MXPA96001191A - Tetrahidropiridinas (or 4-hidroxipiperidinas) alquilazo - Google Patents

Abstract

Compounds of the general formula (I) are described for drugs that have therapeutic use in the treatment of anxiety, psychosis, epilepsy, seizure, motor problems, amnesia, cerebrovascular diseases, dementia sen

Description

TETRAHIDROPTRIDINAS (? ^ -HIDROXIPIPERIDINAS) ALKYLAZOLES DESCRIPTION OF THE INVENTION The present invention relates to new < a: W-ar i ltet rah ídrop go id ies and? + - ar i J piper id iles united; allo les of formula ge er l (I) (I) and their physiologically acceptable salts, to the processes for their preparation, to their use as medicaments, and to the pharmaceutical compositions which the subject-matter of the present invention can also be used in the industry. Pharmaceutics as intermediates and for the preparation of drugs, and to computans possess potent affinity for the sigma - / / or SHT receptors and are consequently potentially useful in the treatment of certain psychic and neurological disorders of human beings. and other mammals, there are evidences that implicate sigma receptors in the treatment of psychosis, such as rjmcozole, and others, Drug C v. Res. , -'905, 5, &tisopirfin Ja Jn, HG. / Utrcs., Fnc. JIJ ?, PS L in hirm? OL, 19 &7, 2, 12?) Show an affinity 53 n 11 icat i goes by Jes receivers siyma. On the other hand, studies of the biology and function of the siqma receptors indicate that the ligands of the sigma receptor may be effective in the treatment of certain motor disorders, in particular with ntington, dyslonia and Tüurttee syndrome. The use of sigma receptors in the substance nigca allows its use in the Parkinson's disease hcacamieita 'Walter, J.M. v col. Pharmacological Reviews, 1990,? -2, 355). Some ligands of the sigma receptors are related to the modulation of the effects mediated by the MMDA receptor and act as an ischemic agents in in vivo tests (rao, T.S. et al., Molecular Pharmacology, 199U, 37, 97fi), being able to use and the - with ulsion Irsissr C. NEu rotransmissions VII, 1991). It has been described that ligands of sigma receptors show anti-amnestic effects in animal models (Early et al., Brain Research 1991, 5 >, 2 &1. Sigma l ganoos influence the levels of oil: Icol ina in animal models (Matsuno and others., Brian Relean h 1992, 575, dlS ', and therefore, are used in the treatment of dementia sin !, for example of type A -th ^ im e. Lo ligands? 5-HT receptors, ?? particular - »p cagan istas or n partial agonist 5-HT, sample an > Anxiolytic activity, cnt i depros i va proven (olitz, D.A., Druqs, 1991, Wl, il). Also, agents with potent affinity for sigma / p 5-HT reagents can be used for the indicated therapies. In the bibliography there are examples of '- + - ar 11- L, 2, 3,' +, 6-t et rali yurtfi r id j ñas and L + - p iWL í lrox íp iper idas, without Tioargj, we do not know u?? tpan described asues in which q > ~? This is the ube-struc tures are united in nitrogen of a ring of a ol using an unsubstituted chemical chain. Related references: Davis l .. Temple et al., U.S Patent W, 20,131; 16-mctr o 196 ?. Richard A. Slennop et al., 3. Med. Chem., 199, 3, • 3360-5. Jean-Lu Malleron et al., J. Med. Chem. 1991, 3 '- +, Henning Boctcher et al. , 3. Med. Chen., 1992, 35, WOP -2. Zhuihua Sui et al., Gynthesis, 1993, 603-6. David T. S (Buster et al., J. Theft., 1993, 36, 39? 3-? 6. David 3. Wustcow and others., Chem., Lßtt 1993, 3, 277-60, Shirna ak i Naphiro < / others .. Can. Pat. Auu. , CA Nosoi.i'Oj hetÍOS previously described um s rie da N- azoles nniocs to nitrogen ae diverse, et eroci c JOS, useful as non-benzodiazard agents for the treatment of anxiety '' Euronean patents EF 362637; EP 497659 / EP 502766) and for the treatment of other ordering of the EPT 429360 EP 497656). In the patents cited, compounds of the formula ## STR00001 ## are described, whereby H represents in each case a nitrogen atom, whereby a piperazine ring is consequently treated. In the present invention, the piperazine ring is replaced by a pipepdine or a hydroxidine. The compounds object of the present invention correspond to the general formula (I).

(I) in which RL, Ra R identical or different represent each one of them a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a perha radical or a radical, a radical or a radical replaced or a vical, HÍCOHI1Ü. In addition, adjacent radicals can form an aromatic or satiny ion. A represents a carbon atom and the dashed line represents an additional bond, or A represents a carbon atom attached to a hydropy group and C-OM) and the dotted line represents a lack of additional bonding. n can have values of 2 to 6, with 4, 7 being preferable to represent a nitrogen atom or carbon atom substudy which can be represented by C- t +. -a »represents a nitrogen atom or a carbon atom subsumed which can be represented by C-Rs. Z represents a nitrogen atom or a substituted carbon atom that can be represented by C-R7. R «f» Ra? R * and f'n equal or different represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a hi-oxoyl radical, an alkoxy radical, - one carbaxyl radical, one carboxamide radical, one alkyl radical of alkyl, one plo or substituted aryl radical, or two adjacent radicals can form part of another cycle, aromatic or not. The present invention also relates to the physiologically acceptable salts of the coo < puestcs of general formula (I); and particularly the salts of hydrochloric, bronthical, sulfuric, phosphoric, acetic, lactic, malonic ico, succinic, qlutápic, fumaric, mlic, tartaric, citric, ascorbic, aleo, benzoic acids, in i lac t. or, • - j n -MTI i. c o, = a i. i c 11 i c o,: l L. i ü C 'rent ICI IJUÜÍÍ jf i Ionic. represents an azole, with the exception of tetrazoles for J s as Zi, Z.j. and 7 ... t simultaneously represent a nitrogen atom. When Rt «, Rs, R,;, R r are not part of another aromatic cycle or not, it is preferably an azoi for which only one of ZJ., 7-j, or Xl + represents a nitrogen atom, in particularly a pyrazole < Z: L or Z1 + = N) or an imidazole (Z - ^ - ^ N. When Rt +, Ra, R,., Or R -, are part of another aromatic cycle or not, the "azol" component of the an The aforementioned is fundamental, that is, it does not include radials such as β, carbonyls, pyrroloas, and radicals that include the carbonic and lesal functions such as pyrazolones, olone, benzimidazoles, and, in general, heterocycles. which comprise a carbonyl function, preferably, when R, Pj, R, or R are part of another aromatic cycle or not, the aforementioned radical preferably represents a bicyclic radical, especially an indal, indazole, a ben im dazol or a benzo ri zol.

For alkyl, linear or branched, preferably a lower alkyl of Ct-Ct +, especially a T.et i J o, an ethyl or a propyl, this definition also being applied to the rest of the alkyls of the alkoxyl and alkyl carboxylate radicals. By substituted or substituted aryl, it is preferable to understand a phenyl, occasionally substituted by one or more radicals selected from halogens and linear or branched mikyl. Halogen pair is fluorine, chlorine or bromine, with chlorine being preferred. Finally, perhaloqenaalqui la, is understood a linear or branched alkyl radical in which all the hydrogen atoms are replaced by halogens, preferably it is a radical per f luaraa.lquilo, especially tri f iuorometilo. The new derivatives of general formula (I) can be prepared according to the following procedures: Procedure A By reaction of a spirane derivative of the general formula (II) t-n the ual R i- < -d have the significance indicated above, can have values of 0 to 4 and X represents a leaving group, such as chlorine, bromine, mesyloxy or tosyloxy, with a nitrogen heterocycle of general formula (III). in which ZL, Z: E, Z. + and Z6 have the significance indicated above. The reaction is carried out in dimethyl sulfoxide solution, di et alfor, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as ether or an ether such as azoxide. . This reaction is preferably carried out in the presence of a base such as potassium carbon or tritium. The reaction temperature fluctuates between the ambient temperature and the solvent, ie, the reaction times vary from 1 to 24 hours.

Procedure B By reaction, "one poL" between a derivative of general formula (IV), an alkylating agent of general formula ',) and a nitrogenated heterocycle of general formula (III).

(IV) (V) (III) where R ,, R.?, R.3, A, X, n- Z-l, Z; B, A. + /? A Fill the meaning previously inaccurate. The reaction is carried out in a stirred solution, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene, or an aliphatic hydrocarbon such as hexane or an ester such as a cyclodextrin. . This reaction is preferably carried out in the presence of a base such as potassium carbonate or r iseti J i na. The reaction temperature oscillates between the ambient temperature and the reflux temperature of the disalveite used. The reaction times oscillate in 1 and 24 hours.

L Procedure C The preparation of the compounds of the general formula (I) can be carried out by reaction under alkylation conditions of the amines of the general formula (IV) (IV) in which R, R; i ?, R; 3 and A have the sig nification indicated above, with the compounds of general formula (VI) (SAW) in which Z, n, Zt, Zv, A1 + and Rl + have the sig nification indicated above. The reaction is carried out in dimethyl sulphuric acid solution, d and 1.1 ammonide, an alcohol such as ethanol, - '> The aromatic hydrocarbon is a toluene or an aliphatic hydrocarbon such as hexane or an ether such as diovan. This reaction is preferably carried out in the presence of a base such as potassium carbonate or tri-lactam. The reaction temperature ranges from room temperature to reflux temperature of the solvent used. The reaction times range from 1 to 24 hours.

Procedure D The preparation of the compounds of the general formula (I) can be carried out by reaction under alkylation conditions of a compound of the general formula (VII) (Vile) in which R, Ra, P and A have the sigificacin indicated above, with a nitrogen heterocycle with formula gene to (III) (III) in which ZL, "... j., L + v A cieñen i significaci n indicated an i ra to .. The reaction is effected in solution of <i line i Isul fox ido, d í e 111 f or on the way, an alcohol such as ethanol, an aromatic hydrocarbon t < al as toluene or an allytic hydrocarbon such as hexane or an ether such as dioxane, is reacted Preferably, it is carried out in the presence of a base such as potassium carbonate or tin. The reaction temperature oscillates between the ambient temperature and the reflux temperature of the solvent used. 24 hours.

Procedure E By dehydration of compounds of general formula (i) (I) in which RR, "P:" n ZS "z" "ti nen the significance indicated above, represtrita an atom of a hioruxilo group 'C-DH), Id J. i r.ea μunteaaa reirei'íita careicia The reaction is effected in acidic t by acid, hydrochloric acid, trifluoroacetic acid, sulfuric or phosphoric acid, or by treatment with thionyl chloride in benzene. The reaction oscillates between the ambient temperature and the 1 &0 ° C. The reaction points vary between 1 and 24 hours.

Procedure F By addition of organometallic reagents for example phenyllithium or magnesium phen-bromide to compounds of general formula (VIII) (VIII) where n, ZL, Z.jj, 7l + and Rl + have the significance indicated above. The reaction is carried out in a solution of an inert solvent which generates an ether, such as by the extraction of the oxetane, the hydrochloride or the ethyl ether. The reaction temperature varies between the ambient temperature and the reflux temperature or the solvent used. Reaction times range from 5 minutes v 24 hoc < s.

Procedure G By reduction of the carbonyl of the amide group of compounds of the general formula (IX) (DC) in which Rt, R.B, R: u, A n, Z, Z, Z.?, Zt "and k? Fill the significance indicated above. The reaction is preferably carried out in an inert organic solvent such as ethyl ether or tetrahydrofuran with reducing agents such as LiAlH, AlH or diboxi. The reaction temperature oscillates between the ambient temperature and the reflux temperature of the solvent used. Lm reaction times range from 5 minutes to 24 hor \ < : > .

Procedure H By reaction of a compound of general formula. (I) with a non-toxic mineral or organic acid in a suitable solvent, which may be for example an alcohol such as methane, ethanol or any one of the propanols or butanols, an ester such as ethyl acetate or a nitrile like ceton 11 ri lo; v using the usual techniques of pre-icing, crystallization, etc., the corresponding salt is obtained. The mineral acid is chosen, among others, from hydrochloric acid, hydrochloric acid, sulfuric acid or phosphoric acid; and the organic acid among mono, di or tricarbides such as acetic, lactic, alginic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, or lactic acid. , cinnamic, salicylic and acides alkyl, cycloalkyl, or phonic ion. The mona or di-salts of acid may be formed and these salts may be in anhydrous or hydrated form. The present invention is illustrated by the following examples, given simply by way of illustration and it is understood that in no way can they limit the specific nature of the process or the extension of the invention.

IfS PROCEDURE A EXAMPLE 1 Preparation of 4-chloro-1-C4- < 4-h? Dro ?? - 4-phenyl-1- pipepdinil) but? LJ-1H-pyrazole The meicla of 15. < > g (45 mmoles) of Sh id i ox L-ß-fn 11-5-a.k.k.?? C4,? Udeca, 5.4 g (53 mmoles) of 4-chloropyride and 13.2 g of basic carbonate in 2 < ") 0 mi of d 11 ormamida is heated < - refluxed for 20 hours, then, to dryness under reduced pressure, a chloroform redissolved and washed repeatedly with nyua. The organic phase is dried with anhydrous sodium sulfate and evaporated under reduced pressure, obtaining a crude oil which is suspended in ethyl ether, filtered cold and washed with ethyl ether to obtain 12.4 g (37.1 mms) of 4-gold-1- 14- (-h? Dro? -4-feni 1-1-p iper ídin 11) but 111- H-pi r zol.The melting point and the data is associ ical It will give the inspiration of this product are in table i.

PROCEDURE B EXAMPLE 7 Preparation of 4-chloro-C4-h? Drox? -4- (3-tri-f-louromene-1) -l-p? Pepd? N? Libu? L > - lH-pi razol The mixture of td, 6 q '5 mmoles of 4-h id GO? ? -4- (3- f r i i 1 tinroTet 11 f in 11) -i-p iper idi na '. t > ß q of 1, 4-d íbromobut ano / - * 3o q potassium carbonate in, 'n > p > i of d i met 11 ti > r r measure was warm reflowed for 4 hours. Then, do you swim 3? q > , 35 mmole to 4 - 1 gold, and bring it to reflux (4 hours D, not to dryness under reduced pressure, redissolve = .t chloroform> repeatedly washed in. The organic phase Dry an anhydrous sodium sulfate and evaporate at reduced pressure to obtain a crude oil that purifies by chromatography on silica gel, 9.7 g (24.2 mmol and 4-c) are obtained. o-1-- '' 4- L 4-h id ra - >? -4-í 3-tr if iuo or? lfen? i) -l- ipr idinilUbut? l > -lH-p? razal. The specific data for the identification of this product can be found in Table 1.

PROCEDURE C EXAMPLE 14A Preparation of l-C4-C4-f or ll- (1,, 3,6-tetrahydropipdinyl) Ibutillindol The mixture of 4.dg '30 mmol) of 4-f in ll, 2, 3,6- tetrahydrapyr id ina, 6.22 g of l- (4-chlorobut 11) mdal, A.3 g of potassium carbonate * -nl '.O mi of diu et i lf or amide is heated at 90 ° C for 3 hours. Then, it is evolved. dryness under reduced pressure, redissolve in chloroform and wash again with water. The organic phase is dried with anhydrous sodium sulphide and evaporated under reduced pressure, or a (When 5.7 g (17.3 m oles) of l-f4-C4-f is purified in 1-i-ln '-1, 2, 3, 6-tet rah? Crop? r id i mi jbut 1 > i ndcl. The spectroscopic data for the ideification of this product can be found in the table El.

PROCEDURE D EXAMPLE 21A Preparation of 4-chloro-l-C4-C "+ -phenyl-l- < 1, 2,3,6-tetrahydropyridinyl) Ipropyl) J.propil} -lH-p? razol To the suspension of 1.0 g of NaH in dime i 1 formamide a solution of 2.05 g (20 mmol.es) of 4-chloropyrazole in d i et i lfor amide is added dropwise. The white suspension is heated 30 minutes at 100 ° C, cooled and 4.7 g (20 mmoles) of dissolved 1- (3-chlorohydro-1) -4- phenylis, 2,3,6-tetrahydropyridine are added. in d ime i 1 formamide. Heat to reflux for 2 hours. After evaporation to dryness, the residue is extracted with chloroform, washed with water and dried. Eeca with sulphate «ródico. The resulting fluoride is purified by chromatography on silica gel. 5.2 g (17.2 mmoles) of 4-cloco-l-C4-l.4-f are obtained in i 1-1- (1, 2, 3, 6- tet rahiciropí ríd ni 1) lpri'p ?. 1 > -1 H-p i r zol. The specific data for the iden- tification of this product can be found in Table II.

PROCEDURE AND EXAMPLE 2A Preparation of 1-C4-C4-phenyl-1 < 1, 2,3,6-tetarhydro-pyridinyl) 3buyil > -lH-ben imidazole The solution of 13.4 g (3 &.2 mmoles; 'd l-C4- (4 ~ hicirox? -4-feni 1-1-p? pepd in 11) but i 13 -.1 H- Benzyl idazoi, 150 ml of conc HCl and 75 ml of ethanol is refluxed for 6 hours, then the ethanol is evaporated, the aqueous solution is cooled, made basic with dilute NaOH and extracted with chloroform. The organic phase is dried with anhydrous sodium sulfate and evaporated under reduced pressure, obtaining a crude product which is purified by silica gel over silica gel, yielding <? .lq (27.5 mmol) of 1 g. - C4-E4-Í in i ll- (1, 2, 3,6-te rahidro i idinil) 1butii> -lH-benzimid zal.The melting point and the data are »pectros > The identification of this product can be found in the table El.

PROCEDURE F EXAMPLE 11 Preparation of 4,5-d? Chloro-1- (4-C4-hydroxy-4- (4-methylphenyl) -l-piperid? Nil3bu il> -2-methyl-1H-imidazole to a suspension of 1.03 g (ti. moles; of MgCla in ml of anhydrous tet rah urane urane at -40 ° C and under an atmosphere of 11 ° C. : and ipace a _ca uc i n ce J. ? > g d tmoJ t-. e 4 r. ? ciara-2-n t? l-l- < 4-E4-o a-l-íoec? D? N] l? Ut? L > -lH-? m? dazol in 10 ml of THF anh. The complexion is left in agitation for 10 minutes at a continuous ion, at -4o ° C, a 6-fold solution of 1.0 M solution, of 4-mat bromide, and 1 limagine. The resulting suspension is allowed to stir 15 minutes at -40 ° C and 3 hours at room temperature. Then, aqueous ammonium chloride solution is added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with the oform. The chloroform phase is washed with water, dried with anhydrous sodium sulfate. and it is evaporated to dryness obtaining a liquid which is purified by chromatography on silica gel yielding 1.02 g (2.6 mmoles) of 4,5-d? cl-l-C4-C4-h? ci or -4- (4-met i lfen? l) -i-pi.-1-yl-butyl 1 > -2-met i l-lH-imi dazol. The spectroscopic data for the identification of this product can be found in Table I.

PROCEDURE G EXAMPLE 16A Preparation of 1-C4-C4-phen-1-l- (1, 2,3,6-tetarh? Dropyridinyl) Ibu il > -iH-p? razal To the solution gives 3.3 q (10 moles) of 1- C4-C4 -f in 11- 1"1, 2, 3, or-tetrahicirop? r? d? n 11) j3-? xo-but iij - 'H-pira: oi -n 25 ml of THF are added 2.' "of LiAlH.The resulting mixture of reflux for 2 hours. By injections of H2O, the inorganic salts are filtered and the THF evaporated to yield 2, og (6.2 moles).; from 1- < 4-r4-ten? L-l- '.1, 2,3, o-tet rah íuropir i d i n i i) Jbut 11 -1 H-? razol. The melting point and the data is eroscopic for the identification of this product can be found in table l.

PROCEDURE H EXAMPLE HAS Preparation of 4,5-dichloro-2-methyl-l- hydrochloride. { 4-C4-phenyl-1- (1, 2,3,6-tetrahydrapyridinyl) 3-butyl > -iH-imidazole To the solution of 7.4 g (20.3 mmoles) of 4,5-diclaro-2-methyl-l-4-E4-f nyl-1- (1, 2,3,4,6-te rah? clropyrid? l) 3-1 H-imidazole in 15 ml of ice-cold etanal abs, added 2.5 ml of a solution of tanol / citric acid 6.4 NI. After a few minutes a precipitate appears, which is filtered, washed with cold ethanol and dried, obtaining 7.7 g (.19.2 mmoles) of 4,5-d-chloro-2-met hydrochloride 11-1. f4-E4-fen 11-1- (1, 2, 3, -tetrah id ron go id ini l) Dbutil > -lH- imidazole. The melting point and the specific optical data for the identification of this product can be found in the table LE.

? I L? I (Cont) I i TABLE I (Coni) NJ i TABLE 1 (Continued) I Ni -J I (Continued inußción) I 00 I G? BL? II ? or u U X s d u? U x? X U? X u d O or X u I? I1L? II (Cont) I I TABLE 11 < With t Injection) TABLE II (Continued) I U) (Jl I TABLE II (Continued) I Os) i TABLE II (Continued) i TABLE II (Continued) I 00 00 I TABLE II (With inuación) I UJ I '.' BIOLOGICAL TESTS "BINDING" TO THE RECEPTOR SEROTONINE (5HT -L-3- 3e used homogenate or rat hippocampus following a moa ificat ion of the 3. 3. Pouloul, 3. Neu- ?, W7''2, 329 -B (19ci6) .Co or radiolinking was used PH3 & -pH-DPAT and to measure the non-specific binding and used the incubation time was 15 Tiinulo? The temperature of 37 ° C. The radial band attached to the filter was separated by filtration on glass fiber filters and the radioactivity retained on the filter was determined by liquid scintillation. liquid scintillation The inhibition constants (K-. n) were calculated by linear regression analysis. The FBPA / L p? AND program (MU? SCJ? and Ro bard, Analytical Sioc hemistr, 107,? < . (19ß) " "BINDI G" TO THE SIGMA RECEIVER The brain tissue (less cerebellum) of guinea pig was used following a modification of the method of L. Radesca et al., 3. Med Chem., 3 '- *, 3? 5ft-0¿ > 5 (1991). Co or radiol i gando - > < _ > used (:? 1H) '+) -5-PPP and to measure the binding or specific tdal halope was used. The incubation time was 120 minutes Lina t e-mpe-r atura of? 5 °. Fl rad? Ol igan or protein bound was Lrl - Filter by filter with fiber filters and the radioactivity retained on it. filter was determined by FTiteJleo liquid. The up ttes of? Nh? B? C? n go t-nM) were calt. They were analyzed by non-linear regression analysis using the EBDA'LT AND program (Mnn ap v Rod ard, Analvtical Biocbemistry 107, 220 (19 * 50).

TABLE III BINDING K) Sigma 5-HT "Kl% Des Ki% Des Ej emp lo (nM) (10 '* M) (nM) (10-H) 1 6.6 93 2 15 90 5 6.4 94 12 6 4.3 95 the 46 86 37 94 2a 82 78 3a 11 97 56 90 4a 11 93 199 72 5a 19 96 6.1 97 aa 91 9.0 100 7a 96 0.4 98 8a 97 90 9a 97 4.6 100 10a 40 88 1.3 100 1 the 92 93 14a 94 94 15a 8.4 94 98 16a 17 95 86 BMY 14802 733 k2 L omologi daily? -n medicine hu p i e ta i.iwprenlids ent l milligram v Only thousand q-mas of product that p? toe; i-r? dmj n i btreaa in one or verj trmßs. The cu'ifpsiciures -are prepared in forms compatible with the pathway of ucilizada νismi-ion, such as for example camor ¬ ttruts, dragees, capsules, suppositories, dissolutions or susp ions. These compositions are preaired by known methods and comprise from 1 to 6 weight of the active principle (L ostipposes "formulated as" to 1 / v W? 99 by weight of the pharmaceuticals anropiated and compatible with the principle active and the physical form of the composition used.An example is imprisoned the formula of a tablet containing a proUut_to of the invention.

E1EHPLQ OF FORMULA BY COMPRESS Example lia 5 g Crystalline cellulose 25 ing. Pavidana r 90 5 mg Pregel starch 3 née 3 mg Colloidal silica dioxide 1 mg Magnesium stearate 1 mg Weight to al l OO nriq

Claims (3)

NOVELTY OF THE INVENTION CLAIMS
1. The compounds of the formula (I) (I) in which R i R.? and Ra identical or different represent each of a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a radical radical or a radical, a substituted aryl or aryl radical or an alkoxyl radical; in addition two advacentes radicals can form an aromatic or saturated cycle; A represents a carbon atom and the dotted line represents an additional bond, or A represents a carbon atom attached to a hydroxyl group (C-ÜH) and the dotted line represents a lack of additional bond; n can have values from 2 to 6, with 4 being preferable; 2 L represents a nitrogen lathe to a substituted carbon atom which < Can e represent by C-Rt +; ~? represents a nitrogen atom or a carbon atom substituted q.jtí can be represented by C-R ?. 2t < . represents a nitrogen atom and a hydrogen atom which is to be e = 11-JG per? .- rt ,; L = or different resents a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a hydroxyl radical, an alcopyl radical, a carbon radical, a carba radical > < m? da, a radical carboxy lato of alkyl, a radical aplo or apJo i-ubbtiLui or, or two advacentes radicals can be part of another cycle, -Temático or not. 2. The compounds included? = I the general formula (I) according to claim 1, further characterized in that they are selected from the following l -upo: 1-4-chloro-1-t4-t4-α-drox? - -phen-1-p? pep? n? I) but? ll-1H-p? razol 2 - 4.5-d? chloro-l - [4- (4-h? drox? -4-fen? l-1? pSP? n? l? but? l] -2-? et? l-IH-iiidazol 3-1 -I4- (4-fpdrox? -4 -phen? llp? pepd? n? l) but? 11-1 H-benz or dazol 4-l-14- (4-h? dpox? -4-phen? ltp? per? d? n? l) but? l] -1H-112,4-tp -zoI 5 -4-chloro-1- {4-l4- (4-clopofen? l) -4-h? dri) x? -lp? pepd? n? llbut? l) -) Hp? razol d - 4,5-d? Chlor-1- (4- [4-hydrox? -4- (4-chlorophen? L) -1-p? Per? Di (i? Llbut? L) -2-? et? l-lH - ??? dazol? - 4-dopo-l - (4-1 -h? drox? -4- (3-tpfluopo? et? lfen? l) -1-p? pepid? n? llbut? l) -1 H-pirizol 3 - 4 5-d? chloro-l- (4-I -h? drox? -4- (3-tPifluoro? et? lfen? ll-1-p? pepd? n ? l] but? l) -2-? et? l-IH-??? dazol "- 4, 5-dulo-l - (4-14-14-f luorof in? l-4-h? drox? -lp? pepd? n? Ilbut? l | -2-? et? l-lH - ??? dazol O - H4-uh? droxt-4-fen? I -! - p? pepd? n? lJbut? l !? i) dol '1 - 4 5-d? chloro -! - (4- [4-h ? ??? 4- (4-? et? lfen? ll-1-p? pepd? n? llbut? ll-2-? et? l-lH - ??? dazol 12 - l-! 4- ( 4-h? Drox? -4-fen? Llp? Pepd? N? L] but? Ll-lH-pipazole 13-i -I4- (4-h? Drox? -4-fen? Llp? Pepd? N? llbut? ll-1H-? ndazol 14-2- [4- (4-hydrox? -4-fentl-lp? pepd? n? l) but? ll-2H-? ndazol 15-4-clopo-1 - (4- [4-h? Drox? -4- (4-? Et? Lfen? Ll-1-p? Pepd? N? L] but? L) -1 H-p? Razol 16 - 4-clopo- l- (4-l4-h? dpox? -4- (4-? ethox? phen? l) -lp? pep? d? n? llb? t? l | -1H-pipazole l? - i- [4-i4-h? drox? -4-ff (i? llp? pep? dtn? l) but? ll-2-phen? l-1H-??? dólol '8-l-'4 - [4-h? Drox? -4- (4-? Et? Lfen? L) -1-p? PePid? N? Ll ut?) -lH-benz ??? dazol '9 - 4 5-d ? phen? l-1-H-l4-h? drox? -4-phen? l-1-p? pep? d? n? I) but? ll-1H - ??? dazol i 25 - 4-clopo -l- (4- (4-h? dP? x? -4- (1-naft? l) -lp? pepd? n? llbut? l | -1H-p? razol 4-C1O? -1- 4 -l4-? d ', ox? * -! 2-naft? ll-1-p? pepd? n? llbut? l) -H-pipazole 4b 22-4-c! gold-1- (4-! 4 -pheny? ll- (1, 2,3, tetrahydropipdinil JJbuti 1? -IH-pyrazole: 3 - '-. {4- 4-phen? 1 - "-f 1, 2, 2, 6-tetra ? rop? r? d? n? 13) util.}. -lH-bepc? «idazaI 4 - '- (4-l4-phen? l-1-'l 2, 1.6-tetrah? drcp? ridipilJJbutll] - 1H-1, 2, -tr? Azol 25-4-chloro-l-. {4- [4- (4-cloP? Phen? L] -l- [l, 2.3.6-tetpah? DPop? Pd ? n? ll] but? l] -1H-pipazole U.- 4,5-d? chloro-l- (4- (4- (4-chlorophen? l) -! - (1, 2,3,6 -tetrah? drop? r? d? n?]] but? I) -2-? et? l-1H-??? dazol 27-4-chloro-l- (4- [4-y3-tpfluoro? et? Ifen? i) -lU, 2,3, á-tetrah? dpopiPid? n? l] Jbut? l] -lH-p? razol
2. 2. 3 - . 23 - 4,5-d-chloro-2-? Et? H- (4- [4- (3-tr? Muoro? Ettlfen? Ll-1- (1,2,3,6-tetrah? Drop? R ? d? n?) lbut? l) -1H-mdazole 29 - 4-chloro-1- (4- [4- (4-fluophophen? l) -1-í1,2,3ld-tetpah? drop? pd ? n? ll) but? l) -1 H-p? razol 30.- 4,5-d? clopo-1- (4- [4- (4-fluorofen? l) -1- (l, 2,3 , 6-tetpaf ?? dpop? R? D? Nil) lbut? L) -2-? Et? L-1H-??? dazol 31-415-d? Chlor-1- (4- [4-phen? l-1- (1, 213, d-tetral? DropiPidi? LJbut? L) -2-? Et? L-1H - ??? dazol 32.- hydrochloride of 4,5-dic! Oro-l- (4-í - fen? ll- (1,213, or-tetrah? drop? pd? n? l) lbut? U-2-? et? l-1H-mdazole 33-diclopfudrate of 415-d? clopo-l- (4- [4 -fen?! - 1- (1,2,3, .- tetrahydro? ddin? l) lbut? i-2-et? l-1H-mdazole 34 -l- (4- (4- ( 4-fluophenone? -1) -1- (1,2,3, d-tetpal? Drop? R? Din? L) lbut? L) mdol 35-l-í4- [4-phen? Ll- [l, 2,3, é-tetpah? Dpop? Pdin? L) lbut? L) i ?? da 36.- 4, 5-d? Chlor-2-? Et? 1-1- { 4-14-14 -? et? lfen? l 1-1-11,2, 3, í-tetpahidropiridinilJbutilHH-i.idazol 37 - l- (4- (4-fen? l-1- (1,2,3, d-tetpah ? drop? ridinil) lbut? l) -1H-? Ípazol 38.-! - (4-í-phenyl? -1- (1I2I3, .- tetrah? dropipidin? lJlbutil) -1H-indazol 39-2- [ 4- [4-phenol-1- (1) 2,3, 1-tetpahydropyrinyl] -lbutyl) -2H-indazole 40-4-cioro-1- (4- [4- (4 -? et? lfep? l) -1- (1,2,3, í-tetrah? dpop? pdin? l)] but? l) -1 H-p? razol (1-4-ciopo-l- (4 - [4- (4-? Etox? Phen? I) -1- (1,2,31-tetpah? Dpop? Pdin? L)) but? L) -1 H-p? Razo¡-4-chloro-1 - (4- [4-phen? L-1- (1,2,3, d-tetpah? Dpop? Pdin? L] lprop? L) -1 H-p? Razol 43 - 4l5-d? Chloro- 1- (4- (4- fen? -l- (112,31d-tetraf? drop? pdin? lllprop? ll-2-? et? l-1-H - ??? dazol 44 -. 44- 2-phen? L-1- (4- [4-phen? L-1- (1,2,3,6-tetPah? DPop? R? D? N? L) lbut? Il-1H-? ??? dazol 45 - l- (4- (4- (4-? et? Ifen? l] -l- (1,21 1d-tetrah? drop? r? d? n? l) lbut? ¡) -! H-benzodiazole 46 - 4,5-d? Phen? I-1 - (-14-f eni 1 -! - 11.2,
3. 3. é-tetraft idrspir idiml J] buti 1.}. -1 H -indazole 47-4-cyclo-1- (4-f4- (1-naphthl) -1- (1,2,3,6-tetpahydpop? pdi (i? l) lbut? l) -1H -pipazole 48-4-cioP? -1- (4- [4- (2-naphthl) -1- (112,3,6-tetpai? drop? r? dinil) lbut? l) -1H- pipazole 49-l- (2- (4- (4-fluorophen? l) -1- (1,2,3, d-tetrah? dropiPidin? l)! et? l) -1H-benzyldazole. 50 - 1- (4-t4-phen? L-1- (1,2,3,6-tetpah? Dpop? R? D? N? L] Jbüt? L.}. -1H-benc? DIAZOL 51-l- (4-14- (4-fluorophen?) -1-1,2,3, dt trah? drop? pdin? lIlbut? ll-lH-bepc ?? dazol. 52 - Hydrochloride of 1- (4- (4-f4-fIuorofen? l) -1- (1,2,3,6-tetrah? drop? pd? n? l) lbut? l) -1 H -benz ??? dazol 53 -. 53 - 4,5-d? Chloro-2-? Et? L-1- (4- (4- (3-tpfluoP? Iet? Lfen? Ll-1- (1,2,3, d-tetrah Hydrochloride ? dpop? p-dinilllbutill-lH-aiudazol. Chlorohydrate of 4-chloro-W4-1 - (4-fluorofeml) -1- (1,2,3,6-tetrah? Drop? R? A? Nn] lbut? L) -tH-p? - 'azol Hydrochloride of 1 4-l4-phen? ll- (i, 2,3,6-tetrah? drop? ridin? l)! but? ll-1H-? ndazole 4,5-d? chlor-1- hydrolide (4- (4- (4-fluophophen? Ll-1- (1,2,3, d-tetrah? Arop? Pd? N? Lllbut? L) -2-? Ethyl-IH-mdazole - Hydrochloride 4- (4-chlorophen? L) -1- (4- (4-phen? L-1- (1, 2,3,? -tetrah? Drop? Pd? N? L) lbut? Ll-1H-p ? - razol - 4- (4-clophophen? lJ-1- (4- [4-phen? l-1-lll21 (6-tetrah? dPop? r? d? n? l] lbut? l) -1H- p? razol - 1- (4- [4- (4-fluorophen? ll-1- (1,2,3, d-tetrah? dropiPidm? l)] butyl] -1H-tPiazole - 1 - Hydrochloride (4-14- (4-f luorofenyl 1-1 - (1,2,3,6-tetrah? DropiPid? UDlbut? L) -1 H-tpazol-1-. {4- (4- ( 4-f luorof eni 11-1 - (1,2, 3, d-tetrah? Drop? R? Dm? L) Jbut? L) -2-? Et? L-! H-benz? Dazole. l- (4- [4- (4-fluorophen? l) -1- (1,2,3,6-tetrah? drop? r? d? n? l] Ibut? l) -1H-? ndazol-2 - (4- (4- (4-fluorophen? Ll-1- [112,31í-tetrah? DPopiPid? N? L) lbut? L) -2H-? Ndazol - 2- (4- (4- ( 4-fluorophen? L) -1- (ll2,3,6-tetPah? Drop? R? D? N? L)! But? L) -2H-benzotr? Azole. 2- | 4- [4- (4-fluorophen? Ll-1- (1,121,6-tetrah? Drop? Pd? N? L] lbut? Ll-2H-benzothPiazole - • 1- (4- (4) hydrochloride - (4-FluoPophen? L) -1- (1l2,3,6-tetrah? Drop? R? D? N? L) lbut? L) -1H-benzotr? Aol. - • 1 - (4-1-U-fluorofen11) -1- (1,2, 3, 6-tetrah? Drop? R? D? N? L)] but 1) -1H-bepzatPiazole - • Hydrochloride of 4 -cloro-1-. { 4- [4- (4-chlorophen? L) -1- (1,2,316-tetrah? Drop? R? D? N? L) lbut? L) -1H-p? - razol • - Clorhdrate of 1- ( 4-M-phen? L-1- (1,2,3,6-tetrahydro? D? N? L) lbut? L] -1H-p? Razol. • - 1- (4- Hydrochloride (4-phenol-1- (112,3,6-tetrah? Drop? Pd? N? L) lbut? L) -1H-tpazol-2-phenyl? -1-hydrochloride (4-14-) fen? l-1- (1,2,3,6-tetrah? drop? r? d? n? l)] but? l) -1H-? ndazol - 1- (4- [4-fent) ll - (! 12,3, I-tetrahydrochloride dropiPid? N? Lllbut? L) -lH-p? Rrol-l- (4- (4-phen? l-1- (1,2,3,6-tetrah? drop? r? d? n? l) lbut? l) -1 H -pyrrol-4- (4-clophophen? l) -1- (4 - (4-H? Drox? -4-phen? L-1-p? Per? Dm? L) but? Ll-1H-p? Razo? -? - (4- (4- (4-fluorophen? ) -4-h? Drox? -1-p? Per? D? N? Llbut? Ll-1H-benz? Dazol-4-cloPo-1- { 4-14-h? Dpox? -4 - (3-tpfluoro? Et? Lfen? L) -1-p? Pepd? N? L) but? Ll-lH-p? Razol-l- (4- (4- (4-fluorofen? Ll-4- h? drox? -1-p? pepd? n? llbut? ll-1H-? ndazol - 2-14-14- (4-f luorof in? l) -4-h? drox? -1-p? per ? d? n? llbut?) -2H-? ndazol - 2-14-14- (4-f luorof in? l) -4-h? drox? -1-p? per? d? n? llbut? ll-2H-benzotr? aolol-i 14-Ul 4-f luorof in? l) -4-h? drox? -1-p? per? d? n? l luthyl-IH-benzotriazole 3-chloro-1- ! 4- [4-feml-1- (1,2,3,6-tetrah? Drop? R? Di! Ul) lbut? I) -IH-? Ndazole - 3-chlorohydrochloride -! - (4 -! 4-fep? L-1- (1, 2,3, -tetrah? Drop? Pd? N? L)] but? L) -1H-? Ndazol H / i. - Preparation of the preparation of OSO compounds Any of claims 1 or S, characterized by at least one of the following reactions: 3.1: by reaction of a compound that will be one of the general formula (II ) m I '(II) in which R, P.s, R.3 A, m and X have the signification indicated above, with a nitrogenous hetc roc tion of the general formula (III) 0 ("I) in which and have the sigificacin indicated canter íormente; 3.2- By "one pot" reaction between a general formula (IV) solvent, an alkylating agent of the general formula and a nitrogenous heterocycle of the general formula (III): where 'P, P. 7-l + l read the = i and i fication indicated --interior; 3. or reaction under alkylation conditions of the amines of general formula (IV) in which Rt, R.-¡, R; 3 and A have the signification indicated above, with the derivatives of general formula (VI) (SAW) where X, n, Z t,. '.. j.,' /. < . and R? have the sign indicated above; 3.L + - For reaction under conditions of -r - 'OU i.] Ation of an ompute of tormu the yener. VINE (VII) n which A ', L, R; B, R; 3 n,,' < and have the significance indicated above, with a nitrogenated heretocycle of general formula (III) HN Z ' (III) in which ZL, 7 ..? 1 2t + and R, ¡, have the significance indicated above; 3.5- For de_- > h ratification of compounds of general formula (I) (I) indicated dignifi cation. -U 11 er 101 ti ei ite, M I prem ea a carbon eternal joined to a bidroxila runo (C-QH) and the dashed line represents lack of additional bond; 3. - For the addition of organometallic reagents, for example feml-lithium or bromide of f n i I agnesium to compounds of general formula (VIII) (VIII) in which n, ZL, Z ^, Zt + and RA have the sig indication indicated above; 3.7- By reduction of comnue those of general formula (£ X) (IX) in which R L, R.j ,, R.- ,, A, n, L 7 and R? For the sig nification indicated above. 4 -.- As 'Tedi amentos, ls co puest s formula f in r i' I), ^ u f iliological salts ent e t t, c > b J is of c formi d with some of claims 1 or 2, in particular as' i ea ícamentcs c jn therapeutic activity for the treatment of anxiety, psychosis, epilepsy, seizure, oronlemas of matrimony, amnesia, diseases c rebro seu i are, senile dementia. 5. Pharmaceutical compositions, characterized by the fact of containing, in addition to a pharmaceutically acceptable excipient, according to any of claims 1 or?. . TETRAHIDRQPIRIDI AS (or + -HIDR0XIPIPERIDINAS) ALQUILAZ0LE5 SUMMARY OF THE INVENTION Compounds of the general formula are described. (I) for drugs that have therapeutic use in the treatment of anxiety, psychosis, epilepsy, seizure, motor problems, amnesia, diseases < : erebrovascu 1 ares, dementia is i 1. CA / mvs *