MXPA97006133A - 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 - Google Patents

Abstract

The invention relates to the use of 8- derivatives. { a- [4-aryl (or heteroaryl) -1-piperazinyl] -butyl} -1-h-azole, as well as its physiologically acceptable salts, for the manufacture of drugs for the treatment of obesity-compulsive disorders, sleep apnea, sexual dysfunction, emesis and the sea

Description

USE OF L- DERIVATIVES. { 4- -ARIL (Q HETEROARID-1- PIPERAZINILH-BUTILJ-LH-AZOL FOR LFL PREPARATION OF A MEDICINAL PRODUCT INTENDED FOR THE TREATMENT OF OBSESSIVE-COMPULSIVE DISORDERS, SLEEP APNEA, SEXUAL DYSFUNCTIONS, EMESIS AND DIZZINESS IN THE MAMMALS, INCLUDING THE MAN The present invention relates to the use of l- derivatives. { 4-C4-apl (or heteroap Dl-piperazinylD-butyl.) -1-H-azole, as well as its physiologically acceptable salts, for the manufacture of medicaments for the treatment of obsessive-compulsive disorders, apnea of sleep, sexual dysfunction, emesis and dizziness The compounds to which the present invention relates have been described in European Patent EP-0382637 and EP-44 (J765) as well as in European Patent EP-05G2786, which relates to a process for the preparation of the derivatives of anl (or heteroapl) -pipera il-but-l-azoles In Patents EEP-0382637 and EP- -0497659 we have claimed the use of these compounds for the treatment of certain diseases of the central nervous system.Rhora we have discovered that the derivatives of ariKo heteroapl) - ?? perapm 1-but Ll-ales show an anti-obsessive, preventive (^ ß a ar, ne? (jel sleep, which facilitate sexual behavior, antiemetic and antinausea activity and, therefore, are useful in therapeutic prevention and the treatment of obsessive-compulsive disorders, sleep apnea, sexual dysfunctions and nausea and vomiting, in particular those induced by chemotherapy and / or cytotoxic radiotherapy (s) or movement. They are used in preventive or curative treatments, in man and in animals, for depression, obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and dizziness. invention correspond to the general formula I (I) in which Ar represents a nitrogenous aromatic radical or not, selected from among the appendices substituted d, the 2-p indine differently substituted, and the 3- (1,2-ben i otiazole), Zi represents an atom of nitrogen or a carbon atom substituted or not, which may be represented by: C ~ F ?? Z2 represents a nitrogen atom or a carbon atom substituted or not, which can be represented by; C-R2, 2ít represents a nitrogen atom or a carbon atom substituted or not, which may be represented by; C-R .; and Ri, R2, R3 and iguales same or different, and can also be part of a cycle, aromatic or not, represent a hydrogen atom, a halogen, a lower alkyl radical, a nitro radical, a hydroxyl radical, an alkoxy radical , a cyano radical, a hydroxycarbon radical, an alkoxycarbonyl radical, a substituted aryl or aryl radical, a sulphonic radical, a sulphonic acid radical, an ammocarbon radical, whether or not substituted in the amino group, an arnmo radical or substituted mo, and its therapeutically acceptable salts. When Ar represents a rile, differently substituted, it is preferably a radical of formula R8 R7 in which R7, Re V R, equal or different, represent a hydrogen atom, a halogen, an alkyl radical, a perhaiogenoalkyl radical, a hydroxy radical, a cox 1 radical or a cyano radical. According to the invention, alkyl is understood to mean the lower alkanes, preferably Ci-C, linear or branched, optionally more saturated, in particular the methyl, ethyl, propyl, isopropyl, buryl, isobutyl, tertiary, pentat, radicals. Hexyl and its different isomers. This definition also applies to the alkyl residues of coxides. G is understood to be hydrogen, according to the present invention, preferably fluorine, chlorine, bromine or iodine.

According to the invention, aryl is understood to mean an aromatic or heteroaromatic radical, in particular chosen from phenyl radicals, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl, etc., preferably phenyl, optionally substituted, in particular by one or more radicals selected from halogens, lower alkyl, nitro, hydroxy, alkoxy, cyano, hydroxycarbonyl, alkoxycarbonyl radicals , aryl or substituted aryl, sulfonic, sulfone gone, to incarbonyl, substituted or unsubstituted on the amino, arnino or substituted arnino group. In particular, the substituents of the amino group are alkyl or aryl radicals. Therapeutically acceptable compounds are the normal addition salts of organic or inorganic acids, such as hydrochlorides, dihydrochlorides, rnesylates or tosylates. The compounds identified in Examples 1 to 84, which are indicated below, are obtained in accordance with the procedures described in the Patents EP-0382637, EP-0497659 and EP-0502786, and the data for their identification are shown in Table I.

EXAMPLES -) R 1. l-. { 4- C 4- (2-pi rirnidi l) -1-p.iperazi il] -butyl} -pi r ol, 2. l-. { 4-C4- (2-? Irimidinl) -l-p ?? eraz? Nil] -butyl} -carbazole, 3. l ~. { 4-C - (2-p? Pmidinl) -l-piperazin? P -butyl} -indol, 4. 2,3-d? phenyl-l-. { 4 ~ r - (2-p? Rirn? D? Nl) -l-p? Perazin? 3-bu l} -? ndol, 5. 4 ~ carboxarn? do ~ l-. { 4- [4- (2-? Irimidml) -l-piperaziml] -but? L} -lH-? irazol, 6. 4-carboxy-l-. { 4- [4- (2-? Ir? Rn? D? Ni) -l-piperazin iD-butyl] • lH-pi razol, 7. 3 -metí 1 -5 -tri f luoromet? L-l-. { 4- [4- (2 ~ ?? pmi? L) -1 • ?? perazm? L] ~ but? L} -lH-p? razol, 8. 4,5-difen? l-l--. { 4-C4- (2-p? Pmid? Nl) -l -piperaziml] -butyl} - IH- uni azole, 9. 2,4, 5-tnfe? 11- [4-C4- (2-??-prn? d nD-l-piperazinyl-butyl.} - IH-idazole, 10. 4,5-d? phen 1-2-met? ll ~. 4 -C4-- (2-p? Prn dml) ~ lp? Peraz ml] -but? L.]. -lH-? M? Dazol, 11. 4,5-d? Chlor-2-met? Ll- {4-C4- (2- ip di ni) - 1-pi pe ratio in 1] - but i 1.}. -1H- imidazole, 12. 2-e li- C4-C ~ (2-? ? prn? Lnl) -lp ?? eraz? nl] • but? l.}. -lH ~? m? dazol, 13. 2- feml- l- { 4-C4- (2- ?? prnidml) -l- ?? peraz? nl] -but? l) -lH ~? m? dazol, 14. 4-drnetox? c rboml - 1 ~. { - [4 - (2-p? Pm? D? Ni) -l-piperazim p-but? L} -lH-? m? dazol, 15. 4- fen i-l-. { 4-C4- (2-p? Prnid ni) -l ~? pear imll -butil} - 1H- an i azol, 16. l-. { 4-C4- (2-p? R? M? D? Nl) -l-p? Peraz? N? L] -but? L} -lH-benzir dazol, 17. l-. { 4- C - (2-p? R? M? Nl) -l-p? Peraz? Nil] -but? L} ~ 3H-? Rn? Dazor5,4-b] p? Ri? Na, 18. l-. { 4-C4- (2 ~ p? Prn? D? Nl) -1-pi? Eraz? N? LII-but? 1 J - 1H-? Rn? Dazo [5,4-b] p? Rid? a, 19. l-. { 4-C - (2-p? R? Rn? D? Nl) -l ~ p? Peraz n l] -but? L} ~ lH-benzotpazol, 20. 2- chloro- 1-. { 4- C4- (2- pipmidml) -l ~ ?? peraz? Ml3-but il) -lH-benziní dazol, 21. 1- [4- C 4- (2-p? R? M? D? Nl) -l- pipera?.! n? l3-but? l} -lH-1, 2,4-tri zol, 22. 2-. { 4- C4 - (? - p? R? M? D? Nl ll-piperazinill ut? I.) -2H-benzot pazol, 23. 2 - et ll- { 4-C4 ~ (2-p ? pmi il) -1-p peraz? ml] -butyl.}. -lH-benz rnidazole, 24. 5,6-dimet 11-1 { 4 - [4 - (2-pi pm di ni) - 1 - eg raz ni 1] -but i l.}. - lH-benzimidazole, 25. 1 - { 4-C4 - (2-p? R? Rn? Dinl) ~ 1 -pi e raz mil] - bul 11.}. - 1H-pL azole, 26. 3,5-dirneti 1 - 1 - { 4 - C 4 - (2 - ?? prní di ni) - 1 - pi pe raz nor 13 -but? l.}. -lH-p razol, 27. 3,5-d? rnet? l- 4-mtro-l - { 4 - C4- (2 - ?? r? rn? nl ) -lp ?? eraz? n? l] -but? l.}. -lH-? razol, 28. 4-rnet? ii-- { 4 - C - (-p? nrn?? ni) - 1 - ?? p raz?? P-butyl.}. -lH- ?? razol, 29. 1 - { 4-C 4- (2-pyrimidi ni) -1-pipe razinill-but.il.} .1H-irni azole, 30. 4-brorno-3,5-d.irnetil-l- { 4-C4- (2-pyrimidinl) -l-pi pe raz. I. Ni 1 -buti 13- -1H- pyrazole, 31. 4-nitro-l-. {4-C4 ~ (2-? Irirnidinl) -l-piperazinyl-butyl} -. 1H-pyrazole, 32. 4-chloro-l-dihydrochloride {4-C4- (2-pyrimidinl) -] .- pipe razi i 1 -buti 1} -1H- pi azol, 3. 4-ethoxycarbonyl-l-. { 4 ~ [4- (2-pyrimid.inl) -l-piperazinyl-3-butyl} -lH-pyrazole, 34. 3-rnethyl-5-phenyl-1-. { 4- [4 ~ (2 ~ pir.i.rnidinl) -l-? Iperazinyl-butyl} -lH-pyrazole, 35. 4-bromo-l-C4-C4- (2-pyrirnidinyl) -l-pi? erazinyl3-butii} -1H- pyrazole, 36. 24-cyano-l-. { 4 ~ C4- (2-pyrimidinyl) -l.-pi? Erazinyl-3-butyl} - 1H- pyrazole, 37. - f 1 uo ro- 1 -. { - [4 - (2 - pi rimi di ni) - 1 -pipe razi ni 1 - buti 1} -lH-pi razol, 38. 4 ~ arnino-l-. { 4 ~ [4- (2-? Irirnidinl) -1-piperazinyl-3-butyl} -1H- pyrazole, 39. 4 -eti 1 sul f onarni do- 1 -. { 4-y 4- C 2 -pi ri i di ni) -1-pip r zinyl-3-butyl} -lH-? irazol, 40. 4-benzarni do- 1 - [4 - C 4 - (2 - pi ri i di ni) - 1 - pipe razi ni 13 -but i l} - IH - pi razo 1., 4.1 .. 4-acetarnido-l ~. { 4-C4- (2 ~ pi.rirni.dinl) -l-pi? Erazinyl-3-butyl} -l.H-pi azol, 42. 4- (2-but? l) am? no-1-. { 4-r4- (2-? Inmid? Nl) -l-p? Perazm? L -but? L} - lH ~ p? azol, 43. 3-chloro-4-luoroyl-. { 4-E 4- (2 - ?? pm? D? Nl) -l-pipe raz thousand 3 -but? L} -lH ~ p? razol, 44. 4- (4-rnetox? phen? l) -l-. { 4 ~ [4- (2-p? R? M d nl) -l-piperaziml 3-but? I} -] H - ?? razol, 45. 4- (4-chlorophen? L) -l ~. { 4-r4 ~ (2-p? R? Rn? D? L) -l p? Peraz? Ml3-but? L} -lH-p? azole, 46. 4- (1-pyrrol? l) -l-. { 4- C4- (- ?? ±? Dml) ~ l-p? Peraz? N? L3-butyl} - IH-p azol, 47. 4-phen l-l- £ 4- C - (2-p? Prn? D l) -l - ?? peraz? N? L3- ut? l} -lH-pi razol, 48. 3,5-d? Fen? L ~ l-. { 4-C4- (2-p? Pm d? Nl) - 1-p? Peraz? thousand-but? l} -lH ~ p? razol, 49. 4- fen? lsulfarno? l-l-. { 4- [4- (2-p? Pm? D? Nl) -1-piperaz i 13 -but? L} -lH-? razol, 50. 4- (3-methybenzene) sulphamoyl-1 ~ [4- T4 - (2-p? prn? d? ni) -1-piperazi il -but? l} -lH-? razol, 51. 4 ~ but? lsul farnoil - l-. { 4-T4- (2-p? Pm? Dinl) -1-piperazinyl-butyl} - H-pi razol, 52. 4-prop? Lsulfamo? L-l-. { 4-C4- (2-pir? M? D? Nl) -1- ?? ? erazm? l3-but? l} -lH-pyrazole, 53. 4-et? lsulfame? l-l ~. { 4-C4- (2-? Pm? D nl) ~ l-p? Peraz? Ru] 3-butyl} -IH-pi razol, 54. 3,5-d? Nt? I-4 ~ (M, N-dirnetyl sulphon) -i- [4 - [4 - (? -pi prnid l) ~ 1 -p ? peraz? ml3-but]} ~ 1H- irazole, 55. 4-N-methersulfamo? L ~ l-. { 4- [4- (2-pir? Id? Nl) -l-p ?? eraz? Ml3-but? I} ~ iH-p? razol, 56. 4-sulfon? co-l-. { 4-t - (2-p? Nm? D? Nl) -l-p ?? eraz? Ml3-butyl} -lH ~ p? razol, 57. l-. { 4- [4 ~ (2-p? Pm? Dml) ~ l-p? Peraz? N? P-but? L} -lH-írmdazol, 58. 2-rnet? l-l-. { 4- [4- (2-p? R? Rn? D? Nl) -l-p? Peraz? Nil3-but? L} -lH-midazole, 59. 4,5-d-loro-l-. { 4 ~ C4- (2- ??? m? D? Nl) ~ l-p? Peraz? N? 3-but? L] -lH-? M? Dazol, 60. 4-chloro-l-. { 4-C - (4-rnetox? Phen? L) ~ l- p? Eraz? N? L3-bu? L} -lH-pi razol, 61. 4, 5-d? chlor-2 ~ met? l ~ l -. { 4-E - (-metox? Phen? L) -] - piperazi m l3-but? L} -lH- i idazol, 62 4-chloro-l-. { 4 - [4- (-rnet oxyphenyl) -l-p perazmyl-butyl} -lH-pi-razol, 63. 4.5 ~ d-chloro ~ 2- l-l- [4- C4- (2-met-oxifem-1) -l-piperazim-l3-butyl} -lH-? m? dazol, 64. 4- chloro- 1 ~. { 4 - C4- (3-metos.? Fe il) -1- iperazi ni 13-but? L) -lH-pi razol, 65. 1 ~. { 4 ~ E4 - (-nethoxyphenyl) - l-p peraz? Ml3-but? I3 ~ u-? ~ ?? rrol, 66. 1 -. { 4- (2-? Nex? Phen?) - 1- pi pe razi ni 13 -but l? -lH-pi rol, 67. 1-C4-T4- (phen l) -l-piperazim 13-- but? l3- IH-p rroJ, F >; 8. 4-chloro-l -. { 4- -I-phenyl) -l-p? Pera? N l3-buta l} -m- pyrrole, 69. 4,5-d? chlor-2-met? l-l-. { 4-E4- (feml) -l ~ piperazn? N3-butyl} - 1H- imidazole, 70. 4-chloro-l-. { 4- 4- (2-chlorophen? L) -l-p? Perazm? L -but? L} -lH-p razol, 71. 4,5-d? chlor-2-me il-l-. { 4 ~ E - (2-chlorophen? L) -l-pi pe razi i 13 -butyl} -IH-i i dazol, 72. 4-chloro-l-. { 4- (3-chlorophen? L) -1-piperazyl-butyl} -lH-- ?? razol, 73. 4,5-d? chloro ~ 2- et? l-l ~. { 4 - 4- (-c? Anophen? L) -1-piperaz or 13 -but? L} -lH-? measure? ol, 74. 4,5-d? chlor-2-met? l-l-C4-E4- (2-fluorofen? l) -l-p i pe raz thousand 3 -but 11} - 1H- 1 my dazol, 75. 4-chloro-l-. { 4-E4- (2-c? Anophen? L) - I ~ p ?? eraz? N? L -L > ut l3-lH-pyrazole, 76. 4, 5-d? chloro-2-met? l-l-. { 4-E4 ~ (3-tp fluorornet ifeml) -1 pipe razi i 1 l-but? I} -lH-? m? dazol, 77. 4 ~ chloro-l-. { -E4- (3-tr? F luoro eti lfeni 1) -1 piperazi mi 3-but? L} -lH-p? razol, 78. 4 -chloro- 1-Í4-E4- (2-f luorofe i 1) ~ 1- pipo raz m 13 -butyl} -lH-pi razol, 79. 4-chloro-l-. { 4-C4- (1, 2-benz? Sot azol -3-? 1) -l-p? Eraz? -but? I} -lH-p? razol, 80. 4,5-d? chloro ~ 2-m t l-l-. { 4-E4- (1, 2-be? Sot? Ol-3-? L) -1 -? perazi i ll ~ but? l} -lH ~ íní dazol, 81. l-. { 4-E4- (1, 2-benzene? Azole-3?) -l-p? Eraz? N? L3-buti 1.}. -1H-1, 2, 4 -triazole, 82. 1 ~. { 4-C4- (1, 2-benzisothiazol-3-yl) -l-piperazinyl-3-butyl} -m-benzimidazole, 83. 4-brorno-l-. { 4-E4 ~ (5-bromo? Irirnidin-2-yl) ~ l-piperazinyl-3-butyl} -lH-? irazol, 84. 4-chloro ~ l-. { 4-l4- (5-bromopyrimidin-2-yl) ~ pipe razi ni 1.3 -but i 1.}. -1H- pyrazole., TABLE X ro TABLE I (continued) CJ TABLE 1 (Continued) TABLE I (ContinuedJ I-1 TABLE 1 (Continued) C51 TABLE i (Continued) TABLE I (Continued) GD TABLE I (Continued) ua TABLE 1 (Continued) or TABLE I (Continued) 1- TABLE I (Continued.) ro TABLE I (Continued) ro co TABLE I (Continued) ro 4 ^ TABLE I (Continued) ro TABLE I (Continued) ro C3n TABLE I (Continued) ro -vi TABLE i (Continued) CXI TABLE I (Continued) ro US TABLE I (Continued) Cü TABLE I (Continued) TABLE I (Continued) or TABLE I (Continued) THE \ TABLE I (Continued) TABLE I (Continued) TABLE I (Continued) yes TABLE I (Continued) -sl TABLE I (Continued) ? you TABLE I (Continued) CO v-3 TABLE I (Continued) TABLE 1 (Continued) TABLE I (Continued) / Ar - N A? (CH ^ - N \ The following examples illustrate the properties of some derivatives that fall within the scope of the present invention.

I. OBSESSIVE-COMPULSIVE DISORDERS Since it is believed that serotonin (5-HT) is involved in the pathophysiology of affective disorders, to determine the "live" dynamics of serotonin function in obsessive-compulsive disorders, paradigms have been widely used. pharmacological stimulation, among others. The precursors of 5-HT (or-tpptophan, 5-h? Drox? Tryptophan), the inhibitors and / or the reuptake releasers of 5-1-17 (DL-fenfl? Ranma) and the agonists that act directly on 5-HT (rn-CPP, HK-212, buspirone) have deserved considerable attention in-as much as possible probes of the functional state of the central neuronal system of 5-HT in various affective disorders, without so much the specificity by the 5-HT system, in general, as the selectivity for the subtypes of 5-HT receptors, in particular, continue to be questioned (Murp et al., D. Clin, Psych a + r and 47; -15, 1985; Murphy e + col. :: Br. K. Psychiatry 155 (suppl 8): 15-24, 1989; Van de kar, SD: Neurosci Biobehav, Rev. 13; 237-246, 1989). On the other hand, there is growing evidence that the ligands of SHTIA b? Spirona, gep rone and ipspirone are active anxiolytics, possibly with anti-obsessive properties, although their mechanism of action is not very clear (Leech et al .: Life Sc. 46: 1271-1277, 1990). During the study of the anxiolytic activity of the agents with affinity for the 5-HTIA receptor, one of the most important tests is that which determines the aversion behavior of the mice in a box with a highly illuminated compartment, clear box , and another dark compartment (light / dark box) (Costal 1 et al., 3. Pharmacol.Exp.262 (1): 90-98, 1992). 3e place the rabones in the illuminated compartment, which is aversive and causes them a state of anxiety. This results in a leakage reaction to the dark compartment, which can be associated with obsessive-compulsive behavior. The results obtained (see table) show that the lesopi + rón, at all the doses tested, delays the appearance of the obsessive-compulsive behavior of displacement to the dark zone, so that the latency time increases clearly.

Treatment Latency from clear zone to dark zone Control group (vehicle 10 seconds Lesopi + rum 0.0001 mg / kg, 15 seconds LesopL + rón 0.01 mg / kg, 20 seconds Lesopy 0.5 rng / g,? P 24 seconds II- ñPNEfl DEL SUEÑO Sleep apneas comprise a series of disorders of different importance. Sleep apneas are classified as obstructive, central or mixed, depending on whether there is presence or absence of respiratory efforts during the periods in which the air flow stops. Obstructive and mixed apneas are the most frequent. They present obstructive sleep apnea syndrome, in which recurrent and sporadic collapses of the upper respiratory pathways are observed during sleep. If the collapse is complete, there is no air circulation 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 feels fatigued and sleepy during the day, for no apparent reason. These episodes of recurrent apnea with hypoxia and fragmented sleep can lead to serious neurological and cardiac consequences. Until now, the pharmacological treatment of sleep apnea has had little success. Recently, some publications have pointed out the eventual utility of buspirone, a 5HTIA agonist, in sleep apnea disorders (Plendeison et al., 3. Clin Psychop arrnacol, 1991, 11 (i): 71). In order to determine the action of the lesop tron on respiration and sleep and, therefore, the possible use of this agent in sleep apnea, its effect on the response of the rat has been studied, following the work performed with buspirone for this purpose (tlendeson et al., Am. Rev. Respir Dis. 14 (6): 1527-1530, 1990). The results obtained show that the lesopitron, at doses of 10 and 30 mg / kg, i.v., leads to a significant increase in the respiratory rate, as well as pulmonary ventilation in the anesthetized rat.

RESPIRATORY ACTION OF THE LESOPITRON IN THE ROTO ANESTESIADA WITH URETANO Dosage lesopitron Lung ventilation Increase of (rng / kg, iv) (maximum increase) respiratory rate (inspi rac / ini) 0. 3 10% 9 1 20% 15 3 20% 18 10 22% 20 30 44% 23 The roencephalographic study of rat sleep showed that the lesopitron, at 5 mg / kg, significantly increases sleep latitude, while decreasing the total sleep time, that is, increasing the wakefulness time. .

ELECTROENCEPHALOGRAFICO STUDY OF THE DREAM IN THE RAT Group Latency of sleep (min) Time of vigil (min) without REM REM Group cont rol (vehicle) 32 i 3 62 90 Lesopí tron (5 mg / kg, se) 71 4 (+) 194 ± 14 (*) 130 ± 4 (*) Summarizing the results obtained, it can be affirmed that the lesopitron can be a respiratory stimulant with persistent effects during sleep. Therefore, it is adequate in the treatment of sleep apnea.

III. SEXUAL DYSFUNCTION The etiology of sexual dysfunction may include psychological factors, personal and situational reasons, physical factors and, also, side effects of far-sleeping agents. Given that sexual dysfunction can come from a great variety of underlying causes, which can range from purely psychogenic to totally physical causes, it would not be realistic to expect that a single treatment modality could be effective in all cases, in practice As usual, sexual dysfunction is considered 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 may even not 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 purpose. The activation of 5HTIA receptors seems to facilitate the sexual behavior of the male rat, since 8-OH-DPAT increases the number of couplings and decreases the latency of ejaculate (Murphy et al .: 3. Clin. Psychiatry 47: 9 -15, 1986; Mur phy et al .: Br-. K. Psychiatry 155 (suppl 8): 15-24, 1989). Similar effects have been found with other selective products for the 5-HTIA co receptor or buspirone, gepirone or ipsopyrone. However, it is not known whether the effect of 5HTIA agonists on the sexual behavior of male or female rats is provoked, either by the stimulation by these products of the SHTIA autoreceptors (this reduces the synthesis of 5-HT and decreases the serotonergic function) or by the stimulation of postsmaptically located receptors. In order to demonstrate the ability of lesopitron to improve sexual dysfunction, its action on the sexual behavior of male rats has been evaluated. With this objective, the methodology described by M.M. Fore an et al. O. Pharrnacol. Exp. Ther. 270 (3): 1270-1281 (1994). The main index used to evaluate the action of the product has been the LE (time necessary to achieve ejaculation, or ejaculation latency after penetration).

Dosage of% inhibition of the latency of lesopitron ejaculation (LE) * in relation to the control group 0. 1 40% 1 60% 10 70% * LE for the group treated with vehicle: 745 ± 30 seconds. The results obtained with the lesopitron demonstrate the activity of the product facilitating the sexual behavior of the rats.

IV. EMESIS The compounds of the invention have been studied for their effects on emesis in the ferret, according to a method described by Coetall et al. (Neuropharnacology, 1986, 25, 959-961). Ferrets of both sexes (0.7-1.4 kg) are conditioned individually at 21 ± 1 ° C and fed normally. Compound 32 is administered to a vehicle subcutaneously as pretreatment for 15 minutes before the administration of cisplatm (10 mg / kg v.v. through a fi bular ugular cannula).

S observe the animals at the beginning of the emesis and then, for 240 minutes. Emesis is characterized by rhythmic abdominal contractions, either associated with the expulsion of solid or liquid matter (ie, vomiting), or not associated in the passage of material through the mouth (nausea). and record the number of episodes and nausea or vomiting. The compound of Example 32 is capable of antagonizing the emesis induced by the cisplatm (Figure 1). Figure 1: The compound of example 32 is able to antagonize the emesis induced by the cisplatm in the ferret.

The animals receive a vehicle (V, n = 7) or the compound of example 32 (0.05-0.5 mg / kg sC, n = 4) for each dose, 15 minutes before the intravenous administration of cisplatin (10). mg / kg). The animals are observed for 240 minutes. A significant difference with respect to V is indicated sP < 0.05 (Mann-Whitney U test). It is understood that, in human therapy, the dose of administration is a function of the severity of the condition to be treated. It is generally between 5 and 100 mg / kg. The derivatives of the invention will be administered, for example, ba or tablet form, dragees or intravenously. Next, two particular galenic forms are indicated by way of example.

EXAMPLE OF FORMULA BY COMPRESS Compound of example 32 20 rng Lactose 50 mg Microcrystalline cellulose 20 rng Povidone 5 mg Pregelatinized starch 3 rng Colloidal silicon dioxide 1 mg Magnesium stearate 1 mg Weight the tablet 1.00 rng EXAMPLE OF FORMULA BY GRAGEA Compound of Example 32 20 rng Polyoxyethylenated Giicerin 125 mg Glycerin Behenate 5 rng 150 mg Excipient: soft gelatine c.s. > EXAMPLE OF FORMULA BY INJECTABLE VIAL Compound of example 32 4 g 20 rng Sodium chloride 15 mg 50 ng Water for injection c.e.p, 2 rng 20 rng Taking into account the interesting pharmacological properties associated with 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 for the treatment of obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and. dizziness. In particular, for the manufacture of antiobsessive agents, preventive of sleep apnea, which facilitate sexual behavior, antiemetics and ninaausea.

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1.- New use of compounds of the general formula I Ar - NT N- (CH2> 4 - N "" '3 / z L2 wherein Ar represents a nitrogenous aromatic radical or not, chosen from differently substituted aryls, the 2-pyridine differently substituted, and 3- (1,2-benzisothiazole), Zi represents a nitrogen atom or a substituted carbon atom or not, which may be represented by: C-Ri, Z2 represents a nitrogen atom or a carbon atom substituted or not, which may be represented by; C-R2, Zi, represents a nitrogen atom or a carbon atom substituted or not, which can be represented by; CR.;, And Ri, R2, R3 and R1 / the same or different, and may also be part of a cycle, aromatic or not, represents a hydrogen atom, a halogen, a lower alkyl radical, a nitro radical, a radical hydroxy, an alkoxy radical, a cyano radical, a hydroxycarbony radical, an alkoxycarbonyl radical, an aplo or substituted aryl radical, a sulphonic radical, a radical suphthalene or, an arninocarbonyl radical, substituted or not in the amino group, a radical aioo arni or substituted, and
2. Therapeutically acceptable salts for the manufacture of a medicament for the treatment of obsessive-compulsive disorders, sleep apnea, sexual dysfunction, emesis and dizziness in mammals , including man. 2. New use according to claim 1, characterized in that the compounds of general formula I are selected from the following group: l-. { 4- [4 ~ (2-p? R? Rn? D? ND-1 - ?? pe razi ni 11- but 11.}. -pyrrole, l- { 4- [4- (2-pyrirnidinl) - 1 -pipe raz my 13-but? L.}. -carbazol, l- { 4- [4- (2-piri idinl) -1 -pipe razi ni 13 - but? L.}. -? Ndol , 2,3 ~ d? Fen? L ~ l ~ { 4 ~ r4- (2 - ?? ±? D? Nl) -1- ?? perazmill-but? L.}. -? Ndol, 4- carboxarn? do-l- { 4-r 4 - (2 - pi rimi di ni) - 1 - pi pe ra n 1 - ut 113 - 1H - pi razol, 4 - ca rbox i -l- [4 - C4- (2-p? R? M? D? Nl) -lp? Eraz? Ml -but? L.}.-LH-pyrazole, 3-rnetyl-5-t rifluorornet ll- C4-T 4- ( 2-p? R? N? Ml) ~ l-p? Peraz? Ml3-butil.}. -1H- pi razol, 4, 5-d? Phen? Ll- {4 -T4 ™ (2- ??? rn? d? nl) -1-r) i eraz? ml 3 ~ b? t? l} -lH-? m? dazol, 2,4,5-tpphenyl-1-. { 4-C4- (2-? Rinu ti l) -l-pi erazi mi 3 - but? L} -lH-? rn? dazol, 4, 5- di feni 1-2-metii-i - (4 - [4 - (2-riyl) -1 -piperazi mi -but? l.}. -lH-i my dazol,? , 5-d-chloro-2-methyl-l- {4-C4- (-pyruni inl) -lp ?? ra ini 13-butyl.} - IH-irnidazole, 2-et i11- {4-C4- (2-pyrirnidinyl) -1-pi and azine 13 -bu? L.}. -lH-? M? Dazole, 2-phen? Ll-. {4-r - (2-pyrinidyryl ) -1-piper-azine 13 -but? L.}. -lH-? Rn? Dazol, 4-dmethoxycarbon? Ll- {4-r4- (2-? Rimid l) -1-p ? er-azi ml3-but? l.]. ~ 1H-uni dazol, 4-phenol-l-. {4-r4 - (2-p? prn? dml) - 1-p? pera? n 13-but 11] - 1H-irm dazol, l- { 4- [4- (2 - ?? pmidi ni) - 1 ~ p? Per azi or 13-huta l.}. - H-ben imi dazol, l- {4-r4- (2-r? rn? nl) -l-piperazyl nyl-but i l.} -3H-imidazo [5, 4-b pyridine, l-. {4-E4- (2-pyrimidinyl) -l-piperazinyl-butyl} -lH-imidazor5,4-b3pi idine, 1- (4- [4 ~ (2-pyridinidinl) -l- piperazinyl-butyl, .lH-benzotriazole, 2-chloro-1- {4- [4- (2-pyrirn? dinl) -l-piperaznyl-3-butyl} -lH-benzimidazole, 1- {4-C4- (2-pirirnidinl) -l-pi? Erazim l3-butyl} -lH-1, 2,4-triazole, 2-. { 4-C4- (2 ~ pir? Mid? Nl) -l-piperazine? -butyl} -2H-benzotriazole, 2-rnetyl-1 ~. { 4- [4- (2-pyrimid? Nl) -l ~ p? Perazin? 3-but? L} ~ lH-benzim dazol, 5,6-dimethyl-l-. { 4-C4- (2-pir? Midinl) -l-piperazmi l3-but? L} -lH- benzimidazole, 1 -. { - T? - (2-pipm? D? Nl) -1-pi per-azi my 3- but 113-IH-pyrazole, 3,5-dirnethyl-1-. { 4-C4 - (2-pyrirnid? Nl) -l-? Iperazinyl -but ii -m-pi razol, 3, 5-dimethyl-4-ni ro-1-. { 4-C4- (2-pyrirnidinD-1-pipe razi ni 1 -butyl.) - IH-pi azol, 4-? Nyl-i- {4-C4- (2-pyrimidinl) -l-piperazi il3 -butil.}. -iH-pi razol, l- { 4- [p- (2-pi rirnidml) - 1 -? iperaz n? l3-but il) -m-imi dazol, 4-bro 3,5-d? Rnetil- l-. { 4 ~ r - (2 ~ p? Prnidinl) ~ 1 -piperazi i 1 -buti l} -lH-? i razol, 4 -ni tro-1 -. { 4- [4- (2-pyrim? Dinl) -1-piper-azin-l3-butyl} -lH-p? razol, di-chloro-l-hydrochloride. { 4-r4- (2-p? R? Midi ni) -l-? Ip razini 13-butyl} -m-pyrazole, 4-ethoxycarbonyl-1 -. { 4-1.4- (2-pyrimidinyl) -1- perazini! 3-butyl3-lH-pi-razol, 3-rnetyl-5-phenol-1 -. { 4 -E4- (-p? Ri idinl) -1- piperazi ni 13 but? I >; -iH- ?? razol, 4-br-omo-l -. { 4-C4-Í2-pyrimidi ni l-l-piperazinyl 3-b? T? L} ~ lH-pyr-azol, 24-c? an ~ l- [4-C4- (2-? rirní di ni) -1-pi? erazinil3-b? ti l} -lH ~ pir-azol, 4-fluoro-l-. { 4 - [4- (2 - ?? prnid? L) -l-pipera i ni 13- useful} - lH-pi razol, 4-am no-1 -. { 4-T - (2-pi rirní di l) -1-piperazini 1 -butyl} - lH-pi razol, 4-rnet 11 s? l fonami do- 1 -. { 4 - [4 - (2 - p i r n i di n l) - 1 - p i pe raz i ni 1 -but 11.}. - lH-pyrazole, 4-benzamido-l-. { 4 ~ E4- (2-p? Ri idinl) -l-piperaz? N? L3 ~ b? T? I} -m-p? razol, 4-aceta-do-l - C4 - 4- (2-p? pm? d? nl) -l-pipe razi ni 13 -but? l} -lH-p? azol, 4- (2-but? l) am? no-1-. { 4-C4- (2-piprnidml) -l ~ p ?? eraz? N? L -but? L} -lH-p? razol, 3-chloro-4- fluoro-1- C4-C4- (2-p? r? m? d? nl) -1 -? peraz? n? l3-but? i} -iH-p? razol, 4- (4-methox? phen?) -l-. { 4-C4- (2-p? Pm? D? Nl) -l-p? eraz? nil -butil} -lH-pi razol, 4- (4-chlorophen? l) -l-. { 4 ~ r4- (2-p? Pm? D? Nl) ~ 1 -pipe razi ni 1 -but? L} -lH-pi razol, 4- (l-pyrolyl) -l-. { 4-t4- (2-pyrirnidinl) -1- p ?? eraz? Ml3-but? l} -lH - ?? razol, 4-fen? l-l -. { 4- T4- (2-p r? Rn? D l) -l ~ ??? eraz? N? L3 -but? L} -lH- ?? razol, 3,5- diphenyl -1-. { 4-C4- (2-p? Pm? D? ND -l-??? peraz? N? 3-bu? 1.}. -1H-pyrazole, 4-phensulfame? -1-. 4-C4- (2 - ?? r?? D? Nl) -l ~ p? Peraz? Nil3 ~ but j 1.}. -1H-pi razol, 4- í 3-met? L benzene) sul famoi 1 -1 ~. { 4-C4- (2 - ?? r? M? D? Nl) -1 -? Peraz? N? L3-but? L} - H-pi razol, 4-but? ls? lfarno? l ~ l-. { 4 - [4- (2-pi i írnid l) -1-μ ?? eraz? Ml3-buti l} ~ lH-p? razol, 4-propilsul f moi l-l-. { 4-C4- (2-p? Pm? D? Nl) -l- ?? peraz? N? L3-but? l} -JH-pi r-azol, 4-et Lls? Lfa oil - 1-. { 4 -f4- (2-p? P? N?? L) -1-? Peraz? N? L3-b? T? L} -lH-p? razol, 3, 5-d? met? l-4- (N, N ~ dirnetii sul fonarní do) -l ~. { 4-C - (2-? Pmi ml) ~ l - ?? peraz? N? L -buti]} ~ 1H- pi razol, 4 -N-rnet? Lsulfa? No? L-1 - C4-C4- (2-p? R? Rn? D? Ni) -1 -p? Peraz? Ml -but? L} -lH-p? razol, 4-s? lfón? co-l-. { 4- [4- (2-pi prnidinl) -l - p? Peraz? N? L3- but j i} -lH-p? razol, l-. { 4-C4- (2-pi r? Rn? D? Nl) -l-p? Peraz? N? L -but? L} -lH-i i azol, 2-met? l-l -. { 4-C4- (2- ?? -? M? D? Ni) -1- pi erazi ni 13-bu? l} -lH-? rn? dazol, 4,5- say lo or -1-. { 4-C4- (2-p? P? N? D? Nl) -l- pipera i ni 13 -but 11.}. - IH-imi dazol, 4-chloro-l-. { 4-C4- (4-methox? Phen? L) -1-p? per zi n? l3-but? l} -lH - ?? razol, 4,5-d? chloro-2-met? l-l-. { 4- [4- (4-methox? Phen? L) -l-p? Peraz? N? 3-butyl} - lH-i i dazol, 4-chloro- 1-. { 4- [4- (2-methox? Phen? L) -l-piperazinyl-3-butyl} -lH-pi razol, 4,5-d? chloro-2-met? l-l-. { 4-r4- (2-rnetoxyphenyl) -l- ??? peraz? N? 3-b? T l} -lH- íní azole, 4-clo or -l-. { 4- [4- (3- etoe? Phen? L) -1- ??? peraz? N? L3-but? I} -iH - ?? razol, l-. { 4-C4- (4-methoxy? Pheni 1) -1 -piperazi ni 13 -but? L} -iH-p? rrol, l-. { 4-T4- (2-rnetox i fen? L) -l-p? Peraz? N? L -but? L} -lH- pirrol, l-. { 4 ~ C4- (fen? L) -l - ??? eraz? N? L3-but? I} -m-p? rrol / 4-chloro-l-. { 4-C4- (fen? L) -l-piperazi n? L3-b? T? L} -lH-pir-rol, 4, 5 ~ d? chlor-2-rnet il- (4-T4- (phenyl) -1-p.?peraz? ml3- but? l.} - IH-irm dazol, 4-chloro-l-C4-C4- (2 ~ chloropheni D ~ lp? Peraz? N? L -b? T? L.).-LH-p? Razol, 4, 5 -di chloro- 2-rnetil- l-. {4-C4- (2-chlorophen? l) -lp? peraz? n? l 3-but l.}. ~ lH-? m? dazole, 4-chloro-l -. {4- C4- (3-chlorophen? 1) -l-pi? Eraz? N? L -but? L.}. -m-pyrazole, 4,5-dichloro-2-rnet? L -i- [4-T4- (2-c? Anophen? L) -1-pi perazi ml3-but? L.} - IH-irnidazole, 4,5-d? Chloro-2-rnet? Ll- (4-C4- (2-fluorofeml ) -l -p? p raz? n? l3-b? t? l.]. -lH-? m? dazol, 4-chloro-l ~ { 4- C4- (2-cyano fertile) -1 - piperazi ni 1 - b? t? l.]. - lH pi razol, 4,5-di chloro- 2 -methyl- {4 C-I 3 ~ t rifluoro eti 1 feml) -1-p ? pera? nl 3-b? ti i.}. - IH- irní dazol, 4-chloro-l- { 4- [4- (3-t ri? uoror orne til feni 1) -] -pi pe-? azi i 13-but? l.) - 1H-pi razol, 4-chloro- 1 ~ { 4-T - (2-f 1 uorofeni 1) -1 - ?? p> eraz? n? l3 -but? l.).-lH-p? razol, 4-chloro-l - {4-C4 - (1, 2 ~ benz? sot? azol -3-? l) - 1-piperaziml-3-but il.}. -lH-p? razol, 4,5-d? chlor-2-rnet? l-l -. { 4-E4- (1, 2-benz? Sot? Azole-3-? L) -1-piperazi or 1 -bu ti 1.}. -1H- imidazole, l ~. { 4 ~ f 4 - (1, -benz? Sothiazol -3-ll) -l-p? Peraz? N? L -but? L} ~ lH-l, 2,4-tr? azol, 1-Í4-T4- (1, 7-benz? sot? aolol-3? l) -l-p? per-az? ml3-bu? l} -lH-benz? ? dazol, 4- brorno-l-. { 4-t4- (5-bromo? Irimidin-2-yl) -l-piperazinyl] -butyl} -lH-pi razol, 4-chloro-l ~. { 4- [4 ~ (5-brornopyrirnidin-2-yl-l-piperazinyl-1-butyl} -lH-pi-p rol
3. 3.- New use of 4-chloro-l-. {4-C4- dihydrochloride ( 2-pyrimidinyl) -1-piperazinyl 3-butyl.} - m-pi-razo for the preparation of a medicament for the treatment of obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and of dizziness in mammals, including man.