MXPA99010800A - Anti-inflammatory piperazinyl-benzyl-tetrazole derivatives and intermediates thereof - Google Patents

Abstract

Tetrazoles and their pharmaceutically acceptable salts which are selective agonists for the delta opioid receptor, particularly useful in the treatment of inflammatory diseases such as arthritis, psoriasis, asthma, inflammatory bowel disease, disorders of respiratory function, gastro-intestinal disorders such as functional bowel disease and functional GI disorders, of formula (I), wherein R1 is H, C2-C6 alkanoyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)-(C1-C4 alkyl), (C1-C4 alkoxy)-(C1-C4 alkyl), carboxy-(C1-C4 alkyl), aryl-(C1-C4 alkyl) or heteroaryl-(C1-C4 alkyl);R2 and R3 are each independently H or C1-C4 alkyl;R4 is selected from (i) H, (ii) a group of the formula R6-(CH2)m-Z-(CH2)n-, where m is 0, 1, 2 or 3, n is 1, 2 or 3, Z is a direct link or O, and R6 is -CO2H or -CO2(C1-C4 alkyl), and (iii) a group of formula (a) where R7 is H or C1-C4 alkyl;and R5 is hydroxy, C1-C4 alkoxy or -NHSO2(C1-C4 alkyl);with the proviso that when Z is O, m is 1, 2, or 3 and n is 2 or 3.

Description

ANTI-INFLAMMATORY DERIVATIVES OF TETRAZQL-BENCILO- P1PERAZ1N1LO AND INTERMEDIARIES OF THE SAME This invention relates to tetrazole derivatives which have utility as ligands for opioid receptors. More particularly, this invention relates to tetrazoles, their preparation and their use as selective delta receptor agonists. In the scientific literature, at least three types of opioid receptors (mu, delta and kappa) are described and documented. The three receptors are present in the central and peripheral nervous system of many species including the human being. It is known that the activation of delta receptors produces antinociception in rodents and can induce analgesia in humans, in addition to influencing the motility of the gastrointestinal tract [see Burks, T.K. (1995) in "The pharmacology of opioid peptides", Tseng L.F. ed. Harwood Academic Publishers]. A new class of tetrazole derivatives have been discovered which are potent and selective opioid delta receptor agonists and which are useful for preventing or treating inflammatory diseases, such as arthritis, psoriasis, asthma or inflammatory bowel disease, function disorders. respiratory, gastrointestinal disorders, such as functional bowel disease, functional Gl disorders, such as irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia or others associated with disorders of motility or secretion, disorders of the tract urogenital, such as incontinence, as analgesics to treat pain, including non-somatic pain, or as immunosuppressants to prevent rejection of organ transplants and skin grafts. Thus, the invention provides compounds of the formula: and their pharmaceutically acceptable salts; wherein R1 is H, C2-C6 alkanoyl, C- | -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, (C-cycloalkyl) - (C-? -C4 alkyl), (C 1 -C 4 alkoxy) - (C 1 -C 4 alkyl), carboxy (C 1 -C 4 alkyl), aryl (C 1 -C 6 alkyl) or heteroaryl (C 1 -C 4 alkyl); each of R2 and R3 is, independently, H or C? -C alkyl; R4 is selected from (i) H, (ii) a group of the formula R6- (CH2) mZ- (CH2) n-, where m is 0, 1, 2, or 3, n is 1, 2 or 3, Z is a direct bond or O, and R6 is -CO2H or -CO2 (C-alkyl? C), and (ii) a group of the formula wherein R7 is H or C1-C4 alkyl; and R5 is hydroxy, alkoxy 0-4 or -NHSO2 (C1-C4 alkyl); with the proviso that when Z is O, m is 1, 2 or 3 and n is 2 or 3. When appropriate, the alkyl, alkanoyl, alkoxy, alkenyl and alkynyl groups may have straight or branched chain. Preferred aryl groups are phenyl and naphthyl, both optionally substituted with up to three substituents selected, each independently from halo, trifluoromethyl, C 1 -C 4 alkyl and C 1 alkoxy. C4 More preferably, "aryl" is phenyl optionally substituted with one or two substituents as defined above. "Halo" means F, Cl, Br or I. Preferred heteroaryl groups include 5- or 6-membered aromatic heterocyclic groups, such as thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazolyl. Thiazol-1-yl is the most preferred heteroaryl group. Preferred alkyl groups are methyl and ethyl. Preferred alkoxy groups are methoxy and ethoxy. The preferred alkanoyl group is acetyl. The preferred alkenyl group is allyl. The preferred alkynyl group is vinyl. The preferred cycloalkyl group is cyclopropyl.

The tetrazole group is preferably attached to the 3 or 4 position of the adjacent phenyl ring. R1 is, preferably H, allyl, benzyl, C-t_C4 alkyl or (C3-C7 cycloalkyl) methyl; more preferably allyl; Preferably, each of R2 and R3 is, independently, H or methyl; more preferably both are methyl or H; even more preferably both are methyl. R5 is preferably hydroxy, methoxy or -NHSO2Me; more preferably hydroxy. Preferably, R4 is H or a group of the formula (a) - (CH2) pCO2H or - (CH2) pCO2 (aIqui or C, .C4) where p is 1, 2, 3 or 4, (b) - ( CH2) 2-O-CH2CO2H, (c) - (CH2) 2-O-CH2CO2 (alkyl dC ^ o (d); where R7 is H or C? C4 alkyl. In R4, the preferred alkyl group is ethyl. The preferred individual compounds are those of Examples 1, 4, 24, 27, 36, 42, 94, 96, 104 and 107. The preferred stereochemistry of the compounds of formula (i) is as follows: Such compounds are prepared in the easiest way by the use of starting materials with the appropriate stereochemistry. The compounds of the formula (!) Can be prepared by conventional routes such as those indicated in the following examples and preparations and in WO-A-9315062.

Route A The compounds of formula (!) In which R5 is hydroxy can be prepared by reaction of the corresponding methoxy compounds of the formula (I) with boron tribromide. Preferably, boron tribromide in dichloromethane is added to a solution of the methoxy starting material in dichloromethane, and the mixture is stirred at room temperature for a few hours. The product can then be isolated and purified by conventional techniques. It is also possible to remove the hydroxy protecting group from the corresponding hydroxy-protected compound, typified by the conversion of t-butyldimethylsilyloxy to hydroxy using tetraethylammonium fluoride.

Route B The compounds (I) are those that R _ 4 is H, can be prepared by the reaction of a corresponding nitrile of the formula: - wherein R1, R2, R3, R4 and R5 are as defined for formula (I), with dibutyltin oxide and trimethylsilyl azide. The reaction is typically carried out in a suitable organic solvent, such as dry toluene, at a temperature of about 50 ° C at reflux temperature. If necessary, a hydroxy group represented by R5 can be protected prior to the reaction, for example, with a t-butyldimethylsilyl protecting group, and the protecting group can be subsequently removed by a conventional technique.

Route C The compounds (I) wherein R4 is (i) R6- (CH2) mZ- (CH2) n -where R6 is -CO2 (C? C4 alkyl) and Z, m and n are as defined for the formula (I) or (ii) where R7 is C? C4 alkyl, they can be prepared by the alkylation of the corresponding compounds in which R4 is H, with an alkylating agent of the formula, respectively: where Z, m and n are as defined for formula (I), R6 and R7 are defined in this procedure and Q1 is a leaving group, preferably Br. The reaction is typically carried out in the presence of a base such as potassium carbonate or of cesium, in a suitable organic solvent, for example, acetonitrile, under gentle reflux. This reaction generally produces a mixture of compounds in which R4 is attached to positions 1 and 2 of the tetrazole ring. When a compound in which R5 is hydroxy is required, it may be necessary to protect the hydroxy group before the reaction, such as by a t-butylmethylsilyl group, which can be removed conventionally after the reaction, for example, by the use of fluoride of tetraethylammonium. In an alternative alkylation process, the corresponding compound wherein R 4 is H, is first reacted with a strong base, such as sodium ethoxide (prepared by the addition of sodium metal to ethanol) and then with compound III, no additional basis is necessary.

Route D Compounds (I) wherein R6 is -CO2H can be prepared by hydrolysis, preferably alkaline hydrolysis, of the corresponding ethers in which R6 is C? C4 alkyl. The reaction is typically carried out with aqueous sodium hydroxide in methanol or in a mixture of dioxane and methanol at room temperature.

Route E Compounds (I) in which R6 is -CO2H can also be prepared by hydrolysis of the corresponding compounds in which R4 is NC- (CH2) mZ- (CH2) n-, where Z, m and n are as they have been defined for formula (I). Acid hydrolysis using gaseous hydrogen chloride in ethanol is preferred.

Route F The compounds (I) wherein R 4 is 1- [CH 2 CO 2 (C 1 -C 4 alkyl)] and R is -OH can be prepared by ring closure by the reaction of a compound of the formula: wherein R, R and R are as defined for formula (I) and Q is a hydroxy protecting group, such as t-butyldimethylsilyl, with diethyl azidodicarboxylate, triphenyl phosphine and trimethylsilyl azide in a suitable organic solvent such as toluene. Generally, the protecting group Q2 is removed under the reaction conditions.

Route G The compounds (I) can be prepared by the reaction of an aldehyde of the formula: wherein R4 is as defined for formula (I), with a compound of the formula: - wherein R1, R2 and R3 are as defined for formula (I), in the presence of benzotriazole, typically under reflux, in an organic solvent such as toluene, with azeotropic removal of water, followed by cooling, for example -20 ° C and reaction with a Grignard reagent of the formula: - wherein R is -OQ wherein Q is a hydroxy protecting group such as trimethylsilyl. Any hydroxy protecting group that is present is generally removed by the reaction conditions or subsequently removed by a conventional technique.

Route H Compounds in which R1 is H can be prepared by reaction of the corresponding compound wherein R1 is allyl with tris (triphenylphosphine) radium (I) chloride, typically under mild reflux in a solvent system such as aqueous acetonitrile.

Route I The compounds of formula (I) in which R 4 is R 6 - (CH 2) m Z - (CH 2) n - attached to the 1-position of the tetrazole ring and Z, m, n, R 1, R 2, R 3, R 5 and R6 are as defined for formula (I), they can be prepared as follows: - 1. PC l5 toluene 2. Trimethylsilyl azide Route J The compounds of the formula (I) wherein R5 is -NHSO2 (C1-C4 alkyl) can be prepared by reacting the corresponding amino-substituted compounds with a C1-C4 alkanesulfonyl chloride, typically in the presence of an acceptor of acids.

Route K The compounds of the formula (I) wherein R 1 is C 2 -C 6 alkyl, aryl- (C 1 -C 4 alkyl) or heteroaryl- (C 1 -C 4 alkyl) can be prepared by the reductive alkylation of the corresponding compounds wherein R1 is H, using the appropriate aldehyde (C1-C5 alkyl) CHO, aryl. CHO or heteroaryl. CHO and a reducing agent, such as sodium triacetoxyborohydride. The invention also includes any new intermediates described herein, particularly those of the formula (II). The intermediates necessary for the process described above, can be prepared by conventional procedures such as those indicated in the following preparations, for example, as indicated below: 1. Benzotriazole R) 1, D R2 and R are as defined for formula (I); TBS = t-butyldimethylsilyl. 1. Benzotriazole, POCI3 / Pyridine R1, R2 and R3 are as defined for formula (I) and R5 is C1-C4 alkoxy or -NHSO2 (C1-C4 alkyl). Tetraethylammonium fluoride / THF (d) Tris (triphenylphosphine) rhodium (l), acetonitrile / water chloride Dibutyltinium trimethylsilyl azide oxide, toluene NC- (CH2) m-Z- (CH2) n-Br / K2C03 (C1-C) alkoxy Hydrolysis (for example, aqueous NaOH) Hydrochloride The pharmaceutically acceptable acid addition salts are formed from acids that form non-toxic salts and are examples of the hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate salts, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulfonate, benzenesulfonate and p_-toluenesulfonate. The pharmaceutically acceptable base salts are formed from bases which form non-toxic salts and examples are the calcium, lithium, magnesium, potassium, sodium, zinc, ethanolamine, diethanolamine and triethanolamine salts. For a review of the appropriate bases, see Berge et al., J. Pharm. Sci., 66, 1-19 (1977). As will be apparent, the compounds of the formula (I) will contain one or more asymmetric carbon atoms and, therefore, will exist in two or more ether-isomeric forms, or they can exist as tautomers. The present invention includes the individual etereoisomers and tautomers of the compounds of formula (I) and mixtures thereof. The separation of the diastereoisomers can be achieved by conventional techniques, for example, by fractional crystallization, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. A single enantiomer of a compound of the formula (I) can also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the corresponding racemate using a suitable chiral support, or by fractional crystallization of the diastereoisomeric salts formed by the reaction of the corresponding racemate with a suitable optically active acid or base.

Receptor Binding Assays Opioid receptor binding assays (mu and kappa) were performed on guinea pig brain membrane preparations. Binding assays were performed at 25 ° C for 60 minutes in 50 mM Tris buffer (pH 7.4). [3 H] -DAMGO (2 nM) and [3 H] -U-69,593 (2 nM) were used to label the mu and kappa receptor binding sites, respvely. The protein concentration was approximately 200 μg / well. The non-specific binding with naloxone 10 μM was defined. Delta delta binding assays were performed on a stable line of CHO cells expressing the human delta receptor. The binding assay was performed at 25 ° C for 120 minutes in 50 mM Tris buffer (pH 7.4). [3 H] -SNC-80 was used to label the delta receptor binding sites. The protein concentration was approximately 12.5 μg / well. The non-specific binding was defined with naltrexone 10μM. The binding reaction was terminated by rapid filtration through glass fiber filters, and the samples were washed with Tris buffer. 50 mM (pH 7.4) cooling with ice. All tests were performed in duplicate / triplicate.

Studies in isolated tissues The opioid activity (delta, mu and kappa) was studied in two isolated tissues, in the mouse vas deferens (MVD) (d) and in the myenteric plexus of guinea pig with attached longitudinal muscle (GP; P) ( μ and K). MVD (strain DC1, Charles River, 25-35 g) was suspended in 15 ml of organ bath containing Krebs buffer without Mg ++ of the following composition (mM): NaCl, 1 19; KCl, 4.7; NaHCO3, 25; KH2PO4, 1.2; CaCl2, 2.5 and glucose, 1 1. The buffer was gassed with 95% O2 and 5% CO. The tissues were suspended between platinum elodes, attached to a metric transducer with a voltage of 500 mg and stimulated with pulses of 0.03 Hz of amplitude from 1 msec to supraximal voltage. The IC5o values were determined by regression analysis of the concentration-response curves for the inhibition of elically induced contractions, in the presence of 300 nmol of the mu-selve selve CTOP antagonist. This test is a measure of agonism d. Myenteric guinea pig plexuses (Porcellus strain, male, 450-500 g, Dunkin Hartley) were suspended with longitudinal muscle segments attached, with 1 g of tension, in Krebs buffer and stimulated with 0.1 Hz pulses of 1 msec amplitude at a supramaximal voltage. The functional activity Mu was determined in the presence of 10 nmoles of norBNI with 1 μmol of the selve mu agonist, DAMGO, added to the bath at the end of the experiment, to define the maximum response. This test is a measurement of mu functional agonism.

The kappa functional activity was determined in the presence of CTOP 1 μM with 1 μmol of the selve kappa agonist U-69.593 added at the end of the experiment to define a maximum response. All contraction height inhibitions for the test compounds were expressed as a percentage of the inhibition obtained with the conventional agonist and the corresponding IC5o value determined. DAMGO is [D-AIa2, N-MePhe4, Gly5-ol] enkephalin) U69593 is ((5a, 7a, 8b) - (+) - N -methyl-N- (7- [1-pyrrolidinyl] -1 -oxaspiro [4,5] dec-8-yl) -benzeneacetamide) SNC-80 is (+) - 4 - [(aR) -a ((2S, 5R) -4-allyl-2> 5-dimethyl-1- pperazinyl) -3-methoxybenzyl] -N, N-diethylbenzamide NorBNI is nor-binaltorphimine CTOP is 1,2-Dithia-5,8,11, 14,17-pentaazacycloheicosan, a cyclic peptide derivative DPDPEm is [D-Pen2 , D-Pen5] enkephalin) [3HJ-DAMGO, [3H] -U69593, norBNI and CTOP can be purchased from DuPont, Amersham International, RBI and DuPont respvely. [3 H] -SNC80 was prepared by Amersham International. In general, a therapeutically effve oral or intravenous daily dose of the compounds of formula (I) and their salts, probably varies between 0.01 and 50 mg / kg of body weight of the subjto be treated, preferably of 0. 1 to 20 mg / kg. The compounds of the formula (I) and their salts can also be administered by intravenous infusion at a dose that probably varies between 0.001 and 10 mg / kg / hour. The tablets or capsules of the compounds can be administered individually or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations. The doctor will determine the actual dose that is the most appropriate for an individual patient and will vary with the age, weight and response of the particular patient. The above doses are exemplary of the average case. Of course, there may be individual cases where larger or smaller dosage intervals are desired, and such ranges are within the scope of this invention. Alternatively, the compounds of the formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or fine powder. An alternative means of transdermal administration is through the use of a skin patch. For example, they can be incorporated in a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They may also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin, together with stabilizers and preservatives when necessary.

The following examples illustrate the preparation of the compounds (I) and the preparations illustrate the preparation of new starting materials.

EXAMPLE 1 (+) - 5-. { 4-r (R) - - (2 (S), 5 (R) -4-alH-2,5-dimethyl-1-p-piperazinyl) -3-hydroxybenzphenyl) -1 H-tetrazole Boron tribromide (1M solution in dichloromethane, 10 ml) was added to a solution of the compound of example 52 (1 g) in dry dichloromethane (20 ml) and the resulting solution / suspension was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo and the residue was basified with a methanolic ammonium hydroxide solution and evaporated again. The residue was purified by column chromatography on silica gel using a gradient elution (dichloromethane / methanol / ammonium hydroxide; 93/7/1 to 80/20/3) to produce a foam. This material was further purified on a reverse phase polystyrene resin using gradient elution (100% water / 0% acetonitrile at 0% water / 100% acetonitrile). The acetonitrile was evaporated in vacuo and the remaining aqueous solution was frozen and lyophilized to yield the title compound as a fine white powder, 762 mg. dH (300 MHz, de-DMSO): 9.27 (1H, sa), 7.93 (2H, d), 7.52 (2H, d), 7.13 (1H, t), 6.80-6.60 (3H, m), 5.82. (1 H, m), 5.30-5.15 (2H, m), 5.04 (1 H, s), 3.37 (1H, dd), 3.10 (1 H, dd), 2.92 (1 H, m), 2.82 (1H , m), 2.70 (1 H, m), 2.66 (1 H, m), 2.36 (1 H, m), 1.97 (1 H, dd), 1.10 (3 H, d), 1.02 (3 H, d). m / z: 405 (MH +) Found: C, 63.82; H, 7.04; N, 20.09. C23H28N6O «0.1 NH4Br requires C, 63.90; H, 7.09; N, 19.76%. [a] D + 13.4 °; c = 0.112, methanol EXAMPLE 2. +) - 5- (4-r (R) - - (2 (S), 5 (R) -4-ethyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzyl-1H-tetrazol A solution of the compound of preparation 8 (241 mg), dibutyltin oxide (102 mg) and trimethylsilyl azide (619 mg) in dry toluene (10 ml) were heated together under gentle reflux for 18 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (80/22/3 dichloromethane / methanol / ammonia) to yield the title compound after trituration with ethyl acetate , 193 mg. m / z: 393 (MH +) Rf: 0.22 (80/20/3 dichloromethane / methanol / ammonia) Found: C, 64.99; H, 7.31; N, 19.89. C22H28N6O "3 / 5H2O" 1 / 6EtOAc requires C, 65.12; H, 7.36; NI, 20.09%. [a] D + 10.8 °; (c = 0.12, methanol) EXAMPLE 3 TO 12 The following compounds of the general formula or salts thereof, were prepared from the corresponding nitriles (see Preparations 9a 13, 16 and 21 to 24) by procedures similar to those used in Example 2.

Notes: a) solvent system 80/20/3 dichloromethane / methanol / ammonia; b) c = 0.1, methanol; c) [a] 365 -45 ° * (c 0.1, methanol); ** d) [a] 436-28 ° (c 0.1, methanol); *** e) [a] 365 -34 °. (c 0.1 methanol); EXAMPLE 3 (+) - 5- (4-r (R) -a- (2 (S), 5 (R) -4-propyl-2,5-dimethyl-1-piperazinin-3-hydroxybencipphenyl. 1 H-tetrazole EXAMPLE 4 (-) - 5-γ4-r (R) -a- (2S), 5 (R) -4-benzyl-2,5-d.methyl-1-piperazinyl) -3-hydroxybencipphenyl} -1 H-tetrazole EXAMPLE 5 (-) - 5-f4-r (R) -a- (2 (S), 5 (R) -4-thiazol-2-ylmethyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenyl } -1 H-tetrazole EXAMPLE 6 (+) - 5- ^ 4-r (R), (X- (2 (S), 5 (R) -4-methyl-2,5-dimethyl-1-piperazinin-3-hydroxy! benzyl, phenyl.} -1 H-tetrazole EXAMPLE 7 (+) - 5-. { 4-r (R) -a- (2 (S), 5fR) -4-carboxymethyl-2,5-d-methyl-1-piperazinop-3-hydroxybenzylphenyl > -1 H-tetrazole EXAMPLE 8 (-) - 5- (4-r (R) -a- (2 (S), 5 (R) -4-acetyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzyl , phenyl.}. -1 H-tetrazole EXAMPLE 9 (-) - 5- ^ 4-r (R -a- (2fS), 5 (R) -4-Cyclopropylmethyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzylphenyl H-tetrazole EXAMPLE 10 (-5-f4-r (R) -a-r2fS), 5 (R) -4- (4-fluorobenzin-2,5-di-ethyl-1-piperazinyl-3-hydroxybenzylphenyl > 1 H-tetrazole EXAMPLE 11 (-) - 5-f4-r (R) - - (2 (S) .5 (R) -4- (4-methoxybenzin-2,5-dimethyl-1-piperazinin-3-hydroxy-cy.cmfenir.-1 H-tetrazole EXAMPLE 12 -5- (4-r (R) -a- (2S), 5-R) -4- (4-trifluoror-ethylbenzin-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenirM H-tetrazole EXAMPLES 13 and 14, 5- (4-((R. -A- (2 (S., 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenyl > -2-tetrazolyl )ethyl acetate. , 5-t4-r (R) -a- (2fS), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzephenol]} -1-tetrazoiyil, ethyl acetate.

A solution of the compound of preparation 28 (1704 g), ethyl bromoacetate (501 mg) and potassium carbonate (1.38 g) in acetonitrile (40 ml) was heated to gentle reflux for 2 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with more ethyl acetate. The combined organic extracts were washed with water, saturated brine solution, dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran (20 ml) and tetraethylammonium fluoride (1.11 g) in water (2 ml) was added. The mixture was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and saturated brine solution, dried (MgSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (100% hexane to 40% ethyl acetate / hexane) to yield the N-2 isomer, 1.20 g, followed by the N-1 isomer, 248 mg. Isomer N-2: (example 13) m / z: 541 (MH +) Rf: 0.33 (1/1 hexane / ethyl acetate) Isomer N-1: (example 14) m / z: 541 (MH +) Rf: 0.26 (1/1 hexane / ethyl acetate) EXAMPLE 13 dH (300 MHz, CDCl 3): 7.60 (2H, d), 7.48 (2H, d), 7.34-7.16 (6H, m), 6.80-6.62 (3H, m), 5.18 (2H, s), 5.12 (1 H, s), 4.24 (2H, q), 3.92 (1H, d), 3.20 (1H, d), 2.80-2.56 (4H, m), 2.04 (2H, m), 1.24 (3H, q) , 1.10 (6H, m).

EXAMPLE 14 dH (300 MHz, CDCl 3): 8.18 (2H, d), 7.56 (2H, d), 7.36-7.12 (6H, m), 6.82-6.64 (3H, m), 5.42 (2H, s), 5.20 (1 H, sa), 5.10 (1 H, s), 4.28 (2H, q), 3.92 (1 H, d), 3.20 (1H, d), 2.78-2.56 (4H, m), 2.02 (2H, m) , 1.28 (3H, q), 1.10 (6H, m).

EXAMPLE 15 TO 18 The following compounds of the general formula: are prepared by alkylation of the compound of preparation 28 with an ethyl 4-bromobutyrate or ethyl 5-bromovalerate, as appropriate, by procedures similar to those used in example 13/14.

EXAMPLE 15 - (5-i4-r (R) -a- (2 (S) .5 (R) -4-Benzyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzepiphenyl-tetrahydroxyethylbutyrate EXAMPLE 16 - (5-f4-r (R) -a- (2.S), 5 ^ R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzophenyl} -2-ethyl tetrazolybutyrate EXAMPLE 17 - (5-l4-r (R) - - (2 (S..5 (R) -4-benzyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzophenyl-1-tetrazolyl ethyl valerate.

EXAMPLE 18 - (5-f4-r (R) -a- (2 (S) .5 (R) -4-Benzyl-2,5-dimethyl-1-p-piperazin-3-hydroxybenzylphenyl> 2-tetrazolyl ethyl valerate.

EXAMPLE 15 dH (300 MHz, CDCl 3): 7.60 (4H, m), 7.36-7.16 (6H, m), 6.80-6.70 (2H, m), 6.62 (1H, m), 5.28 (1H, s), 5.16 (1H , s), 4.52 (2H, t), 4.06 (2H, q), 3.96 (1H, d), 3.20 (1H, d), 2.80-2.56 (4H, m), 2.40 (2H, m), 2.24 ( 2H, m), 2.00 (2H, m), 1.22 (3H, t), 1.10 (6H, m).

EXAMPLE 16 dH (300 MHz, CDCl 3): 8.02 (2H, d), 7.48 (2H, d), 7.36-7.10 (6H, m), 6.78 (1H, d), 6.70 (1H, d), 6.64 (1H, s) ), 5.40 (1H, sa), 5.10 (1H, s), 4.72 (2H, m), 4.16 (2H, m), 3.96 (1H, d), 3.20 (1H, d), 2.80-2.56 (4H, m), 2.40 (4H, m), 2.02 (2H, m), 1.24 (3H, t), 1.10 (3H, d), 1.08 (3H, d).

EXAMPLE 17 dH (300 MHz, CDCl 3): 8.02 (2H, d), 7.56 (2H, d), 7.36-7.16 (6H, m), 6 ^ 80 (1H, d), 6.70 (2H, m), 5.18 (1H , sa), 5.18 (1H, s), 5.10 (1H, s), 4.64 (2H, t), 4.16 (2H, q), 3.92 (1H, d), 3.20 (1H, d), 2.78-2.54 ( 4H, m), 2.38 (2H, t), 2.18-1.98 (4H, m), 1.72 (2H, m), 1.24 (3H, t), 1.08 (6H, m).

EXAMPLE 18 dH (300 MHz, CDCl 3): 7.64 (2H, d), 7.58 (2H, d), 7.36-7.18 (6H, m), 6.78 (2H, m), 6.60 (1H, s), 5.20 (1H , s), 4.42 (2H, t), 4.10 (2H, t), 3.96 (1H, d), 3.20 (1H, d), 2.80-2.56 (4H, m), 2.28 (2H, t), 2.00 (3H, m), 1.60 (4H, m), 1.22 (3H, t), 1.10 (6H, m).

EXAMPLE 19 F +) - 5-f 4 -R (R) -a- (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl > -2-tetrazolyl) acetic Aqueous sodium hydroxide (2N, 3 ml) was added to a solution of the compound of example 13 (1.15 g) in methanol (30 ml) and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with 2 N hydrochloric acid (3 ml) and then evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to give the title compound, 977 mg. m / z: 513 (MH +) Rf: 0.45 (80/20/3 dichloromethane / methanol / ammonium hydroxide) [a] D + 6.2 ° (c 0.1, methanol) Found: C, 63.57; H, 6.49; N, 16.61. C29H32N6O3.2 / 3H2O.1 / 3NH3 requires C, 65.68; H, 6.53; N, 16.72%.

EXAMPLES 20 TO 24 The following compounds of the general formula: or salts thereof, were prepared by hydrolysis of the corresponding esters (see examples 14 to 18) by procedures similar to those used in example 19.

EXAMPLE 20 Acid (-) - (5- { 4 - [(R) -a- (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3- hydroxy benzyl] phenyl} -1-tetrazolyl) acetic acid.

EXAMPLE 21 Acid (-) - 4-f5-f4-rfR) -a- 2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybencipphenyl) -1- tetrazolyl) butyric.

EXAMPLE 22 F -) - 4-5 5 - (4-r (R) - - (2) (S), 5fR) -4-benzyl-2,5-dimethyl-1-piperazin-3-acid hydroxybenzylphenyl > -2-tetrazolyl) butyric.

EXAMPLE 23 Acid f -) - 5- (5-f4-r (R) -a- (2 (S) .5 (R) -4-Benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenyl > -2-tetrazolyl) butyric.

EXAMPLE 24 F-) - 5-.5-4 4-R (R) - - (2fS), 5 R R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hiroxybenzylcarbaryl acid} -2-tetrazolyl, valeric.

EXAMPLE 25 Acid (+) - (5-f4-r (R) -a- (2.S) .5 (R) -4-Benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenyl > -2-tetrazolyl) ethoxyacetic To a solution of the first compound of preparation 29 (1.40 g) in ethanol (125 ml) was cooled to 0 ° C and saturated with hydrogen chloride gas. After 30 minutes, the solvent was evaporated to dryness in vacuo to yield a colorless oil. The intermediate ether was dissolved in water (50 ml), cooled to 0 ° C and treated with water (50 ml). The solution was allowed to warm to room temperature overnight, after which an aqueous solution of sodium hydroxide (5 N, 7.5 ml) was added and the resulting solution was allowed to stir at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C, acidified to pH 2 and immediately re-basified to pH 9 with 880 ammonium hydroxide. The solvents were evaporated to dryness in vacuo and the residue was purified by gel column chromatography. of silica (80/20/3 dichloromethane / methanol / ammonia) to give the title compound as a gum. The gum was triturated with diethyl ether and filtered to yield the product as a white solid, 1.06 g. m / z: 557 (MH +) Rf: 0.36 (80/20/3 dichloromethane / methanol / ammonia) Found: C, 64.73; H, 6.69; N, 15.63. C31H36N6? 4.2 / 3H2O.1 / 3NH3 requires C, 64.83; H, 6.73; N, 15.44%. [a] D + 2.5 ° (c 0.12, methanol) EXAMPLE 26 Acid (5 4-r (R) - - (2 (S). 5 (R), 4-benzyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzepiphenyl) -1-tetrazol Detoxyacetic A solution of the second compound of preparation 29 (137 mg) in ethanol (10 ml) was saturated with hydrogen chloride gas and stirred at room temperature for 1 hour. The solvent was evaporated in vacuo to yield a colorless foam which was dissolved in aqueous ethanol (50%, 10 ml) and stirred at room temperature for 1 hour, after which sodium hydroxide (51 mg) was added and stirring was continued for 18 hours. The solution was acidified to pH 3.5 with concentrated hydrochloric acid and then basified with ammonium hydroxide solution. The solution was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane / methanol / ammonium hydroxide; 80/20/3) to yield the title compound as a colorless foam, 68 mg. dH (400 MHz, de-DMSO): 7.80 (2H, d), 7.58 (2H, d), 7.28 (4H, m), 7.20 (1H, m), 7.12 (1H, t), 6.72 (1 H, m), 6.65 (2H, m), 5.08 (1H, sa), 4.60 (2H, m), 3.90 (2H, m), 3.80 (1 H, m), 3.64 (2H, s), 3.22 (1 H, m), 2.70-2.50 (4H, m), 2.00 (1 H, m), 1.90 (1 H, m), 1.04 (6H, m). Found: C, 64.36; H, 6.63; N, 15.77. C3iH36N6O4.1 / 2Na »1 / 2NH3 requires C, 64.39; H, 6.49; N, 15.75%.

EXAMPLE 27 3- (5-4 4-R (R) -a- (2 (S), 5 (R) -4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl, phenyl .} -2-tetrazoliDpropiónico.

Sodium metal (28.5 mg) was added to ethanol (6 ml) and allowed to dissolve before adding the compound of preparation 31 (643 mg) and the reaction mixture was brought to reflux. After 5 minutes, methyl 3-bromopropionate (0.135 ml) was added and the reaction mixture was heated with stirring for 18 hours. The solvent was removed by evaporation in vacuo and the residue was purified by column chromatography on silica gel using gradient elution (99/1 / 0.25 to 80/20/3, dichloromethane / methanol / ammonium hydroxide) to yield the intermediate, 165 mg. The intermediate (165 mg) was dissolved in acetonitrile (10 ml) and tetraethylammonium fluoride (39.5 mg) was added. The reaction mixture was stirred for 10 minutes at room temperature and then diluted with water and extracted with ethyl acetate (3X). The combined organic extracts were washed with saturated brine, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica (97.5 / 2.5 / 0.5, dichloromethane / methanol / ammonium hydroxide) to yield an intermediate in the form of a 1: 1 mixture of methyl and ethyl esters, 72 mg. To a solution of above intermediate (72 mg) in methanol (1.8 ml), a methanolic solution of potassium hydroxide (3 M, 58 μl) and water (0.9 ml) was added. The reaction mixture was stirred at room temperature for 18 hours and then quenched with dilute hydrochloric acid to pH 5.5. The mixture was evaporated to dryness in vacuo and the residue was first purified by column chromatography on silica gel (85/15/3, dichloromethane / methanol / ammonium hydroxide) and secondly on reverse phase resin using gradient elution. (100/0 to 45/55; water / acetonitrile) to yield the title compound after lyophilization, 40 mg. m / z: 477 (MH +) Found: C, 62.75; H, 6.93; N, 16.89. C26H32N6O3.6 / 5H2O requires C, 62.78; H, 6.96; N, 16.87%.

EXAMPLE 27 dH (400 MHz, de-DMSO): 9.30 (1 H, s a), 7.90 (2H, d), 7.50 (2H, d), 7.06 (1 H, t), 6.64 (3 H, m), 5.75 (1 H, m), 5.10 (1 H, d), 5.06 (1 H, d), 4.96 (1 H, s), 4.80 (2 H, t), 3.10 (2H, m), 2.94 (2H, t), 2.80 (1H, dd), 2.68 (1H, d), 2.50 (3H, m), 2.06 (1H, m), 1.82 ( 1 H, t), 1.06 (3H, d), 0.90 (3H, d).

EXAMPLES 28 AND 29 5-, 5-. { 3- (R) -a- (2 (S), 5_R, -4-allyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzyl, phenyl) -2-tetrazolyl) ethyl valerate -.5-.R.-a- (2 (S., 5R, -4-allyl-2,5-dimethyl-1-piperazinyl-3-hydroxybenzophenyl) -1-tetrazolyl) valerate of ethyl A mixture of the compound of preparation 32 (2.3 g), potassium carbonate (1.8 g) and ethyl 5-bromovalerate (928 mg) in acetonitrile (60 ml) was heated to gentle reflux for 18 hours. The cooled reaction mixture was poured into water, extracted into ethyl acetate, dried (sodium sulfate) and evaporated to dryness in vacuo. The crude intermediate was dissolved in acetonitrile (15 ml) and tetraethylammonium fluoride (328 mg) was added. After 20 minutes of stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate), and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (99/1 / 0.5, diethyl ether / ethanol / ammonium hydroxide) to yield the N-2 isomer, 1550 mg. m / z: 533 (MH +) Rf: 0.53 (97/3/1, diethyl ether / ethanol / ammonium hydroxide) and the N-1 isomer, 225 mg. m / z: 533 (MH +) Rf: 0.39 (97/3/1; diethyl ether / ethanol / ammonium hydroxide) EXAMPLE 28 dH (400 MHz, CDCl 3): 8.16 (1H, s), 7.93 (1H, d), 7.53 (1H, d), 7.36 (1H, t), 7.12 (1H, t), 6.73 (1H, d), 6.63 (2H, m), 5.83 (1H, m), 5.72 (1H, sa), 5.20-5.06 (3H, m), 4.63 (2H, t), 4.10 (2H, q), 3.33 (1H, dd) , 2.85 (1H, dd), 2.80 (1H, dd), 2.68 (1H, m), 2.60 (1H, d), 2.56 (1H, m), 2.33 (2H, t), 2.16 (1H, dd), 2.06 (2H, m), 1.96 (1H, m), 1.70 (2H, m), 1.20 (3H, t), 1.15 (3H, d), 0.98 (3H, d).

EXAMPLE 29 .dH (400 MHz, CDCl 3): 7.76 (1H, d), 7.58 (2H, m), 7.50 (1H, t), 7.18 (1H, t), 6.73 (2H, m), 6.63 (1H, s) , 6.38 (1H, sa), 5.86 (1H, m), 5.30-5.13 (3H, m), 4.33 (2H, t), 4.13 (2H, q), 3.36 (1H, dd), 2.86 (2H, m ), 2.70 (1H, m), 2.60 (1H, m), 2.50 (1H, m), 2.28 (2H, t), 2.16 (1H, dd), 1.98 (1H, dd), 1.90 ( 2H, m), 1.58 (2H, m), 1.26 (3H, t), 1.18 (3H, d), 1.00 (3H, d).

EXAMPLE 30 Acid, +, - 5-.5- (3 - .. R) -a-, 2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinO-3-hydroxybenc Nfenil > -2-tetrazolyl) valeric Aqueous sodium hydroxide (2N, 2 mL) was added to a solution of the compound of Example 28 (1.15 g) in dioxane (4 mL) and methanol (2 mL) and the mixture was stirred at room temperature for 90 minutes. The reaction was quenched with 2N hydrochloric acid (3 ml) and then evaporated to dryness in vacuo. The residue was purified by column chromatography on polystyrene resin using gradient elution (water / acetonitrile, 100/0 to 40/60) to yield the title compound after lyophilization, 690 mg. Rf: 0.20 (80/20/3, dichloromethane / methanol / ammonium hydroxide) m / z: 505 (MH +) [garlic +13.6 (c = 0.11, methanol) Found: C, 64.83; H, 7.10; N. 16.21. C28H36N6O3. 7 / 10H2O requires C, 65.02; H, 7.29; N, 16.25%.

EXAMPLE 31 Acid (+. -5-.5- { 3-rR) -a- (2 (S), 5. R) -4-allyl-2, 5-dimethyl-1-piperazin-3 - hydroxybencipphenyl > -1- tetrazolyl) valeric Aqueous sodium hydroxide (2N, 1 ml) was added to a solution of the compound of example 29 (225 mg) in dioxane (2 ml) and methanol (1 ml) and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with 2 N hydrochloric acid (3 ml) and then evaporated to dryness in vacuo. The residue was purified by column chromatography on polystyrene resin using gradient elution (water / acetonitrile; 100/0 to 0/100) to yield the title compound after lyophilization, 169 mg. Rf: 0.21 (80/20/3, dichloromethane / methanol / ammonium hydroxide) m / z: 505 (MH +) [a] D + 13.54 (c 0.1 1 methanol) EXAMPLE 31 dH (400 MHz, d6-DMSO): 11.2 (1 H, sa), 7.76-7.48 (4H, m), 7.06 (1 H, t), 6.70 (2H, m), 6.60 (1 H, d) 5.76 (1 H, m), 5.20-5.00 (3h, m), 4.40 (2H, m), 3.30 (1 H, sa), 3.16 (1 H, m), 2.90-2.40 (5H, m), 2.16- 1.98 (3H, m), 1.90-1.68 (3H, m), 1.38 (2H, m), 1.06 (3H, d) 0.92 (3H, d).

EXAMPLES 32 and 33, 5-f3-r (R.-a-.2 (S), 5 (R) -4-allyl, 2, 5-dirnethyl-1-piperainyl) -3-hydroxybenzepiphenyl) -2-tetrazolyl .ethyl acetate .5-. { 3-rR-a-.2 (S .. 5 (R-allyl 2,5-d.methyl-1-piperazinyl-3-hydroxymer.c.l.fer.il.l.l.-1-tetrazolyl, ethyl acetate A mixture of the compound of preparation 33 (2.3 g), potassium carbonate (1.8 g) and ethyl bromoacetate (702 mg) in acetonitrile (60 ml) was heated under gentle reflux for 3 hours. The cooled reaction mixture was poured into water, extracted into ethyl acetate, dried (sodium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (90/10 / 0.75, hexane / isopropanol / ammonium hydroxide) to yield two products in the order of elution isomer N-2, 1200 mg. m / z: 491 (MH +) Rf: 0.21 (95/5, dichloromethane / methanol) and the N-1 isomer, 140 mg m / z: 491 (MH +) Rf: 0.23 (95/5, dichloromethane / methanol) EXAMPLE 32 dH (300 MHz, d6-DMSO): 9.30 (1H, s), 8.10 (1H, s), 7.86 (1H, d), 7.58 (1H, d), 7.50 (1H, t), 7.14 (1H, t ), 6.74-6.64 (3H, m), 5.86 (2H, s), 5.76 (1H, m), 5.20-5.00 (3H, m), 4.20 (2H, q), 3.16 (1H, m), 2.85 ( 1H, dd), 2.73 (1H, d) 2.56 (3H, m), 2.10 (1H, dd), 1.90 (1H, dd), 1.20 (3H, t), 1.06 (3H, d) 0.96 (3H, d ).

EXAMPLE 33 dH (300 MHz, CDCl 3): 7.70 (2H, m), 7.56 (1H, d), 7.48 (1H, t), 7. 18 (1H, t), 6.74 (2H, d), 6.60 (1H, s), 5.86 (1H, m), 5.70 (1H, sa), 5.30-5.10 (5H, m), 4.18 (2H, q) , 3.38 (1H, dd), 2.86 (2H, m), 2.66 (1H, m), 2.54 (2H, m) 2.16 (1H, t), 1.94 (1H, t), 1.18 (6H, m), 1.00 (3H, d).

EXAMPLES 34 AND 35 Acid (+) - (5- (3-rR) -a- (2- (S), 5 (R) -4-allyl-2,5-dimethyl-1-pperazinin-3- hydroxybenzylphenyl.} -2-tetrazolyl) acetic acid Acid, 5- (3-_. R) -a- (2-, S), 5 .R.-4-allyl-2,5-dimetH-1-piperazinyl, -3-hydroxybenzylphenyl > -1-tetrazolyl) acetic The following compound of the formula: They were prepared from the corresponding esters (see examples 32 and 33) by procedures similar to those of example 31. Isomer N-2 (example 34) m / z: 463 (MH +) Rf: 0.22 (80/20/3 dichloromethane / methanol / ammonium hydroxide) Found: C, 62.71; H, 6.65; N, 17.66. C25H30H6O3.9 / 10H2O requires C, 62. 72; H, 6.69; N, 17.55%. [a] D + 19.8 ° (c = 0.113, methanol) Isomer N-1 (example 35) m / z: 463 (MH +) Rf: 0.27 (80/20/3, dichloromethane / methanol / ammonium hydroxide) Found: C , 60.86; H, 6.60; N, 17.02. C25H3oN6? 3.8 / 5H2O requires C, 61. eleven; H, 6.81; N, 17.10%.

EXAMPLE 36 Acid (+. -5- (5- { 4-rR) -a-.2, S), 5, R) -4-allyl-2, 5-dimethyl-1-piperazinyl) -3- HydroxybenzylphenylM-tetrazoliOvaleric To a solution of the compound of example 53 (2.42 g) in dichloromethane (50 ml) was added boron tribromide (18 ml of a 1 M solution in dichloromethane), and the resulting solution was stirred at room temperature for 3 hours. The mixture was evaporated to dryness in vacuo, the residue was basified with ethanolic ammonia and re-evaporated to dryness. A solution of the residue in ethanol (120 ml) and dioxane (20 ml) was added to an aqueous solution of sodium hydroxide (2N, 26 ml) and stirred at room temperature for 18 hours. The solution was acidified to pH 3 with hydrochloric acid, immediately after it was re-basified to pH 9 with 880 ammonia solution and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3, dichloromethane / methanol / ammonia) to yield the title compound which was further purified by chromatography on polystyrene resin (gradient elution: 100% water to 40% acetonitrile / water). The aqueous solution of the product was lyophilized to yield the title compound as a white, flocculent solid, 0.545 g. m / z: 505 (MH +) Rf: 0.22 (80/20/3, dichloromethane / methanol / ammonia) Found: C, 64.48; H, 7.25; N, 16.14. C28H36H6O3.H2O requires C. 64.35; H, 7.33; N, 16.08%. [a] D + 21.8 ° EXAMPLE 37 Acid 5- (5- { 4-rR) -o (2, S), 5 (R) -4-Allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzophenyl } -1-tetrazolyl) valeric To a solution of the compound of Example 53 (350 mg) in dioxane (20 ml) and methanol (6 ml), 1N aqueous sodium hydroxide solution (3.2 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, acidified to pH 2 with hydrochloric acid and immediately basified to pH 9 with 880 ammonia. Rotary evaporation followed by purification of the residue by column chromatography on phase polystyrene resin. Reverse using gradient elution (100% water to 100% acetonitrile) afforded the title compound as a colorless solid, 272 mg. m / z: 519 (MH +) Rf: 0.33 (80/20/3; dichloromethane / methanol / ammonia EXAMPLE 37 dH (300 MHz, CDCl 3): 7.59 (4H, m), 7.22 (1 H, m), 6.90 (2H, m), 6.69 (1 H, m), 5.87 (2H, m), 5.22 (3H, m ), 4.48 (2H, t), 3.78 (3H, s), 3.40 (1H, m), 2.89 (1H, m), 2.70 (3H, m), 2.20 (4H, m), 1.83 (2H, m), 1..58 (2H, m), 1.08 (6H, m).

EXAMPLE 38 Acetate of .5- (4-rR-a- (2 (S), 5 (R.-4-allyl-2. 5-dimethyl-1-piperazinyl-3-hydroxybenzylphenyl > -1- tetrazolyl) methyl Diethyl azidodicarboxylate (1.46 g) was added to an ice-cold solution of the compound of preparation 40 (3.96 g), triphenylphosphine (2.26 g) and trimethylsilyl azide (1.16 g) in dry toluene (15 ml). The reaction was stirred at 0 ° C for 1 hour, at room temperature for 18 hours and at 50 ° C for 5 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel using gradient elution. (dichloromethane at 95/5 dichloromethane / methanol) to yield the title compound, 520 mg. m / z: 477 (mH +) Rf: 0.25 (95/5 / 0.5, dichloromethane / methanol / ammonia) EXAMPLE 38 dH (300 MHz, d6-DMSO): 9.30 (1H, sa), 7.72 (2H, d), 7.57 (2H, d), 7.17 (1H, t), 6.72 (2H, m), 6.63 (1H , m), 5.90 (1 H, m), 5.38-5.18 (5H, m), 3.82 (3H, s), 3.60 (1 H, sa), 3.43 (1 H, m), 2.90 (2H, m) , 2.68 (1 H, m), 2.57 (2H, m), 2.18 (1 H, m), 1.98 (1 H, m), 1.20 (3H, d), 1.03 (3H, d).

EXAMPLE 39 Acid, +) -, 5-. { 4 -. (R) -a- (2.S), 5 (R) -4-a »il-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenol} -1-tetrazolyl) acetic To a portion 38 (515 mg) in dioxane (8 ml) and methanol (20 ml), a 5 N aqueous solution of sodium hydroxide (2.16 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, acidified to pH 2 with hydrochloric acid and immediately basified to pH 10 with 880 ammonia. Rotary evaporation followed by purification of the residue by column chromatography on silica gel ( 80/20/3 dichloromethane / methanol / ammonia) and on reverse phase polystyrene resin using gradient elution (100% water / 0% acetonitrile at 100% acetonitrile / 0% water) produced the title compound in form of a solid, 373 mg. m / z: 463 (MH +) Rf: 0.23 (80/20/3 dichloromethane / methanol / ammonia) [a] D + 17.6 ° (c 0.125, methanol) Found: C, 62.94; H, 6.67; N, 17.90. C25H30N6O3.4 / 5H2O requires C, 62.96; H, 6.68; N, 17.62%.

EXAMPLE 40 AND 41, + .- 5-, 5-. { 4-,. R) -a- (2, S), 5 (R) -4-allyl-2, 5-dimethyl-1-piperazinyl) -3-hydroxybencipfenol} -2-Tetrazolyl ethylvalerate - (5- (4-r, R) -a- (2, S), 5 (R.-4-allyl-2, 5-dimethyl-1-piperazinyl) -3- hydroxyl.c «l.phenyl .}. -1. Tetrazolyl) ethyl valerate A mixture of the compound of preparation 31 (2 g), potassium carbonate (1.60 g) and ethyl 5-bromovalerate (807 mg) in acetonitrile (20 ml) was heated under gentle reflux for 18 hours. The cooled reaction mixture was poured into water, extracted into ethyl acetate, dried (sodium sulfate) and evaporated to dryness in vacuo. The crude intermediate was dissolved in acetonitrile (20 ml) and tetraethylammonium fluoride (865 mg) was added. After 20 minutes stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (90/10 / 0.75, hexane / isopropanol / ammonium hydroxide) to yield the N-2 isomer, 1.60 g. m / z: 533 (MH +) Rf: 0.30 (85/15/1, hexane / isopropanol / ammonium hydroxide) and the N-1 isomer, 150 mg m / z: 533 (MH +) Rf: 0.48 (93/7 / 1; dichloromethane / methanol / ammonium hydroxide) EXAMPLE 40 [a] D + 18.7 ° (c = 0.1 1, methanol) Found. C, 67.34; H, 7.71; N, 15.39. C30H4oH6O3 requires C, 67.64; 7.57; N, 15.78%.

EXAMPLE 41 dH (300 MHz, CDCl 3): 7.64 (2H, d), 7.58 (2H, d), 7.18 (1H, t), 6.70 (2H, m), 6.62 (1 H, s), 5.88 (1H, m), 5.30 (1 H, s), 5.22 (1 H, d), 4.96 (1H, d), 4.42 (2H, t) , 4.10 (2H, q), 3.38 (1H, dd), 2.90 (2H, m), 2.72 (1H, m), 2.56 (2H, m), 2.30 (2H, t), 2.18 (1H, t). 1.98 (3H, m), 1.62 (2H, m), 1.22 (6H, m), 1.02 (3H, d).

EXAMPLE 42 Acid, +, - 5- (5-f4 -, (R) -a- (2.S), 5 (R) -4-allyl-2, 5-dimethyl-1-piperazinyl, -3 - hydroxybenzepiphenyl.

A solution of the compound of preparation 1 (40 mg), benzotriazole (30.9 g) and the compound of preparation 43 (78.4 g) in toluene (780 ml) was heated to reflux with azeotropic removal of water for 24 hours. The solution was cooled to -20 ° C for the dropwise addition of 3-trimethylsilyloxyphenylmagnesium bromide [704 ml of a solution prepared from 158.7 g of the preparation compound 44 and magnesium filings (17.3 g) in tetrahydrofuran ( 800 ml)] at a speed such as to maintain the internal temperature in the range of -20 to -15 ° C. The resulting solution was stirred at -20 ° C for 5 minutes and then warmed to room temperature overnight. The reaction was quenched with 10% aqueous solution of ammonium chloride (2,000 ml). The organic phase was washed with water (1,000 ml), dried (MgSO 4) and evaporated to dryness in vacuo to yield the ethyl ester of the title compound, 101 g, in the form of a red oil which was identical to compound of Example 40. m / z: 533 (MH +) Rf: 0.30 (85/15/1, hexane / isopropanol / ammonium hydroxide) To a solution of the intermediate ester (14 g) in tetrahydrofuran (90 ml), sodium hydroxide solution (86 ml of a 2N solution) was added and the mixture was stirred at room temperature for 18 hours. The layers were separated and the aqueous solution was cooled in an ice bath for the addition of 2 N hydrochloric acid (86 ml) for 20 minutes. The aqueous solution was extracted with ethyl acetate (2 x 75 ml). The combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonia) to yield the title compound, 5.2 g. m / z: 505 (MH +) Rf: 0.28 (80/20/3 dichloromethane / methanol / ammonia) [a] D + 18.5 ° (C 0.124, methanol) Found: C, 64.85; H, 7.16; N, 16.28. C28H36H6O3.4 / 5H2O requires C, 64. 79; H, 7.30; N, 16.19%.

EXAMPLE 42 dH (400 MHz, de-DMSO): 9.20 (1H, sa), 7.96 (2H, d), 7.53 (2H, d), 7.53 (2H, d), 7.12 (1H, t), 6.66 (3H, m ), 5.77 (1H, m), 5.18 (1H, m), 5.13 (1H, d), 5.07 (1H, s), 4.69 (2H, t), 3.36 (1H, sa), 3.15 (1H, dd) , 2.84 (1H, dd), 2.73 (1H, dd), 2.65-2.47 (3H, m), 2.15 (2H, t) .2.07 (1H, dd), 1.95 (2H, m), 1.86 (1H, m ), 1.46 (2H, m), 1.07 (3H, d), 0.94 (3H, d).

EXAMPLE 43 Acid f + .- 5- (5-í4-rR-a-.2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenill-2-tetrazoliOetox ?acetic A solution of the compound from preparation 41 (3.46 g) in ethanol (200 ml) was cooled to 0 ° C and saturated with hydrogen chloride gas. After 30 minutes, the solvent was evaporated to dryness in vacuo to yield a colorless oil. The intermediate ether was dissolved in water (50 ml), cooled to 0 ° C and treated with water (50 ml). The solution was allowed to warm to room temperature overnight, after which an aqueous solution of sodium hydroxide (5 N, 7.5 ml) was added and the resulting solution was allowed to stir at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C, acidified to pH 2 and immediately re-basified to pH 9 with 880 ammonium hydroxide. The solvents were evaporated to dryness in vacuo and the residue was purified by gel column chromatography. of silica (80/20/3 dichloromethane / methanol / ammonia) to give the title compound as a gum. The gum was dissolved in water and lyophilized to yield the desired product as a white solid, 3.30 g. m / z: 506 (MH +) P. f: 137-140 ° Rf: 0.18 (80/20/3 dichloromethane / methanol / ammonia) Found: C, 62.15, H, 6.83; N, 16.23. C27H34N6O4.4 / 5H2O requires C, 62.24; H, 6.89; N, 16.13%. [d] D + 17.3 ° (c 0.11, methanol) EXAMPLE 44 Acid (5-. {4-r (R.-o> (2 (S), 5 (R.-2,5-dimetiM-piperazinyl , -3- hydroxybenzylphenyl > -2-tetrazolyl ethoxyacetic H Tris (triphenylphosphine) radium (I) chloride (100 mg) was added to a solution of the compound of Example 43 (620 mg) in acetonitrile (20 ml) and water (5 ml). The reaction mixture was heated under gentle reflux and the solvent was allowed to slowly distil off. An additional amount of acetonitrile / water (100 ml, 4: 1 v / v) was added at a rate such as to maintain a standing distillation. After the solvent addition was complete, distillation was continued until the volume was reduced to approximately 50 ml. The cooled solution was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 123 mg, together with the unreacted starting material, 460 mg. m / z: 467 (MH +) Rf: 0.06 (80/20/3-dichloromethane / methanol / ammonia) EXAMPLE 44 dH (400 MHz, d6-DMSO): 8.00 (2H, d), 7.52 (2H, d), 7.18 (1H, t), 6.80-6.60 (3H, m), 4.86 (2H, m), 4.02 ( 2H, m), 3.80 (2H, s), 3.50-3.00 (6H, ma), 2.66 (2H, m), 1.85 (2H, m), 1.17 (3H, d), 1.02 (3H, d) .

EXAMPLE 45 AND 46 (5-f4-r) -a- (2 (S), 5 (R) -4-allyl-2,5-dirnethyl-1-piperazinin-3-methoxybenzylphenyl-2-tetrazolyl) acetate of etiio and 5-f4-r (R) -a- (2 (S), 5 (R) -4-allyl-2,5-d-methyl-1-piperazin-3-methoxy-benzepiphenol > - 1-Tetrazol and ethyl acetate A mixture of the compound of Example 52 (1.0 g), potassium carbonate (990 mg) and ethyl bromoacetate (256 μl) in dry dichloromethane (30 ml) was heated under gentle reflux for 18 hours. The cooled reaction mixture was poured into water, extracted with dichloromethane, dried (sodium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (90/10 / 0.75, hexane / isopropanol / ammonium hydroxide) to yield the N-2 isomer (example 45), 620 mg, followed by the N-1 isomer (example 46), 518 mg.

EXAMPLE 45 m / z: 505 (MH +) Rf. 0.29 (90/10 / 0.75, hexane / isopropanol / hydroxyammonium) EXAMPLE 46 m / z: 505 (MH +) Rf: 0.14 (90/10 / 0.75, hexane / isopropanol / ammonium hydroxide) EXAMPLE 45 dH (300 MHz, CDCl 3): 8.07 (2H, d), 7.58 (2H, d), 7.23 (1H, m), 6.8 (3H, m), 5.86 (1H, m), 5.43 (2H, s ), 5.19 (3H, m), 4.30 (2H, q), 3.79 (3H, s), 3.38 (1H, dd), 2.84 (2H, m), 2.63 (2H, m), 2.51 (1H, m), 2.14 (1 H, m), 1.93 (1 H, m), 1.30 (3 H, t), 1.20 (3 H, d), 1.00 (3 H, d).

EXAMPLE 46 dH (300 MHz, CDCl 3): 7.65 (4H, q), 7.27 (1 H, m), 6.3 (3H, m), 5.86 (1 H, m), 5.30-5.10 (5H, m), 4.28 (2H , q), 3.80 (3H, s), 3.37 (1 H, dd), 2.90-2.40 (5H, m), 2.15 (1 H, m), 1.93 (1 H, m), 1.27 (3H, t) , 1.20 (3H, d), 1.00 (3H, d).

EXAMPLE 47 (5- {4-r (R) -a-f2 (S) .5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzylphenyl-2-tetrazolyl) ethyl acetate Boron tribromide (1 M in dichloromethane, 2.46 mL) was added to a solution of the compound of Example 45 (620 mg) and stirred at room temperature for 6 hours. The reaction mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (95/5 / 0.5 to 80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 212 mg. m / z: 491 (MH +) Rf: 0.50 (93/7/1 dichloromethane / methanol / ammonium hydroxide) EXAMPLE 47 dH (300 MHz, CDCl 3): 8.07 (2H, d), 7.57 (2H, d), 7.17 (1H, t), 6.73 (3H, m), 5.88 (1H, m), 5.40 (2H, m ), 5.20-5.10 (3H, m), 4.28 (2H, q), 3.36 (1 H, dd), 2.88 (1 H, dd), 2.82 (1 H, m), 2.78-2.44 (3H, m) , 2.17 (1 H, dd), 1.98 (1 H, dd), 1.50 (1 H, sa), 1.30 (3H, t), 1.17 (3H, d), 1.00 (3H, d).

EXAMPLE 48 Acid (+) -> 5 - (4-rIR) -a-f2 S) .5 (R) -4-allyl-2,5-dimethyl-1-piperazinin-3-hydroxybenzylphenyl > -2-tetrazolyl) acetic To a solution of the compound of Example 47 (168 mg) in dioxane (4 ml) and methanol (6 ml), 2N aqueous sodium hydroxide solution (0.86 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, acidified to pH with 2N hydrochloric acid and immediately basified to pH 10 with 880 ammonia. Rotary evaporation followed by purification of the residue by column chromatography on silica gel ( 80/20/3 dichloromethane / methanol / ammonia) and on reverse phase polystyrene resin using gradient elution (100% water / 0% acetonitrile at 100% acetonitrile / 0% water) produced the title compound in form of a solid after lyophilization, 130 mg. m / z: 462 (MH +) Rf: 0.21 (80/20/3 dichloromethane / methanol / ammonia) [a] D + 20 ° (c 0.12 methanol) Found: C, 62.17; H, 6.60; N, 17.25. C25H3oN6? 3.H2O requires C, 62.48; H, 6.71; N, 17.49%.

EXAMPLES 49 AND 50 (+) - 2- (5- {4-rfR, S) - - (4-benzyl-1-piperazinii) -3-hydroxybenzinophenyl > -2- ethyl tetrazolyl.acetate Y. (+) - 2- (5-f4-r (R, S) -a- (4-benzyl-1-piperazinyl) -3-hydroxybenzylphenyl-tetraethyl ethyl acetate A solution of the compound of preparation 4 (b) (0.54 g), ethyl bromoacetate (167 mg) and cesium carbonate (0.49 g) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours.

The reaction mixture was partitioned between saturated sodium chloride solution and ethyl acetate. The aqueous layer was separated and extracted with more ethyl acetate. The combined organic extracts were washed with water, saturated brine solution, dried (sodium sulfate) and evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran (20 ml) and tetramethylammonium fluoride (400 g) in water (2 ml) was added. The mixture was stirred at room temperature for 12 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and saturated brine solution, dried (magnesium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (25-50% ethyl acetate / hexane) to produce, in order of elution., the N-2 isomer, 310 mg, followed by the N-1 isomer, 75 mg. Isomer N-2 (example 49): m / z: 513 (MH +) dH (300 MHz, d6-DMSO): 9.28 (1 H, s), 7.94 (2H, d), 7.56 (2H, d), 7.32 -7.14 (5H, m), 7.06 (1H, t), 6.80 (2H, m), 6.56 (1H, d), 5.82 (2H, s), 4.26 (1H, s), 4.20 (2H, q), 3.46 (2H, s), 2.50-2.20 (8H, m), 1.20 (3H, t). Isomer N-1 (example 50): m / z: 513 (MH +) dH (400 MHz, d6-DMSO): 9.30 (1 H, s), 7.68 (2H, d), 7.60 (2H, d), 7.40 -7.20 (5H, m), 7.08 (1H, t), 6.84 (2H, m), 6.58 (1H, d), 5.6 (2H, s), 4.30 (1H, s), 4.06 (2H, q), 3.48 (2H, s), 2.50-2.20 (8H, m), 1.04 (3H, t).

EXAMPLE 51 Acid (+) - 2- (5- { 4-r, R, S-a- (4-benzyl-1-piperazinyl) -3-hydroxybenzylphenol. tetrazole and acetic acid Aqueous sodium hydroxide (2 N, 0.5 ml) was added to a solution of the compound of example 50 (70 mg) in methanol (10 ml) and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with 2N hydrochloric acid (3 ml) and then evaporated to dryness in vacuo.

The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 68 mg. m / z: 485 (MH +) dH (400 MHz, de-DMSO): 7.74 (2H, d), 7.60 (2H, d), 7.40-7.00 (6H, m), 6.84 (2H, m), 6.60 (1 H, m), 5.14 (2H, s), 4.32 (1 H, s), 3.70 (2H, s), 3. 18 (1 H, s), 2.70-2.30 (8H, m).

Found: C, 60.38; H, 5.80; N, 16.51. C27H28N6O3.Na.3 / 2H2O.1 / 4NH3 requires C, 60.33; H, 5.73; N, 16.29%.

EXAMPLE 52 4-r (R) - - (2 (S) -5ÍR) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzylphenyltetrazole A solution of the compound of preparation 3 (3.26 g), dibutyltin oxide (780 mg) and trimethylsilyl azide (2.54 g) in dry toluene was stirred at 70 ° C under nitrogen for 48 hours, after which the reaction was interrupted by the addition of 2N hydrochloric acid. The pH of the solution was adjusted to pH 10 by the addition of 0.880 ammonia solution, pre-absorption silica gel was added and the solvents were evaporated in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (85/15/2 to 80/20/3 dichloromethane / methanol / ammonia) to yield the title compound as a brown gum, 3.28 g. m / z420 (MH +) Rf: 0.31 (80/20/3 dichloromethane / methanol / ammonia) dH (300 MHz, CdCI3): 8.04 (2H, d), 7.43 (2H, d), 7.15 (1H, t), 6.93 (1H, sa), 6.74 (3H, m), 5.93 (1H, m), 5.32 (2H, n), 5.04 (1H, s), 3.68 (3H, s), 3.58 (1H, m), 3.28 (1H, m), 3.09 (1H, m), 2.97 (2H, m), 2.80 (1H, m), 2.55 (1H, m), 2.30 (1H, m), 1.18 (6H, 2xd) EXAMPLE 53 5- (5-f4-r (R) -a- (2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzylphenyl) -1-tetrazolyl ethyl valerate Phosphorus pentachloride (1.53 g) was added to a solution of the compound of preparation 36 (2.95 g) in dry toluene (75 ml) and the resulting mixture was stirred at 75 ° C for 2 hours. The solution was cooled to room temperature and trimethylsilyl azide (1.17 g) was added. The reaction mixture was maintained at room temperature with stirring for 18 hours. The solution was diluted with ethyl acetate (150 ml) and washed with saturated sodium hydrogen carbonate and the organic extracts were evaporated to dryness in vacuo. The brown residue was purified by column chromatography on silica gel (98/2, dichloromethane / methanol) to yield the title compound, 2.43 g. m / z: 547 (MH +) Rf: 0.39 (95/5, dichloromethane / methanol) dH (300 MHz, CDCl 3): 7.65 (2H, d), 7.58 (2H, d), 7.25 (1H, t), 6.80 (3H, q), 5.87 (1H, m), 5.18 (3H, m), 4.42 (2H, t), 4.12 (2H, q), 3.78 (3H, s), 3.35 (1H, dd) , 2.85 (2H, m), 2.60 (3H, m), 2.31 (2H, t), 2.15 (1H, m), 2.00 (3H, m), 1.68 (2H, m), 1.20 (6H, m) , 1.00 (3H, d).

EXAMPLE 54 4-5. { , (R_-a- (2- (S) -5.R) -4-allyl-2,5-d-methyl-1-piperazinyl) -3-methanesulfonylbenzylphenyl > -1 H-tetrazole To a suspension of the anilinotetrazole of preparation 48; (600 mg, 0.0015 mol) in tetrahydrofuran, triethylamine (61 mg, 0.0016 mol) was added to give a bright yellow solution. Trimethylsilyl chloride (178 mg, 0.0016 mol) was added and stirring was continued for 1.5 hours. Precipitated triethylamine hydrochloride. Pyridine (468 ml, 0.0060 mole) was added followed by methanesulfonyl chloride (344 mg, 0.0030 mole) and the reaction was stirred at room temperature for 18 hours. Water was added (10 ml) and the reaction was acidified to pH 2 with concentrated hydrochloric acid; then basified with ammonium hydroxide solution (bp = 0.880). The mixture was subjected to rotary evaporation to dryness and the residue was reabsorbed onto silica. This was then chromatographed on silica; eluent 90/0 / 1.5 - > 80/20/1 CH2Cl2 / MeOH / NH4OH to give 220 mg of the desired product. m / z: 483 (MH +) dH (400 MHz, de-DMSO): 7.94 (2H, d), 7.46 (2H, d), 7.32 (1H, t), 7. 20 (1 H, s), 7.10 (1 H, d), 7.02 (1 H, d), 5.80 (1 H, m), 5.26 (H, d), 5.20 (1 H, d), 5.12 (1 H , s), 3.36 (1 H, dd), 3.18 (1 H, s), 3.04 (H, dd), 2.94 (3 H, s), 2.88 (1 H, d), 2.74 (1 H, m), 2.68-2.56 (2H, m), 2.32 (1H, dd), 1.88 (1H, d), 1.12 (3H, d), 1.00 (3H, d).

EXAMPLE 55 (+) - r (R, S) -a- (4-allyl-1-piperazir-yl) -3- (hydroxybenzyl) phenyltetrazole Tetraethylammonium fluoride (288 mg) was added to a solution of the compound of preparation 50 (500 mg) in acetonitrile (10 ml) and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was then evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide). This material was further purified on reverse phase polystyrene resin, using gradient elution (90 / 10-50 / 50 water / acetonitrile). The acetonitrile was evaporated in vacuo and the resulting aqueous solution was frozen and lyophilized to yield the title compound as a white solid, 131 mg. m / z: 377 (MH +) Rf: 0.24 (70/30/3 ethyl acetate / methanol / dimethylamine) dH (400 MHz, DMSO-de): 7.82 (2H, d), 7.49 (2H, d), 7.08. (1 H, dd), 6.86 (2 H, m), 6.58 (1 H, d), 5.60 (1 H, m), 5.20 (2 H, m), 4.26 (1 H, s), 3.10 (2 H, d ), 2.58 (4H, m), 2.38 (4H, m).

EXAMPLES 56 AND 57 (+ - (5-f4-r (R.sup.-α-4-allyl-1-piperazin »n-3-hydroxybenzylphenol-1-tetrazoly-ethyl acetate) (+) - (5-f4-r (R.S) -a- (4-aHl-1-piperazir-yl) -3-hydroxybenzylphenyl > -2- tetrazole &Ethyl Pacetate Potassium carbonate (1.27 g) and ethyl bromoacetate (344 μl) were added to a solution of the compound of preparation 50 (1.5 g) in acetonitrile (60 ml) and the reaction was stirred under reflux for 20 hours. After cooling, water was added and the reaction mixture was extracted with ethyl acetate (3 X 50 ml), the combined organic extracts were dried (Na2SO) and evaporated to dryness in vacuo. This material was redissolved in acetonitrile (10 ml), tetraethylammonium fluoride (694 mg) was added and the reaction was stirred at room temperature for one hour. Water was added and the mixture was extracted with ethyl acetate (2 x 20 ml), the combined organic extracts were dried (Na2SO) and evaporated to dryness in vacuo to give an orange foam. The residue was purified by column chromatography on silica gel using gradient elution (70 / 30-100 / 0 ethyl acetate / hexane) to yield the N2 isomer, 270 mg. m / z: 463 (MH +) Rf: 0.25 (ethyl acetate) dH (300 MHz, DMSO-d6): 9.30 (1 H, s), 7.98 (2H, d), 7.58 (2H, d), 7.06 ( 1 H, dd), 6.85 (2 H, m), 6.56 (1 H, d), 5.84 (2 H, s), 5.76 (1 H, m), 5.10 (2 H, m), 4.25 (1 H, s) , 4.19 (2H, q), 2.92 (2H, d), 2.34 (8H, m), 1.18 (3H, t). and the N1 isomer, 35 mg. Rf: 0.13 (ethyl acetate) EXAMPLE 58 +) - 4-5-f4-r (R.S) -a- (4-allyl-1-piperazinopropyl-3-hydroxybenzylphenyl) -1- tetrzolyl ethylbutyrate Tetraethylammonium fluoride (67 mg) was added to a solution of the first compound of the drawings of preparation 51 (200 mg) in acetonitrile (4 ml) and the reaction was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic extracts were dried (NA2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (85/15 / 1.5-80 / 20 / 1.5 hexane / isopropanol / ammonium hydroxide) to yield the title compound, 130 mg. m / z: 491 (MH +) Rf: 0.24 (80/20 / 1.5 hexane / isopropanol / ammonium hydroxide) dH (300 MHz, CDCl 3): 7.60 (4H, s), 7.14 (1 H, dd), 6.96 (1 H, d), .88 (1 H, s), 6.67 (1 H, d), 5.86 (1 H, m), 5.16 (2 H, m), 4.48 (2 H, t), 4.26 (1 H, s ), .02 (2H, q), 3.02 (2H, d), 2.49 (8H, m), 2.38 (2H, t), 2.24 (2H, m), 1.20 (3H, t).

EXAMPLE 59 (+) - 4- (5-f4-r (R.S) -a- (4-allyl-1-piperaziniP-3-hydroxybenzylphenyl> 2-ethyl tetrazolybutyrate The title compound was prepared using the second compound of the drawings of Preparation 51, following a procedure similar to that described in Example 58, and was obtained with a yield of 69%. m / z: 491 (MH +) Rf: 0.38 (80/20 / 1.5 hexane / isopropanol / ammonium hydroxide) dH (300 MHz, DMSO-dβ): 9.29 (1 H, s), 7.96 (2H, d), 7.55 (2H, d), 7.05 (1H, dd), 6.82 (2H, m), .54 (1H, d), 5.78 (1H, m), 5.10 (2H, m), 4.74 (2H, t ) 4.22 (1 H, s), 4.00 (2H, q), .90 (2H, d), 2.35 (10H, m), 2.18 (2H, m), 1.14 (3H, t).

EXAMPLE 60 Acid f +) - f5-. { 4-r (R, S) -a- (4-allyl-1-piperaziniP-3-hydroxybenzylfenin> 2-tetrazole and Pac 2N Aqueous sodium hydroxide solution (1 ml) was added to a solution of the compound of example 57 (250 mg) in methanol (2 ml) and dioxane (4 ml) and the reaction was stirred at room temperature for one hour. The pH of the reaction was adjusted to 5 using 2N aqueous hydrochloric acid and the mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (70/30/3 ethyl acetate) / methane / ammonium hydroxide) and this material was further purified on a reverse phase polystyrene resin using a gradient solution (80 / 20-50 / 50 water / acetonitrile). The acetonitrile was evaporated in vacuo and the remaining aqueous solution was frozen and lyophilized to yield the title compound as a white solid, 190 mg. m / z: 435 (MH +) Rf: 0.2 (80/20/3 diclomerate / methanol / ammonium hydroxide) dH (300 MHz, DMSO-dβ): 9.40 (1H, sa), 7.99 (2H, d), 7.57 (2H, d), 7.08 (1H, dd), 6.84 (2H, m), 6.58 (1H, d), 5.83 (1H, m), 5.47 (2H, s), 5.26 (2H, m) , 4.30 (1 H, s), 3.28 (2H, d), 2.74 (4H, m), 2.40 (4H, m).

EXAMPLE 61 to 63 The following compounds of the general formula They were prepared by hydrolysis of the corresponding esters, Examples 56, 58 and 59, by procedures similar to those used in Example 60. (a): 80/20/3 dichloromethane / methanol / ammonium hydroxide.

EXAMPLE 61 +) - f5-f4-r.R, S) -a- (4-allyl-1-piperazir-iP-3-hydroxybenzylphenyl) -1- tetrazolyPacetic acid.

EXAMPLE 62 +) - 4- (5- (4-R) -S-4-allyl-1-piperazine-3-hydroxybenzylphen-1-tetrazolympyryric acid.

EXAMPLE 63 (+) - 4- (5-. {4-R (R, S) -a- (4-allyl-1-piperazin-P-3-hydroxybenzylphenyl) -2- tetrazolyP.butyric acid.

EXAMPLE 64 (+) - 5- (5-. {4 (R: S) -a- (4-allyl-1-piperazinopropylamine-3-methoxybenzylphenyl) -1-tetrazolyl ethyl) valerate A solution of the compound of preparation 57 (582 mg) and phosphorus pentachloride (386 mg) in dry toluene (30 ml) was stirred at 70 ° C for 90 minutes. After cooling, trimethylsilyl azide (785 μl) was added and the reaction was stirred at room temperature for 72 hours. A saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with water and brine, then dried (Na 2 SO 4) and evaporated to dryness in vacuo to give a brown gum. The residue was purified by column chromatography on silica gel (80/20 / 1.5 hexane / isopropanol / ammonium hydroxide) to yield the title compound, 218 mg. m / z: 519 (MH +) dH (300 MHz, DMSO-CDCl 3): 8.17 (2H, d), 7.78 (2H, d), 7.59 (1 H, s), 7.37 (2H, m) 6.92 (1 H , d), 6.12 (1 H, m), 5.60 (2 H, m), 5.08 (1 H, s), 4.40 (2 H, t), 4.22 (2 H, m), 4.08 (2 H, q), 3.94 ( 2H, m), 3.68 (3H, s), 3.68 (2H, d), 3.52 (4H, m), 2.30 (2H, t), 1.99 (2H, m), 1.64 (2H, m), 1.22 (3H, t).

EXAMPLE 65 Acid (+) - 5- (5-f4-IYR, S) -a- (4-allyl-1-piperaziniP-3-hydroxybenzylphenyl) -1-tetrazolyP-valeric acid.

A solution of boron tribromide in dichloromethane (10.5, 1M) was added dropwise to a solution of the compound of Example 64 (2.73 g) in dichloromethane (25 ml) and the reaction was stirred under a nitrogen atmosphere at room temperature for 6 hours. hor s Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with dichloromethane (3 x 50 ml). The combined organic extracts were washed with water and brine, dried (Na2SO) and evaporated to dryness in vacuo to give a brown foam. A solution of this material in dioxane (10 ml), methanol (5 ml) and a 2 N aqueous solution of sodium hydroxide (3 ml) was stirred at room temperature for 20 hours. The mixture was acidified using 2N hydrochloric acid, then basified using ammonium hydroxide solution and the mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) and further purified on a reverse phase polystyrene resin using gradient elution (100 / 0-0 / 100 water / acetonitrile). The acetonitrile was evaporated in vacuo and the remaining aqueous solution was frozen and lyophilized to yield the title compound as a white solid, 238 mg. m / z: 477 (MH +) dH (300 MHz, DMSO-d6): 10.50 (1H, sa), 7.70 (2H, d), 7.61 (2H, d), 7.08 (1H, dd), 6.84 ( 2H, m), 6.57 (1H, d), 5.79 (1H, m), 5.12 (2H, m), 4.44 (2H, t), 4.33 (1H, s), 3.20 (1H sa), 2.94 (2H, d), 2.40 (4H, m), 2.34 (4H, m), 2.15 (2H, t), 1.82 (2H, m), 1.44 (2H, m). Found; C, 63.60; H, 6.83; N, 17.05. C26H32N6O3.4 / 5H2O requires C, 63.60; H, 6.90; N, 17.12%.

EXAMPLE 66 (+) - 2- (5- {4-r (R, S) -a- (ethyl 4-allyl-l-piperazin-P-3-hydroxybenzylphenyl-2-tetrazolyPethoxyacetate) An ice-cooled solution of the compound of Preparation 59 (1.6 g) in ethanol (50 ml) was saturated with hydrogen chloride gas and stirred for 45 minutes. The reaction mixture was evaporated to dryness in vacuo to give a white solid. A solution of this material in ethanol (5 ml) was cooled to 0 ° C and water (5 ml) was added. The resulting solution was stirred at 0 ° C for 90 minutes, ammonium hydroxide solution was added and the mixture was extracted with dichloromethane (2 x 25 ml). The combined organic extracts were dried (Na 2 S 4) and evaporated to dryness in vacuo to give a white foam. The residue was purified by column chromatography on silica gel (95/5 / 0.5 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 1.24 g. m / z: 5.07 (MH +) Rf: 0.59 (90/10/1 diethyl ether / ethanol / ammonium hydroxide) dH (400 MHz, CDCl 3) 8.07 (2H, d), 7.54 (2H, d), 7.15 (1H , dd), 6.98 (1 H, d), 6.90 (1 H, s), 6.66 (1 H, d), 6.14 (1 H, sa), 5.88 (1 H, m), 5.18 (2 H, m) , 4.87 (2H, t), 4.19 (5H, m), 4.08 (2H, s), 3.04 (2H, d), 2.52 (8H, m), 1.26 (3H, t). Found: C, 63.38; H, 6.69; N, 16.46. C27H34N6O4.1 / 5H2O requires C, 63.56; H, 6.80; N, 16.47%.

EXAMPLE 67 Acid. +) - 2-f5-f4-r (R.sub.S) -a-f4-allyl-1-piperazine-3-hydroxybencipphenyl > -2- tetrazolyPethoxyacetic The title compound was prepared using the compound of Example 66, following a procedure similar to that described in Example 60 and obtained as a white solid, in 63% yield. m / z 479 (MH +) Rf: 0.2 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, CDCl 3): 9.29 (1H, sa), 7.94 (2H, d), 7.54 (2H, d), 7.06 (1 H, dd), 6.81 (2 H, m), 6.54 (1 H, d) 5.75 (1 H, m), 5.09 (2 H, m), 4.86 (2 H, t), 4.22 (1 H, s), 4.00 (2H, t), 3.95 (2H, s), 3.54 (1H, s), 2.90 (2H, d), 2.34 (8H, m). Found: C, 59.42; H, 6.14; N, 16.31. C25H3oN6? 4.3 / 2H2O requires C, 59.39; H, 6.58; N, 16.62%.

EXAMPLE 68 AND 69 (+) - 4- (5-γ4-R (R, S) - - (4-benzyl-1-piperazinyl-3-hydroxybenzinophenyl > -1- ethyl tetrazolyP-butyrate (+) - 4- (5- { 4-r (R.S) -a- (4-benzyl-1-plperazinyl-3-hydroxybenzylphenyl > -2- ethyl tetrazolybutyrate A suspension of the compound of preparation 4b (1.62 g), potassium carbonate (1.25 g) and ethyl 4-bromoburithane (430 μl) in acetonitrile (25 ml) was stirred under reflux for 18 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The phases were separated, the aqueous layer was extracted with more ethyl acetate and the combined organic extracts were dried (MgSO 4) and evaporated to dryness in vacuo to give a yellow gum. Tetraethylammonium fluoride (0.8 g) was added to a solution of this material in tetrahydrofuran (20 ml) and the solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous ammonium chloride solution. The phases were separated, the aqueous layer was extracted with more ethyl acetate and the combined organic extracts were dried (MgSO 4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (50/50 ethyl acetate / hexane) to yield the N-2 isomer, 1.02 g. m / z: 542 (M 2 H +) d H (400 MHz, DMSO-d 6): 9.29 (1 H, s), 7.97 (2 H, d), 7.55 (2 H, d), 7.26 (5 H, m), 7.06 (1 H, dd), 6.68 (2H, m), 6.57 (1H, d), 4.74 (2H, t), 4.28 (1H, s), 4.02 (2H, q), 3.46 (2H, s), 2.30 -2.48 (8H, m), 2.19 (2H, m), 1.14 (3H, t). Followed by the N1 isomer, 0.14 g. m / z: 542 (MH +) dH (400 MHz, DMSO-d6): 9.30 (1 H, s), 7.72 (2H, d), 7.62 (2H, d), 7.26 (5H, m), 7.07 (1 H, dd), 6.84 (2H, m), 6.58 (1H, d), 4.48 (2H, t), 4.32 (1H, s), 3.92 (2H, q), 3.47 (2H, s), 2.22 -2.44 (8H, m), 2.05 (2H, m), 1.08 (3H, t).

EXAMPLES 70 AND 71 (+) - 5- (5-f4-r (R.S) -oc- (4-benzyl-1-piperazinyl-3-hydroxybenzinophenyl > -1- ethyl tetrazolol) (+) - 5- (5-i4-r (R, S) -a-f4-benzyl-1-piperazinyl-3-hydroxybenzylphenyl-2-tetrazoliPvalerate ethyl The title compounds were prepared following the procedure described in Example 68 and 69, using the compound of Preparation 4b, 5-ethyl bromovalerate and were obtained with a yield of 10% and 56% respectively. Isomer N1, m / z: 555 (MH +). dH (400 MHz, DMSO-d6): 9.32 (1 H, s), 7.72 (2H, d), 7.61 (2H, d), 7.28 (5H, m), 7. 08 (1 H, dd), 6.84 (2 H, m), 6.58 (1 H, d), 4.45 (2 H, t), 4.30 (1 H, s), 3.97 (2 H, q), 3.47 (2 H, s ), 2.31-2.46 (8H, m), 2.23 (2H, t), 1.81 (2H, m), 1.46 (2H, m), 1. 12 (3H, t). and the N2 isomer. m / z: 555 (MH +). dH (400 MHz, DMSO-d6): 9.29 (1 H, s), 7.97 (2H, d), 7.56 (2H, d), 7.27 (5H, m), 7. 06 (1 H, dd), 6.83 (2H, m), 6.57 (1 H, d), 4.70 (2H, t), 4.27 (1 H, s), 4.03 (2H, q), 3.48 (2H, s) ), 2.26-2.48 (8H, m), 1.98 (2H, m), 1.52 (2H, m), 1.16 (3H, t).

EXAMPLE 72 Acid +) - (5-f4-r (R.S) - - (4-benzyl-1-piperaziniP-3-hydroxybenzylphenyl > -2- tetrazoli Pacético 2N Aqueous sodium hydroxide solution (1.05 ml) was added to a solution of the compound of Example 49 (540 mg) in methanol (15 ml) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH 6 using 2N hydrochloric acid and then evaporated to dryness in vacuo. The residue was purified by chromatography 5 Column on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to give the title compound as a colorless foam, 340 mg. m / z: 485 (MH +) dH (300 MHz, DMSO-d6): 7.97 (2H, d), 7.55 (2H, d), 7.30 (5H, m), 7.04 (1H, dd), 6.82 (2H , m), 6.56 (1 H, d), 5.36 (2H, s), 4.28 (1 H, s), 3.62 (2H, s), 2.30- 2.62 (8H, m).

EXAMPLES 73 TO 76 The following compounds of the general formula they were prepared by hydrolysis of the corresponding esters, by procedures similar to those used in Example 72. 6 EXAMPLE 73 Acid (+) - 4- (5- {4-f (R, S) -a- (4-benzyl-l-piperazinopropy-3-hydroxybenzylphenyl > -1- tetrazolympbutyric acid.

EXAMPLE 74 Acid (+) - 4-5-f4-rfR, S) -a- (4-benzyl-1-piperaziniP-3-hydroxybenzylphenyl > -2- tetrazolympbutyric.

EXAMPLE 75 Acid (+) - 5- (5-f4-r (R.S) -a- (4-benzyl-1-piperazinyl) -3-hydroxybenzylphenyl> -2- tetrazolyPvaleric.

EXAMPLE 76 Acid (+) - 5- (5-f4-r (R.S) - - (4-benzyl-1-piperaziniP-3-hydroxybenzinophenyl > -2- tetrazolyPvaleric EXAMPLE 77 Acid (+) - 2- (5- { 4-r (R, S) -a- (4-ber_cyl-1-piperazyl-P-3-hydroxylbenzylpheni) - 1 - tetrazole and ethoxyacetic Hydrogen chloride gas was passed through a solution of the first compound of the drawings of Preparation 60 (180 mg) in ethanol (10 ml) and the reaction was stirred at room temperature for one hour. The reaction mixture was then evaporated to dryness in vacuo to give a colorless foam. This material was dissolved in aqueous ethanol (15 ml), sodium hydroxide (40 mg) was added and the reaction was stirred at room temperature for 72 hours. The reaction mixture was acidified to pH 3.5 using 2 N hydrochloric acid solution, rebasified with ammonium hydroxide solution and the mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to give the title compound as a colorless foam, 150 mg. Rf: 0.37 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, DMSO-de): 7.80 (2H, d), 7.58 (2H, d), 7.26 (5H, m), 7.05 (1 H, dd), 6.82 (2H, m), 6.56 (1 H, d), 4.56 (2H, t), 4.28 (1H, s), 3.86 (2H, t), 3.74 (2H, s), 3.46 (2H, s), 2.20-2.45 (8H, m).

EXAMPLES 78 Acid ±) -2- (5-f4-r (R, S) -oc- (4-benzyl-1-piperazin-P-3-hydroxybenzinophenyP-2-tetrazolyPethoxyacetic The title compound was prepared using the second compound of the drawings of preparation 60, following the procedure described in example 77 and was obtained in the form of a colorless foam, (65%).

Rf: 0.34 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, DMSO-d6): 7.97 (2H, d), 7.55 (2H, d), 7.26 (5H, m), 7.05 (1H , dd), 6.82 (2H, m), 6.55 (1H, d), 4.85 (2H, t), 4.24 (1H, s), 4.00 (2H, t), 3.80 (2H, s), 3.45 ( 2H, s), 2.20-2.45 (8H, m).

EXAMPLES 79 TO 82 The following compounds of the general formula were prepared from the corresponding amides (preparations 62 to 65) by procedures similar to that described in example 53 Example 79 5- (5- {4-r (R) -a- (2 (S), 5 (R -4-propyl-2,5-dimethyl-1-piperazinopropymethoxy) -3-methoxybenzylphenyl} - 1 -tetrazoli ethyl ethylvalerate.

EXAMPLES 80 5- (5- (4 -, R) -a-.2, S, 5 (R, -4-butyl-2,5-dimethyl-1-piperaziniP-3-methoxSbencipphenyl) -1-tetrazoliPvalerate of ethyl EXAMPLE 81 - (5-f4-r (R) -a- (2 (S, 5, R-cyclopropylmethyl-2,5-dimethyl-1-piperazinopyr-3-methoxybenzylphenyl> -1-tetrazolyP-valerate) ethyl EXAMPLE 82 5- (5- { 4-r (R.-a- (2 (S), 5 (R.-4- / so-but-1-2,5-dimethyl-1-pperazinone -3- methoxybenzylphenyl-1-tetrzoliethylvalerate EXAMPLES 83 to 86 The following compounds of the general formula: were prepared from the corresponding esters (Example 79 to 82) by procedures similar to those described in Example 36.

EXAMPLE 83 Acid (+ .- 5- (5- (4-r (R.-a- (2 (S), 5 (R.-4-propyl-2,5-dimethyl-1-piperaziniP-3-hydroxyl Benzyl.phenyl) -1-tetrazoliDvaleric.

EXAMPLE 84 Acid (+) - 5- (5-f4 -, (R.-a-.2, S., 5 (R.-4-Butyl-2,5-d.methyl-1-piperaziniP-3-hydroxybenzyl. fer.iP-1 -tetrazoliPvalerico.

EXAMPLE 85 Acid, +) - 5-.5-4-r (R.-a-.2.S), 5 (R.-4-cyclopropylmethyl-2,5-dimethyl-1-piperazinopropyl-3-hydroxybenzinophenyl) - 1 -Valleytetrazoli.

EXAMPLE 86 Acid (+, - 5- (5 ~ f4-., R) -a- (2 (S), 5, R) -4-iso-butyl-2,5-dimethyl-1-piperaziniP-3 HydroxybenzylPenyl &- Tetrazolium EXAMPLE 87 Acid 5- (5- (4-r (R) -a- (2 (S), 5 (R) -2,5-dimethyl-1-piperaziniD-3-hydroxybenzylphenyl > -2-tetrazoliumPvaleric.

H Tris (triphenylphosphine) rhodium (I) chloride (200 mg) was added to a solution of the compound of example 42 (500 mg) in acetonitrile (160 ml) and water (40 ml). The reaction mixture was heated to gentle reflux and the solvent was allowed to slowly distil off. More acetonitrile / water (200 ml, 4: 1 v / v) was added at a rate such as to maintain a standing distillation. After completing the addition of the solvent, the distillation was continued until the volume was reduced to approximately 60 ml. The cooled solution was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated brine. The solution was dried (magnesium sulfate), evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (70/30/4 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 360 mg. m / z: 465 (MH +) Rf: 0.09 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, DMSO-de): 7.98 (2H, d), 7.50 (2H, d), 7.16 ( 1 H, t), 6.74-6.50 (3H, m), 5.26 (1 H, s), 4.70 (2H, t), 3.30 (2H, a), 2.84 (1 H, d), 2.60-2.18 (4H , m), 1.96 (1 H, m), 1.66-1.40 (3H, m), 1.10 (3H, d), 0.86 (3H, d). m / z: 465 (MH +) Found: C, 62.71; H, 7.14; N, 16.95 C25H32N6? 3 1.0H2O requires C, 62.22; H, 7.10; N, 17.41% EXAMPLE 88 Acid (+) - 5- (5-f4-r (R) -a- (2 (S) .5 (R) -4-propyl-2,5-dimethyl-1-piperazin-P-3-hydroxybenzyl pfenil > -1 -tetrazoliPvalerico.

To a solution of the compound of example 87 (350 mg), propionaldehyde (102 μl) and glacial acetic acid (53 μl) in dry dimethylformamide (20 ml) was added, with stirring, sodium triacetoxyborohydride (486 mg). The resulting mixture was stirred at room temperature for 18 hours, after which it was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol) to give the title compound as a beige solid. The compound was further purified on reverse phase polystyrene resin (100% water to 100% acetonitrile in 10% increments) to produce, after lyophilization, the title compound as a white flocculent powder, 273 mg . m / z: 507 (MH +) Rf: 0.18 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, DMSO-de): 7.97 (2H, d), 7.56 (2H, d), 7.12 ( 1 H, t), 6.74-6.50 (3H, m), 4.95 (1 H, s), 4.70 (2H, t), 2.77 (1 H, d), 2.68-2.37 (4H, m), 2.21 (2H , t), 2.08 (2H, m), 1.90 (3H, m), 1.49 (2H, m), 1.35 (2H, m), 1 .08 (3H, d), 0.90 (3H, d), 0.80 ( 3H, d). Found: C, 64.17; H, 7.63; N, 16.07 C28H38N6O3 1.0H2O requires C, 64.10; H, 7.68; N, 16.02% [a] D + 17.6 ° (c = 0.106, methanol).

EXAMPLES 89 AND 90 (5-f4-r (R) -a- (2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperaziniP-3-hydroxybenzylphenyl-2-tetrazoliP-4-methylbenzoate of methyl and - (5-T4-rR-a- (2, S) .5 (R) -4-allyl-2,5-dimethyl-1-piperazinopropylamine-3-hydroxybenzylphenyl-1-tetrazoly-4-methylbenzoate methyl A solution of the compound of preparation 31 (1.07 g), potassium carbonate (855 mg) and methyl 4- (bromomethyl) benzoate (544 mg) in dry acetonitrile (15 ml) was heated to reflux for 18 hours. To the cooled mixture was added tetraethylammonium fluoride (462 mg), the resulting mixture was stirred for 30 minutes and concentrated to a volume of 3 ml in vacuo. The residue was partitioned between ethyl acetate and 2% aqueous sodium hydrogen carbonate solution and the layers were separated. The aqueous phase was extracted with additional ethyl acetate and the combined organic extracts were dried (magnesium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (85/15/1 to 80/20 / 1.5 pentane / isopropanol / ammonium hydroxide) to yield the N-2 isomer, 605 mg. Rf: 0.21 (85/15/1 pentane / isopropanol / ammonium hydroxide) dH (300 MHz, CDCl 3): 8.00 (2H, d), 7.57 (2H, d), 7.43 (1 H, m), 6.80-6.60 ( 3H, m), 5.98-5.80 (1H, m), 5.25-5.05 (3H, m), 4.95 (1H, s), 3.90 (3H, s), 3.43-3.33 (1H, m), 3.00 -2.43 (5H, m), 2.23-2.03 (1H, m), 2.02-1.93 (1H, m), 1.17 (3H, d), 1.00 (3H, d). followed by the N-1 isomer, 160 mg. Rf: 0.10 (85/15/1 pentane / isopropanol / ammonium hydroxide) dH (300 MHz, CDCl 3): 7.98 (2H, d), 7.53 (2H, d), 7.43 (1 H, m), 7.23-7.10 ( 3H, m), 6.73 (2H, m), 6.57 (1 H, s), 5.93-5.77 (1 H, m), 5.25-5.05 (3H, m), 4.95 (1 H, s), 3.90 (3H , s), 3.43-3.33 (1 H, m), 3.00-2.43 (5H, m), 2.23-2.03 (1 H, m), 2.02-1.93 (1 H, m), 1.17 (3H, d), 1.00 (3H, d).

EXAMPLE 91 (5-γ4-r (R) -a- (2 (S), 5 (R) -2,5-dimethyl-1-piperazinopropyl-3-hydroxybenzylpheniP-2-tetrazoli-P-4-methylbenzoate) The compound of the following formula: a procedure similar to that described in Preparation 61 was prepared using the compound of Example 89. Rf: 0.08 (9/1 dichloromethane / methanol) dH (400 MHz, CDCl 3): 8.00 (4H, m), 7.63 (1 H, m), 7.55-7.35 (4H, m), 7.15 (1 H, m), 6.67-6.63 (2H, m), 6.60 (1 H, s), 5.80 (2H, m), 5.25 (1H, m), 3.88 (3H, s), 2.90 (2H, m), 2.63 (2H, m), 2.43 (1 H, m), 2.00 (1 H, m), 1.65 (1 H, m), 1.10 ( 3H, d), 0.90 (3H, d).

EXAMPLE 92 (5- {4-r (R) -a- (2 (S), 5. R. -2.5-dimethyl-1-piperaziniP-3-hydroxybenzophenyl) -1-tetrazoliP-4-methylbenzoate of methyl The compound of the following formula: was prepared by a procedure similar to that described in Preparation 61, using the compound of Example 90. Rf: 0.05 (9/1; dichloromethane / methanol) dH (400 MHz, CDCl 3): 7.97 (2H, m), 7.67 (2H , m), 7.57-7.38 (4H, m), 7.15 (1 H, m), 6.78 (1 H, m), 6.65 (1 H, m), 6.52 (1 H, sa), 5.65 (2 H, s ), 5.28 (1 H, m), 3.90 (3 H, s), 2.90 (2 H, m), 2.67 (1 H, m), 2.53 (1 H, m), 2.38 (1 H, sa), 1.97 ( 1 H, m), 1.62 (1 H, m), 1.13 (3 H, d), 0.93 (3 H, d) EXAMPLE 93 .5-. { 4-r (R.-a- (2 (S), 5, R) -4-benzyl-2,5-dimethyl-1-piperazirtiD-3-hydroxy-benzophenyphenyl-2-tetrazoyl-P-4-ethylbenzoate The compound of the following formula: was prepared by reductive alkylation of the compound of Example 91 with benzaldehyde, using a procedure similar to that described in Preparation 8. Rf: 0.27 (96/4, dichloromethane / methanol) dH (400 MHz, CDCIe): 8.07 (4H, m) , 7.53 (2H, m), 7.43 (2H, m), 7.35-7.10 (6H, m), 6.83-6.65 (3H, m), 5.83 (2H, s), 5.10 (1H, m), 4.83 ( 1 H, sa), 3.90 (3 H, s), 3.87 (1 H, da), 3.23 (1 H, da), 2.77-2.50 (4H, m), 2.08-1.93 (2H, m), 1.10 (6H , m).

EXAMPLE 94 Acid- (5- {4 -, (R.sup.-a- (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazineP-3-hydroxybencipphenyl- 2-tetrazol-P-4-methylbenzoic acid The compound of the following formula: was prepared by hydrolysis of the compound of Example 93 using a procedure similar to that described in Example 19. Rf: 0.40 (76/20/4, dichloromethane / methanol / ammonium hydroxide) m / z: 589 (MH +) dH (400 MHz, DMSO-de): 8.00-7.85 (4H, m), 7.50 (2H, m), 7.38 (2H, m), 7.30-7.03 (6H, m), 6.77-6.60 (3H, m), 6.02 (2H, s), 4.95 (1 H, m), 3.75 (1 H, day), 3. 27 (1 H, d a), 2.73-2.27 (4H, m), 2.03-1.87 (2H, m), 1.00 (6H, m). Found: C, 66.86; H, 6.06; N, 13.12 C 35 H 36 N 6 O 32 25 H 2 O requires C, 66.80; H, 6.49; N, 13.35% EXAMPLE 95 (5-γ4-r (R) -a- (2 (S, 5 (R) -4-benzyl-2,5-dimethyl-1-piperazin-3-hydroxybenzylphenyl} -1- methyl tetrazoliP-4-methylbenzoate The compound of the following formula: was prepared by reductive alkylation of the compound of example 92 with benzaldehyde using similar procedure to that described in preparation 8. Rf: 0.15 (4/5; ethyl acetate / pentane) EXAMPLE 96 Acid- (5- (4-r (R) -a- (2 (S .. 5 (R) -4-benzyl-2,5-dimethyl-1-piperaziniP-3-hydroxybenzylphenyl > -1- tetrazoliP-4-methylbenzoic The compound of the following formula: was prepared by hydrolysis of the compound of Example 95 using a procedure similar to that described in Example 19. m / z: 589 (MH +) dH (300 MHz, DMSO-de): 9.33, (1 H, s), 7.93 (2H , m), 7.70-7.03 (12H, m) 6.65 (3H, m), 5.85 (2H, s), 5.00 (1H, ma), 3.80 (1H, m) 3.20 (1H,), 2.17-1.80 (6H, m), 1.08 (6H, m) . Found: C, 67.73; H, 6.23;, N 12.94. C 35 H 36 N 6 3.2, OH 2 O requires C, 67.28; H, 6.45 N, 13.45%.

EXAMPLE 97 5- (5- (4 -. (R) -a- (2.S). 5 (R-Benzyl-2-methyl-1-piperazinopropyl-3-hydroxybenzylphenyl, -2-tetrazoSi!) Ethyl valerate The compound of the following formula: was prepared using a procedure similar to that described in Example 42, using the compounds of Preparations 43, 44 and 66. Rf: 0.4 (1/1; ethyl acetate / pentane) dH (400 MHz, CDCl 3): 8.02 (2H , d), 7.55 (2H, d), 7.30-7.20 (5H, m) 7.12 (1 H, m), 6.88 (1 H, m), 6.78 (1 H, s), 6.63 (1 H, m) , 4.85 (1 H, sa) 4.64 (2H, t), 4.12 (2H, q), 3.47 (2H, q), 2.87 (1 H, sa), 2.65-2.30 (8H, m), 2.06 (2H, m), 1.69 (2 H, m), 1.24 (3 H, t), 1.11 (3 H, d).

EXAMPLE 98 Acid (+) - 5- (5- (4-r (R) -a- (2 (S), 5 (R.-4-benzyl-2-methyl-1-piperaziniD-3-hydroxybencipfenylj-2 -TetrazoliPvalerico The compound of the following formula. was prepared by hydrolysis of the compound of Example 97, using a procedure similar to that described in Example 19. Rf. 0.25 (80/20/4, dichloromethane / methanol / ammonium hydroxide) m / z: 542 (MH +) dH (400 MHz, DMSO-de): 7.94 (2H, d), 7.56 (2H, d), 7.35-7.15 (5H, m) 7.05 (1 H, dd), 6.80 (2 H, m), 6.57 (1 H, m), 4.64 (3 H, m) 3.40 (2 H, m), 2.84 (1 H, m), 2.60-2.20 (6H, m ), 1.91 (4H, m), 1.40 (2H, t), 1.02 (3H, d). Found: C, 63.09; H, 6.58, N 4.14. C3? H36N6O3. 2.75H2O requires C, 63.03; H, 7.09 N, 14.24%. [a] D + 31 ° (c = 0.1, methanol) EXAMPLE 99. + .- 3-. { 5 -_ (R) -a-.2.S .. 5 (R) -4-allyl-2.5.dimethyl-1-piperazinopropyl-3-hydroxybenzyl-tetrazole P benzene The compound of the following formula: was prepared by desilylation of the compound of preparation 33 using a procedure similar to that described in Example 35. Rf. 0.23 (80/20/3 dichloromethane / methanol / ammonium hydroxide) m / z: 405 (MH +) dH (400 MHz, DMSO-de): 9.35 (1 H, br), 8.16 (1 H, s), 7.82 ( 1 H, m) 7.42 (1 H, m), 7.13 (1 H, t), 6.73 (2 H, m), 6.66 (1 H, m) 5.82 (1 H, m), 5.25 (2 H, m), 5.02 (1 H, sa), 3.38-3.13 (4H, m), 2.93 (1 H, m), 2.82 (1 H, m), 2.68 (2H, m), 2.39 (1 H, m), 2.0 (1 H, m), 1.10 (3H, d), 1.04 (3H, d). [α] D + 25.1 ° (c = 0.1 1, methanol) EXAMPLE 100 Preparation of the benzathine salt of the compound of Example 42 N, N-dibenzylethylenediamine (1.19 g, 4.96 mmol), the compound of Example 42 (5 g, 9.91 mmol) and 5% v / v of water in methyl ethyl ketone (12 ml) were heated to reflux. The clear mixture was allowed to cool to room temperature and was stirred for 48 hours. The white crystalline suspension was removed by filtration, washed with cold solvent (3.1 ml) and dried under vacuum at room temperature for 18 hours. 3.46 g (55%) of the salt was obtained as a white solid with a sudden melting point of 139 ° C. HPLC analysis showed that it was present in 19.7% of dibenzylethylenediamine and 80% of compound of Example 42 by total area analysis. Water was present at 0.3%. This gave a stoichiometric ratio of compound based on 1: 0: 5. Molecular formula C36.3H46-6NI7.o? 3.? C.H.N Theorics% C, 69.14; % H, 7.45; % N, 15.55. Real% C, 68.90; % H, 7.92; % N, 15.56 EXAMPLES 101 to 103 The following compounds of the general formula: were prepared by a procedure similar to that described in Preparation 5, using the corresponding aldehydes (Preparations 67, 69 and 70) and the corresponding piperazine derivatives (of Preparation 26 or of Preparation 66).

EXAMPLE 101, 5-. { 4 -, (R.-a- (2 (S). 5 (R) -4-Benzyl-2,5-dimethyl-1-piperazin-D-3-hydroxy-benzepiphenyl-2-tetrazoli-P-3-methyl-methyl-benzoate EXAMPLE 102 3-.5- (4-r (R) -a- (2 (S) .5 (R.-4-benzyl-2-methyl-1-p »peraziniP-3-hydroxybenzylphenyl > -2- ethyl tetrazole P-propionate EXAMPLE 103 4- (5- (4-r (R) -a-22 (S) -4-benzyl-2-methyl-1-piperazinopropyl-3-hiroxybenzylphenyl-2-tetrazoli-pbutanoate EXAMPLE 104 _5- (4-r (R) -a- (2 (S), 5 .R.-4-benzyl-2,5-dimethyl-1-piperaziniP-3-hydroxybenzylphenyl.) -1- methyl tetrazoliP-3-methylbenzoate The compound of the following formula: was prepared using a procedure similar to that described in Preparation 5, using the compounds of Preparations 26, 44 and 68. Rf: 0.31 (dichloromethane / methanol / ammonium hydroxide; 95/5 / 0.5) m / z: 603 (MH +) EXAMPLES 105-107 The following compounds of the general formula: were prepared by hydrolysis of the corresponding esters using a procedure similar to that described in Example 19 EXAMPLE 105 Acid (5- {4-r.R) -a-.2 (S), 5 R) -4-benzyl-2,5-dimethyl-1-piperazinopropy-3-hydroxybenzyl-phenyl} -2-tetrazoliP-4-methylbenzoic acid EXAMPLE 106 3- (5- (4 -, (R.-a- (2, S), 4-benzyl-2-methyll-1-piperazin-D-3-hydroxy benzylphenyl-2-tetrazolyp- acid. propionic EXAMPLE 107 4-, 5- {4-r (R.-a- (2.S) -4-benzyl-2-methyl-1-piperaziniP-3-hydroxybenzepiphenyl-2-tetrazole-butanoic acid.

EXAMPLE 108 Acid (5- { 4-_. R_-a- (2.S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperaziniP-3-hydroxybencipphenyl-tetrahydroxy-4- methylbenzoic The compound of the following formula: was prepared using a procedure similar to that described in Example 19, using the compound of Example 104. R: 023 (dichloromethane / methanol / ammonium hydroxide; 95/5 / 0.5) m / z: 589 (MH +) dH (300 MHz, d6.DMSO): 7.83 (1 H, d), 7.68 (3 H, d), 7.55 (2 H, d), 7.41 (1 H, t), 7.35-7.09 (1 H, m), 6.68 (3 H, m ) 5.88 (2H, s), 5.00 (1 H, s), 3.77 (1 H, d), 3.25 (1 H, d), 2.60 (4H, m), 2.00 (1 H, m, 1.88 (1 H , mj, 1.03 (6H, m).

Found: C, 69.21; H, 6.04, N 13.84. C 35 H 36 N 6 O 3 H 2 O requires C, 69.29; H, 6.31 N, 13.85%.

EXAMPLE 109 The opioid delta agonist activity of several compounds in vas deferens of mice (as described below) was determined with the following results: PREPARATIONS PREPARATION 1 (-) - (2R, 5S) -1-allyl-2,5-dimethylpiperazine H It was heated at 85 ° C, with stirring, trans-2,5-dimethylpiperazine (600 g), suspended in toluene (1200 ml), at which temperature the solid was completely dissolved. The solution was allowed to cool gradually to room temperature with stirring, allowing the solid to precipitate slowly, and then cooled to 10 ° C using an ice bath. The solid was filtered, washed with more cold toluene (250 ml) and dried under vacuum (50 ° C) overnight to give a crystalline yellow solid (518.5 g). The recrystallized trans-2,5-dimethylpiperazine (259.5 g) was suspended in cyclohexane (2.59 I) at room temperature. Sodium hydroxide solution (5M, 500 ml) was added in one portion with tretrabutylammonium chloride (4.3 g) and the reaction mixture was stirred while adding allyl bromide solution (302.4 g) in cyclohexane (300 ml) in a current, for about 30 minutes. The temperature of the reaction mixture slowly increased to 33 ° C for 30 minutes and was stirred for an additional 1 hour. Analysis by TLC showed that the organic phase contained most of the mono-allylated product, with traces of bis-allylated impurities and starting material. The aqueous extract contained most of the starting material and some mono-allylated product. The two phases were separated and the aqueous phase was stirred with more cyclohexane (2.5 I). Allyl bromide (82.5 g) in cyclohexane (100 ml) and sodium hydroxide solution (5M) were added., 136 ml) and the mixture was stirred at room temperature for 1 hour. The phases were separated and the two cyclohexane phases were combined. The cyclohexane phase was washed countercurrently with NaOH (1 M, 200 ml) to remove traces of the starting material and this wash was added to the aqueous phase and kept on one side. The organic extracts (which contained only mono- and bis-allylated material) were stirred with H2O (1.5 I) and the pH of the mixture was adjusted precisely to 8 using concentrated HCl. TLC showed that the aqueous extract contained mono with some traces of bis. The organic extract contained bis with some traces of monkey. The layers were separated and the pH of the aqueous extract was adjusted to 13.5 using NaOH (10 M) and extracted with CH2Cl2 (4 x 1 1). The aqueous washes previously retained were extracted with CH2Cl2 (4 x 11). The combined organic extracts were dried over MgSO4 and distilled (50 ° C) to yield racemic 1-allyl-2,5-dimethylpiperazine as a mobile yellow oil (278.9 g, 80%). [Rf = 0.4 (CH2Cl2.MeOH / NH3; 80: 20: 1) A solution of racemic 1-allyl-2,5-dimethylpiperazine (537.7 g) in acetone (1075 ml) was added in one portion to a stirred solution of (1 R, 3S) - (+) - camphoric acid in acetone (5.2 I) at 40 ° C. Stirring was continued at 40 ° C and a white precipitate began to form after approximately five minutes, which soon became very thick. The reaction mixture was stirred under gentle reflux for 1 hour before cooling to 10 ° C in an ice bath, and filtered. The precipitate was suspended and washed with more acetone (2 I), then washed on the filter layer with more acetone (1 I). The (+) - (2S, 5R) -1-allyl-2,5-dimethylpiperazine camphoric acid salt was dried under vacuum (60 ° C) overnight to yield a white solid (577 g). The crude (-) - (2R, 5S) -1-allyl-2,5-dimethylpiperazine enriched (185.5 g) was redissolved in acetone (370 ml) and added to a solution of di-p-tolyl-D- acid Tartaric monohydrate (486.5 g) in acetone (6.8 L) at 40 ° C. The reaction mixture was heated to gentle reflux for 1 hour. The reaction mixture was cooled to 10 ° C in an ice bath, filtered, washed with more acetone (3 x 500 ml) and dried under vacuum (60 ° C) overnight to produce the tartrate salt in the form of a solid white (466.4 g, mp 191.7 ° C). The di-p-tolyl-D-tartrate salt (466.4 g) was completely dissolved in methanol (10 I) at gentle reflux. The resulting light yellow solution was distilled at atmospheric pressure to about half of its original volume. The resulting clear solution was allowed to cool to room temperature and was stirred for 72 hours, during which time a thick white precipitate formed. The precipitate was filtered, washed with more methanol (2 x 500 ml) and dried under vacuum (50 ° C) overnight to produce a white solid (382.1 g, m.p. 194.3 ° C).

A solution of sodium hydroxide (2M, 3 I) and dichloromethane (3 I) were stirred together at room temperature. The above di-p-tolyl-D-tartrate salt (371.4 g) was added in one portion and the mixture was stirred for one hour. The phases were separated and the aqueous phase was washed with more CH 2 Cl 2 (3 x 11). The organic extracts were combined and evaporated in vacuo to yield the title compound (-) - (2R-5S) -1-allyl-2,5-dimethylpiperazine as a mobile yellow oil (104.3 g). Rf: 0.30 (93/7/1; dichloromethane / methanol / ammonium hydroxide) [a] D 54.8 ° (c = 1.19, ethanol).

PREPARATION 2 2-4-r.R. -1-_ (2S, 5R.-4-allyl-2,5-dimethyl-1-piperazinylM (3-methoxyphenyl-D-methylphenyl-4,4-dimethyl-4,5-dihydro-1,3-oxazole A solution of the Compound of Preparation 1 (1.5 g), benzotriazole (1.16 g) and 4 - [(4,4-dimethyl) -1, 3-oxazolin-2-yl] -banzaldehyde (1.98 g) (preparation 45) in toluene (25 ml) was heated to reflux with azeotropic removal of water 3.5 hours. The solution was cooled to room temperature and added to a cold (-10 ° C) solution of 3-methoxyphenylmagnesium bromide (prepared from 3.64 g of the corresponding bromide and 0.475 g of magnesium filings) in tetrahydrofuran (40 ml). at a tai speed to maintain the internal temperature in the range of -10 ° C to 0 ° C. The resulting solution was stirred at 0 ° C for 15 minutes, at room temperature for 30 minutes and then quenched with 2N hydrochloric acid solution. The layers were separated and the aqueous solution was extracted with diethyl ether (2x). The combined organic extracts were discarded. The aqueous solution was basified to pH 9 and extracted with diethyl ether (3x). The combined extracts were washed successively with water, 2N sodium hydroxide, water and brine. The organic extracts were dried (Na2SO) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (30% Et2O / CH2CI2 + 1% MeOH) to yield the title compound. The aS diastereomer was also isolated. m / z: 476 (MH +) PREPARATION 3 4-í (R) -1 - 2S. 5R) -4-allyl-2,5-dimethyl-1-piperazinylM - (3-methoxyphenimethylbenzonitrile Phosphorus oxychloride (4.04 ml) was added dropwise to a stirred suspension of the compound of preparation 2 (4.93 g) in dry pyridine (30 ml). The dark brown solution was stirred at 85-95 ° C for 18 hours, cooled in an ice bath and quenched with excess 2 N sodium hydroxide solution. Extraction with dichloromethane followed by drying (sodium sulfate) and evaporation under vacuum, gave a semi-solid brown. The residue was purified by flash chromatography on silica gel (20% diethyl ether in dichloromethane) to yield the title compound, 3.21 g. m / z: 376 (MH +) Rf: 0.42 (70/30 / 0.1 dichloromethane / diethyl ether / methanol) PREPARATION 4 (a) (+) - 4-cyano-r (RS) -a- (4-benzyl-1 -piperaziniD-3-fer-butyl-methyl-silyloxybenzinbenzene. t-butyldimethylsilyl] A solution of (±) 1-benzylpiperazine (8.8 g), benzotriazole (5.95 g) and 4-cyanobenzaldehyde (6.55 g) in toluene (150 ml) was heated to reflux with azeotropic removal of water for 30 minutes. The solution was cooled to room temperature and added to a cold (-25 ° C) solution of 3-tert-butyldimethylsilyloxyphenylmagnesium bromide (prepared from 28.7 g of the corresponding bromide and 2.43 g of magnesium filings) in tetrahydrofuran (100 ml. ) at an interval such as to maintain the internal temperature in the range of -20 ° C. The resulting solution was stirred at 0 ° C for 15 minutes, at room temperature for 30 minutes and then quenched with saturated aqueous ammonium chloride solution. The layers were separated and the aqueous solution was extracted with diethyl ether (2 × 200 ml). The combined organic extracts were dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (5-20% ethyl acetate / hexane) to yield the title compound, 17.0 g. m / z: 498 (MH +) dH (400 MHz, CDCl 3): 7.72 (2H, d), 7.56 (2H, d), 7.32-7.10 (6H, m), 6. 95 (1 H, d), 6.86 (1 H, s), 6.66 (1 H, d), 4.40 (1 H, s), 3.44 (2 H, s), 2.46-2.20 (8 H, m), 0.90 ( 9H, s), 0.14 (6H, s). (b) f ±) -r (R, S) -a- (4-benzyl-1-piperaziniP-3-tert-butyldimethylsilyloxybenzyl phenyltetrazole) A solution of the first compound of part (a) (8.5 g), dibutyltin oxide (1.05 mg) and trimethylsilyl azide (4.3 g) in dry toluene (50 ml) were heated together under gentle reflux for 5 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by silica gel column chromatography (80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 8.06 g. m / z: 541 (MH +) dH (400 MHz, CDCl 3): 7.90 (2H, d), 7.48 (2H, d), 7.34-7.20 (5H, m), 7.14 (1H, t), 7.00 (1 H, d), 6.94 (1 H, s), 6.68 (1 H, d), 4.32 (1 H, s), 3.56 (2 H, 's), 2.50-2.28 (8 H, m), 0.90 (9 H, s), 0.16 (6H, s).

PREPARATION 5 + -4-cyano-r (R) -a- (2fS), 5 (R) -4-allyl-2,5-dimethyl-1-piperaziniP-3-tert-butyldimethylsilyloxybencipbenzene.

A solution of (-) - (2R, 5S) -1-allyl-2,5-dimethylpiperazine (21.6 g), benzotriazole (16.68 g) and 4-cyanobenzaldehyde (18.35 g) in toluene (800 ml) was heated at gentle reflux with azeotropic removal of water for 3 hours. The solution was cooled to room temperature and added to a cooled solution (-10 ° C) of 3-tert-butyldimethylsilyloxyphenylmagnesium bromide (prepared from 79 g of the corresponding bromide and 6.8 g of magnesium filings) in tetrahydrofuran (500 ml. ) at such a speed as to maintain the internal temperature in the range of 10 ° C to 0 ° C. The resulting solution was stirred at 0 ° C for 15 minutes, at room temperature for 30 minutes and then quenched with saturated aqueous ammonium chloride solution. The layers were separated and the aqueous solution was extracted with diethyl ether (2x200 ml). The combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (5-20% ethyl acetate / dichloromethane) to yield the title compound, 4 - [(R) -a- (2 (S), 5 (R) -4-Allyl-2,5-dimethyl-1-piperazinyl) -3-ferc-butyldimethylsilyloxybenzyl] cyanobenzene, 32.9 g. m / z: 476 (MH +) Rf: 0.35 (90/10/2, hexane / ethyl acetate / diethylamine) Found: C, 72.26; H, 8.78; N, 8.09. C29H41N3Si.3 / 10 EtOAc requires C, 72.23; H, 8.71; N, 8.37%. [α] D + 22.9 ° (c = 0.1 12, methanol).

PREPARATION 6 4-ff R) -1-r (2 (S 5 R -alyl-2,5-dimethyl-1-piperazinop P-1 - (3-bdroxypheni Prnenylbenzonitrile.

A solution of the compound of preparation 5 (4.75 g) and tetraethylammonium fluoride (3.70 g) in tetrahydrofuran (100 ml) was stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (hexane to ethyl acetate) to give the title compound, 3.46 g. m / z: 362 (MH +) Rf: 0.21 (1/1 hexane / ethyl acetate) PREPARATION 7 4 -, (R. -1 -_ (2S.5R.-2,5-dimethyl-1-piperaziniP-1 -I3- hdroxifeniPmetinbenzonitrilo.

Tris (triphenylphosphine) rhodium chloride (1) (1.0 g) was added to a solution of the compound of preparation 6 (3.37 g) in acetonitrile (80 ml) and water (20 ml). The reaction mixture was heated to gentle reflux and the solvent was allowed to slowly distil off. More acetonitrile / water (100 ml, 4: 1 v: v) was added at a rate such as to maintain a standing distillation. After completing the addition of the solvent, distillation was continued until the volume was reduced to approximately 50 ml. The cooled solution was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 2.48 g. m / z: 322 (MH +) Rf: 0.20 (97/3/1 dichloromethane / methanol / ammonia) PREPARATION 8 4- R.-1 -_ (2S.5R) -4-ethyl-2,5-dimethyl-1 -piperaziniPI-1-3-hydroxypheni-Primethyl-benzonitrile.

To a solution of the compound of preparation 7 (482 mg) in acetonitrile (132 mg) in tetrahydrofuran (10 ml) containing glacial acetic acid (100 mg) was added sodium triacetoxyborohydride (636 mg). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated brine. The organic phase was dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (100% dichloromethane to 6% methane / dichloromethane) to yield the title compound as a white foam, 295 mg. m / z: 350 (MH +) Rf: 0.32 (93/7/1 dichloromethane / methanol / ammonia) PREPARATIONS 9 TO 13 The following compounds of the general formula: or salts thereof, were prepared from the compound of preparation 7, by reductive alkylation with the appropriate aldehyde by procedures similar to those used in preparation 8. solvent system dichloromethane / methanol / ammonia PREPARATION 9. KRM -r (2S, 5R) -4-propyl-2,5-dimethyl-1-piperaziniPI-1 - (3-hydroxy-phenyl-phenyl-benzonitrile.

PREPARATION 10. Tf R) -1-r (2S, 5R) -4-benzyl-2,5-dlmethyl-1-piperazinopi-1 - (3-hydroxy-phenyl-phenyl-1-benzonitrile.

PREPARATION 11. ff R.-1-rf2S, 5R) -2,5-dimethyl-4-f 1.3-thiazol-2-ylmethyl-1-piperazinyl-1-f3-hydroxy-phenyl-benzonitrile.

PREPARATION 12. Ff R -rf2S.5R) -2.4.5-trimethyl-1-piperazinophenyl-3-hydroxy-phenyl-phenyl ether.

PREPARATION 13. Acid (2S .5R) -4-.f R) -1-f4-cyanopheniP-1 -f3-hydroxypheniPmetip-2,5-dimethyl-1 • piperazinylacetic acid PREPARATION 14 4-Ff R) -1-rf2fS, 5R) -2,5-dimethyl-1-piperaziniP-1-f3-f-tert-butyldimethylsilyloxy) phenylPetipbenzonitrile.

Tris (triphenylphosphine) rhodium (I) chloride (0.77 g) was added to a solution of the compound of preparation 5 (10 g) in acetonitrile (80 ml) and water (20 ml). The reaction mixture was heated to gentle reflux and the solvent was allowed to slowly distil off. More acetonitrile / water (100 ml, 4: 1 v / v) was added at a rate such as to maintain a standing distillation. After the addition of the solvent was complete, the distillation was continued until the volume was reduced to approximately 50 ml. The cooled solution was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the organic phase was dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (90/10/2 dichloromethane / methanol / ammonium hydroxide) to yield the title compound, 8.60 g. m / z: 436 (MH +) Rf: 0.31 (93/7/1 diclomethane / methanol / ammonia) PREPARATION 15 4-. f R) -1 -IT2f S, 5R) -4-acetyl-2,5-dimethyl-1-piperaziniP-1 - (3 -tetrabutyldimethylsilyloxy) phenylmethylenebenzonitrile.

A solution of the compound of preparation 14 (870 mg), triethylamine (303 mg) and acetic anhydride (224 mg) in dichloromethane (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane (3x50 ml). The combined extracts were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate) to give the title compound, 781 mg. m / z: 478 (MH +) Rf: 0.43 (ethyl acetate) PREPARATION 16 4-ff R.-1 -. (2f S, 5R) -4-acetyl-2,5-dimethyl-1-piperazinyl-1-f3- (hydroxypheniPmetiPmetinbenzonitrile.

To a solution of the compound of preparation 15 (775 mg) in tetrahydrofuran (19 ml) was added a solution of tetraethylammonium fluoride (600 mg) in water (1 ml) and the resulting mixture was stirred at room temperature for 22 hours. The mixture was partitioned between ethyl acetate and water and the layers separated. The organic extracts were washed with water and saturated brine solution, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate) to yield the title compound, 616 mg. m / z: 364 (MH +) Rf: 0.27 (ethyl acetate) PREPARATION 17 4 - (R) -1 -ff2S, 5R) -4-cyclopropylmethyl-2,5-dimethyl-1-piperazinyl-1-f3- (tert-butyldimethylsilyloxpfeniPmethylmethylbenzonitrile.

To a solution of the compound of preparation 14 (870 mg) and cyclopropanecarboxaldehyde (168 mg) in tetrahydrofuran (20 ml) containing glacial acetic acid (132 mg) was added sodium triacetoxyborohydride (848 mg). The mixture was stirred at room temperature for 1.5 hours, then poured into ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic phase was dried (MgSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (100% hexane to 50% hexane / ethyl acetate) to give the title compound as a gum, 789 mg. m / z: 490 (MH +) Rf: 0.57 (ethyl acetate) PREPARATIONS 18 TO 20 The following compounds of the general formula: or salts thereof, were prepared from the compound of preparation 14 by reductive alkylation with the appropriate aldehyde by procedures similar to those used in preparation 17.

PREPARATION 18. ff R) -1-rf2S, 5R) -4-f4-fluorobenzPI-2,5-dimethyl-1-1-piperazinophenyl-3-f-tert-butyldimethylsilyophexypheni-P-methylbenzonitrile.

PREPARATION 19. TfR) -1-rf2S, 5R) -4-f4-methoxybenzyl-2,5-dimethyl-1-piperaziniP1-1-f3-f-tert-butyldimethylsilyl oxyphenylDmethylbenzonitrile.

PREPARATION 20. ff R) -1-K2S .5R.-4-f4-trifluoromethylbenzyl, -2,5-dimethyl-1-piperazinin-1- (3-fterc-butyldimethylsilyophexypheniP-methylenebenzonitrile.

PREPARATION 21 4-.f R) -1-rf2S, 5R) -4-cyclopropylmethyl-2,5-dimethyl-1-piperazinyl-1-f3-hydroxy-phenyl-p-methyl-p-tributybenitrile.

To a solution of the compound of preparation 17 (786 mg) in tetrahydrofuran (18 ml) was added a solution of tetraethylammonium fluoride (592 mg) in water (2 ml) and the resulting mixture was stirred at room temperature for 20 hours. The mixture was partitioned between ethyl acetate and water and the layers separated. The organic extracts were washed with water and saturated brine solution, dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate) to yield the title compound, 617 mg. m / z: 376 (MH +) Rf: 0.35 (ethyl acetate) PREPARATIONS 22 TO 24 The following compounds of the general formula: or salts thereof, were prepared by distillation of the corresponding silyl esters (see Preparations 18 to 20) by procedures similar to that described in Preparation 21.

PREPARATION 22. T (R) -1 - (2S, 5R) -2,5-d.methyl-4-r4-fluorobencip-1-piperazinyl-1 - (3-hydroxy-phenyl) -piphenylbenzonitrile.

PREPARATION 23. Tf R) -1-f2S, 5R) -2,5-dimethyl-4-r4-methoxy-benzyl-1-piperazinyl-1- (3-hydroxy-phenyl-phenyl-benzonitrile.

PREPARATION 24. [(R) -1 - (2S, 5R) -2,5-Dimethyl-4- [4- (trifluoromethyl) benzyl] -1-piperazinyl-1 - (3-hydroxyphenyl) methyl] benzonitrile.

PREPARATION 25 (2S, 5R) -1-Allyl-4-benzyl-2,5-dimethylpiperazine To a suspension of the (+) - (2S, R) -1-allyl-2,5-dimethylpiperazine camphoric acid salt of preparation 1 (78.2 g) and benzaldehyde (26.5 g) in tetrahydrofuran (500 ml) which containing glacial acetic acid (2 ml), sodium triacetoxyborohydride (93.3 g) was added in portions over 10 minutes. The resulting mixture was stirred at room temperature for 4 hours. The reaction was partitioned between ethyl acetate (1500 ml) and aqueous sodium hydroxide (750 ml of a 2 N solution). The layers were separated and the organic phase was washed with 10% sodium metabisulfite solution (200 ml) and the saturated brine solution. The organic layer was dried (MgSO 4) and evaporated to dryness in vacuo to give the title compound, 52.1 g. m / z: 245 (MH +) Rf: 0.63 (93/7/1 dichloromethane / methanol / ammonium hydroxide) PREPARATION 26 f -) - (2R, 5S) -1-benzyl-2,5-dimethylpiperazine Tris (triphenylphosphine) rhodium (I) chloride (3 g) was added to a solution of the compound of preparation 25 (52.1 g) in acetonitrile (400 ml) and water (80 ml). The reaction mixture was heated to gentle reflux and the solvent was allowed to slowly distil off. More acetonitrile / water was added (250 ml; 4: 1 v / v) at a speed such as to maintain a stationary distillation. After completing the addition of the solvent, the distillation continued until the volume was reduced to approximately 200 ml. The cooled solution was partitioned between ethyl acetate and hydrochloric acid 2 N. The layers were separated and the organic phase was extracted with more 0.5N hydrochloric acid. The combined aqueous extracts were basified with solution 2 N of sodium hydroxide and extracted in dichloromethane. The combined organic extracts were dried (MgSO 4) and evaporated to dryness in vacuo to yield the title compound, 38.2 g. m / z: 205 (MH +) Rf: 0.27 (93/7/1 dichloromethane / methanol / ammonia) [a] D -113 ° C (c = 0.2, methanol) PREPARATION 27, (RH-f2S, 5R) -2,5-dinrtethyl-4-benzyl-1-piperazinyl-1 - (3-tert-butyldimethylsilyl-D-oxyphenyl-phenyl-N-benzonitrile, and ff SM -f2S, 5R) -2.5 -Dimethyl-4-benzyl-1-piperazinyl-1-f3-tert-butyldidmethylsilyPoxypheniPmetinbenzonitrile.

A solution of the compound of preparation 26 (10.2 g), benzotriazole (5.95 g), and 4-cyanobenzaldehyde (6.55 g) in toluene (150 ml) was heated to reflux with azeotropic removal of water for 3 hours. The solution was cooled to room temperature and a cold solution (-25 ° C) of 3-tert-butyldimethylsilyloxyphenyl magnesium bromide (prepared from 28.7 g of the corresponding bromide and 2.4 g of magnesium filings) in tetrahydrofuran ( 100 ml) at a speed such as to maintain the internal temperature at -25 ° C. The resulting solution was stirred at 0 ° C for 15 minutes, at room temperature for 30 minutes and then quenched with 2N sodium hydroxide solution. The layers were separated and the aqueous solution was extracted with ethyl acetate (2x). The combined organic extracts were washed with water and brine. The organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (100% dichloromethane to 10% ethyl acetate / dichloromethane) to give the title compounds. The aR diastereomer was the first to elute, 17.38 g m / z: 526 (MH +) Rf: 0.62 (3/1 hexane / ethyl acetate). The diastereomer S was also isolated and eluted in second place, 2.61 g. m / z: 526 (MH +) Rf: 0.53 (3/1 hexane / ethyl acetate) PREPARATION 28 rfR.-a-f2 (S), 5fR, -4-benzyl-2,5-dimethyl-1-piperaziniP-3-f-fer- butyldimethylsilyoxy-phenylbenzyl-tetrazol.

A solution of the first compound of preparation 27 (7.88 g), dibutyltin oxide (750 mg) and trimethylsilyl azide (3.45 g) in dry toluene (50 ml) were heated together at gentle reflux for 5.5 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (85/15/2 dichloromethane / methane / ammonium hydroxide) to yield the title compound, 7.45 g. m / z: 569 (MH +) Rf: 0.44 (80/20/3 dichloromethane / methanol / ammonia) PREPARATION 29 and 30 2-, 2-f5-4-, f R) -1 -rf2S, 5R, -4- Benzyl-2,5-d-methyl-1-piperazinyl M -f3-hydroxyphen-P -methylphenyl-2H-1,2,3,4-tetrazol-2-iPethoxy-1-acetonitrile and 2-f2- (5-4-r (S) - 1-r (2S, 5R) -4-benzyl-2,5-dimethyl-1-piperazinyl-3-hydroxy-phenyl-2H-1,2,3,4-tetrazol-1-iPethoxy-acetonitrile A solution of the compound of preparation 28 (2.12 g), 5-bromo-3-oxopentanenitrile (620 mg) and potassium carbonate (1.38 g) in acetonitrile (40 ml) was heated to gentle reflux for 2.5 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with more ethyl acetate. The combined organic extracts were washed with water, saturated brine solution, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was dissolved in tetrahydrofuran (20 ml) and tetraethylammonium fluoride (1.48 g) in water (2 ml) was added. The mixture was stirred at room temperature for 20 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with water and saturated brine solution, dried (MgSO 4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (100% hexane to 60% ethyl acetate / hexane) to yield the N-2 isomer, 1.43 g, followed by the N-1 isomer, 137 mg. Data for the N-2 isomer: m / z: 538 (MH +) Rf: 0.26 (1/1 ethyl acetate / hexane) Data for the N-1 isomer: m / z: 538 (MH +) Rf: 0.16 (1 / 1 ethyl acetate / hexane) PREPARATION 31 4-5-rfR) -a-f2fS), 5fR) -4-allyl-2,5-dimethyl-1-piperaziniP-3-tert-butyldimethylsilyloxybencip-tetrazoline-P-benzene A solution of the compound of preparation 5 (8.1 g), dibutyltin oxide (3.0 g) and trimethylsilyl azide (9.96 g) in dry toluene (60 ml) was heated at 80 ° C for 72 hours under nitrogen. To the cooled reaction mixture was added 880 ammonium hydroxide solution and the layers were separated. The aqueous solution was diluted with water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water and saturated brine, dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (90/10/2 to 80/20/3 dichloromethane / methanol / ammonia) to yield the title compound, 7.76. 9-m / z: 519 (MH +) Rf: 0.40 (80/20/3 dichloromethane / methanol / ammonia) PREPARATION 32 3-cyano-, (R, -a- (2 (S), 5 (R.-4-allyl-2,5-dimethyl-1-piperazinyl) -3-tert-butyldimethylsilyloxybenzylbenzene The compound of the following formula: was prepared by a procedure similar to that used in preparation 5 but using 3-cyanobenzaldehyde. m / z: 476 (MH +) Rf 0.35 (90/10/2, hexane / isopropanol / ammonium hydroxide) Found: C 72.68; H, 8.71, N, 8.28. C29H41N3OSi requires C, 73.21; H, 8. 69; N, 8.83%.

PREPARATION 33 f +) - 3-. { 5-rfR) -a-f2fS), 5fR) -4-allyl-2,5-dimethyl-1-piperaziniP-3-tert-butyldimethylsilyloxybenzyl-tetrazolipbenzene A mixture of the compound of preparation 32 (5 g), azidotrimethylsilane (2.67 g) and dibutyltin oxide (0.94 g) in toluene was heated, with stirring, at 70 ° C for 72 hours. The cooled reaction mixture was poured into ammonium hydroxide and ethyl acetate and the layers were separated. The ammonium hydroxide solution was diluted with water and extracted with more ethyl acetate (2 x). The combined organic extracts were washed with saturated brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane / methanol / ammonium hydroxide; 80/20/3) to yield the title compound, 4.91 g. m / z: 519 (MH +) Rf: 0.25 (80/20/3, ethyl acetate / methanol / ammonium hydroxide) [a] D + 22.6 ° (c = 0.124, methanol) Found: C 64.71; H, 8.16; N, 15.70. C29H42N6OS¡. H2O requires C, 64.89; H, 8.26; N, 15.66%.

PREPARATION 34 (+ -4-ffR) -1-r (2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinophenyl-methyl-3-methoxyphenyl-phenyl-methylbenzoate.

A solution of the compound of preparation 1 (11.55 g), benzotriazole (8.93 g) and methyl 4-formylbenzoate (12.32 g) in toluene (100 ml) was heated to reflux with azeotropic removal of water for 3 hours. The solution was cooled and added to a cooled solution (-20 ° C) of 3-methoxyphenylmagnesium bromide (prepared from 28.05 g of 3-bromoanisole and 3.65 g of magnesium filings) in tetrahydrofuran (100 ml) to a speed such as to maintain the internal temperature in the range of -20 ° to -15 ° C. The resulting solution was stirred at -20 ° C for 5 minutes and then warmed to room temperature and quenched with saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the aqueous solution was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (Hexane to 50% ethyl acetate / hexane) to yield the title compound, 27.95 g). m /: 409 (MH +) Rf: 0.31 (95/5 / 0.5, hexane / isopropanol / ammonium hydroxide) [a] D + 20.7 ° (c = 0.145, methanol) Found: C, 71.12; H, 7.66, N, 6.58. C25H32N2O3. 1/5 H2O requires C, 71. 13; H, 6.67; N, 6.58%.

PREPARATION 35 F +) - 4-rfRH-rf2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinopropyl-1-f3-methoxy-phenyl-phenyl-benzoic acid To a solution of the compound of preparation 34 (27.9 g) in methanol (200 ml), aqueous 2N sodium hydroxide solution was added. The resulting suspension was stirred at room temperature for 20 hours and then at 50 ° C for 2 hours. Solid sodium hydroxide (3.2 g) was added and the mixture was heated at 50 ° C for an additional hour. The cooled solution was evaporated to dryness and the residue was purified by column chromatography on silica gel (dichloromethane / methanol / ammonium hydroxide; 77/20/3) to produce the title compound, 1.06 g. dH (300 MHz, CDCl 3): 7.97 (2H, d), 7.52 (2H, d), 7.23 (1H, m), 6.79 (3H, m), 6.60 (1H, vsa), 5.91 (1H, m), 5.23 (3H, m), 3.77 (3H, s), 3.41 (1 H, dd), 3.02 (1 H, dd), 2.90 (1 H, m), 2.80 (1 H, m), 2.64 (2H, m), 2.28 (1 H, m), 2.05 (1 H, m), 1.19 (3H, d), 1 .05 (3H, d). m / z: 395 (MH +) [a] D + 17.1 ° c = 0.105, methanol.

PREPARATION 36 5- (4-, (R) -1-rf2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl-M -f3-methoxyphenyl-p-methylphenylcarboxamido) ethyl pentanoate A solution of the compound of preparation 35 (2512 g), 1-h id roxy benzotriazole (1.55 g), diisopropylethylamine (2.44 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1464 g) in dry dichloromethane (30 ml) was stirred under nitrogen for 1 hour. To this mixture was added ethyl 5-aminovalerate.HCl (1.39 g) and more dichloromethane (10 ml). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (100 ml) and washed with water (20 ml). The organic solution was dried (sodium sulfate) and evaporated in vacuo. The brown residue was purified by column chromatography on silica gel (98/2, dichloromethane / methanol) to yield the title compound, 2965 g. m / z: 522 (MN +) Rf: 0.31 (95/5, dichloromethane / methanol) PREPARATION 37 4-, f R.-1-rf2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinylM -, 3 methyl-methyl-butyldimethylsilyloxy-phenylbenzoate A solution of (-) - (2R, 5S) -1-aIiI-2,5-dimethylpiperazine (22.26 g), benzotriazole (17.18 g) and methyl 4-formylbenzoate (23.7 g) in toluene (400 ml) was heated at reflux with azeotropic removal of water for 3 hours. The solution was cooled and added to a cooled (-20 ° C) solution of 3-ferc-butyldimethylsilyoxyphenylmagnesium bromide (prepared from 82.9 g of the corresponding bromide and 7.29 g of magnesium filings) in tetrahydrofuran (300 ml) at a speed such as to maintain the internal temperature in the range of -20 to -15 ° C. The resulting solution was stirred at -20 ° C for 1.5 hours and then warmed to room temperature and quenched with saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the aqueous solution was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were dried (MgSO4) and dried. they evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel (85/15/2 hexane / ethyl acetate / diethyl amine) to give the title compound, 54.45 g. m / z: 509 (MH + Rf: 0.44 (93/7/1 dichloromethane / methanol / ammonium hydroxide) PREPARATION 38 Acid f + .- 4-ff R.-1-rf2S.5R) -4-allyl-2,5-dimethyl-1-piperazinyl-l-3-hydroxy-phenyl-pentambenzoic To a solution of the compound of preparation 37 (54.45 g) in methanol (150 ml) and dioxane (100 ml), sodium hydroxide (214 ml of 5 N aqueous solution) was added. The resulting solution was stirred at room temperature for 18 hours, cooled to 0 ° C and neutralized to pH 7-8 with hydrochloric acid. The solution was evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel using gradient elution (95/5 / 0.5 to 80/20/3 dichloromethane / methanol / ammonium hydroxide) to yield the title compound. title, 25.98 g. m / z: 381 (MH +) Rf: 0.14 (80/20/3 dichloromethane / methanol / ammonium hydroxide) [a] D + 25.4 ° (c = 0.12, methanol) PREPARATION 39 f + .- 2-f4-ff R) -1-rf2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl-methyl-3-hydroxy-phenyl-methylcarboxamido) methyl acetate A solution of the compound of preparation 38 (1 1.3 g), 1-hydroxybenzotriazole (7.22 g), diisopropylethylamine (21.4 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.83 g) and hydrochloride glycine methyl ester (4.48 g) in dry dichloromethane (150 ml), was stirred at room temperature for 48 hours. The solution was washed with water and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (93/2 / 0.5 ethyl acetate / methanol / ammonia) to give the title compound, 12.8 g. m / z: 452 (MH +) Rf: 0.4 (95/5 / 0.5 ethyl acetate / methanol / ammonia) [a] D + 20.8 ° (c = 0.13, methanol) PREPARATION 40 2-f4-fR) -1-rf2S, 5R.-4-allyl-2,5-d.methyl-1-piperazinylM -, 3-fer-butyldimethylsilylphenylphenyl, -phenylcarboxamido) acetate methyl A solution of the compound of preparation 39 (10 g), imidazole (1.58 g) and chlorotercbutyldimethylsilane (3.5 g) in dichloromethane (60 ml) was stirred under nitrogen for 18 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed successively with water (50 ml) and hydrogen 69 saturated aqueous sodium carbonate (50 ml), dried over sodium sulfate and evaporated in vacuo to yield the title compound, 12.29 g. m / z: 566 (MH +) Rf: 0.62 (95/5 / 0.5 dichloromethane / methanol / ammonia) PREPARATION 41 2-f2-f5-4-rf R) -1-rf2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl M -f3-hydroxy-phenyl-phenyl-2H-1,2,3,4-tetrazole -2-iPethoxy1acetonitrile A solution of the compound of preparation 31 (5.34 g), 2-bromoethoxyacetonitrile (1.47 g) and potassium carbonate (3.88 g) in 2-butanone (60 ml) was heated to gentle reflux for 18 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with more ethyl acetate. The combined organic extracts were washed with water, saturated brine solution, dried (Na 2 SO 4) and evaporated to dryness in vacuo to give a brown gum. The residue was purified by column chromatography on silica gel (95/5 / 0.5 diethyl ether / ethanol / ammonia) to yield the title compound, 3.46 g. m / z: 488 (MH +) Rf: 0.61 (95/5 / 0.5 diethyl ether / ethanol / ammonium hydroxide) PREPARATION 42 4-ff.-1, 2,3,4-tetrazol-5-8Pbenzaldehyde Trimethylsilyl azide (25 g) and dibutyltin oxide (8.8 g) were added to a solution of 4-cyanobenzaldehyde (13 g) in toluene (200 ml). The reaction was stirred with heating at 50 ° C for 1 hour, then heated at 96 ° C for 30 minutes and kept at this temperature for 3 hours. The solvent was evaporated in vacuo to yield an orange oil which was purified by column chromatography on silica gel (ethyl acetate). The crude product was dissolved in toluene under reflux and allowed to cool with stirring overnight. The resulting suspension was granulated in an ice bath for 1 hour, filtered and washed with cold toluene. The filtrate was evaporated in vacuo to yield a solid. The solid was dissolved in refluxing ethyl acetate (250 ml) and concentrated to 60 ml by rotary evaporation. The solution was cooled to room temperature and then granulated in an ice bath. The slurry was collected by filtration, washed and dried, with heating in a vacuum oven, to yield the title compound, 12-9.

PREPARATION 43 5-r5- (4-formylpheniD-2 / - / - 1, ethyl 2,3,4-tetrazol-2-ippentanoate A mixture of the compound of preparation 42 (450 g), potassium carbonate (715.5 g) and ethyl 5-bromovalerate (593.1 g) in acetonitrile (4500 ml) was heated to reflux for 5 hours. The suspension was cooled to room temperature and water (4500 ml) was added. The aqueous portion was separated and extracted with ethyl acetate (4500 ml). The combined organic portions were washed with water (2000 ml) and evaporated to dryness in vacuo to yield the title compound as a faint pale orange solid, 928 g. m / z: 303 (MH +) dH (300 MHz, CDCl 3): 10.1 (1 H, s), 8.32 (2H, d), 8.05 (2H, d), 4.70 (2H, t), 4.1 (2H, q ), 2.40 (2H, t), 2.15 (2H, m), 1.72 (2H, m), 1.22 (3H, t).

PREPARATION 44 3-bromo-ftrimetilsililoxpbenceno To a stirred solution of 3-bromophenol (382.3 g) in acetonitrile (1725 ml) under nitrogen, hexamethyldisilazane (235.6 g) was added over 20 minutes. Chlorotrimethylsilane was added dropwise to the clear solution for 20 minutes with stirring and the resulting white suspension was stirred at room temperature overnight. The suspension was removed by filtration and washed with acetonitrile (200 ml). The filtrate was evaporated in vacuo to obtain a light yellow oil which was distilled under vacuum (72 ° C at 0.5 mm Hg) to give the title compound, 541 g, as a colorless oil. dH (300 MHz, CDCl 3): 7.10 (2H, m), 7.04 (1 H, m), 6.80 (1 H, m), 0.3 (9H, s). 1 PREPARATION 45 4- (4,5-dihydro-4,4-dimethyl-2-oxazoliD-benzaldehyde N-Butyl lithium (9.44 ml, 2.5 N solution in hexanes) was added to a solution of 2- (4-bromophenyl) -4,5-dihydro-4,4-dimethyl-oxazole [A.l. Meyers and others, J.O.C., 1974, 39, 2787] (5 g) in tetrahydrofuran (80 ml) at -78 ° C. The reddish solution was stirred at -78 ° C for 15 minutes before adding dimethylformamide (2.3 g) dropwise. The resulting deep red solution was allowed to warm to room temperature, quenched with ammonium chloride solution and extracted into ether. The combined extracts were washed with brine, dried (sodium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography (30% ethyl acetate / hexane) to give the title compound as a colorless liquid, 3.01 g. m / z: 204 (MH +) dH (300 MHz, CDCl 3): 10.04 (1H, s), 8.10 (2H, d), 7.88 (2H, d), 4.12 (2H, s), 1.38 (6H, s ).

PREPARATION 46 4-rfR) -a-f2 (S), 5fR) -4-allyl-2,5-dimethyl-1-piperaziniP-3-f2,5-dimethylpyrrole-1-Pbencinbenzonitrile The title compound was prepared in a manner similar to that of Preparation 5 using the same starting materials except that 3- (2,5-dimethyl-1-yl) phenylmagnesium bromide was used. m / z: 439 (MH +) dH (300 MHz, de-DMSO): 7.76 (2H, d), 7.58 (2H, d), 7.50 (1H, t), 7. 32 (1H, d), 7.18 (1H, d), 7.02 (1H, d), 5.84-5.70 (3H, m), 5.32 (1H, s), 5.14 (1H, d), 5.08 (1H, d), 3.30 (1H, s), 3.18 (1H, m), 2.84 (1H, dd), 2.66 (1H, d), 2. 60-2.42 (2H, m), 2.10 (1H, dd), 1.92 (6H, s), 1.72 (1H, m), 1.10 (3H, d), 0.92 (3H, d).

PREPARATION 47 4-rfR) - -f2fS), 5fR) -4-allyl-2,5-dimethyl-1-piperaziniP-3-f2,5-dimethylpyrrole-1-Pbencinophenyltetrazole The title compound was prepared in a manner similar to that of the procedure of Example 52 using the compound of preparation 46. m / z: 482 (MH +) dH (300 MHz, d6-DMSO): 7.94 (2H, d), 7.60-7.44 (3H, m), 7.40 (1H, d), 7.20 (1H, d), 7.08 (1H, s), 5.82 (1H, m), 5.76 (2H, s), 5.36-5.18 (3H, m), 3.36 (1H, dd ), 3.10 (1 H, m), 2.90 (1 H, d), 2.80 (1 H, m), 2.72 (1 H, d), 2.62 (1 H, d), 2.36 (1 H, m), 2.00-1.90 (8H, m), 1.18 (3H, d), 1.02 (3H, d). 7 PREPARATION 48 4-rfR) -o -f2fS), 5fR) -4-allyl-2,5-dimethyl-1-piperaziniP-3-aminobenzylphenyltetrazole A mixture of the dimethylpyrrole starting material of preparation 47 (170 mg, 0.00035 mol) and hydroxylamine hydrochloride (74 mg, 0.00105 mol) in ethanol (3 ml) was heated to reflux for 3 days. The solvent was removed by rotary evaporation. The brown residue was then chromatographed on silica; eluent 90/10/1 - > 85/15/2 CH2Cl2 / MeOH / NH4OH to give 54 mg (38%) of the desired product. m / z: 404 (MH +) dH (300 MHz, de-DMSO): 7.92 (2H, d), 7.50 (2H, d), 6.97 (1H, t), 6.45 (3H, m), 5.80 (1 H, m), 5.25 (2H, m), 4.92 (1 H, sa); 2.55- > 3.50 (7H, m); 2.20 - > 2.40 (2H, m), 1.95 (2H, m), 1.00 (6H, 2xd).

PREPARATION 49 (+) - 4-cyano-, (R, S) -a-f4-allyl-1-piperazin-8D-3-tert-butyldimethylsilyloxybencipbenzene A solution of 1-allyl piperazine (12.9 g), benzotriazole (11.9 g) and 4-cyanobenzaldehyde (13.1 g) in toluene (350 ml) was heated to reflux with azeotropic removal of water for one hour. The solution was allowed to cool to room temperature and then added to a cooled solution (-10 ° C) of 3-ferd-butyldimethylsi-II-oxyphenylmagnesium bromide (prepared from 57.2 g of the corresponding bromide and 4.86 g of magnesium filings) in tetrahydrofuran (350 ml), at a speed such that the internal temperature was not higher than 0 ° C. The resulting solution was stirred at 0 ° C for 15 minutes, followed by 30 minutes at room temperature. After saturated aqueous solution of ammonium chloride was carefully added, the phases were separated and the aqueous layer was extracted with diethyl ether (2 x 500 ml). The combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel (95/5 / 0.25 hexane / isopropanol / ammonium hydroxide) to give the title compound (40 g). m / z: 447 (M +) Rf: 0.46 (90/10 / 0.75 hexane / isopropanol / ammonium hydroxide) dH (400 MHz, CDCl 3): 7.49-7.65 (4H, m), 7.12 (1 H, dd), 6.82 (1 H, d), 6.84 (1 H, s), 6.68 (1 H, d), 5.84 (1 H, m), 5.15 (2 H, m), 4.20 (1 H, s), 3.00 (2 H, d), 2.44 (8H, m), 0.96 (9H, s), 0.15 (6H, s).

PREPARATION 50 (+ .- r (R, S) -a-f4-allyl-1-piperaziniP-3-fer-butyldimethylsilyoxybenzylphenyltetrazole A solution of the compound of preparation 49 (11 g), dibutyltin oxide (2.86 g) and trimethylsilyl azide (9.22 g) in toluene (100 ml) was heated to reflux for 48 hours. After cooling, the reaction mixture was partitioned between ammonium hydroxide solution and ethyl acetate. The phases were separated and the aqueous phase was extracted with more ethyl acetate (2 x 200 ml). The combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (90/10 / 2-85 / 15 / 2.5 dichloromethane / methanol / ammonium hydroxide) to yield the title compound. m / z: 491 (MH +) Rf: 0.35 (80/20/3 dichloromethane / methanol / ammonium hydroxide) dH (400 MHz, DMSO-de): 7.90 (2H, d), 7.50 (2H, d), 7.12 ( 1 H, m), 6.87 (1 H, d), 6.90 (1 H, s), 6.63 (1 H, d), 5.77 (1 H, m), 5.20 (2 H, m), 4.34 (1 H, s), 3.16 (2H, d), 2.61 (4H, m), 2.36 (4H, m), 0.88 (9H, s), 0.1 1 (6H, s).

PREPARATION 51 f + .- 4-f5- (4-rfR, S) -o f4-allyl-1-piperaziniP-3-fer-butyldimethylsilyloxybenzylphenylphenyl} -1-ethyl tetrabutyrate and f + .- 4-f5-. { 4-rfR, S.-a-f4-allyl-1-piperaziniP-3-fer-butyldimethylsilyloxybenzophenylphenyl > -2 -tetrazoli Ethyl butyrate A suspension of the compound of preparation 50 (1 g) and bis (tri-n-butyltin) oxide (596 mg) in ethanol (5 ml) was stirred under reflux for 2 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo to yield a brown oil. This material was then heated to reflux in ethyl 4-bromobutyrate (16 ml) for 90 minutes and, after cooling, the mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (50 / 50-100 / 0 ethyl acetate / hexane) to yield the N-2 isomer, 550 mg. m / z 605 (MH +) Rf: 0.19 (50/50 ethyl acetate / hexane) d (300 MHz, DMSO-d6): 7.95 (2H, d), 7.56 (2H, d), 7.14 (1H, dd) ), 6. 99 (1 H, d), 6.93 (1 H, s), 6.64 (1 H, d), 5.76 (1 H, m), 5.10 (2 H, m), 4.72 (2 H, t), 4.32 (1 H , s), 4.00 (2H, q), 2.92 (2H, d), 2.37 (10H, m), 2.19 (2H, m), 1.14 (3H, t), 0.88 (9H, s), 0.15 (6H, s). and the N-1 isomer, 200 mg. m / z: 605 (MH +) Rf: 0.06 (50/50 ethyl acetate / hexane) dH (300 MHz, DMSO-de): 7.72 (2H, d), 7.61 (2H, d), 7.16 (1H, dd), 7.00 (1 H, d), 6.84 (1 H, s), 6.66 (1 H, d), 5.78 (1 H, m), 5.12 (2 H, m), 4.47 (2 H, t), 4.38 (1 H, s), 3.82 (2H, q), 2.93 (2H, d), 2.34 (10H, m), 2.03 (2H, m), 1.08 (3H, t), 0.90 (9H, s), 0.14 (6H, s).

PREPARATION 52 Alcohol (+) - 4-bromo-a- (3-methoxybenzene) benzyl A solution of n-butyl lithium in tetrahydrofuran (10.8 ml, 2.5 M) was added dropwise to a cooled solution (-78 ° C) of 3-bromoanisole (50.5 g) in tetrahydrofuran (200 ml) and the resulting suspension was stirred at -78 ° C under a nitrogen atmosphere for one hour. This suspension was then introduced via a cannula into a cooled solution (-78 ° C) of 4-bromobenzaldehyde (50 g) in tetrahydrofuran (200 ml) and the reaction was maintained at this temperature for 3 hours. Saturated aqueous ammonium chloride solution was added and the mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were washed with water and evaporated to dryness in vacuo. The residue was suspended between diethyl ether (200 ml) and saturated aqueous sodium metabisulfite solution (200 ml) and the mixture was filtered to remove the resulting white precipitate. The filtrate was separated and the organic layer was dried (MgSO4) and evaporated to dryness in vacuo to give a yellow oil. This was triturated with pentane to yield the title compound as a crystalline yellow solid, 42 g. m / z: 293 (MH +) dH (300 MHz, CDCl 3): 7.46 (2H, d), 7.26 (3H, m), 6.90 (2H, m), 6.81 (1H, d), 5.76 (1H, s), 3.80 (3H, s), 2.25 (1 H, s).

PREPARATION 53 Chloride of (±) -4-bromo-oc- (3-methoxybenzene) benzyl A solution of thionyl chloride (21 ml) in dichloromethane (80 ml) was added dropwise to an ice cold solution of the compound of preparation 52 (42 g) in dichloromethane (400 ml) and the reaction was stirred at room temperature. environment for 90 minutes. The mixture was then evaporated to dryness in vacuo and azeotropically with toluene, to yield the title compound as a brown solid, 45 g. dH (300 MHz, CDCl 3): 7.48 (2H, d), 7.29 (3H, m), 6.95 (2H, m), 6.84 (1H, d), 6.03 (1H, s), 3.80 (3H, s ).

PREPARATION 54 f +) - 4-bromo-rfR.S) -a-f4-allyl-1-piperaziniP-3-methoxybenzinbenzene A suspension of 1-allyl piperazine (2.65 g), the compound of preparation 53 (7.85 g) and potassium carbonate (14.5 g) in acetonitrile (50 ml), was heated under a nitrogen atmosphere at reflux for 18 hours. After cooling, diethyl ether was added and the mixture was filtered to remove residual solids. The filtrate was washed with water, then with brine and the product was extracted using a 2N aqueous solution of hydrochloric acid (4 x 25 ml). This aqueous solution was then basified with an aqueous solution.

N sodium hydroxide and extracted with diethyl ether (3 x 50 ml). These combined organic extracts were dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound as a brown gum, 7.0 g. m / z: 401 (M +) dH (300 MHz, CDCl 3): 7.38 (2H, d), 7.28 (2H, d), 7.16 (1H, dd), 6.94 (2H, m), 6.71 (1H, d), 5.85 (1 H, m), 5.14 (2 H, m), 4.17 (1 H, s), 3.76 (3 H, s), 3.00 (2 H, d), 2.44 (8 H, m).

PREPARATION 55 Acid (±) -4 -. (R, S) -a- (4-allyl-1-piperaziniP-3-methoxybenzyl, benzoic acid A solution of n-butyl lithium in tetrahydrofuran (1.15 ml, 2.5 M) was added dropwise to a cooled solution (-78 ° C) of the compound of preparation 54 (968 mg) in tetrahydrofuran (10 ml) and the solution The resulting orange was stirred for 15 minutes. Carbon dioxide was bubbled through the reaction mixture and then allowed to warm to room temperature and stirring continued under a nitrogen atmosphere for 72 hours. 2N aqueous hydrochloric acid was added and the resulting mixture basified with ammonium hydroxide solution and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (80/20/3 dichloromethane / methanol / ammonium hydroxide) to give the title compound as a white powder, 470 mg. m / z: 367 (MH +) dH (300 MHz, CDCl 3): 7.88 (2H, d), 7.39 (2H, d), 7.09 (1H, dd), 6.88 (2H, m), 6.64 (1H, d), 5.90 (1 H, m), 5.10 (3 H, m), 4.20 (1 H, s), 3.70 (3 H, s), 3.00 (2 H, d), 2.50 (4 H, m), 2.40 (4 H) , m).

PREPARATION 56 C I or ethyl 5-aminovalerate hydrochloride Hydrogen chloride gas was bubbled through a suspension of 5-aminovaleric acid (12 g) in ethanol (100 ml) and the reaction was stirred under reflux for 90 minutes. After cooling, the mixture was evaporated to dryness in vacuo to give an off-white solid. This material was recrystallized from ethane / diethyl ether to give the title compound, 15.1 g. m / z: 145 (M +) dH (300 MHz, CDCl 3): 8.25 (2H, sa), 4.12 (2H, t), 3.06 (2H, m), 2.36 (2H, t), 1.79 (4H, m) , 1.23 (3H, t).

PREPARATION 57 f + .- 5-. { 4-_R, SH4-allyl-1-piperazin-P-1 -f3-methoxypheniPmetinphenylcarboxamido ethyl alerate A solution of the compound of preparation 55 (470 mg, diisopropylamino (492 μl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (295 mg), 1-hydroxybenzotriazole (312 mg) and the compound of preparation 56 (280 mg) in dry dichloromethane (20 ml) was stirred under a nitrogen atmosphere at room temperature for 18 hours, water (20 ml) was added and the mixture was extracted with dichloromethane (2 x 25 ml). The combined residue was dried (Na2SO) and evaporated to dryness in vacuo The residue was purified by column chromatography on silica gel (95/5 / 0.5 dichloromethane / methanol / ammonium hydroxide) to give the title compound as a oil, 590 mg m / z: 494 (MH +) Rf: 0.47 (95/5 / 0.5 dichloromethane / methanol / hydroxy ammonia) dH (300 MHz, CDCl 3): 7.67 (2H, d), 7.50 (2H, d) , 7.19 (1 H, dd), 6.98 (2 H, m), 6.72 (1 H, d), 5.85 (1 H, m), 5.16 (2 H, m), 4.22 (1 H, s), 4.13 (2 H , q), 3.77 (3H, s), 3.44 (2H, m), 3.00 (2H, d), 2.48 (8H, m), 2.36 (2H, t), 1.67 (4H, m), 1.28 (3H, t).

PREPARATION 58 2-Bromoethoxy acetonitrile Triphenylphosphine (6.80 g) was added portionwise to a cooled solution of 2-hydroxyethoxyacetonitrile (J. Org. Chem 20; 1990, 5337) (2.50 g) and carbon tetrabromide (8.62 g) in acetonitrile, under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours and then evaporated to dryness in vacuo. The residue was triturated with hexane / dichloromethane solution, the resulting mixture was filtered and the filtrate was evaporated to dryness in vacuo to give an oil. This material was purified by column chromatography on silica gel using elution in gradient 66 / 34-50 / 50 hexane / dichloromethane) to yield the title compound as a colorless oil, 3.17 g. m / z: 163 (M +) dH (300 MHz, CDCl 3): 4.35 (2H, s), 3.94 (2H, t), 3.51 (2H, t).

PREPARATION 59 f +) - 2-f5- 4-rfR, S) - -f4-allyl-1-piperaziniP-3-hydroxybenzylphenyl -2- tetrazolyPethoxy acetonitrile A suspension of the compound of example 55 (3.9 g), the compound of preparation 58 (1.26 g) and potassium carbonate (3.3 g) in 2-butanone (120 ml) was heated to reflux for 72 hours. After cooling, water was added and the reaction mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (97 / 3-95 / 5 dichloromethane / methanol) and then once more with (97/3 / 0-90 / 10/2 diethyl ether / ethanol / ammonium hydroxide) to yield the title compound, 1.74 g. m / z: 367 (MH +) Rf: 0.36 (95/5 / 0.5 diethyl ether / ethanol / ammonium hydroxide) dH (400 MHz, CDCl 3): 8.06 (2H, d), 7.54 (2H, d), 7.15 (1 H, dd), 6.98 (1 H, d), 6.91 (1 H, s), 6.66 (1 H, d), 5.88 (1 H, m), 5.32 (1 H, s), 5.17 (2 H, m ), 4.88 (2H, t), 4.22 (5H, m), 3.04 (2H, d), 2.51 (8H, m). Found: C, 64.68; H, 6.33, N, 21.07. C25H29N2O2.1 / 5H2O requires C, 64.83; H, 6.40; N, 21.17%. The N-1 isomer was also isolated, 160 mg.

PREPARATION 60 2- (5- { 4-f ±) -rR, S) -a-f4-benzyl-1-piperaziniP-3-hadroxybenzylphenyl > -1 - tetrazoliPethoxyacetonitrile and 2-f5- (4-f ±) -rR, S) -a-f4-benzyl-1-piperazin-P-3-hydroxybenzylpheniP-2-tetrazoliPethoxyacetonitrile A suspension of the compound of preparation 4b (2.16 g), the compound of preparation 58 (670 mg) and potassium carbonate (1.66 g) in acetonitrile (40 ml) was stirred under reflux for 20 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous solution was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with brine, dried (Na 2 SO 4) and evaporated to dryness in vacuo to give a brown oil. This material was then dissolved in tetrahydrofuran (20 ml), tetraethylammonium fluoride (1.23 g) was added and the reaction was stirred at room temperature for 18 hours. Water was added and the mixture was extracted with ethyl acetate (3 x 30 m). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (75 / 25-65 / 35 hexane / ethyl acetate) and then once more with (95/5 dichloromethane / methanol) to produce the N2 isomer, 1.55 g. m / z: 510 (MH +) dH (400 MHz, DMSO-de): 9.34 (1 H, s), 7.98 (2H, d), 7.57 (2H, d), 7.26 (5H, m), 7.08 (1 H, dd), 6.83 (2H, m), 6.56 (1 H, d), 4.94 (2H, t), 4.48 (2H, s), 4.24 (1 H, s), 4.10 (2H, t), 3.44 (2H, s), 2.22-2.48 (8H, m). and the N1 isomer, 180 mg. m / z: 510 (MH +) dH (400 MHz, DMSO-de): 9.36 (1 H, s), 7.72 (2H, d), 7.61 (2H, d), 7.26 (5H, m), 7.08 (1 H, dd), 6.83 (2H, m), 6.57 (1 H, d), 4.65 (2H, t), 4.40 (2H, s), 4.30 (1 H, s), 3.98 (2H, t), 3.47 (2H, s), 2.30-2.62 (8H, m).

PREPARATION 61 5-f4-ff R) -1-rf2S, 5R) -2,5-dimethyl-1-piperazinyl-3-methoxyphenyl-Phenyl-phenylcarboxamido-ethylvalerate Tris (triphenylphosphine) rhodium (I) chloride (1.0 g) was added to a solution of the compound of preparation 36 (8.12 g) in acetonitrile (160 ml) and water (40 ml). The reaction mixture was heated under gentle reflux and the solvent was allowed to slowly distil off. More acetonitrile / water (100 ml, 4: 1 v / v) was added at a rate such as to maintain a standing distillation. After completing the addition of the solvent, the distillation was continued until the volume was reduced to approximately 60 ml. The cooled solution was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated brine. The solution was dried (magnesium sulfate), evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel using gradient elution (100% dichloromethane at 60/40/1 dichloromethane / methanol / hydroxide ammonium) to yield the title compound, 6.35 g. m / z: 482 (MH +) Rf 0.34 (93/7/1 dichloromethane / methanol / ammonium hydroxide) PREPARATION 62 5-f4-f f R) -1-_ (2S, 5R) -4-propyl-2,5-dimethyl-1-piperazinylM - (3-methoxypheniPmetipphenylcarboxamido) pentanoate ethyl To a solution of the compound of preparation 61 (600 mg), propionaldehyde (102 μg) and glacial acetic acid (100 mg) in dry tetrahydrofuran (20 ml) was added, with stirring, sodium triacetoxyborohydride (636 mg).

The resulting mixture was stirred at room temperature for 18 hours, after which it was poured into ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, saturated brine, dried (magnesium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (100% dichloromethane to 95/5 dichloromethane / methanol) to yield the title compound, 61 mg. m / z: 524 (MH +) Rf 0.62 (93/7/1 dichloromethane / methanol / ammonium hydroxide) PREPARATION 63 TO 65 were prepared from the compound of preparation 61 by reductive alkylation with the appropriate aldehyde using a procedure similar to that described in Preparation 62.

PREPARATION 63: 5-f4-.f RM -r2S, 5R) -4-butyl-2,5-dimethyl-1-piperazinylH-f3-methoxypheniPmetinphenylcarboxamido ^ -pentanoate ethyl PREPARATION 64: -f4-_f RM -IY2S. Ethyl 5R, -4-cyclopropylmethyl-2,5-d, methyl-1-piperazinyl-3-methoxyphenimethylphenylcarbamic acid) pentanoate PREPARATION 85: 5-f4-, f R) -1-rf2S, 5R.-4-iso-butyl-2,5-dimethyl-1-piperazinyl-ethyl-3-methoxyphene-P-methylphenyl-carboxamido.-pentanoate PREPARATION 66 3 (S) -1-benzyl-3-methylpiperazine Joint (S) - (+) - 2-methylpiperazine (2.63 g), benzyl bromide (3.12 ml) and potassium carbonate (5.4 g) in acetonitrile (120 ml) were heated together at 40 ° C for 3 days. The mixture was evaporated to dryness in vacuo and the residue partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried (magnesium sulfate) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (95/5/0 to 92/7/1 dichloromethane / methanol / ammonium hydroxide) to give the title compound as a 1.12 g solid. Rf 0.25 (92/7/1 dichloromethane / methanol / ammonium hydroxide) dp- (300 MHz, CDCl 3): 7.3 (5H, m), 3.5 (2H, s), 2.9 (3H, m), 2.77 (2H, m ), 2.02 (1 H, m), 1.65 (2H, m), 1.02 (3H, m).

PREPARATIONS 67 v 68 3-r5-f4-fomilfeniP-2H-1, 2,3,4-tetrazolyl-2-methyl-methyl-benzoate and 3-Í5- (4-formylpheniD-1 H-1, 2,3,4-tetrazolyl Methyl -2-methylmethylbenzoate A mixture of the compound of preparation 42 (3 g), potassium carbonate (7.2 g) and methyl 2-bromomethylbenzoate (4.35 g) in dry acetonitrile (75 ml) under reflux for 5 hours were heated together. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate, and the organic layer was separated, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by column chromatography on silica gel using gradient elution (80/20 to 50/50 hexane / ethyl acetate) to yield the title compounds. The N-2 isomer eluted first (2.92 g) m / z: 323 (MH +) m.p .: 1 13-1 14 ° C. dH: (400 HNz, CDCl 3): 10.08 (1 H, s), 8.35 (2 H, d), 8.15 (1 H, s), 8.08 (1 H, d), 8.00 (2 H, d), 7.63 (1 H, d), 7.49 (1 H, t), 5.88 (2 H, s), 3.95 (3 H, s). Found: C, 63.29; H, 4.33; N, 17.19. C17H? 4N4O3 requires C, 63.35; H, 4.38; N. 17.38% followed by the isomer N-1 (212 mg) m / z: 323 (MH +) dH: (400 MHz, CDCl 3): 10.12 (1 H, s), 8.04 (3H, m), 7.83 (1 H, s), 7.78 (2H, d), 7. 47 (1 H, t), 7.35 (1 H, d), 5.71 (2 H, s), 3.92 (3 H, s).

PREPARATION 69 3-_5- (ethyl 4-formylpheniP-2H-1,2,3,4-tetrazolyl-2-ippropionate) A mixture of the compound of preparation 42 (3 g), potassium carbonate (8.3 g) and ethyl 3-bromopropionate (4.68 g) in dry acetonitrile (70 ml) was heated at 50 ° C for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was separated, dried (sodium sulfate) and evaporated in vacuo. The crude residue containing the N-1 and N-2 isomers was purified by column chromatography on silica gel (1/2 pentane / ethyl acetate) to give the title compound as a colorless oil, 1 g. dH: (300 HNz, CDCl 3): 10.1 (1 H, s), 8.35 (2H, d), 8.00 (2H, d), 4.98 (2H, t), 4.20 (2H, q), 3.16 (2H, t ), 1.15 (3H, t). 99 PREPARATIONS 70 AND 71 4-r5-f4-formylphenylM H-1, 2, ethyl 3,4-tetrazolyl-2-ipbutanoate 4-r5-f4-formylpheniD-1 H-1,2,3,4-tetrazolyl-2-ylbutanoate ethyl A mixture of the compound of preparation 42 (3 g), potassium carbonate (5.9 g) and methyl 4-bromobutanoate (4.68 g) in dry acetonitrile (70 ml) was heated at 50 ° C for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was separated, dried (sodium sulfate) and evaporated in vacuo. The crude residue containing the N-1 and N-2 isomers was purified by column chromatography on silica gel (1/2 pentane / ethyl acetate) to yield the title compounds as colorless oils. The N-2 isomer eluted first (3.9 g): Rf: 0.5 (: 2; ethyl acetate / pentane) dH: (300 MHz, CDCl 3): 10.1 (1 H, s), 8.33 (2H, d), 8.01 (2H, d), 4.79 (2H, t), 3.70 (3H, s), 2.50-2.35 (4H, m). Followed by the isomer N-1 (0.35 g) Rf: 0.1 (1: 2; ethyl acetate / pentane) dH: (300 MHz, CDCl 3): 10.13 (1 H.) s, 8.10 (2H, d) 7.95 (2H, d), 4.58 (2H, t), 3. 63 (3H, s), 2.42 (2H, t), 2.28 (2H, m).

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula or a pharmaceutically acceptable salt thereof in which R1 is H, C2-C6 alkanoyl, C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) - (C1 alkyl) -C 4), (C 1 -C 4 alkoxy - (CrC 4 alkyl), carboxy (C 1 -C 4 alkyl), aryl (C 1 -C 4 alkyl) or heteroaryl- (C 1 -C 4 alkyl); each of R2 and R3 is, independently, H or C1-C4 alkyl; R4 is selected from (i) H, (ii) a group of the formula R6- (CH2) mZ- (CH2) n-, where m is 0, 1, 2 or 3, n is 1, 2 or 3, Z is a direct bond or O, and R6 is -CO2H or -CO2H or -CO2 (C-1-C4 alkyl), and (iii) a group of the formula wherein R7 is H or C-1-C4 alkyl; and R5 is hydroxy, C1-C4 alkoxy or -NHSO2 (C1-C4 alkyl); with the proviso that Z is O, m is 1, 2 or 3 and n is 2 or 3; and further characterized in that (a) "aryl" is phenyl or naphthyl, both optionally substituted. more than three substituents each independently selected from halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy and (b) "heteroaryl" is a 5- or 6-membered aromatic heterocyclic group.

2. A compound according to claim 1, further characterized in that (a) aryl is phenyl substituted by one or two substituents as defined in claim 1, and (b) heteroaryl is thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl , pyrimidinyl or pyrazolyl.

3. A compound according to any one of the preceding claims, wherein R1 is H, allyl, benzyl, C1-C4 alkyl or (C3-C7 cycloalkyl) methyl.

4. A compound according to claim 4, wherein R1 is allyl.

5. A compound according to any one of the preceding claims, wherein preferably each of R2 and R3 are, independently, H or CH3.

6. A compound according to claim 5, wherein both R2 and R3 are H or both are methyl.

7. A compound according to claim 6, wherein both R2 and R3 are methyl.

8. - A compound according to any one of the preceding claims, wherein R5 is hydroxy, methoxy or -NHSO2Me.

9. A compound according to claim 8, wherein R5 is hydroxy.

10. A compound according to any one of the preceding claims, wherein R4 is H or a group of the formula (a) - (CH2) pCO2H or - (CH2) pCO2 (C1-C4 alkyl) where p is 1, 2, 3 or 4, (b) - (CH2) 2-O-CH2CO2H, (c) - (CH2) 2-O-CH2CO2 (C4 alkyl) or (d); where R7 is H or C1-C4 alkyl.

11. A compound of the formula (I) according to any one of the preceding claims, having the stereochemistry: -

12. - A compound of the formula (I) according to any one of the preceding claims, wherein the tetrazole ring is attached to the 3 or 4 position of the adjacent phenyl ring.

13. - A compound of the formula (I), according to claim 1, which is (+) - 5. { 4 - [(R) -a- (2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl} -1 H-tetrazole; (-)-5-. { 4 - [(R) -a- (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl} -1 H-tetrazoi; 3- (5- { 4 - [(R) -a- (2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] pheny1} -2-tetrazoyl) propionic; (+) - 5- (5- { 4 - [(R) - - (2 (S), 5 (R) -4-Ailyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl acid ] phenyl} -1-tetrazolyl) vaiérico; (+) - 5- (5- { 4 - [(R) -a- (2 (S), 5 (R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3- acid hydroxybenzyl] phenyl.} -2-tetrazolyl) valeric; acid (5- { 4 - [(R) - - (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1 -poperazinyl) -3-hydroxybenzyl] phenol .} -2-tetrazolyl) -4-methylbenzoic acid; (5- {4 - [(R) -a- (2 (S), 5 (R) -4-Benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl}. -2-tetrazoyl) -4-methylbenzoic acid; (5- { 4 - [(R) - - (2 (S), 5 (R) -4-Benzyl-2,5-dimethyl-1-p yperazinyl) -3-hydroxybenzyl] phenyl} -1-tetrazoyl) -4-methylbenzoic acid; (5- {4 - [(R) -a- (2 (S), 5 (R) -4-Benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl}. -2-tetrazoyl) -4-methylbenzoic acid; or (5- {4 - [(R) -a- (2 (S), 5 (R) -4-benzyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl] phenyl}. -1-tetrazolyl) -3-methylbenzoic acid.

14. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims and a pharmaceutically acceptable diluent or carrier; with the proviso that R4 is not H.

15. A compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, for use as a medicament with the proviso that R4 is not H. 16.- The use of a The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 in which R4 is other than H, for the manufacture of a medicament for the treatment or prevention of a disease that requires administration of delta opioid agonists. 17. The use or method according to claim 16, wherein the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a respiratory function disorder, a gastro-intestinal disorder, such as in functional bowel disease, a functional Gl disorder, such as irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia or others associated with disorders of motility or secretion, a disorder of the urogenital tract, such as incontinence, or pain, including non-somatic pain. 18.- A compound of the formula: wherein R1, R2 and R3 are as defined in claim 1 and Q2 is a hydroxy-protective group. 19. A compound of the formula: wherein R 4 is R b - (CH 2) m-Z- (CH 2) n and Z, m, n, R R, R R and R are as defined in claim 1. SUMMARY OF THE INVENTION Tetrazoles and their pharmaceutically acceptable salts which are selective agonists for the delta opioid receptor, particularly useful in the treatment of inflammatory diseases such as arthritis, psoriasis, asthma, inflammatory bowel disease, respiratory function disorders, gastrointestinal disorders such as functional disease of the intestine and functional Gl disorders, of the formula: - wherein R1 is H, C2-C6 alkanoyl, C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyl, (C3-C7 cycloalkyl) - (C1-C4 alkyl), (C-alkoxy) ? -C4) - (C1-C4 alkyl), carboxy (C1-C4 alkyl), aryl (C1-C4 alkyl) or heteroaryl- (C1-C4 alkyl); each of R2 and R3 is, independently, H or C1-C4 alkyl; R4 is selected from (i) H, (ii) a group of the formula R6- (CH2) mZ- (CH2) n-, where m is 0, 1, 2 or 3, n is 1, 2 q 3, Z is a direct bond or O, and R6 is -CO2H or -CO2 (C1-C4 alkyl), and (iii) a group of the formula wherein R7 is H or C? -C4 alkyl; and R5 is hydroxy, C? -C4 alkoxy or -NHSO2 (C? -C alkyl); with the proviso that when Z is O, m is 1, 2 or 3 and n is 2 or 3. P99 / 1484F PF / all *