-6C),

-Z-R 'represents - ^ R' in which is a possible covalent bond,

R 'is phenyl which can be substituted on the ring by 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C), halogen, CN, NO ₂ , CF3, trimethylsilyl, ORa', SRa ', SORa' groups , NRa'Rb ', NRa'CORb', NRa'COORb ', COORa' or CONRa'Rb ',

Ra 'and Rb' are independently H, alkyl, trifluoromethyl or phenyl,

4) either R is Q-CH - for which Q is phenyl substituted by one or more halogen, naphthyl, mdolyl, benzothiophenyl, benzofuranyl, benzyl or 9-fluorenyl, these rings being optionally substituted by alkyl, (2-6C) alkenyl, alkynyl (2-6C), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa, SRa, SORa, S0 ₂ Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb and the mdolyle for before being optionally substituted on nitrogen by alkyl, optionally substituted phenylalkyl, COORa or CONRaRb,

Ri is hydrogen or alkyl,

R ₂ is a group -CO-VW-Rg for which V is 0, S, NH or Nalcoyle, W is a bond or a saturated or saturated hydrocarbon chain having 1 to 6 carbon atoms and Rg is NR ₇ Rg in which R ₇ and Rg are independently H, alkyl, phenyl optionally substituted by 1 or more alkyl, alkyloxy, halo or trifluoromethyl or phenylalkyl optionally substituted on phenyl by 1 or more alkyl, alkyloxy, halo, trifluoromethyl, or an aromatic azacyclic group or non-aromatic or aromatic or non-aromatic azabicyclic, the latter optionally containing one or more additional heteroatoms chosen from N, S, O, NH, Nalkyl or N-alkylphenyl and which may be optionally substituted by alkyl, alkyloxy, oxo, SH, = S, halogen, trifluoromethyl, NRaRb, NRaCORb, CONRaRb, COORa and CH ₂ 0Ra,

R ₃ is hydrogen, alkyl or alkenyl (2-6C),

-Z-R 'represents - ^ R' in which is a possible covalent bond,

R 'is phenyl optionally substituted on the ring by 1 to 3 alkyl groups, alkenyl -2-6C), alkynyl (2-6C), halogen, CN, NO ₂ , CF ₃ , trimethylsilyl, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb in which Ra and Rb are Ra and Rb can be H, alkyl, phenyl or trifluoromethyl,

Ra and Rb are H, alkyl, phenyl or trifluoromethyl,

unless otherwise stated, the radicals and alkyl portions are in a straight or branched or cyclic chain and contain 1 to 6C 5) either R is Q-CH ₂ - for which Q is phenyl substituted by one or more halogen, naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or 9-fluorenyl, these rings being optionally substituted by alkyl, alkenyl (2-6C) , (2-6C) alkynyl, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa, SRa, SORa, S0 ₂ Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb and indolyl which can be optionally substituted on nitrogen by alkyl, optionally substituted phenylalkyl, COORa or CONRaRb,

R-i is hydrogen or alkyl,

R ₂ is a group -CO-Z 'for which Z' is -alkyl-COOH, phenyl, phenylalkyl where each phenyl group is substituted by carboxy;

R ₃ is hydrogen, alkyl or alkenyl (2-6C),

-Z-R 'represents ^ R' in which is a possible covalent bond,

R 'is phenyl optionally substituted on the ring with 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C), halogen, CN, NO ₂ , CF ₃ , trimethylsilyl, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb,

Ra and Rb are independently H, alkyl, phenyl or trifluoromethyl,

6) either R is Q-CH ₂ - for which Q is phenyl substituted by one or more halogen, naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or 9-fluorenyl, these rings being optionally substituted by alkyl, alkenyl (2-6C) , (2-6C) alkynyl, halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa, SRa, SORa, S0 ₂ Ra, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb and indolyl for before being optionally substituted on nitrogen by alkyl, optionally substituted phenylalkyl, COORa or CONRaRb,

R-i is hydrogen or alkyl,

R ₃ is hydrogen, alkyl or alkenyl (2-6C),

X and Y together form an oxo radical and -ZR 'represents a radical -NR4 ~ CH ₂ R' for which R 'is phenyl optionally substituted by 1 to 3 alkyl, alkenyl (2-6C), alkynyl (2-6C) groups , halogen, CN, N0 ₂ , CF ₃ , trimethylsilyl, ORa, SRa, SORa, NRaRb, NRaCORb, NRaCOORb, COORa or CONRaRb in which Ra and Rb are H, alkyl, phenyl or trifluoromethyl, and R4 is H or alkyl and

R ₂ is a group -CO-X2-Y2-R ₆ , X ₂ is a bond, O, S, NH or Nalcoyl, Y ₂ is a bond or alkylidene (1-6C) and R ₆ is NRcRd or an azacyclic group aromatic or non-aromatic or a_. ibicyclic, aromatic or non-aromatic, the latter optionally containing one or more additional heteroatoms chosen from S, O, NH or Nalcoyl and which may be optionally substituted by alkyl, alkyloxy, oxo, SH, = S, halogen, trifluoromethyl, NRaRb, NRaCORb, CONRaRb, COORa and CH ₂ 0Ra,

Ra and Rb are independently H, alkyl, phenyl or trifluoromethyl,

Rc and Rd are independently hydrogen, alkyl, phenyl optionally substituted by alkyl, alkyloxy, halogen or trifluoromethyl or phenylalkyl optionally substituted by alkyl, alkyloxy, halogen or trifluoromethyl,

By way of example, among the derivatives of the class of quaternary salts of substituted piperidines, mention may be made of those of general formula:

1) in which:

J represents (a) an Ar-CXX'-CX "group in which Ar is cycloalkyl (3-7C), pyridyl, thienyl or phenyl optionally substituted by one or more halogen, hydroxy, (1-3C) alkyl, alkyl (1- 3C), trifluoromethyle, X esthydrogene, X 'is hydrogen or is joined to X''to form a carbon-carbon bond or else X and X' form = 0, X '' is hydrogen or with X 'forms a carbon-carbon bond, (b) an Ar- (CH ₂ ) _X -CX1 group in which Ar is as defined above, x is 0 or 1, X1 is hydrogen if x is 0 or represents hydroxy, alkyloxy (1 -4C), acyloxy (1-4C), carboxy, carbalcoxy -1-4C), cyano, NHCOalkyl (alkyl 1 -6C), mercapto, alkylthio (1-4C), or X1 forms with the carbon atom to which it is linked and with the neighboring carbon atom in piperidine a double bond, Q is alkyl or benzyl,

A ^~ is an anion and, in particular, Cl-, Br-, I ^~ , acetate, methane-sulfonate, p. toluenesulfonate,

m is 2 or 3,

Ar 'is thienyl, benzothienyl, naphthyl, indolyl, N-alkyl (1-4C) indolyl, phenyl optionally mono or poly substituted by halogen, trifluoromethyle, alkyl (1-4C), alkyloxy (1-4C), OH or trifluoromethyl) ,

R is hydrogen or alkyl (1-6C),

T is CO or CONH or CSNH,

Z is either H, M or OM when T is CO, or M when T is CONH or CSNH, M is alkyl (1-6C), pyridylalkyl (1 -3C), naphthylalkyl (1-3C) optionally substituted on the naphthyl by halogen, trifluoromethyle, alkyl (1-4C), hydroxy or alkyloxy (1-4C), pyridylthioalkyl ( 1-3C), styryl, phenylalkyl (1 -3C) optionally substituted on the phenyl by one or more halogen, trifluoromethyl, alkyl (1-4C), hydroxy oualkyloxy (1-4C), an aromatic group mono, di or tricyclic optionally substituted or heteroaromatic mono, di or tricyclic can carry one or more substituents in which a carbon atom of the aromatic carbocycle or of the aromatic heterocycle is directly linked to the group T or a benzyl group optionally substituted on the aromatic ring by halogen, trifluoromethyl, alkyl (-4C), OH or alkyloxy (1-4C),

When Z is an aromatic, this may for example be phenyl optionally substituted, naphthyl optionally substituted by [one or more halogen, (1-4C) alkyl, phenyl, cyano, hydroxyalkyl (1-4C), hydroxy, oxo, alkyl ( 1-4C) carbonylammo, alkyloxy-4C) carbonyl, thioalkyl (1-4C)], benzyl optionally substituted by one or more halogen, trifluoromethyl, alkyl (1-4C), alkyloxy (1-4C) or hydroxy. In particular when Z is a phenyl, this can be substituted by one or more halogen, OH, amino, NHCONH ₂ , nitro, CONH ₂ , trifluoromethyl, alkyl (1-10C), alkenyl (2-10C), alkynyl (2 -10C), cycloalkyl (3-8C), bicycloalkyl (4-11C), hydroxyalkyl (1-5C), alkyloxy (1-10C), alkyloxyalkyl (2-10C), alkylalkyloyloxy (3-1 OC), alkyloxyalkyloyloxy (2 -1 OC), alkenyloxy (2-10C), alkenyloxyalkyl (2-10C), alkynyloxyalkyl (3-10C), cycloalcoyloxy (3-8C), alkylthio (1-10C), alkylthioalkyl (2-10C), acylammo (1-7C), aroylam o, benzylammo, acylammoalkyl (2-8C, acyloxy (1-6C), alkyloxycarbonyl (2-5C) cycloalkyloxycarbonyl (4- 8C), alkylammocarbonylammo (2-4C), dialcoylammocarbonylammo (3-7C) ,, (1 -pyrrolidmo) carbonylammo, cycloalcoylammocarbonylammo (4- 8C), alkylammocarbonylammoalkyl (3-9C), dialcoylammocarbonyla- mmoalkyl (4-11 C), (1 -pyrrolidmo) carbonylammoethyl carbon, ammonium cycloalkyl, coyl (5- 12C), alkoxycarbonylammoalkyl (3-12C), cycloalcoyloxycarbonylaminoalkyl (5-12C), carba oylalkyl (2-5C), alkylammocarbonylal- coyle (3-9C), dialkoylammocarbonylalkyl (4-11C), (1-pyrrolι- dme) carbonylmethyl, (1 -piper dmo) carbonylmethyl, (1-pιpérι- do) carbonylethyl, cycloalcoylaminocarbonylalcoyl (2-12C) alkyl (3-1 OC), dialkoylaminocarbonylalcoyloxy (4-10C), (pιpérιdmyl-1) carbonymethoxy, cycloalcoylam ocarbonylalcoyloxy (5-11C).

When Z is a heteroaromatic it can be pyridyl, thiazidolyl, indolyl, mdazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquimolyl, benzoxazolyl îsoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazmyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazmyl, qu azolinyl, acridmyl, isidiazylyl, isothiazolyl, isothiazolyl may be hydrogenated, these heteroaromatics being optionally substituted by one or more alkyl (1-4C), phenyl, cyano, hydroxyalkyl (1-4C), hydroxy, alkyl (1-4C) carbonylam o, alkylcoxyd- 4C) carbonyl or thioalkyl ( 1-4C).

By way of example, among the derivatives of the class of quaternary basic amides, mention may be made of those of general formula:

Ar-T-CO-NR-CH ₂ -C (Q) (Ar ')

Λ

in which: Am ⁺ represents a radical: ^x 1

I

for which X1, X2, X3 form together with the nitrogen atom to which they are bonded, an azabicyclic or azatricyclic system optionally substituted by phenyl or benzyl,

A- is an anion, Ar is a mono, di or tricyclic aromatic or heteroaromatic which can carry one or more substituents, of which a carbon atom of the carbocycle or of the aromatic heterocycle is directly linked to T,

Ar 'is thienyl, benzothienyl, naphthyl, mdolyl or phenyl, optionally ent mono or poly substituted by halogen, trifluoromethyl, alkyl (1-4C) or alkyloxy (1-3C),

T is a direct bond, a hydroxymethylene, alkyloxyethylene (1-4C) or alkylene (1-5C) group,

Z is an optionally substituted mono, di, or tricyclic aromatic or heteroaromatic group,

Q is hydrogen and R is and H, alkyl (1-4C), ω-alkyloxy (1 - 4C) alkyl (2-4C), ω-alkanoyloxy (2-4C) alkyl (2-4C),

or R and Q form a group 1, 2-ethylene, 1, 3-propylene or 1,4-butylene.

When Ar is an aromatic, this may for example be phenyl optionally substituted, naphthyl optionally substituted by [one or more halogen, (1-4C) alkyl, phenyl, cyano, hydroxyalkyl (1-4C), hydroxy, alkyloxy (1- 4C), oxo, alkyl (1-4C) carbonylammo, alkyloxy (1-4C) carbonyl, thioalkyl (1-4C)], mdenyl one or more bonds of which can be hydrogenated and optionally substituted by [one or more halogen, alkyl ( 1-4C), phenyl, cyano, hydroxyalkyl (1-4C), hydroxy, alkyloxy (1-4C), oxo, alkyl (1-4C) carbonylammo, alkyloxy (1-4C) carbonyl, thioalkyl (1-4C)] . In particular when Ar is a phenyl, this can be substituted by one or more halogen, 011, amino, NHC0NH ₂ , nitro, C0NH ₂ , trifluoromethyle, alkyl (1-10C), alkenyl (2-10C), alkynyl (2 -10C), cycloalkyl (3-8C), bicycloalkyl (4-11C), hydroxyalkyl (1-5C), alkyloxy (1-10C), alkyloxyalkyl (2-10C), alkylalkyloyloxy (3-1 OC), alkyloxyalkyloyloxy (2 -1 OC), alkenyloxy (2-1 OC), alkenyloxyalkyl (2-10C), alkynyloxyalkyl (3-10C), cycloalkyloxy (3-8C), alkylthio (1-1 OC), alkylthioalkyl (2-10C) , acylammo (1-7C), aroylamino, benzylammo, acylammoalkyl (2-8C, acyloxy (1-6C), al- coyloxycarbonyle (2-5C) cycloalcoyloxycarbonyle (4-8C), alkyl o-carbonylammo (2-4C), dialcoylammocarbonylammo (3-7C), (1 -pyrrolidmo) carbonylammo, cycloalcoylammocarbonylam o (4-8C), alkylamino- carbonyl -9C), dialkoylammocarbonylammoalkyl (4- 11C), (1 -pyrrolidmo) carbonylammoethyl, (1-pιpérι- do) carbonylammoethyl, cycloalcoylam ocarbonylammoalkyl (5- 12C), alkoxycarbonylammoalkyloycylcoyl (3-12C) alkylcoyl (3-12C) , carbamoylalkoyl (2-5C), alkylammocarbonylalkyl (3-9C), dialkoylaminocarbonylalkyl (4-11C), (1-pyrrolime- carbon) (2-12C), alkylammocarbonylalkoyloxy (3-1 OC), dialkoylammocarbonylalkoyloxy (4- 10C), (pιpérιdmyl-1) carbonymethoxy, cycloalkyllaminocarbonylalkoyloxy (5-11C).

When Ar is a heteroaromatic, it can be pyridyl, thiazidolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolol, quinolyl, issoqumolyl, benzidazolyl, benzoxazolyl yl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyle, pyrazmyle, pyrimidmyle, pyridazmyle, mdolizinyl, phthalazmyl, qumazolmyl, isylamyl, isylazyl, isidiazyl bonds can be hydrogenated, these heteroaromatics being optionally substituted by one or more alkyl (1-4C), phenyl, cyano, hydroxyalkyl (1-4C), hydroxy, alkyl (1-4C) carbonylammo, alkyl-4C-carbonyl or thioalkyl ( 1-4C).

The preparation of the products of general formulas (I), (II), (III), (IV) and (V) can be carried out according to the methods described in patent applications EP 429 366, EP 514 273; EP 514,275; EP 528,495; EP 559,538; EP 591,040; 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 94/01402; WO 94/10167; WO 94/19320; WO 95/14017; US 5457107. Among the antagonists of substance P, one can also cite those described in patents EP428434, EP429466, EP430771, EP443132, EP474561, EP482539, EP499313, EP512902, ΞP517589, EP520555, EP522808, EP532456, EP536817, EP54547, EP54547, EP54547 EP655442,

EP707006, EP708101, EP721778, EP723959, WO90 / 05525, W091 / 18878, W091 / 18899, WO92 / 01688, WO92 / 06079, W092 / 12151, W092 / 15585,

WO92 / 20661, W092 / 21677, W092 / 22569, W092 / 22596, WO92 / 23380,

WO92 / 20676, W092 / 21677, WO93 / 00330, WO93 / 01159, WO93 / 01165,

WO93 / 03429, WO93 / 06099, WO93 / 09116, WO93 / 10073, WO93 / 14084, W093 / 14113, WO93 / 19064, W093 / 21181, W093 / 24465, WO94 / 00440,

WO94 / 02461, WO94 / 03445, WO94 / 04487, WO94 / 04496, WO94 / 05625,

WO94 / 07843, WO94 / 08997, WO94 / 10165, WO94 / 10168, WO94 / 10170,

W094 / 11368, W094 / 13639, W094 / 13663, W094 / 14767, WO94 / 15903,

WO94 / 19320, W094 / 19323, WO94 / 20500, WO94 / 26740, WO95 / 02595, WO95 / 04042, WO95 / 06645, WO95 / 07886, WO95 / 07908, WO95 / 08549,

W095 / 16679, W095 / 17382, W095 / 18124, W095 / 18129, W095 / 19344,

WO95 / 20575, W095 / 21819, W095 / 22525, W095 / 26335, W095 / 26338,

W095 / 26339, W095 / 33744, WO96 / 07649, W096 / 18643, W096 / 2'661,

W095 / 11895, WO96 / 10562, US5162339, US5232929, US5496833, FR2696178, FR2717802, FR2717804, FR2729952, FR2729953, FR2729954.

Among the antagonists of substance P, the following products may in particular be mentioned: LY303870, CP122721, CP96345, CP122999, CP99994, FK888, GR205171, GR203040, L709210, L733060, L736281, L732138, L737488, L740141, L740141, L740147 , CGP49823, SR140333.

The activity of substance P antagonists, which cross the blood-brain barrier, in the treatment of dyskinesias has been demonstrated in the model of dyskinesias induced by haloperidol in rats:

PRINCIPLE:

The model of dyskinesias induced by haloperidol (a classic neuroleptic) is characterized by involuntary movements of the mouth, face, tongue known as "Vacuous Chew g Movement" (VCM) [J0ergensen et al. Psychopharma- cology, 116: 89-92 (1994); Waddmgton Psychopharmacology, 101: 431-447 (1990)].

The decanoate form of haloperidol is capable of inducing in rats from the 4th week after infection, a large number of buccolinguinal movements (very similar to dyskinetic movements occurring in humans following chronic administration of neuroleptics).

TECHNICAL:

Maize Sprague-Dawley rats weighing 200-220 g are kept for at least 5 days before use. The rats are grouped in groups of 3, with free access to food and water. In the morning of the experience, food and water are removed for the duration of the experience.

40 mg / kg of haloperidol decanoate (0.8 ml / kg) are injected into the animals by intramuscular route to induce orofacial dyskinesia. (Jorgensen et al., Psychopharmacol., 116, 89 (1994). The control animals receive an equivalent volume of vehicle used for haloperidol.

6 weeks after the injection of haloperidol decanoate, the animals receive the substance P antagonist, mtra-peritoneally, or its excipient. Dyskinetic behavior characterized by abnormal involuntary buccolingual movements is measured by counting the number of chews 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 which significantly reduces the number of involuntary movements evaluated after its administration compared to the number of involuntary movements evaluated before its administration.

RESULTS:

The following products have been studied: Product 1: [imino-1 (2-methoxyphenyl) -2 ethyl] -2 diphenyl-7,7 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-phenyl-piperidine dihydrochloride:

N H, 2HC1

V Table I

At doses of 10 to 30 mg / kg i.p. the products studied inhibit from 47 to 69% of abnormal oral chewing movements.

The present invention also relates to the preparation of pharmaceutical compositions comprising a substance P antagonist capable of crossing the blood-brain barrier, in the pure state or in the form of a combination 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, intended for the treatment of dyskinesias linked to diseases of the central nervous system.

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

The sterile compositions for parenteral administration which can in particular be used in the form of infusions are preferably aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, it is possible to use water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or the like. suitable organic solvents. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, by for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of 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, semi-synthetic glycerides or polyethylene glycols.

The solid compositions for oral administration can be capsules, tablets, pills, powders or granules. In these compositions, the active principle (optionally associated with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

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

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

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

In general, the doctor will determine the dosage he considers 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 on 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 without limitation, illustrates a composition prepared according to the invention and intended for the treatment of dyskinesias.

Example

Active product tablets having the following composition are prepared according to the usual technique:

- [imino-1 (2-methoxyphenyl) -2 ethyl] - .. diphenyl-7,7 perhydroisoindolone-4- (3aR, 7aR) 25 mg

- starch 83 mg

- silica 30 mg

- magnesium stearate 3 mg

Claims

1 - Application of active principles endowed with an antagonistic activity of substance P and capable of crossing the blood-brain barrier, for the preparation of a medicament intended for the treatment of dyskinesias linked to diseases of the central nervous system.

2 - Application according to claim 1, for the preparation of a medicament for the treatment of tardive dyskinesias.

3 - Application according to claim 1 or 2, characterized in that the active principles endowed with an antagonistic activity of substance P, capable of passing the blood-brain barrier are chosen from the class of derivatives of 1,2-dιamιno ethane or acylammo- 1 ammo-2 ethane antagonists of non-pep- tidic tachykinin receptors, the class of perhydroisoindoles, the class of 3-amιno- quιnuclιdmes-2-substituted, the class of piperidines 2, 3-disubstituted, the class of 3-amιno-pιpérιdmes-2-substituted, class of trisubstituted morpholine derivatives, class of substituted aromatic derivatives, class of quaternary salts of substituted piperidines, or basic quaternary amides.

4 - Application according to one of claims 1 to 3 characterized in that the active principles endowed with an antagonistic activity of substance P, capable of passing the blood-brain barrier are chosen from [ιmιno-1 (2-methoxy-phenyl ) -2 ethyl] -2 dιphenyl-7,7 perhydroιsoιndolone-4- (3aR, 7aR), {(R) -1 - [N- (2-methoxybenzyl) acetylamino] -3- (1H-mdol- 3-yl) -2- [N- (2- (4- (pιpérιdm-1- yl) pιperιdm-1 -yl) acetylamino] -propane}, (2S, 3S) -3- (2-methoxy) hydrochloride -5-tπfluorométhoxybenzyl) -ammo-2-phenyl-pιpé-ridme.

5 - Pharmaceutical composition intended for the application according to one of claims 1 to 4.

6 Preparation of a pharmaceutical composition intended for the application according to one of claims 1 to 4.