MXPA04012489A - 1-phenylalkyl-piperazines. - Google Patents

Abstract

Compounds of formula (I) (R and R1 are a wide range of substituents, Q is CO, CHOH or CHOR2, R2 is alkyl, alkenyl, alkynyl or cycloalkyl group, each of which is optionally substituted, or is alkanoyl, alkanoyoxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminothiocarbonyl, alkylaminothiocarbonyl or dialkylaminothiocarbonyl, R3 is H, alkyl, -alkenyl, alkynyl, cycloalkyl, aryl or heterocyclic group, each of which is optionally substituted, n is 1 or 2, A is a bond or a methylene or ethylene group and R4 is an aryl or heteroaryl group, either of which is optionally substituted) have affinity for serotoninergic receptors. These compounds and their enantiomers, diastereoisomers, N-piperazine oxides, polymorphs, solvates and pharmaceutically acceptable salts are useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to 5-HT1A receptor activity.

Description

1-FÍSNILALQüILPIPERAZINAS DESCRIPTION OF THE INVENTION The invention relates to 1-phenylalkylpiperazines having affinity for serotonergic receptors, to pharmaceutical compositions containing them and to uses of such compounds and compositions. In mammals, urination (the action of urination) is a complex procedure that requires the integrated action of the bladder, its internal and external sphincters, the pelvic floor musculature and neurological control over these muscles at three levels (on the wall of the bladder or the sphincter itself, in the autonomous centers of the spinal cord and in the central nervous system at the level of the micturation center (PMC) in the brainstem (pons) under the control of the cerebral cortex (De Groat, IVeurojbiology of Incontinence, Ciba Foundation Symposium 151: 27, 1990.) Urination results from the contraction of the pubic bladder muscle, which consists of intertwined smooth muscle fibers, under the control of the parasympathetic autonomic nervous system that originates from the sacral spinal cord. A reflex of simple emptying of the sensory nerves is activated for pain, temperature and distension that run from the bladder to the sacral spinal cord. ante, the sensory tracts from the bladder also reach the PMC, which generates nerve impulses that normally suppress sacral suppression of cortical inhibition of the reflex arc, and relax the muscles of the pelvic floor and the external sphincter. Finally contractions of the pubic bladder muscle occur and emptying occurs. Abnormalities in lower urinary tract function, for example, dysuria, incontinence and enuresis, are common in the general population. Dysuria includes urinary frequency, nocturia and tenesmus and may be caused by cystitis (including interstitial cystitis), prostatitis or benign prostatic hyperplasia (BPH), (which affects approximately 70% of older men) or by neurological disorders. Incontinence syndromes include stress incontinence, urgency incontinence, incontinence due to overflow, and mixed incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep. Previously, the treatment of neuromuscular dysfunction of the lower urinary tract involves the administration of compounds that act directly on the bladder muscles such as flavoxate, a spasmolytic drug (Ruffman, &Jt. Med. Res. 16: 317, 1988), which is also active on PMC (Guarneri et al., Drugs of Today, 30:91, 1994), or anticholinergic compounds such as oxybutynin (Andersson, Drugs 36_ 4 ??, 1988) and tolterodine (Nilvebrant, Life Sci. 68 (22-23): 2549, 2001). The use of β-adrenergic receptor antagonists for the treatment of BPH is also common, but is based on a different mechanism of action (Lepor, Urology, 42: 483, 1993). However, treatments that involve direct inhibition of the pelvic musculature (which includes the pubic bladder muscle) can have undesirable side effects, such as incomplete emptying or accommodation paralysis, tachycardia and dry mouth (Andersson, Drugs 3_5: 477 , 1988). Therefore, it would be preferable to use compounds that act via the central nervous system to alter, for example, the sacral spinal reflex or the PMC inhibition pathways in such a way that the normal functioning of the micturition mechanism is restored. US 5346896 describes agents that bind 5 - ???? which can be used in the treatment of CNS disorders, such as, for example, anxiety. EP 0924205 discloses arylpiperazine compounds that bind to 5-HTiA receptors.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds of formula I: wherein: R represents hydrogen or one or more substituents that are selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, hydroxy, halo, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, nitro, amino, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 atoms of carbon, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl from 1 to 6 carbon atoms, N, N-di-alkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of the 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and?,? - di-alkylaminosulfonyl groups of 1 to 6 carbon atoms; i represents a group selected from the group consisting of hydrogen, cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocycloxy, heterocycloalkyl and heterocycloalkoxy groups, each group is optionally substituted with one or more substituents R as defined above; Q represents -C (O) - or -CH (OR2) - wherein R2 represents a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl from 2 to 6 carbon atoms and cycloalkyl groups, wherein each group is optionally substituted with one or more groups which are selected from R5 and R6, wherein R5 is selected from the group consisting of halo, alkoxy of 1 to 6 carbon atoms; carbon, haloalkoxy of 1 to 6 carbon atoms, cyano, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxyalkyl, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, groups N, N -di-alkylaminocarbonyl of 1 to 6 carbon atoms and R6 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy and heteroarylalkoxy groups, each optionally substituted by R, or R2 represents -C (O) -alkyl of 1 to 6 carbon atoms, -C (O) O-alkyl of the 6 át carbon atoms, -C (0) NR7R8 or -C (S) NR7R8 wherein R7 and R8 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R3 represents hydrogen or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl, aryl or heterocycle, each group is optionally substituted with one or more substituents R or Ri defined as in the above; R4 represents an aryl or heterocyclic group, each is optionally substituted with one or more substituents R, as defined above; A represents a bond or (CH2) n; and n is 1 or 2, or an enantiomer, optical isomer, diastereomer, n-oxide (eg, piperazine oxide), crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof. As referred to in the definition of R6, the aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy and heteroarylalkoxy group may be optionally substituted with one or more substituents that are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, hydroxy, halo, alkenyl of 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 6 carbon atoms, alkoxyalkyl, nitro, amino, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 atoms carbon, N, N-dialkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, formyl, alkylcarbonylalkyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and N, N-dialkylaminosulfonyl of 1 to 6 carbon atoms. In preferred embodiments, Q represents -CH (OR2) -, where R2 is as defined above. In a preferred embodiment, the invention provides compounds of formula I as defined above, with the proviso that substituents of formula I are not such that simultaneously R is hydrogen or alkyl of 1 to 6 carbon atoms, Ri is halogen , Q is -C (0) - or -CH (OR2) - wherein R2 is hydrogen, R3 is cycloalkyl or alkyl and R is phenyl substituted with a member selected from the group consisting of alkyl groups of from 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and haloalkoxy of 1 to 6 carbon atoms, A is a bond and n is 1. In another preferred embodiment, the invention provides compounds of formula I as defined above, with the proviso that the substituents of formula I are not such that simultaneously Q is -CH (OR2) wherein R2 is H; R3 is cycloalkyl; R is 2-fluoro, Rx is H, R is 2-methoxyphenyl or 2 - (2,2,2-trifluoroethoxy) phenyl, A is a bond and n is 1. Also preferred is an embodiment wherein the invention provides compounds of formula I as defined in the foregoing, with the proviso that the substituents of formula I are not such that simultaneously Q is -C (0) - or -CH (OR2) - wherein R2 is hydrogen; Ri is H, phenyl or phenyl substituted with halo, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, haloalkyl, nitro, amino, alkylamino of 1 to 6 carbon atoms or dialkylamino of 1 to 6 carbon atoms; R 4 is an unsubstituted aryl group, unsubstituted heteroaryl or an aryl or heteroaryl group substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo , haloalkyl of 1 to 6 carbon atoms, nitro, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 6 carbon atoms, hydroxy, hydroxyalkyl of 1 to 6 carbon atoms, -CONR7R8, wherein R7 and R8 they are independently hydrogen or alkyl of 1 to 6 carbon atoms and -NHS2-alkyl groups of 1 to 6 carbon atoms; A is a link; and R3 represents unsubstituted aryl, unsubstituted heteroaryl or aryl or heteroaryl substituted with one or more substituents that are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, haloalkyl of 1 to 6 carbon atoms, nitro, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, phenyl, halophenyl, alkylphenyl of 1 to 6 carbon atoms and alkoxyphenyl of 1 to 6 atoms of carbon. Also preferred is an embodiment wherein the invention provides compounds of formula I as defined above with the proviso that substituents of formula I are not such that simultaneously Q is -C (O) - or -CH (0R2) - wherein R2 is hydrogen; Ri is H or unsubstituted cycloalkyl or cycloalkyl substituted with alkyl of 1 to 6 carbon atoms; R is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, haloalkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or C 2-6 alkynyl R 4 is an unsubstituted aryl, unsubstituted heteroaryl or an aryl or heteroaryl substituted with 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, haloalkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms and alkynyl groups of 2 to 6 carbon atoms; A is a link; and R3 represents unsubstituted phenyl, unsubstituted naphthyl or unsubstituted cycloalkyl, or phenyl, naphthyl or cycloalkyl substituted with 1 to 3 substituents which are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, haloalkyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms and alkynyl of 2 to 6 carbon atoms. In each of the preferred embodiments, it is further preferred that Q is -CH (0R.2) -. The compounds of formula I may exist as four stereoisomers, which may be present in racemic mixtures or in any other combination. The racemic mixtures can be subjected to enantiomeric enrichment to provide compositions enriched in a particular enantiomer, or separated into one. composition comprising a single enantiomer. Enantiomeric enrichment can be expressed as ee (enantiomeric excess), as defined in the following. Some of the preferred compounds according to the invention are described in the examples. The invention also includes metabolites of the above compounds that have the same type of activity, hereinafter referred to as active metabolites. The present invention also contemplates precursors (prodrugs or prodrugs) which are metabolized in the body to generate any of the above compounds. In another embodiment, the present invention provides pharmaceutical compositions comprising the above compounds, enantiomers, diastereomers, N-piperazine oxides, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts of such compounds of formula I, in admixture with diluents or pharmaceutically carriers. acceptable such as those described. In another embodiment, the invention provides intermediates useful in the synthesis of compounds of formula I. Some of these are included in the claims. Yet another embodiment is a method for reducing the frequency of bladder contractions due to distention of the bladder in a mammal (such as a human) in need thereof by administering an effective amount of at least one compound of the present invention. invention to reduce the frequency of contractions of the bladder due to distention of the bladder in a mammal. Yet another embodiment is a method for increasing the urinary capacity of the bladder in a mammal (such as a human) in need thereof by administering an effective amount of at least one compound of the present invention to increase the urinary capacity of the bladder. for the mammal. Yet another embodiment is a method for treating urinary tract disorders in a mammal (such as a human) in need thereof by administering an effective amount of at least one compound of the present invention to decrease at least one condition between tenesmus. bladder, overactive bladder, increased urinary frequency, decreased urinary distensibility (decreased bladder storage capacity), cystitis (including interstitial cystitis), incontinence, urine leakage, enuresis, dysuria, difficulty in initiating urination, and difficulty in emptying the urine bladder. In still other embodiments, the invention provides methods for treating prior disorders by administering a compound of formula I in combination with other agents such as, for example, one or more additional 5HTiA antagonists, antimuscarinic drugs, α-adrenergic antagonists, the enzyme cyclooxygenase which can inhibit both isozymes COX1 and COX2 or which, alternatively, can be selective for the COX2 isozyme, and NO donor derivatives thereof. In still other embodiments, the invention provides a method of treating a mammal suffering from a central nervous system (CNS) disorder due to serotonergic dysfunction by administering an effective amount of at least one compound of the present invention to treat the disorder. of the SNC. Such dysfunctions include, but are not limited to, anxiety, depression, hypertension, sleep / wake cycle disorders, eating, behavior, sexual dysfunction, and mammalian (particularly human) knowledge disorders associated with stroke, damage, dementia, and dementia. due to neurological development, hyperactivity disorders with deficient attention (ADHD), drug addiction, drug withdrawal syndrome, irritable bowel syndrome and symptoms caused by abstinence or partial withdrawal from the use of nicotine or tobacco. In still another embodiment, the invention provides a method for treating a disorder due to serotonergic dysfunction by delivering a compound of the invention to the environment of a serototinergic 5HTIA receptor, for example to the extracellular medium (or when administering systemically or locally to a mammal that produces such a 5HTiA receptor) an amount of a compound of the invention effective in the treatment of said disorder due to serotonergic dysfunction. In a preferred embodiment, the invention provides methods for treating a mammal, including a human, who suffers from urinary tract disorder by administering at least one compound of the invention to the environment of a 5HTIA receptor in an amount effective to increase the duration of the resting bladder. More highly preferred is when the increase in the duration of the bladder at rest is accompanied with little or no effect (for example decrease or increase) in urination pressure.

Compounds The invention relates to compounds of formula I as described in the foregoing. The invention includes the enantiomers, diastereoisomers, N-piperazine oxides, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts of these compounds as well as active metabolites of these compounds having the same type of activity. The term "haloalkyl" includes alkyl groups substituted by a single halogen atom (monohaloalkyl) and those substituted by more than one halogen atom (polyhaloalkyl). Examples of the latter are the trifluoromethyl and 2,2,2-trifluoroethyl groups. The term haloalkoxy should be interpreted accordingly. Preferred haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy groups. The term "aryl", alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings, wherein such rings may be attached in a predetermined manner or may be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The terms "heterocyclic" and "heterocycle" refer to saturated, partially saturated and unsaturated, heteroatom containing ring-shaped radicals, wherein the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated erocyclic radicals include saturated heteromonocyclic groups containing 1 to 4 nitrogen atoms (eg, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl); saturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example morpholinyl); saturated heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example thiazolidinyl). Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The terms "heterocycle" and "heterocyclic" embrace the term "heteroaryl", which refers to unsaturated heterocyclic radicals. Examples of "heteroaryl" radicals include 5 or 6 unsaturated heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl. , pyridazinyl, triazolyl (for example 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl) tetrazolyl (for example lH-tetrazolyl, 2H-tetrazolyl); unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (for example [1, 5-b] pyridazinyl); 3 to 6 unsaturated heteromonocyclic groups containing an oxygen atom, for example pyranyl, 2-furyl, 3-furyl; heteromonocyclic groups of 5 to 6 unsaturated members containing a sulfur atom, for example 2-thienyl, 3-thienyl; 5 to 6 unsaturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl (for example 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example benzoxazolyl, benzoxadiazolyl); 5 to 6 unsaturated heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (for example 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2,5-thiadiazolyl); unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example benzothiazolyl, benzothiadiazolyl) and the like. The term "heteroaryl" also refers to radicals in which the heterocyclic radicals are fused to aryl radicals. Examples of such bicyclic fused radicals include benzofuran, benzothiophene and the like. Such a "heterocyclic group" may have 1 to 3 substituents such as, for example, and without limitation, lower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include fused or unfused radicals of 5 to 10 members. Examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. The term "cycloalkyl" refers to saturated carbocyclic radicals having 3 to 10 carbon atoms. Preferred cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to 7 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A more preferred cycloalkyl group is cyclohexyl. The term "acyl", used alone or with a term such as "acylamino" indicates a radical provided by the residue after removal of the hydroxyl from a carboxylic acid. Preferred acyl groups are alkanoyl groups such as acetyl. A "metabolite" of a compound described herein is a derivative of a compound which is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" refers to the sum of processes by which a particular substance is changed in a living body. All the compounds present in the body are manipulated by enzymes within the body in order to derive energy or separate them from the body. Specific enzymes produce structural alterations specific to the compound, for example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions. For example, uridine diphosphate glucuronyl transferases catalyze the transfer of glucuronic acid molecule to aromatic alcohols activated, alif ticos alcohols, carboxylic acids, amines and free sulfhydryl groups. Additional information on metabolism can be obtained in The Phaimacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996), pages 11-17. Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells or other in vi tro systems such as cytochromes or microsomes and the analysis of the resulting compounds. Both methods are well known in the art. As used herein, the term "stereoisomers" refers to a compound consisting of the same atoms linked by the same bonds but having different three-dimensional structures which are not interchangeable. Three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are mirror images non-superimposable to each other. As used herein, the term "optical isomer" is equivalent to the term "enantiomer." Compounds that are stereoisomers to each other but not enantiomers to each other are called diastereoisomers. The terms "racemates" or "racemic mixture" refers to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The term "enantiomeric enrichment", as used herein, refers to the increase in the amount of one enantiomer as compared to another. A convenient method of expressing enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which finds use in the following equation: ee = * 100 El + E2 wherein El is the amount of the first enantiomer and E2 is the amount of the second enantiomer. In this way, if the initial ratio of the two enantiomers is 50:50, for example as in that which occurs in a racemic mixture, and a sufficient enantiomeric enrichment to produce a final ratio of 50:30 is what is obtained, ee with Regarding the first enantiomer it is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. According to one embodiment of the invention, an ee greater than 90% is preferred, an ee greater than 95% is more preferred and more preferably more especially an ee greater than 99%. Enantiomeric enrichment is easily determined by a person ordinarily skilled in the art using standard techniques and procedures, such as high-performance liquid chromatography with a chiral column. The choice of the appropriate chiral column, the eluent and the conditions necessary to carry out the separation of the enantiomeric pair are within the knowledge of a person ordinarily skilled in the art. In addition, the enantiomers of the compounds of formula I can be separated by a person ordinarily skilled in the art using standard techniques well known in the art such as those described by J. Jacques et al., "Enantiomers, Racemates, and Resolutions", John iley and Sons, Inc., 1981. Examples of separations include recrystallization techniques or chiral chromatography. Diastereomers differ both in physical properties and in chemical reactivity. A mixture of diastereomers in enantiomeric pairs can be separated on the basis of solubility, fractional crystallization or chromatographic properties, for example, thin layer chromatography, column chromatography or HPLC. The purification of complex mixtures of diastereomers in enantiomers typically requires two steps. In a first step, the mixture of diastereomers is separated into enantiomeric pairs, as described above. In a second step, the enantiomeric pairs are further purified in compositions enriched for one or the other enantiomer, or more preferably they are separated in a composition comprising pure enantiomers. The separation of enantiomers typically requires reaction or molecular interaction with a chiral agent, for example a solvent or a column matrix. Resolution can be obtained, for example, by converting the mixture of enantiomers, for example a racemic mixture, into a mixture of diastereomers by reaction with a pure enantiomer of a second agent, i.e., a separation agent. The two resulting diastereoisomeric products can then be separated. The separated diastereoisomers are then converted back to the pure enantiomers by reversing the initial chemical transformation. The separation of the enantiomers can also be carried out by differences in their non-covalent binding to a chiral substance, for example by chromatography on homochiral absorbents. The non-covalent binding between enantiomers and the chromatographic adsorbent establishes diastereomeric complexes, which generates a differential division in the mobile and bound states in the chromatographic system. The two enantiomers therefore move through the chromatographic system, for example a column, at different speeds, which allows their separation. Chiral separation columns are well known in the art and are commercially available (for example from MetaChem Technologies Inc., a division of ANSYS Technologies, Inc., Lake Forest, CA). The enantiomers can be analyzed and purified using, for example, stationary chiral phases (CSP), for HPLC. Chiral HPLC columns typically contain an enantiomeric compound form immobilized on the surface of a silica packaging material. For chiral resolution to occur, there must be at least three points of simultaneous interaction between the CSPs and another analyte enantiomer where one or more of these interactions is stereochemically dependent. D-phenylglycine and L-leucine are CSP type I and use combinations of P-P interactions, hydrogen bonds, dipole-dipole interactions and steric interactions to obtain chiral recognition. To be separated into a type I column, the analyte enantiomers must contain complementary functionality with that of CSP so that the analyte undergoes essential interactions with the CSP. The sample should preferably contain one of the following functional groups: p-acid or p-base, a hydrogen bond donor or acceptor, or a dipole amide. Derivatization is sometimes used to add interactive sites to these compounds that lack them. The most common derivatives involve the formation of amides from amines and carboxylic acids. MetaChiral ODM * is CSP type II. The primary mechanisms for the formation of solute-CSP complexes are through attractant interactions, but the -2.5- inclusion complexes can also play an important role. Hydrogen bonding, pi-pi and dipole stacking are important for chiral separation in MetaChiral "11 ODM Derivatization is often necessary when the solute molecule does not contain the groups required for solute-column interactions. to benzylamides, it is also required for some strongly polar molecules such as amines and carboxylic acids which otherwise interact too strongly with the stationary phase through non-stereospecific interactions.In some embodiments, the formula I set forth in the above may include a condition that excludes compounds represented by the generic formula described in U.S. Patent No. 5,345,896 In some embodiments, the formula I set forth above may include a condition that excludes compounds represented by the generic formula described in the US patent. US No. 6,358,958 In some modalities , the formula I set forth in the above may include one or more conditions that exclude compounds represented by the generic formulas described both in the US patent. No. 5,346,896 as in the patent of E.U.A. No. 6,358,958. In some embodiments, the compounds represented by the formula I exclude compounds within the formula I that are with the generic formula described in the U.S. patent. No. 5,346,896. Preferred groups in which R represents a hydrogen or a halogen atom or an alkoxy group of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms,?,? - di-aminocarbonyl of 1 to 6 carbon atoms or cyano. A preferred haloalkoxy of R is a polyhaloalkoxy, most preferably trifluoromethoxy. A preferred halogen atom representing R is a fluorine atom. The preferred position for the atoms mentioned in the above and the groups is in the 2-position of the phenyl group to which they are attached. A preferred group is one in which Rx represents a hydrogen atom. It is also preferred when, simultaneously, R represents an additional member which is selected from the groups consisting of the hydroxy, haloalkoxy groups of 1 to 6 carbon atoms, hydroxyalkyl groups of 1 to 6 carbon atoms, alkoxyalkyl, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl , N-alkylaminocarbonyl of 1 to 6 carbon atoms,?,? - dialkylaminocarbonyl of 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and N, N-dialkylaminosulfonyl of 1 to 6 carbon atoms; and Ri represents a member selected from the group consisting of the unsubstituted aryloxy, aralkyl, aralkoxy, heterocycloxy, heterocycloalkyl and heterocycloalkoxy groups, or a member selected from the group consisting of the aryloxy, aralkyl, aralkoxy, heterocycloxy, heterocycloalkyl, heterocycloalkoxy groups , aryl, heterocyclic and cycloalkyl substituted with one or more substituents that are selected from the group consisting of R represents hydrogen, one or more substituents that are selected from the group consisting of the alkylthio groups of 1 to 6 carbon atoms, hydroxy, alkenyl from 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N, -dialkylaminocarbonyl of 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms , alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms,. alkylsulfonyl of 1 to 6 carbon atoms and?,? - dialkylaminosulfonyl of 1 to S carbon atoms. Preferred groups that Q represents are -C (0) - and -CH (OR 2) - wherein R 2 represents a hydrogen atom or alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, -C (0) -alkyl of 1 to 6 carbon atoms, -C (O) -alkyl of 1 to 6 carbon atoms, -C (0) NR7R8 or -C (S) R7R8 in where R7 and R8 are independently hydrogen or alkyl of 1 to 6 carbon atoms. Preferred groups representing R3 are a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl, aryl or heterocycle. It is also preferred when R3 represents hydrogen or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, each group is optionally substituted with one or more substituents R or Ri , defined as in the previous. More preferably, R3 represents a cxclohexyl group. Preferred groups representing R 4 are an aryl or heterocyclic group, each is optionally substituted with one or more substituents that are selected from the group consisting of a halogen atom or alkoxy groups of 1 to 6. carbon atoms or haloalkoxy of 1 to 6 carbon atoms. A preferred halogen atom that is a substituent on R is fluorine. A preferred alkoxy group that is a substituent on R 4 is a methoxy group. A preferred haloalkoxy group which is a substituent e R 4 is a polyhaloalkoxy group, more preferably, a trifluoroethoxy group. A preferred aryl group representing R is a phenyl group. A preferred heterocyclic group representing R is a bicyclic heterocyclic group. More preferably, R4 represents a bicyclic heteroaryl group, more preferably a 2,3-dihydro-1, -benzodioxinyl group. It is also preferred when R 4 represents an aryl or heterocyclic group, substituted with one or more substituents that are selected from the group consisting of haloalkoxy groups of 1 to 6 carbon atoms, alkoxyalkyl, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, acylamino, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and N, N-dialkylaminosulfonyl of 1 to 6 carbon atoms. A preferably represents a bond, preferably n is 1. Also preferred are compounds of formula I wherein simultaneously, R represents a hydrogen or halogen atom or an alkoxy group of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms , -N, N-diaminocarbonyl of 1 to 6 carbon atoms or cyano; Ri represents a hydrogen atom, Q represents -C (0) - or -CH (OR2) - wherein R2 is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms , alkynyl of 2 to 6 carbon atoms, -C (0) -alkyl of 1 to 6 carbon atoms, -C (0) 0-alkyl of 1 to 6 carbon atoms, -C (0) R7R8 or -C (S) NR7R8 wherein R7 and R8 are independently hydrogen or an alkyl group of 1 to 6 carbon atoms; R3 represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl, aryl or heterocycle; R represents an aryl or heterocyclic group, each is optionally substituted with one or more substituents which are selected from the group consisting of a halogen atom or alkoxy groups of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; A represents a link; and n is 2. Also preferred are compounds of formula I represented by the formula. The compounds of formula I can be separated into diastereomeric pairs, for example, by CCD separation. These diastereoisomeric pairs are referred to herein as diastereoisomers with higher Rf CCD; and diastereoisomers with lower RE CCD. The diastereoisomers can be further enriched for a particular enantiomer or they can be separated into a single enantiomer using methods well known in the art such as those described herein.

SYNTHESIS OF THE COMPOUNDS OF THE INVENTION The compounds of the invention are generally prepared according to the following schemes: Scheme 1 The (R + Ri) respect to general I. R2 to general formula and Ra is a lower alkyl group. The starting material (1) is treated with a base, preferably potassium terbutoxide followed by alkylation with 2-bromoacetaldehyde dialkylacetal or another carbonyl-protected 2-haloacetaldehyde (for example, alkyl groups Ra can also be linked in one cycle to provide a dioxolane or dioxane ring). Other alternative and suitable bases for carrying out the condensation include lithium amides, sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and the like, with or without the aid of phase transfer catalysts. The reaction is preferably carried out in a solvent such as dimethyl sulfoxide or toluene at a temperature of from 0 ° C to reflux. The use of 3-bromopropionaldehyde dialkylacetal or another protected 3-halopropionaldehyde in the carbonyl allows obtaining, by the following reaction conditions described in the foregoing in Scheme 1, a compound I having n = 2, as anticipated in the general formula . Treatment of (2) with an acid, such as hydrochloric acid or p-toluenesulfonic acid or trifluoroacetic acid in a suitable organic solvent, provides the aldehyde (3). Generally, the reaction is carried out in a protic solvent such as a mixture of aqueous acid and acetone or tetrahydrofuran at temperatures of about 5 ° to 75 ° C, preferably at room temperature. A preferred and related method is to carry out the reaction in a mixture of aqueous trifluoroacetic acid in a chlorinated solvent at room temperature. The aldehyde (3) is coupled to the desired arylpiperazine (4) by a reduced amination procedure to prepare (5). The reaction is preferably carried out at room temperature in a non-reactive solvent such as dichloromethane or methylene chloride or chloroform in the presence of sodium triacetoxyborohydride and is substantially complete in one to 24 hours (see for example, AF Abdel-Agid, et al. al., J. Org. C em., 61, 3849 (1996)) or can be carried out in a protic solvent (for example methanol) with the aid of sodium cyanoborohydride optionally in the presence of molecular sieves. The reduction of (5) to alcohol (I) is easily carried out using a reducing agent such as sodium borohydride or diisobutylaluminum hydride or other aluminum hydride or boron u. another reduction method for carrying out the conversion of ketone to alcohol very well known to those skilled in the art, for preparing the hydroxy compound (I). The reaction is preferably carried out in an organic solvent such as methanol or methylene chloride or tetrahydrofuran at temperatures of about -20 ° C to room temperature.

Scheme 2 The starting material (1) is commercially available or can be prepared by coupling the appropriate Weinreb amide (6) [See Nahm and Weinreb, Tetrahedron Lett. , 22, 3815, (1981)] with (7), as described in Scheme 2 above, wherein M is a metal salt, such as lithium or magnesium halide.

The reaction is preferably carried out under an atmosphere of nitrogen in an aprotic solvent such as tetrahydrofuran, at ambient or lower temperatures, down to -78 ° C. Alternatively, an ester structure R3COOalkyl can be treated with substituted benzylmagnesium chloride or benzylmagnesium bromide or a lithium derivative under standard conditions well known in the art to provide the ketone of structure (1). An alternative route to obtain compounds (1) is to react the appropriate arylaldehyde with an alkyl nitro derivative in a nitroaldol manner, dehydration of the resulting nitro alcohol followed by reduction of the double bond yielding a 2-nitro (2-Alk) -phenethyl derivative, which can undergo Nef reaction to provide the desired keto derivative 1. This kind of pathway is well documented in the experimental part and in the literature. Preferably and in a related manner to the synthesis of (1) is the palladium catalyzed coupling of acyl halide with a compound (7) where it is a Zn halide. More specifically, the compounds of formula (5) can be prepared following the procedure described in Scheme 3. Unless otherwise indicated cyclohexanecarbonyl chloride to a mixture of a suitable benzylzinc chloride or bromide and a suitable palladium catalyst, for example, dichlorobis (triphenylphosphine) palladium (II) stirred at 0 ° C in a solvent such as tetrahydrofuran. Subsequently stirring is continued at room temperature for 4-24 h. The reaction is then suspended, for example, with a saturated aqueous solution of ammonium chloride. The usual treatment procedure by extraction provides the ketone (8). The ketone (8) can be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent such as ethyl acetate / hexane to provide the purified material. Alternatively, the crude ketone (8) can be transported to step B. In Scheme 3, step B, the ketone (8) is alkylated with bromoacetaldehyde diethylacetal under conditions well known in the art to provide the structure compound ( 9). For example, the ketone (8) is dissolved in a suitable organic solvent such as dimethyl sulfoxide or toluene and treated with a slight excess of a suitable base such as potassium terbutoxide. The reaction is stirred for about 15 to 30 minutes at a temperature between 0 ° C and the reflux temperature of the solvent and diethyl acetal is added dropwise to the bromoacetaldehyde reaction. A person ordinarily skilled in the art will readily appreciate that bromoacetaldehyde dimethylacetal, bromoacetaldehyde ethylene acetal and the like can be used in place of the corresponding diethyl acetal. In Scheme 3, step C, the compound (9) is hydrolyzed under acidic conditions to provide the aldehyde (10) in a manner analogous to the process described in Scheme 1. More specifically, for example, the compound (9) it is dissolved in a suitable organic solvent such as dichloromethane and treated with a suitable acid, such as aqueous trifluoroacetic acid. The reaction mixture is stirred for about 1 to 6 hours at room temperature. The reaction mixture is then diluted with the same solvent, washed with brine, the organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the aldehyde (10). The aldehyde (10) can be purified by techniques well known in the art such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate / hexane. Alternatively, the crude aldehyde (10) can be used directly in step D. In Scheme 3, step D, the aldehyde (10) is reductively aminated, under conditions well known in the art, with piperazine (4) to provide the ketone (5) in a manner analogous to the process described in Scheme I. More specifically, for example, the aldehyde (10) is dissolved in a suitable organic solvent such as methylene chloride. To this solution, approximately 1.05 or more equivalents of piperazine (4) are added. Optionally, acetic acid can be added to aid in the dissolution of piperazine (4). Then about 1.4 to 1.5 equivalents of sodium triacetoxyborohydride are added and the reaction is stirred at room temperature for about 3 to 5 hours.

The reaction is then suspended by addition of a suitable base such as aqueous sodium carbonate or hydroxide, to provide a pH of about 8 to about 12. The suspended reaction is then extracted with a suitable organic solvent, such as methylene chloride. The organic extracts are combined, washed with brine, dried, filtered and concentrated under vacuum to provide the compound of formula (5). This material can then be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate / petroleum ether or hexane. Scheme 4 Alternatively, the compounds of structure (5) can be prepared following the procedure described in Scheme 4. Unless otherwise indicated, all substituents are previously defined. The reagents and starting materials are readily available to a person ordinarily skilled in the art. In Scheme 4, stage A, the aldehyde is combined (11) with a suitable organometallic reagent (12) under conditions well known in the art to provide alcohol 13. Examples of suitable organometallic reagents include Grignard reagents, alkyl lithium reagents, alkyl zinc reagents and the like. Grignard reagents are preferred. For examples of typical Grignard reagents and reaction conditions see J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2a. Edition, McGraw-Hill, pages 836-841 (1977). More specifically, the aldehyde (11) is dissolved in a suitable organic solvent, such as tetrahydrofuran or toluene, cooled to about -5 ° C and treated with about 1.1 to 1.2 equivalents of a Grignard reagent of formula (12). ), where M is MgCl or gBr. The reaction is stirred for about 0.5 to 6 hours, then suspended and the alcohol (13) is isolated by a well-known treatment procedure. In Scheme 4, step B, alcohol (13) is oxidized under standard conditions well known in the art, such as those described by J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2a. Edition, McGraw-Hill, pages 1082-1084 (1977), to provide the ketone (1). (The ketone (1) is the initial material used in Scheme 1 above). Oxidation can also be performed using Swern's standard oxidation conditions. which are well known to a person skilled in the art (Marx, Tidwell-J. Org. Chem. 49, 788 (1984) or the alcohol (13) is dissolved in a suitable organic solvent such as methylene chloride, the solution is cooled with a wet ice-acetone bath and treated with 2.5 to 3.0 equivalents of dimethyl sulfoxide After stirring for about 30 minutes, the reaction is then treated with about 1.8 equivalents of P2O5 The reaction is stirred for about 3 hours and then, preferably, treated for about 30 minutes with about 3.5 equivalents of a suitable amine, such as triethylamine The cooling bath is then removed and the reaction is stirred for about 8 to 16 hours.The ketone (1) is then isolated by standard extraction techniques well known in the art. The art In Scheme 4, step C, the ketone (1) is treated with a suitable base followed by addition of the alkene (15), wherein X is a suitable leaving group, to provide the compound (14). For example, the ketone (1) is combined with an excess of alkene (15) in a suitable organic solvent, such as tetrahydrofuran and cooled with a wet ice-acetone bath. Examples of suitable leaving groups are Cl, Br, I, tosylate, mesylate and the like. The preferred leaving groups are Cl and Br. Approximately 1.1 equivalents of a suitable base are added and the reaction is allowed to stir for about 2 hours at room temperature. Examples of suitable bases are potassium terbutoxide, sodium hydride, NaN (Si (CH3) 3) 2, LDA, KN (Si) CH3) 3) 2, Na H2, sodium ethoxide, sodium methoxide and the like. The preferred suitable base is potassium terbutoxide. The reaction is then suspended with aqueous acid and compound (14) is isolated by usual treatment procedure. In Scheme 4, step D, the compound (14) is treated with a suitable oxidizing agent to provide (the aldehyde (3).) The aldehyde 3 is also prepared in Scheme 1). Examples of oxidized agents are ozone, NaI04 / osmium catalyst and the like. The preferred oxidizing agent is ozone. Examples of suitable reagents and oxidizing conditions are described by J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2a. Edition, McGraw-Hill, pages 1090-1096 (1977). For example, the compound (14) is dissolved in a suitable organic solvent such as methanol, a small amount of Sudan III is added and the solution is cooled to about -20 ° C. Ozone is bubbled into the solution for about 4 hours until the pink color changes to a light yellow color. A reducing agent such as Me2S or tributylphosphine is then added. The concentration provides the intermediate dimethylacetal of the aldehyde (3). This dimethylacetal is easily hydrolyzed under standard acidic conditions to provide the aldehyde (3). Alternatively, direct acid treatment of the crude reaction mixture provides the aldehyde (3). Alternatively, the aldehyde (3) can be obtained directly by ozonolysis of (14) in a solvent that does not form acetal, such as methylene chloride. In Scheme 4, step E, the aldehyde (3) is reductively aminated under conditions analogous to those described in the above in Scheme 3, step D to provide (5). (Compound 5 is also prepared in Scheme I).

Scheme 5 Scheme 5 provides an alternative synthesis for the preparation of the ketone (5). All substituents are as previously defined, unless otherwise indicated. The reagents and starting materials are readily available to a person ordinarily skilled in the art. In Scheme 5, step A, aldehyde (3) is condensed with piperazine (4) under standard conditions well known in the art to provide enamine (15). For example, about 1.05 equivalents of aldehyde (3) dissolved in a suitable organic solvent, such as isopropyl acetate or isopropanol, are added to a pure piperazine (4), in free base form,. Additional organic solvent is added to produce a suspension and the reaction is stirred for about 1 to 2 hours. The enamine (15) is then isolated by standard techniques, such as collection by filtration. In Scheme 5, step B, the enamine (15) is hydrogenated under conditions well known to a person skilled in the art to provide the compound (5). For example, the enamine (15) is combined with a suitable organic solvent, such as isopropyl alcohol and a catalytic amount of 5% palladium on carbon in a Parr bottle. The mixture is placed under 345 kPa (50 psi) of hydrogen and stirred for approximately 2 days at For the synthesis of compounds I, wherein R2 is different from H, the method provided in Scheme 6 is used. The intermediate ketone (2) is reduced with the same reduction methods used in the above in Scheme 1 for the compound (5), which provides intermediates (16), which is etherified by reaction with a base, for example NaH or potassium terbutoxide or Na H2 or LiNH2 or others, in a suitable solvent, for example tetrahydrofuran, which provides the alkoxide which is then reacted with the appropriate R2-X, with the leaving group X (halogen, mesylate or tosylate) and R2 is lower alkyl, at a temperature from 0 ° C to the reflux temperature. The obtained compounds (17) can undergo the same reactions described in Scheme I, which provides product I with R2 different from H. Alternatively, compounds of formula I can be obtained wherein R2 is not a hydrogen atom, when alkylating compounds of formula I wherein R2 is H with the same methods described in the above for alkylating compound 16, limiting this process to alkylation with a highly reactive halide or mesylate / tosylate (for example benzyl bromide) which may be reacting under controlled reaction conditions in both time and temperature, preferably at room temperature. Scheme 7 describes a double functionalization solution for the synthesis of compound (I). This kind of solution can be useful for the synthesis of libraries of compounds (I) that introduce different piperazine portions and different R3 groups at the same time. Compounds of formula (I) can be obtained, wherein R2 represents -C (0) Alk, -C (0) OAlk, -C (0) NRR8 or -C (S) NR7R8 by alkylation or addition reactions from compounds of formula (I) wherein R2 is H. These classes of reactions can be carried out using the appropriate acyl halides, alkyl chloroformates, isocyanates or isothiocyanates in methylene chloride, pyridine or DMF, optionally in the presence of a base such as TEA or NaH, or alternatively (for example, for isothiocyanates) of an acid such as trifluoroacetic acid in a temperature range from room temperature -80 ° C. Scheme 7 In Scheme 7, groups B and R are equal to groups A-R4 and (R + Ri), respectively, as indicated in general formula I; R2 and 3 are the same as indicated in the general formula and Ra is a lower alkyl group or the two Ra groups are linked to form a 1,3-dioxolanyl or 1,3-dioxanyl group. An appropriate commercial benzyl derivative can be reacted (wherein X is halogen or methanesulfonyloxy or p-toluenesulfonyloxy groups) as is well known to those skilled in the art., to provide benzyl cyanide (19). These reagents can be converted according to known alkylation methods into compounds (20) or (28) respectively by reacting them with allyl halides (or allyl mesylates or tosylates) or haloalkylaldehydes in their carbonyl protected form (derivatives of acetals or dioxolanyl, others) . These alkylation reactions can be carried out by the use of bases to generate the reactive benzyl carbanions. Examples of bases used are lithium diisopropylamide (LDA), terbutyllithium, NaH, potassium terbutoxide, sodium amide or potassium amide, or others, in a suitable solvent such as THF, Et20, DMF or other, at a temperature which it varies from -78 ° C to the reflux temperature. A preferred method of alkylation includes the use of hindered bases such as LDA in the presence of hexamethylphosphorus triamide or DMPU at -78 ° C to room temperature. In turn, the compounds (20) can be reduced by the use of diisobutylaluminum hydride (DIBAL-H) in an appropriate solvent (toluene, DMF, CH2C12 or other) at a temperature ranging from -78 ° C to the temperature of reflux of the solvent. The aldehydes (21) obtained in this manner are then protected with carbonyl following methods well known to those skilled in the art to provide the compounds (22) which can be catalytically osmlated (CP Forbes JCS Perkin Trans I, 1979, 906-910 ) or can undergo ozonolysis to provide the compounds (23). The compounds (23) can be reductively aminated as described above to provide the compounds (24). Deprotection by common methods generates the aldehydes (25). Alternatively, the compounds (25) can be obtained from the compounds (20) by applying the osmilation or ozonolysis methods thereon. The cyanopropylaldehydes (26) obtained in this way are then reductively aminated to the compound (27). Repeating the reduction with DIBAL-H described in the above on these compounds provides the aldehydes (25).

The compounds (26) can also be easily obtained from the compounds (28) by simple deprotection in the carbonyl functionality. The reaction of R3-M (wherein M is a metal salt, such as lithium or magnesium halide) with compounds (25) provides the compounds (I). A large amount of organometallic substances such as lithium or magnesium derivatives are commercially available or can be prepared easily and can be reacted in a suitable solvent such as THF, Et20 or others, from -78 ° C to the reflux temperature.

Stereochemistry In Schemes 1, 6 and 7, compounds I are obtained in a mixture without / anti diastereomers with a proportion that depends on the reaction condition used. The diastereoisomers can be separated by standard techniques known to those skilled in the art including fractional crystallization of the bases or their salts or chromatographic techniques such as liquid chromatography or flash chromatography. For the two diastereoisomers, the (+) enantiomer of the formula la can be separated from the (-) enantiomer using techniques and procedures well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions, "John Wiley and Sons, Inc., 1981. For example, chiral chromatography with a suitable organic solvent such as ethanol / acetonitrile and the 20 micron Chiralpak AD package can be used to carry out the separation of the enantiomers. The free bases of formula I, their diastereomers or enantiomers can be converted to the corresponding pharmaceutically acceptable salts under standard conditions well known in the art. For example, the free base of formula I is dissolved in a suitable organic solvent, such as methanol, treated with an equivalent maleic or oxalic acid, for example, one or two equivalents of hydrochloric acid or methanesulfonic acid, for example, and then it is concentrated under vacuum to provide the corresponding pharmaceutically acceptable salt. The residue can then be purified by recrystallization from a suitable organic solvent or a mixture of organic solvent such as methanol / diethylether. The N-oxides of compounds of formula I can be synthesized by simple oxidation procedures well known to those skilled in the art. The oxidation procedure described by P. Brougham et al (Synthesis, 1015-1017, 1987), allows the two nitrogens of the piperazine ring to be differentiated, which allows N-oxides and?,? -Dioxides Combination treatments In some embodiments, urinary tract disorders are treated by administering a compound of formula I in combination with a 5-γ antagonist. additional 0 an antagonist of one or more additional classes of receptors. In preferred embodiments, a compound of formula I is administered in combination with an antagonist of a α-adrenergic or muscarinic receptor. In additional embodiments, lower urinary tract diseases are treated by administering a compound of formula I combined with one or more inhibitors of the enzyme cyclooxygenase, which can inhibit the isozymes COX1 and COX2 or which alternatively can be selective for the isozyme COX2 and NO donor derivatives thereof. Examples of antimuscarinic drugs for administration combined with a compound of formula 1 are oxybutynin, tolterodine, darifenacin and temiverina. A compound of formula I combined with a α-adrenergic antagonist can be administered for the treatment of lower urinary tract symptoms, whether or not these are associated with BPH. Preferred α-adrenergic antagonists for administration in combination with a compound of formula I are, for example, prazosin, doxazosin, terazosin, alfuzosin and tamsulosin. Additional al-adrenergic antagonists suitable for administration in combination with a compound of formula I are described in the U.S. Patents. Nos. 5,990,114; 6,306,861; 6,365,591; 6,387,909 and 6,403,594. Examples of 5 - ???? antagonists which can be administered in combination with a compound of formula I are found in Leonardi et al., J. Pharmacol. Exp. Ther. 299; 1027-1037, 2001 (for example, EC 15/3079), patent of E.U.A. No. 6,071,920, other phenylpiperazine derivatives described in WO 99/06383 and the patent applications of E.U.A. Nos. Of Series 10 / 266,088 and 10 / 266,104 filed on October 7, 2002. Antagonists 5 - ???? additional include DU-125530 and related compounds written in the U.S. patent. No. 5,462,942 and robalzotan and related compounds described in WO 95/11891. Examples of selective COX2 inhibitors that can be administered in combination with a compound of formula I are, without limitation, nimesulide, meloxicam, rofecoxib, celecoxib, parecoxib and valdecoxib. Additional examples of selective C0X2 inhibitors are described, without limitation, in the U.S.A. 6,440,963. Examples of non-selective C0X1-C0X2 inhibitors are, without limitation, acetylsalicylic acid, niflumic acid, flufenamic acid, enfenamic acid, meclofenamic acid, tolfenamic acid, thiaprofenic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, furprofen, indomethacin, acetametacin, proglumetacin. , quetorolaco, diclofenac, etodolaco, sulindaco, fentiazac, tenoxicam, lornoxicam, cinoxicam, ibuproxam, nabumetone, tometi a, amtolmetina. Accordingly, each of the above are non-limiting examples of COX inhibitors that can be administered in combination with a compound of formula I. Examples of derivatives of COX inhibitors that can be administered in combination with a compound of formula I are derivatives of COX inhibitors having nitrate (nitrooxy) or nitrite groups, such as those provided, for example in WO 98/09948, susceptible to release NO in vivo.

Pharmaceutical Compositions The invention further provides pharmaceutical compositions comprising a compound of formula I or an enantiomer, diastereomer, N-piperazine oxide, crystalline form, hydrate, solvate, active metabolite or pharmaceutically acceptable salt of the compound. The pharmaceutical composition may also include optional active ingredients such as a pharmaceutically acceptable carrier or diluent, a flavoring agent, a sweetener, a preservative, a pigment, a binder, a suspending agent, a dispersing agent, a dye, a disintegrator, an excipient, a diluent, a lubricant, an absorption improver, a bactericide and the like, a stabilizer, a plasticizer, an edible oil or any combination of two or more such additives. Suitable pharmaceutically acceptable carriers or diluents include, but are not limited to ethanol, water, glycerol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, phosphate buffered saline, myristyl propionate PPG2, carbonate of magnesium, potassium phosphate, vegetable oil, animal oil and solquetal. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose, sucrose and lactose, corn sweetener, natural and synthetic gums such as acacia gum, tragacanth gum, vegetable gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Suitable disintegrators include, but are not limited to, starch such as corn starch, methylcellulose, agar, ventonite, xanthan gum and the like. Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable suspending agents include, but are not limited to, bentonite. Suitable dispersing and suspending agents include, but are not limited to, synthetic and natural gums such as vegetable gum, tragacanth gum, acacia gum, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and gelatin. Suitable edible oils include, but are not limited to, cottonseed oils, sesame oil, coconut oil, and peanut oil. Examples of additional additives include, but are not limited to sorbitol, talc, stearic acid and dicalcium phosphate.

Unit dosage forms The pharmaceutical composition can be formulated as unit dosage forms, such as tablets, pills, capsules, boluses, powders, granules, sterile parenteral solutions, sterile parenteral suspensions, sterile parenteral emulsions, elixirs, dyes, metered aerosol or aspersions. liquids, drops, ampoules, autoinjector devices or suppositories. The unit dosage forms can be used for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, transdermal patches and a lyophilized composition. In general, any administration system of active ingredients that results in the systemic availability of such ingredients can be used. Preferably, the unit dosage form is an oral dosage form, more preferably a solid oral dosage; therefore, the preferred dosage forms are tablets, pills and capsules. However, parenteral preparations are also preferred. Solid unit dosage forms can be prepared by mixing the active agents of the present invention with a pharmaceutically acceptable carrier and any other desired additive as described above. The mixture is typically combined with a homogeneous mixture of the active agents of the present invention which is obtained and the carrier can be any other desired additive that is formed, i.e., the active agents are dispersed evenly throughout the composition. In this case, the composition can be formed as dry or wet granules. Dosage forms can be formulated, for example, as "immediate release" dosage forms. The "immediate release" dosage forms are typically formulated as tablets that release at least 60% -90% of the active ingredient within the next 30-60 min when tested in a drug dissolution test, for example U.S. Standard Pharmacopoeia <; 711 > . In a preferred embodiment, the immediate dosage forms release 75% of the active ingredient in the next approximately 45 minutes. Dosage forms can also be formulated, for example, as "controlled release" dosage forms. The "controlled", "sustained", "extended" or "time release" dosage forms are equivalent terms and describe the type of active agent administration that occurs when the active agent is released from a release vehicle to an active agent. determinable and manipulable velocity over a period of time, which is generally of the order of minutes, hours or days, and typically varies from about 60 minutes to about 3 days, rather than being immediately dispersed at the entrance to the digestive tract or when puts in contact with gastric fluid. A rate of controlled release can vary as a function of a multiplicity of factors. Factors that alter the rate of administration in controlled release include particle size, compsition, porosity, structure change and hydration degree of a vehicle of administration or of one or several active ingredients, the acidity of the environment (either internal or external to the administered vehicle) and the solubility of the active agent in the physiological environment, i.e., the particular location along the digestive tract. Typical parameters for dissolution tests of controlled release forms are found in U.S. Standard Pharmacopoeia < 724 > . Dosage forms can also be formulated to administer the active agent in multiphasic stages whereby a first fraction of the active ingredient is released at a first rate and at least a second fraction of the active ingredient is released at a second rate. In a preferred embodiment, a dosage form can be formulated to deliver the active agent in a biphasic manner, comprising a first "immediate release phase", wherein a fraction of the active ingredient is administered at a rate set forth in above for immediate release dosage forms and a second "controlled release phase", wherein the remainder of the active ingredient is released in a controlled release manner, as set forth above for controlled release dosage forms. The tablets or pills may be coated or otherwise prepared, so as to form a unit dosage form having delayed or sustained action, such as controlled release and delayed release unit dosage forms. For example, the tablet or pill may comprise an internal dosing component and an external dosage, the latter being in the form of a layer or envelope on top of the former. The two components can be separated by an eccentric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact to the duodenum or to delay its release. Biodegradable polymers for controlling the release of active agents include, but are not limited to, polylactic acid, polyepsilen caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphmatic block copolymers of hydrogels. For liquid dosage forms, the active substances or their physiologically acceptable salts are optionally dissolved, suspended or emulsified with commonly used substances such as solubilizers, emulsifiers or other auxiliaries. Solvents for the active combinations and physiologically acceptable salts may include water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol. Additionally, sugar solutions such as glucose or mannitol solutions can be used. A mixture of the various solvents mentioned in the present invention can also be used. A transdermal dosage form is also contemplated by the present invention. The transdermal forms can be a transdermal diffusion system (transdermal patch) that uses a fluid reservoir or a drug matrix system in adhesive. Other forms of transdermal dosage include, but are not limited to topical gels, lotions, ointments, transmucosal systems and devices and iontophoretic delivery systems (electrical diffusion). The transdermal dosage forms can be used for delayed release and sustained release of the active agents of the present invention. The pharmaceutical compositions and unit dosage forms of the present invention for parenteral administration, and in particular by injection, typically include a pharmaceutically acceptable carrier, as described above. A preferred liquid carrier is vegetable oil. The injection may be, for example, intravenous, epidural, intrathecal, intramuscular, intraluminal, intratracheal or subcutaneous. The active agents can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholines. The active agents of the present invention can also be coupled with soluble polymers such as addressable drug carriers. Such polymers include, but are not limited to, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidephenol and polyethyleneoxypolilysin substituted with palmitoyl residues.

Administration The pharmaceutical composition or unit dosage forms of the present invention can be administered by a variety of routes, such as the oral and enteral routes, intravenous, intramuscular subcutaneous, transdermal, transmucosal (including rectal and buccal) and by inhalation. Oral or transdermal routes are preferred (e.g., solid or liquid formulations or skin patches, respectively). The pharmaceutical composition or unit dosage forms comprise an effective amount of the present invention and can be administered to an animal, preferably a human in need of treatment of neuromuscular dysfunction of the lower urinary tract described, by EJ McGuire in "Campbell" s UROLOGY ", 5th Ed., 616-638, 1986, WB Saunders Company, and patients affected by any physiological dysfunction related to damage to 5-HT1A receptor function. Such dysfunctions include, without limitation, central nervous system disorders such such as depression, anxiety, eating disorders, sexual dysfunction, addiction and related problems As used herein, the term "effective amount" refers to an amount that results in a measurable decrease in at least one symptom or parameter of a specific disorder In a preferred embodiment, the compound treats urinary tract disorders, such as bladder tenesmus, overactive bladder, increased urinary frequency, reduced urinary compliance (reduced storage capacity of the bladder), cystitis (including interstitial cystitis), incontinence, urine leakage, enuresis, dysuria, difficulty in initiating urination and difficulty in urination emptying the bladder, or disorders of the central nervous system due to serotonergic dysfunction (such as anxiety, depression, hypertension, disorders in the sleep / wake cycle, eating behavior, sexual function and knowledge disorder in mammals (particularly a human) associated to apoplexy, damage, dementia and due to neurological development, hyperactivity disorders related to attention deficit (ADHD), drug addiction, drug withdrawal syndrome and irritable bowel syndrome. The pharmaceutical composition or the unit dosage form of the present invention can be administered according to a dosage and administration regime defined by the systematic tests based on the guide lines indicated in the above in order to obtain optimal activity and At the same time minimize the toxicity or side effects for a particular patient. However, such fine adjustment of the therapeutic regimen is customary based on the guidelines provided herein. The dosage of the active agents of the present invention may vary according to a variety of factors such as the conditions of underlying disease, the individual condition, weight, sex and age as well as the mode of administration. An effective amount for treating a disorder can be easily determined by empirical methods known to those of ordinary skill in the art, for example, by establishing a matrix of dosages and frequencies of administration and by comparing a group of experimental units or subjects at each point in time. matrix. The exact amount that will be administered to a patient will vary based on the condition and severity of the disorder as well as the patient's physical condition. A decrease in any measurable symptom or parameter can be determined by a person skilled in the art or reported by the patient to the physician. It will be understood that any attenuation or clinical or statistically significant decrease of any symptom or parameter of urinary tract disorders is within the scope of the invention. A clinically significant attenuation or decrease means perceptible to the patient or to the physician. For example, a single patient suffering from various dysuria symptoms simultaneously such as, for example, urgency and excessive frequency of urination or both, and these can be reduced using the methods of the present invention. In the case of incontinence, any reduction in the frequency or volume of the unwanted passage of urine is considered a beneficial effect of the present method or treatment. The amount of the agent to be administered can vary between about 0.01 and about 25 mg / kg / day, preferably between about 0.1 and about 10 mg / kg / day, and more preferably between 0.2 and about 5 mg / day. kg / day. It will be understood that the pharmaceutical formulations of the present invention do not necessarily need to contain the full amount of the agent that is effective to treat the disorder, since such effective amounts can be achieved by administration of a plurality of doses of such pharmaceutical formulations. In a preferred embodiment of the present invention, the compounds are formulated into capsules or tablets, which preferably contain 50 to 200 mg of the compounds of the invention, and which preferably are administered at a total daily dose of 50 to 400 mg, so preferable 150 to 250 mg and more preferably to approximately 200 mg for relief of urinary incontinence and dysfunctions under treatment with the ligand of the 5-HTiA receptor. A pharmaceutical composition for parenteral administration contains from about 0.01% to about 100% by weight of the active agents of the present invention, based on 100% by weight of the total pharmaceutical composition. Generally, the transdermal dosage forms contain from about 0.01% to about 100% by weight of the active agents versus 100% by total weight of the dosage form. The pharmaceutical composition or the unit dosage form can be administered in a single daily dose, or the total daily dosage can be administered in divided doses. In addition, co-administration or sequential administration of another compound for the treatment of the disorder may be desirable. For example, the compounds of the invention can be administered in combination with more antimuscarinics, α-adrenergic antagonists, 5-HTIA receptor antagonists or COX inhibitors or NO release derivatives, for the treatment of lower urinary tract symptoms. Examples of antimuscarinics, oii-adrenergic antagonists, 5-β-receptor antagonists, COX inhibitors and NO-releasing derivatives thereof are set forth in the foregoing, without limitation. For polytherapy (combined treatment) wherein the compounds are in separate dosage formulations, the compounds may be administered concurrently, or each may be administered in separate alternating times. For example, the compound of the invention can be administered in the morning and the antimuscarinic compound can be administered in the evening, or vice versa. The additional compounds can be administered at specific intervals as well. The order of administration will depend on a variety of factors including age, weight, sex and medical condition of the patient; the severity and etiology of the disorders to be treated, the route of administration, the renal and hepatic function of the patient, the patient's treatment history and the patient's response capacity. The determination of the order of administration can be adjusted with precision and such precision adjustment is customary based on the guidance lines provided herein.

Uses - Methods for treatment Without wishing to be bound by any theory, it is considered that the administration of 5-HTIA receptor antagonists prevents the unwanted activity of the sacral reflex or of the cortical mechanisms that control urination. Thus, it is contemplated that a wide range of neuromuscular dysfunctions of the lower urinary tract can be treated using the compounds of the present invention which include without limitation dysuria, incontinence and enuresis (hyperreactive bladder). Dysuria includes urinary frequency, nocturia, urgency, reduced urinary compliance (reduced bladder storage capacity, difficulty in emptying the bladder, that is, a suboptimal volume of urine is expelled during urination.) Incontinence syndromes include incontinence stress, urgency incontinence and bedwet incontinence, as well as mixed forms of incontinence Enuresis refers to involuntary passage of urine at night or during the period in which the person is asleep.The compounds of the invention may also be useful for the treatment of central nervous system disorders due to serotonergic dysfunction The following examples represent typical synthesis of the compounds of formula I as generally described in the foregoing.These examples are illustrative only and are not intended to limit the invention of The reagents and initial materials are available easily accessible to a person ordinarily skilled in the art.

Example 1 1- [4-Cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyl] -4- [2- (2,2,2-trifluoroethoxy) -phenyl] -piperazine 1-cyclohexyl-2- (2- fluorophenyl) ethanone (Compound) To a mixture of 36 ml of 2-fluorobenzylzinc chloride (0.5 M solution in THF) and 0.008 g of dichlorobis (triphenylphosphine) -palladium (II) stirred at 0 ° C is added dropwise 2.14 ml of cyclohenecarbonyl chloride from a syringe. Subsequently, the reaction mixture is stirred at room temperature for 4 h, suspended with 25 ml of a saturated aqueous solution of ammonium chloride, extracted with 20 ml of EtOAc, which is dried with Na 2 SO and evaporated to dryness at room temperature. This gives 3.52 g of the title compound as a crude product which can be used in the next step without further purification. R N XH. { CDC13 5): .1.10-2.05 (ra, 10H), (tt, 1H), 3.77 (s, 2H), 6.97-7.32 (m, 4H) 4-cyclohexyl-4-oxo-3- (2-fluorophenyl) -butyraldehyde-diethylacetal (Compound Ib) A solution of 5.02 g of Compound I was refluxed in 136 ml of toluene, recovering 35 ml of toluene by distillation to remove water. Subsequently, 3.18 g of potassium terbutoxide are added and stirring and reflux are continued for 30 minutes; the reaction mixture is cooled to 80 ° C and 4.27 ml of 2-bromoacetaldehyde diethylacetal are added. After 18 h at reflux temperature, the reaction mixture is cooled to room temperature, suspended with 30 ml of a saturated aqueous solution of ammonium chloride, extracted with 30 ml of EtOAc, which is dried (Na 2 SO 4) and evaporate to dryness in vacuo which provides a product which is purified by flash chromatography (petroleum ether-EtOAc 92.5: 7.5) which gives 2.97 g of the pure title product. _ RM ¾ (CDC13 < 5): 1.00-2.10 (m, 17H), 2.20-2.52 (m, 2H), 3.30-3.72 (m, 4H), 4.25-4.45 (m, 2H), 6.90-7.35 ( m, 4H). Upper Diasteroisomer by Rf in CCD 4-cyclohexyl-3 - (2-fluorophenyl) -4-hydroxybutyral of idioethylacetal (Compound le) Lower diasteroisomer by Rf in CCD 4-cyclohexyl-3- (2-fluorophenyl) -4-hydroxybutyraldehydedietylacetal To one solution of 0.84 g of Compound Ib in 25 ml of eOH, stirred at 0 ° C, 0.095 g of NaBH 4 are added and the mixture is stirred at room temperature for 5 h. The solvent is evaporated and the crude reaction product is taken up in 15 ml of H20 and extracted with EtOAc (2 x 15 ml). The organic layer is separated, washed with brine (2 x 15 ml), dried with Na 2 SO and evaporated to dryness in vacuo to give a crude product which was purified by flash chromatography (petroleum ether-EtOAc, gradient from 92: 8 to 85:15) which gives Compound le (upper Rf ) (0.56 g, 63%) and the corresponding Compound with lower Rf (4.8%). CCD eluting with petroleum ether EtOAc 9: 1. you: NMR? . { CDC13 d): 0.90-1.35 (m, 12H), 1.50-1.95 (m, 5H and OH), 2.00-2.10 (m, 2H), 3.25-3.75 (m, 6H), 4.25 (t, 1H), 6.95 -7.30 (m, 3H), 7.40-7.55 (m, 1H) 4-cyclohexyl-3- (2-fluorophenyl) -4-methoxybutylaldehyde diethylacetal (Compound Id) To a solution of 0.514 g of Compound le in 2 ml of anhydrous DMF stirred at room temperature, 0.091 g of 60% NaH are added. The reaction mixture is stirred at room temperature for 1 h, then 0.142 ml of methyl iodide is added and the resulting mixture is stirred at room temperature for 2 h. Subsequently, the reaction mixture is poured into 30 ml of water, extracted with 2 x 20 ml of EtOAc, which is washed, dried with Na 2 SO and evaporated to dryness in vacuo which gives 0.50 g of the title compound as a crude product, which can be used in the next stage without further purification. RMN R. { CDC13 5): 0.90-1.40 (m, 12H), 1.50-1.90 (m, 5H), 1.92-2.20 (m, 2H), 3.05 (t, 1H), 3.20 (s, 3H), 3.20-3.70 ( m, 5H), 4.05-4.18 (m, 1H), 6.90-7.20 (m, 3H), 7.40-7.55 (m, 1H) 4-cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyraldehyde (Compound le) A mixture of 0.502 g of Compound Id, 3.5 ml of 50% aqueous trifluoroacetic acid and 7 ml of CH2C12 is stirred for 2 h at room temperature and then diluted with 8 ml of CH2C12. The organic layer is separated, washed with brine (2 x 15 ml), dried with Na 2 SO 4 and evaporated to dryness in vacuo to provide 0.365 g of a crude product which is used in the next step without further purification. XH NMR (CDC13 d): 0.95-1.40 (m, 6H), 1.41-2.00 (m, 5H), 2.65-2.95 (m, 2H), 3.05-3.15 (m, 1H), 3.35, 3.37 (2s, 3H), 3.70-3.90 (m, 1H), 6.90-7.25 (m, 3H), 7.40- 7.55 (m, 1H), 9.65 (s, 1H). 1- [4-cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyl] -4- [2- (2,2,2-trifluoroethoxy) phenyl] -piperazine A mixture of 0.212 g of Compound le, 0.237 g of 1- [2- (2, 2, 2-trifluoroethoxy) -phenyl] -piperazine hydrochloride, 0.24 g of sodium triacetoxyborohydride, 0.11 ml of AcOH and 6 ml of CH2C12 is stirred at room temperature for 1 h, is maintained in Resting overnight, becomes alkaline with 20% aqueous Na2CO3. The organic layer is separated, washed with brine (2 x 30 ml), dried with Na 2 SO 4 and evaporated to dryness in vacuo to provide 0.46 g of a crude product which is purified by flash chromatography (petroleum ether - EtOAc 7 : 3) what provides the title compound (0.25 g, 62%). 1H-NMR (CDC13 d): 0.95-1.30 (m, 6h), 1.55-2.50. { m, 9h), 2.45-270 (m, 4H), 3.00-3.20 (m, 5H), 3.20-3.38 (m, 4H), 435 (c, 2H), 6.85-7.20 (m, 7H), 7.40- 7.55 (m, 1H).

Example 2 1- (4-Fluoro-2-methoxyphenyl) -4- [4-oxo-3- (2-trifluoromethoxy-phenyl) -pentyl] -piperazine 1- (2-trifluoromethoxyphenyl) -propan-2 -one (Compound 2a) A solution of 1.9 g of 1- (2-trifluoromethoxy) -benzaldehyde, 4 ml of EtOH, 1.3 ml of 96% 2-nitroethane and 0.10 ml of n-butylamine is stirred at reflux for 18 h. Subsequently, it is diluted with H20, extracted with EtOAc (2 x 30 mL), washed with H20 (2 x 30 mL), brine, dried with Na2SO4 and evaporated under vacuum to provide 2.47 g of an orange oil which is purify by flash chromatography (PE-EtOAc 100: 5). Evaporation of the collected fractions gives 1.60 g of 2-nitro-3- (3-trifluoromethoxyphenyl) -prop-2-ene as a light yellow oil. 1 H NMR (CDC13 d): 2.35 (s, 3H), 7.30-7.55 (m, 4H), 8.10 (s, 1H) A mixture of 1.6 g of the above compound, 0.024 g is heated at reflux and stirred for 7.5 h. of Fe (Cl04) 3, 3.0 g of Fe and 6 ml of H20. After allowing to stand overnight at room temperature, 2.80 ml of 37% HCl are added and the mixture is heated for 1 h. After cooling, the mixture is extracted with EtOAc (3 x 40 mL), which is dried with Na 2 SO 4 and evaporated in vacuo to provide 1.28 g of the title compound as an orange oil. X H NMR (CDC13 d): 2.22 (s, 3 H), 3.77 (s, 2 H), 7.15-7.40 (m, 4 H). -4-0x0-3- (2-trifluoromethoxyphenyl) -pentanaldietylacetal (Compound 2b) To a suspension of 1.87 g of an oil dispersion of 60% NaH in 10 ml of anhydrous DMF is added dropwise, during 6 min, under a nitrogen stream, a solution of Compound 2a in 15 ml of DMF and the reaction mixture is stirred at room temperature for 3 h. After allowing to stand overnight, 0.447 g of 2-bromoacetaldehyde-diethylacetal 97% are added in 5 ml of DMF; The mixture is stirred at room temperature for 30 min and then at 80 ° C for 3 h. Subsequently, the mixture is diluted with 250 ml of H20, acidified with 2N HCl, extracted with Et20 (3 x 50 ml), washed with 40 ml of H20, dried with Na2SO4 and evaporated under vacuum, which provides a product crude (brownish oil) which is purified by flash chromatography (PE-EtOAc 100: 2) to provide 1.44 g of Compound 2b as a yellowish oil.

RM 1 H (CDC13 d): 1.08-1.32 (m, 6H), 1.75-1.95 (m, 1H), 2.08 (s, 3H), 2.35-2.60 (m, 1H), 3.20-3.80 (m, 4H), 4.20-4.40 (2H), 7.15-7.35 (4H). 4-OXO-3- (2-trifluoromethoxyphenyl) -pentanal (Compound 2c) The title compound is obtained by following the procedure described for Compound 1 but using Compound 2b as the starting material instead of Compound id. After the usual treatment procedure, the title compound (99%) is obtained and used without further purification in the next step. NMR ¾ (CDC23 5): 2.12 (s, 3H), 2.58 (dd, 1H), 3.40 (dd, 1H), 4.61 (dd, 1H), 7.11-7.40 (m, 4H), 9.75 (s, 1H) 1- (4-fluoro-2-methoxyphenyl) -4- [4-oxo-3- (2-trifluoromethoxyphenyl) -pentyl] -piperazine The title compound is obtained following the procedure described for the Compound of Example 1, but using as Compound 2c instead of Compound le and 1- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. Purification by flash chromatography (PE-EtOAc 7: 3) gives the title compound (60%). Oil. H-NMR (CDC23 d): 1.65-1.85 (m, 1H), 2.10 (s, 3H), 2.25-2.45 (m, 3H), 2.50-2.70 (m, 4H), 2.85-3.10 (m, 4H), 3.82 (s, 3H), 4.15-4.31 (m, 1H), 6.50-6.68 (m, 2H), 6.78-6.90 (m, 1H), 7.20-7.35 (m, 4H).

EXAMPLE 3 1- (4-Fluoro-2-methoxyphenyl) -4- [4-hydroxy-3- (2-trifluoromethoxy-phenyl) -pentyl] -piperazine The title compound is synthesized using the method described for the Compound le but starting at from the Compound of Example 2 instead of Compound Ib. After the usual treatment procedure, the title compound is isolated (93.1%) and characterized by LC (liquid chromatography) as a mixture of diastereoisomers (S; SR-RS, RS 78.8: 20.5). LC purity: 98.6% R XH (CDC13 d): 0.95; 1.07 (2d, 3H), 1.80-2.10 (tti, 2H), 2.35-2.50 (m, 2H), 2.60-2.85 (m, 4H), 2.92-3.18 (m, 4H), 3.18-3.35 (m, 1H) ), 3.80 (s, 3H), 4.00-4.20 (m, 1H), 4.60-6.10 (broad, 1H), 6.50-6.70 (m, 2H), 6.78-6.95 (m, 1H), 7.15-7.35 (m , 3H), 7.60-7.75 (m, 1H).

Example 4 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- [4-oxo-3- (2-trifluoromethoxyphenyl) -pentyl] piperazine The title compound is obtained following the procedure described for the Compound of Example 1, but using Compound 2c as the starting material, instead of Compound le and 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -piperazine instead of 1- ( 2, 2, 2-trifluoroethoxyphenyl) -piperazine. Purification by flash chromatography (PE-EtOAc 7: 3) gives the title compound (33%). Oil XH NMR (CDC13 d): 1.65 -1.85 (m, 1H), 2.10 (S, 3H), 2.25-2.40 (m, 3H), 2.50-2.70 (m, 4H), 2.90-3.15 (m, 4H), 4.18-4.40 (m, 4H), 6.48-6.65 (m, 2H), 6.70-6.82 (m, 1H), 7.20-7.35 (m, 4H).

Example 5 1- [5- (2-dihydro-1,4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxy-phenyl) -pentyl] -piperazine The title compound is synthesized using the method described for Compound 1 but from Compound of Example 4 instead of Compound Ib. After the usual treatment procedure, the title compound is isolated (92.7%) and characterized by liquid chromatography as a mixture of diastereoisomers (RS, SR-RS, RS 72.9: 19.4). Purity, determined by liquid chromatography: 92.3% NMR (CDC13 d): 0.95; 1.07 (2d, 3H), 1.80 2.15 (m, 2H), 2.30-2.50 (m, 2H), 2.60-2.85 (m, 4H), 3.00-3.20 (m, 4H), 3.20-3.40 (m, 1 H), 4.00-4.15 (m, 1H) ), 4.15-4.40 (m, 4H), 4.60-6.20 (broad, 1H), 6.45-6.65 (m, 2H), 6.65-6.85 (m, 1H), 7.15-7.30 (m, 3H), 7.60-7.75 (m, 1H).

Example 6 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- [4-hydroxy-3- (2-rifluoromethylphenyl) -hexyl] -piperazine 2-allyl-2- (2- trifluoromethoxyphenyl) acetonitrile (Compound 6a) To 2.74 ml of a 2M solution of LDA in THF cooled to -78 ° C is added dropwise 2- (2-trifluoromethoxyphenyl) acetonitrile in 20 ml of THF; The mixture is stirred at the same temperature for 10 min. Subsequently, a mixture of 0.474 ml of allyl bromide and 0.446 g of HMPTA is added and the reaction is stirred at -78 ° C for 2 h, then it is brought to room temperature by spontaneous heating. After allowing to stand overnight, it is suspended with a saturated aqueous solution of NH 4 Cl and extracted with EtOAc. The combined extracts are dried with Na2SO4 and evaporated to dryness. The product is purified by flash chromatography (PE-EtOAc 95: 5) which gives the title product as 1.015 g of a light yellow oil. 1H-NMR (CDC13 d): 2.60 (t, 2H), 4.15-4.26 (m, 1H), 5.16-5.29 (m, 2H), 5.79-5.91 (m, 1H), 7.28-7.41 (m, 3H), 7.51-7.67 (m, 1H). 2- (2-trifluoromethoxyphenyl) -pent-4-enal (Compound 6b) To a solution of 0.88 g of Compound 6a in 50 ml of anhydrous toluene is added dropwise, at room temperature, 4.01 ml of DIBAL-H (2M solution). in toluene) for 10 min. The reaction mixture is stirred at room temperature for 2 h, diluted with 0.01 N HCl, extracted with EtOAc (2 x 50 mL); The combined extracts are washed with H20, dried with Na2SO4 and evaporated to dryness in vacuo. Compound 6b is obtained as a light yellow oil and used in the next step without further purification. NMR ½ (CDC13 < 5): 2.49-2.68 (m, 1 H), 2.80-2.95 (m, 1H), 4.02-4.15 (m, 1H), 5.12-5.26 (m, 2H), 5.57-5.85 (ra, 1H), 7.28-7.37 (m, 4H), 9.75 (broad s, 1H) 2- [1- [3-butenyl-1- (2-trifluoromethoxy-phenyl)]] -1,3-dioxolane (Compound 6c) ) A solution of 0.72 g of Compound 6b, 0.052 g of p-toluenesulfonic acid monohydrate, 0.328 ml of ethylene glycol in 30 ml of toluene is stirred under reflux for 8 h. Subsequently, the solvent is removed by evaporation under vacuum, diluted with EtOAc and aqueous NaHCO 3.; the organic layer is separated, dried over Na2SO4 and evaporated to dryness in vacuo. The crude product is purified by flash chromatography (PE-EtOAc 95: 5) which gives 0.85 g of the title product as a light yellow oil. NMR LH (CDC13 d): 2.39-2.51 (m, 1H), 2.52-2.79 (m, 1H), 3.46-3.57 (m, 1H), 3.80-3.92 (m, 4H), 4.88-4.95 (m, 2H ), 4.96-5.12 (m, 1H), 5.72-5.81 (m, 1H), 7.21-7.33 (m, 3H), 7.33-7.45 (m, 1?). 3- [1, 3-dioxolan-2-yl] -3- (2-trifluoromethoxy-phenyl)] -radionaldehyde (Compound 6d) To a biphasic mixture of 0.31 g of Compound 6c, 10 ml of Et20 and 10 ml of vigorously stirred H20, 0.196 ml of Os04 are added followed by the addition of 3.6 g of NalCv in aliquots, for a period of 20 min. After 6 h, the organic layer is separated, the aqueous layer is extracted with Et20, the combined organic layers are dried with Na2SO4 and evaporated to dryness in vacuo. The crude product is purified by flash chromatography (PE-EtOAc 8) to provide 0.311 g of the title product. 1H NMR (CDC13 d): 2.52-2.69 (m, 1H), 2.88-3.03 (m, 1H), 3.81-3.93 (m, 4H), 3.94-4.15 (m, 1 H), 5.03-5.08 (m, 1H), 7.22-7.38 (m, 3H), 7.39-7.55 (m, 1H), 9.76 (broad s, 1H). 1- (2,3-dihydro-l, -benzodioxin-5-yl) -4- [3- (1,3-dioxolan-2-yl) -3- (2-trifluoromethoxyphenyl) -propyl] -piperazine (Compound 6e) The title compound is obtained following the procedure described for the Compound of Example 1, but using Compound 6d as the starting material instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5) -yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. Purification by flash chromatography (PE-EtOAc 1: 1) gives the title compound (61%). Oil. NMR ¾ (CDC13 d): 1.80-2.01 (m, 1H), 2.02-2.44 (m, 3H), 2.45-2.71 (m, 4H), 2.92-3.07 (m, 4H), 3.41-3.61 (m, 1H ), 3.81-3.93 (m, 4H), 4.21-4.39 (m, 4H), 5.01-5.05 (m, 1H), 6.49-6.57 (m, 2H), 6.71-6.82 (m, 1H), 7.21-7.39 (m, 3H), 7.41-7.58 (m, 1H). 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -4- [3-formyl -3- (2-trifluoromethoxyphenyl) -propyl] -piperazine (Compound 6f) A mixture of 0.12 g of the Compound 6e, 0.005 g of 4-toluenesulfonic acid monohydrate, 1 ml of H20 and 7 ml of dioxane are stirred under reflux for 24 h. Subsequently the solvent is removed by evaporation in vacuo, the residue is diluted with EtOAc and aqueous NaOH; the organic layer is separated, dried over Na2SC > 4 and evaporated to dryness in vacuo. The crude product is obtained as a light yellow oil and used in the next step without further purification. RMN ¾. { CDC13 d): 1.79-1.99 (m, 1H), 2.25-2.49 (m, 3H), 2.50-2.71 (m, 4H), 2.91-3.12 (m, 4H), 4.07-4.15 (m, 1H), 4.16 -4.39 (m, 4H), 6.48-6.61 (m, 2H), 6.73-6.86 (m, 1H), 7.20-7.38 (m, 3H), 9.81 (broad s, 1H). 4,4-diethoxy-2- (2-trifluoromethoxyphenyl) -butyronitrile (Compound 6g) The title compound is synthesized following the reported procedure for Compound 6a but using 2-bromoacetaldehyde diethylacetal instead of allyl bromide. After spontaneous heating at room temperature for 2 hours, the reaction mixture is refluxed for an additional 2 h. After the usual treatment procedure, the crude product is purified by flash chromatography (PE-EtOAc 95: 5) which gives the title product (47.7%) as a light yellow oil. RN 1H (CDC13 ¿5): 1.12-1.35 (ra, 6H), 2.07-2.27 (m, 2H), 3.50-3.71 (m, 4H), 4.22-4.38 (m, 1H), 4.65-4.71 (m, 1H), 7.19-7.48 (m, 3H), 7.49-7.63 (m, 1H). 4-OXO-2- (2-trifluoromethoxy-phenyl) -butyronitrile (Compound 6h) The title compound is obtained by following the procedure described for Compound 1 but using Compound 6g instead of Compound Id as the starting material. usual treatment the title compound obtained in this manner is used without further purification in the next step. RMN ?? (CDC13 d): 2.98-3.31 (m, 2H), 4.65-4.78 (m, 1H), 4.65-4.71 (m, 1H), 7.22-7.49 (m, 3H), 7.51-7.66 (m, 1H), 9.81 (broad s, 1H). 1- [3-Cyano-3- (2-trifluoromethoxyphenyl) -propyl] -4- (2,3-dihydrobenzo-1,4-dioxin-5-yl) -piperazine (Compound 6i) The title compound is obtained by following the procedure described for the Compound of Example 1 but using Compound 6h as the starting material instead of Compound le and 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. Purification by flash chromatography (PE-EtOAc 1: 1) gives the title compound (93%). Oil RMN ¾. { CDC13 d): 1.99-2.14 (m, 1H), 2.49.-2.71 (m, 3H), 3.01-3.19 (m, 4H), 4.20-4.38 (m, 4H), 4.40-4.55 (m, 1H), 6.49-6.65 (m, 3H), 6.72-6.88 (m, 1H), 7.24-7.41 (m, 3H), 7.52-7.68 (m, 1H). 1- (2,3-dihydro-l, -benzodioxin-5-yl) -4- [3-formyl-3- (2-trifluoromethoxyphenyl) -propyl] -piperazine (Compound 6f) To a solution of 0.414 g of the Compound 6i in 50 ml of anhydrous CH2C12 is added dropwise, at -78 ° C, 1.2 ml of 1 M DIBAL-H in toluene. The reaction is allowed to warm and stir overnight; subsequently, it is diluted with water, extracted with CH2C12 (2 x 50 ml); The combined extracts are washed with H20, dried with Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (CH2Cl2-MeOH 95: 5) gives the title compound (0.23 g, 55.3%). Oil. 1- [5- (1,4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxyphenyl) -hexyl] -piperazine In a solution of 0.1 g of Compound 6f in 10 ml of THF cooled to 0 -5 ° C a 1M solution of ethylmagnesium bromide in 0.888 ml of THF is added dropwise. The reaction mixture is allowed to warm to room temperature and is stirred at the same temperature for 3 h. Subsequently, it is suspended with a saturated aqueous solution of, NH 4 Cl, becomes alkaline and extracted with EtoAc. The combined extracts are dried with Na2SO4 and evaporated to dryness. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 97: 3) which gives the title product as a yellow glassy oil (84.4%). NMR ¾ (CDC13 5): 0.86-0.99 (m, 3H), 1.21-1.35 (m, 2H), 1.36-1.65 (m, 1H), 1.66-1.89 (m, 1H), 1.90-2.21 (m, 2H) ), 2.25-2.95 (m, 6H), 2.96-3.27 (m, 4H), 3.61-3.80 (m, 1H), 4.21-4.41 (m, 4H), 6.49-6.61 (m, 2H), 6.65-6.86 (m, 1H), 7.15-7.39 (m, 4H). [M + H] + = 481.6 Example 7 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxy-phenyl) -hex-5-enyl] -piperazine The product of the title by the same procedure described for the Compound of Example 6 but using Compound 6f and vinylmagnesium bromide (1M in THF) instead of ethylmagnesium bromide in THF. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 95: 5) which gives the title product as a yellow glassy oil (42.6%). RMN ?? (CDC13 5): 1.76-1.98 (m, 1H), 1.99-2.28 (m, 1H), 2.29-2.51 (m, 2H), 2.52-2.89 (m, 4H), 2.89-3.25 (m, 6H), 4.20-4.43 (m, 4H), 4.65-5.31 (m, 3H), 5.61-5.70 (m, 1H), 6.49-6.62 (m, 2H), 6.70-6.89 (m, 1H), 7.15-7.42 (m , 4H). [+ H] + = 479.5 Example 8 1- [5- (2,3-dihydro-1,4-benzodioxinyl)] -4- [4-hydroxy-5-methyl-3- (2-trifluoromethoxyphenyl) -hexyl] -piperazine The product of the title by the same procedure described for the compound of Example 6 but using Compound 6f and isopropylmagnesium chloride (2 M in THF) instead of ethylmagnesium bromide in THF. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 97: 3) which gives the title product as a yellow glassy oil (30.9%) RM XH. { CDC13 < 5): 0.78-0.98 (m, 6H), 1.15-1.45 (m, 2H), 1.71-1.91 (m, 2H), 1.92-2.19 (m, 1H), 2.25-2.51 (m, 2H), 2.52- 2.95 (m, 4H), 3.01-3.29 (m, 5H), 3.51-3.72 (m, 1H), 4.19-4.40 (m, 4H), 6.47-6.63 (m, 2H), 6.67-6.87 (m, 1H) ), 7.15-7.41 (m, 4H). [M + H] + = 495.6 EXAMPLE 9 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- [4-methoxy-3- (2-trifluoromethoxyphenyl) -5- exeyl] -piperazine, -dietoxy-2- ( 2-trichloromethoxyphenyl) -butyraldehyde (Compound 9a) The title compound is prepared following the procedure described in Compound 6f (alternative method) but starting from Compound 6g instead of Compound 6i. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 99: 1), which gives the title product as a yellow glassy oil (41.9%). RM XH (CDCl3 d): 1.11-1.34 (m, 6H); 1.85-2.04 (m, 1 HOUR); 2.41-2.62 (m, 1H); 3.34-3.77 (m, 4H); 4.08-4.19 (m, 1 HOUR); 4.39-4.51 (mr 1H); 7.19-7.42 (m, 4H); 9.66 (s, 1H). 6,6-diethoxy-4- (2-trifluoromethoxyphenyl) -hex-l-en-3-ol (Compound 9b) The title product is obtained by the same procedure described for the compound of Example 6 but using vinylmagnesium bromide ( 1M in THF) instead of ethylmagnesium bromide in THF and starting with compound 9a. The crude product is purified by flash chromatography (PE-EtOAc 4: 6). Performance 63.1%. RM 1H (CDCl 3 d): 1.04-1.32 (m, 6H); 1.93-2.09 (m, 1H), 2.01-2.39 (m, 1H), 2.51 (broad s, 1H); 3.28-3.75 (m; 5H); 4.18-4.36 (m, 2H); .5.01-5.22 (m, 2H); 5.67-5.87 (m, 1H), 7.14-7.43 (m, 4H). 4-methoxy-3- (2-trifluoromethoxyphenyl) -but-3-enaldietylacetal (Compound 9c) The title compound is synthesized as described for Compound Id using compound 9b as the starting material instead of Compound le. The crude product is used in the next step without further purification. 1 H NMR (CDCl 3 d): 1.01-1.42 (m, 6H); 1.86-2.04 (ra, 1H), 2.24-2.43 (m, 1H); 3.24 (s, 3H); 3.30-3.79 (m, 6H); 4.13-4.28 (m, 1H); 4.98-5.17 (m, 2H); 5.50-5.71 (m, 1H); 7.13-7.29 (m, 3H); 7.31-7.48 (m, 1H). 4-methoxy-3- (2-trifluoromethoxyphenyl) -but-3-enal (Compound 9d) The title compound is obtained by following the procedure described for Compound 1 but using Compound 9c instead of Compound Id as starting material. After the usual treatment procedure, the title compound obtained in this way is used without further purification in the next step.

NMR ¾ (CDCl 3 d): 2.58-2.76 (m, 1H); 2.81-3.06 (m, 1H), 3.24 (s, 3H), 3.59-3.72 (m, 1H); 3.73-3.91 (m, 1H); 4.99-5.17 (m, 2H); 5.43-5.67 (m, 1H), 7.13-7.41 (m, 4H); 9.61-9.69 (m, 1H). 1- [5- (2,3-dihydro-l, 4-benzodioxyl)] -4- [4-methoxy-3- (2-trifluoromethoxyphenyl) -5-hexenyl] -piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound 9d instead of Compound le and 1- (2, 3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The yield after flash chromatography (PE-acetone 6: 4) is 34.5%. RMN ¾. { CDCI3 d): 1.74-1.93 (m, 1H), 2.09-2.42 (m, 3H), 2.48-2.71 (m, 4H) / 2.89-3.28 (m, 4H); 3.18-3.31 (m, 4H); 3.54-3.68 (m, 1H), 4.17-4.38 (m, 4H); 4.96-5.30 (m, 2H); 5.47-5.68 (m, 1H); 6.47-6.63 (m, 2H); 6.71-6.85 (m, 1H); 7.12-7.31 (m, 3H); 7.32-7.48 (m, 1H).

Example 10 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -heptyl] -piperazine 4 -oxo-3-phenylheptanaldietylacetal (Compound 10a) The title compound is prepared following the method described for Compound 2b, but using 1-phenyl-2-pentanone instead of Compound 2a. The crude product is purified by flash chromatography (EtOAc-PE 95: 5). Yield: 59.2%. XH NMR. { CDC13 d): 0.78-0.88 (m, 3H), 1.10-1.31 (m, 8H), 1.42 1-72 (m, 2H), 2.38-2.50 (m, 3H), 3.31-3.90 (m, 4H), 4.18-4.35 (m, 1H), 7.05-7.42 (m, 5H). 4-hydroxy-3-phenylheptanaldietylacetal (Compound 10b) The title compound is obtained by following the procedure described for Compound 1, but using Compound 10a as the starting material instead of Compound Ib. After the usual treatment procedure, the crude product is purified by flash chromatography (EtOAc-PE 2: 8). Performance: 73.3%. X H NMR (CDCl 3 d): 0.70-0.82 (m, 3H), 0.90-1.48 (m, 12H), 2.10-2.57 (m, 2H), 3.32-3.94 (m, 4H), 4.08-4.30 (m, 1 H), 5.18-5.35 (m, 1H), 7.05-7.42 (m, 5H). 4-methoxy-3-phenylheptanaldietylacetal (Compound 10c) The title compound is obtained following the procedure described for Compound Id, but using Compound 10b instead of Compound le as starting material. The title product is used in the next step without further purification. RMN ¾. { CDC13 < 5): 0.70-0.82 (m, 3H), 1.02-1.48 (m, 12H), 2.02-2.15 (m, 1H), 2.95-3.01 (m, 1H), 3.20-3.80 (m, 7H), 4.15- 4.35 (m, 1H), 7.05-7.42 (m, 5H). 4-methoxy-3-phenylheptanal (Compound 10d) The title compound is obtained by following the procedure described for Compound 1, but using Compound 10c instead of Compound le as starting material. The title product is used in the next step without further purification. NMR ¾ (CDCI3 d): 0.70-1.59 (m, 7H), 2.81-2.95 (m, 2H), 3.22-3.61 (m, 5H), 7.05-7.42 (m, 5H), 9.75 (s, 1H). 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -heptyl] -piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound lOd instead of Compound le and 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The yield after flash chromatography (EtOAc-PE-MeOH / NH3 1: 1: 0.2 to 8: 2: 0.2) is 39.5%. XH NMR (CDCl3 d): 0.78-0.91 (m, 3H), 1.20-1.48 (m, 4H), 1.90-2.07 (m, 2H), 2.19-2.33 (m, 2H), 2.50-2.68 (m, 4H) ), 2.80-2.91 (ra, 1H), 2.99-3.12 (m, 4H), 3.18-3.30 (m, 1H), 3.35 (s, 3H), 4.20-4.38 (m, 4H), 6.48-6.62 (m , 2H), 6.78 (s, 1H), 7.25-7.33 (m, 5H).

Example 11 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -pentyl] -piperazine 4-γ-3-phenylpentanaldietylacetal (Compound lia) The title compound is prepared using the method described for Compound 2b but using 1-phenylacetone (commercially available) instead of Compound 2a. The crude product is used in the next step without further purification. Yield: 93%. RM 1 H (CDCl 3 d). : 1.10-1.25 (m, 6H), 1.82-2.17 (m, 4H), 2.32-2.50 (m, 1H), 3.30-3.70 (m, 4H), 3.82 (t, 1H), 4.23-4.33 (m, 1H), 7.15-7.39 (m, 5H). 4-Hydroxy-3-phenylpentanaldletylacetal (Compound 11b) The title compound is obtained by following the procedure described for Compound 1, but using Compound Ilia instead of Compound ib as starting material. After the usual treatment procedure, the crude product is used in the next step without further purification. Yield: 60%. 1 H NMR. { CDC13 d): 1.00-1.32 (m, 9H), 2.05-2.15 (m, 1H), 1.89-2.17 (m, 2H), 2.68-2.81 (m, 1H), 3.28-3.71 (m, 4H), 3.82 -4.02 (m, 1H), 4.15-4.26 (m, 1H), 7.12-7.41 (m, 5H). 4-methoxy-3-phenylpentanaldletylacetal (Compound lie) The title compound is obtained following the procedure described for the Compound. Id, but using Compound 11b as the starting material instead of Compound le. The crude product is purified by flash chromatography (EtOAc 5-PE 95). 4-methoxy-3-phenylpentanal (Compound lid) The title compound is obtained following the procedure described for Compound 1, but using Compound 11c instead of Compound Id as starting material. The title product is used in the following stage without further purification. 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -pentyl] -piperazine The title compound is prepared using the method described for the Compound of Example 1, but using compound 9d instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2,2, 2-trifluoroethoxyphenyl) -piperazine. The yield after flash chromatography (EtOAc-PE-MeOH / H3 8: 2: 0.1 to 8: 2: 0.3) is 15.5%. XH NMR. { CDC13 d): 1.04 (d, 3H), 1.88-2.05 (m, 2H), 2.18-2.31 (m, 2H), 2.50-2.68 (m, 4H), 2.73-2.85 (m, 1H), 2.97-3.12 (m, 4H), 3.30 (s, 3H), 3.42-3.50 (m, 1H), 4.18-4.38 (m, 4H), 6.48-6.62 (m, 2H), 6.71-6.82 (t, 1H), 7.15 -7.33 (m, 5H).

Example 12 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- [(propoxy-3-phenyl) -heptyl] -piperazine 4-propoxy-3-phenylheptanal (Compound 12a) Obtained the title compound following the procedure described for Compound Id, but using Compound 10b instead of Compound le as starting material. The crude product is purified by flash chromatography (EtOAc 5-PE 95). 4 -propoxy -3-phenylheptanal (Compound 12b) The title compound is obtained following the procedure described for Compound Id, but using as an initial material of Compound 12a instead of Compound le. The crude product is used in the next step without further purification. 1- [5- (2,3-dihydro-l, 4-benzodioxinyl) 3 -4- [(4-methoxy-3-phenyl) -heptyl] -piperazine The title compound is prepared using the method described for the Compound of Example 1, but using compound 12b instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2,2, 2-trifluoroethoxyphenyl) -piperazine. The yield after flash chromatography (EtOAc-PE-MeOH / H3 4: 6: 0.1 to EtOAc-MeOH / H3) is 9.5%. XH NMR (CDC13 d): 0.72-0.92 (m, 6H), 1.15-1.61 (m, 6H), 1.89-2.08 (ra, 2H), 2.18-2.31 (m, 2H), 2.50-2.68 (m, 4H), 2.78-2.92 (m, 1H), 2.97-3.12 (m, 4H), 3.28- 3.43 (m, 3H), 4.18-4.38 (m, 4H), 6.48-6.62 (m, 2H), 6.71-6.82 (t, 1H), 7.15-7.33 (m, 5H).

Example 13 1- [3- (2-cyano-phenyl) -4-cyclohexyl-4-oxobutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl) -piperazine 2- (2-cyclohexyl-2- oxoethyl) -benzonitrile (Compound 13a) To a solution of 0.47 g of 2-tolunitrile in 4 ml of THF are added 0.535 ml of 1,3-dimethyl-3, 5,6-tetrahydro-2 (1H) -pyrimidinone ( DMPU) and the mixture is cooled to -78 ° C; 2 ml of a 2M solution of LDA in THF are added dropwise over 5 min, then the reaction mixture is stirred at the same temperature for 15 min, followed by dropwise addition of 0.757 g of N-methyl-N-methoxycyclohexanecarboxamide in 4 mi of THF. After 1 h of stirring at -78 ° C, the reaction mixture is suspended with a 10% aqueous solution of NHC1. The temperature is allowed to rise to room temperature and the mixture is extracted with EtOAc (2 x 20 mL), washed with 30 mL of brine, dried over Na 2 SO 4 and evaporated to dryness in vacuo. The crude product is purified by flash chromatography (PE-EtOAc 85:15 to 1: 1) to provide 0.34 g of the title compound. XH NMR (CDC13 d): 1.10-2.05 (m, 10H), 2.45-2.602 (m, 1H); 4.00 (m, 2H); 7.20-7.43 (m, 2H); 7.48-7.70 (m, 2H); 3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyraldehyde diethylacetal (Compound 13b) The title compound is prepared using the method described for Compound 2b but using Compound 13a instead of Compound 2a. The crude product is purified by flash chromatography (toluene-EtOAc 97: 3). Yield: 39.1%. N XH (CDC13 d): 1.05-1.90 (m, 15H), 1.90-2.05 (m, 2H); 2.32-2.60 (m, 2H); 3.20-3.70 (m, 4H); 4.30 (t, 1H); 4.55 (t, 1H); 7.30-7.45 (m, 2H); 7.55 (dd, 1H); 7.68 (dd, 1H) 3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyraldehyde (Compound 13c) The title compound is obtained following the procedure described for Compound Id, but using Compound 13b as the starting material instead of the Compound le. The crude product is used in the next step without further purification. NMR? (CDC13 d): 1.00-1.90 (m, 10H); 2.05-2.15 (m, 1H); 2.35-2.50 (m, 1H); 2.70 (dd, 1H); 3.45 (dd, 1H); 4.85 (dd, 1H); 7.25 (dd, 1H); 7.30-7.40 (m, 1H); 7.50-7.60 (m, 1H); 7.75 (dd, 1H) 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- [5- (2,3-dihydro-1, -benzodioxinyl)] - piperazine The compound is prepared of the title using the method described for the Compound of Example 1, but using Compound 13c instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2,2, 2-trifluoroethoxyphenyl) -piperaine. The crude product is purified by flash chromatography (PE: EtOAc 6: 4) to give the title compound (79.5%). M ÍCDC13 5.}. : 1.10-2.10 (m, 11H); 2.20-2.50 (m, 4H); 2.50-2.75 (m, 4H); 2.92-3.20 (m, 4H); 4.20-4.38 (m, 4H); 4.55 (t, 1H); 6.48-6.65 (m, 2H); 6.70-6.85 (m, 1H), 7.30-7.45 (m, 2H); 7.45-7.60 (m, 1H); 7.65-7.75 (m, 1 H).

Example 14 (RS, SR) -1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-l, -benzodioxinyl)] -piperazine Synthesized the title compound using the method described for Compound le, but from the Compound of Example 14, instead of Compound Ib. After the usual treatment procedure, the crude product is purified by flash chromatography (PE-EtOAc-NH3 / MeOH 65: 35: 3) to give the title compound (70.5%). 1 H NMR [CDC13 d): 0.80-1.40 (m, 7H); 1.45-1.80 (m, 5H); 1.85-2.05 (m, 1H); 2.20-2.50 (m, 2H) 2.50-2.80 (m, 4H); 2.95-3.20 (m, 4H); 3.30-3.50 (m, 1H); 3.50-3.65 (m, 1H); 4.20-4.40 (m, 4H); 4.40-5.90 (broad s, 1H); 6.50-6.67 (m, 2H); 6.70-6.85 (m, 1H); 7.20-7.40 (m, 1H); 7.50-7.68 (m, 2H); 7.93-8.08 (m, 1H) Example 14a (RS) -1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-1, 4- benzodioxinyl)] -piperazine (enantiomer a Rt = 30,298 min) This compound is obtained from the Compound of Example 14 by separating by chiral column chromatography using Chiralpak AD (0.46 x 25 cm), eluting with 95: 5 n-hexane-EtOH. (flow = 1 ml / min, UV detector 254 nm). Example 14b (SR) -1- [3- (2-Cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl) -piperazine (enantiomer a) Rt = 34.834 min) This compound is obtained from the Compound of Example 14 by separating by chiral column chromatography using Chiralpak AD (0.46 x 25 cm), eluting with 95: 5 n-hexane-EtOH (flow = 1 ml / min; UV detector 254 nm).

Example 15 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine The title compound is prepared using the method described for the Example Compound 1 but using Compound 13c instead of Compound le and l- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: EtOAc 6: 4) to give the title compound (82%).

NMR ¾ [CDC13 d): 1.00-2.10 (m, 11H); 2.15-2.75 (m, 8H); 2.75-3.15 (m, 4H) 3.90 (s, 3H); 4.55 (t, 1H); 6.50-6.70 (m, 2H); 6.80-6.95 (m, 1H); 7.30-7.42 (m, 2H); 7.45-7.60 (m, 1H); 7.60-7.72 (m, 1H).

Example 16 1- [3- (2-Cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- (4-fluoro-2-nithoxyphenyl) -piperazine The title compound is synthesized using the method described for the Compound but starting from the compound of Example 14 instead of Compound Ib. After the usual treatment procedure, the crude product is purified by flash chromatography (PE-EtOAc-NH3 / MeOH 65: 35: 3) which gives the title compound (51.3%). RM ¾. { COCI3 d): 0.90-1.20 (m, 6H); 1 .40 -1 .85 (m, 5H); 1.90 -2.10 (m, 2H); 2.20-2. 45 (m, 2H); 2. 50- 2.85 (m, 4H); 2 .90 -3.15 (m, 4H); 3.32-3.50 (m, 1H) 3. 50-3. 65 (m, 1 HOUR); 3. 95 (s, 3H); 4.60-5.20 (broad s, 1H); 6 .55 -6 .68 (m, 2H); 6.80-6.92 (m, 1H); 7.28-7. 36 (m, 1H); 7. 45-7. 68 (m, 2H); 7. 95- 8.05 (m, 1H) Example 17 1- (4-cyclohexyl-4-methoxy-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine 4,4-dimethoxy-2-phenylbutyronitrile (Compound 17a) The title compound is synthesized following the reported procedure for Compound 6b, but using 2-bromoacetaldehydedimethylacetal instead of allyl bromide and phenylacetonitrile instead of 2-trifluoromethoxyphenylacetonitrile. After spontaneous heating to room temperature for 2 hours, the reaction mixture is refluxed for an additional 2 h. After the usual treatment procedure, the crude product is purified by flash chromatography (PE-EtOAc 9: 1) which gives the title product (72.1%) as a light yellow oil. X H NMR (CDC13 d): 2.02-2.36 (m, 2H); 3.39 (d, 6H); 3.76-4.01 (m, 1H); 4.41-4.54 (m, 1H); 7.30-7.48 (m, 5H). 4,4-dimethoxy-2-phenylbutyraldehyde (Compound 17b) The title compound is obtained following the procedure described for Compound 6f (alternative method) but using Compound 17a instead of Compound 6i as an initial material. After the usual work-up procedure, the crude product is purified by flash chromatography (CH2C12-EtOAc 95: 5) to give the title compound (73.2%). 1 H NMR (CDC13 d): 1.83-2.02 (m, 1H); 2.39-2.58 (m, 1H); 3.32 (d, 6H); 3.66-3.81 (m, 1H); 4.23-4.38 (m, 1H); 7.07-7.48 (m, 5H); 9.61-9.70 (m, 1H). 4-Cyclohexyl-4-hydroxy-3-phenylbutyraldehyde dimethylacetal (Compound 17c) The title compound is obtained following the procedure described for the Compound of Example 6 but using Compound 17b as starting material instead of Compound 6f and cyclohexylmagnesium chloride (solution 2M in THF) instead of ethylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-Acetone 9: 1) which gives the title product (55%). RMN ¾. { CDC13 d): 0.97-2.09 (m, 12H); 2.27-2.45 (m, 1H); 2.88-3.03 (m, 1H); 3.31 (d, 6H); 3.41-3.53. { m, 1H); 4.11-4.22 (m, 1H); 7.21-7.43 (m, 5H). The OH signal is not detectable. 4-Cyclohexyl-4-methoxy-3-phenylbutyraldehyde dimethylacetal (Compound 17d) The title compound is synthesized as described for Compound Id using Compound 17c as the starting material instead of Compound le. After extraction with E20, the crude product is purified by flash chromatography (PE-EtOAc 8: 2) which gives the title product (71.4%). 1 H NMR (CDC13 d): 0.98-1.37 (m, 6H); 1.49-1.98 (m, 6H); 2.17-2.33 (m, 1H); 2.82-3.02 (m, 2H); 3.21 (dd, 6H) 3.37 (s, 3H); 3.94-4.08 (m, 1H); 7.17-7.39 (m, 5H). 4-cyclohexyl-4-methoxy-3-phenylbutyraldehyde (Compound 17e) The title compound is obtained following the procedure described for Compound le, but using Compound 17d as the starting material instead of Compound Id. The title product is used. in the next stage without further purification. X H NMR (CDCl 3 d): 0.93-1.86 (m, 12H); 2.61-2.79 (m, 2H); 3.01-3.16 (m, 1H); 3.31 (s, 3H); 3.41-3.59 (m, 1H); 7.15-7.39 (ra, 5H); 9.53-9_.61 (m, 1H). 1- (4-Cyclohexyl-4-methoxy-3-eneylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] - piperazine The title compound is prepared using the method described for compound of Example 1, but using compound 17e instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) ) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 75:25) to give the title compound (77.4%). X H NMR (CDC13 d): 0.97-1.31 (m, 6H); 1.48-1.99 (m, 6H); 2.07-2.28 (m, 3H); 2.42-2.67 (m, 4H); 2.71-2.90 (m, 1H); 2.92-3.26 (m, 5H); 3.3 (s, 3H); 4.17-4.38 (m, 4H); 6.45-6.64 (m, 2H); 6.66-6.84 (m, 1H); 7.12-7.34 (m, 5H).

Example 18 1- (4-cyclohexyl-4-methoxy-3-phenylbutyl) -4- (4-fl-o-2-methoxyphenyl) -piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound 17e instead of Compound le and 1- (4-fluoro-2-methoxyphenyl) -piperazine instead of l- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2C0 75:25) to provide the title compound (79.8%). RMN lH. { CDC13 5): 0.97-1.37 (m, 6H); 1.46-1.98 (m, 6H); 2.07-2.31 (m, 3H); 2.42-2.71 (ra, 4H); 2.74-2.80 (m, 1H); 2.81-3.18 (m, 5H); 3.39 (s, 3H); 3.81 (s, 3H); 6.49-6.68 (m, 2H); 6.77-6.92. (m, 1H); 7.13-7.38 (m, 5H).

Example 19 1- (4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine 4-cyclohexyl-4-ethoxy-3-phenylbutyraldehyde dimethyl acetal (Compound 19a) The title compound is synthesized as described for Compound Id using Compound 17c as the starting material instead of Compound le and ethyl iodide instead of methyl iodide. After extraction with E20, the crude product is purified by flash chromatography (PE-EtOAc 8: 2) which provides the title product (50.7%). RMN ¾. { CDCl 3 d): 0.91-1.34 (m, 9H); 1.42-1.99 (m, 6H); 2.14-2.34 (m, lh); 2.80-2.94 (m, 1H); 3.00-3.11 (m, 1H); 3.22 (d, 6H); 3.41-3.57 (m, 2H); 3.92-4.08 (m, 1H); 7.14-7.35 (m, 5H). 4-cyclohexyl-4-ethoxy-3-phenylbutyraldehyde (Compound 19b) The title compound is obtained by following the procedure described for Compound 1, but using Compound 19a as the starting material instead of Compound Id. title in the next stage without further purification. 1 H NMR. { CDC13 d): 0.91-1.39 (m, 8H) 1.48-1.88 (m, 6H); 2.57-2.89 (m, 2H), -3.08-3.20 (m, 1H); 3.23 -3.40 (m, 1H); 3.41-3.61 (m, 2H); 7.13-7.38 (m, 5H); 9.57-9.66 (m, 1H). 1- (4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] - piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound 19b instead of Compound le and 1- (2, 3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 8: 2) to give the title compound (60.6%). NMR ¾ (CDCl 3 6): 0.97-1.32 (m, 9H); 1.42-1.99 (m, 6H); 2.04-2.36 (m, 3H); 2.46-2.69 (m, 4H); 2.71-2.90 (m, 1H); 2.94-3.21 (m, 5H); 3.26-3.61 (m, 2H); 4.17-4.39 (m, 4H); 6.48-6.74 (m, 2H); 6.68-6.83 (m, 1 H); 7.14-7.37 (m, 5H).

EXAMPLE 20 1- (4-Cyclohexyl-4-ethoxy-3-phenylbutyl) -4- (4-γ-2-methoxyphenyl) -piperazine The title compound is prepared using the method described for the Compound of Example 1 but using Compound 19b instead of Compound le and l- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 75:25) to give the title compound (73%). R N ¾ (CDC13 d): 0.96-1.40 (m, 9H); 1.44-1.99 (m, 6H); 2.05-2.34 (m, 3H); 2.42-2.69 (m, 4H); 2.74-2.90 (m, 1H); 2.92-3.16 (m, 5H); 3.21-3.60 (m, 2H); 4.83 (s, 3H); 6.52-6.68 (m, 2H); 6.78-6.93 (m, 1H); 7.12-7.36 (m # 5H).

Example 21 1- (4 ^ allyloxy-4-cyclohexyl-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine 4-allyloxy-4-cyclohexyl-3-phenylbutyraldehyde dimethyl acetal (Compound 21a) The title compound is synthesized as described for Compound Id using Compound 17c as the starting material instead of Compound le and allyl bromide instead of methyl iodide. The reaction mixture is stirred for 8 h at room temperature and for 5 h at 45 ° C. Extraction with Et20 and purification by column chromatography (PE-EtOAc 85:15) gives the title compound (48.5%). 1 H NMR (CDC13 5): 0.94-1.38 (m, 6H); 1.51-2.01 (m, 6H); 2.16-2.34 (m, 1H); 2.82-3.01 (m, 1H); 3.07-3.19 (m, 1H); 3.21 (d, 6H); 3.72-3.88 (m, 1H); 3.90-4.07 (m, 2H); 5.04-5.32 (m, 2H); 5.77-6.00 (m, 1H); 7.16-7.37 (m, 5H). 4-allyloxy-4-cyclohexyl-3-phenylbutyraldehyde (Compound 21b) The title compound is obtained by following the procedure described for Compound 1, but using Compound 21a as the starting material instead of Compound Id. title in the next stage without further purification (99.3%). NMR ¾ (CDC23 < 5): 0.93-1.41 (m, 6H); 1.47-2.01 (m, 6H); 2.62-2.91 (m, 1H); 3.14-3.29 (m, 1H); 3.41-3.60 (m, 1H); 3.71-4.03 (m, 2H); 5.01-5.32 (m, 2H); 5.73-5.98 (m, 1H); 7.08-7.41 (m, 5H); 9.56-9.69 (m, 1H). 1- (4-allyloxy-4-cyclohexyl-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl) (-) -piperazine The title compound is prepared using the method described for Compound of Example 1, but using Compound 21b, instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2- trifluoroethoxyphenyl) -piperazine The crude product is purified by flash chromatography (PE: Me2CO 7: 3) to give the title compound (64.1%). NMR? (CDC13 d): 0.98-1.40 (m, 6H); 1.98 (m, 6H), 1.88-2.00 (m, 2H), 2.08-2.31 (m, 3H), 2.39-2.71 (m, 4H), 2.2.78-2.94 (m, 1H), 2.96-3.21 (m , 5H), 3.72-4.06 (m, 2H), 4.68-4.87 (m, 4H), 5.05-5.34 (m, 2H), 5.81-6.02 (m, 1H), 6.47-6.63 (mr 2H), 6.80- 6.88 (m, 1H); 7.11-7.37 (m, 5H). [M + H] "= 491 Example 22 1- (4-Allyloxy-4-cyclohexyl-3-eneylbutyl) -4- (4-fluoro-2-methoxypheni1) -iperazine The title compound is prepared using the method described for the Compound of Example 1 but using Compound 21b instead of Compound le and 1- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 7: 3) to give the title compound (77.1%). NMR ¾ (CDC13 d): 0.98-1.41 (m, 6H); 1.47-2.01 (m, 6H); 2.09-2.28 (m, 3H); 2.41-2.70 (m, 4H); 2.79-2.92 (m, 1H); 2.93-3.09 (m, 4H); 3.11-3.22 (m, 1H); 3.77-3.89 (m, 4H); 3.39-4.08 (m, 1H); 5.07-5.34 (m, 2H); 5.79-6.01 (m, 1H); 6.51-6.68 (m, 2H); 6.69-6.92 (m, 1H); 7.13-7.37 (m, 5H). [M + H] + = 481 EXAMPLE 23 1- (4-Cyclohexyl-3-phenyl-4-propargiloxybutyl) -4- [5- (2,3-dihydro-1, 4-benzodioxinyl)] -piperazine 4-cyclohexyl- 3-phenyl-4-propargyloxybutyraldehyde-dimethylacetal (Compound 23a) The title compound is synthesized as described for Compound Id using compound 17c instead of Compound 1 and propargyl bromide instead of methyl iodide. The reaction mixture is stirred for 8 h at room temperature and for 5 h at 45 ° C. Coil extraction Et20. and purification by column chromatography (PE-EtOAc 85:15) gives the title compound (50%). XH NMR (CDC13 < 5): 0.90-1.41 (m, 6H); 1.48-1.74 (m, 5H); 1.75-1.89 (m, 1H); 1.90-2.04 (m, 1H); 2.18-2.37 (m, 1H); 2.38-2.44 (m, 1H); 2.88-3.04 (m, 1H); 3.21 (d, 6H); 3.90-4.17 (m, 3H); 7.12-7.37 (m, 5H). 4-cyclohexyl-3-pheny1-4-propargyloxy -3-phenylbutyraldehyde (Compound 23b) The title compound is obtained by following the procedure described for Compound 1, but using Compound 23a as starting material, instead of Compound Id. use the title product in the next step without further purification (99%). 1 H NMR (CDC13 d): 0.81-1.41 (m, 6H); 1.49-1.90 (m, 5H); 2.39-2.51 (m, 1H); 2.66-2.88 (m, 1H); 2.89-3.08 (m, 1H); 3.31-3.42 (m, 1H); 3.43-6.59 (m, 1H); 3.97-4.19 (m, 2H); 7.12-7.39 (m, 5H); 9.57-9.69 (m, 1H). 1- (4-cyclohexyl-3-phenyl-4-propargiloxybutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] - piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound 23 instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2C0 7: 3) to give the title compound (67.1%). NMR ¾ (CDC13 d): 0.98-1.39 (m, 6H); 1.48-1.99 (m, 6H); 2.11-2.29 (m, 3H); 2.39-2.46 (m, 1H); 2.47-2.71 (m, 4H) 2.82-3.96 (m, 1H); 2.97-3.12 (m, 4H); 3.17-3.29 (m, 1H) / 3.95-4.16 (m, 2H); 4.17-4.38 (m, 4H); 6.48-6.72 (m, 2H); 6.69-6.83 (m, 1H) 7.12-7.35 (m; 5H) [M + H] + = 489 Example 24 1- (4-cyclohexyl-3-phenyl-4-propargiloxybutyl) -4- (4-fluoro-2-methoxy-phenyl) -piperazine The title compound is prepared using the method described for the Compound of Example 1 but using the Compound 23b instead of Compound le and l- (4-fluoro-2-methoxyphenyl) -piperazine instead of l- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 8: 2) to give the title compound (66.2%).

MN 1 H (CDCl 3 d): 0.99-1.41 (m, 6H); 1.51-2.00 (m, 6H); 2.11-2.29 (m, 3H); 2.39-2.46 (m, 1H); 2.47-2.70 (m, 4H); 2.78-3.12 (m, 5H); 3.13-3.29 (m, 1H); 3.81 (s, 3H); 3.96-4.17 (m, 2H); 6.51-6.67 (m, 2H); 6.79-7.94 (m, 1H); 7.11-7.34 (m, 5H). [M + H] + = 479.

Example 25 1- (4-cyclohexyl-3-phenyl-4-propoxybutyl) -4- [5- (2,3-dihydro-l-4-benzodioxiriyl)] -piperazine 4-cyclohexyl-3-phenyl-4-propoxyburaraldehyde dimethylacetal ( Compound 25a) The title compound is synthesized as described for Compound Id using Compound 17c as the starting material instead of Compound le and propyl bromide instead of methyl iodide. The reaction mixture is stirred for 8 h at room temperature and for 45 h at 45 ° C. Extraction with Et20 and purification by column chromatography (PE-EtOAc 85:15) provide the title compound (32.7%). NMR ¾ (CDC13 d): 0.91 (t, 3H); 0.99-1.32 (m, 6H), 1.45-1.98 (m, 10H) / 2.19-2.38 (m, 1H); 2.83-2.99 (m, 1H); 3.01-3.10 (m, 1H); 3.16-3.29 (m, 5H); 3.31-3.5 (m, 1H); 3.91-4.08 (m, 1H); 7.13-7.34 (m, 5H). 4-cyclohexyl-3-phenyl-4-propoxybutyraldehyde (Compound 25b) The title compound is obtained by following the procedure described for Compound le, but using Compound 25a as the starting material instead of Compound Id. The title product is used. in the next stage without further purification (99.3%). RM 1 H (CDC13 6): 0.80-0.95 (m, 3H); 0.96-1.37 (m, 6H); 1.41-1.88 (m, 7H); 2.57-3.09 (m, 3H); : 3.11-3.59 (m, 3H); 7.11-7.39 (m, 5H); 9.10-9.15 (m, 1H). 1- (4-cyclohexyl-3-phenyl-4-propoxybutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] - piperazine The title compound is prepared using the method described for the Compound of Example 1, but using Compound 25b instead of Compound le and 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 8: 2) to give the title compound (50.7%). X H NMR (CDC13 d): 0.93 (t, 3H); 0.99-1.37 (m, 6H); 1. 44-1.98 (m, 8H); 2.10-2.31 (m, 3H); 2.41-2.69 (m, 4H); 2. 72-2.90 (m, 1H); 2.95-3.18 (m, 5H); 3.20-3.98 (m, 2H); 4.19-4.37 (m, 4H); 6.48-6.67 (M, 2H); 6.69-6.83 (m, 1H); 7. 11-7.36 (m, 5H). [M + H] + = 493.

Example 26 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenyl) -hexylpiperazine 4- OXO-2-phenylburitonitrile (Compound 26a) The compound is obtained of the title following the procedure described for Compound 1 but using as the starting material Compound 17a instead of Compound Id. After the usual treatment procedure, the title compound obtained in this manner is used without further purification in the next step. NMR ¾ (CDC13 d): 2.94-3.29 (m, 2H), 4.31-4.45 (m, 1H), 7.30-7.48 (m, 5H), 9.78 (broad s, 1H). 1- (3-cyano-3-phenylpropyl) -4- (2,3-dihydrobenzo-1,4-dioxin-5-yl) -piperazine (Compound 26b) The title compound is obtained following the procedure described for the compound of Example 1, but using Compound 26a as starting material instead of Compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2 -trifluoroethoxyphenyl) -piperazine. Purification by flash chromatography (PE-EtOAc 4: 6) gives the title compound (85%). Oil 1H-NMR (CDCl3 d): 2.01-2.29 (m, 2H), 2.31-2.72 (m, 6H), 3.02-3.22 (m, 4H), 4.03-4.18 (m, 1H), 4.19-4.38 (m, 4H ), 6.50-6.62 (m, 2H), 6.73-6.85 (m, 1H), 7.31-7.42 (m, 5H). 1- (2,3-dihydrobenzo-l, 4-dioxin-5-yl) -4- (3-formyl-3-phenylpropyl) -piperazine (Compound 26c) The title compound is obtained following the procedure described for the Compound 6f (alternative method) but using Compound 26b instead of Compound 6h as the starting material. Purification by flash chromatography (CH2C12-MeOH 95: 5) gives the title compound (60%). Oil. RM ¾. { CDC13 d): 1.88-2.02 (m, 1H), 2.30-2.51 (m, 3H), 2.52-2.98 (m, 4H), 2.99-3.31 (m, 4H), 3.63-3.77 (m, 1H), 4.20 -4.41 (m, 4H), 6.48-6.67 (m, 2H), 6.68-6.85 (m, 1H) 7.21-7.43 (m, 5H), 9.79 (broad s, 1H). 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhexyl) -piperazine The title compound is obtained following the procedure described for the Compound of Example 6 but using Compound 26c as the starting material instead of Compound 6f. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 97: 3) which gives the title product as a yellow glassy oil (22.6%). XH NMR (CDCl3 d): 0.79-1.01 (m, 3H), 1.02-1.79 (m, 4H), 1.80-1.98 (m, 1H), 1.99-2.24 (m, 1H), 2.26-2.96 (m, 6H) ), 2.98-3.33 (m, 4H), 3.41-3.79 (m, 1H), 4.18-4.38 (m, 4H), 6.45-6.68 (m, 2H), 6.69-6.87 (m, 1H), 7.19-7.38 (m, 5H).

[M + H] + = 397.4 Example 27 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenyl) -heptyl] -piperazine The title compound is obtained together with the compound of Example 12 as the main impurity. Purify by flash chromatography (EtOAc-MeOH / NH3 95: 5). 1H-NMR (CDC13 5): 0.78-0.92 (m, 3H), 1.15-1.3 (m, 5H), 1.80-2.08 (m, 2H), 2.28-2.40 (m, 2H), 2.52-2.83 (m, 5H) ), 3.02-3.18 (m, 4H), 3.65-3.79 (m, 1H), 4.16-4.32 (m, 4H), 6.48-6.62 (m, 2H), 6.71-6.82 (t, 1H), 7.15-7.33 (m, 5H).

Example 28 1- [5- (2,3-dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhex-5-enyl] -piperazine The title compound is obtained following the procedure described for Compound of Example 6 but using as starting material Compound 26c instead of Compound 6f and vinylmagnesium chloride (1M solution in THF) instead of ethylmagnesium chloride The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 97 : 3) which gives the title product as a yellow glassy oil (66%) XH NMR {CDC13 d): 1.35-1.85 (broad, 1H), 1.86-2.28 (m, 2H), 2.30-2.91 (m, 7H), 2.98-3.25 (m, 4H), 3.43-3.81 (m, 1H), "4.19-4.40 (m, 4H), 4.90-5.35 (m, 2H), 5.66-5.89 (m, 1H) ), 6.47-6.69 (m, 2H), 6.71-6.85 (m, 1H), 7.14-7.42 (m, 5H). [M + H] + = 395.3 EXAMPLE 29 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-5-methyl-3-phenyl) -hexyl] -piperazine The title compound is obtained by following the procedure described for the Compound of Example 6, but using as the starting material Compound 26c instead of Compound 6f and isopropylmagnesium chloride (2M solution in THF) instead of ethylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 98: 2) which gives the title product as a white solid (35%). 1H-NMR (CDC13 d): 0.73-0.95 (m, 6H), 1.30-1.48 (m, 1H), 1.76-1.95 (m, 1 H), 1.96-2.21 (m, 1H), 2.22-2.48 (m, 2H), 2.49-2.95 (m, 5H), 2.96-3.28 (m, 4H), 3.52-3.73 (m, 1H), 4.19-4.41 (m, 4H), 5.02-5.68 (s broad, 1H), 6.49 -6.63 (m, 2H), 6.75-6.87 (m, 1H), 7.15-7.39 (m, 5H). [M + H] + = 411.7 EXAMPLE 30 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenyl) -pentyl] -piperazine The title compound is obtained following the procedure described for the Compound of Example 6 but using as the starting material Compound 26c instead of Compound 6f and methylmagnesium bromide (3M solution in THF) instead of ethylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 99: 1) which gives the title product as a white solid (42%) characterized as a 7: 3 mixture (RS, RS) - (RS, SR ). 1 H NMR (CDC13 5): 0.85-1.15 (m, 3H), 1.41-1.67 (m, 2H), 1.74-1.95 (m, 1H), 1.96-2.24 (m, 1H), 2.25-3.29 (m, 10H), 3.81-3.99 (m, 1H), 4.19-4.39 (m, 4H), 6.50- 6.65 (m, 2H), 6.72-6.87 (m, 1H), 7.14-7.41 (m, 5H). [M + H] + = 383.6 EXAMPLE 31 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-idroxy-3-phenyl-ept-5-ynyl) -piperazine The title compound is obtained following the procedure described for the compound of Example 6 but using as the starting material Compound 26c instead of Compound 6f and 1-propynylmagnesium bromide (0.5M solution in THF) instead of ethylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-MeOH / NH3 99: 1) which gives the title product as a light yellow solid (35%). 1 H NMR (CDCl 3 d): 1.72-1.89 (m, 3H), 1.91-2.21 2H), 2.30-2.50 (m, 2H), 2.51-2.82 (m, 4H), 2.38-3.24 5H), 3.51-3.73 (m, 1?), 4.20-4.41 (m, 4H), 4.42-4.61 1H), 6.48-6.63 (ra, 2H), 6.73-6.82 (ni, 1H), 7.20-7.39 5H). [M + HJ + = 407.4 EXAMPLE 32 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhept-5-enyl) -piperazine The title compound is obtained following the procedure described for Compound of Example 6 but using as the starting material Compound 26c instead of Compound 6f and 1-propenylmagnesium bromide (0.5M solution in THF) instead of ethylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-MeOH / H3 99: 1) which gives the title product as a light yellow solid (83%). 1 H NMR (CDCl 3 d): 1.31-2.31 (m, 8H), 2.32-2.91 (m, 6H), 2.92-3.28 (m, 4H), 4.17-4.33 (m, 4H), 5.23-5.75 (m, 2H), 6.48-6.63 (m, 2H), 6.71 -6.84 (m, 1H), 7.12-7.39 (m, 5H). [M + H] + = 409.6 Example 33 1- [5- (2, 3-dihydro-1,4-benzodioxini)] -4- (4-hydroxy-3-phenylhex-5-ynyl) -piperazine The title compound is obtained following the procedure described for Compound of Example 6 but using as the starting material Compound 26c instead of Compound 6f and 1-ethynylmagnesium bromide (0.5M solution in THF) instead of ethylmagnesium chloride. The crude product is purified twice, first by flash chromatography (CH2C12-MeOH / NH3 99: 1) followed by preparative liquid chromatography which gives the title product as a white solid (8%). NMR ¾ (CDC13 < 5): 1.11-1.99 (broad, 1H), 2.01-2.25 (m, 2H), 2.27-2.31 (m, 1H), 2.34-2.37 (m, 2H), 2.61-2.82 (m , 4H), 2.85-3.22 (m, 5H), 4.18-4.32 (m, 4H), 6.47-6.62 (m, 2H), 6.74-6.86 (m, 1H), 7.19-7.41 (m, 5H). [+ H] + = 393.7.

EXAMPLE 34 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhe t-6-enyl) -piperazine The title compound is obtained following the procedure described for the compound of Example 6 but using as the starting material compound 26c instead of compound 6f and allylmagnesium bromide (solution in 1M THF) instead of ethylmagnesium chloride. The crude material is purified by flash chromatography (CH2Cl2-MeOH / NH3 99: 1) which gives the title product as a brownish oil (27%).

NMR-H1 (CDCI3, d): 1.41-1.72 (broad, 1?), 1.73-2.25 (ra, 4H), 2.26-2.50 (m, 2H), 2.51-2.91 (m, 5H), 3.03-3.24 ( m, 4H), 3.78-3.92 (m, 1H), 4.20-4.39 (m, 4H), 4.92-5.17 (m, 2H), 5.73-5.95 (m, 1H), 6.51-6.64 (m, 2H), 6.67-6.84 (m, 1H), 7.11-7.40 (m, 5H). [M + H] + = 409.7 Example 35 1- [5- (2,3-Dihydro-1, -benzodioxinyl)] -4- (4-hydroxy-6-methy1-3-phenylhept-5-enyl) -piperazine The title compound is obtained by following the procedure described for the compound of Example 6 but using as compound 26c instead of compound 6f? 2-methyl-1-propenylmagnesium bromide (solution in THF 0.5) instead of ethylmagnesium chloride. The crude product is double purified by flash chromatography (CH2Cl2-MeOH / H3 99: 1) followed by preparative liquid chromatography which gives the title compound as a white solid (10%). NMR-H1 (CDCI3, d): 1.12-1.85 (m, 8H), 1.87-2.02 (m, 1H), 2.03-2.29 (m, 1H), 2.30-2.91 (m, 6H), 2.93-3.21 (m , 4H), 4.17-4.35 (ni, 4H), 4.36-4.48 (m, 1H), 4.96-5.22 (m, 1H), 6.48-6.62 (m, 2H), 6.75-6.85 (m, 1H), 7.12 -7.38 (m, 5H). [M + H] + = 423.8 Example 36 1- [5- (2,3-Dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-6-methyl-3-phenyl) -heptyl] -piperazine To a solution of 0.708 ml of 2M isobutylmagnesium chloride in THF, 0.226 g of LiC104 are added in 3 ml of THF. The mixture is stirred at room temperature for 1 h; subsequently 0.13 g of compound 26c in 3 ml of THF are added dropwise. Allow the reaction mixture to stir at room temperature for 3 h and then suspend with saturated aqueous NH 4 Cl solution, turn alkaline and extract with EtOAc. The combined extracts are dried with Na2SO4 and evaporated to dryness. The crude product is purified by flash chromatography (CH2C12-MeOH 99: 1) which gives the title product as an ivory white solid (54.6%). NMR-H1 (CDCl3, d): 0.68-1.01 (m, 8H), 1.12-1.38 (m, 2H), 1.65-1.85 (m, 1H), 2.03-2.29 (m, 1H), 2.30-2.52 (m , 1H), 2.53-2.83 (m, 2H), 2.84-3.47 (m, 9H), 3.73-3.92 (m, 1H), 4.18-4.39 (m, 4H), 6.49-6.65 (m, 2H), 6.67 -6.87 (m, 1H), 7.10-7.40 (m, 5H). [M + H] + = 425.2 Example 37 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylbutyl] piperazine The title compound is obtained together with the compound of Example 36. The purification by flash chromatography gives the title product as an oil.H NMR (CDC13 / 5): 1.36-1.64 (m, 1H), 1.81-2.05 (m, 2H), 2.50-2.73 (m, 4H), 2.75 -2.93 (m, 2H), 2.94-3.27 (m, 4H), 3.62-3.72 (m, 2H), 4.20-4.39 (m, 4H), 6.10-6.45 (broad, 1H), 6.46-6.62 (m, 2H), 6.70-6.83 (m, 1H), 7.13-7.37 (m, 5H). [M + H] + = 369.7 Example 38 (RS, SR) -1- [5- (2, 3-Dihydro-1,4-benzodioxinyl)] -4- (4-hydroxy-3-phenylpe thi) -piperazine The title compound is obtained together with The compound of Example 11. Purification by flash chromatography affords the title product as an oil, characterized as a pure diastereomer (RS, SR). RMN-1 !! (CDC13, d):? "·" > Wu,,, -.21 (m, 3H), 2.32-2.45 (m, 2H), 2.46-2.83 (m, 5H), 2.95-3.17 (m, 4H), 3.92-4.01 (m, 1H), 4.18 -4.37 (m, 4H), 6.45-6.61 (m, 2H), 6.72-6.85 (m, 1H), 7.11-7.38 (m, 5H). [M + H] + = 383.6 Example 39 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-oxobutyl] -4- [5 (2,3-dihydro-l 4-benzodioxinyl)] -piperazine 2- (2-cyclohexyl-2- oxoethyl) -?,? - dimethylbenzamide (Compound 39a) The title compound is obtained as described for compound 13a after usual work up processing, the crude material is purified by flash chromatography (PE-EtOAc 1: 1) to provide the title compound (34-6%). R N-1H (COCI, d): 1.11-1.50 (m, 5H); 1.61-1.98 (m, 6H); 2.84 (d, 3H); 3.04 (d, 3H); 3.81-4, 02 (m, 2H); 7.11-7.42 (m, 5H). [M + H] + = 274 4-cyclohexyl-3- (2-dimethylaminocarbonyl) -4-oxobutyraldehyde dimethylacetal (compound 39b) The title compound is prepared using the method described for compound 2b but using compound 39a instead of compound 2a. The crude product is purified by flash chromatography (PE-Me2C0 75:25).

Performance: 21.3%. RMN-1 !! (CDC13, d): 0.94-1.49 (m, 5H); 1.51-1.83 (m, 5H); 1.84-2.01 (m, 1H); 1.36-1.69 (m, 2H); 2.88 (s, 3H); 3.18 (s, 3H); 3.31 (d, 6H); 4.12-4.34 (m, 2H); 7.12- 7.39 (m, 4H). 4-cyclohexyl-3- (2-dimethylaminocarbonyl) -4-oxybutyraldehyde (compound 39c) The title compound is obtained following the procedure described for compound Id, but using as the starting material compound 39b instead of compound Ic. The crude product is used in the next step without further purification. NMR- ?? (CDC13 / d): 0.90-2.12 (m, 12 H); 2.60-3.32 (m, 8H); 4.39-4.58 (m, IH); 7.04-7.51 (m, -4H); 9.63 - 9.72 (m, 1H). 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-oxobutyl] -4- [5- (2 -3-dihydro-l / 4-benzodioxinyl)] -piperazine The title compound is prepared using the method described for the compound of Example 1 but using compound 39c instead of the compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: e2C0 6: 4) to give the title compound (65%). RMN-1 !! (CDC13, d): 1.03-2.01 (m, 11H); 2.23-2.42 (m, 3H); 2.44-2.72 (m, 5H) 2.91 (s, 3H); 3.97-3.13 (m, 4H); 3.19 (s, 3H); 4.13-4.38 (m, 5H); 6.48-6.63 (m, 2H); 6.70-6.84 (m, IH); 7.13-7.39 (m, 4H). [M + H] + = 520 Example 40 1- [4-Cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine The title compound is synthesized using the method described for compound Ic but starting from the compound of Example 39 instead of compound Ib. After the procedure of. usual treatment, the crude product is purified by flash chromatography (PE-Me2CONH3 / MeOH 7: 3: 0.2) which gives the title compound (65.2) [M + H] + = 522.45 Example 41 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) piperazine The title compound is prepared using the method described for the compound of Example 1 but using compound 39c instead of the compound le and 1- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE: Me2CO 6: 4) to give the title compound (64.5%). RM - ^ - H (CDC13, d): 1.03-2.02 (m, 11H); 2.17-2.37 (m, 3H); 2.41-2.73 (m, 5H); 2.94 (s, 3H); 2.95-3.12 (m, 4H); 3.17 (s, 3H); 3.85 (s, 3H); 4.11-4.27 (m, 1H); 6.51-6.69 (m, 2H); 6.78-6.92 (m, 1H); 7.12-7.41 (m, 4H). [M + H] + = 510 Example 42 1- [4-Cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-hydroxybutyl] 4- (4-fluoro-2-methoxyphenyl) The title compound is synthesized using the method described for the compound but starting from the compound of Example 41 instead of compound Ib. After the usual treatment procedure, the crude product is purified by flash chromatography (PE Me2CONH3 / MeOH 75: 25: 0.2) which gives the title compound (64.2%). [M + H] + = 512.6 EXAMPLE 43 1- [3- (2-Cyanophenyl) -4-oxopentyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine 3- (2-cyanophenyl) -4-oxopentanaldehydedietylacetal (Compound 43a) The title compound is prepared using the method described for compound 2b but using 1- (2-cyanophenyl) -propan-2-one (RA Bruce, Org. Prep. Proc. Int. 407-412, 1999 ) instead of compound 2a. The crude product is purified by flash chromatography (PE-EtOAc 8: 2). Yield: 13%. RMN-1 !! (CDC13, d) .1.10-1.29 (m, 6H), 1.87-2.04 (m, 1H), 2.14 (s, 3H), 2.42-2.59 (m, 1H), 3.31-3.71 (m, 4H), 4.28 -4.43 (m, 2H), 7.30-7.41 (m, 2H), 7.51, -7.72 (m, 2H). 3- (2-cyanophenyl) -4-oxopentanaldehyde (Compound 43b) The title compound is obtained following the procedure described for compound Id, but using as the starting material compound 43b instead of compound le. The crude product is used in the next step without further purification. 1- [3- (2-Cyanophenyl) -4-oxopentyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] - piperazine The title compound is prepared using the method described for the compound of Example 1 but using compound 43b instead of compound le and 1- (2,3-dihydro-l, 4-benzodioxin-5-yl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) - piperazine. The crude product is purified by flash chromatography (PE: EtOAc 6: 4) to give the title compound (43.8%). RMN-1 !! (CDC13, d): 1.75-1.92 (ra, 1H), 2.21 (s, 3H), 2.30-2.41 (m, 3H), 2.41-2.69 (m, 4H), 2.92-3.12 (m, 4H), 4.19 -4.40 (m, 5H), 6.48-6.62 (m, 2H), 6.71-6.82 (t, 1H), 7.30-7.43 (m, 2H), 7.51-7.72 (m, 2H).

Example 44 1- [4-cyclohexyl-3- (2-trifluoromethoxyphenyl) -4-oxobutyl] -4- (4-indolyl) -piperazine 1-cyclohexyl-2- (2-trifluoromethoxyphenyl) ethanone (Compound 44a) A mixture of 1.26 g of 2-trifluoromethoxybenzyl chloride, 0.59 g of zinc powder and 1,2-DME is refluxed for 3 h, cooled to room temperature. It is then filtered and 0.02 g of dichlorobis (triphenylphosphine) palladium (II) is added followed by 0.72 ml of cyclohexanecarbonyl chloride to the stirred filtrate at room temperature. Subsequently the reaction mixture is stirred at reflux for 4 h, and cooled to room temperature. After the usual treatment procedure (see compound 1), the crude product is purified by flash chromatography (methyl etherbutylether-PE 96: 4) to provide 0.22 g of the title compound. R N-1 !! (CDC13, d): 1.10-2.00 (m, 10H); 3.80 (s, 3H); 7.18-7.40 (m, 4H); 4-cyclohexyl-4-oxo-3- (2-trifluoromethoxy-phenyl) -butyraldehyde-diethylacetal (Compound 44b) To a solution of 0.22 g of compound 44a in 1 ml of DMSO is added 0.091 g of potassium terbutoxide at room temperature. After 15 min 0.12 ml of 2-bromoacetaldehyde diethylacetal are added and the reaction mixture is heated at 50 ° C for 5 h. Subsequently, it is cooled to room temperature, diluted with water and extracted with methyl etherbutylether, which is dried with Na 2 SO 4 and evaporated to dryness in vacuo which provides a crude product which is purified by flash chromatography (methyltebutyl ether- 93: 7). ) which provides 0.092 g of the pure title product. RMN-1 !! (CDCl 3, d): 1.00-2.10 (m, 17H); 2.10-2.45 (m, 2H); 3.75 (c, 4H); 4.32 (t, 1H); 4.50 (t, 1H); 7.10-7.40 (m, 4H). 4-cyclohexyl-4-oxo-3- (2-trifluoromethoxy-phenyl) -butyraldehyde (Compound 44c) 0.09 g of compound 44b, 1.1 ml of 1N HC1 and 5 ml of acetone are stirred at room temperature for 4 h. Evaporation and extraction with CH2C12 gives the title compound, which is used in the next step without further purification. NMR - ^ - H (CDCl 3, d): 0.80-1.95 (m, 9H); 1.95-2.15 (m, 1H); 2.25-2.45 (m, 1H); 2.52 (dd, 1H); 3.40 (dd, 1H); 4.80 (dd, 1H); 7.10-7.40 (m, 4H); 9.75 (s, 1H) 1- [4-cyclohexyl-3- (2-trifluoromethoxyphenyl) -4-oxobutyl] -4- (4-indolyl) piperazine The title compound is prepared using the method described for the compound of Example 1 but using compound 44c in instead of the compound le and 1- (4-indolyl) piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product was purified by flash chromatography (PE: EtOAc 6: 4) to give the title compound (53%). R N-1 !! (CDCI3, d): 1.00-2.10 (m, 11H); 2.20-2.50 (m, 4H); 2.50-2.80 (m, 4H); 3.15-3.40 (m, 4H); 4.50 (t, 1H); 6.50 (d, 1H); 7.60 (dd, 1H); 7.007.20 (m, 3H); 7.20-7.35 (m, 4H); 8.15 (s, 1H) Example 45 (RS, SR) 1- [4-acetoxy-4-cyclohexyl-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine 1-cyclohexyl-2- (2-fluorophenyl) ethanone (Compound 45a) To a mixture of 36 my 2-fluorobenzylzinc chloride (0.5 M solution in THF) and 0.008 g of dichlorobis (triphenylphosphine) -palladium (II) stirred at 0 ° C, is added dropwise by means of a syringe 2.14 ml of cyclohexanecarbonyl chloride. Subsequently, the reaction mixture is stirred at room temperature for 4 hours, suspended with 25 ml of a saturated aqueous solution of ammonium chloride, extracted with 20 ml of EtOAc, which is dried with Na 2 SO 4 and evaporated to dryness at room temperature. This gives 3.52 g of the title compound as a crude product, which can be used in the next step without further purification. NMR-1! * (CDC13, d): 1.10-2.05 (m, 10H), 2.47 (tt, 1H), 3.77 (s, 2H), 6.97-7.32 (m, 4H) 4-cyclohexyl-4-oxo- 3- (2-fluorophenyl) -butyraldehyde diethyl acetal (compound 45b) A solution of 5.02 g of compound 45a in 136 ml of toluene is heated to reflux, recovering 35 ml of toluene by distillation to remove water. Subsequently 3.18 g of potassium terbutoxide are added and stirring is continued at reflux for 30 min. The reaction mixture is cooled to 80 ° C and 4.27 ml of 2-bromoacetaldehyde diethylacetal are added. After refluxing for 18 h, the reaction mixture is cooled to room temperature, suspended with a saturated aqueous solution of 30 ml of ammonium chloride, extracted with 30 ml of EtOAc, which is dried with Na 2 SO 4 and evaporated to dryness under vacuum, which gives the crude product which is purified by flash chromatography (petroleum ether-EtOAc 92.5: 7.5), which gives 2.97 g of the pure title product. NMR- ^ (CDC13 / d): 1.00-2. 1 0 (m, 17H), 2.20-2.52 (m, 2H), 3.30-3.72 (m, 4H), 4.25-4.45 (m, 2H), 6.90-7.35 (m, 4H) 4-cyclohexyl-4-oxo-3- (2-fluorophenyl-butyraldehyde (Compound 45c) A mixture of 1.12 g of compound 45b, 9 ml of 50% aqueous trifluoroacetic acid and 18 ml of CH 2 C 12 is stirred for 2 h at room temperature and then it is diluted with 10 ml of CH2C12, the organic layer is separated, washed with brine (2 x 15 ml), dried with Na2SO4 and evaporated to dryness in vacuo to give 0.88 g of the crude product using in the next step without purification. Additional: RMN-XH (CDC13, d): 0.90-2.1 0 (m, 10H), 2.25-2.70 (m, 2H), 3.12-3.52 (m, 1H), 4.60-4.80 (m, 1H), 6.95- 7.40 (m, 4H), 9.75 (s, 1H) 1- [4-Cyclo-Exyl-3- (2-fluorophenyl) -4-oxobutyl] -4- (2-methoxyphenyl) piperazine (Compound 45d) A mixture of 0.88 g of compound 45c, 0.84 g of hydrochloride of 1- ( 2-methoxyphenyl) -piperazine, 1.06 g of sodium triacetoxyborohydride and 33 ml of CH2C12 are stirred at room temperature for 1 h, kept overnight at rest, and made alkaline with 20% aqueous Na2CO3. The organic layer is separated, washed with brine (2 x 30 ml), dried with Na 2 SO 4 and evaporated to dryness in vacuo to give a crude product 1.46 g which is used in the next step without further purification. A sample is purified by flash chromatography (petroleum ether-EtOAc 6: 4) which gives a pure sample. NMR-XH (CDC13, d): 1.05-2.00 (m, 11H), 2.20-2.44 (m, 4H), 2.45-2.72 (m, 4H), 2.90-3.20 (m, 4?), 3.85 (s, 3?) (RS, SR) -1- [4-cyclohexyl-3- (2-fluoro-phenyl) -4-dihydrobutil] -4- (2-methoxyphenyl) -piperazine (Compound 45e) To a solution of 1.46 g of compound 45d in 33 ml of stirred eOH at 0 ° C. 0.19 g of NaBH 4 are added and the mixture is stirred at room temperature for 4 h. The solvent is evaporated and the crude reaction is taken up with H20 and extracted with EtOAc. The organic layer is separated, washed with brine (2 x 25 ml), dried with Na 2 SO 4 and evaporated to dryness in vacuo to give a crude product which is purified by sequential flash chromatography (petroleum ether-EtOAc-2N ammonia in methanol 75: 25: 2; petroleum ether-EtOAc-2N ammonia in methanol 80: 20: 2) which gives 0.82 g of Compound 45e (Rf in upper CCD, eluent: petroleum ether-EtOAc-2N ammonia in methanol 70: 30: 2). RMN-1 !! (CDC13, d): 0.80-1.40 (m, 6H), 1.50-1.82 (m, 4H), 1.85-2.10 (m, 3H), 2.21-2.45 (m, 2H), 2.52-2.85 (ra, 4H) , 2.98-3.26 (m, 4H), 3.28-3.42 (m, 1H), 3.50-3.60 (m, 1H), 3.85 (s, 3H), 6.80-7.30 (m, 7H), 7.62-7.80 (m, 1 HOUR); OH peak not detectable.

(IR, 2S) l-cyclohexyl-4- [4- (2-methoxyphenyl) -piperazin-1-yl] -2- (2-fluorophenyl) -butan-1-ol (Compound 45eA) This compound is obtained by chromatography in a chiral column over compound 45e using Chiralpak AD (0.46 x 25 cm), eluting with n-hexane-EtOAc 95: 5 (flow = 0.5 ml / min, UV detector 247 nm). (1R, 2R) l-cyclohexyl-4- [4- (2-methoxyphenyl) -piperazin-1-yl] -2- (2-fluorophenyl) -butan-1-ol (Compound 45 eB) This compound is obtained by Chiral column chromatography on compound 45e using Chiralpak AD (0.46 x 25 cm), eluting with n-hexane-EtOH 95: 5 (flow = 0.5 ml / min, UV detector 247 nm). The absolute stereochemistry of the 45eB compound, in the form of its salts with hydrogen bromide, is determined by X-ray diffraction of single crystal, as follows. X-ray single-glass diffraction experiment: A single crystal is selected as a needle for X-ray diffraction analysis and mounted on a glass fiber. The data is collected in a Rigaku Rapid cylinder plate image plate X-ray area detector with detector aperture = 45.0 x 25.6 cm. It is controlled by a PC PC based on Windows 2000 with Rapid Auto Software version 1.06 (Rigaku, 2000) at low temperature (-120 ° K) with mirrors Micromax-002 micro-Confocal GuK radiation [A (CuKa) = 1.5405Á] . The indexing is done from three oscillations of 3o in frames that are exposed for 360 seconds. All reflections are measured in five groups of images with six frames in each group; Exposure times are 160 seconds per degree. Among them, five groups of images are at angles f = 0o, 90o, 180o, 270o with? = 50 ° and f = 0 °, with? = 0o, all the frames are d? = 30 ° and which make 2 Gmax = 136.3 °. The sample / detectors distance of 12.74 cm. The data reduction program Rapid Auto version 1.06 (Rigaku, 2000), determined that the Laue group is -1, a total of 7,986 reflections were integrated for structure and refinement solution. Results of a single crystal: The structure is solved by direct methods using SIR92 (Altomare et al., 1994). All calculations are performed using CrystalStructure 3.0 (MSC / Rigaku, 2002, Watkin et al., 1996, Canuthers and Watkin, 1979) as a crystallographic software package. The test solution obtains 38 atoms that are different from hydrogen in the asymmetric unit. The least squares refinement includes all the different atomic coordinates of hydrogen and the anisotropic thermal parameters. The final cycle of least squares matrix refinement. complete on F is based on 6,297 reflections with I > - - 3s (?), Which converge with agreement factors: R = 0.071, S = 2.224, Rw = 0.073. The absolute configuration is determined using the parameter Flack x calculated, which is 0.00 with esd = 0.04. The expected values are 0.0 (within 3 esd) for correction and +1.0 for inverted absolute structure. References: Altomare, A., Cascarano, G., Giacovazzo, C. Gualgliardi, A., Burla, M., Polidori, G., and Camalli, M., (1994) SIR92, J. Appl. Cryst. , 27, 435. Carruthers, J.R. and Watkin, D.J. (1979), Acta Cryst, A35, 698-699. Rigaku (2000), Rapid Auto, Rigaku Corporation, Tokyo, Japan. Rigaku and Rigaku / MSC, (2000-2002), Crystal Structure Analysis Software, CrystalStructure Version 3.00, Rigaku / MSC, 9009 New Trails Drive, The Woodlands, TX, USA 77381-5209.

Rigaku, 3-9-12 Akishima, Tokyo 196-8666, Japan. Watkin, D.J., Prout, C.K. Carruthers, J.R. & Betteridge, P.W., CRYSTALS Issue 10, Chemical Crystallography Laboratory, Oxford, UK.

(RS, SR) 1- [4-acetoxy-4-cyclohexyl-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine To a solution of 0.135 g of Compound 45e and 0.043 ml of TEA in 5 ml of CH2C12 stirred at 0-5 ° C, 0.021 ml of acetyl chloride are added. Subsequently, the reaction mixture is stirred at room temperature for 4 h, washed with 5% aqueous NaHC03 (1 x 10 ml), H20) (2 xl5ml), dried over Na2SO4 and evaporated under vacuum to provide 0.143 g of the product of the title. - ^ (COCI3, S): S 0.80-1.25 (m, 5H); i.25-1.50 (m, 1H); 1.50-1.90 (m, 7H); 1.95 (s, 3H); 2.10-2.40 (m, 2H); 2.40-2.65 (m, 4H); 2.90-3.15 (m, 4H); 3.38-3.55 (m, 1H); 3.85 (m, 3H); 5.05 (t, 1H); 6.80-7.25 (m, 7H); 7.30-7.45 (m, 1H) Example 46 (RS, SR) 1- [4-cyclohexyl-3- (2-fluorophenyl) -4-methoxycarbonyloxybutyl] -4- (2-methoxyphenyl) -piperazine To a solution of 0.112 g of compound 45e in 0.8 ml of pyridine After stirring at 0 ° C, 0.022 ml of methyl chloroformate were added. The reaction mixture is stirred at room temperature for 4 days and at 40 ° C for 5 h. An additional 0.045 ml of methyl chloroformate is added, it is heated at 40 ° C for 4 h. After 3 days at room temperature, 0.045 ml of methyl chloroformate are added and the mixture is stirred at room temperature for 6 h. After cooling, it is poured into water and extracted with EtOAc (2 x I5ml), washed with 2 x I5ml of H20, dried with Na2SO4 and evaporated to dryness in vacuo. The crude product is purified by flash chromatography at (PE-EtOAc-NH3 / MeOH 75: 25: 2.5) to provide 0.022 g of the title product. RMN-1 !! (CDC13, d): 0.80-2.05 (m, 13H); 2.10-2.40 (m, 2H); 2.40-2.75 (m, 4H); 2.90-3.20 (m, 4H); 3.38-3.60 (m, 1H); 3.70 (m, 3H); 3.85 (m, 3H); 4.88 (t, 1H); 6.80-7.25 (m, 7H); 7.38-7.50 (m, 1H) Example 47 (RS, SR) 1- [4-Cyclohexyl-4-ethylaminocarbonyloxy-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine To a solution of 0.126 g of Compound 45e in 0.5 ml of pyridine stirred at 0 ° C, 0.113 of ethyl isocyanate are added. The reaction mixture is stirred at room temperature for 24 h and at 50 ° C for 3 h. After cooling, it is poured into water and extracted with Et20, washed with H20, dried with Na2SO4 and evaporated to dryness in vacuo to give 0.108 g of the title product. RMN-1 !! (CDC13, d): 0.90-1.40 (m, 9H); 1.60-2.10 (m, 7H); 2.10-2.40 (m, 2H); 2.50-2.65 (m, 4H); 2.95-3.30 (m, 6H); 3.40-3.55 (m, 1H); 3.85 (s, 3H); 4.50 (t, lH); 4.90 (t, 1H); 6.80-7.22 (m, 7H); 7.32-7.45 (m, 1H) Example 48 (RS, SR) 1- [4-aminocarbonyloxy-4-cyclohexyl-3- (2-fluorophenyl) butyl] -4- (2-methoxyphenyl) -piperazine To a solution of 0.124 g of compound 45e in 5 ml of CH2C12 is added potassium cyanate. The suspension stirred at room temperature is added 0.087 ml of trifluoroacetic acid. After 24 h at room temperature and 5 h at 40 ° C, an additional 0.17 ml of trifluoroacetic acid are added. After 6 h at 40 ° C, the reaction mixture is cooled, evaporated to dryness, diluted with water and 2N NaOH, extracted with EtOAc; The extract is washed with H20, dried with Na2SO4 and evaporated to dryness in vacuo. The product is purified by flash chromatography to PE-EtOAc-H3 / MeOH 75: 25: 2.5) to provide 0.064 g of the title product. RMN-1 !! (CDC13 / d): 0.90-1.50 (m, 6H); 1.50-2.05 (m, 7H); 2.10-2.40 (m, 2H); 2.50-2.70 (m, 4H); 2.95-3.15 (m, 4H); 3.40-3.55 (m, 1H); 3.85 (s, 3H); 4.45 (s, 2H); 4.85-4.95 (m, 1H); 6.80-7.26 (m, 7H); 7.32 -7.45 (m, 1H) Example 49 1- [5- (2,3-Dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-5,5-dimethyl-3-phenyl) -hexyl] -piperazine The title compound is synthesized following the procedure described for the compound of example 36 but using terbutilmagnesium chloride (1N in THF) instead of isobutylmagnesium chloride. The mixture is stirred at room temperature for 3 h. The crude product is purified by flash chromatography (CH2C12-MEOH 99: 1) which gives the title product as a brownish solid (15.%). RMN-1 !! (COCI 3, d): 0.88 (m, 9H), 1.31-1.48 (m, 2H), 1.73-1.97 (m, 1H), 1.96-2.21 (m, 1H), 2.22-2.48 (m, 2H), 2.49-2.97 (m, 5H), 2.99-3.28 (m, 4H), 3.61-3.73 (m, 1H), 4.19-4.41 (m, 4H), 6.49-6.63 (m, 2H), 6.75-6.87 (m , 1H), 7.15-7.44 (m, 5H). [M + H] + = 425.7 Example 50 1- (4-Fluoro-2-methoxyphenyl) -4- [(4-hydroxy-3-phenyl) -hept-5-ynyl] piperazine 1- (3-cyano-3-phenylpropyl) -4- (4 -fluoro-2-methoxyphenyl) -piperazine (Compound 50a) The title compound is obtained by following the procedure described for the compound of example 1 but using as the starting material the compound 26a instead of the compound le and 1- (4-fluoro) -2-methoxyphenyl) -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) piperazine. Purification by flash chromatography (PE-EtOAc 4: 6) gives the title compound (90%). oil. RMN-1 !! (CDC13, S) 1.94-2.29 (m, 2H); 2.36-2.79 (m, 6H); 2.97-3.14 (m, 4H); 3.85 (s, 3H); 4.01-4.12 (m, 1H); 6.54-6.71 (m, 2H); 6.82-7.97 (m, 1H); 7.28-7.47 (m, 5H). 1- (4-Fluoro-2-methoxyphenyl) -4- (3-formyl-3-phenylpropyl) -piperazine (Compound 50b) The title compound is obtained following the procedure described for compound 6f (alternative method) but using as starting material compound 50a instead of compound 6h. Purification by flash chromatography (CH2C12 = MeOH 95: 5) gives the title compound (55%). oil. RM - ^ - H (CDC13, d): 1.81-2.00 (m, 1H); 2.24-2.48 (m, 3H); 2.49-3.82 (m, 4H); 3.87-3.19 (m, 4H); 3.61-3.73 (m, 1H); 3.84 (s; 3H); 6.53-6.71 (m, 2H); 6.80-6.94 (m, 1H); 7.12-7.45 (m, 5H); 9.68-9.79 (m, 1H). 1- (4-Fluoro-2-methoxyphenyl) -4- [(4-hydroxy-3-phenyl) -hept-5-ynyl] -piperazine The title compound is obtained following the procedure described for the compound of Example 36 but using as the starting material compound 50b instead of compound 26c and using 1-propynylmagnesium bromide (0.5 N in THF) instead of a solution in isobutylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12 MEOH 99: 1) which gives the title product as a yellow glassy oil (22.6%). RM - ^ (CDCI3, d): 0.84-1.17 (m, 3H), 1.40-1.70 (m, 2H), 1.74-1.90 (m, 1H), 1.93-2.22 (m, 1H), 2.25-3.29 (m , 10H), 3.80 (s, 3H), 3.84-3.99 (m, 1H), 6.50-6.65 (m, 2H), 6.70-6.90 (m, 1H), 7.14-7.38 (m, 5H). [M + H] + = 397.2 Example 51 (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4- [(4-hydroxy-3-phenyl) -hep-5-enyl] -piperazine (1: 1 mixture) The compound of the title following the procedure described for the compound of example 36 but using as the starting material compound 50b instead of compound 26c and using 1-propenylmagnesium bromide (0.5 N in THF) instead of a solution of isobutylmagnesium chloride. The crude product is purified by flash chromatography (CH2C12-MEOH 99: 1) which gives the title compound as a yellow glassy oil (30%). NMR- ^ (CDC13, d): 1.17-1.73 (m, 4H), 1.92-2.51 (m, 2H), 2.52-3.42 (m, 11H), 3.83 (s, 3H), 4.22-4.65 (m, 1H ), 5.28-5.75 (m, 2H), 6.50-6.64 (m, 2H), 6.72-6.91 (m, 1H), 7.13-7.41 (m, 5H). [M + H] + = 399.2 Additional purification by liquid chromatography-preparative mass spectrum provides isolation of the following compounds: Example 52 (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4- [(4-hydroxy-3-phenyl) -hep-5-enyl] -piperazine (mixture 5:95) NMR-1 !! (CDCI3, d): 1.24-1.43 (m, 3H) (1.74-1.91 (m, 2H), 1.92-3.12 (m, 12H), 3.82 (s, 3H), 4.41-4.55 (m, 1H), 5.18 -5.65 (m, 2H), 6.48-6.59 (m, 2H), 6.71-6.91 (m, 1H), 7.137.43 (m, 5H). [M + H] + = 399.2 Example 53 (E) -1- (4-fluoro-2-methoxyphenyl) -4- [(4-hydroxy-3-phenyl) -hept-5-eneyl] -piperazine (RS, RS: RS, SR, mixture 9 : 1) RMN-Hi (CDC13, d): 1.44-1.59 (m, 4H), 1.71-2.03 (m, 2H), 2.32-3.15 (m, 11H), 3.84 (s, 3H), 4.09-4.12 (m, 1H), 5.15-5.23 (m, 1H), 5.34-5.49 (m, 1H), 6.48 -6.60 (m, 2H), 6.706.92 (m, 1H), 7.13-7.43 (m, 5H). [M + H] + = 399.2 Example 54 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- [(4-hydroxy-5-methyl-3-phenyl) -hex-5 -enyl] -piperazine (RS, RS: RS, SR 6: 4) The title compound is synthesized following the procedure described for the compound of example 36 but using isopropenylmagnesium bromide (0.5 N in THF) instead of a solution of isobutylmagnesium chloride. The mixture is stirred at room temperature for 3 h. The product is purified by flash chromatography (CH2C12-MeOH 99: 1) which gives the title product as a brownish solid (38%).

RMN-1 !! (CDC13, d): 1.65-1.79 (m, 3H), 2.03-2.12 (m, 1H), 2.32-2.48 (m, 1H), 2.57-2.78 (m, 1H), 2.79-3.42 (m, 12H) , 4.21-4.45 (m, 4H), 4.65-4.95 (m, 2H), 6.49-6.58 (m, 1H), 6.60-6.65 (m, 1H), 6.72-6.79 (m, 1H), 7.19-7.41 ( m, 5H). [M + H] + = 409.6 EXAMPLE 55 1- [5- (2, 3-Dihydro-1,4-benzodioxinyl)] -4- [(4-hydroxy-6-methyl-3-phenyl) -hept-6-enyl] -piperazine The compound of the title following the procedure described for the compound of example 36 but using 2-methylallylmagnesium chloride (0.5N in THF), instead of a solution of isobutylmagnesium chloride. The mixture is stirred at room temperature for 3 h. The crude product is purified by flash chromatography (CH2Cl2-MeOH 99: 1) which gives the title product as a brownish solid (48%). NMR- ^ (CDC13, d): 1.68-1.73 (m, 3H), 1.94-2.05 (m, 2H), 2.06-2.18 (m, 1H), 2.19-2.31 (m, 1H), 2.47-2.51 (m , 1H), 2.52-3.42 (m, 12H), 4.23-4.44 (m, 4H), 4.62-4.93 (m, 2H), 6.49-6.53 (m7 1H), 6.62-6.65 (m, 1H), 6.77- 6.84 (m, 1H), 7.21-7.48 (m, 5H). [M + H] + = 423.6 Example 56 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- [4-hydroxy-4- (2-thienyl) -3-phenylbutyl] -piperazine The title compound is synthesized following the procedure described for the compound of example 36 but using 2-thienylmagnesium bromide (1M in THF), instead of a solution of isobutylmagnesium chloride. The mixture is stirred at room temperature for 3 h. The crude product is purified by flash chromatography (CH2Cl2-MeOH 99: 1) which gives the title product as a brownish solid (33%).

Example 57 1- [5- (2, 3-dihydro-1,4-benzodioxinyl)] -4- [(4-hydroxy-3-phenyl) octyl] -piperazine The title compound is synthesized following the procedure described for compound of example 36 but using n-butylmagnesium chloride (2M in THF) instead of a solution of isobutylmagnesium chloride. The mixture is stirred at room temperature for 3 h. The crude product is purified by flash chromatography (CH2C12-MeOH 99: 1), which gives the title product as a brownish solid (48%). MN-1 !! (CDC13, d): 0.61-0.78 (m, 3H), 1.02-1.31 (m, 6H), 1.94-2.06 (m, 1H), 2.26-2.48 (m, 1H), 2.51-2.61 (m, 2H) , 2.62-3.32 (m, 10H), 3.62-3.74 (m, 1H), 4.23-4.44 (m, 4H), 6.47-6.50 (m, 1H), 6.61-6.65 (m, 1H), 6.79-6.84 ( m, 1H); 7.21-7.51 (m, 5H).

[M + H] + = 425.4 Example 58 1- (4-Fluoro-2-methoxyphenyl) -4- [(4-methoxy-3-phenyl) -hept-5-ynyl] -piperazine 4-hydroxy-3-phenylhept-5-inaldehyde dimethyl acetal (Compound 58a) The title compound is obtained by following the procedure described for the compound of Example 6 using compound 17b instead of compound 6f and 1-propynylmagnesium chloride (2M solution in THP) as an initial material instead of ethylmagnesium chlorine. The crude product is purified by flash chromatography (EtOAc-PE 3: 7) which gives the title product (81%). NMR-1! - (CDC13, d): 1.78-1.88 (m, 3H), 1.91-2.21 (m, 3H), 2.92-3.08 (m, 1H), 3.20-3.35 (ra, 7H), 4.18-4.24 (m, 1H), 7.20-7.39 (m, 5H). -methoxy -3-phenylhept-5-inaldehyde dimethylacetal (Compound 58b) The compound is synthesized as described for compound Id using as the starting material compound 58a instead of compound le. After extraction with EtOAc, the crude product is used without further purification in the next step. 4-methoxy-3-phenylhepb-5-inaldehyde (Compound 58c) The title compound is obtained by following the. procedure described for the compound le, but using as the starting material the compound 58b instead of the compound Id. The title product is used in the next step without further purification. 1- (4-Fluoro-2-methoxyphenyl) -4- [(4-methoxy-3-phenyl) -hept-5-ynyl] -piperazine The title compound is prepared using the method described for the compound of example 1, but using compound 58c instead of the compound le and 1- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography (PE-EtOAc 3: 7) to give the title compound (17.5%). R N - ^ - H (CDC13, d): 1.68 and 1.83 (2s, 3H), 1.88-2.05 (ra, 2H), 2.15-2.48 (m, 4H), 2.48-2.78 (m, 4H), 2.81- 2.90 (m, 1H); 2.90-3.15 (m, 2H); 3.25 and 3.40 (2 x s, 3H); 3.76 (m, 3H); 3.93-3.98 (m, 1H); 6.48-6.57 (m, 2H); 6.76 (dd, 1H), 7.22-7.48 (m, 5H). [M + H] + = 411.13.

Example 59 (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4- [(4-methoxy-3-phenyl) -hep-5-enyl] -piperazine (diastereomer with rf of higher CCD) 4 -hydroxy-3-phenylhept-5-enaldehydedimethylacetal (Compound 59a) The title compound is obtained following the procedure described for the compound of Example 6 but using as an initial material compound 17b instead of compound 6f and 1-propenylmagnesium chloride (2M solution in THF) instead of ethylmagnesium chloride . The crude product is purified by flash chromatography (PE-EtOAc-7: 3) which gives the title product (42%). RM - ^ (CDC13, d): 1.50 and 1.60 (2 d, 3H), 1.85-2.04 (m, 2H), 2.15-2.38 (m, 1H), 2.78-2.92 (m, 1H), 3.22 and 3.38 ( 4 xs, 6H), 4.10-4.24 (m, 1H), 4.58 (dd, 1H), 5.22-5.59 (m, 2H), 7.20-7.39 (m, 5H). 4-methoxy-3-phenylhept-5-enaldehydedimethylacetal (Compound 59b) The title compound is synthesized as described for compound Id using as the starting material compound 59a instead of compound le. After extraction with EtOAc, the crude product is used in the next step without further purification. RMN-1 !! (CDC13, d): 1.10 and 1.75 (m, 3H), 1.85-2.35 (m, 2H), 2.63-3.05 (m, 1H), 3.12-3.52 (m, 9H), 4.10-4.24 (m, 1H) , 4.58 (dd, 1H), 5.22-5.59 (m, 2H), 7.12-7.39 (m, 5H). 4-methoxy-3-phenylhepb-5-enaldehyde (Compound 59c) The title compound is obtained following the procedure described for the compound le, but using as the starting material the compound 59b instead of the compound Id. title in the next stage without further purification. 1- (4-Fluoro-2-methoxyphenyl) -4- [(4-methoxy-3-phenyl) -hep-5-enyl] -piperazine The title compound is prepared using the method described for the compound of example 1, but using compound 59c instead of the compound le and l- (4-fluoro-2-methoxyphenyl) -piperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) piperazine. The crude product is purified by flash chromatography (PE: EtOAc 4: 6) to give the title compound (13.2%). RMN-1 !! (CDC13, d): 1.45 and 1.63 (2d, 3H); 1.68-1.81 (m, 1H), 1.88-2.05 (m, 1H), 2.08-2.27 (m, 2H), 2.42-2.58 (m, 4H); 2.63-2.75 (m, 1H); 2.88-3.00 (m, 4H), 3.08 and 3.13 (2 x s, 3H), 3.52 and 4.05 (2d, 1H); 3.75 (s, 3H), 5.05-5.23 (m, 1H), 5.47-5.71 (m, 1H), 6.48-6.57 (m, 2H), 6.76 (m, 1H), 7.05-7.32 (m, 5H). [M + H] + = 413.34.

Example 60 (E, Z) -1- (4-fluoro-2-methoxy-phenyl) -4- [(4-methoxy-3-phenyl) -hep-5-enyl] -piperazine (diastereomer of rf lower CCD) The title compound is isolated during the purification step of Example 59. RMN-Hi (CDC13, d): 1.48 and 1.60 (2d, 3H), 1.79-2.12 (m, 2H), 2.18-2.40 (m, 2H) , 2.22-2.78 (m, 5H); 2.92-3.13 (m, 4H); 3.25 and 3.30 (2s, 3H); 3.57 and 4.08 (2t, 1H); 3.85 (s, 3H), 5.11-5.23 (m, 1H), 5.39-5.65 (m, 1H), 6.58-6.69 (m, 2H), 6.82-6.91 (m, 1H), 7.15-7.35 (ra, 5H) ). [M + H] + = 413.34 Example 61 1- [4-Cyclohexyl-3- (2-methoxymethylphenyl) -4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine 2-methoxymethylbenzyl bromide (Compound 61a) A mixture of 1.2 g of 2-methoxymethylbenzyl alcohol (J. Chem. Soc, 1954, 2819-2826), 2.5 g of triphenylphosphine, 3.14 g of tetrabromomethane and 50 ml of CH2C12 are stirred at room temperature for 2 h. Subsequently, the reaction mixture is evaporated to dryness in vacuo and purified by flash chromatography (CH2C12) to provide 1.62 g of the title compound. RM - ^ (CDC13, d): 3.42 (d, 3H), 4.60 (s, 2H), 4.65 (s, 2H), 7.15-7.30 (m, 3H), 7.22-7.45 (m, 4H). 1-cyclohexyl-2- (2-methoxymethylphenyl) ethanone (Compound 61b) To a suspension of 1.44 g of Zn (Cu) (prepared as described in Org Syn. 5, 855) in 5 ml of anhydrous benzene stirred at room temperature At room temperature under nitrogen, a solution of 1.6 g of compound 61a and 1.17 ml of N, N-dimethylacetamide in 10 ml of benzene is added dropwise. The mixture is stirred at room temperature for 1 h, and then refluxed for 4 h. After cooling to 60 ° C, a solution of 0.073 g of palladium tetrakistriphenylphosphine in 3 ml of benzene is added followed by a solution of 0.55 ml of cyclohexanecarbonyl chloride in 3 ml of benzene. The reaction mixture is stirred for 2.5 h at room temperature. After standing overnight, the mixture is diluted with EtOAc and filtered on a Celite panel; The filtrate is washed with a saturated aqueous solution of ammonium chloride, aqueous NaHCC and brine, dried and evaporated to dryness. The crude product is purified by flash chromatography (PE-EtOAc 100: 4) to provide 1 g of the title compound. NMR- ^ (CDC13, d): 1.10-2.05 (m, 10H), 2.25-2.48 (m, 1H), 3.40 (s, 3H), 4.50 (s, 2H), 5.18 (s, 2H), 7.25- 7.50 (m, 4H). 4-cyclohexyl-4-oxo-3- (2-methoxymethylphenyl) -butyraldehyde-diethylacetal (Compound 61c) The title compound is prepared using the method described for compound 2b but using compound 61b instead of 1- (2 - trifluoromethoxyphenyl) -propan-2-one. The usual treatment procedure and purification provide the title compound. 4-cyclohexyl-4-oxo-3- (2-methoxymethylphenyl) -butyraldehyde (Compound 61d) The title compound is obtained following the procedure described for the compound le, but using as the starting material the compound 61c instead of the compound Id The title product is used in the next step without further purification. 1- [4-cyclohexyl-3- (2-methoxymethylphenyl) -4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine The title compound is prepared using the method described for the compound of example 1, but using compound 61d instead of the compound le and 1- (4-fluoro-2-methoxyphenyl) iperazine instead of 1- (2,2,2-trifluoroethoxyphenyl) piperazine. The crude product is purified by flash chromatography (PE: EtOAc 6: 4) to provide the title compound. [M + H] + = 483.6.

Example 62 · 1- [4-cyclohexyl-4-hydroxy-3- (2-methoxymethylphenyl) -butyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine The title compound is synthesized using the method described for compound it but from the compound of Example 61 instead of compound Ib. The title compound is isolated after the usual treatment procedure. [M + H] + = 485.5 EXAMPLE 63 1- [5- (2,3-Dihydro-1,4-benzodioxinyl)] -4- [4-cyclohexyl-3- (2-methoxymethylphenyl) -4-oxobutyl] -piperazine The title compound is prepared using the method described for the compound of Example 1, but using compound 61d instead of the compound le and 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -piperazine instead of 1- (2, 2, 2-trifluoroethoxyphenyl) -piperazine. The crude product is purified by flash chromatography to provide the title compound. [M + H] + = 493.7 Example 64 1- [4-Cyclohexyl-4-hydroxy-3- (2-methoxymethylphenyl) -butyl] -4- (2,3-dihydro-1,4-benzodioxinyl) -piperazine The title compound is synthesized using the method described for the compound le but from the compound of example 63 instead of compound Ib. The title compound is isolated after the usual treatment procedure. [M + H] + = 495.5 Example 65 (RS, SR) 1- [4-cyclohexyl-4-methylated inofcio-carbonyloxy-3- (2-fl orophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine To a solution of 0.088 g of the compound 45e in 0.6 ml of pyridine stirred at 0 ° C, 0.073 g of methyl isothiocyanate are added. The reaction mixture is stirred at room temperature for 24 h and at 100 ° C for 10 h. After cooling, it is poured into water and extracted with Et20, washed with H20, dried with Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography affords 0.04 g of the title product. [M + H] + = 514.4.

Example 66: Radioligand binding to recombinant 5-HTiA receptors A. Method: A genomic clone encoding the human 5HTiA serotonergic receptor is stably transfected in a human cell line (HeLa). The HeLa cells are grown as monolayers in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, 0.1 mg / ml gentamicin and 5% carbon dioxide, at 37 ° C. The cells are separated from the growth flask at 95% confluence by a cell scraper and are frozen in cold 5 mM Tris and 5 mM EDTA buffer (pH 7.4). The homogenates are centrifuged at 40,000 x g x 20 minutes and the pellets are resuspended in a small volume of cold 5 mM Tris and buffer 5 mM EDTA (pH 7.4) and immediately frozen and stored at -70 ° C until use. On the day of the experiment, the cell membranes are resuspended in incubation buffer: 50 mM Tris hydrochloride (pH 7.4), 2.5 mM MgCl 2, 10 mM pargyline (Fargin et al., Nature 335, 358-360, 1988). The membranes are incubated in a final volume of 1 ml for 30 minutes at 30 ° C with 1 nM [3H] 8-OH-DPAT, in the absence or presence of the test compounds. The non-specific binding is determined in the presence of 10 μ 5-HT. Incubation is stopped by the addition of cold Tris hydrochloride buffer and rapid filtration through a Whatman-GF / D or Schleicher- &-Schuell-GF52 filter previously treated with 0.2% polyethyleneimine.

B. Results The affinities of the test compounds are evaluated as inhibition of the specific binding of radioligand to 5-γ-receptors. (IC50) by using the Allfit non-linear curve fitting program (De Lean et al., Am.JPhysiol. 235, E97-E102 (1978) .The IC50 value is converted to an affinity constant (Ki). by the equation of Cheng &Prusoff (Cheng Y. C, Prusoff WH, Biochem Pha.rma.col.22, 3099-3108 (1973)) The results presented in Table 1 show that the compounds of the invention tested have a high affinity for the 5 - ???? receptor.

TABLE 1 Affinity of binding by 5HTIA receptors Example Ki (nM) 1 1.45 5 8.31 6 3.66 7 7.27 9 1.90 10 1.68 11 3.65 12 13 14 14 to 14b fifteen 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 1.47 36 0.56 37 5.03 39 2.92 40 1.84 42 4.87 44 1.14 45 0.54 46 0.72 47 0.85 48 0.36 EXAMPLE 67 Effects on the contractions of bladder-induced rhythmic bladder emptying in anesthetized rats A. Method Female Sprague-Dawley rats weighing 225-275 g (Crl: COm (SD) IGS BR, Charles River Italy) are used. . The animals are housed with free access to food and water and are kept in a forced cycle of alternating 12-hour light-dark, at 22-24 ° C for at least a week, except during the experiment. The activity of rhythmic contractions of emptying of the bladder are evaluated according to the Dray method (Dray J., Phar Acol.Methods, 13: 157, 1985), with some modifications as in Guarneri. { Guarneri, Pharmacol. Res. 27: 173, 1993). Briefly, the rats are anesthetized by subcutaneous injection of 1.25 g / kg (5 ml / kg) of urethane, after which the urinary bladder is catheterized via the urethra using polyethylene PE50 as a tubing filled with physiological saline. The catheter is tied in place with a ligature around the external urethral orifice and connected to conventional pressure transducers (Statham P23 ID / P23 XL). The intravesical pressure is displayed continuously in a chart recorder (Battaglia Rangoni KV 135 with DCI / TI amplifier). The bladder is then filled by means of the recording catheter with increasing volumes of warm saline solution (37 ° C) until the contraction reflex occurs to empty the bladder (usually 0.8-1.5 ml). For intravenous injection of bioactive compounds, a PE 50 polyethylene tubing filled with physiological saline solution is inserted into the jugular vein. From the cystometrogram, the number of contractions recorded 15 minutes before (basal values) and after the treatment, as well as the average amplitude of these contractions (mean height of the peaks, in mm Hg) are evaluated. Since most compounds produce an effect that is relatively rapid onset and that leads to a complete cessation of bladder contractions, bioactivity is conveniently calculated by measuring the duration of the resting bladder (ie, the period of time during which they do not produce contractions). The number of tested animals shows a reduction in the number of contractions greater than 30% to that observed in the basal period, which is also recorded. To compare the potency of the tested compounds to inhibit contractions of bladder emptying, the effective doses resulting in the disappearance of contractions for a time of 10 minutes (DEiomin) are calculated by means of linear regression using the minimum method squares. The extrapolar doses which induce a reduction in the number of contractions greater than 30% in 50% of the treated rats (ED50) is evaluated by the Bliss method (Bliss CI, Quart J Pharm Pharmacol 11, 192-216 , 1938).

N. Results Rapid distention of the urinary bladder in urethane-anesthetized rats produces a series of rhythmic contractions for bladder emptying whose characteristics have already been described (Maggi et al., Brain Res. 380: 83, 1986; Maggi et al., J. Pharmacol. Exp. Ther. , 230: 500, 1984). The frequency of these contractions is related to the afferent sensory arm of the micturition reflex and to the integrity of the micturition center, while its amplitude depends on the function of the reflex efferent arm. In this model system, compounds that act primarily on the central nervous system (such as morphine) cause a blockage in voiding contractions, while drugs that act on the pubic muscle, such as oxybutynin, decrease the amplitude of contractions of the bladder. Table 2 shows the results obtained.TABLE 2 Effects of rhythmic contractions of emptying of the bladder after intravenous administration n.a. = not active; there was no significant reduction in the height of the peaks. The data represent the DE10min values (the extrapolated dose that induces 10 minutes of disappearance of the contractions), the ED50 values (frequency) (the extrapolated doses that induce a reduction in the number of contractions> 30% in 50% of the. treated rats), and ED50 values (amplitude) (the extrapolated doses that induce a 30% reduction in the amplitude of the contractions in 50% of the treated rats). The compounds of the present invention inhibit the frequency of urination without effects on its amplitude.

Example 68 Effect on cystometric parameters in conscious rats after oral administration A. Method: Male Sprague-Dawley rats [Crl: CD * ® (SD) IGS BR) of 300-400 g supplied by Charles River Italy, Animals are used. they were housed with free access to food and water and kept in a forced cycle of 12 hours of light / 12 hours of darkness at a temperature of 22-24 ° C, except during the experiment. To quantify the urodynamic parameters of conscious rats, cystometrographic studies were performed according to the previously reported procedure (Guarneri et al., Pharmacol. Res. 24: 175, 1991). Briefly, the rats were anesthetized by intraperitoneal administration of 3 ml / kg of equitensin solution (30 mg / kg of pentobarbital and 125 mg / kg of doral hydrate) and placed in the supine position. An incision is made in the midline approximately 10 mm long in the affected and cleaned abdominal wall. The urinary bladder is gently released from the adherent tissues, emptied and then cannulated via an inclusion in the body of the bladder using a polyethylene cannula (internal diameter 0.58 mm, external diameter 0.96 mm), which is permanently sutured with silk thread. The cannula is externalized through a subcutaneous tunnel in the retroscapular area and is connected to a plastic adapter in order to avoid the risk of the animal withdrawing it. For drug tests, rats are used one day after implantation. On the day of the experiment, the rats are placed in modified Bollman cages, ie, stationary cages that are large enough to allow the rats to adopt a normal crouching posture, but sufficiently narrow to prevent them from turning around. After a stabilization period of approximately 20 minutes, the free tip of the bladder cannula is connected through a T-tube to a pressure transducer (Statham P23XL) and a peristaltic pump (Gilson minipuls 2) Continuous infusion of warm saline solution (37 ° C) into the urinary bladder at a constant rate of 0.1 ml / minute. The intraluminal pressure signal during infusion of saline solution into the bladder is recorded continuously in a polygraph (Rectigraph-8K San-ei with amplifier BM614 / 2 from Biomedical Mangoni). The cystometrogram is used to evaluate the urodynamic parameters of bladder volume capacity (BVC9 and urination pressure (MP).) BVC (in me) is defined as the volume of saline administered by infusion to the bladder necessary to induce a contraction of pubic bladder muscle followed by micturition MP (in mm Hg) is defined as the maximum intravesical pressure caused by contraction during micturition, initial values BVC and MP were evaluated as the mean of the values observed in the cystometrograms recorded in a Initial period of 30-60 minutes After the determination of the initial values of BVC and MP, the infusion is interrupted and the test compounds are administered orally via a tube to the stomach, the infusion is reinitiated to the bladder and the evaluate the changes in BVC and MP from the average values obtained in the cystometrograms observed during 1, 2, 3, 4 and 5 hours after treatment. These are administered in a volume of 2 ml / kg and groups of control animals receive the same amount of vehicle orally (0.5% methocel in water).

Statistical analysis Data are expressed as mean + standard error. The changes in percent of BVC and MP versas the basal values, as well as the values? (difference in my of mm Hg) of BVC and MP (BVC or MP in a time "x" minus the basal value), were also evaluated for each rat / time. The data is reported as% of changes versus baseline values. The statistical analysis of the BVC and MP values, as well as in the values? It is performed by the software (SAS / STAT version 6.12) The observed differences between the vehicle (control) and the test treatments on the? values of BVC and MP are evaluated, while the differences between the values at different times versus the values Basics are analyzed on the original BVC and MP data.

Example 69 Inhibition of Stereotyping (Rhythmic Stretching of the Anterior Paw) Induced by 8-OH-DPAT in Rats (Postsynaptic Antagonism) A. Method: The inhibitory effect of 5-HTiA receptor antagonists on the anterior paw stretch is evaluated stereotyped in rats by subcutaneous injection of 8-OH-DPAT, by Ticklebank method (Tricklebank et al., 'Eur. J. Pharmacol., 117: 15, 1985) with minor modifications as described in the following. Male Sprague_Dawley rats · [Crl: CDMR (SD) IGS BR) with a weight of 150-175 g of Charles River Italy were used. It houses animals with free access to food and water and are kept in forced cycles of 12 hours of light / 12 hours of darkness at a temperature of 22-24 ° C. On the day of the experiment, the rats are placed in clear plastic containers 10-15 minutes before administration of the vehicle or the compounds to be tested. For evaluation of the antagonist activity after oral administration, the compounds are administered 1 and 4 hours before the induction of stereotyping by 8-OH-DPAT (1 mg / kg, subcutaneously). Observation sessions last 30 seconds and begin 3 minutes after treatment with 8-OH-DPAT and are repeated every 3 minutes for a period of 15 minutes. The appearance of the symptom induced by postsynaptic stimulation of 5-HTiA is noted, and the intensity is graded using an intensity scale in which: O = absent, 1 = equivocal, 2 = present and 3 = intense. The behavior ratings for treated rats accumulate during the observation time (5 observation periods) and are expressed as the average of 4 rats / doses. The change in mean values of treated animals compared to the control group (to which vehicle is administered), expressed as percent inhibition, is used to quantify the antagonist activity. b. Result Table 3 shows the results obtained. The compounds of the present invention, in particular example 45, show a potent long-lasting inhibition of stereotypy induced by 8-OH-DPAT.

TABLE 3 Inhibition of anterior leg stretching induced by 8-OK-DPAT in rats (postsynaptic antagonism)

Claims (17)

1. alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, hydroxy, alkenyl of 2 to 6 carbon atoms, alkyi of 2 to 6 carbon atoms, haloalkyl from 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, nitro, amino, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) ) -aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, acylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl from 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N, N-di-alkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxy alkyl, alkylaminocarbonylalkyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and N, N-di-alkylaminosulfonyl of 1 to 6 carbon atoms; Ri represents a hydrogen atom or one or more substituents which are selected from cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocycloxy, heterocycloalkyl and heterocycloalkoxy groups, each group is optionally substituted with one or more substituents R as defined in previous; Q represents a group of the formula -C (O) - or -CH (OH) - or -CH (OR2) - wherein R2 represents an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms , alkynyl of 2 to 6 carbon atoms or cycloalkyl, each of which is optionally substituted with one or more groups which are selected from R5 and R6, wherein R5 represents a halogen atom or an alkoxy group of 1 to 6 atoms of carbon, haloalkoxy of 1 to 6 carbon atoms, cyano, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxyalkyl, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms or?,? -di-alkylaminocarbonyl of 1 to 6 carbon atoms and R6 represents an aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy or heteroarylalkoxy group, each of which is optionally substituted with a group R as defined above, or R2 represents a group of the formula -C (0) -alkyl of 1 to 6 carbon atoms, -C (0) 0-alkyl of 1 to 6 carbon atoms, -C (0) NR7R8 or -C (S) NR7R8 wherein R7 and Rs independently represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; R3 represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl, aryl or heterocyclic, each group is optionally substituted with one or more substituents R or Ri defined as in the above; R4 represents an aryl or heterocyclic group, each is optionally substituted with one or more substituents R, as defined above; A represents a bond or a methylene or ethylene group; and n is 1 or 2, with the proviso that the compounds in which Q represents simultaneously -C (0) - or -CH (OH) -; R represents a hydrogen atom or one or more halogen atoms or alkyl, alkoxy, haloalkyl, nitro, amino, alkylamino or dialkylamino groups; Ra. represents a hydrogen atom, an unsubstituted phenyl group or a phenyl group substituted with one or more halogen atoms or alkyl or alkoxy groups; R4 represents an unsubstituted aryl or heteroaryl group or an aryl or heteroaryl group substituted with one or more halogen atoms or alkyl, alkoxy, haloalkyl, nitro, amino, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, -CONR7R8 or - HS02-alkyl groups; and R3 represents an unsubstituted aryl or heteroaryl group or an aryl or heteroaryl group substituted with one or more halogen atoms or alkyl, alkoxy, haloalkyl, nitro, amino, alkylamino, dialkylamino, phenyl, halophenyl, alkylphenyl or alkoxyphenyl groups; with the additional proviso that compounds are also excluded where Q represents simultaneously -C (O) - or -CH (OH) -; R represents a hydrogen or halogen atom or an alkyl, alkoxy, haloalkyl, alkylthio, alkenyl or alkynyl group; Ri represents a hydrogen atom or a cycloalkyl or alkylcycloalkyl group; R 4 represents an unsubstituted aryl or heteroaryl group, or an aryl or heteroaryl group substituted with one to three halogen atoms or alkyl, alkoxy, haloalkyl, alkylthio, alkenyl or alkynyl groups; and R3 represents the unsubstituted forms of phenyl, naphthyl or cycloalkyl, or a phenyl, naphthyl or cycloalkyl group substituted with one or two halogen atoms, or alkyl, alkoxy, haloalkyl, alkylthio, alkenyl or alkynyl groups; or an enantiomer, optical isomer, diastereomer, N-oxide (for example N-piperazine oxide), crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof. 2. The compound having the general formula I wherein R, R1 R3, R4, Q, A and n are as defined in claim 1, with the proviso that if Q represents a group of the formula -C (O) - or -CH (OH) - and R3 represents a cycloalkyl, aryl or heteroaryl group, then R represents one or more hydroxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, acylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, cyano, aminocarbonyl, N- groups alkylaminocarbonyl, N, N-dialkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino, alkylsulfinyl, alkylsulfonyl or N, N-dialkylaminosulfonyl. The compound as described in claim 1, wherein: R represents one or more hydroxy groups, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, aminoalkyl of 1 to 6 carbon atoms carbon, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N- C 1 -C 6 alkylaminocarbonyl, β, β-dialkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms and?,? - dialkylaminosulfonyl of 1 to 6 carbon atoms; or Ri represents the unsubstituted form of an aryloxy, aralkyl, aralkoxy, heterocycloxy, heterocycloalkyl or heterocycloalkoxy group, or an aryloxy, aralkyl, aralkoxy, heterocycloxy, heterocycloalkyl, heterocycloalkoxy, aryl, heterocyclic or cycloalkyl group substituted with one or more alkylthio groups of 1 to 6 carbon atoms, hydroxy, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N, N-dialkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of? to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms or α, ? -Dialkylaminosulfonyl of 1 to 6 carbon atoms. The compound as described in claim 1 or claim 2, wherein R represents a hydrogen or halogen atom, or a haloalkoxy group of 1 to 6 carbon atoms, cyano, N, N-diaminocarbonyl of 1 to 6 carbon atoms or alkoxy (of 1 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms. 5. The compound as described in claim 4, wherein R represents a hydrogen or fluorine atom or a trifluoromethoxy, cyano, N, N-dimethylaminocarbonyl or methoxymethyl group. The compound as described in claim 4 or claim 5, wherein the R substituent is attached to the phenyl group at the 2-position. 7. The compound as described in any of claims 1, 2 or 4 to 6 , wherein R3 represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms, each group is optionally substituted with one or more substituents R or Ri, as described in claim 1. 8. The compound as described in claim 7, wherein R3 represents a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, vinyl, allyl, prop-1-enyl, 1-methylvinyl, 2-methylallyl, ethynyl or propyl-1-ynyl. 9. The compound as described in any of claims 1, 2 or 4 to 6, wherein R3 represents a cyclohexyl or 2-thienyl group. The compound as described in any one of claims 1, 2 or 4 to 9, wherein R 4 represents an unsubstituted heterocyclic group or a phenyl group substituted with one or more halogen atoms or alkyl groups of 1 to 6 carbon atoms. carbon, alkoxy of 1 to 6 carbon atoms or haloalkoxy of 1 to 6 carbon atoms. 11. The compound as described in claim 10, wherein R4 represents a 5- (2,3-dihydro-1,4-benzodioxinyl), 4-indolyl, 8-quinolyl, 2-methoxyphenyl, 2, S- group dimethylphenyl, 4-fluoro-2-methoxyphenyl or 2- (2,2,2-trifluoroethoxy) phenyl. 12. The compound as described in any of claims 1, 2 or 4 to 11, wherein Q represents a group of the formula -C (0). - -CH (OH) -, -CH (OR2) -, -CH (0-C (0) -alkyl of 1 to 6 carbon atoms, -CH (0-C (O) 0-alkyl of 1 to 6 carbon atoms, -CH (0) -C (0) NR7R3) or -CH (0-C (S) NR7R8 wherein R2 represents an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms, and each of R7 and Ra independently represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms 13. The compound as described in claim 12, wherein Q represents a carbonyl group, hydroxymethylene, methoxymethylene, ethoxymethylene, propoxymethylene, alxymethylene, prop-2 - (inyloxymethylene, acetoxymethylene, methoxycarbonyloxymethylene, aminocarbonyloxymethylene, N-ethylaminocarbonyloxymethylene or N-methylaminothiocarbonyloxymethylene.) 14. The compound as described in claim 1, which is one of: · 1- [4-cyclohexyl-3- (2-fluorophenyl) -4-methoxybutyl] -4- [2- (2, 2, 2-trifluoroethoxy) -phenyl] -piperazine; 4 -fluoro-2-methoxyphenyl) -4- [4-??? -3- (2-trifluoromethoxyphenyl) -pentyl] -piperazine; 1- (4-fluoro-2-methoxyphenyl) -4- [4-hydroxy-3- (2-trifluoromethoxyphenyl) -pentyl] -piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [4-??? -3- (2-trifluorora-ethoxyphenyl) -penti1] -perazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxyphenyl) -pentyl] -piperazine; 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxyphenyl) -hexyl] -piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [4-hydroxy-3- (2-trifluoromethoxy-phenyl) -hex-5-enyl] -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- [4-hydroxy-5-methyl-3- (2-trifluoromethoxyphenyl) -hexyl] -piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [4-methoxy-3- (2-trifluoromethoxyphenyl) -5-hexenyl] -piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -heptyl] -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- [(4-methoxy-3-phenyl) -pentyl] -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- [(4-propoxy-3-phenyl) -heptyl] -piperazine; · 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- [5- (2,3-dihydro-l, 4-benzodioxinyl)] piperazine; • (RS, SR) -1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; · (RS) -1- [3- (2-Cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; , • (SR) -1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; • 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine; • 1- [3- (2-cyanophenyl) -4-cyclohexyl-4-hydroxybutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine; · 1- (4-cyclohexyl-4-methoxy-3-phenylbutyl) -4- [5 (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; 1- (4-cyclohexyl-4-methoxy-3-phenylbutyl) -4- (4-fluoro-2-oxyphenyl) -piperazine; 1- (4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; 1- (4-cyclohexyl-4-ethoxy-3-phenylbutyl) -4- (4-fluoro-2-methoxyphenyl) -piperazine; • 1- (4-alxy-4-cyclohexyl-3-phenylbutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine, - 1- (4-alxy-4-) cyclohexyl-3-phenylbutyl) -4- (4-fluoro-2-methoxyphenyl) -piperazine; 1- (4-cyclohexyl-3-phenyl-4-propargiloxybutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; · 1- (4-cyclohexyl-3-phenyl-4-propargiloxybutyl) -4- (4-fluoro-2-methoxyphenyl) -piperazine; 1- (4-cyclohexyl-3-phenyl-4-propoxybutyl) -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhexy1) piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylheptyl] -piperazine; • 1- [5- (2,3-dihydro-1, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhex-5-enyl) -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-5-methyl-3-phenylhexyl] -piperazine; • 1- [5- (2,3- dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylpenti1) -piperazine; 1- [5- (2,3-dihydro-1,4-benzodioxinyl)] -4- (4- hydroxy-3-phenylhept-5-ynyl) -piperazine; 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhept-5-enyl) - piperazine; (E, Z) -1- (4-fluoro-2-methoxyphenyl) (-4 - [(4-methoxy-3-phenyl) -hep-5-enyl] -piperazine (higher diastereomer by rf in CCD ), • (E, Z) -1- (4-fluoro-2-methoxyphenyl) -4- [(4-methoxy-3-phenyl) -hep-5-enyl] -piperazine (higher diastereomer by rf in CCD) • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhex-5-ynyl) -piperazine, - • 1- [5- (2, 3 -dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylhept-6-enyl) -piperazine; • 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4 - (4-hydroxy-6-methyl-3-phenylhep-5-enyl) -piperazine; 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4 - (4-hydroxy-6-methyl-3-phenylheptyl] -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-3-phenylbutyl) piperazine; • (RS, SR) -1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-dihydro-3-phenylpentyl) -piperazine; • 1- [4-cyclohexyl-3- (2-dimethylamino-carbonylphenyl) -4-oxobutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-hydroxybutyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; • 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine; · 1- [4-cyclohexyl-3- (2-dimethylaminocarbonylphenyl) -4-hydroxybutyl] -4- (4-fluoro-2-methoxyphenyl) piperazine; • 1- [3- (2-cyanophenyl) -4-oxopentyl] -4- [5- (2,3-dihydro-1,4-benzodioxinyl)] -piperazine; · 1- [4-cyclohexyl-3- (2-trifluoromethoxyphenyl) -4-oxobutyl] -4- (4-indolyl) -piperazine; • (RS, SR) 1- [4-acetoxy-4-cyclohexyl-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine; • (RS, SR) 1- [4-cyclohexyl-3- (2-fluorophenyl) -4-methoxycarbonyloxybutyl] -4- (2-methoxyphenyl) -piperazine; • (RS, SR) 1- [4-cyclohexyl-4-ethylaminocarbonyloxy-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine; • (RS, SR) 1- [4-aminocarbonyloxy-4-cyclohexyl 3- (2-fluorophenyl) util] -4- (2-methoxyphenyl) -piperazine; • 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-5,5-dimethyl-3-phenylhexyl) -piperazine; • 1- (4-fluoro-2-methoxyphenyl) -4- [(4-dihydro-3-phenyl-ept-5-ynyl) piperazine; • (?,?) -1- (4-fluoro-2-methoxyphenyl) -4- (4-hydroxy-3-pheny1he t-5-eni1] -piperazine; • (E) -1- (4-fluoro-2-methoxyphenyl) -4- (4-hydroxy 3-phenylhept-5-enyl) ) -piperazine; 1- [5- (2, 3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-5-methyl-3-phenylhex-5-enyl] -piperazine; [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- (4-hydroxy-6-methyl-3-phenylhept-6-enyl] -piperazine; • 1- [5- (2, 3 -dihydro-l, 4-benzodioxinyl)] -4- [4-hydroxy-4- (2-thienyl) -3-phenylbutyl) -piperazine; 1- [5- (2,3-dihydro-l, 4- benzodioxinyl)] -4- (4-hydroxy-3-phenyloctyl) -piperazine; 1- (4-fluoro-2-methoxyphenyl) -4- (4-methoxy-3-phenylhept-5-ynyl) -piperazine; 1- [4-cyclohexyl-3- (2-methoxymethylphenyl) -4-oxobutyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine; 1- [4-cyclohexyl-4-hydroxy-3- (2 -methoxymethylphenyl) -butyl] -4- (4-fluoro-2-methoxyphenyl) -piperazine; 1- [5- (2,3-dihydro-l, 4-benzodioxinyl)] -4- [ 4-cyclohexyl-3- (2-methoxymethylphenyl) -4-oxobutyl] -piperazine; • 1- [4-cyclohexyl-4-hydroxy-3- (2-methoxymethylphenyl) -butyl] -4- (2,3-dihydro-1,4-benzodioxinyl) -piperazine; and • (RS, SR) 1- [4-cyclohexyl-4-phenylaminothio-carbonyloxy-3- (2-fluorophenyl) -butyl] -4- (2-methoxyphenyl) -piperazine; 15. A pharmaceutical composition comprising a compound as described in any of claims 1 to 14, mixed with a pharmaceutically acceptable diluent, excipient or carrier. 16. A compound represented by the formula where: M represents the group 0-Ra - > -CHO "Ra, O R represents hydrogen or one or more substituents selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, hydroxy, halo, alkenyl from 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, nitro, amino, aminoalkyl of 1 to 6 carbon atoms carbon, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms , aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N, N-dialkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl from 1 to 6 carbon atoms, alkylcar bonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, and N, N-dialkylaminosulfonyl of 1 to 6 carbon atoms; Ri represents a member selected from the group consisting of hydrogen and the cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocycloxy, heterocycloalkyl, and heterocycloalkoxy groups, each group is optionally substituted with one or more R substituents as defined herein. previous; Q represents -C (O) - or -CH (OR2) - wherein R2 represents a member selected from the group consisting of hydrogen, and alkyl groups of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, carbon, alkynyl of 2 to 6 carbon atoms and cycloalkyl, wherein each group is optionally substituted with one or more groups which are selected from R5 and R6, wherein R5 is selected from the group consisting of halo, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cyano, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkoxyalkyl, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N, N-dialkylaminocarbonyl of 1 to 6 carbon atoms, and R6 is selected from the group consisting of the aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy and heteroarylalkoxy groups, each optionally substituted with R, or R2 represents -C (0) - alkyl of 1 to 6 carbon atoms, -C (O) O-alkyl of the 6th carbon atoms, -C (0) NR7Ra or -C (S) NR7R8 wherein R7 and R8 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R3 represents hydrogen or an alkyl group of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl, aryl or heterocycle, each group is optionally substituted with one or more substituents R or Ri, defined as in the above; Ra represents alkyl groups of 1 to 6 carbon atoms which may be the same or different, or together form an alkylene chain of 3 to 5 carbons; and n is 0 or 1, with the proviso that compounds are excluded where simultaneously Q represents -C (O) -; M represents -CHO; R represents hydrogen, alkyl, alkoxy, halogen, haloalkyl, alkylthio, alkenyl or alkynyl; Ri represents hydrogen or unsubstituted cycloalkyl or cycloalkyl substituted with alkyl; and R3 represents an unsubstituted phenyl, unsubstituted naphthyl or unsubstituted cycloalkyl, or phenyl, naphthyl or cycloalkyl group substituted with one or two substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl, alkylthio, cycloalkyl, alkenyl and alkynyl. 17. A c or by the formula: where W represents the group R represents hydrogen or one or more substituents which are selected from the group consisting of the alkyl groups of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, hydroxy, halo, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl, nitro, amino, aminoalkyl of 1 to 6 carbon atoms, alkyl (of 1 to 6 carbon atoms) -aminoalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 atoms of carbon, dialkylamino of 1 to 6 carbon atoms, acylamino, alkylsulfonylamino of 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 6 carbon atoms, cyano, aminocarbonyl, N-alkylaminocarbonyl of 1 to 6 carbon atoms, N , N-dialkylaminocarbonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, alkylcarbonylalkyl, formyl, alkanoyloxyalkyl, alkylaminocarbonylamino of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alquilsu lfonyl of 1 to 6 carbon atoms and N, N-dialkylaminosulfonyl of 1 to 6 carbon atoms; Ri represents a member selected from the group consisting of hydrogen, and the cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic, heterocycloxy, heterocycloalkyl and heterocycloalkoxy groups, each group is optionally substituted with one or more substituents R as defined in the above; Z represents a group -CHO or -CH (ORa) 2 / represents a single or double bond, Ra represents alkyl groups of 1 to 6 carbon atoms which may be the same or different, or together form an alkylene chain of 3 to 5 carbons; and L represents an aryl or heterocyclic group, each is optionally substituted with one or more substituents R as defined in the above A represents a bond or (CH2) n; and n is 0 or 1. aminothiocarbonyl, R3 is H, an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclic group, each of which is optionally substituted, n is 1 or 2, A is a bond or a methylene or ethylene group and R4 is a group aryl or heteroaryl, any of which is optionally substituted), which has affinity for serotonergic receptors. These compounds and their enantiomers, diastereoisomers, n-piperazine oxides, polymorphs, solvates and pharmaceutically acceptable salts are useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to the activity of the 5-HTiA receptor.