WO1997021439A1 - Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness - Google Patents

Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness Download PDF

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Publication number
WO1997021439A1
WO1997021439A1 PCT/EP1996/005736 EP9605736W WO9721439A1 WO 1997021439 A1 WO1997021439 A1 WO 1997021439A1 EP 9605736 W EP9605736 W EP 9605736W WO 9721439 A1 WO9721439 A1 WO 9721439A1
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Prior art keywords
butyl
piperazinyl
pyrimidinyl
pyrazole
imidazole
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PCT/EP1996/005736
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French (fr)
Inventor
Jordi Frigola-Constansa
Original Assignee
Laboratorios Del Dr. Esteve, S.A.
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Priority to JP9521756A priority Critical patent/JPH11501051A/en
Priority to PL96321779A priority patent/PL321779A1/en
Priority to IL12146196A priority patent/IL121461A0/en
Priority to EP96944029A priority patent/EP0808166A1/en
Priority to AU13764/97A priority patent/AU716665B2/en
Publication of WO1997021439A1 publication Critical patent/WO1997021439A1/en
Priority to NO973589A priority patent/NO973589L/en
Priority to MXPA/A/1997/006133A priority patent/MXPA97006133A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of 1- ⁇ 4- [4-aryl (or heteroaryl) -1-piperazinyl] -butyl ⁇ - 1-H-azole derivatives as well as their physiologically acceptable salts, for the manufacture of medicaments for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, Pemesis and motion sickness.
  • the aryl (or heteroaryl) - piperazinyl-butyl-azole derivatives show anti-obsessive activity, preventive of sleep apnea, which facilitates sexual, anti-magnetic and anti-nausea behavior and therefore they are useful in therapy for the prevention and treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction and nausea and vomiting, in particular induced by chemotherapy and / or cytotoxic radiotherapy (s) or movement.
  • the compounds are intended for preventive or curative treatments in humans and in animals for depression, obsessive compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness.
  • Ar represents an aromatic radical, nitrogenous or not, chosen from differently substituted aryls, 2-pyrimidine differently substituted, and 3- (1, 2-benzisothiazole),
  • Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 1 ,
  • Z2 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 2 ,
  • Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 4 ,
  • R 1 , R 2 , R 3 and R 4 identical or different, which can also form part of another cycle, aromatic or not, represent a hydrogen atom, a halogen, a lower alkyl radical, a nitro radical, a hydroxy radical, an alkoxy radical, a cyano radical, a hydroxycarbonyl radical, an alkoxycarbonyl radical, an aryl or substituted aryl radical, a sulfonic radical, a sulfonamido radical, an aminocarbonyl radical, substituted or not on the amino group, an amino radical or substituted amino,
  • Ar represents a differently substituted aryl, it is preferably a radical of formula
  • alkyl is understood to mean, according to the invention, lower alkyls, preferably C 1 -C 6 , linear or branched, optionally unsaturated, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl radicals and their different isomers. This definition also applies to the alkyl residues of the alkoxy.
  • halogen is meant according to the present invention preferably fluorine, chlorine, bromine or iodine.
  • aryl is understood in particular according to the invention an aromatic or heteroaromatic radical, in particular chosen from the radicals phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl, etc., preferably phenyl, optionally substituted, in particular by one or more radicals selected from halogens, lower alkyl radicals, nitro, hydroxy, alkoxy, cyano, hydroxycarbonyl, alkoxycarbonyl , aryl or substituted aryl, sulfonic, sulfonamido, aminocarbonyl, substituted or not on the amino, amino or substituted amino group.
  • aromatic or heteroaromatic radical in particular chosen from the radicals phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl, etc., preferably phenyl, optionally substituted, in particular by one or more radicals selected from halogens, lower
  • the substituents of the amino group are in particular alkyl or aryl radicals.
  • therapeutically acceptable salts is meant the usual salts of addition of organic or inorganic acids, such as hydrochlorides, dihydrochlorides, mesylates or tosylates.
  • serotonin (5-HT) is involved in the pathophysiology of affective disorders
  • pharmacological stimulation paradigms have been widely used to determine the "in vivo" dynamics of serotonin function in obsessive disorder compulsive, among others.
  • mice are placed in the illuminated compartment which becomes aversive to them and causes them a state of anxiety. This causes a flight response to the dark compartment, which may be associated with obsessive compulsive behavior.
  • the results obtained demonstrate that the lesopitron, at all the doses tested, delays the onset of obsessive-compulsive behavior of movement to the dark zone because the latency time clearly increases.
  • Sleep apnea includes a series of disorders of different magnitudes. Sleep apnea is classified as obstructive, central or mixed, depending on the presence or absence of respiratory effort during periods when the air flow is stopped. Obstructive and mixed apneas are the most frequent. They present with obstructive sleep apnea syndrome, in which recurrent and sporadic collapse of the upper respiratory tract is observed during sleep. If the collapse is complete, there is no air flow through the nose and mouth, and breathing stops. The usual result is a partial awakening of sleep and a return to normal breathing. In many cases the patient does not remember these episodes of apnea, but he feels tired and sleepy during the day, for no apparent reason. These episodes of recurrent apnea with hypoxemia and fragmented sleep can lead to serious neurological and cardiac consequences.
  • the rat electroencephalographic sleep study demonstrated that the 5 mg / kg lesopitron significantly increases the latency of sleep, at the same time as it decreases the total sleep time, that is, it increases waking time.
  • lesopitron can be a respiratory stimulant with persistent effects during sleep. It is therefore indicated for the treatment of sleep apnea.
  • the etiology of sexual dysfunction may include psychological factors, interpersonal and situational reasons, physical factors and, also, side effects of pharmacological agents. Since sexual dysfunction can be from a wide variety of these underlying causes, which can range from purely psychogenic to completely physical, it would be unrealistic to hope that only one treatment modality could become effective in any case. In usual clinical practice, sexual dysfunction is treated by determining the underlying causes and treating them when possible. In many cases the identification of the underlying causes of male and female sexual dysfunction is very complex, or even cannot be determined with certainty. The psychopharmacological treatment of sexual dysfunction is currently in its infancy. The use of drugs for the treatment of sexual dysfunction has had little success, which is evidenced by the absence of a widely accepted and recognized treatment for this use.
  • the results obtained with the lesopitron demonstrate the activity of the product by facilitating the sexual behavior of the rats.
  • the compounds of the invention have been studied as to their effects on emesis in ferrets according to a method described by Costall et al. (Neuropharmacology, 1986, 25, 9S9-961).
  • Ferrets of both sexes were individually conditioned at 21 ⁇ 1 ° C and fed normally. They were then administered the compound of Example 32 or a vehicle subcutaneously as a pretreatment 15 minutes before administration of cisplatin (10 mg / kg i.v. by way of a fixed jugular cannula). The animals were observed at the start of emesis, and after, for 240 minutes. Emesis was characterized by rhythmic abdominal contractions, either associated with the expulsion of solid or liquid matter (i.e. vomiting), or not associated with the passage of material through the mouth (nausea). The number of episodes and nausea or vomiting were recorded.
  • the compound of Example 32 is capable of antagonizing the emesis induced by cisplatin ( Figure 1).
  • FIG. 1 The compound of Example 32 is capable of antagonizing the emesis induced by cisplatin in the ferret.
  • the animals were observed for 240 minutes.
  • a significant difference compared to V is indicated sP ⁇ 0.05 (Mann-Whitney U test).
  • the administration dose is of course a function of the severity of the condition to be treated. It will generally be between about 5 and about 100 mg / day.
  • the derivatives of the invention will, for example, be administered in the form of tablets, capsules, or else intravenously. Two specific dosage forms will be indicated below, by way of examples.
  • the present invention extends to the application of these compounds as medicaments, to the pharmaceutical compositions containing them and to their use for the manufacture of medicaments intended for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, emesis and motion sickness.
  • the manufacture of antiobsessive agents preventive of sleep apnea, which facilitate sexual behavior, antiemetic and anti-nausea.

Abstract

The invention relates to the use of derivatives of 1-{4-[4-aryl(or heteroaryl)-1-piperazinyl]-butyl}-1H-azole, as well as physiologically acceptable salts thereof, for the fabrication of medicaments intented to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness.

Description

MEDICAMENT DESTINE AU TRAITEMENT DES TROUBLES OBSESSIFS COMPULSI FS , DE L'APNEE DU SOMMEIL DES DYSFONCTIONS SEXUELLES, DE L ' EMESE ET DU MAL DES TRANSPORTS  MEDICINE FOR THE TREATMENT OF COMPULSIVE OBSESSIVE DISORDERS, SLEEP APNEA, SEXUAL DYSFUNCTIONS, EMESIS AND SICKNESS
La présente invention concerne l'utilisation des dérivés de 1-{4-[4-aryl (ou hétéroaryl)-1-pipérazinyl]-butyl}- 1-H-azole ainsi que de leurs sels physiologiquement acceptables, pour la fabrication de médicaments destinés au traitement des troubles obsessifs compulsifs, de l'apnée du sommeil, des dysfonctions sexuelles, de Pémèse et du mal des transports. The present invention relates to the use of 1- {4- [4-aryl (or heteroaryl) -1-piperazinyl] -butyl} - 1-H-azole derivatives as well as their physiologically acceptable salts, for the manufacture of medicaments for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, Pemesis and motion sickness.
Les composés auxquels se rapporte la présente invention ont été décrits dans les brevets européens EP-0 382 637 et EF-0 497 659, ainsi que dans le brevet européen EP-0 502 786 qui concerne un procédé de préparation de dérivés d'aryl (ou hétéroaryl)-pipérazinyl-butyl-azoles. Dans les brevets EP- 0 382 637 et EP-0 497 659, nous avons revendiqué l'utilisation de ces composés pour le traitement de certaines maladies du système nerveux central. Nous avons maintenant découvert que les dérivés d'aryl (ou hétéroaryl)- pipérazinyl-butyl-azoles montrent une activité antiobsessive, préventive de l'apnée du sommeil, qui facilite le comportement sexuel, anticmétique et antinausée et que par conséquent ils sont utiles en thérapeutique pour la prévention et le traitement des troubles obsessifs compulsifs, de l'apnée du sommeil, des dysfonctions sexuelles et des nausées et vomissements, en particulier induits par la chimiothérapie et/ou la radiothérapie cytotoxique(s) ou le mouvement. En particulier les composés sont destinés aux traitements préventifs ou curatifs chez l'homme et chez l'animal de la dépression, les troubles obsessifs compulsifs, l'apnée du sommeil, les dysfonctions sexuelles, l'émèse et le mal des transports.  The compounds to which the present invention relates have been described in European patents EP-0 382 637 and EF-0 497 659, as well as in European patent EP-0 502 786 which relates to a process for the preparation of aryl derivatives ( or heteroaryl) -piperazinyl-butyl-azoles. In patents EP-0 382 637 and EP-0 497 659, we claimed the use of these compounds for the treatment of certain diseases of the central nervous system. We have now discovered that the aryl (or heteroaryl) - piperazinyl-butyl-azole derivatives show anti-obsessive activity, preventive of sleep apnea, which facilitates sexual, anti-magnetic and anti-nausea behavior and therefore they are useful in therapy for the prevention and treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction and nausea and vomiting, in particular induced by chemotherapy and / or cytotoxic radiotherapy (s) or movement. In particular, the compounds are intended for preventive or curative treatments in humans and in animals for depression, obsessive compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness.
Les composés préconisés dans le cadre de la présente invention répondent à la formule générale I  The compounds recommended in the context of the present invention correspond to the general formula I
Figure imgf000003_0001
Figure imgf000003_0001
dans laquelle Ar représente un radical aromatique azoté ou non, choisi parmi les aryles différemment substitués, la 2-pyrimidine différemment substituée, et le 3-( 1 ,2-benzisothiazole), in which Ar represents an aromatic radical, nitrogenous or not, chosen from differently substituted aryls, 2-pyrimidine differently substituted, and 3- (1, 2-benzisothiazole),
Z1 représente un atome d'azote ou un atome de carbone substitué ou non, qu'on peut représenter par : C-R 1, Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 1 ,
Z2 représente un atome d'azote ou un atome de carbone substitué ou non, qu'on peut représenter par : C-R2, Z2 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 2 ,
Z4 représente un atome d'azote ou un atome de carbone substitué ou non, qu'on peut représenter par : C-R4, Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom, which can be represented by: CR 4 ,
et R1, R2, R3 et R4, identiques ou différents, pouvant également former partie d'un autre cycle, aromatique ou non, représentent un atome d'hydrogène, un halogène, un radical alkyle inférieur, un radical nitro, un radical hydroxy, un radical alcoxy, un radical cyano, un radical hydroxycarbonyle, un radical alcoxycarbonyle, un radical aryle ou aryle substitué, un radical sulfonique, un radical sulfonamido, un radical aminocarbonyle, substitués ou non sur le groupement amino, un radical amino ou amino substitué, and R 1 , R 2 , R 3 and R 4 , identical or different, which can also form part of another cycle, aromatic or not, represent a hydrogen atom, a halogen, a lower alkyl radical, a nitro radical, a hydroxy radical, an alkoxy radical, a cyano radical, a hydroxycarbonyl radical, an alkoxycarbonyl radical, an aryl or substituted aryl radical, a sulfonic radical, a sulfonamido radical, an aminocarbonyl radical, substituted or not on the amino group, an amino radical or substituted amino,
et leurs sels thérapeutiquement acceptables. and their therapeutically acceptable salts.
Lorsque Ar représente un aryle, différemment substitué, il s'agit de préférence d'un radical de formule  When Ar represents a differently substituted aryl, it is preferably a radical of formula
Figure imgf000004_0001
Figure imgf000004_0001
dans laquelle R7, R8 et R9 identiques ou différents représentent un atome d'hydrogène, un halogène, un radical alkyle, un radical perhalogénoalkyle, un radical hydroxy, un radical alcoxy ou un radical cyano. in which R 7 , R 8 and R 9, which are identical or different, represent a hydrogen atom, a halogen, an alkyl radical, a perhaloalkyl radical, a hydroxy radical, an alkoxy radical or a cyano radical.
Par alkyle, on entend selon l'invention les alkyles inférieurs, de préférence en C 1-C6, linéaires ou ramifiés, éventuellement insaturés, en particulier les radicaux méthyle, éthyle, propyle, isopropyle, butyle, isobutvle, tertiobutyle, pentyle, hexyle et leurs différents isomères. Cette définition s'applique également pour les restes alkyles des alcoxy. The term “alkyl” is understood to mean, according to the invention, lower alkyls, preferably C 1 -C 6 , linear or branched, optionally unsaturated, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl radicals and their different isomers. This definition also applies to the alkyl residues of the alkoxy.
Par halogène, on entend selon la présente invention de préférence le fluor, le chlore, le brome ou l'iode.  By halogen is meant according to the present invention preferably fluorine, chlorine, bromine or iodine.
Par aryle on entend notamment selon l'invention un radical aromatique ou hétéroaromatique, en particulier choisi parmi les radicaux phényle, naphtyle, anthryle, phénantryle, pyridyle, pyrimidyle, etc., de préférence phényle, éventuellement substitués, en particulier par un ou plusieurs radicaux sélectionnés parmi les halogènes, les radicaux alkyle inférieur, nitro, hydroxy, alcoxy, cyano, hydroxycarbonyle, alcoxycarbonyle, aryle ou aryle substitué, sulfoniquc, sulfonamido, aminocarbonyle, substitués ou non sur le groupement amino, amino ou amino substitué. By aryl is understood in particular according to the invention an aromatic or heteroaromatic radical, in particular chosen from the radicals phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl, etc., preferably phenyl, optionally substituted, in particular by one or more radicals selected from halogens, lower alkyl radicals, nitro, hydroxy, alkoxy, cyano, hydroxycarbonyl, alkoxycarbonyl , aryl or substituted aryl, sulfonic, sulfonamido, aminocarbonyl, substituted or not on the amino, amino or substituted amino group.
Les substituants du groupement amino sont en particulier des radicaux alkyles ou aryles.  The substituents of the amino group are in particular alkyl or aryl radicals.
Par sels thérapeutiquement acceptables, on entend les sels usuels d'addition d'acides organiques ou inorganiques, tels que les chlorhydrates, dichlorhydrates, mésylates ou tosylates.  By therapeutically acceptable salts is meant the usual salts of addition of organic or inorganic acids, such as hydrochlorides, dihydrochlorides, mesylates or tosylates.
Les composés identifiés dans les exemples 1 à 84 ci-après sont obtenus par les procédures décrites dans les brevets EP-0382637, EP-0497659 et EP-0502786, et les données pour leur identification sont exposées dans le The compounds identified in examples 1 to 84 below are obtained by the procedures described in patents EP-0382637, EP-0497659 and EP-0502786, and the data for their identification are set out in the
Tableau I. Table I.
EXEMPLES EXAMPLES
1. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-bulyl}-pyrrole,  1. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -bulyl} -pyrrole,
2. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-carbazole, 2. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -carbazole,
3. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-indole,  3. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -indole,
4. 2,3-diphényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-indole, 4. 2,3-diphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -indole,
5. 4-carboxamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 5. 4-carboxamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
6. 4-carboxy-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,6. 4-carboxy-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
7. 3-méthyl-5-trifluorométhyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl}- butyl}-1H-pyrazole, 7. 3-methyl-5-trifluoromethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl} - butyl} -1H-pyrazole,
8. 4,5-diphényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- imidazole,  8. 4,5-diphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- imidazole,
9. 2,4,5-triphényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- imidazole, 9. 2,4,5-triphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- imidazole,
10. 4,5-diphényl-2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]- butyl}-1H-imidazole, 10. 4,5-diphenyl-2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] - butyl} -1H-imidazole,
11. 4,5,-dichloro-2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-piplérazinyl]-butyl}- 1H-imidazole,  11. 4,5, -dichloro-2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piplerazinyl] -butyl} - 1H-imidazole,
12. 2-éthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 12. 2-ethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
13. 2-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 14. 4-méthoxycarbonyle-1-{4-(4-(2-pyrimidinyl)-1-pipérazinyl]- butyl}-1H-imidazole, 13. 2-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole, 14. 4-methoxycarbonyl-1- {4- (4- (2-pyrimidinyl) -1-piperazinyl] - butyl} -1H-imidazole,
15. 4-phényl-1-{4-[4-(2-pyrimidinyl)-1-piplérazinyl]-butyl}-1H-imidazole, 15. 4-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piplerazinyl] -butyl} -1H-imidazole,
16. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-benzimidazole, 17. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-3H-imidazo[5,4-b] pyridine, 16. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-benzimidazole, 17. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl } -3H-imidazo [5,4-b] pyridine,
18. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazo[4,5-b] pyridine, 18. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazo [4,5-b] pyridine,
19. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-benzotriazole, 19. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-benzotriazole,
20. 2-chloro-1-(4-[4-(2-pyrimidinyl)- 1-pipérazinyl]-butyl}- 1H- benzimidazole, 20. 2-chloro-1- (4- [4- (2-pyrimidinyl) - 1-piperazinyl] -butyl} - 1H- benzimidazole,
21. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-1,2,4-triazole,  21. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-1,2,4-triazole,
22. 2-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-2H-benzotriazole,  22. 2- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -2H-benzotriazole,
23. 2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyI]-butyl}-1H- benzimidazole,  23. 2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyI] -butyl} -1H-benzimidazole,
24. 5,6-diméthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl)-1H- benzimidazole,  24. 5,6-dimethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl) -1H-benzimidazole,
25. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,  25. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
26. 3,5-diméthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  26. 3,5-dimethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
27. 3,5-diméthyl-4-nitro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyli-1H- pyrazole,  27. 3,5-dimethyl-4-nitro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyli-1H- pyrazole,
28. 4-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 28. 4-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
29. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 29. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
30. 4-bromo-3,5-diméthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole, 30. 4-bromo-3,5-dimethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
31. 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 31. 4-nitro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
32. 4-chloro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole dichlorhydrate, 32. 4-chloro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole dihydrochloride,
33. 4-éthoxycarbonyle-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 33. 4-ethoxycarbonyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
34. 3-méthyl-5-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  34. 3-methyl-5-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
35. 4-bromo-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 36. 4-cyano-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 35. 4-bromo-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole, 36. 4-cyano-1- {4- [4- (2-pyrimidinyl ) -1-piperazinyl] -butyl} -1H-pyrazole,
37. 4-fluoro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,37. 4-fluoro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
38. 4-amino-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 39. 4-méthylsulfonamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole, 38. 4-amino-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole, 39. 4-methylsulfonamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
40. 4-benzamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  40. 4-benzamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
41. 4-acétamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,41. 4-acetamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
42. 4-(2-butyl)amino-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 42. 4- (2-butyl) amino-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
43. 3-chloro-4-fluoro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  43. 3-chloro-4-fluoro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
44. 4-(4-méthoxyphényl)-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole, 44. 4- (4-methoxyphenyl) -1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
45. 4-(4-chlorophényl)-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  45. 4- (4-chlorophenyl) -1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
46. 4-(1-pyrrolyl)-1-{4-[4-(2-pyrimidinyI)-1-pipérazinyl]-butyl}-1H- pyrazole,  46. 4- (1-pyrrolyl) -1- {4- [4- (2-pyrimidinyI) -1-piperazinyl] -butyl} -1H- pyrazole,
47. 4-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 47. 4-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
48. 3,5-diphényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 48. 3,5-diphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
49. 4-phénylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  49. 4-phenylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
50. 4-(4-méthylbenzène)sulfamoyI-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]- butyl}-1H-pyrazole,  50. 4- (4-methylbenzene) sulfamoyI-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] - butyl} -1H-pyrazole,
51. 4-butylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  51. 4-butylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
52. 4-propylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 52. 4-propylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
53. 4-éthylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  53. 4-ethylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
54. 3,5-diméthyl-4-(N,N-diméthylsulfonamido)-1-{4-[4-(2-pyrimidinyl)-1- pipérazinyl]-butyl}-1H-pyrazole,  54. 3,5-dimethyl-4- (N, N-dimethylsulfonamido) -1- {4- [4- (2-pyrimidinyl) -1- piperazinyl] -butyl} -1H-pyrazole,
55. 4-N-méthylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole,  55. 4-N-methylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
56. 4-sulfonique-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  56. 4-sulfonic-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
57. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1-imidazole, 57. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1-imidazole,
58. 2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 59. 4,5-dichloro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- imidazole, 58. 2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole, 59. 4,5-dichloro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- imidazole,
60. 4-chloro-1-{4-[4-(4-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  60. 4-chloro-1- {4- [4- (4-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
61. 4,5-dichloro-2-méthyI-1-{4-[4-(4-méthoxyphényl)-1-pipérazinyl]- butyl}-1H-imidazole, 61. 4,5-dichloro-2-methyI-1- {4- [4- (4- (4-methoxyphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
62. 4-chloro-1-[4-[4-(2-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  62. 4-chloro-1- [4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
63. 4,5-dichloro-2-méthyl-1-{4-[4-(2-méthoxyphényl)-1-pipérazinyl]- butyl}-1H-imidazole,  63. 4,5-dichloro-2-methyl-1- {4- [4- (2-methoxyphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
64. 4-chloro-1-{4-[4-(3-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  64. 4-chloro-1- {4- [4- (3-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
65. 1-{4-[4-(4-métho.xyphényl)-1-pipérazinyl]-butyl}-pyrrole,  65. 1- {4- [4- (4-metho.xyphenyl) -1-piperazinyl] -butyl} -pyrrole,
66. 1-{4-[4-(2-méthoxyphényl)-1-pipérazinyl]-butyl}-pyrrole,  66. 1- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -pyrrole,
67. 1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-pyrrole, 67. 1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -pyrrole,
68. 4-chloro-1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-1H-pyrazole,  68. 4-chloro-1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
69. 4,5-dichloro-2-méthyl-1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-1H- imidazole,  69. 4,5-dichloro-2-methyl-1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -1H- imidazole,
70. 4-chloro-1-{4-[4-(2-chlorophényl)-1-pipérazinyI]-butyI}-1H-pyrazoIe, 71. 4,5-dichloro-2-méthyl-1-{4-[4-(2-chlorophényl)-1-pipérazinyI]-butyl}- 1H-imidazole,  70. 4-chloro-1- {4- [4- (2-chlorophenyl) -1-pipérazinyI] -butyI} -1H-pyrazoIe, 71. 4,5-dichloro-2-methyl-1- {4- [ 4- (2-chlorophenyl) -1-pipérazinyI] -butyl} - 1H-imidazole,
72. 4-chloro-1-{4-[4-(3-chlorophényl)-1-pipérazinyl]-butyl}-1H-pyrazole, 72. 4-chloro-1- {4- [4- (3-chlorophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
73. 4,5-dichloro-2-méthyl-1-{4-[4-(2-cyanophényl)-1-pipérazinyl]-butyl}- 1H-imidazole, 73. 4,5-dichloro-2-methyl-1- {4- [4- (2-cyanophenyl) -1-piperazinyl] -butyl} - 1H-imidazole,
74. 4,5-dichloro-2-méthyl-1-{4-[4-(2-fluorophényl)-1-pipcrazinyl]-butyl}- 1H-imidazole, 74. 4,5-dichloro-2-methyl-1- {4- [4- (2-fluorophenyl) -1-pipcrazinyl] -butyl} - 1H-imidazole,
75. 4-chloro-1-{4-[4-(2-cyanophényl)-1-pipérazinyl]-butyl}-1H-pyrazole, 75. 4-chloro-1- {4- [4- (2-cyanophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
76. 4,5-dichloro-2-méthyl-1-{4-[4-(3-trifluorométhylphényl)-1-pipérazinyl]- butyl}-1H-imidazole, 76. 4,5-dichloro-2-methyl-1- {4- [4- (3-trifluoromethylphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
77. 4-chloro-1-{4-[4-(3-trifluorométhylphényl)-1-pipérazinyl]-butyl}-1H- pyrazole, 77. 4-chloro-1- {4- [4- (3-trifluoromethylphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
78. 4-chloro-1-{4-[4-(2-fluorophényl)-1-pipérazinyl]-butyl}-1H-pyrazole, 78. 4-chloro-1- {4- [4- (2-fluorophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
79. 4-chloro-1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyl}-1H- pyrazole, 79. 4-chloro-1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl} -1H- pyrazole,
80. 4,5-dichloro-2-méthyl-1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]- butyl}-1H-imidazole, 81. 1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyl}-1H-1,2,4- triazole, 80. 4,5-dichloro-2-methyl-1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] - butyl} -1H-imidazole, 81. 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl} -1H-1,2,4- triazole,
82. 1-{4-[4-( 1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyI)-1 H- benzimidazole,  82. 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyI) -1 H- benzimidazole,
83. 4-bromo-1-{4-[4-(5-bromopyrimidin-2-yl)-1-pipérazinyI]-butyl}-1H- pyrazole,  83. 4-bromo-1- {4- [4- (5-bromopyrimidin-2-yl) -1-pipérazinyI] -butyl} -1H- pyrazole,
84. 4-chloro-{4-[4-(5-bromopyrimidin-2-yl)-1-pipérazinyl]-butyl}-1H- pyrazole. 84. 4-chloro- {4- [4- (5-bromopyrimidin-2-yl) -1-piperazinyl] -butyl} -1H-pyrazole.
Figure imgf000010_0001
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Les exemples suivants illustrent les propriétés de quelques dérivés entrant dans le cadre de la présente invention.
Figure imgf000039_0001
Figure imgf000040_0001
The following examples illustrate the properties of some derivatives falling within the scope of the present invention.
I. TROUBLE OBSESSIF COMPULSIF I. COMPULSIVE OBSESSIVE DISORDER
Vu que l'on croit que la sérotonine (5-HT) est impliquée dans la pathophysiologie des troubles affectifs, les paradigmes de stimulation pharmacologique ont été largement utilisés pour déterminer la dynamique "in vivo" de la fonction de la sérotonine dans le trouble obsessif compulsif, parmi d'autres. Les précurseurs de 5-HT ( α-tryptophane, 5-hydroxytryptophane), les inhibiteurs et/ou les libérateurs de la récaptation de 5-HT (DL-fenfluramine) et les agonistes qui agissent directement sur la 5-HT (m-CPP, MK-212, buspirone) ont attiré une attention considérable en tant que possibles sondes de l'état fonctionnel du système neuronal central de la 5 -HT dans plusieurs troubles affectifs, bien que tant la spécificité pour le système de la 5-HT, en général, que la sélectivité pour les sous types des récepteurs de la 5-HT, en particulier, continuent à être contestées ( Murphy et col. : J. Clin. Since it is believed that serotonin (5-HT) is involved in the pathophysiology of affective disorders, pharmacological stimulation paradigms have been widely used to determine the "in vivo" dynamics of serotonin function in obsessive disorder compulsive, among others. Precursors of 5-HT (α-tryptophan, 5-hydroxytryptophan), inhibitors and / or liberators of 5-HT (DL-fenfluramine) rehabilitation and agonists which act directly on 5-HT (m-CPP , MK-212, buspirone) have drawn considerable attention as possible probes of the functional state of the central neural system of 5-HT in several affective disorders, although both specificity for the 5-HT system, in general, that the selectivity for 5-HT receptor subtypes, in particular, continues to be disputed (Murphy et al.: J. Clin.
Psychiatry 47 : 9-15, 1 986 ; Murphy et col. : Br. K. Psychiatry 155 (suppl. 8) :Psychiatry 47: 9-15, 1,986; Murphy et al. : Br. K. Psychiatry 155 (suppl. 8):
15-24, 1 989 ; Van de Kar, S.D. : Neurosci. Biobehav. Rev. 13 : 237-246, 1 989). 15-24, 1,989; Van de Kar, S.D.: Neurosci. Biobehav. Rev. 13: 237-246, 1,989).
D'autre part, il y a une évidence croissante que les ligants 5-HT1A buspirone, gepirone et ipsapirone sont des anxiolytiques actifs, éventuellement avec des propriétés antiobsessives, quoique leur mécanisme d'action ne soit pas très clair ( Lesch et col. : Life Sci. 46 : 1271- 1277, 1 990). On the other hand, there is growing evidence that the ligands 5-HT 1A buspirone, gepirone and ipsapirone are active anxiolytics, possibly with anti-obsessive properties, although their mechanism of action is not very clear (Lesch et al. : Life Sci. 46: 1271-1277, 1990).
Lors de l'étude de l'activité anxiolytique des agents avec affinité pour le récepteur 5-HT1 A, un des tests les plus représentatifs est celui qui détermine le comportement aversif des souris dans une boîte avec un compartiment très illuminé, boîte claire, et l'autre obscur (boîte claire /obscure) (Costall et col. : J. Pharmacol. Exp. Ther. 262 (1) : 90-98, 1992). When studying the anxiolytic activity of agents with affinity for the 5-HT 1 A receptor, one of the most representative tests is that which determines the aversive behavior of mice in a box with a very bright compartment, clear box, and the other obscure (clear / obscure box) (Costall et al.: J. Pharmacol. Exp. Ther. 262 (1): 90-98, 1992).
Les souris sont placées dans le compartiment illuminé qui leur devient aversif et leur provoque un étal d'anxiété. Ceci provoque une réaction de fuite vers le compartiment obscur, ce qui peut être associé à un comportement obsessif compulsif. Les résultats obtenus (voir tableau) démontrent que le lésopitron, à toutes les doses essayées retarde l'apparition du comportement obsessif compulsif de déplacement à la zone obscure du fait que le temps de latence augmente clairement.
Figure imgf000042_0001
The mice are placed in the illuminated compartment which becomes aversive to them and causes them a state of anxiety. This causes a flight response to the dark compartment, which may be associated with obsessive compulsive behavior. The results obtained (see table) demonstrate that the lesopitron, at all the doses tested, delays the onset of obsessive-compulsive behavior of movement to the dark zone because the latency time clearly increases.
Figure imgf000042_0001
II. APNEE DU SOMMEIL  II. SLEEP APNEA
Les apnées du sommeil comprennent une série de troubles de différentes importances. Les apnées du sommeil sont classifiées comme obstructives, centrales ou mixtes, selon la présence ou l'absence d'efforts respiratoires pendant les périodes où le flux d'air est arrêté. Les apnées obstructives et mixtes sont les plus fréquentes. Elles présentent le syndrome de l'apnée obstructive du sommeil, dans lequel on observe des collapsus récurrents et sporadiques des voies respiratoires supérieures pendant le sommeil. Si le collapsus est complet, il n'y a pas de circulation d'air à travers le nez et la bouche, et la respiration s'arrête. Le résultat habituel est un éveillement partiel du sommeil et un retour à la respiration normale. Dans plusieurs cas le patient ne se souvient pas de ces épisodes d'apnée, mais il se sent fatigué et avec du sommeil pendant le jour, sans aucune raison apparente. Ces épisodes d'apnée récurrente avec hypoxémie et sommeil fragmenté peuvent entraîner de sérieuses conséquences neurologiques et cardiaques.  Sleep apnea includes a series of disorders of different magnitudes. Sleep apnea is classified as obstructive, central or mixed, depending on the presence or absence of respiratory effort during periods when the air flow is stopped. Obstructive and mixed apneas are the most frequent. They present with obstructive sleep apnea syndrome, in which recurrent and sporadic collapse of the upper respiratory tract is observed during sleep. If the collapse is complete, there is no air flow through the nose and mouth, and breathing stops. The usual result is a partial awakening of sleep and a return to normal breathing. In many cases the patient does not remember these episodes of apnea, but he feels tired and sleepy during the day, for no apparent reason. These episodes of recurrent apnea with hypoxemia and fragmented sleep can lead to serious neurological and cardiac consequences.
Jusqu'à présent, le traitement pharmacologique de l'apnée du sommeil a connu peu de succès. Récemment, quelques publications ont signalé l'éventuelle utilité de la buspirone, un agoniste 5-HT1 A, dans les troubles d'apnée du sommeil (Mendelson et col., J. Clin. Psychopharmacol. 1991 11 (1) :71). So far, the pharmacological treatment of sleep apnea has had little success. Recently, a few publications have reported the possible usefulness of buspirone, a 5-HT 1 A agonist, in sleep apnea disorders (Mendelson et al., J. Clin. Psychopharmacol. 1991 11 (1): 71) .
Afin de déterminer l'action du lésopitron sur la respiration et le sommeil, et par conséquent la possible utilisation de cet agent dans l'apnée du sommeil, on a étudié son effet sur la respiration du rat, suivant le travail effectué à ce propos pour la buspirone (Mendelson et col, Am. Rev. Respir. Dis. 14 (6) : 1527-1530, 1990).  In order to determine the action of lesopitron on respiration and sleep, and therefore the possible use of this agent in sleep apnea, its effect on rat respiration has been studied, according to the work carried out on this subject to buspirone (Mendelson et al, Am. Rev. Respir. Dis. 14 (6): 1527-1530, 1990).
Les résultats obtenus démontrent que le lésopitron aux doses de 10 et de 30 mg/kg, i.v., donne lieu à une augmentation significative du rythme respiratoire, ainsi que de la ventilation pulmonaire chez le rat anesthésié. Action respiratoire de lésopitron chez le rat anesthésié avec urétane. The results obtained demonstrate that the lesopitron at the doses of 10 and 30 mg / kg, iv, gives rise to a significant increase in the respiratory rate, as well as in the pulmonary ventilation in the anesthetized rat. Respiratory action of lesopitron in rats anesthetized with urethane.
Figure imgf000043_0001
Figure imgf000043_0001
L'étude électroencéphalographique du sommeil du rat a démontré que le lésopitron à 5 mg/kg augmente significativement la latence du sommeil, en même temps qu'il diminue le temps total de sommeil, c'est-à-dire, qu'il augmente le temps d'éveil.  The rat electroencephalographic sleep study demonstrated that the 5 mg / kg lesopitron significantly increases the latency of sleep, at the same time as it decreases the total sleep time, that is, it increases waking time.
Etude électroencéphalographique du sommeil chez le rat. Electroencephalographic sleep study in rats.
Figure imgf000043_0002
Figure imgf000043_0002
En résumant les résultats obtenus, on peut affirmer que le lésopitron peut être un stimulant respiratoire avec des effets persistants pendant le sommeil. Il est par conséquent indiqué dans le traitement des apnées du sommeil.  Summarizing the results obtained, it can be stated that lesopitron can be a respiratory stimulant with persistent effects during sleep. It is therefore indicated for the treatment of sleep apnea.
III. DYSFONCTION SEXUELLE III. SEXUAL DYSFUNCTION
L'étiologie de la dysfonction sexuelle peut inclure des facteurs psychologiques, des raisons interpersonnelles et de situation, des facteurs physiques et, aussi, des effets secondaires d'agents pharmacologiques. Etant donné que la dysfonction sexuelle peut être d'une grande variété de ces causes sous-jacentes, qui peuvent aller de celles purement psychogéniques à des causes tout à fait physiques, il ne serait pas réaliste d'espérer qu'une seule modalité de traitement pourrait devenir efficace dans tous les cas. Dans la pratique clinique habituelle, la dysfonction sexuelle est traitée en déterminant les causes sous-jacentes et en les traitant lorsqu'il est possible. Dans plusieurs cas l'identification des causes sous-jacentes de la dysfonction sexuelle de l'homme et de la femme est très complexe, ou même, elle ne peut pas être déterminée avec certitude. Le traitement psychopharmacologique de la dysfonction sexuelle en est actuellement à ses débuts. L'utilisation de médicaments pour le traitement de la dysfonction sexuelle a connu peu de succès, ce qui est mis en évidence par l'absence d'un traitement largement accepté et reconnu pour cet usage. The etiology of sexual dysfunction may include psychological factors, interpersonal and situational reasons, physical factors and, also, side effects of pharmacological agents. Since sexual dysfunction can be from a wide variety of these underlying causes, which can range from purely psychogenic to completely physical, it would be unrealistic to hope that only one treatment modality could become effective in any case. In usual clinical practice, sexual dysfunction is treated by determining the underlying causes and treating them when possible. In many cases the identification of the underlying causes of male and female sexual dysfunction is very complex, or even cannot be determined with certainty. The psychopharmacological treatment of sexual dysfunction is currently in its infancy. The use of drugs for the treatment of sexual dysfunction has had little success, which is evidenced by the absence of a widely accepted and recognized treatment for this use.
L'aclivation des récepteurs 5 -HT1 A semble faciliter les comportements sexuels du rat mâle, étant donné que le 8-OH-DPAT augmente le nombre d'accouplements et diminue la latence de l'éjaculation ( Murphy et col. : J. Clin. Psychiatry 47 : 9-15, 1986 ; Murphy et col. : Br. K. Psychiatry 155 (suppl. 8) : 15-24, 1 989). On a trouvé des effets similaires avec d'autres produits sélectifs pour le récepteur 5-HT1A comme la buspirone, la gepironc ou l'ipsapirone. Néanmoins, on ne sait pas si l'effet des agonistes 5-HT 1 A dans le comportement sexuel des rats mâles ou femelles est provoqué, soit par la stimulation par ces produits des autorécepteurs 5-HT1 A - ceci réduit la synthèse de la 5-HT et fait diminuer la fonction sérotoninergique - soit par la stimulation des récepteurs localisés post-synaptiquement. Activation of the 5-HT 1 A receptors seems to facilitate the sexual behavior of the male rat, since 8-OH-DPAT increases the number of matings and decreases the latency of ejaculation (Murphy et al.: J. Clin. Psychiatry 47: 9-15, 1986; Murphy et al .: Br. K. Psychiatry 155 (suppl. 8): 15-24, 1 989). Similar effects have been found with other products selective for the 5-HT 1A receptor such as buspirone, gepironc or ipsapirone. However, it is not known whether the effect of 5-HT 1 A agonists in the sexual behavior of male or female rats is caused, either by the stimulation by these products of the 5-HT 1 A autoreceptors - this reduces the synthesis of 5-HT and decreases serotonergic function - either by stimulating localized receptors post-synaptically.
Afin de démontrer la capacité du lésopitron pour améliorer la dysfonction sexuelle, on a évalué son action dans le comportement sexuel des rats mâles. A ce sujet, on a suivi la méthodologie décrite par M. M. Foreman et col. ( J. Pharmacol. Exp. Ther. 270 (3) : 1270-1281 (1 994)). L'index principal utilisé pour évaluer l'action du produit a été le LE (temps nécessaire pour atteindre l'éjaculation, ou latence d'éjaculation après l'intromission).
Figure imgf000045_0001
In order to demonstrate the capacity of the lesopitron to improve sexual dysfunction, its action in the sexual behavior of male rats was evaluated. In this regard, we followed the methodology described by MM Foreman et al. (J. Pharmacol. Exp. Ther. 270 (3): 1270-1281 (1 994)). The main index used to evaluate the action of the product was the LE (time required to reach ejaculation, or ejaculation latency after the intromission).
Figure imgf000045_0001
Les résultats obtenus avec le lésopitron démontrent l'activité du produit en facilitant le comportement sexuel des rats.  The results obtained with the lesopitron demonstrate the activity of the product by facilitating the sexual behavior of the rats.
IV. EMESE IV. EMESE
Les composés de l'invention ont été étudiés quant à leurs effets sur l'émèse chez le furet selon une méthode décrite par Costall et al. (Neuropharmacology, 1986, 25, 9S9-961 ).  The compounds of the invention have been studied as to their effects on emesis in ferrets according to a method described by Costall et al. (Neuropharmacology, 1986, 25, 9S9-961).
Des furets des deux sexes (0,7 - 1,4 kg) ont été conditionnés individuellement à 21 ± 1°C et ils ont été alimentés normalement. On leur a administré, alors, le composé de l'exemple 32 ou un véhicule par voie souscutanée comme un prétraitement de 15 minutes avant l'administration de cisplatine ( 10 mg/kg i.v. par voie d'une canule jugulaire fixe). Les animaux ont été observés au début de l'émèse, et après, pendant 240 minutes. L'émèse était caractérisée par les contractions abdominales rythmiques, soit associées avec l'expulsion de matière solide ou liquide (c'est-à-dire vomissement), soit non associées avec le passage de matériel par la bouche (nausée). Le nombre d'épisodes et les nausées ou les vomissements ont été enregistrés.  Ferrets of both sexes (0.7 - 1.4 kg) were individually conditioned at 21 ± 1 ° C and fed normally. They were then administered the compound of Example 32 or a vehicle subcutaneously as a pretreatment 15 minutes before administration of cisplatin (10 mg / kg i.v. by way of a fixed jugular cannula). The animals were observed at the start of emesis, and after, for 240 minutes. Emesis was characterized by rhythmic abdominal contractions, either associated with the expulsion of solid or liquid matter (i.e. vomiting), or not associated with the passage of material through the mouth (nausea). The number of episodes and nausea or vomiting were recorded.
Le composé de l'exemple 32 est capable d'antagoniser l'émèse induite par la cisplatine (Figure 1 ).  The compound of Example 32 is capable of antagonizing the emesis induced by cisplatin (Figure 1).
Figure 1 : Le composé de l'exemple 32 est capable d'antagoniser l'émèse induite par cisplatine chez le furet. Les animaux ont reçu un véhicule (V, n = 7) ou le composé de l'exemple 32 (0,05-0,5 mg/kg s.c., n = 4) pour chaque niveau de dose 15 minutes avant l'administration intraveineuse de cisplatine ( 10 mg/kg). Les animaux ont été observés pendant 240 minutes. Une différence significative comparée à V est indiquée sP < 0,05 (Mann- Whitney U test). En thérapeutique humaine, la dose d'administration est bien entendu fonction de la gravité de l'affection à traiter. Elle sera généralement comprise entre environ 5 et environ 100 mg/jour. Les dérivés de l'invention seront, par exemple, administrés sous forme de comprimés, de gélules, ou bien par voie intraveineuse. On indiquera ci-après, à titre d'exemples, deux formes galéniques particulières. Figure 1: The compound of Example 32 is capable of antagonizing the emesis induced by cisplatin in the ferret. The animals received a vehicle (V, n = 7) or the compound of Example 32 (0.05-0.5 mg / kg sc, n = 4) for each dose level 15 minutes before intravenous administration cisplatin (10 mg / kg). The animals were observed for 240 minutes. A significant difference compared to V is indicated sP <0.05 (Mann-Whitney U test). In human therapy, the administration dose is of course a function of the severity of the condition to be treated. It will generally be between about 5 and about 100 mg / day. The derivatives of the invention will, for example, be administered in the form of tablets, capsules, or else intravenously. Two specific dosage forms will be indicated below, by way of examples.
Exemple de formule par comprimé Example of formula per tablet
Composé de l'exemple 32 20 mg Compound of Example 32 20 mg
Lactose 50 mg Lactose 50 mg
Cellulose microcristalline 20 mg  Microcrystalline cellulose 20 mg
Povidone 5 mg Povidone 5 mg
Amidon prégélatinisé 3 mg  Pregelatinized starch 3 mg
Dioxyde de silice colloïdale 1 mg Colloidal silicon dioxide 1 mg
Stéarate de magnésium 1 mg Magnesium stearate 1 mg
Poids comprimé 100 mg  Tablet weight 100 mg
Exemple de formule par gélule  Example of formula per capsule
Composé de l'exemple 32 20 mg  Compound of Example 32 20 mg
Glycérine polyoxyéthylénée 125 mg  Polyoxyethylene glycerine 125 mg
Béhénate de glycérine 5 mg Glycerin behenate 5 mg
150 mg  150 mg
Excipient : gélatine molle q.s. Excipient: soft gelatin q.s.
Exemple de formule par ampoule injectable  Example of formula per injectable ampoule
Composé de l'exemple 32 4 mg 8 mg Compound of Example 32 4 mg 8 mg
Chlorure sodique 15 mg 30 mg Sodium chloride 15 mg 30 mg
Eau pour injection c.s.p. 2 ml 4 ml  Water for injection c.s.p. 2 ml 4 ml
Compte tenu des propriétés pharmacologiques intéressantes attachées aux composés de formule générale I, la présente invention s'étend à l'application de ces composés à titre de médicaments, aux compositions pharmaceutiques les contenant et à leur utilisation pour la fabrication de médicaments destinés au traitement des troubles obsessifs compulsifs, de l'apnée du sommeil, des dysfonctions sexuelles, de l'émèse et du mal des transports. En particulier pour la fabrication d'agents antiobsessifs, préventifs de l'apnée du sommeil, qui facilitent le comportement sexuel, antiémétiques et antinausées. Given the advantageous pharmacological properties attached to the compounds of general formula I, the present invention extends to the application of these compounds as medicaments, to the pharmaceutical compositions containing them and to their use for the manufacture of medicaments intended for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, emesis and motion sickness. In particular for the manufacture of antiobsessive agents, preventive of sleep apnea, which facilitate sexual behavior, antiemetic and anti-nausea.

Claims

REVENDICATIONS
1/ Utilisation de composés de formule générale I
Figure imgf000047_0001
dans laquelle 1 / Use of compounds of general formula I
Figure imgf000047_0001
in which
Ar représente un radical aromatique azoté ou non, choisi parmi les aryles différemment substitués, la 2-pyrimidine différemment substituée, et le 3-( 1 ,2-benzisothiazole),  Ar represents an aromatic radical, nitrogenous or not, chosen from differently substituted aryls, 2-pyrimidine differently substituted, and 3- (1, 2-benzisothiazole),
Z1 représente un atome d'azote ou un atome de carbone substitué ou non qu'on peut représenter par : C-R1, Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom which can be represented by: CR 1 ,
Z2 représente un atome d'azote ou un atome de carbone substitué ou non qu'on peut représenter par : C-R2, Z2 represents a nitrogen atom or a substituted or unsubstituted carbon atom which can be represented by: CR 2 ,
Z4 représente un atome d'azote ou un atome de carbone substitué ou non qu'on peut représenter par : C-R4, Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom which can be represented by: CR 4 ,
et R1, R2, R3 et R4, identiques ou différents, pouvant également former partie d'un autre cycle, aromatique ou non, représentent un atome d'hydrogène, un halogène, un radical alkyle inférieur, un radical nitro, un radical hydroxy, un radical alcoxy, un radical cyano, un radical hydroxycarbonyle, un radical alco.xycarbonyle, un radical aryle ou aryle substitué, un radical sulfonique, un radical sulfonamido, un radical aminocarbonylc, substitués ou non sur le groupement amino, un radical amino ou amino substitué, and R 1 , R 2 , R 3 and R 4 , identical or different, which can also form part of another cycle, aromatic or not, represent a hydrogen atom, a halogen, a lower alkyl radical, a nitro radical, a hydroxy radical, an alkoxy radical, a cyano radical, a hydroxycarbonyl radical, an alco.xycarbonyl radical, an aryl or substituted aryl radical, a sulphonic radical, a sulphonamido radical, an aminocarbonyl radical, substituted or unsubstituted on the amino group, a amino or substituted amino radical,
et leurs sels thérapeutiquement acceptables, and their therapeutically acceptable salts,
pour la préparation d'un médicament destiné au traitement des troubles obsessifs compulsifs, de l'apnée du sommeil, des dysfonctions sexuelles, de l'émèse et du mal des transports chez les mammifères, l'homme inclus.  for the preparation of a medicament for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, emesis and motion sickness in mammals, including humans.
2/ Utilisation selon la revendication 1 , caractérisée en ce que les composés de formule générale I sont sélectionnés parmi le groupe suivant : 1. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-bulyl}-pyrrole,  2 / Use according to claim 1, characterized in that the compounds of general formula I are selected from the following group: 1. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -bulyl} -pyrrole ,
2. 1-{4-[4-(2-pyrimidinyl)- 1-pipérazinyl]-butyl}-carbazole,  2. 1- {4- [4- (2-pyrimidinyl) - 1-piperazinyl] -butyl} -carbazole,
3. 1- {4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-indole,  3. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -indole,
4. 2,3-diphényl- 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-indole, 4. 2,3-diphenyl- 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -indole,
5. 4-carboxami do- 1 - { 4-[ 4-( 2-pyrimi dinyl )- 1 -p ipéraziny1]- buty l } -1 H- pyrazole, 5. 4-carboxami do- 1 - {4- [4- (2-pyrimi dinyl) - 1 -p ipéraziny1] - buty l} -1 H- pyrazole,
6. 4-carboxy-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,6. 4-carboxy-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
7. 3-méthyl-5-trifluorométhyl-1-{4-|4-(2-pyrimidinyl)-1-pipérazinyl}- butyl}-1H-pyrazole, 7. 3-methyl-5-trifluoromethyl-1- {4- | 4- (2-pyrimidinyl) -1-piperazinyl} - butyl} -1H-pyrazole,
8. 4,5-diphényl-1-{4-[4-(2-pyrimidinyl)-pipérazinyl]-butyl}-1H-imidazole,  8. 4,5-diphenyl-1- {4- [4- (2-pyrimidinyl) -piperazinyl] -butyl} -1H-imidazole,
9. 2,4,5-triphényl-1-{4-[4-(2-pyrimidinyI)-1-pipérazinyl]-butyl}-1H- imidazole, 9. 2,4,5-triphenyl-1- {4- [4- (2-pyrimidinyI) -1-piperazinyl] -butyl} -1H- imidazole,
10. 4,5-diphényl-2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-imidazole,  10. 4,5-diphenyl-2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-imidazole,
11. 4,5,-dichloro-2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-imidazole,  11. 4,5, -dichloro-2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-imidazole,
12. 2-éthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 12. 2-ethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
13. 2-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole,13. 2-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
14. 4-méthoxycarbonyle-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-imidazole, 14. 4-methoxycarbonyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-imidazole,
15. 4-phényl-1-{4-[4-(2-pyrimidinyl)-1-piplérazinyl]-butyl}-1H-imidazole,15. 4-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piplerazinyl] -butyl} -1H-imidazole,
16. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-benzimidazole, 16. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-benzimidazole,
17. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-3H-imidazo[5,4-b] pyridine,  17. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -3H-imidazo [5,4-b] pyridine,
18. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl)-1 H-imidazo[4,5-b] pyridine,  18. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl) -1 H-imidazo [4,5-b] pyridine,
19. 1-{4-[4-(2-pyrimidinyl)-1-pipérainyl]-butyl}-1H-benzotriazole,  19. 1- {4- [4- (2-pyrimidinyl) -1-pipérainyl] -butyl} -1H-benzotriazole,
20. 2-chloro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1 H- benzimidazole,  20. 2-chloro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1 H- benzimidazole,
21. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-1,2,4-triazole,  21. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-1,2,4-triazole,
22. 2-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-2H-benzotriazole, 22. 2- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -2H-benzotriazole,
23. 2-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1 H- benzimidazole,  23. 2-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1 H- benzimidazole,
24. 5,6-diméthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl)-1H- benzimidazole,  24. 5,6-dimethyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl) -1H-benzimidazole,
25. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 25. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
26. 3,5-diméthyl-1-{4-[4-{2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  26. 3,5-dimethyl-1- {4- [4- {2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
27. 3,5-diméthyl-4-nitro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  27. 3,5-dimethyl-4-nitro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
28. 4-méthyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 28. 4-methyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
29. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 29. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
30. 4-bromo-3,5-diméthyl-1-{4-[4-(2-pyrimidinyI)-1-pipérazinyl]-butyl}- 1H-pyrazole, 30. 4-bromo-3,5-dimethyl-1- {4- [4- (2-pyrimidinyI) -1-piperazinyl] -butyl} - 1H-pyrazole,
31. 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl]-1H-pyrazole, 31. 4-nitro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl] -1H-pyrazole,
32. 4-chloro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole dichlorhydrate, 32. 4-chloro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole dihydrochloride,
33. 4-éthoxycarbonyle-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  33. 4-ethoxycarbonyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
34. 3-méthyl-5-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  34. 3-methyl-5-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
35. 4-bromo-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,35. 4-bromo-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
36. 4-cyano-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,36. 4-cyano-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
37. 4-fluoro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,37. 4-fluoro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
38. 4-amino-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,38. 4-amino-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
39. 4-méthylsulfonamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole, 39. 4-methylsulfonamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
40. 4-benzamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  40. 4-benzamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
41. 4-acétamido-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole, 41. 4-acetamido-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
42. 4-(2-butyl)amino-1-|4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 42. 4- (2-butyl) amino-1- | 4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
43. 3-chloro-4-fluoro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  43. 3-chloro-4-fluoro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
44. 4-(4-méthoxyphényl)-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole,  44. 4- (4-methoxyphenyl) -1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
45. 4-(4-chlorophényl)-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 45. 4- (4-chlorophenyl) -1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
46. 4-(1-pyrrolyl)-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  46. 4- (1-pyrrolyl) -1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
47. 4-phényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-pyrazole,  47. 4-phenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-pyrazole,
48. 3,5-diphényl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 48. 3,5-diphenyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
49. 4-phénylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  49. 4-phenylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
50. 4-(4-méthylbenzène)sulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]- butyl}-1H-pyrazole,  50. 4- (4-methylbenzene) sulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] - butyl} -1H-pyrazole,
51. 4-butylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butylj-1H- pyrazole, 51. 4-butylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butylj-1H- pyrazole,
52. 4-propylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole, 52. 4-propylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
53. 4-éthylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  53. 4-ethylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
54. 3,5-diméthyl-4-(N,N-diméthylsulfonamido)-1-{4-[4-(2-pyrimidinyl)-1- pipérazinyl]-butyl}-1H-pyrazole, 54. 3,5-dimethyl-4- (N, N-dimethylsulfonamido) -1- {4- [4- (2-pyrimidinyl) -1- piperazinyl] -butyl} -1H-pyrazole,
55. 4-N-méthylsulfamoyl-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}- 1H-pyrazole,  55. 4-N-methylsulfamoyl-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} - 1H-pyrazole,
56. 4-sulfonique-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- pyrazole,  56. 4-sulfonic-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- pyrazole,
57. 1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1-imidazole,  57. 1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1-imidazole,
58. 2-méthyl-1-|4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H-imidazole, 58. 2-methyl-1- | 4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H-imidazole,
59. 4,5-dichloro-1-{4-[4-(2-pyrimidinyl)-1-pipérazinyl]-butyl}-1H- imidazole, 59. 4,5-dichloro-1- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -1H- imidazole,
60. 4-chloro-1-{4-[4-(4-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole, 60. 4-chloro-1- {4- [4- (4-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
61. 4,5-dichloro-2-méthyl-1-{4-[4-(4-méthoxyphényl)-1-pipérazinyl]- butyl}-1H-imidazole,  61. 4,5-dichloro-2-methyl-1- {4- [4- (4-methoxyphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
62. 4-chloro-1-{4-[4-(2-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  62. 4-chloro-1- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
63. 4,5-dichloro-2-méthyl-1-{4-[4-(2-méthoxyphényl)-1-pipérazinyl]- butyl}-1H-imidazole,  63. 4,5-dichloro-2-methyl-1- {4- [4- (2-methoxyphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
64. 4-chloro-1-{4-[4-(3-méthoxyphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  64. 4-chloro-1- {4- [4- (3-methoxyphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
65. 1-{4-[4-(4-méthoxyphényl)-1-pipérazinyl]-butyl}-pyrrole, 65. 1- {4- [4- (4-methoxyphenyl) -1-piperazinyl] -butyl} -pyrrole,
66. 1-{4-[4-(2-methoxyphényl)-1-pipérazinyl]-butyl}-pyrrole,  66. 1- {4- [4- (2-methoxyphenyl) -1-piperazinyl] -butyl} -pyrrole,
67. 1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-pyrrole,  67. 1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -pyrrole,
68. 4-chloro-1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-1H-pyrazole,  68. 4-chloro-1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
69. 4,5-dichloro-2-méthyl-1-{4-[4-(phényl)-1-pipérazinyl]-butyl}-1H- imidazole,  69. 4,5-dichloro-2-methyl-1- {4- [4- (phenyl) -1-piperazinyl] -butyl} -1H- imidazole,
70. 4-chloro-1-{4-[4-(2-chlorophényl)-1-pipérazinyl]-butyl}-1H-pyrazole, 70. 4-chloro-1- {4- [4- (2-chlorophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
71. 4,5-dichloro-2-méthyl-1-{4-[4-(2-chlorophényl)-1-pipérazinyl]-butyl}- 1H-imidazole, 71. 4,5-dichloro-2-methyl-1- {4- [4- (2-chlorophenyl) -1-piperazinyl] -butyl} - 1H-imidazole,
72. 4-chloro-1-{4-[4-(3-chlorophényl)-1-pipérazinyl]-butyl}-1H-pyrazole,  72. 4-chloro-1- {4- [4- (3-chlorophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
73. 4,5-dichloro-2-méthyl-1-{4-[4-(2-cyanophényl)-1-pipérazinyl]-butyl}- 1H-imidazole, 73. 4,5-dichloro-2-methyl-1- {4- [4- (2-cyanophenyl) -1-piperazinyl] -butyl} - 1H-imidazole,
74. 4,5-dichloro-2-méthyl-1-{4-[4-(2-fluorophényl)-1-pipérazinyl]-butyl}- 1H-imidazole, 74. 4,5-dichloro-2-methyl-1- {4- [4- (2-fluorophenyl) -1-piperazinyl] -butyl} - 1H-imidazole,
75. 4-chloro-1-{4-[4-(2-cyanophényl)-1-pipérazinyl]-butyl}-1H-pyrazole, 75. 4-chloro-1- {4- [4- (2-cyanophenyl) -1-piperazinyl] -butyl} -1H-pyrazole,
76. 4,5-dichloro-2-méthyl-1-{4-[4-(3-trifluorométhylphényl)-1-pipérazinyl]- butyl}-1H-imidazole, 76. 4,5-dichloro-2-methyl-1- {4- [4- (3-trifluoromethylphenyl) -1-piperazinyl] - butyl} -1H-imidazole,
77. 4-chloro-1-{4-[4-(3-trifluorométhylphényl)-1-pipérazinyl]-butyl}-1H- pyrazole,  77. 4-chloro-1- {4- [4- (3-trifluoromethylphenyl) -1-piperazinyl] -butyl} -1H- pyrazole,
78. 4-chloro-1-{4-[4-(2-fluorophényl)-1-pipérazinyI]-butyl}-1H-pyrazole, 78. 4-chloro-1- {4- [4- (2-fluorophenyl) -1-pipérazinyI] -butyl} -1H-pyrazole,
79. 4-chloro-1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyl}-1H- pyrazole, 79. 4-chloro-1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl} -1H- pyrazole,
80. 4,5-dichloro-2-méthyl-1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]- butyl}-1H-imidazole,  80. 4,5-dichloro-2-methyl-1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] - butyl} -1H-imidazole,
81. 1-{4-[4-(1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyl}-lH-1,2,4- triazole,  81. 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl} -1H-1,2,4- triazole,
82. 1-{4-[4-( 1,2-benzisothiazol-3-yl)-1-pipérazinyl]-butyl)-1 H- benzimidazole, 82. 1- {4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -butyl) -1 H- benzimidazole,
83. 4-bromo-1-{4-[4-(5-bromopyrimidin-2-yl)-1-pipérazinyl]-butyl}-1H- pyrazole,  83. 4-bromo-1- {4- [4- (5-bromopyrimidin-2-yl) -1-piperazinyl] -butyl} -1H- pyrazole,
84. 4-chloro-{4-[4-(5-bromopyrimidin-2-yl)-1-pipérazinyl]-butyl}-1H- pyrazole.  84. 4-chloro- {4- [4- (5-bromopyrimidin-2-yl) -1-piperazinyl] -butyl} -1H-pyrazole.
3/ Utilisation du dichlorhydrate de 4-chIoro-1-{4-[4-(2-pyrimidin-yl)-1-pipérazinyl]-butyl}-1H-pyrazole, pour la préparation d'un médicament destiné au traitement des troubles obsessifs compulsifs, de l'apnée du sommeil, des dysfonctions sexuelles, de l'émèse et du mal des transports chez les mammifères, l'homme inclus.  3 / Use of 4-chloro-1- {4- [4- (2-pyrimidin-yl) -1-piperazinyl] -butyl} -1H-pyrazole dihydrochloride for the preparation of a medicament intended for the treatment of disorders obsessive compulsive, sleep apnea, sexual dysfunction, emesis and motion sickness in mammals, humans included.
PCT/EP1996/005736 1995-12-12 1996-12-11 Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness WO1997021439A1 (en)

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JP9521756A JPH11501051A (en) 1995-12-12 1996-12-11 Medications intended to treat obsessive-compulsive disorder, sleep apnea, sexual dysfunction, vomiting and motion sickness
PL96321779A PL321779A1 (en) 1995-12-12 1996-12-11 Drug for use in therapy of obsessive-compulsive neurosis, sleep apnoea, secsual activity disorders, vomiting and kinetosis
IL12146196A IL121461A0 (en) 1995-12-12 1996-12-11 Use of 1-[4-[4-aryl (or heteroaryl)-1-piperazinyl]butyl]-1H-azole derivatives
EP96944029A EP0808166A1 (en) 1995-12-12 1996-12-11 Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness
AU13764/97A AU716665B2 (en) 1995-12-12 1996-12-11 Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness
NO973589A NO973589L (en) 1995-12-12 1997-08-04 Drugs for the treatment of obsessive-compulsive disorder, sleep apnea, sexual dysfunction, emesis and travel sickness
MXPA/A/1997/006133A MXPA97006133A (en) 1995-12-12 1997-08-11 Use of derivatives of 1-. { 4- [4-aril (o heteroaril) -1-piperazinil] -butil} -1h-azol for the preparation of a medicinal product intended for the treatment of obsessive-compulsive disorders, of the apnea delsueño, of the sexual dysfunctions, of the eme

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FR9514690A FR2742052B1 (en) 1995-12-12 1995-12-12 USE OF DERIVATIVES 1- (4- (4-ARYL (OR HETEROARYL) -1-PIPER AZINYL) -BUTY) -1H-AZOLE FOR THE TREATMENT OF DEPRESSION, OBSESSIVE COMPULSIVE DISORDERS, SLEEP APNEA, SEXUAL DYSFUNCTIONS , Emese and motion sickness

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US6046331A (en) * 1998-12-17 2000-04-04 Synaptic Pharmaceutical Corporation Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
US6579896B2 (en) 2000-09-06 2003-06-17 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
US6635633B2 (en) 2000-08-14 2003-10-21 Ortho-Pharmaceutical, Inc. Substituted pyrazoles
US6953793B2 (en) 2000-08-14 2005-10-11 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
WO2005094827A1 (en) * 2004-03-30 2005-10-13 Kestrel Pharmaceuticals Inc. Methods for treating sexual dysfunction
WO2006116614A1 (en) 2005-04-26 2006-11-02 Hypnion, Inc. Benzisoxazole piperidine compounds and methods of use thereof
WO2006116615A1 (en) 2005-04-26 2006-11-02 Hypnion, Inc. Benzisoxazole piperazine compounds and methods of use thereof
GB2435827A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Use of substituted piperazine compounds for the treatment of food related disorders
US7309703B2 (en) 2000-08-14 2007-12-18 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7332494B2 (en) 2000-08-14 2008-02-19 Janssen Pharmaceutica, N.V. Method for treating allergies using substituted pyrazoles

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FR2763950A1 (en) * 1997-06-02 1998-12-04 Esteve Labor Dr 2- {4- [4- (4,5-DICHLORO-2-METHYLIMIDAZOL-1-YL) BUTYL] -1- PIPERAZINYL} -5-FLUOROPYRIMIDINE, ITS PREPARATION AND ITS THERAPEUTIC USE
WO1998055476A1 (en) * 1997-06-02 1998-12-10 Laboratorios Del Dr. Esteve, S.A. 2-{4-[4-(4,5-dichloro-2- methylimidazol-1-yl)butyl] -1-piperazinyl}-5-fluoropyrimidine, preparation and therapeutic use
ES2149691A1 (en) * 1997-06-02 2000-11-01 Esteve Labor Dr 2- 4-[4-(4, 5-dichloro -2-methylimidazol-1-yl) butyl]-1-piperazinyl -5-fluoropyrimidine,preparation and therapeutic use
US6303608B1 (en) 1997-06-02 2001-10-16 Laboratorios Del Dr. Esteve, S.A. 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]-1-piperazinyl}-5-fluoropyrimidine, its preparation and its therapeutic use
US6346620B1 (en) 1997-06-02 2002-02-12 Laboratories Del Dr. Esteve S.A. Methods for preparation of 2-(4-(4-(4,5-dichloro-2-methylimidazol-1-yl)butyl)-1-piperazinyl)-5-fluoropyrimidine and salts thereof
US6046331A (en) * 1998-12-17 2000-04-04 Synaptic Pharmaceutical Corporation Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
US6949540B2 (en) 2000-08-14 2005-09-27 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7589202B2 (en) 2000-08-14 2009-09-15 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6635633B2 (en) 2000-08-14 2003-10-21 Ortho-Pharmaceutical, Inc. Substituted pyrazoles
US6936603B2 (en) 2000-08-14 2005-08-30 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7393850B2 (en) 2000-08-14 2008-07-01 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6951851B2 (en) 2000-08-14 2005-10-04 Hui Cai Substituted pyrazoles
US6953793B2 (en) 2000-08-14 2005-10-11 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7772236B2 (en) 2000-08-14 2010-08-10 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7452890B2 (en) 2000-08-14 2008-11-18 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7429591B2 (en) 2000-08-14 2008-09-30 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7265102B2 (en) 2000-08-14 2007-09-04 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7417046B2 (en) 2000-08-14 2008-08-26 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7309703B2 (en) 2000-08-14 2007-12-18 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US7332494B2 (en) 2000-08-14 2008-02-19 Janssen Pharmaceutica, N.V. Method for treating allergies using substituted pyrazoles
US7388011B2 (en) 2000-08-14 2008-06-17 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrazoles
US6583155B2 (en) 2000-09-06 2003-06-24 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
US6579896B2 (en) 2000-09-06 2003-06-17 Ortho-Mcneil Pharmaceutical, Inc. Method for treating allergies using substituted pyrazoles
WO2005094827A1 (en) * 2004-03-30 2005-10-13 Kestrel Pharmaceuticals Inc. Methods for treating sexual dysfunction
WO2006116615A1 (en) 2005-04-26 2006-11-02 Hypnion, Inc. Benzisoxazole piperazine compounds and methods of use thereof
WO2006116614A1 (en) 2005-04-26 2006-11-02 Hypnion, Inc. Benzisoxazole piperidine compounds and methods of use thereof
US7494998B2 (en) 2005-04-26 2009-02-24 Hypnion, Inc. Benzisoxazole piperazine compounds and methods of use thereof
GB2435827A (en) * 2006-03-09 2007-09-12 Del Dr Esteve S A Spain Lab Use of substituted piperazine compounds for the treatment of food related disorders

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JPH11501051A (en) 1999-01-26
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TR199700794T1 (en) 1997-11-21

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