MXPA97007454A - Hydroxamic pirrolidinil acid compounds and their product procedure - Google Patents

Abstract

The present invention relates to a compound of the formula: (SEE FORMULA) (I) and its pharmaceutically acceptable salts, wherein A is hydrogen, hydroxyl or OY, wherein Y is a hydroxyl group; Ar is a substituted phenyl optionally don one or more substituents selected from halo, hydroxyl, a C 1 -C 4 alkyl, CF 3, a C 1 -C 4 alkoxy C 1 -C 4 alkyloxy and C 1 -C 4 carboxyalkyloxy; X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl , 1-tetralon-6-yl, C 1 -C 4 -alkylenedioxy, pyridyl and thienyl, these groups optionally being substituted by up to three substituents selected from halo, a C 1 -C 4 alkyl, a C 1 -C 4 alkoxyl, hydroxyl, NO 2, CF 3 and SO 2 CH 3; and R is hydrogen, a C 1 -C 4 alkyl or a hydroxy protecting group

Description

PIRROLIDINIL ACID HYDROXUPINE COMPOUNDS AND ITS PRODUCTION PROCEDURE TECHNICAL FIELD This invention relates to novel hydroxamic acid derivatives and their pharmaceutically acceptable salts and to pharmaceutical compositions containing them, these compounds and compositions are useful as analgesic, antimicrobial, diuretic agents. anesthetics or neuroprotectants, or as an agent for the treatment of stroke or intestinal functional diseases such as abdominal pain, for the treatment of a mammal / especially a human subject.

PREVIOUS TECHNIQUE Opioid analgesics such as morphine are therapeutically useful, but their use is strictly limited due to their side effects such as drug dependence. flsí, analgesic is desired with a high utility and a low tendency to cause drug dependence. Numerous pharmacological and biochemical studies have been conducted to discover opioid peptides and opioid receptors, and the discovery of the opioid receptor subtypes u, d, k in the peripheral nerves of various species, including human, has initiated the creation of new analgesics. As it is believed that opioid analgesics such as morphine act as receptor agonists u, it has been investigated to separate the action based on an agonist from the receptor-action based on a μ receptor agonist. Recently selective k-agonists have been reported from the above point of view, or for example, EMD-60400: fl. Barber et al., Naunyn-chmled. Rrch. Pharmacol., 345 (upl.), Flbst. 456. Some of them have now been studied in clinical trials (NED, rFS, rEV., 1, 525 (1992)). However, even when a selective receptor agonist is employed, the use of high doses may result in side effects such as sedation. It would therefore be desirable to provide compounds that have a better agonist activity or the opium receptor of k and, specifically, compounds that only have a low sedative activity.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound with the following formula: OR (D and the salts of the same, in which fl is hydrogen, hydroxyl or OY, in which Y is a hydroxyl protecting group; F is an optionally substituted phenotype with one or more substitutents (preferably up to three ) selected from halo, hydroxyl, a Ci-alkyl, an alkoxy or Ci -CA, OF3, a C 1 -C 4 alkoxy, C 1 -C 4 alkyloxy, and carboxyalkyl oxyl CI -CA,; X is phenyl, n-ethyl, bifeyl, m-hanyl, benzofarranyl, benzothiophene, l-tetralone-6-lyo, C1-C4-alkenyloxy, pyridyl, furyl and thienyl, these groups being optionally substituted with up to three substituents. selected from halo, an Ci-Ci alkyl, an Ci-C4 alkoxy, hydroxy, NO2, CF3 and SO2CH3; and R is hydrogen, a Ci-C¿ alkyl, or a hydroxyl protecting group. The hydroxaric acid derivatives of the present invention of formula (I), wherein fl is hydrogen or hydroxyl and R is hydrogen or a Ci-C¿ alkyl, have a significant agonist activity by the opioid receptor (> Therefore, these k-agonists are especially useful as an analgesic agent in mammals, especially in humans, they are also useful as anti-inflammatory, diuretic, anesthetic or neuroprotective agents, or as an agent for the treatment of stroke or functional intestinal diseases or pain. For the treatment of a mammal, especially a human subject, the present invention also provides a pharmaceutical composition useful as an analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agent, or as an agent for the treatment of stroke. or intestinal functional diseases such as abdominal pain, for the treatment of a mammal, especially a human subject, comprising a therapeutically effective amount of a hydroxannic acid of formula (T), wherein fl is hydrogen or hydroxyl and R is hydrogen or a CiCt alkyl, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier. The compounds of formula (I), in which OY or OR or both represent a protected hydroxyl group, are useful as chemical intermediates of the agonist k of formula (I). Typical hydroxyl protecting groups are benzyl, trifenium, tetrahydropyranyl, inetoimethyl, and Ri 2R3. wherein R1, R2 and R3 are each a C? -C6 alkyl or femlo. A preferred group of agonist compounds of the present invention is formed by the compounds of formula (T), wherein fl is hydrogen or hydroxyl, flr is phenyl, X is a phenyl substituted with up to three its <• i tients selected from chlorine, methyl and CF3, more preferably 3,4-dichlorophenyl, and R is hydrogen. The preferred configuration of the carbon atom to which the group Or is attached is (S). Preferred individual compounds of the invention are: 2- (3,4-d-chloro in? L) -Nh? Drox? -Np- (S) -fen? L-2- (l-pyrrolidinyl) et? L3acetam? Da; N-hydroxy-N-C1- (S) -feml ~ 2- (1-pyrrolidol) et 11] ~ 2 ~ (2,3, B-trichlorophemethyl) acetamide; N-hydroxy? N-Cl- (S) -phenyl? 2- (l-?? rrol? D? N? L) et? L] -2 ~ (4-t r? Uoromethylphenyl) acet amide; N-h? Drox -N-Cl ~ (S) -phen? L-2- (l? Rrol? D? Nil) et? ] ~ 2- (2,4, 6 ~ tr? Rnet? Lfen? L) acetam? to; 2- (3,4-d chlorophen? L) -Nh? Drox? -N-C2- (3- () -h? Drox? Rrol? Dm-1-? L) -l- (S) - fen? let? l-lacetam? da; 2- (4-bromophen? L) -Nh? Drox? -N-C2- (3 ~ ((=.) -hi drox i pi rrol i din-? L) -l- (S) -femlet? l-! acetarn? a; N-hi roxy -N-C2- (3- () -hydroxypyrrolidi n-1-? l) -J- (S) -femletii J-2- (4-tpfluorornet? lfen? l Acetate? 2- (4-chlorophen? l) -Nh? drox? -N ~ C2- (3- (S) -hydr-oxypyrrol d? n ~ l-? l) ~ l- () -fen? let? 1 acet arn ida; 2- (2,3-d? chlorophenyl) -Nh? drox? -N-C2- (3- (S) -hi drox ípi rrol i dm-l-? ) -l- (S) - phenylethyl ketamine, 2- (2, -d? chlorof in? l) -Nh? drox? -N? - (3- (S) -h? drox? p? rrol? d ? nl-? l) -l- (S) -fen? let? l-lacetam? da; 2- (2,5-d? chlorofeml) -Nh? drox? ~ N-T2- (3 - () - h? drox ??? rrol? d? nl-? l) -l ~ (S) -femlet? i] acetam? da; 2- (2,6-d? chlorophen? l) -Nh? drox? -N -r2- (3 ~ (S) -h-hydroxypyrrolidin-1-yl) -1- (S) -phenyletipacetami daz-N-hydroxy-pyrrolidin-1-yl -l-1) -phenylethyl] -2- (2, 3, 6-chloro-phenyl) -aceta-ida; 2- (3,4-d? Chlorophen? L) -N-C - (3- (S) -hydroxy? Inrol? Dm-l-? L) -l- (S) -phenylethylHacetam; and 2- (3,4-d methylphenyl) -N-hydrox? -N- [2- (3- (S) ~ hydroxypyridine-1-yl) -L- (S) -phenylethyl-acetamide- Also, the present invention provides a compound of formula and salts thereof, wherein fl is hydrogen, hydroxyl or OY, wherein Y is a hydroxyl protecting group; Ar is a phenyl optionally substituted with one or more substituents selected from halo, hydroxyl, a Ci-Ci alkyl, a Ci-t alkoxy, CF3, a Ci-C- alkoxy? -alkyloxy Ci -C "and carboxyalkyloxyC Ci -C \; R is hydrogen, a Ci-C¿ alkyl or a hydroxyl protecting group. These compounds of formula (II) can be used as intermediates to prepare the compounds of formula (T). In addition, the present invention provides methods of producing the hydroxaromatic compounds of formula (T) and their intermediate compounds of formula (TI).

DETAILED DESCRIPTION OF THE INVENTION The k-agonists of formula (I) of this invention can be prepared by various methods. For example, they can be easily prepared according to the procedure shown in Scheme 1.

SCHEME 1 l and alkylation H OL: leaving group / * XP: protective group A ': H or protected hydroxyl R (DLO) Thus, the agonist compounds k of formula (I), in which fl is hydrogen or hydroxyl and R is hydrogen, can be prepare by reaction of a compound of formula (VI) with a carboxylic acid of formula XCH2COOH, followed by The elimination of the protecting group P and the protecting group of fli if necessary, is a conventional acyl ation reaction, which can be carried out employing standard procedures, well known to those skilled in the art, however, A convenient way of acylating a compound of formula (VI) with an acid of formula XCH 2 COOH comprises coupling the two compounds in the presence of a carhodi irnide compound. A particularly suitable carbodiZed compound is the hydrochloride of L-et? L-3-O-dirnet 1 larninopropiDicarbodiimide, which is sometimes referred to as hydrosoluble carbodiunide, or USC. This reaction is carried out by contacting practically equivalent amounts of the acid and the amine with a small excess of the carbodurnide in an appropriate solvent at a temperature in the range of -30 to 100 ° C, usually 0 to 30 ° C. suitable solvents include inactive aromatic hydrocarbons, esters, halogenated hydrocarbons, especially dichloromethane. The reaction lasts between 30 minutes to 24 hours, usually 30 minutes to 3 hours at room temperature, the product can be isolated and analyzed by standard techniques1. The protecting group P, and any protecting group of fli, is removed by the process suitable for the particular protective group chosen. Thus, a typical protective group is benzyl. This can be removed by catalytic hydrogenation. Suitable catalysts for hydrogenation are Pd / C, Pearlman catalyst, black Pd or Pd / BaSO-; , especially the Pd / C 10%. An additional protective group suitable for P and Al is the tetrahydropyranyl group (THP). This can be eliminated1 by acid-catalyzed hydrolysis. Suitable acid catalysts are organic acids, inorganic acids or acids of Le is as AcOH, p-TsOH, HCl, Me2fllCl etc., especially HCl. The agonist compounds k of formula (I), in which R is a C? -C-? Alkyl group can be prepared by alkylator, of the corresponding compounds of formula (I) in which R is hydroxyl. This alkylation can be carried out by conventional procedures. An especially convenient process involves base catalyzed alkylation using alkyl halide in the presence of a phase transfer catalyst such as tetra-n-butylammonium bisulfate. The intermediate hydroxylamino of formula (VI) can be prepared from alcohol (V), by treatment with rnetanosulfonyl chloride in the presence of a base such as triethylamine followed by the addition of a protected hydroxylamine (NH3OP)., The alcohol (V) is obtained from the appropriate ethanolarn compound (TIT) and the appropriate ethane compound of formula (IV). The compounds of formula (III) and (IV) are known compounds, which can be prepared by known methods, or are analogs of known compounds, which can be prepared by procedures analogous to known procedures. The immediate compounds of the formula (119 in which Ar is a substituted phenyl can be prepared according to the procedures shown in Scheme 2 below.

SCHEME 2 (V) (V? D (DO OQ (Q is, for example, halo, a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy, a C 1 -C 4 alkoxy-Ci-Cal alkyloxy or CF 3, n = .1.-5, preferably 1-3) . In Scheme 2 above, a compound (VII) can be reacted with a substituted styrene oxide (VIII) to form a mixture of compounds (IX) and (X). This reaction could be carried out in the absence or presence of an inert solvent in the reaction (eg, methanol (MeOH), ethanol (EtOH), isopropyl alcohol, tetrahydrofuran (THF), dioxane, dirnethylformamide (DMF), dimethylsulfoxide (DMSO) , rnetylene chloride (CH2Cl2), water, benzene, toluene, n-hexane, cyclohexane) at a temperature between -78 ° C to the reflux temperature of the solvent, preferably from 0 ° C to 25 ° C for 5 minutes at 48 ° C. preferably from 0.5 to 12 hours. A compound (II ') can be prepared from the mixture of a compound (IX) and a compound (X) under the same conditions as already described in Scheme 1. According to the above procedures, it can be determined from selectively the R and S configuration of the compounds (TX) and (X). In addition, in the above processes, the 2-tosylate of a 1-phenol can be used as 1-tu-do-1, 2-ethanediol in place of the substituted styrene oxide (VIII). The compounds of formula (I) of this invention are basic, and can therefore form acid addition salts. All these salts are enclosed within the scope of this invention. However, it is necessary to use acid addition salts that are pharmaceutically acceptable for administration to a mammal. The acid addition beads can be prepared by standard procedures, e.g., by contacting the acidic and basic compounds in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. The typical salts that can be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succmate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulphonate, oxalate and oato (1, 1 '-met? len-b? s ~ (2-hydroxy-3-naphthoate)). The compounds of formula (I) of this invention, wherein R is hydrogen, are acids and will form basic salts. All these salts are within the scope of this invention. However, it is necessary to use a basic salt that is pharmaceutically acceptable for its admi- nation to a mammal. The basic salts can be prepared by standard procedures, e.g., by contacting the acidic and basic compounds in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. Typical base salts that can be formed are the sodium, potassium, calcium and magnesium salts, and also those with ammonia and amines, such as ethylenema, diethiamine, tetylamine, cyclohexylamine, pi-endin and morphol salts. Also included within the scope of this invention are the bioprecursors (also called prodrugs) of the agonist compounds k of formula (I) "A bioprecursor of a 1-appa agonist of formula (I) is a chemical derivative thereof which is converted with ease in the original compound of formula (I) in biological systems. Specifically, a bioprecursor of a k agonist of formula (I) is converted to the original compound of formula (I) after the bioprecursor has been administered and absorbed by a mammal, e.g., a human subject. For example, it is possible to prepare a bioprecursor of a k-agonist of the invention of formula (T) in which one of the two groups A and OR is hydroxyl by preparing an ester of the hydroxyl group. When from A and OR only one is a hydroxyl group, only rnonoesteree is possible. When A and OR are both hydroxyl, mono- and diesters (which may be the same or different) can be prepared. Typical esters are simple alkanoate esters, such as acetate, propionate or, butyrate, etc. In addition, when A or OR is a hydroxyl group, bioprecursors can be prepared by linking the hydroxyl group to an acyloxy and yl derivative (eg, a pivaloi loxirhene derivative) by reaction with an acyl loxinethyl halide (eg, sodium chloride). aloi loxirnet io). The agonist compounds 1- of the present invention of formula (I) have significant agonist activity by the op oid receptors k and are therefore useful as analgesic, antiflamatory, diuretic, anesthetizing and neuroprotective agents, or as an agent for the treatment of apoplexy or intestinal functional diseases with abdominal pain, for the treatment of mammals, especially humans who need such agents. The activity of the agonist compounds of formula (I) of the present invention is demonstrated by the opioid receptor binding activity. Said activity could be determined in guinea pig whole-brain furnace, as described by Regina A. et al. in 3. Receptor Res. 12: 171-180, 1992. Briefly, the tissue homogenate is incubated at 25 ° C for 30 minutes in the presence of labeled ligand and the test compounds. The μ centers are labeled with (3H) - [D-Ala2, hePhe4, Gly-ol5] encephalone (DAMGO) 1 nM, the centers 6 are labeled with (3H) ~ rD-Pen2.5] encephalone ( DPDPE) l nM and centers l <; per (3H) -CI-977 0.5 nM. Nespecific binding is measured by the use of CI-977 ((> •) 1 μM, DAMGO (μ) 1 μM, DPDPE (6) 1 μM The data are expressed as IC-50 values obtained by a program of non-linear fit using the Cheng and Prusoff equation Some compounds prepared in the Examples showed a low IC 50 value in the range of 0.01 to 100 nM The activity of the agonist compounds k can also be demonstrated by the formal test ina described by Ulheeler-Acoto, H. and Col. in Psychopharrnacology W 35-44, 1991. In this test, male SD rats (80-100 g) are injected subcutaneously with a test compound dissolved in 0.1% hyprornelose. in saline solution or vehicle After 30 minutes, 50 L of a 2% solution of formaldehyde was injected into a hind paw The number of larnettes of the injected paw was measured per observation period 15 to 30 minutes after the injection of fornaline and expressed as% inhibition compare with the vehicle group ivo turf. The activity of the k-agonists can also be demonstrated by assay in a rotary bar as described by Hayes, A. G. et al. in Br. 3. Pharmacol. 79: 731-736, 1983. In this test, a group of 6 to 10 male SD rats (100-120 g) are selected for their ability to maintain equilibrium in a rotating rod (9 cm diameter, rotational speed of 5 rprn). The test rats were then injected subcutaneously with a test compound diethylcellulose 0.1% in aligna solution. Animals were reanalyzed 30 minutes after treatment; a rat that falls from the bar more than twice in 150 seconds is considered to have an engine deterioration and the performance of the animal (ie, the time on the rotary bar) is recorded. In the control group the DEso value is observed, defined as the dose of drug that reduces the action time by half. The k-agonist compounds of formula (I) of this invention can be administered to mammals orally, parenterally or topically. In general, these compounds are administered in the most desirable manner to humans in doses ranging between 0.01 rng and 50 rng per day, although variations will necessarily be made depending on the weight and condition of the subject to be treated, the state of the disease a treat and the specific route of administration chosen. However, a dosage level that is within the range of 0.01 ng to 1 mg per kg of body weight per day, in single or starting dose is used in the most desirable manner in humans for the treatment of pain in a post-operative patient. operatopo.

The compounds of the present invention could be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated above, and such administration can be carried out in single or multiple doses. More specifically, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, that is, they could be coated with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, chips, tablets, hard candies, powders. , aerosols, creams, balms, suppositories, gelatins, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5% to 70% by weight, preferably between 10% and 50% by weight. For oral administration, tablets containing various excipients co or icrocrystalline cellulose, sodium citrate, calcium carbonate, phosphate and glycine could be used together with various disintegrants such as starch and preferably corn starch, potato or tapioca, alginic acid and certain complex silicates together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for compression purposes. Solid compositions of a similar type could also be used as a gelatin capsule filler; among the preferred materials in this respect also include lactose or milk sugar as well as high molecular weight polyethylene glycols, when aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient could be combined with various sweetening agents and flavors, dyes or coloring matters and, if desired, also ernulous agents and / or suspending agents together with diluents co or water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention may be employed either in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions could be suitably buffered (preferably at a pH> 8) if necessary and the liquid diluent first becomes isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily achieved by conventional pharmaceutical techniques well known to those skilled in the art. Additionally it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this would preferably be done by creams, gelatins, gels, pastes, ointments and the like according to conventional pharmaceutical practice.

EXAMPLES AND PREPARATIONS The present invention is illustrated by the following examples and preparations. However, it should be understood that the invention is not limited to the specific details of these examples and preparations. Melting points were taken with a Buchi micro-point fusion device and are not corrected. The absorption spectra of infrared (IR) radiation were measured in a Shimazu infrared spectrometer (IR-470). Nuclear magnetic resonance spectra of H and 13c (NMR) were measured in CDI3 with? N spectrometer or 30EL NMR (ZJNM-GX270, 270 MHz) unless otherwise indicated and the positions of the peaks are expressed in parts per million (ppm) below the tetramethylsilane. The shapes of the peaks are indicated as follows: s. singlet; d, doublet; t, tpplete; rn, multiplict; a, wide.

PREPARATION 1 (S) -N-benzyloxy-l-phenyl-2-pyrrolidinoethylamine To a stirring solution of (R) -2-enyl-2-pyrrolidinoethan (E. Brown et al., Tetrahedron: Assi etry, 2, 339, 1991; 4.78 g, 25 mmol) and triethylanine (3.95 rnL, 28 rnrnoles ) in CH2C.I2 (50 mL) was added rnetanosul fonilo chloride (2 mL, 26 mmol) dropwise at 0 ° C (ice bath). After 3 hours of stirring at 0 ° C to room temperature, the reaction mixture was washed with saturated aqueous NaHC 3 solution, dried (a 2 SO 3) and concentrated to give 5.88 g of a mixture of a yellow solid and a viscous brown oil. To this mixture was added O-benzylhydroxylamine (prepared from 5.99 g (37.5 mmol) of 0-benzylhydroxylamine hydrochloride per basification) and ethanol (6 mL) and the mixture was stirred at 80 ° C for 1 hour. The solvent was evaporated to give 9.47 g of white solid which was collected by filtration and washed with ethanol / ether to give 6.96 g (83.7%) of the hydrochloride salt of. desired product as a white crystalline solid, e.g. fus 161-162 ° C. 1 H NMR (270 MHz, CDCl 3 - 6 7.44-7.25 (10H, rn), 6.40 (1H, sa), 4.68 (1H, d, 3 = 11.7 Hz), 4.68-4.62 (1H, rn), 4.63 (1H, d, 3 = 1.1.7 Hz), 3.90-3.70 (1H, m), 3.60 (1H, dd, 3 = 7.7, 13.2 Hz), 3.55-3.40 (1H, m), 3.05 (1H, dd, 3 = 5.5, .13.2 Hz), 2.80-2.65 (1H, m), 2.65-2.45 (1H, rn), 2.25-2.05 (2H, rn), 2.05-1.80 (3H, rn) Anal.Cal, for C? 9H 4 20- HC1_C, 68.56; H, 7.57; N, 8.42; Cl, 10.65 Found: C, 68.36; H, 7.70; N, 8.39; Cl, 11.13 This hydrochloride salt (80 rng) was basified with solution of ammonium hydroxide was extracted with CH 2 Cl-2, dried (N 2 SO.sub.0) and concentrated to give 67 mg of a free amine derivative with a colorless oil: 1 H NMR (270 MHz, CDCl 3) ß 7.46-7.12 ( 10H, rn), 6.53 (1H, sa), 4.53 (1H, d, 3-11.0 Hz), 4.45 (1H, d, = 11.4 Hz), 3. 20 (1H, dd, 3 = 3.7, 11.4 Hz), 2.90 (1H, dd, 3 = 11.4, 12.5 Hz), 2.70-2.60 (2H, m), 2.50-2.35 (2H, m), 2.28 (1H, dd, -. = 4. 0, 12.5 1Hz), 1.80-1.70 (4H, m). IR (pure): 3250 crn-l. Ca] D = + 44.6 (c = 0.67, MeOH).

EXAMPLE 1 N-benzyloxy-2- (3, -dichloro phenyl) -N-Cl- (S) -phenyl-2- (1- pyrrolidi iDe il-lacetamide To a stirring solution of (S) -l- (2-0-benzylhydroxylamino-2-phenylethyl)? Irrolidine hydrochloride (2.88 g. 8. 65 mrnols) and 3-dichlorophenylacetic acid (2.05 g, 10 rnrols) in CH2Cl2 (30 rnL) was added 1-ethyl-3-hydrochloride. (3-dirnethylamino? Ropil) carbodiimide (2.30 g. 12 rnmoles) at 00 room temperature. After one hour of stirring, the reaction mixture was washed with water and saturated aqueous solution of NaHCO 3, dried (a 2 SO 3) and concentrated to give 4.44 g of a viscous light brown oil. Methane was added to this oil! (2 rnL) and allowed to stand for one hour. The white crystalline solid that appeared was collected by filtration to give 1.60 g of white powder. The filtrate was concentrated to give 2.84 g of oil and solid mixture, which was purified by column chromatography (silica gel, 100 g, CH 2 Cl / MeOH: 40/1) to give 0.82 g of a transparent yellow oil, which was crystallized by rnetanol (0.2 rnL), the total yield was 2.42 g (57.9%), P. fus, 88.5-90 ° C., 1 H NMR (270 MHz, CDCI3) &7.46-7.21 (12H, rn), 6.98 (1H, dd, 3 = 2.2, 8.4 Hz), 5.80-5.65 (1H, m), 4.73 (1H, d, 3 = 10.3 Hz), 4.43 (1.H, d, 3 = 10.6 Hz), 3.77 ( 1H, d, 3 = 15.8, Hz), 3.61-3.51 (2H,, including 1H, d, 3 = 15.4 Hz to 3.54 pprn), 2.75-2.60 (3H, rn), 2.55-2.40 (2H, m), 1.80-1.50 (4H, rn). IR (nujol): 1,570 cm-1.

EXAMPLE 2 2- (3,4-dichlorophenyl) -N-hydroxy-N - [.l- (S) -phenyl-2- (l- pyrrolidinyl-9-ethyl-3-acetamide A mixture slurry of N-benzyloxy-2- (3,4-dichlorophen-1) -Np- (S) -phenyl-2- (1-) was stirred at room temperature for 13 hours under hydrogen atmosphere. pyrrolidiniumethyl] acetarnide (1.60 g, 3.3 mmol), 10% palladium on carbon (0.16 g) and methanol saturated with gas HCl (20 nmol) in methanol (20 rnL) After removal of the catalyst by filtration through Celite, the filtrate was concentrated to give 1.63 g of a viscous oil of violet color, which was basified with NH 4 OH and extracted with CH 2 Cl 3 (3 x 20 L). The combined extract was dried (Na2c-0-.) And concentrated to give a brown crystalline solid, which was collected by filtration and washed with ether / hexane to give 1.04 g (80%) of a pale yellow powder. . P. fus. 118-120 ° C. 1 H NMR (270 MHz, CDCl 3) 6 7.44 (1 H, d, j = 1.8 H), 7.37-7.24 (6 H, m, including 1 H, d, 3 = 8.4 Hz at 7.36 pprn), 7.17 (1 H, dd, 3 = 1.8, 8.4 Hz), 5.56 (1H, dd, 3- 5.9, 10.3 Hz), 3.90 (1H, d, 3 = 14.3 Hz), 3.70 (1H, d, 3 = 13.9 Hz), 3.31 (1H, dd , 3 = 10.6, 12.5 Hz), 2.73 (IH, dd, 3 = 5.9, 12.5 Hz), 2.60-2.45 (4H, rn), 1.80-1.55 (4H, rn). IR (CH2Cl2): 3450.1650 cm ~ l. MS rn / z: 394 (M + +2, 0.48), 392 (M +, ll), 211 (4.8), 173 (3.1), 149 (12.9), 132 (12.8), 99 (28.8), 84 (100) . 925 rng of this crystalline solid was dissolved in CH2Cl2 (10 mL). To this solution was added ether saturated with gas HCl (10 L) at room temperature. The solution of the mixture was concentrated to give a white crystalline solid, which was collected by filtration and washed with ether to give 971 mg of the hydrochloride salt as a white powder. P. fus. 161-162 ° C. Ca] D = + 119.8 (c = 0.884, MeOH). Anal. Cale. for C20H22Cl2N2O. HCl- H2O; C, 54.75: H, . 51; N, 6.38. Found: C, 54.96; H, 5.49; N, 6.44.

EXAMPLE 3 2- (3,4-dichlorophenyl) -N-methoxy-N- [l- (S) -phenyl-2- (l- pyrrolidinylDetylJacetamide A mixture of 2- (3,4-d? Chlorophen? L) -N-hydroxy-N-p- (S) -fen? Was stirred at room temperature for three hours. 1-2- (1- ρrol? D? N? L) et? Pacetam? Da (598 mg, 1.5 mmol), tetrabutylammonium bisulfate (10 mg), aqueous solution of 50% NaOH (linL) and iodomethane ( 0.12 L, 2 immoles) in toluene (4 rnL). The mixture was extracted with ethyl acetate (2 x 20 rnL). the combined extract was washed with brine, dried (Na2 0") and concentrated to give 1.06 g of viscous brown oil, which was purified by column chromatography (60 g of silica gel, CH2Cl2 / MeOH: 20/1 ) to give 304 mg of a yellow viscous oil (49.8%). 1 H NMR (270 MHZ, CDC13) d 7.41-7.26 (7H, m), 7.09 (1H, dd, 3 = 1.8 Hz, 8.1 Hz), 5.70-5.60 (1H, rn), 3.83 (1H, d, 3 = . 4 Hz), 3.65 (lH, d, J = 15.4Hz), 3.50 (3H, s), 3.5 (1H, dd, 3 = 9.9, 12.5 Hz), 2.75-2.57 (3H,, including 1H, dd, 3 = 4.8, 12. 5 Hz to 2.50 ppm), 2.55-2.40 (2H,), 1.70 (4H, m). IR (pure): 1670 crn-l. 304 rng of this crystalline solid was dissolved in MeOH (5 L). To this solution was added ether saturated with gas HCl (5 rnL) at room temperature. The solution of the mixture was concentrated to give a white crystalline solid, which was collected by filtration and washed with ether to give 277 mg of the hydrochloride salt as a white powder. P. fus. 165-166 ° C. Anal. Cale, for C21H24CI2N2O2 • HCl- 0.5 H2O: C, 55.70: H, 5.79, 6.19. Found: C, 55.53; H, 5.80; N, 6.19.

EXAMPLE 4 N-hydroxy-N- Cl- (S) -phenyl-2- (l-pyrrolidinyl) ethyl 3-2- (2,3,6-trichloro phenyl) acetamide Was it prepared from (S) -l ~ (2-0-benzylh? Drox? Larn? No-2 ~ phenylethyl)? The invention is carried out with a yield of 66.6% according to a procedure similar to that described in Examples 2 and 3. P. fus. 172.8-177 ° C (hydrochloride salt). 1 H NMR (270 MHz, free amine, CDCl 3) 7.44-7.20 (8H, n), 5.61 (1H, dd, 3 = 5.9 Hz, 10.6 Hz), 4.36 (1H, d, 3 = 16.9 Hz), 4.26 (1H , d, 3 = 17.2 Hz), 3.40 (1H, dd, 3 = 10.6, 12.5 Hz), 2.80 (1H, dd, 3 = 5.9, 12.5 Hz), 2.76-2.55 (4H, m), 1.90-1.70 ( 4 H, rn). TR (pure free amine): 1650 cm-i. Anal. Cale, for O20H21CI3N2O2 • HCl- 0.5 H2O: C, 50.76: H, 4.90, 5.92. Found: C, 50.58; H, 4.65; N, 5.83.

EXAMPLE 5 N-hydroxy-N- [l- (S) -phenyl-2-yl-pyrrolidinyl) ethyl] -2- (4- tri fluoromethyl eni 1) cetamide It was prepared from (S) ~ l ~ (2-0-benzylhydrolamino-2-phenylethyl) pyrrolidine in 68% yield according to a procedure similar to that described in Examples 2 and 3. P. fus. 217-218.5 ° C (hydrochloride salt). 1 H NMR (270 MHz, free amine, CDCl 3) d 7.55 (2H, d, 3 = 8.4 Hz), 7.45 (2H, d, 3 = 8.1 Hz), 7.40-7.20 (6H, rn), 5.57 (JH, dd, 3 = 5.9 Hz, 10.3 Hz), 4.00 (1H, d, 3 = 13.9 Hz), 3.81 (1H, d, 3 = 13.9 Hz), 3.30 (1H, dd, 3 = 10.6, 12.5 Hz), 2.71 (1H, dd, 3 = 5.9, 12.5 Hz), 2.60-2.40 (4H, n), 1.80-1.50 (4H,). TR (pure free amine): 3150, 1650 crn-l. Anal. Cale. for C2iH23F3 2? 2- HC1- H20: C, 56.44: H, 5.86; N 6.27. Found: C, 56.16; H, 5.77; N, 6.76.

EXAMPLE 6 N-hydroxy-2- (l-naphthyl) -N-I-l- (S) -phen? L-2- (l- pi rrol i di nil) ethyl-acetamide It was prepared from (S) -l ~ (2-0 ~ benzylhydroxylene-2-enylethylpyrrolidine with a yield of 65.1% according to a procedure similar to that described in Examples 2 and 3. P. fus 81.0-83.5 ° C (chlorhi salt) 1 H NMR (270 MHz, free amine, CDC13) d 7.55-7.20 (13H, n), 5.59 (1H, dd, 3 = 5.9 Hz, 10.3 Hz) , 4.43 (1H, d, 3 = 14. 7 Hz), 4.10 (1H, d, 3 = 15.0 Hz), 3.31 (1H, dd, 3 = 11.0, 12.1 Hz), 2.65 (1H, dd, 3 = 5.9, 12.5 H), 2.55-2.35 (4H, rn), 1.60- 1.35 (4H, m). TR (pure free amine): 3150, 1650 crn-l. Anal. Cale, for 24H26N2O2 • HCl- 1.2 H2O: C, 66.64: H, 6. 85, N, 6.48.

Found: C, 66.93; H, 6.50; N, 6.02.

EXAMPLE 7 N-hydroxy-N- Cl- (S) -phenyl-2- (l-? Irrolidinyl) ethyl 3-2- (2,4,6-trimethylphenyl) acetamide It was prepared from (S) -l- (2-0-benzyl-1-hydroxylamino-2-pheni-leti-D-pyrrolidine in 58.9% yield according to a procedure similar to that described in Examples 2 and 3. P. fus. 186-187.2 ° C (hydrochloride salt). 1 H NMR (270 MHz, free amine, CDC13) d 7.42-7.24 (6H, m), 6.82 (2H, s), 5.70-5.55 (1H, m), 3.86 (2H, sa), 3.38 (1H, dd, 3 = 10.6 Hz, 12.1 Hz), 2.74 (1H, dd, 3 = 5.9 12.5 Hz), 2.70- 2.55 (4H, m), 2.22 (9H, s), 1.85-1.75 (4H, m). TR (pure free amine): 3220, 1640 crn-i. Anal. Cale, for C23H30 2O2 • HCl- 1.3 H2O: C, 64.79: H, 7.94, N, 6.57. Found: C, 64.51; H, 7.48; N, 6.31.

EXAMPLE 8 N -hydroxy-2- (4-pyridyl) -N-. L- (S-phenyl-2- (l-pyrrolidinyl) ethyl 3-acetamide It was prepared from (S) -l- (2-0 ~ benzylhydroxylamino-2-phenylethyl)? Irrolidine with a yield of 67.9% according to a similar procedure to. described in Examples 2 and 3. 1 H NMR (270 MHz, free amine, CDC13) d 8.46 (2H, d, 3 = 5.9 Hz), 7.40-7.18 (8H, rn), 5.61 (1H, dd, 3 = 5.5, 10.6 Hz), 3.91 (1H, d, 3 = 14.3 Hz), 3.77 (1H, d, 3 = 13.9 Hz), 3.33 (1H, dd, 3 = 11.0, 12.1 Hz), 2.68 (1H, dd, 3 = 5.5, 12.5 Hz), 2.57-2.40 (4H, rn), 1.80-1.55 (4H,). IR (pure free amine): 1640 crn ~ ?.

EXAMPLE 9 2- (benzo-b3furan-4-yl) -N-hydroxy-N-l- (S) -phenyl-2- (l- pyrrolidinyl? Ethyl acetamide It was prepared from (S) ~ l- (2-0-benzylhydroxylamino-2-phenylethyl) pyrrolidine in a yield of 73.5% according to a procedure similar to that described in Examples 2 and 3. H NMR (270 MHz, free amine, CDCl3) d 7.59 (1H, d, 3 = 1.8 Hz), 7.45-7.20 (9H,), 6.98 (IH, sa), 5.58 (1H, dd, 3 = 5.9, 10.6 Hz), 4.24 (1H , d, 3 = - 13.6 Hz), 3.91 (1H, d, 3 = 13.6 Hz), 3.28 (1H, dd, 3 = 11.3, 11.7 Hz), 2.68 (IH, dd, 3 = 5.9, 12.5 Hz), 2.45-2.30 (4H, rn), 1.60-1.30 (4H, rn). TR (pure free amine): 1650 cm-1.

PREPARATION 2 1,4-diiodo-2- (S) - (etra-idropyranyloxy) butane To a stirring solution of (S) - (-) - 1,2-b-tannol (10.61 g, 0.1 mol) in pipdin (100 L) was added in poroionee p-toluenesulfonyl chloride (38.13 g, 0.2 moles) at 0 ° C. After hours of stirring, the reaction mixture was poured into an aqueous solution of 10% HCl including ice and acidified to pH 2. The mixture was extracted with ethyl acetate (3 x 150 mL). The combined extract was washed with brine, dried (Na2S0-) and concentrated to give 42.88 g of colorless oil. A mixture of this crude ditosylate (42.88 g, 0.1 mol) and Nal (44.97 g, 0.3 mol) in acetone (300 rnL) was refluxed with stirring for 5 hours, the solid precipitate was removed by filtration and the filtrate was concentrated . The residue was dissolved in ethyl acetate and washed with an aqueous solution of N 2 2? 2 and brine, after drying (N 2? 4) the solvent was evaporated and the residue was purified by column chromatography (250 g. silica gel, hexane / ethyl acetate: 10/1) to give 24.81 g of colorless oil. A mixture of this oil (24.81 g, 76.1 rnmoles), 3,4-d? H? Dro-2H-p? Rano (21.9 mL, 0.24 moles) and p-toluensul fonato of pyridmium (125 mg) in CH2CI2 (100 L) was stirred at room temperature for 12 hours. The reaction mixture was expressed by cprn CH 2 Cl 2 (100 mL) was washed with aqueous NaHC 2 solution and dried (N 2 0). Evaporation of the solvent gave 33.56 g of pale yellow oil, which was purified by column chromatography (250 g of silica gel, hexane / ethyl acetate: 20/1) to give 28.75 g (70.1% for the three steps) of a colorless oil. H NMR (270 MHz, CDCl 3) d 4.80-4.75 (1H, rn), 402-3.85 (1H, rn), 3.70-3.17 (6H, m), 2.27-2.01 (2H, rn), 1.90-1.55 ( 6H, rn).

PREPARATION 3 2- (R) -phenyl-2- (3- (S) -tetrahydropyranyloxypyrrolidin-1-yl) ethanol A suspension mixes 1, 4-d iodine-2- (S) - (tetrahydro? Can? Lox?) Butane (12.50 g, 30 mmol), R - (-) - phenylglycol (3.43 g, 25 mmol) and K2CO3 (6.91 g, 50 mol) in ethanol (50 rnL) was refluxed with stirring for 6 hours. The white solid was removed by filtration and the filtrate was concentrated. The residue was diluted with aqueous NaHCO 3 solution (30 rnL) and extracted with CH 2 Cl 2 (3 x 20 mL). After drying 1 (a 2 0), the solvent was evaporated to give 9.54 g of a clear yellow oil, which was purified by column chromatography (150 g of silica gel, CH 2 Cl 2 / MeOH: 20 l) give 7.22 g (99%) of colorless viscous oil. 1 H NMR (270 MHz, CDCl 3) d 7.37-7.27 (5H, rn), 4.61-4.51 (1H, rn), 4.40-4.28 (1H,), 3.91 -3.75 (3H, m), 3.55-3.42 (2H, rn), 2.92-2.72 (1H, rn), 2.70-2.57 (2H, m), 2 , 55-2.25 (2H, rn), 2.20-1.95 (1H, in), 1.93-1.60 (3H, m), 1.60-1.45 (4H, n) . TR (pur): 3450 cm ~ 1.

PREPARATION 4 1- (S) - phenyl-N-tetrahydropyranyloxy-2- (3- (S) -etherahydropyranyloxypyrroline din-1-yl) eti sheet It was prepared from 2- (R) ~ phenyl? -2- (3- (S) ~ tetrahydro? Can? Lox? Rrol? D? Nl-? L) ethanol and o-tet rahydropyranylhydroxylanine (RN Uarrener and EN Cain, Angew, Chern, Tnt, Edit, 5, 511, 1996) with a performance of 42.5% as a brown oil according to the procedure similar to that described in Preparation l. 1 H NMR (270 MHz, CDCl 3) d 7.45-7.25 (5H, rn), 6.51 (1H, sa), 4.80-4.73 (1H,), 4.65-4.55 (1H,), 4.45-4.33 (1H, rn), 4.28-4.15 (1H, m), 4.00-3.75 (2H, m), 3.70-2, 55 (9H,), 2.30-2.05 (1H, rn), 1.90-1.35 (12H, rn).

EXAMPLE 10 2- (3,4-dichlorophenyl) -N-tetrahydropyranyloxy-N-C2- (3- (S) -tetrahydropyranyloxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from l- (S) ~ phen l-N-tetrah? Drop? Ran? Lox? -2- (3- (S) -tetrahydropyranyloxypyrrolidol-l-yl) ethylarn? Na and 3,4-dichlorophenylacetic acid with a yield of 69.8% as a viscous transparent brown oil according to a procedure similar to that described in Example 1. 1 H NMR (270 MHz, CDC13) d 7.43-7.15 (7. 4H, m), 6.98-6.91 (0.6H, rn), 5.69 (0.4H, dd, 3 = 4.0, 11.0 Hz), 5.58 (0.6H, dd, 3 = 4.8, 11.4 Hz), 5.35-5.20 (1H, rn), 4 , 65-4.53 (1H, rn), 4.41-4.21 (1H, m), 4.15-3.80 (4H, m), 3.68-3.10 (4H, m) , 3.03-2.80 (2H, rn), 2.70-2.35 (3H,), 2.20-1.10 (13H, rn). ? R (pure): 1660 crn- 1.

EXAMPLE 11 2- (3,4-dichlorophenyl) -n-hydroxy-n-C2- (3- (s) -hydroxypyrrolidin-1-yl) -1- (s) -phenylethylacetamide A mixture of 2- (3,4-dichlorophenol) -N-tetrahydropyranyloxy iN- [2- (3- (S) -tetrahydropyranylox? Pyrrole? Din-l-? Was stirred at room temperature for seven hours. ) -l- (S) - femlet? i3acetam? da (1.13 g, 1.96 mmol) and MeOH saturated with gae HCl (4 rnL) in MeOH (20 mL). The solvent was evaporated. The residue was basified with saturated aqueous solution of NaHC 3, extracted with CH 2 Cl 2 and dried (Na 2 SO 3). Evaporation of the solvent gave 0.80 g of a viscous brown oil, which was crystallized by adding ether and scraping. The crystalline solid was collected by filtration and washed with ether to give 377 mg (47.1%) of a white powder. P. fus. 98.5-99.5"C. 1 H NMR (270 MHz, CDCl 3) 6 7.45-7.20 (7H, rn), 7.14 (1H, dd, 3 = 1.8, 9.9 Hz), 5.62 (1H, dd, 3 = 5.5, 11.0 Hz), 5.00-3.00 (2H, almost flat sa), 4.35-4 , 25 (1H, m), 3.85 (1H, d, 3 = 14.3 Hz), 3.73 (1H, d, 3 = 13.9 Hz), 3.38 (1H, dd, 3- 11.0, 12.5 Hz), 2.95 (1H, td, 3 = 5.1, 8.8 Hz), 2.73 (1H, d, 3 = 10.6 Hz), 2.65 ( 1H, dd, 3 = 5.5, 12.5 Hz), 2.51 (1H, dd, 3 = 5.5, 10.6 Hz), 2.40-2.27 (JH, rn), 2 , 22-2.07 (1H, rn), 1.65-1.50 (1H, rn). TR (Nujol): 3070, 1640 crn "1. FM / Z: 412 (M + + 4, 10.3), 410 M + + 2, 85.7), 408 (M +, 100), 304 (8.6) , 149 (50.2), 114 (22.7), 112 (24.2), Hydrochloride salt, mp 65.5-67.0 ° C, Anal.Cal, for C20H22CI2N2O3 -HCl -0, 5 H2O: C, 52.82; H, 5.32; N, 6.16. Found: C, 53.09; H, 5.29; N, 6.17.

PREPARATION 5 (R) - (-) - 2- (4-fl uoro feni Dglicí nol It was prepared from 4-fluoro-D-α-phenylglycine with a yield of 88% according to the procedure of D.A. Evans (Organic Synthesis, 68, 77). 1 H NMR (270 MHz, CDC13) d 7.30 (2H, dd, 3 = 5.5, 8.4 Hz), 7.03 (2H, t, 3 = 8.4 Hz), 4.05 (1H , dd, 3 = 4.4, 8.1 Hz), 3.71 (1H, dd, 3 = 4.4, 10.6 Hz), 3.53 (1H, dd, 3 = 8.4, 10 , 6 Hz), 2.19 (3H, sa). IR (KBr): 3350, 3280 crn- 1.

PREPARATION 6 2- (R) - (r-fluorophenyl) -2- (3- (S) -te-rahydropyranyloxypyrrolidin-yl) ethanol It was prepared from (R) - (-) - 2- (4-fluoropheni 1) -glycine in a yield of 68.8% according to a procedure similar to that described in Preparation 3. 1 H NMR (270 MHz, CDCl 3) d 7.31-7.26 (2H, rn), 7.03 (2H, dd, 3 = 8.4, 8.8 Hz), 4.65-4.51 (1H, m) , 4.40-4.27 (1H, m), 3.90-3.75 (3H, rn), 3.55-3.40 (2H, rn), 2.90-2.70 (1H, rn), 2.70-2.50 (2H, rn), 2.50-2.35 (1H, rn), 2.30-1.95 (2H, rn), 1.95-1.60 ( 3H, rn), 1.60-1.45 (4H, rn).

IR (pure): 3450 cm- 1.

EXAMPLE 12 2- (3, -dichloro phenyl) -n-Cl- (s) - (- fluorophenyl) ethyl-2- (3- (s) -hydroxypyrrolidin-1-yl) 3-n-nidroxyacetamide It was prepared from 2- (R) - (4-fluorophen? L) -2- (3 ~ (S) -tetrah? Dro? Ran? Lox? Pyrrole? D? Nl-il) ethanol and 3,4-dichlorophellatic acid with a yield of 52.8% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) 6 7.41-7.26 (4H, rn), 7.12 (1H, dd, 3 = 1.8, 8.1 Hz), 6.99 (2H, dd, 3 = 8.4, 8.8 Hz), 5.60 (1H, dd, 3 = 5.1, 11.0 Hz), 4.35-4.25 (1H, m), 3.82 (1H, d, 3 = 13.9 Hz), 3.72 (1H, d, 3 = 14.3 Hz), 3.71 (IH, s), 3.58 (1H, s), 3.35 (1H, dd, 3 = 11.7, 12, 1 Hz), 3.00-2.90 (1H, rn), 2.73 (1H, da, 3 = 11.0 Hz), 2.58 (1H, dd, 3 = 5.1, 12.5 Hz), 2.51 (1H, dd, 3 = 5.5, 10.6 Hz), 2.37-2.10 (2H, rn), 1.65-1.55 (1H, in). IR (pure): 3200, 1640 cm ~ i. MS rn / z: 426 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H21C12FN2O3 -HCl -0.7 H2O: C, 50.43; H, 4.95; N, 5.88. Found: C, 50.80; H, 4.96; N, 5.45., EXAMPLE 13 2- (4-bromoenyl) -N-idroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) ~ phenyl-2- (3 ~ (S) -tetrahydropranyloxypyrrolidin-1-yl) ethanol and 4-brorophenylacetic acid with a yield of 44.6% according to a similar procedure. to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.50-7.14 (9H, m), 5.60 (IH, dd, 3 = 5.1 , 11.0 Hz), 4.28-4.22 (1H,), 3.90 (1H, d, 3 = 13.6 Hz), 3.70 (1H, d, 3 = 13.9 Hz) , 3.33 (1H, dd, 3 = 11.0, 12.5 Hz), 2.92-2.82 (1H, m), 2.72-2.64 (2H, m), 2.50 (1H, dd, 3 = 5.5, 10.6 Hz), 2.38-2.28 (1H, rn), 2.20 (2H, sa), 2.16-2, 01 (1H, in ), 1.60-1.50 (1H,). IR (pure): 3200, 1630 crn-l. MS rn / z: 418 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H23 BrN2? 3 -CH1-0.5 H2O: C, 51.68; H, 5.42; N, 6.03. Found: C, 51.75; H, 5.51; N, 5.71.

EXAMPLE 14 2- (3-bromophenyl) -N-idrxi-N- [2- (3- (S? -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydropyranilox? Pyrrol? Din-l-yl) ethanol and 3-b-romophenylacetic acid with a yield of 29.8% of according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3? &7, 51-7,15 (9H, m), 5.62 (IH, dd , 3 = 5.5, 11.0 Hz), 4.28-4.20 (1H,), 3.94 (1H, d, 3 = 13.9 Hz), 3.70 (1H, d, 3 = 13.6 Hz), 3.35 (1H, dd, 3 = 11.4, 12.5 H), 2.92-2.83 (1H, m), 2.70-2.62 (2H, m), 2.18-2.03 (1H, rn), 1.60-1.46 (1H, m) IR (pure): 3200, 1630 arr., MS m / Z: 4L8 (M +). Hydrochloride salt: amorphous solid, Anal.Cal, for C2? H23Br 2? 3"HCI-H2O: C, 50.70; H, 5.53; N, 5.91 Found: C, 50.57; H, 5.58; N, 5.90.

EXAMPLE 15 2- (4-flurophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenii-2 ~ (3- (S) ~ tetrahydro? Can? Lox? Rrol? D? Nl-? L) ethanol and 4- fl uorofeni lacet acid ico with a yield of 23.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHZ, CDC13) d 7.40-7.22 (7H, m), 7.10-6.95 (2H, rn), 5.67-5.61 (1H, m), 4.34-4.22 (1H, m), 3.92 (1H, d, 3 = 13 , 6 Hz), 3.73 (1H, d, 3 = 13.9 Hz), 3.36 (1H, dd, 3 = 10.6, 12.5 Hz), 2.96-2.86 (1H ,), 2.76-2.82 (2H,), 2.58-2.48 (IH, rn), 2.40-2.28 (1H, rn), 2.24-1.70 (3H , rn), 1.64-1.48 (1H,). IR (pure): 3400, 1630 crn- 1. MS in / z: 358 (11+). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H23FN2O3-HCl-0.4 H20: C, 59.74; H, 6.22; N, 6.97. Found: C, 59.81; H, 6.43; N, 6.88.

EXAMPLE 16 2- (3,4-dimethyloxyphenyl) -N-hydroxy-N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenyl-beta-3-acetamide It was prepared from 2- (R) -phenyl ~ 2 ~ (3- (S) -tetrahydropyranyloxypyrrole din-l-yl) ethanol and 3,4-dirnetoxifemlacetic acid with a yield of 10.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.40-7.22 (5H, m), 6.95-6.78 (3H, rn ), 5.70-5.60 (1H,), 4.25-4.15 (1H, rn), 3.91 (1H, d, 3 = 13.9 Hz), 3.88 (3H, s) ), 3.87 (3H, s), 3.68 (1H, d, 3 = 13.9 (Hz), 3.33 (1H, dd, 3 = 11.4, 11.7 Hz), 2, 90-2.78 (1H,), 2.74-2.60 (2H, rn), 2.47 (1H, dd, 3 = 5.1, 10.6 Hz), 2.34-2.20 (1H, rn), 2.14-1.98 (1H, rn), L, 90 (2H, sa), 1.50-1.36 (1H, rn) IR (pure): 3400, 1640 crn -l "MS m / z: 400 (M +). Hydrochloride salt: solid or amorphous, Anal, Cale, for C22H28FN2O5 -HCl -2.7 H20: C, 54.42; H, 7.14; N, ,77. Found: C, 54.31; H, 6.77; N, 5.92.

EXAMPLE 17 N -hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-2- (3-tri fluoromethyl) acetamide It was prepared from 2- (R) -phenyl-2- (3 ~ (S) -tetr-c.hydro-iranyloxypyrrolidin-1-yl) ethanol and 3-tri fluoromethyl phenylacetic acid in a yield of 18.9% of according to a procedure similar to that described in Preparation 4 and examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.60-7.26 (9H, rn), 5.75-5.65 (1H, rn), 4.35-4.25 (1H, m), 3.99 (1H, d, 3 = 14.3 Hz), 3.86 (1H, d, 3 = 14.3 Hz) , 3.54-3.38 (1H, m), 3.04-2.94 (1H, rn), 2.84-2.40 (6H, rn), 2.20-2.06 (1H, rn), 1.70-1.55 (1H,). TR (pure): 3350, 1630 crn-l. MS m / z: 408 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C21H23F3N2O3 -HCl -1.9 H2O: C, 54.70; H, 5.64; N, 6.08. Found: C, 54.83; H, 5.97; N, 6.21.

EXAMPLE 18 N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3- 2- (4-rifluoromethyl-phenyl) -acetamide It was prepared from 2 ~ (R) -phenyl-2- (3- (S) -tetrahydro-iranyloxypyrrolidin-1-yl) ethanol and 4-trifluoromethyl-phenyl-acetic acid with a yield of 35.4% according to with a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.56 (2 H, d, 3 = 8.1 Hz), 7.44 ( 2H, d, 3 = 8.1 Hz), 7.33-7.26 (5H, m), 5.65 (1H, dd, 3 = 5.9, 11.0 Hz), 4.35-4 , 20 (1H, m), 3.99 (1H, d, 3 = 14.3 H), 3.85 (1H, d, 3 = 13.9 Hz), 3.41 (1H, dd, 3 = 12.1, 12.5 Hz), 3.00-2.90 (1H, rn), 2.82-2.02 (7H, rn), 1.64-1.50 (1H, rn). TR (pure): 3100, 1650 crn ~ 1. MS rn / z: 408 (M +). Hydrochloride salt: p. fus 142.5-144.2 aC. Anal. Cale, for C 21 H 23 F 3 N 2 O 3 -HCl-0.2 H 2 O: C, 56.24; H, 5.48; N, 6.25. Found: C, 56.27; H, 5.6.1; N, 6.08.

EXAMPLE 19 2- (4-bi-enyl) -N-hydroxy-N-2- (3- (S) -nidroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydropyranyloxypyrrolidin-1-yl) ethanol and 4-bi-phenylacetic acid with a yield of 38.8% according to a procedure similar to that is described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) d 7.60-7.26 (14H, rn), 5.66 (1H, dd, 3 = 5.1, 11 , 0 HZ), 4.20-4.14 (1H, m), 4.04 (1H, d, 3 = 13.6 Hz), 3.76 (1H, d, 3 = 13.2 Hz), 3.35 (1H, dd, 3 = 10.3, 13.6 Hz), 2.90-2.80 (1H,), 2.73-2.63 (2H,), 2.55-2, 45 (1H,), 2.35-2.22 (1H, rn), 2.10-1.96 (1H, rn), 1.90 (2H, sa), 1.50-1.35 (1 .H, rn). MS m / z: 417 (M + H) +. Hydrochloride salt: p. fus 163.8-1.65.5 ° C. Anal. Cale. for C 26 H 28 2 O 3 -HCl-0.5 H 2 O: C, 67.60; H, 6.55; N, 6.06. Found: C, 67.77; H, 6.42; N, 5.76.

EXAMPLE 20 N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phemlethyl-3- (4-nitrophenyl) acetamide It was prepared from 2- (R) -phen? L-2 ~ (3- (S) ~ tetrah? Drop? Ran? Lox? P? Rrol? D? Nl-? L) ethanol and 4-mtrofen lactic acid with a yield of 11.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 8.14 (2H, d, 3 = 8, 8 Hz), 7.44 (2H, d, 3 = 8.8 Hz), 7.35-7.16 (5H, m), 5.74 (1H, dd, 3 = 4.8, 10.3 Hz), 4.46-4.38 (1H, rn), 4.03 (1H, d, 3 = 15.0 Hz), 3.96 (1H, d, 3-15.0 Hz), 3, 64-3.50 (1H, m), 3.20-3.10 (1H, m), 2.96 (1H, da, 3 = 10.3 Hz), 2.90-2.74 (3H, n), 2.66 (2H, ea), 2.30-2.16 (1H, rn), 1.84-1.70 (IH, rn). TR (pure): 3400, 1630 crn-l. MS rn / z: 385 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C20H23N3O5 -HCl -1.5 H20: C, 53.51; H, 6.06; N, 9.36. Found: C, 53.71; H, 6.01; N, 9.11.

EXAMPLE 21 N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3- (3-nitrophenyl) acetamide It was prepared from 2- (R) -phenyl-2- (3 ~ (S) -tetrahydropyranyloxypropyl din-1-yl) ethanol and 3-mprophenylacetic acid with a yield of 11.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 8.17-8.08 (2H, rn), 7.66-7.20 (7H, rn) , 5.64 (IH, dd, 3 = 5.9, 11.0 Hz), 4.38-4.30 (1H,), 4.03 (1H, d, 3 = 14.7 Hz), 3 , 90 (1H, d, 3 = 14.3 Hz), 3.50-3.38 (1H, rn), 3.06-2.94 (1H, n), 2.84-2.70 (2H , rn), 2.66-2.56 (1H,), 2.50-2.32 (IH, m), 2.20-2.04 (JH, rn), 1.96 (2H, sa) , 1.70-1.50 (1H, rn).

MS rn / z: 386 (M + H) +. Hydrochloride salt: p. fus 154.3-155.5 ° C. Anal. Cale. for C20H23N3OS -HCl -0.3 H2O: C, 56.22; H, 5.80; N, 9.83. Found: C, 56.29; H, 5.80; N, 9.55.

EXAMPLE 22 2- (4-chloro-enyl) -N-hydroxy-N- [2- (3- (S) -idroxypyrrolidin-1-yl) -1- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phen? -2- (3- (S) -tetrah? Drop? Ran? Lox? P? Rrol? D? Nl-? L) ethanol and 4-chlorofemlacet acid with a yield of 49.4% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) d 7.40-7.20 (9H, m), 5.65 (IH, dd, 3) 5.1, 11.0 Hz), 5.00-3.30 (2H, very widespread), 4.35-4.25 (1H, rn), 3, 86 (1H, d, 3 = 13.9 Hz), 3.74 (1H, d, 3 = 13.9 Hz), 3.40 (1H, dd, 3 = 11.7, 12.1 Hz), 3.02-2.90 (IH, rn), 2.75 (1H, da, 3 = 10.6 Hz), 2.61 (1H, dd, 3 = 5.1, 12.5 Hz), 2 , 51 (IH, dd, 3 = - 5.1, .3 Hz), 2.40-2.25 (1H, m), 2.23-2.08 (IH, rn), 1.65-1.50 (IH, rn). IR (pure): 3400, 1630 crn- 1. MS rn / z: 374 (M +). Hydrochloride salt: p. fus 146, 5-147.3 ° C. Anal. Cale, for C20H23CIN2O3 -HC1-0, 3H2O: C, 57.64; H, 5.95; N, 6.72. Found: C, 57.87; H, 5.88; N, 6.78. k l EXAMPLE 23 2- (3-Chloroenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydropyran? Lox? Pi rrolidin-1-y1) ethanol and 3-clo-ofenylacetic acid with a yield of 29.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.34-7.20 (9H, rn), 5.75-5 , 62 (1H,), 4.35-4.25 (1H, rn), 3.94 (1H, d, J = 1.39 Hz), 3.74 (1H, d, 3 = 13.9 Hz ), 3.45 (1H, dd, 3 = 9.5 12.1 H), 3.05-2.92 (1H, rn), 2.80 (1H, da, 3 = 10.6 Hz), 2.77-2.30 (3H, rn), 3.80-2.30 (2H, almost flat peak), 2.23-2.06 (1H, m), 1.68-1.54 (1H , rn). IR (pure): 3350, 1630 an- 1. MS m / Z: 374 (M +). Hydrochloride salt: p. fus 113.2-114.3 ° C. Anal. Cale, for C20H23CIN2O3 -HCl-0.4 H20: C, 57.40; H, 5.97; N, 6.69. Found: C, 57.79; H, 5.84; N, 6.74.

EXAMPLE 24 2- (2-chlorophenyl) -N-hydroxy-N-2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydropyraniloxyrrolidin-1-yl) ethanol and 2-chlorophenolacetic acid with a yield of 31.2% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) 6 7.45-7.16 (9H, m), 5.85-5.70 (1H , rn), 4.44-4.34 (1H, rn), 4.14 (IH, d, 3 = 16.1 Hz), 3.91 (1H, d, 3 = 16.1 Hz), 3 , 68-3.48 (1H, rn), 3.24-3.10 (1H, m), 2.98-2.40 (6H, rn), 2.34-2.18 (1H,), 1.86-1.70 (1H,). IR (pure): 3400, 1640 crn "1. EM rn / z: 374 (M +). Hydrochloride salt: p.mult 146 ° C. Anal.Cal, for C20H23CIN2O3 -HCl> H20: C, 55.95; H, 6.10; N, 6.52, Found: C, 56.18; H, 6.00; N, 6.55.

EXAMPLE 25 N -hydroxy-N --- 2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3- (2, 3, 5-trichlorophenyl) acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydro-iranyloxypyrrolidin-1-yl) ethanol and 2, 3, 5-trichlorophenylacetic acid with a yield of 51.6% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) d 7.45-7.26 (6H, rn), 7.14 (1H, d, 3 = 2 , 2 Hz), 5.70 (1H, dd, 3 = 4.8, 11.0 Hz), 4.48-4.30 (1H, rn), 4.20-3, 00) (2H, sa very extended), 4.06 (1H, d, 3 = 16.5 Hz), 3.90 (1H, d, 3 = 16.1 Hz), 3.50 (1H, dd, 3 = 11.4, 12.1 Hz), 3.20-3.10 (1H, rn), 2.86 (1H, da, 3 = 10.3 Hz), 2.75-2.60 (2H,), 2.55 -2.35 (1H,), 2.35-2.20 (1H, m), 1.85-1.70 (lh, rn). IR (pure): 3400, 1640 crn-l. MS rn / z: 444 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H21Cl3N2O3 -HC1-H20: C, 48.21; H, 4.86; N, .62. Found: C, 48.56; H, 5.17; N, 5.40.

EXAMPLE 26 N-hydroxy-N- [2- (3- (5) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3- (2, 4,6-trichlorophenyl) acetamide It was prepared from 2- (R) -phen? L-2- (3- (S) -tetrah? Dropiraniloxypyrrolidin-1-yl) ethanol and 2,4,6-trichlorophenolacetic acid with a yield of 14.0% of according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.50-7.26 (7H, m), 5.60 (1H, dd, 3 = 4.8, 11.4 Hz), 4.47-4.38 (1H,), 4 , 19 (2H, s), 3.49 (1H, dd, 3 = 11.7, 12.1 Hz), 3.25-3.10 (1H, m), 2.84 (1H, da, 3 = 9.5 Hz), 2.75-2.60 (2H,), 2.50-2.35 (2H,), 2.35-2.20 (2H, m), 1.90-1, 70 (1H, rn). TR (pure): 3450 1640 cm ~ 1. MS rn / z: 442 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C20H21CI3N2O3 -HC1 -0.2 H20: C, 49.65; H, 4.67; N, 5.79. Found: C, 49.42; H, 4.39; N, 5.96.

EXAMPLE 27 N-hydroxy-N --- 2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-2- (2,4,6-trimethylphenyl) acetamide It was prepared from 2- (R) -phen? J -2- (3- (S) -tet rah? Dro? Ran? Lox? P? Rrol? D? Nl-? L) ethanol and acid 2, 4,6-tprnethyiphenylacetic with a 67.8% yield according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) 6 7, 45-7.25 (5H, rn), 6.81 (2H, s), 5.80-5.65 (1H, m), 4.40-4.30 (1H,), 3.86 (2H, s), 3 , 49 (1H, dd, 3 = 11.7, 13.2 Hz), 3.20-3.10 (1H, rn), 2.80 (1H, da, 3 = 10.3 Hz), 2, 65-2.05 (2H, m), 2.35-2.25 (3H, rn), 2.23 (3H, s), 2.18 (6H, s), 1.90-1.65 ( 1H, rn), 1.65-1.50 (1H, rn). TR (pure): 3250, 1630 c - 1. MS rn / z: 382 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C23H3? N? 3HCl-0, H2O: C, 64.01; H, 7.57; N, 6.49. Found: C, 64.08; H, 7.85; N, 6.61.

EXAMPLE 28 2- (2,3-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydro-iranyloxypyrrolidin-1-yl) ethanol and 2, 3-dichlorophenylacetic acid in 56% yield according to an procedure similar to that described in Preparation 4 and Examplese 10 and 11. 1 H NMR (270 MHz, CDC.I3) d 7.50-7.05 (8H, m), 5.69 (1H, dd , 3 = 5.1, 11.4 Hz), 5.00-3.00 (2H, almost flat sa), 4.45-4.35 (1H, rn), 4.1.0 (1H, d, 3 = 16.1 Hz), 3.92 (1H, d, 3 = 16.1 Hz), 3.48 (1.H, dd, 3 = 11.7, 12.1 Hz), 3.20-3 , 10 (1H, m), 2.82 (1H, d, 3 = 10.3 Hz), 2.70-2.55 (2H, rn), 2.45-2.20 (2H, m), 1.80-1.70 (1H, rn). IR (pure): 3200, 1640 crn-l. MS m / z: 408 (M +). Hydrochloride salt: p. fus 155.3-1.58.1 ° C. Anal. Cale, for C20H22Cl2N2O3 -HCl: C, 53.89; H, 5.20; N, 6.28.

Found: C, 53.72; H, 5.24; N, 6.16.

EXAMPLE 29 2- (2,4-d-chlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-l) -l- (S) -phemlethyl-3-acetamide It was prepared from 2- (R) -phen? L-2- (3- (S) -tetrahydro? Can? Lox? Rrol? D? Nl-? L) ethanol and acid 2, 4 -dichlorophenylacetic with a yield of 71.9% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHZ, CDC13) d 7.45-7.15 (8H, m) , 5.69 (1H, dd, 3 = 5.1, 11.4 Hz), 6.50-4.50 (2H, almost flat sa), 4.35-4.25 (1H, m), 4 , 00 (1H, d, 3 = 16.1 Hz), 3.86 (1H, d, 3 = 16.1 Hz), 3.47 (1H, dd, 3 = 11.7, 12.1 Hz) , 3.20-3.10 (IH, m), 2.83 (1H, d, 3 == 10.6 Hz), 2.61 (2H, dd, 3 = 5.5, 12.1 Hz) , 2, 45-2.20 (2H, rn), 1.80-1.65 (1H, m). IR (pure): 3200, 1635 crn-. MS rn / z: 408 (M +). Hydrochloride salt: p-fus. 149-151.5 ° C. Anal. Cale, for C20H22Cl2 2O3 -HCl-0.2 H2O: C, 53.46; H, 5.25; N, 6.23. Found: C, 53.46; H, 5.19; N, 6.19.

EXAMPLE 30 2- (2, 5-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-l-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (R) -phenyl-2- (3- (S) -tetrahydro? Ramlox? Pyrrole? Din-l-? L) ethanol and 2, 5-dichloro-phenylacetic acid with A yield of 56.3% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) 6 7.45-7.15 (8H, rn) , 5.69 (1H, dd, J = 5.1, 11.0 Hz), 5.60-4.50 (2H, almost flat sa), 4.35-4.25 (1H, rn), 4 , 03 (1H, d, 3 = 16.1 Hz), 3.86 (1H, d, 3 = 16.1 H), 3.47 (1H, t, 3 = 11.7 Hz), 3.20 -3.10 (1H, m), 2.82 (1H, d, 3 = 10.6 Hz), 2.63 (2H, dd, 3 = 5.1, 12.1 Hz), 2.45- 2.20 (2H, rn), 1.85-1.70 (1H, rn). 1 H NMR (270 MHz, CDCl 3) d 7.45-7.15 (8H, rn), 5.69 (1H, dd, - = 5.1, 11.0 Hz), 5.60-4.50 (2H, sa almost flat), 4.35-4.25 (1H, rn), 4.03 (1H, d, 3 = 16.1 Hz), 3.86 (1H, d, 3 = 16.1 Hz), 3.47 (IH, t, 3 = 11.7 Hz), 3.20-3.10 (1H, m), 2.82 (JH, d, 3 = 10.6 Hz), 2.63 (2H, dd, 3 = 5.1, 12.1 Hz), 2.45-2.20 (2H,), 1.85-1.70 (1H, rn). TR (pure): 3200, 1635 cm-1. MS rn / z: 408 (M +). Hydrochloride salt: p. fus 157.5-158.2 ° C. Anal. Cale. for C20H22Cl2N2O3 -HCl-0.2 H20: C, 53.46; H, 5.25; N, 6.23. Found: C, 53.35; H, 5.21; N, 6.14.

PREPARATION 7 2- (3- (S) -methoxymethyloxypyrrolidin-1-yl) -2- (R) -phenylethanol To a stirring solution of (S) - (-) - butane riol (10, 61 g, 0.1 mol) in pipdin (50 mL) was added in portions p-toluenesulfonyl chloride (38.13 g, 0.2 mol) at 0 ° C (ice bath). After one hour of stirring, the reaction mixture was poured into an aqueous solution of c-HCl including ice and acidified to pH 2. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried (Na2SO-i) and concentrated to give 36.22 g of light brown transparent oil. To a stirring solution of this crude ditosylate (36.22 g) and ethylal (50 inL) in CH2Cl2 (50 L) was added P2O5 (20 g). After one hour of stirring, another 10 g of Je P2OS was added to the reaction mixture. After two hours of stirring, the CH2Cl2 layer was separated. The residual dark brown solid was washed with CH2Cl2. The combined CH 2 Cl 2 layer was washed with an aqueous solution of NaHC 3, dried (Na 2 SO 3) and concentrated to give 38.51 g of viscous brown oil. A mixture of this oil (38.51 g, 84 rnmolee), (R) - (-) -2-fen? Lgl? Cmol (10.97 g, 80 rnrn) and tpetiiamine (23 mL, 160 mmol) in ethanol (40 ml.) Was refluxed with stirring for 15 hours. The solvent was evaporated and the residue was dissolved in CH 2 Cl 2 (200 L), washed with an aqueous solution of NaHC 3 and brine, dried (Na 2 SO 3) and concentrated to give 28.43 g of a viscous brown oil. The oil was purified by column chromatography (200 g of silica gel, CH 2 Cl 2 / methanol: 40/1 to 20/1) to give 9.74 g (48.4%) of a transparent brown viscose oil. 1 H NMR (270 MHz, CDCI3) d 7.40-7.25 (5H, n), 4.62 (1H, d, 3 = 7.0 Hz), 4.58 (1H, d, 3 = 6.6 Hz), 4, 26-4.18 (1H, rn), 3.92 (1H, dd, 3 = 6.2, 11.0 Hz), 3.82 (1H, dd, 3 = 5.5, 11.0 Hz) , 3.54 (2H, t, 3 = 5.9 Hz), 3.33 (3H, s), 2.93 (1H, sa), 2.85-2.66 (3H, rn), 2, 56-2.47 (IH, rn), 2.16-2.02 (1H, rn), 1.88-1.77 (1H, rn).

EXAMPLE 31 2- (2,6-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-l-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (3 - (?) - methox-rnetiloxypyrrolidin-11-11) - (R) -phenylatenol and 2,6-d? Chlorophen-acetic acid with a yield of 47.2% according to a sun Llar-ai procedure which is described in Preparation 4 and Examples 10 and ll. 1 H NMR (270 MHz, CDCl 3) d 7.50-7.25 (7H, m), 7.20-7.10 (1H, rn), 5.71 (1H, dd, 3 = 5.1, 11 , 4 Hz), 5.40-3.70 (2H, almost flat sa) 4.50-4.40 (1H, rn), 4.25 (2H, s), 3.50 (1H, dd, 3 = 11.0, 12.5 Hz), 3.28-3.15 (IH, m), 2.87 (1H, d, 3 = 10.3 Hz), 2.75-2.55 (2H,), 1.90-1, 70 (1H, rn). IR (KBr): 3400, 1640 crn ~ 1. MS rn / z: 408 (M +). Hydrochloride salt: p. fus 95.5-96.8 ° C. Anal. Cale. for C20H22Cl2N2O3 -HCl -0.5 H20: C, 52.82; H, 5.32; N, 6, 16. Found: C, 52.61; H, 5.13; N, 6.10.

EXAMPLE 32 2- (3,5-dichloro-enyl) -N-idroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (3- (S) -methoxymethioxyap-r? Rrol? D? Nl-? L) -2- (R) -phemlatenol and 3,5-dichlorofemlacetic acid with a yield of 47.8% of according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) d 7.45-7.15 (8H, rn), 5.63 (IH, dde, J = 5.5, 11.0 Hz) , 4.50-3.00 (2H, ea caei plane), 4.40-4.28 (1H, rn), 3.87 (1H, d, 3 = 14.3 Hz), 3.71 (1H , d, 3 = 14.3 Hz), 3.39 (1H, dd, 3 = 11.4, 12.1 Hz), 3.05-2.95 (1H, rn), 2.74 (1H, d, 3 = 11.0 Hz), 2.65 (1H, dd, 3 = 5.5, 12.5 Hz), 2.54 (1H, dd, 3 = 5.5, 10.6 Hz), 2.45-2.30 (IH, rn), 2.25-2.10 (lH, m), 1.70-1.55 (1H,). IR (pure): 408, 1650 ern "1.

MS / z 408 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H22Cl2N2O3 -HC1-2 H2O: C, 49.86; H, 5.65; N, 5.81. Found: C, 49.49; H, 5.53; N, 5.59.

EXAMPLE 26 N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-2- (2,3,6-trichlorophenyl) acetamide It was prepared from 2 ~ (3- (S) -rnetoxymethyloxypyrrolidin-1-yl) -2- (R) -phenylethanol and 2,3,6-trichlorophenolacetic acid with a yield of 46.7% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDCl 3) d 7.45-7.20 (7H, rn), 5.69 (1H, dd, 3 = 4.8, 11.0 Hz) , 5.00-3.50 (2H, almost flat sa), 4.50-4.40 (1H, rn), 4.29 (2H, s), 3.49 (1H, t, 3 = 11, 7 Hz), 3.25-3.15 (1H, rn), 2.85 (1H, d, 3 = 10.3 Hz), 2.70-2.60 (2H, m), 2.45- 2.20 (2H, rn), 1.90-1.70 (1H, n). IR (KBr-): 3400, 1640 ern "1. MS rn / z: 442 (M *). Hydrochloride salt: mp 102-103 ° C Anal.Cal, for C20H21CI3N2O3 -HCl -H20: C, 48.21; H, 4.86; N, .62.

Found: C, 48.40; H, 4.64; N, 5.52.

EXAMPLE 34 2- (benzoCb3 uran-4-yl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl-3-acetamide It was prepared from 2- (3- (S) -rnetoxirnethyl-ox? P? Rrolid? Nl-il) -2- (R) -phenylethenol and 4-benzole, bifuranacetic acid with a yield of 57.5% according to with a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.64 (1 H, d, 3 = 2.2 Hz), 7.50-7.25 (7H, m), 7.14 (1H, d, 3 = 7.3 Hz), 6.84 (1H, dd, 3 =: 0.7, 2.2Hz), 5.61 (1H, dd 3 = 5.5, 11.4 Hz), 4.24 (LH, d, 3 = 13.6 Hz), 4.05-3.95 (1H, in), 3.91 (IH, d, 3 = 13.2 Hz), 3.31 (1H, dd, 3 = 11.7, 12.1 Hz), 2.75-2.65 (1H, rn), 2.63-2.50 (2H, rn), 2.30 (JH, dd, 3 = 5.1, 10.3 Hz), 2.20-2.10 (1H, m), 2.00-1.85 (1H, rn). IR (pure): 3400, 1635 cm-1. MS m / z: 380 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C22H24 2O4 -HCl -1.1 H2O: C, 60.51; H, 6.28; N, 6.41. Found: C, 60.31; H, 5.98; N, 6.47.

EXAMPLE 35 N-hydroxy-N --- 2- (3- (S) -hydroxypyrrolidin-l-yl) -l- (S) -phenylethyl-2- (l-tetralon-6-yl) acetamide It was prepared from 2- (3- (S) -rnetoxymethaloxypyrrole dm-1-yl) -2- (R) -phenylethanol and acetic acid (l-tetralone-6) with a yield of 59.4. % according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.96 (1 H, d, 3 = 8.1 Hz), 7.40 -7.18 (7H, m), 5.66 (1H, dd, 3 = 5.5, 11.0 Hz), 4.30-4.20 (1H, rn), 3.94 (JH, d) , 30 14.3 Hz), 3.81 (1H, d, 3 = 13.9 Hz), 3.80-2.00 (2H, almost flat sa), 3.40 (1H, dd, 3 = 11 , 7, 12.1 Hz), 3.00-2.85 (3H, rn), 2.80-2.50 (5H, rn), 2.45-2.30 (1H, n), 2, 20-2.05 (3H,), 1.65-1.50 (JH, n). TR (pure): 3400, 1680, 1640 cm-1. MS / z: 408 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C24H28 2O4 -HCl -1, 2H2O: C, 61.78; H, 6.78; N, 6.00. Found: C, 61.60; H, 6.59; N, 6.35.

EXAMPLE 36 2- (3, 4-dimethyl enyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl acetamide It was prepared from 2- (3- (S) -rnetox-netiloxiprrolidin-1-? L) -2- (R) -phenylethanol and 3,4-dineti-phenylacetic acid with a yield of 66.8% according to a procedure similar to that described in Preparation 6 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7, 45-7.25 (5H, m), 7.20-7.00 (3H, rn), 5.66 (1H, dd, 3 = 5.1, 11.4 Hz), 4.25-4.10 (1H, m), 3.87 (1H, d, 3 = 13 , 9 Hz), 3.67 (1H, d, 3 = 13.9 Hz), 3.37 (1H, dd, 3 = 11.7, 12.1 Hz), 3.00-2.85 (1H , m), 2.71 (IN, d, 3 = 9.9 Hz), 2.55 (1H, dd, 3 = 1.5, 12.5 Hz), 2.42 (1H, dd, 3 = 5.1, 9, g Hz), 2.35-2.05 (9H,, including every 3H, s, at 2.22 and 2.21 pprn), 1.80-1.35 (2H, m) . IR (pure): 3350, 1630 crn-l. MS rn / z: 368 (M +). Hydrochloride salt: amorphous solid. Anal. Cale. for C22H28N2O3 -HC1-1.8 H20: C, 60.42; H, 7.51; N, 6.41. Found: C, 60.51; H, 7.71; N, 6.29.

EXAMPLE 37 2- (3,4-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (R) -phenylethyl-3-acetamide It was prepared from 2- (3- (S) -rnetox? Rnet? Lox? P? Rrol? D? Nl-? L) -2- (S) -phenylethenol and 3,4-dichlorophenylacetic acid with a yield of 32.8% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.45-7.25 (7H, m), 7.13 (1H , dd, 3 = 1.5, 8.1 Hz), 5.61 (1H, dd, 3 = 5.5, 10.6 Hz), 5.00-3.90 (2H, almost flat sa), 4.45-4.35 (1H, m), 3.85 (1H, d, 3 = 14.7 Hz), 3.77 (1H, d, 3 = 14.3 Hz), 3.37 (1H , dd, 3 = 11.0, 12.5 Hz), 2.89 (1H, dd, 3 = 4.7, 8.4 Hz), 2.80-2.60 (3H, m), 2, 45-2.35 (1H, rn), 2.15-2.00 (IH, in), 1.80-1.65 (1H,). IR (KBr): 3450, 2350, 1650 crn-l. MS rn / z: 408 (M +). P. fus. 125.5-126.0 ° C. Ccr] D = - 95.4 ° (c = 0.218, methanol) Anal. Cale, for C20H22Cl2N2O3: C, 58.69; H, 5.42; N, 6.84. Found: C, 58.51; H, 5.42; N, 6.70.

EXAMPLE 38 2- (benzoCb3thiophen-4-yl) -N-idroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (3- (S) -rnetox? Rnet? Ioxyro-r? Din-l-yl) -2- (R) -phenylethenol and acid (benzol.b3t? ofen-4 ~? l) acetic with a yield of 48.8% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7 , 79 (1H, d, 3 = 7.7 Hz), 7.66 (1H, d, 3 = 5.5 Hz), 7.50-7.20 (8H, m), 5.50 (1H, dd, 3 = 5.5, 11.4 Hz), 4.60-3.20 (2H, almost flat sa), 4.32 (1H, d, 3 = 13.6 H), 4.01 (1H , d, 3 = 13.6 Hz), 4.00-3.90 (1H, m), 3.30 (1H, dd, 3 = 11.7, 12.1 Hz), 2.70-2, 45 (3H, m), 2.28 (1H, dd, 3 = 5.1, 1.0.3 Hz), 2.20-2.10 (1H,), 1.95-1.80 (1H,), 1.20-1.05 (1H,). TR (pure): 3400, 3200, 1630 crn "1. MS m / z: 396 (M +). Hydrochloride salt: amorphous solid, Anal.Cal for C22H24N2O3 -HCl -0.5 H20: C, 59.79; H, 5.93; N, 6.34. Found: C, 59.85; H, 6.09; N, 6.27.

EXAMPLE 40 N-hydroxy-N-C2- (3- (S) -h? Droxipyrrolidin-l-yl) -l- (S) -phenylethyl-3- (3,4-methylenedioxy) -acetamide It was prepared from 2- (3 - (S) -rnetox? Rnet? Lox? P? Rrol? D? Nl ~ il) -2- (R) -phenol and 3, 4-rnetylenedioxifemlacetic acid with a yield of 59.7% according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.45-7.25 (5H, m),. ,, 35-6.70 (3H,? N), 5.92 (2H, s), 5.66 (1H, dd, 3 = 5.5, 11.4 Hz), 4.50-3.30 (2H, almost flat sa), 4.30-4.20 (1H, m), 3.86 (1H, d, 3 = 13.6 Hz), 3.64 (1H, d, 3 = 13.9 Hz), 3.39 (1H, t, 3 = 12.1 Hz), 3.05-2.95 (LH, n), 2.72 (1H, d, 3 = 10.3 Hz), 2, 59 (1H, dd, 3 = 5.5, 12.5 Hz), 2.48 (1H, dd, 3 = 5.5, 10.3 Hz), 2.35-2.10 (2H, rn), 1.65-1.50 (1H, in). IR (pure): 3400, 3250, 1630 cpr1. FM rn / z: 384 (M +). SaJ hydrochloride: amorphous solid. Anal. Cale. for C2lH2"2? s -HCl-l, 4H2O: C, 56.54; H, 6.28; N, 6.28. Found: C, 56.74; H, 6.38; N, 5.89.

EXAMPLE 41 2- (3, 5-diflurophenyl) -N-hydroxy-N-E2- (3- (S) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide It was prepared from 2- (3- (S) ~ rnetox? Net? Lox p? Rrol? D? Nl-? L) -2- (R) -phen? Latenol and 3,5-difluorophenylacetic acid with a 40.0% yield according to a procedure similar to that described in Preparation 4 and Examples 10 and 11. 1 H NMR (270 MHz, CDC13) d 7.40-7.25 (5H, rn), 6.82 (2H, d, 3 = 8.1 Hz), 6.72-6.64 (1H, rn), 5.65 (IH, dd, J = 5.1, 11.0 Hz), 5.30-4.20 (2H, sa almost flat), 4.40-4.30 (1H,), 3.86 (1H, d, 3 = 14.3 Hz), 3.74 (1H, d, 3 = 14.3 Hz), 3, 41 (1H, dd, 3 = 11.7 12.1 Hz), 3.10-2.95 (1H, rn), 2.76 (1H, d, 3 = 10.6 H), 2.61 ( 1H, dd, 3 = 5.1, 12.5 Hz), 2.52 (1H, dd, 3 = 5.5, 10.6 Hz), 2.40-2.10 (2H,), 1.70-1.55 (1H,). TR (pure): 3350, 3200, 1630 crn-l. MS m / z: 376 (M +). Hydrochloride salt: amorphous solid. Anal. Cale, for C20H22F2N2O3 -HCl-0.5 H2O: C, 56.94; H, 5.73; N, 6.64. Found: C, 57.01; H, 5.93; N, 6.45.

PREPARATION 8 l-benzyl-3- (R) -tetrahydropyranyloxypyrrolidine To a stirring solution of (R) - (+) - 1-benzyl-3-pyrrolidinol (5.00 g, 28 mmol) and D-canfr-10-s-1-methyl acid (6.97 g, mmoles) in CH 2 Cl 2 (10 mL) was added 3, 4-dihydro-2H-α-urane (20 rnL) at room temperature and the reaction mixture was stirred for 14 hours (in most cases, the reaction it was finished after the exothermic reaction became less violent). The reaction mixture was diluted with CH2Cl2 (100 rnL), washed with saturated aqueous solution of NaHC3, dried (Na2S0-) and concentrated to give a brown oil. This was purified by column chromatography (silica gel, 200 g; CH 2 Cl 2 / MeOH: 40/1 as eluent) to give 8.78 g (97.6%) of the desired compound as a brown oil. 1 H NMR (270 MHz, CDCl 3) d 7.34-7.22 (5H, rn), 4.61 (0.5H, dd, 3 = 2.9, 4.4 Hz), 4.54 (0, 5H, dd, 3 = 2.9, 4.4 Hz), 4.42-4.31 (1H, m), 3.90-3.79 (1H, rn), 3.67 (1H, d, 3 = 12.8 H), 3.59 (0.5H, d, 3 = 12.8 H), 3.58 (0.5H, d, 3 = 12.8 Hz), 3.50-3, 40 (1H, rn), 2.88 (0.5H, dd, 3 = 6.6, 10.3 Hz), 2.74-2.45 (3.5H, rn), 2.25-2.05 (1H, rn), 1.95-1.45 (7H, rn).

PREPARATION 9 3- (R) -Tetrahydropylarsiloxypyrrolidine A mixture of l-benzyl-3- (R) -tetrahydropyranyloxypyrrolidine (8.78 g, 27.3 mmol) and Pearlman's catalyst (3.50 g) in MeOH (100 rnl) was stirred at room temperature for four hours under hydrogen atmosphere. After removing the catalyst by filtration through Celite, the filtrate was concentrated to give 5.74 g of a clear light brown oil. He used the following reaction without pupil. H NMR (270 MHz, CDCl 3) d 4.62 (1H, sa), 4.45-4.30 (1H, in), 3.90-3.80 (1H, m), 3.55-3.45 (1H, m), 3.20-2.80 (5H, rn ), 2.00-L.40 (8H, m).

PREPARATION 10 l- (S) -Fenyl-2- (3- (R) -tetrahydropyranyloxypyrrolidin-1-yl) ethanol and 2- (R) -phenyl-2- (3- (R) -tetrahydropyranyl-oxypyrrolidin-1- iDetanol A mixture of 3- (R) -tetrah? Drop? Ran? Lox? Prolide (1.43 g, 8.32 min.) And oxide "Je (S) ~ (-) -est was refluxed with stirring for one hour. urn (1.00 g, 8.32 rnrols) in EtOH (10 mL). Evaporation of the solvent gave 3098 g of brown oil, which was purified by column chromatography. (silica gel, 100 g; CH2Cl2 / MeOH: 40/1 to 15/1 as eluent) to give 1.68 g (69.3%) of clear light brown oil as a mixture of approximately 2 to 1 of the title compounds in which l- (S) -phenyl-2- (3- (R) -tetrahydropyranyloxypyrrolidin-1-yl) ethanol was the main one. H H NMR (270 MHz, CDC13) 7. 7.40-7.24 (5H,? L), 4.72 and 4.68 (total 0.67H, each appears d, 3 = 2.6 Hz, EIGHT), 4.63-4.55 (1H, m, PhCHO and EIGHT), 4.43-4.25 (1H, ra, 0CHCH2N), 3.89-3.81 (1.67H, rn), 3.52-3.46 (1.33H, m), 2.88-2.47 (5.33H, rn), 2.15 -1.90 (2H, m), 1.86-1.66 (3H, rn), 1.58-1.51 (4H, rn).

EXAMPLE 42 2- (3-4-Dichlorophenyl) -N-1-l- (S) -phenyl-2- (3- (R) -te-rahydro-pyranyloxypropyl-n-1-yl) ethyl-3N-tetrahydropyranyl-oxyacetamine To a stirring solution of l- (S) -phenyl-2- (3- (R) -tetrahydro? Iranyloxy? Irrolidin-1-yl) ethanol (1.67 g, 5.73 mol) and Et3N (0.96 ml, 6.88 m moles) in CH 2 Cl 2 (20 ml) was added drop or drop mesyl chloride (0.53 rnl, 6.88 rnmoles) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with aqueous NaHCO 3 solution, dried (a 2 SO 3) and concentrated to give 2.02 g of a brown oil. This oil was used in the next reaction without being purified. 1H RMM (270 MHz, CDC.1-3) 6 7.42-7.30 (5H, rn), 4.94 (1H, dd, 3 = 5.9, 8.1 Hz, PhCHCl), 4.60 and 4.52 (total 1H, each rn, EIGHT), 4.35-4.31 (1H, m, OCHCH2N), 3.88-3.82 (1H, rn), 3.48-3.45 (1H, m), 3.25-3.17 (1H, m), 3.02-2.69 (3H,), 2.66-2.50 (3H,) , 1.88-1.67 (3H,), 1.56-1.51 (4H, m). A mixture of the crude chloride derivative (2.02 g, 5.73 rnmoles) and 0- (tetrahydropranyl Jhydroxylannine (0.806 g, 6.88 mmol) in EtOH (10 nl) was refluxed with stirring during 0. 5 hours. The reaction mixture was concentrated, diluted with CH2Cl2 (30 ml), washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO-;) and concentrated to give 2.59 g of a brown oil. This oil was used in the next reaction without being purified. A mixture of the above cross-linked amine derivative (2.59 g, 5.73 mmol), 3,4-dichlorophenylacetic acid (1.41 g, 6.88 mmol) and l-ethyl-3- (3-diracrylaminopro-yl) -carbodiimide hydrochloride (abbreviated as USC , 1.32 g, 6.88 mrnols) in CH2Cl2 (15 rnl) was stirred at room temperature for 0.5 hours. The reaction mixture was washed with saturated aqueous NaHC 3 solution and brine, dried (Na 2 O 2) and concentrated to give 4.12 g of a brown oil. This oil is purified by chromatography on a column (silica gel, 100 g, CH2Cl2 / MeOH: 50/1 to 40/1 as eluent) to give 2.22 g (67.1%) pale yellow oil axis.

EXAMPLE 43 2- (3,4-Dichlorophenyl) -N-hydroxy-N- [2- (3- (R) -hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide A mixture of the above amide derivative (2.20 g, 3.81 mol) and MeOH containing HCL gas (10 rnl) was stirred at room temperature for 1 hour. The reaction mixture was concentrated or basified with aqueous NH 3 solution and extracted with CH 2 Cl 2 (30 rnl). The extract was washed with brine, dried (Na2 0-v) and concentrated to give a light brown powder. This was collected by filtration and washed with hexane to give 1117 g (71.6%) of light brown powder. 1 H NMR (270 MHz, CDCl 3) & 7.41-7.28 (7H, m), 7.13 (JH, dd, 3 = 1.8, 8.4 Hz), 5.61 (1H, dd, 3 = 5.5, JO, 6 Hz), 4.50-3.50 (2H , sa almost piano), 4.40-4.35 (1H, rn), 3.85 (1H, d, 3 = 14.7 Hz), 3.77 (1H, d, J = 14.3 Hz), 3.38 (1H, dd, 3 = 11.0, 12.1 Hz), 2.94-2.85 (1H,), 2.74-2.63 ( 3H, rn), 2.44-2.35 (1H, in), 2.15-2.01 (1H,), 1.80-1.95 (1H, m). IR (KBr1): 3250, 1650 cm-1. MS m / z: 408 (M +). Sal clo hydrate: amorphous solid. Anal. Cale. for C2? H2 Cl2N20-HCl • 0.8 H2O: C, 52.20; H, 5.39; N, 6.09. Found: C, 52.22; H, 5.39; N, 5.12.

EXAMPLE 44 2- (3,4-dichlorophenyl) -N-hydroxy-N-C2- (3) - (R) -hydroxypyrrolidin-1-yl) -1- (R) -phenylethylacetamide It was prepared from 3- (R) -tetrahydropyrianyl-oxypyrrolidine and (R) - (+) - -duranary oxide with a yield of 33.3% according to the similar procedure described in Examples 3 to 5. H NMR (270 MH, CDC13) d 7.38 (1H, d, 3 = 8.4 Hz), 7.36-7.25 (6H, m), 7.13 (1H, dd, 3 = 1.8, 8 , 1 Hz), 5.64 (1H, dd, 3 = 5.1, 11.0 Hz), 5.00-3.50 (2H, almost flat), 4.35-4.25 (1H, rn), 3.84 (1H, d, 3 = 14.3 Hz), 3.73 (1H, d, 3 = 13.2 Hz), 3.40 (1H, dd, 3 = 11.4, 12.5 Hz), 3.05-2.95 ( 1H,), 2.74 (1H, da, 3 = 10.3 Hz), 2.62 (1H, dd, 3 = 5.1, 12.5 Hz), 2.51 (1H, dd, 3 = 5.5, 10.6 Hz), 2.40-2.25-2.10 (1H, m), 1.70-1.55 (1H, m). IR (KBr): 3400, 3200, 1640 crn-l. MS m / Z: 408 (M +). Salt clophidrate: only amorphous. Anal. Cale, for C20H22Cl2N2O3-HCl • 0.5H2O: C, 52.82; H, 5.32; N, 6.16. Found: C, 52.17; H, 5.59; N, 6.15.

PREPARATION 11 (S) -l-O-Methylphenyl) -l, 2-ethanediol stirred at 0 ° C for 3.5 hours a mixture of 3- rnetylstyrene (1.69 rnl, 12.7 mmol) and AD-rnix-cr (17.78 g, 12.7 rnrnoies) in water (65 ml) and t-BuOH (65 ml). To this reaction mixture was added Na2SO3 (20 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried (Na2 0) and concentrated to give 2.07 g of a clear standing oil, which was purified by column chromatography (silica gel, 110 g, ethyl acetate / hexane : 3/2) to give L.89 g (98%) of the desired product as a light brown oil. iH NMR (270 MHz, CDC1-3) d 7.24 (1H, dd, 3 = 7.3, 7.7 Hz), 7.19-7.09 (3H, m), 4.77 (1H, dd, 3 = 3.7, 8.1 Hz), 3.74 (1H, dd, 3 = 3.7, 11.4 Hz), 3.65 (1H, dd, 3 = 8.1, 11.4 Hz), 2.82 (1H, sa), 2.35 (3H, s), 1.77 (1H, sa).

PREPARATION 12 2-Tosylate (S) -l- (3-methylphenyl) -l, 2-ethanediol To a stirring solution of (S) -l- (3-rnet? Lfen? L) -l, 2-ethanod? Ol 1.78 g, 11.7 mmoles) in pipdin (35 rnl) was added chlorurue of p-toluenesulfonyl (2.46 g, 12..9 rnrnoles) and 4-d? Rnet? Iam? Nop? Pd? Na (1.58 g, 12.9 rnmoles) at 0 ° C and the reaction mixture was stirred at 0 ° C to room temperature environment for 17 hours. The reaction mixture was acidified with aqueous 6N HCl solution and extracted with CH2Cl2. The extract was washed with water and brine, dried (N 2? 4) and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography (silica gel, 100 g.; ethyl acetate / hexane: 1/9 to 1/3) to give 2.63 g (73%) of the desired product as a cairo yellow oil. S? optical purity was 97% estimated by HPLC using a qui ral stationary fse (Chiralp AS, Daicel Chemical Industries, eluted with n-hexane / EtOH: 98/2, detection time: 55 minutes for the (R) isomer and 59 minutes for the (S) isomer, i H NMR (270 MHz, CDCl 3) &7.77 (2 H, d, 3 = 8.4 Hz), 7.33 (2H, d, 3 = 8.1 Hz), 7.22 (1H, dd, 3 = 7.7, 8.1 Hz), 7.15-7.05 (3H, rn), 4 , 94 (1H, ddd, 3 = 2.9, 2.9, 8.4 Hz), 4.15 (JH, dd, 3 = 2.9, 10.3 Hz), 4.04 (1H, dd , 3 = 8.4, 10.3 Hz), 2.54 (1H, da, 3 = 2.9 Hz), 2.45 (3, s), 2.33 (3H, s), 1.58 (3H, s).

PREPARATION 13 2- (3- (S) -methoxymethyloxypyrrolidin-1-yl) -l- (S) - (3-methyl-enyl) tanol and 2- (3- (S) -methoxymethyloxypyrrolidin-1-yl) -2- (R) - (3-methyl pheni 1) ethanol A mixture of (S) -l- (3-rnethylphenyl) -J-, 2-ethanediol 2-tosylate was refluxed with 2-hour stirring. (2.63 g, 8.59 mmol), (S) -3-methoxyrnethyloxy-pyrrolidine (1.24 g, 9.45 mmol) and K2CO3 (1.31 g, 9.45 mmol) in ethanol (25 nl). After removing the solvent by evaporation, the residue was diluted with water and extracted with CH2Cl2. The extract was washed with brine, dried (Na2SO) and concentrated to give 2. 11 g of brown oil, which was purified by column chromatography (silica gel, 110 g; CH 2 Cl 2 / MeOH: 15/1 to 10/1) to give 1.72 g (76%) of a mixture 3 to 2 of the desired products as a light brown oil. iH NMR (270 MHz, CDC13) 6 7.26-7.05 (4H, m), 4.68 (0.6H, dd; 3 = 2.9, 10.6 Hz, PhCHOH), 4.67 ( 0.6H, d, 3 = 7.0 Hz, OCH2O), 4.63 (0.6H, d, 3 = 6.6 Hz, OCH2O), 4.62 (0.4H, d, 3 = 7, 0 Hz, 0CH2O), 4.59 (0.4H, d, 3 = 7.0H, OCH2?), 4.34-4.24 (0.6H, rn, OCHCH2N), 4.24-4, 16 (0.4H, m, OCHCH2N), 3.88 (04H, dd, 3 = 6.2, 10.6 Hz, CHCH2OH), 3.79 (0.4H, dd, 3 = 5.8, 11 , 0 H, CHCH2OH), 3.47 (0.4H, dd, 3 = 5.8, 6.2 Hz NCHPh), 3.38 (l, 8H, s), 3.33 (1.2H, s ), 3.05-2.92 (1.2H, m), 2.82-2.40 (4H, rn), 2.35 (3H, s), 2.25-1.50 (3H, m ).

EXAMPLE 45 2- (3,4-Dichlorophenyl) -N-C2- (3- (5) -methoxymethyloxy-pyrrolidin-1-yl) -1- (S) - (3-methylphenyl) ethyl-3-N-tetrahydropyranyloxyacetamide It was prepared from a mixture of 2 ~ (3 - (S) -rnetoxirneti lox? pyrrol? din-1-? 1) -1- (S) - (3-methyl phenyl) ethanol and 2- (3- (S ) -rnetox? rnetilox? p? rrol? d? nl ~ il) -2- (R) - (3-methyl phenyl) ethanol with a 60% yield according to the procedure similar to that described in Example 4. i H NMR (270 MHz, CDCl 3) d 7.39 (0.5 H, d, 3 = 1.8 Hz), 7.35 (0.5 h, d, j = 8.4 hZ), 7, 27-7.02 (5.5h, M), 6.96 (0.5h, dd, 3- 1.8, 8.4 hZ), 5.65 (0.5h, dd j = 5.1, 11.4 hZ, PhCHN), 5.52 (0.5H, dd, 3 = 4.8, 11.0 Hz, PhCHN), 5.30-5.20 (1H, rn, NOCHO), 4.64 (0.5H, d, 3 =, 6 Hz, 0CH20), 4.63 (0.5H, d, 3 = 7.0 Hz, 0CH.20), 4.60 (0.5H, d, 3 = 6.6 Hz, OCH2?), 4.30-4.20 (0.5H, rn, 0CHCH2N), 4.20-4.10 (0.5H, m, OCHCH2N), 4.06-3.85 (3H, rn), 3.56-3.36 (1.5H, m), 3.35 (1.5H, s, OMe), 3.34 (1.5H, s, OMe), 3.24 -3.10 (0.5H, m), 3.01-2.80 (2H, m), 2.66-2.40 (3H, rn), 2.34 ( 1, 5H, s), 2.28 (1.5H, s), 2.15-1.15 (8H,? n).

EXAMPLE 46 2- (3,4-Dichlorophenyl) -N-hydroxy_N_C2- (3- (S) -hydroxy-pyrrolidin-1-yl) -l- (S) - (3-methylphenyl) ethyl 3-acetamine Prepared from 2- (3,4-dichlorophen? L) -N-C2- (3- (S) -ethoxymethylloxypyrrolid? Nl-? L) -l- (S) - (3-methylphenyl) ethyl-N-terahydropyranyloxyacetarnide with a yield of 77% % according to the procedure similar to that described in Example 5. iH NMR (270 MH, CDCI3? d 7.42-7.05 (7H, rn), 5.59 (1H, dd, 3 = 5.1, 11.0 Hz, PhCHN), 4.35-4.25 (lH, rn, CHOH), 3.85 (1H, d, 3 = 14.3 Hz, C0CH_2P ), 3.74 (1H, d, 3 = 15.8 H, C0CH_2Ph), 3.50-2.50 (2H, sa almost piano, 2x OH), 3.38 (1H, dd, 3 = 11, 7, 12.1 Hz), 3.00-2.90 (1H, rn), 2.73 (1H, da, 3 = 10.6 Hz), 2.62 (1H, dd, 3 = 5.1 , 12.5 Hz), 2.53 (1H, dd, 3 = 5.5, 10.6 Hz), 2.40-2.25 (4H, rn, including 3H, sa 2.30 pprn), 2 , 23-2.07 (1H, rn), 1.65-1.55 (1H, rn). IR (pure): 3350, 1650 cm ~ i. Hydrochloride salt: amorphous solid. Anal. Cale, for C21H2-ICI2N2O3-CHI-1.5 H2O: C, 51.81,; H, 5.80; N, 5.75.

Found: C, 51.85; H, 5.72; N, 5.47.

EXAMPLE 47 N --- l- (S) - (4-chlorophenyl) -2- (3- (S) -hydroxypyrrolidin-1-yl) ethyl 3-2- (3, 4-di chloro-phenyl) -N- hydrox y cet amide Prepared from 4-chlorostyrene and 3- (S) -rnetoxymethyloxypyrrolidine with an overall yield of 12% by a process similar to that described in Examples 7 to 11. iH RMM (270 MHz, CDC13) d 7.40 (1H, d, 3- 2.2Hz), 7.36 (1H, d, 3 = 8.4 Hz), 7.30-7.20 (4H, M), 7.14 (1H, dd, 3 = 2.2, 8.1 Hz), 5 , 58 (1H, dd, 3 = 5.1, 11.0 Hz, PhCHN), 5.00-300 (2H, sa almost flat, 2x OH), 4.35-4.25 (1H,, CHOH), 3.85 (IH, d, 3 = 14.3 Hz, CHCH2Ph), 3.72 (1H, d) , 3 = 13.9 Hz, C0CH2Ph), 3.33 (1H, t, 3 = 11.7 Hz), 3.00-2.85 (1H, m), 2.74 (IH, da, 3 = .3 Hz), 2.65 (IH, dd, 3 = 5.1, 12.5 Hz), 2.60-2.45 (IH, rn), 2.45-2.25 (1H, rn ), 2.25-2.05 (1H, rn), 1.70-1.50 (IH, rn). Amorphous solid hydrochloride salt. TR (KBr): 3400, 3100, 1650 crn ~ 1. MS rn / z: 443 (M + H) +. Anal. Cale, for C 20 H 21 Cl 3 N 2 O 3 -CH 1 -0, 7 H 2 O: C, 48.74; H, 4.79; M, 5.68. Found: C, 49.15; H, 5.21; N, 5.58.

EXAMPLE 48 2- (3,4-dichloroenyl) -N-hydroxy-N-E2- (3- (S) -hydroxy-pyrrolidin-1-yl) -l- (S) - (4-methoxyphenyl) ethyl-3-acetamide and 2- (3,4-dichlorophenyl) -N-hydroxy-N-E2- (3- (S) -hydroxy-pyrrolidin-1-yl) (R) - (4-methoxyphenyl) -ethyl-3-acetamide It was prepared from rnetoxin styrene 7 3 - (S) -rnetoxirnethyloxypyrrolidine with an overall yield of 5.2% according to a procedure similar to that described in Examples 7 to 11. In this case, recrystallisation occurs in position 1 to give the title compounds during the following reactions (mesylation, addition of THPONH2 and aci lion). i H NMR (270 MHz, CDCl 3) d 7.40-7.26 (4H,), 7.12 (0.5H, dd, 3 = 2.2 8.4 Hz), 7.11 (0.5H, dd, 3 = 2.6, 8.4 Hz), 6.84 (2H, d, 3 = 8.4 H), 5.70-5.60 (1H, rn, PhCHN), 4.50-4 , 40 (l <Q, 5H, rn, CHOH), 4.50-3.00 (2H, almost flat, 2x OH), 4.40-4.30 (0.5H, m, CHOH), 3.84 (1H, d, 3 = 14.3 Hz, C0CH2Ph), 3.79 (3H, s), 3.73 (1H, d, 3 = 14.7 C0CH2Ph), 3.65-3.40 (1H, rn), 3.15-3.00 (1H,), 2.90-2.40 (4H, m), 2.30-2.10 (1H, n), 1.90-1, 78 (0.5H, m), 1.78-1.60 (0.5H, m). Salt (KBr-): 3400, 3150, 1650 cm- i. MS rn / a: 438 (M +). Anal. Cale, for C21H2-1CI2N2O4-CHI-2.5 H2O: C, 48.43; H, 5.8; N, 5.38. Found: C, 48.21; H, 5.75; N, 5.35.

EXAMPLE 49 2- (3,4-Dichlorophenyl) -N-hydroxy-NE- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) - (4-trifluoromethylphenyl) -yl-3-acetamide Was prepared from 4 -trif luorometi lest i rein and 3- (S) -methoxymethyloxy? irrolidine with an overall yield of .3% according to a procedure similar to the one described in Examples 7 to 11. iH RMHz (270 MHz, CDC13) d 7.60-7.35 (6H, m), 7.20-7 , 10 (IH, rn), 5.65 (1H, dd, 3 = 5.5 11.0 Hz, PhCHN), 4.40-4.30 (1H, rn, CHOH), 3.90 (1H, d, 3 = 13.9 Hz, C0CH2Ph), 3.73 (1H, d, 3 = 12.5 Hz, COCH ^ Ph), 3.34 (1H, dd, 3 = 11.0, 12.5 H), 3.00- 2.90 (1H, rn), 2.75-2 , 65 (2H, rn), 2.54 (1H, dd, 3 = 5.1, 10.6 Hz), 2.50-2.00 (4H, m), 1.70-1.55 (1H , m). TR (pure): 3,400, 3250, 1635 crn-1. MS rn / z: 476 (M +). Hydrochloride salt: amorphous solid Anal. Cale, for C 21 H 1 Cl 2 F 3 N 2 O 3 -HCl 2 H 2 O: C, 45.88; H, 4.77; N, 5.10. Found: C, 45.90; H, 4.83; N, 4.71.

PREPARATION 14 (S) -l- (4-methylphenyl) -l, 2-ethanediol 2-tosylate Was prepared from 4-rneti-styrene with an overall yield of 75% according to a procedure similar to that described in Examples 7 and 8. The optical purity was 98.3% estimated by HPLC analysis. 1 H NMR (270 MHz, CDCl 3) 6 7.77 (2 H, d, 3 = 8, 1 Hz), 7.33 (2H, d, J = 8.4 H), 7.20 (2H, d, 3 = 8.1 Hz), 7.14 (2H, d, 3 = 8.1 Hz), 5.00-4.90 (IH, rn), 4.13 (1H, dd, 3 = 3.3, 10.3 Hz), 4.03 (1H, d, 3 = 8.4, 10.3 Hz), 2.49 (1H, d, 3 = 2.9 Hz), 2.45 (3H, s), 1.57 (3H , s).

PREPARATION 15 Oxide of (S) -4-methylstyrene A mixture of 2-toselate of (S) -l- (4-methyl-enyl) -1,2-ethanedio (4.13 g, 13.5 mmol) and an aqueous solution 50% NaOH (5 mL) in THF (25 LO was stirred for one hour at room temperature and for two hours at 50 [deg.] C. After cooling to room temperature, the reaction mixture was diluted with water and extracted with The ethyl acetate was washed with water and brine, dried (N 2 SO 3) and concentrated to give 1.59 g (88%) of the desired compound as a pale brown oil.This oil was used in the following reaction without iH NMR (270 MHz, CDCl3) d 7.20-7.10 (4H, n), 3.83 (1H, dd, 3 = 2.6 4.0 Hz), 3.13 (IH, dd , 3 = 4.0, 5.5 Hz), 2.80 (1H, dd, 3 =, 0, 5.5 Hz), 2.80 (1H, dd, 3 = 2, 6, 5, 5 H ), 2, 34 (3H, s).

PREPARATION 16 2- (3- (S) -methoxymethyloxypyrrolidin-1-yl) -1- (S) - (4-methyl enyl ethanol and 2- (3- (S) -methoxymethyloxypyrrolidin-1-yl) -2- ( R) - (-methyl enyl ethanol) A mixture of (S) -4-methersethenol oxide (1.59 g, 11.9 mmol) and 3- (S) -inethoxyrnethyloxypyrrolidine was refluxed for seven hours. (1.55 g, 11.9 mmol) in isopropanol (25 rnL) The solvent was evaporated and the residue was purified by column chromatography (silica gel, 150 g, - CH 2 Cl 2 / MeOH: 50/1 to 15 / 1) to give 2.29 g (76%) of the desired products as a pale brown oil.This was a mixture of 3 to 2 of the title compounds.IH NMR (270 MHz, CDC13) d 7.26 (1 , 2H, d, 3 = 8.1 H), 7.21-7.10 (2.8H, m), 4.75-4.55 (2.6H,, including 0.6H, d, 3 = 6.6 Hz at 4.66 pprn, 0.6H , d, 3 = 7.0 Hz at 4.63 ppm, 0.4H, d, 3 = 7.0 Hz at 4.62 ppm, 0.4H, d, 3 = 7.0 Hz at 4.58 ppm ), 4.35-4.23 (0.6H, n, OCHCH2N), 4.23-415 (0.4H, rn, 0CHCH2N), 3.87 (0.4H, dd, 3 = 6.2 10 , 6 Hz, CHCH ^ OH), 3.77 (0.4H, dd, 3 = 5.9, 10.6 Hz, CHCHOH), 3.49 (0.4H, dd, 3 = 5.9, 6 , 2 Hz, NCHPh), 3.38 (l, 8H, s), 3.33 (1.2H, s), 3.05-2.90 (1.2H, rn), 2.54 (IH, dd, 3 = 5.1, 10.6 Hz), 2.50-200 (4H, rn), 2.80-2.40 (5H, m), 2.34 (3H, s), 2.25 -2.00 (1H, m), 1.95-1.75 (IH, m).

EXAMPLE 50 2- (3,4-Dichlorophenyl) -N-hydroxy-N-E2- (3- (S) -hydroxy-pyrrolidin-1-yl) -l- (S) - (4-phenyl-phenyl) -ethyl-3-acetamide Was prepared from 2- (3- (S) ~ rnetox? met? lox-p? rrol? d? nl-? l) -l- (S) - (4-rnet? lfen? l) ethanol and 2- ( 3- (S) ~ inetoxymethyloxypyrrolidin-1-yl) -2- (R) - (4-methylphenyl) ethanol with an overall yield of 29.5% according to a procedure similar to that described in Examples 10 and 11 1 H NMR (270 MHz, CDC13) d 7.40-7.30 (2H, rn), 7.23 (2H, ap.d., 3 = 8.1 Hz), 7.11 (3H, ap.d. , 3 = 7.7 Hz), 5.64 (1H, dd, 3 = 5.1, 11.4 Hz, PhCHN), 5.00-3.00 (2H, almost flat sa, 2x OH), 4 , 40-4.30 (1H, rn, CHOH), 3.84 (1H, d, 3 = 14.7 Hz, C0CH2Ph), 3.73 (1H, d, 3 = 14.3 Hz, C0CH2Ph), 3.46 (1H, dd, 3 = 11.4, 12.1 Hz), 3.10-2.95 (1H, rn), 2.83 (1H, da, 3 = 11.0 Hz), 2 , 75-2.40 (3H,), 2.32 (3H, rn) 2.32 (3H, s), 2.25-2.10 (1H, rn), 1.75-1.60 (JH , rn). Amorphous solid hydrochloride salt MS / z: 422 (M +). IR (KBr-): 3420, 3180, 1650 cn "1. Anal.Cal, for C21H2ACI2N2O3 -HCl-0.5 H2O: C, 53.80, H, 5.59; N, 5.98. C, 53.51; H, 5.67; N, 6.0.

PREPARATION 17 (S) -1- (3-methoxymethyloxyphenyl) -1,2-ethanediol Prepared from 3-methoxyrnethyloxystyrene (prepared by methoxymethylation of 3-hydroxystyrene in conventional manner) with a quantitative yield according to a procedure similar to that described in Example 7. iH NMR (270 MHz, CDCl 3) d 7.25 (1H, dd, 3 = 7.7 8.1 Hz), 7.03 (1H, d, 3 = 1.8 Hz), 6.98-6.92 (2H, rn), 5.15 (2H, s, OCH2? Me), 4.74 (1H, dd, 3 = 3.3 8.1 Hz, ArCHOH), 3.7.1 (1H, da, 3 = 9.9 Hz, CHCH20H), 3.65-3, 55 (2H, rn, inclusive 1H, dd, 3 = 8.1 11.0 Hz to 3.6.1 ppm CHC OH), 3.44 (2H, s, 0CH20Me), 3.14 (1H, sa OH).

PREPARATION 18 (S) -l- (3-methoxymethyloxyphenyl) -1,2-ethanediol-2-tosylate prepared from (S) -l- (3-r-methoxyrnethyloxyphenyl) -1,2-ethanediol in a yield of 64 & according to a procedure similar to that described in Example 8. Its optical purity was 96% estimated by HPLC. iH NMR, CDCl 3) d 7.77 (2H, d, 3 = 8.4 Hz), 7.34 (2H, d, 3 = 8.1 Hz), 7.25 (1H, dd, 3 = 7, 7, 8.4 Hz), 7.00-6.92 (3H, rn), 5.15 (2H, s), 4.95 (1H, ddd, 3 = 3.3, 3.3, 8, 4 Hz, ArCHOH), 415 (1H, dd, 3 = e, e, 10.3 Hz, CHCHOYs), 4.03 (1H, dd, 3 = 8.4, 10.3 Hz, CHCH20Ts), 3, 46 (3H, s, 0CH20Me), 2.65 (1H, d, 3 = 3.3 H, ArCHOH), 2.45 (3H, s, PhMe).

EXAMPLE 51 2- (3,4-Dichlorogenyl) -N-El- (S) - (3-methoxymethyloxyphenyl) -2- (3- (S) -tetrahydropyranyloxypyrrolidin-1-yl) ethyl 3-N-tetranidropyranyloxyacetamide It was prepared starting from 2-tosylate of CS) -l- (3-r-methoxymethyloxyphenyl) -1,2-ethanediol with an overall yield of 52% according to the procedure similar to that described in Examples 9 and .1.0. ! H NMR (270 MHz, CDC.I3) 6 7.40-6.91 (7H, rn), 5.65 (0.5H, dd, 3 = 3.3, 9.9, Hz, PhCHN), 5.54 (0, 5H, dd, 3 = 4.4, 11.0 Hz, PhCHN), 5.35-5.25 (1H, m, NOCHO), 5.19 (0.5H, d, 3 = 6.6 Hz , EIGHT), 5.15 (0.5H, d, 3 = 6.6 Hz, EIGHT), 5.14 (0.5H, d, 3 = 7.0 Hz, EIGHT) 5.10 (0.5H , d, 3 = 7.0 Hz, EIGHT), 4.65-4.55 (1H, rn, CHOCHO), 4,404.30 (0.5H, ifl, OCHCHG2N), 4.10-3.85 (4H , rn, including 0.5H, d, 3 = 16.5 Hz to 4.06 ppm, 0.5 H, d, 3 = 16.5 Hz to 3.92 ppm and 1H, s, to 3.92 ppm , COC Ph), 3.68-3.15 (6H, m, each including 1.5H, s, at 3.47 and 3.46 ppm, OMe), 3.02-2.80 (2H, rn ), 2.66-2.35 (3H, m), 2.20-1.15 (14H, rn).

EXAMPLE 52 2- (3,4-dichloro-enyl) -N-hydroxy-N-Cl- (S) - (3-hydroxyphenyl) -2- (3- (S) -hydroxypyrroline-1-yl) ethyl-3-acetamide It was prepared from 2- (3,4-d? Chlorofeml) -N-Cl- (S) - (3-rnetox? Met? Lox? Phen? L) -2- (3- (S) ~ tetrah? Drop? ? -pyrrolidin-1-ethyl] -N-tetrahydropyranyloxyacetamide with a yield of 46% according to the procedure similar to that described in Example 11. i H NMR (270 MHz, CDCl 3) d 7.56 (1H, s) , kPhOH), 7.40 (1H, d, 3 = 1, 8 Hz), 7.37 (1H, d, 3 = 8, 4 Hz), 7, 17 (1H, dd, 3 = 1.8, 8.1 Hz), 7.11 (1H, dd, 3 = 7.7, 8.1 Hz), 6.90-6.70 (3H, rn), 5.56 (1H, dd , J = 5.1 10.6 Hz, PhCHN), 4.30-4.20 (1H, m, CHOH), 3.90 (1H, d, 3 = 15.0 Hz, C0CH2Ph), 3.74 (1H, d, 3 = 14.5 Hz, C0CH_2Ph), 4.50-2.50 (2H, almost broad sa, 2z OH), 3.32 (1H, dd, 3 = 11.4, 11.7 Hz), 3.00-2.85 (IH,), 2.75-2.55 C3H, rn, including 1H, dd, 3 = 5.1 11.0 Hz), 2.40-2.30 ( 1H, rn), 2.15-2.00 (1H, rn), 1.80-1.60 (1H, rn). IR (kbR): 3350, 3200, 1630 CM "1. Ern M / Z: 424 (m +) Free amine: p.m. 151, 6-153, 1 ° C. Anal.Cal, for C20H22CI2N2O4-7 H2O : C, 54.85, H, 5.39, N, 6.40, Found: C, 54.70, H, 4.99, N, 6.42.

The chemical structures of the compounds prepared in Examples 1 to 52 are summarized in the following table.

TABLE (D Ex.nQ A Ar R X 1 hydrogen (S) - phenyl benzyl 3,4-dichlorophenyl 2 hydrogen (S) - phenyl 3,4-dichlorophenyl hydrogen 3 hydrogen (S) - 3,4-dichlorophenyl methyl phenyl 4 hydrogen (S) ~ phenyl hydrogen 2,3,6- t ri cio ro feni lo hydrogen (S) - phenyl hydrogen 4-trif luorornetyl faith ilo 6 hydrogen (S) - phenyl hydrogen 1-naphthyl 7 hydrogen (S) - phenyl hydrogen 2,4,6-trirnethyl phenyl 8 hydrogen (S) - phenyl hydrogen 4-? Iridyl 9 hydrogen (S) ~ phenyl hydrogen benzo [1 f u ra n ~ 4-yl 10 (S) -tetrahydro- (S) phenyl tetrahydro-3,4-dichlorophenypyranyloxy pyranoloxy lo 11 (S) -hydroxy. (S) -phenyl hydrogen 3,4-dichloro phenyl 12 (S) -hydroxyl (S) -4- hydrogen 3,4-dichlorophe- thofenyl nyl 13 (S) -hydroxyl (S) -phenyl hydrogen 4-bromo phenyl 14 (S) -hydroxyl (S) -phenyl hydrogen 3-bro n phenyl (S) -hydroxyl (S) -phenyl hydrogen 3,4-dirnetoxyphenyl Ex.nQ A Ar RX 17 (S) -hydroxyl (S) -phenyl hydrogen 3-trifluoromethyl-phenyl 18 (S) -hydroxyl (S) -phenyl hydrogen 4-tri fluoromethyl-phenyl 19 (S) - hydroxyl (S-phenyl hydrogen 4-biphenyl 20 (S) -hydroxyl (S) -pheni hydrogen 4-nitrophenyl 21 (S) -hydroxyl (S-phenyl hydrogen 3-nitro phenyl 22 (S) -hydroxyl (S.- phenyl hydrogen 4-chloro phenyl 23 (S) -hydroxyl (Si-phenyl) hydrogen 3-chlorophenyl 24 (S) -hydroxyl (S 1 -phenyl hydrogen 2-chloro phenyl 25 (S) -hydroxyl (S-phenyl hydrogen 2 3 5 - tri chlorine feni 26 (S) -hydroxyl (S 1 -phenyl hydrogen 2,4,6- 10 t rielo rofen.il or 27 (S) - hydroxyl or (S1-phenyl hydrogen 2,4,6-trimethyl phenyl) 28 (S) -hydroxyl (S-phenyl hydrogen 2,3-dichloro fe¬ nyl 29 (S) -hydroxyl (S-phenyl hydrogen 2,4-di chloro phenyl 30 (S) -hydroxyl (S 1- phenyl hydrogen 2,5-dichloro phenyl 20 31 (S) -hydroxyl (S) -pheni the hydrogen 2,6-di-chloro-phenyl 32 (S) -hydroxyl (s: -phenyl-hydrogen 3, 5-dichloro-phenyl-33 (S) -hydroxyl (S-phenyl hydrogen 2,3,6- 'P trichloro phenyl Ej.nQ A A4 R X 34 (S) -hydroxyl (S) -phenyl hydrogen benzoC .lfuran-4-30 yl 35 (S) -hydroxyl (S) -phenyl hydrogen l-tetralon-6-yl 36 (S) -hydroxyl (S) -phenyl hydrogen 3,4-dimeti l f i i no 37 (S) -hydroxyl (S) - phenyl hydrogen 3,4-di chloro phenyl lo 38 (S) -hydroxyl (S) phenyl hydrogen 3,4-fluorophenol 39 (S) -hydroxyl (S) -phenyl hydrogen benzoCb3thiophen-4-yl 40 (?) -hydroxyl (S) -phenyl, 3,4-methylenedioeiphenyl 41 (S) -hydroxyl (S) -phenyl hydrogen 3,5-difluorophenyl-42 (R) -tetrahydro- (S) -phenyl-tetrahydro-3,4-dichlorophenypyranyloxy-pyranyl nile 43 (R) -hydroxyl (S) ) -3-dichlorophenyl hydrogen phenyl 44 (R) -hydroxyl (R) -phenyl 3,4-dichlorophenyl hydrogen 45 (S) -rnetoxi- (S) ~ 3-rnet.-tetrahydro-3,4-dichlorophenyl methylox i. phenyl pyranyl 46 (S) -hydroxyl (S) -3-methyl-hydrogen 3,4-dichlorophenyl phenyl 47 (S) -hydroxyl (S) -4-chloro-hydrogen 3,4-dichlorophenyl phenyl 48 (S) - hydroxyl (S) -4- hydrogen 3,4-dichlorophenyl rneto ifenyl Ex.nQ A Ar RX 49 (S) -hydroxyl (S) -4-tri- hydrogen 3,4-dichlorophenyl fl uorornetyl-phenyl 50 (S) -hydroxyl (S) -4- hydrogen 3,4-dichlorophenyl useful phenyl 51 (S) -tetrahydro- (S) -3- tetrahydro-3,4-dichlorophenyl pyranyloxymethoxy-pyranyl-rhenyl-amino-52-S-hydroxy (S) -3- hydrogen-3,4-dichlorophenyl-hydroxy phenyl

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. A compound with the following formula: (T) and the salts of the same, wherein A is hydrogen, hydroxyl or OY, wherein Y is a hydroxyl protecting group; Ar 1 is a phenyl substituted optionally with one or more substitutions selected from halo, hydroxyl, a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy, CF 3, a C 1 -C 4 alkoxy C 1 -C 4 alkyloxy and C 1 -C 4 alkylacyloxy C4; X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, l-tetralon-6-yl, alkylenedioxy Ci-C, p-dyl, furyl and timly, these groups being optionally substituted with up to three substitutes? selected from halo, a Ci-C * alkyl, a Ci-C-alkoxy, hydroxyl, NO2, CF3 and SO2 CH3, and R is hydrogen, a Ci-C4 alkyl or a hydroxyl protecting group.

2. A compound according to claim 1 wherein A is hydrogen or hydroxyl and R is hydrogen or? N C1-C4 alkyl.

3. A compound according to claim 2 wherein Ar is phenyl.

4. A compound according to claim 3 wherein X is a phenyl substituted with up to three substitutes selected from chlorine, methyl and CF3, and R is hydrogen.

5. A compound according to claim 4 wherein X is 3,4-dichlorophenyl.

6. A compound according to claim 4 selected from 2- (3,4-dichlorophenyl) -N-hydroxy-N-Cl- (S) -phenyl-2- (l-pyrrolidin) eti?] Acetamide; N-hi d rox i -N- 1 - (S) -pheni 1 - 2 - (1-pi r rol i di n) et i 1] -2- (2, 3, 6-tri chlorofenyl acetamid; N-hydroxy-N-. L- (S) -phenyl-2 ~ (l-? I rolidin) ethyl -2- (4-t ri f 1? Or romet i 1 pheny1) acetamide; N-hydroxy -N-Cl- (S) -feni 1-2- (1-pyrrolidine) et.i 13-2- (2, 4, 6 - 1 ri et i 1 pheny1) acetamide, - 2- (3 , 4-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) ~ hydroxypyrrolidin-1-yl) -l- (S) -phenylethyl-3-acetamide, -2- (4-bromophenyl) -N-hydroxy-N -C2- (3- (S) -hydroxy? -rolidolidin-1-yl) -l- (S) -phenylethyl-acetamide, -N-hydroxy-N-C2- (3- (S) -hydroxy-pyrroline in- l ~ il) -l ~ (S) ~ phenylethyl -2- (4-t if luoromethyl phenyl) acetamide; 2- (4 ~ chlorophenyl) -N-hydroxy-N-C2- (3- (S) -h? drox pyrrolidin-1-yl) -l- (S) -phenylethi-acetamide; 2- (2,3-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrrolidin-1-yl) -l - (S) -phenylethyl acetamide: 2- (2,4-dichlorophenyl) -N-hydroxy-N-r2- (3- (S) -hydro-pyrrolidin-1-yl) -l- (S) -phenylethyl aceta? ni da; 2- (2,5-d? chlorophenyl) -N-hydroxy-N-C2- (3 (S) -hydroxypi-rrolidin-1-yl) -l- (S) -phenyl ethenyl3acetarnide; 2- (2,6-dichlorophenyl) -N-hydroxy-N-C2- (3- (S) -hydroxypyrroli din-1 -yl) -l-phen? ietil3acetarn? da; Nh? Drox? -N- £ -2 ~ (3- (S) -h? Droxipyrrolidin-l-il) -l- (S) ~ f eni let 11-2- (2, 3, 6 - 1 ri chlorine feni 1) acetamide, 2- (3,4-dichlorophenyl) -N-C2- (3- (S) -hi drox i pyrroli din-l-yl) -l- (S) -phenylethyl acetamide; and 2- (3,4-d? rnetiifen? l) -N-hydroxy-N- [2- (3-CS) -hydroxypyridyl idyl-l) -l- (S) -phenyl? -acetamide.

7. A compound according to claim 1 wherein A is OY and R is a protecting group of the hydroxyl and wherein the hydroxyl protecting groups are selected from benzyl, triphenyl and ilo, tetrahydropyranyl, netoxirnetyl and RiR-R3Si , wherein Ri, R2 and 3 are each an alkyl of Ci-Cß or phenyl.

8. A pharmaceutical composition useful as an analgesic, anti-inflammatory, diuretic, anesthetic or neoprotective agent, or as an agent for the treatment of stroke or intestinal functional diseases such as abdominal pain, which comprises a compound according to claim 1 , and a pharmaceutically inert vehicle.

9. A method of treating a medical condition for which agostasis activity against the kappa opioid receptor is needed in a mammalian subject which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1. 1.

10. A compound of formula and the salts of the rni srno, wherein A is hydrogen, hydroxyl or OY, wherein Y in a hydroxyl protecting group, - Ar is a phenyl substituted optionally with one or more substituents selected from halo, hydroxyl, an alkyl C 1 -C 4 -alkyloxy Ci-C 1, and carboxyalkyloxy C 1 -C¿ >; R is hydrogen, a C 1 -C 0 alkyl or a hydroxyl protecting group. A process for producing a compound of formula (II), which comprises reacting an ethanolamine compound of formula (III) with a hydroxylamine of formula (IV): (III) (IV) to obtain a compound of formula (V): and then reacting a compound of the formula (V) with methanesulfonyl chloride in the presence of a base followed by the addition of a protected hydroxylamine and, if necessary, removal of the protecting group. 12. A process for producing a compound of formula (II), which comprises reacting a pyrrolidinyl compound of formula (VII) with a substituted or unsubstituted phenyl oxide of formula (VIII): (VII) (VIII) to obtain a mixture of a compound of formula (IX) and a compound of formula (X); < ?) (X) and then reacting the obtained mixture with methanesulfonyl chloride in the presence of a base followed by the addition of a protected hydroxylanine and, if necessary, removal of the protecting group. 13. A process for producing a compound of formula (I), which comprises reacting a compound of formula (II) in which R is a protective group of the hydroxyl with a carboxylic acid of formula XCH2COOH, removing the protective group of the compound obtained, followed, if necessary, by the alkylation of the compound obtained. SUMMARY OF THE INVENTION A compound of formula: Ar 0) and its pharmaceutically acceptable salts, wherein A is hydrogen, hydroxyl or OY, in which Y is a hydroxyl protecting group, - Ar is a phenyl optionally substituted with one or more substituents selected from halo, hydroxyl, a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy, CF 3, a C 1 -C 4 alkoxy C 1 -C 4 alkyloxy and C 1 -C 4 carboxy yl xyloxy; X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl, alkylenedioxy Ci-C, pyridyl, furyl and thienyl, these groups optionally being substituted up to three substituents selected from halo, a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy, hydroxyl, NO 2, CF 3 and SO 2 CH 3; and R is hydrogen, a C1-C-1 alkyl or a hydroxyl protecting group. These compounds and the pharmaceutical compositions containing them are useful as analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agents, or as an agent for the treatment of stroke or intestinal functional diseases such as abdominal pain, for the treatment of a mammal, especially a human subject. In addition, the present invention provides processes for reducing the hydroxamic compounds of formula (I) and their intermediate compounds of formula (II). PF / 1ss * elp * f c * apm * P97 / 848F