PRODUCTION PROCESS 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, antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. Background Art

Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as μ, δ, K at a peripheral nerve in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a μ-receptor agonist, separating the action based on a ^-receptor agonist from the action based on μ-receptor agonist has been investigated. Recently /(-selective agonists have been reported from the above viewpoint for example, EMD-60400: A. Barber et al. , Naunyn-Schmled. Arch. Pharmacol. , 345 (Suppl.): Abst 456. Some of them actually have been studied in clinical trials (Med. Res. Rev. , 12, 525 (1992)).

However, even when a selective /(-receptor agonist is employed, use of high doses can give rise to side effects such as sedation. Therefore, it would be desired to provide compounds having better agonist activity toward opioid /(-receptor, and in particular compounds having only low sedative activity.

Brief Disclosure of the Invention The present invention provides a compound of the following formula:

and the salts thereof, wherein

A is hydrogen, hydroxy or OY , wherein Y is a hydroxy protecting group, Ar is phenyl optionally substituted with one or more (preferably up to three) substituents selected from halo, hydroxy, C,-C ₄ alkyl, C,-C ₄ alkoxy, CF ₃ , C,-C ₄ alkoxy-C,-C alkyloxy , and carboxy-C,-C ₄ alkyloxy, X is phenyl, naphthyl, biphenyl , indanyl, benzofuranyl, benzothiophenyl, 1- tetralone-6-yl, C,-C ₄ alkylenedioxy, pyπdyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C,- C ₄ alkyl, C,-C ₄ alkoxy, hydroxy, N0 ₂ , CF ₃ and SO ₂ CH ₃ ; and

R is hydrogen, C,-C ₄ alkyl or a hydroxy protecting group

The hydroxamic acid derivatives of the present invention of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C,-C ₄ alkyl, exhibit significant agonist activity toward opioid /(-receptor Therefore these K agonists are particularly useful as an analgesic agent in mammals, especially humans. They are also useful as antunflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.

Accordingly, the present invention also provides a pharmaceutical composition useful as an analgesic, antunflammatory, diuretic, anesthetic or neuroprotective agent, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject, which comprises a therapeutically effective amount of a hydroxamic acid of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C,-C ₄ alkyl, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

The compounds of formula (I), wherein either or both of OY and OR represent a protected hydroxy group, are useful as chemical intermediates to the K agonist of

formula (I). Typical hydroxy protecting groups are benzyl, triphenylmethyl, tetrahydropyranyl, methoxymethyl and R'RR ³ Si, wherein R',R ² and R ³ are each C,- C ₆ alkyl or phenyl.

A preferred group of K agonists compounds of the present invention consists of the compounds of formula (I), wherein A is hydrogen or hydroxy, Ar is phenyl, X is phenyl substituted with up to three substituents selected from chloro, methyl and

CF ₃ ,more preferably 3,4-dichlorophenyl, and R is hydrogen. The preferred configulation of the carbon atom to which the group Ar is attached is (S).

Preferred individual compounds of the invention are: 2-(3,4-DichlorophenyI)-N-hydroxy-N-[l-(5)-phenyl-2-(l- pyrrolidinyl)ethyl]acetamide;

N-Hydroxy-N-[ 1 -(5) -phenyl -2- ( 1 - pyrrol id i n y l)ethyl]-2- (2,3,6- trichlorophenyl)acetamide;

N-Hydroxy-N-[l-(5)-phenyl-2-(l-pyrrolidinyl)ethyl]-2-(4- trifluoromethylphenyl)acetamide;

N-Hydroxy-N-[l-(5)-phenyl-2-(l-pyrrolidinyl)ethyl]-2-(2,4 ,6- trirnethylphenyl)acetamide;

2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(-S)-hydroxypyrr olidin-l-yl)-l-(S)- phenylethyl]acetamide; 2-(4-Bromophenyl)-N-hydroxy-N-[2-(3-(5)-hydroxypyrrolidin-l- yl)-l-(S)- phenylethyljacetamide;

N-Hydroxy-N-[2-(3-(5)-hydroxypyrrolidin-l-yl)-l-(5)-pheny lethyl]-2-(4- trifluoromethylphenyl)acetamide;

2-(4-Chlorophenyl)-N-hydroxy-N-[2-(3-(5)-hydroxypyrrolidi n-l-yl)-l-(5)- phenylethyl]acetamide;

2-(2,3-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrro lidin-l-yl)-l-(S)- phenylethyl]acetamide;

2-(2,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrro lidin-l-yl)-l-(5)- phenylethyljacetamide; 2-(2,5-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolid in-l-yl)-l-(5)-

phenylethyl]acetamide;

2-( 2, 6-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)- hydroxypyrrolidin-1-yl )-1-(S)-phenylethyl]acetamide;

N-Hydroxy-N- [2-( 3-( S)-hydroxypyrrolidin-1-yl )-1-(S )- phenylethyl] -2-( 2,3, 6-trichlorophenyl )acetamide;

2-(3, 4-Dichlorophenyl )-N- [2-(3-(S)-hydroxypyrrolidin- 1-y1 )-1-(S)-phenylethyl]acetamide; and

2-(3,4-Dimethylphenyl )-N-hydroxy-N-[2-( 3-(S)- hydroxypyrrolidin-1-yl )-1-(S)-phenylethyl]acetamide. Further, the present invention provides a compound of the formula:

(π)

and the salts thereof, wherein

A is hydrogen, hydroxy or OY, wherein Y is hydroxy protecting group; Ar is phenyl optionally substituted with one or more substituents selected from halo, hydroxy, C ₁ -C ₄ alkyl,

C ₁ -C ₄ alkoxy, CF ₃ , C _: -C ₄ alkoxy-C ₁ -C ₄ alkyloxy, and carboxy-C ₁ -C ₄ alkyloxy; R is hydrogen, C _l -C ₄ alkyl or a hydroxy protecting group. These compounds of formula (II) can be used as intermediates to prepare the compounds of formula ( I ) .

Further, the present invention provides processes for producing the hydroxamic compounds of formula ( I ) and their intermediate compounds of formula ( II ) . Detailed Disclosure of the Invention

The K agonists of formula ( I ) of this invention can be prepared by a numbers of methods. For example, they can be readily prepared according to the procedure shown in Scheme ( I ) .

Scheme 1

O L : leaving group

P : protecting group A : H or protected hydroxy

OR

(I)

Thus, the K agonists compounds of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen, can be prepared by reaction of a compound of the formula (VI) with a carboxylic acid of the formula XCH ₂ COOH, followed by removal of the protecting group P, and the protecting group in A' if necessary. This is a conventional acylation reaction, which can be carried out using standard methods, well-known to

those skilled in the art However, a convenient way of acylating a compound of formula (VI) with an acid of the formula XCH ₂ COOH comprises coupling the two compounds in the presence of a carbodπmide compound An especially convenient carbodnmide compound is l -ethyl-3-(3-dιmethylaminopropyl)carbodiimide hydrochloπde, which is sometimes l eferred to as water-soluble carbodiimide, or WSC.

This reaction is carried out by contacting substantially equivalent amounts of the acid and amine with a small excess of the carbodnmide in an appropriate solvent at a temperature in the range from -30 to 100°C, usually from 0 to 30°C. Appropriate solvents are inactive aromatic hydrocarbons, ethers, halogenated hydrocarbons, especially dichloromethane The reaction takes about 30 minutes to 24 hours, usually

30 minutes to 3 hours at room temperature. The product can be isolated and purified by standard techniques

The protecting group P, and any protecting group in A ¹ , is removed by the appropriate method for the particular protecting group chosen. Thus, a typical protecting group is benzyl This can be removed by catalytic hydrogenation.

Appropriate catalysts for hydrogenation are Pd/C, Pearlman's catalyst, Pd black, or Pd/BaSO , especially 10% Pd/C.

A further convenient protecting group for P and A ¹ is the tetrahydropyranyl group (THP) This can be removed by acid-catalyzed hydrolysis. Appropriate acid catalysts are organic acid, inorganic acid, or Lewis acid such as AcOH, /?-TsOH, HC1,

M^AICI etc. , especially HC1.

The K agonist compounds of formula (I), wherein R is a C^C^ alkyl group, can be prepared by alkylation of the corresponding compounds of formula (I), wherein R is hydroxy This alkylation can be carried out by standard methods. A particularly convenient method involves base catalyzed alkylation using alkyl ha de in the presence of phase transfer catalyst such as tetra-n-buthylammonium hydrogen sulfate. The intermediate hydroxylamine of the formula (VI) can be prepared from the alcohol (V), by treatment with methanesulfonyl chloride in the presence of a base such as triethylamine followed by addition of a protected hydroxylamine (NH ₂ OP). The alcohol (V) is obtained from the appropriate ethanolamine compound (III) and the appropriate ethane compound of the formula (IV).

The compounds of formula (III) and (IV) are either known compounds, which can be made by the known methods, or they are analogs of known compounds, which can be prepared by methods analogous to the known methods.

The intermediate compounds of formula (II) wherein Ar is substituted phenyl can be prepared according to the procedures shown in the following Scheme 2. Scheme 2

(no

(Q is, for example, halo, C ₄ alkyl, C,-C ₄ alkoxy, C,-C ₄ alkoxy-C,-C ₄ alkyloxy or CF ₃ , n = 1-5, preferably 1-3)

In the above Scheme 2, a compound (VII) can be reacted with a substituted- styrene oxide (VIII) to form a mixture of a compounds (IX) and (X). This reaction may be carried out in the absence or presence of a reaction inert solvent (e.g. , methanol (MeOH), ethanol (EtOH), isopropylalcohol, tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (CH ₂ C1 ₂ ), water, benzene, toluene, n-hexane, cyclohexane) at a temperature from -78 °C to reflux temperature of the solvent, preferably from 0 °C to 25 °C for 5 minutes to 48

hours preferably from 0.5 to 12 hours. A compound (IF) 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, R, S configuration of compounds (IX) and (X) can be selectively determined. In addition, in the above procedures, 1- substιtutedphenyl- l ,2-ethanedιol 2-tosylate can be used instead of the substituted- styrene oxide (VIII).

The compounds of formula (I) of this invention are basic, and therefore they will form acid-addition salts All such salts are within the scope of this invention. However, it is necessary to use an acid addition salts which is pharmaceutically- acceptable for administration to a mammal The acid-addition salts can be prepared by standard methods, e.g. , by contacting the basic and acidic 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 salts which can be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, -toluenesulfonate, oxalate and pamoate (l , l '-methylene-bιs-(2-hydroxy-3-naphtoate)) salts.

The compounds of formula (I) of this invention, wherein R is hydrogen, are acidic, and they will form base salts. All such salts are within the scope of this invention. However, it is necessary to use a base salt which is pharmaceutically- acceptable for administration to a mammal. The base salts can be prepared by standard methods , 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 which can be formed are the sodium, potassium, calcium and magnesium salts, and also salts with ammonia and amines, such as ethylamine, diethylamine, tπethylamine, cyclohexylamine, pipeπdine and inorpholine salts.

Also included within the scope of this invention are bioprecursors (also called pro-drugs) of the K agonist compounds of the formula (I). A bioprecursor of a kappa agonist of formula (I) is a chemical derivative thereof which is readily converted back

into the parent compound of formula (I) in biological systems. In particular, a bioprecursor of a K agonist of formula (I) is converted back to the parent compound of formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, e.g , a human subject. For example, it is possible to make a bioprecursor of a K agonist or the i nvention of formula (I) in which one or both of A and OR is hydroxy groups by making an ester of the hydroxy group. When only one of A and OR is a hydroxy group, only mono-esters are possible. When both A and OR are hydroxy, mono- and di-esters (which can be the same or different) can be made. Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when A or OR is a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxymethyl derivative (e.g. , a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e. g. , pivaloyloxymethyl chloride).

The K agonists compounds of the present invention of formula (I) exhibit significant agonist activity toward opioid /(-receptor and are thus useful as analgesic, antunflammatory, diuretic, anesthetic and neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject, for the treatment of mammals, especially humans in need of such agents The activity of the /(-agonists compounds of formula (I) of the present invention, is demonstrated by the opioid receptor binding activity. Such activity may be determined in homogenates from guinea pig whole brain, as described by Regina, A. et al. in J. Receptor Res. 12: 171 - 180, 1992 In summary, tissue homogenate is incubated at 25°C for 30 min in the presence of labelled gand and test compounds. The μ-sites are labelled by I nM of (3H)-[D-Ala2,MePhe4,Gly-ol5]enkephalιn

(DAMGO), the δ-sites by 1 nM of (3H)-[D-Pen2,5]enkephalιn (DPDPE) and the /(-sites by 0.5 nM (3H)-CI-977. The non specific binding is measured by use of 1 mM CI- 977 (*), 1 mM (DAMGO) ( *), I mM (DPDPE) (δ). Data are expressed as the IC ₅₀ values obtained by a non-linear fitting program using the Cheng and Prusoff equation. Some compounds prepared in the Examples showed a low IC _S0 value in the range of

0.01 to 100 nM

The activity of the K agonists compounds can also be demonstrated by the Formalin Test as described by Wheeler-Aceto, H. et al. in Psychopharmacology 104: 35-44, 1991. In this testing, male SD rats (80- 100 g) are injected s.c with a test compound dissolved in 0 1 % methyl cellulose saline or vehicle. After 30 mm. , 50 ml of a 2 % formalin are injected into a hind paw The number of licking the injected paw per observation period is measured 15-30 min after the injection of formalin and expressed as % inhibition compared to the respective vehicle group.

The activity of the K agonists can also be demonstrated by the Rotarod Test as described by Hayes, A G et al in Br J Pharmacol 79- 731-736, 1983. In this testing, a group of 6- 10 male SD rats (100- 120 g) are selected for their ability to balance on a rotating rod (diameter 9 cm, rate of rotation 5 r p.m.) The selected rats are then injected s c with a test compound dissolved in 0. 1 % methyl cellulose saline. The animals are tested again 30 mm after treatment, a rat falling off the bar more than twice within 150 seconds is considered to be showing motor impairment and the animal's performance (i.e. , time on the rotarod) are recorded. The ED ₅₀ value, defined as the dose of the drug which halves the performance time is observed in the control group

The K agonists compounds of formula (1) of this invention can be administered via either the oral , parentera! or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.01 g to 50 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen However, a dosage level that is in the range of from 0 01 mg to 1 mg per kg of body weight per day, single or devided dosage is most desirably employed in humans for the treatment of pain in a postoperative patient.

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable earners or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e. , they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets,

capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, stenle aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5 % to 70% by weight, preferably 10% to 50% by weight.

For oral administration , tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, algimc acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene grycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavonng agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well , together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH > 8) if necessary and the liquid diluent first rendered lsotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra¬ muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard 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 may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard 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 melting point apparatus and uncorrected. Infrared Ray absorption spectra (IR) were measured by a Shimazu infrared spectrometer (IR-470). 'H and ¹³ C nuclear magnetic resonance spectra (NMR) were measured in CDC1 ₃ by a JEOL NMR spectrometer (JNM-GX270, 270MHz) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows- s, singlet; d, doublet, t, triplet; m, multiplet; br, broad.

Preparation 1 (5)-N-Benzylo\v-l-phenyl-2-pyrrolidinoethylamine To a stirred solution of (/?)-2-phenyl-2-pyrrolιdιnoethanol (E. Brown et al,

Tetrahedron. Asymmetry, 1991 , 2, 339, 4.78g, 25mmol) and tnethylamine (3.95ml, 28mmol) m CH ₂ C1 ₂ (50ml) was added methanesulfonyl chloride (2ml, 26mmol) dropwise at 0 °C (ice bath) After 3h stirring at 0 °C to room temperature (rt), the reaction mixture was washed with saturated NaHC0 ₃ aqueous solution, dried (Na ₂ SO ₄ ), and concentrated to give 5 88g of yellow solid and brown viscous oil mixture. To this mixture was added 0-benzylhydroxylamine(this was prepared from O- benzylhydroxylamine hydrochlonde 5.99g (37.5mmol) by basification) and ethanol (6ml) and the mixture was stirred at 80 °C for lh The solvent was evaporated to give 9.47g of white solid which was collected by filtration and washed with ethanol/ether to afford 6.96g (83 7%) of hydrochlonde salt of desired product as white crystalline, mp 161 -162 °C

'H NMR (270MHz, CDC1 d 7 44-7.25 (10H , m), 6 40 (1 H, br.s), 4.68 (1H, d, J = 1 1.7Hz), 4.68-4.62 ( 1 H , m), 4 63 ( 1 H , d, J = 1 1 7Hz), 3.90-3 70 (1H, m), 3.60 (1H, dd, J = 7.7, 13.2Hz), 3.55-3 40 ( 1 H, m), 3.05 ( 1 H, dd, J = 5.5, 13.2Hz), 2.80-2.65 (1H, m), 2.65-2.45 ( 1 H, m), 2.25-2.05 (2H, m), 2.05- 1.80 (3H, m).

Anal. Calcd for C _l9 H ₂ N ₂ O HCl C, 68.56 ; H, 7.57; N, 8.42 ; Cl, 10.65.

Found : C, 68.36 ; H, 770 ; N, 8.39 , Cl, 11 13.

This hydrochlonde salt (80mg) was basified with ammonium hydroxide solution, extracted with CH ₂ C1 ₂ , dried (Na ₂ S0), and concentrated to give 67mg of free amine derivative as a colorless oil Η NMR (270MHz, CDC1,) δ 746 - 7.12 (10H, m), 6.53 (IH, br.s), 4.53 (IH, d, J

= 11.0Hz), 4.45 (IH, d, J = 114Hz), 4.20 (IH, dd, J = 3.7, 11.4Hz), 2.90 (IH, dd, J = 11.4, 12.5Hz), 270 - 260 (2H, m), 250 - 2.35 (2H, m), 2.28 (IH, dd, J = 4.0, 12.5Hz), 1.80 - 1.70 (4H, m) IR(neat) : 3250cm '. [α] _D = +44.6(c= 067, MeOH)

Example 1 N-Benzyloxy-2-(3.4-dichlo ophenyl)-N-fl-(S)-phenyl-2-(l- pyrrolidinvDethvπncetnmide

To a stirred solution of (5> l-(2-0-benzy]hydroxylammo-2-phenyl- ethyl)pyrrolidιne hydrochlonde (2.88g, 8.65mmol) and 3,4-dichlorophenylacetic acid

(2.05g, lOmmol) in CH ₂ C1 ₂ (30ml) was added 1 -ethy 1-3 - (3- dιmethylamιnopropyl)carbodιιmιde hydrochlonde (2.30g, 12mmol) at room temperature. After lhr stirring, the reaction mixture was washed with water and saturated NaHC0 ₃ aqueous solution, dried (Na ₂ S0), and concentrated to give 4.44g of pale brown viscous oil To this oil was added methanol (2ml) and stood for lhr.

The white crystalline appeared was collected by filtration to give 1.60g of white powder. The filtrate was concentrated to afford 2.84g of oil and solid mixture, which was purified by column chromatograplιy(sιlιca gel, lOOg, CH ₂ Cl ₂ /MeOH: 40/1) to give 0.82g of clear yellow viscous oil, which was crystallized by addition of methanol (0.2ml).

Total yield was 2.42g(57.9%) p 88.5-90 °C .

'H NMR (270MHz, CDCI ₃ ) δ 7.46 - 7.21 (12H, m), 6.98 (IH, dd, J = 2.2, 8.4Hz), 5.80- 5.65 (IH, m),4.73(lH, d, J = 10.3Hz), 4.43 (IH, d, J = 10.6Hz), 3.77 (IH, d, J = 15.8Hz), 3.61 - 3.51 (2H, m, including IH, d, J = 15.4Hz at 3.54ppm), 2.75 - 2.60 (3H, m), 2.55 - 2.40 (2H, m), 1.80 - 1.50 (4H, m).

IR(Nujol) : 1670cm ¹ .

Example 2 2- ⁽ 3.4-Dichlorophenyl ⁾ -N-hvclroxy-N-ri- ⁽ S ⁾ -phenyl-2- ⁽ l-pyrrolidinyl ⁾ ethyllacetamide

AsuspensionmixtureofN-benzyloxy-2-(3,4-dichlorophenyl)-N- [ l-(S)-phenyl-2- (l-pyrrolidinyl)ethyl]acetamide ( 1 .60g, 3.3mmol) , 10% palladium on carbon (0. 16g), and HC1 gas saturated methanol (20ml) in methanol (20ml) was stirred under hydrogen atmosphere at room temperature for 13h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give 1 .63g of violet colored viscous oil, which was basified with NH ₄ OH and extracted with CH ₂ C1 ₂ (20ml x 3). The extract combined was dried (Na ₂ S0 ₄ ) and concentrated to afford a brown colored crystalline, which was collected by filtration and washed with ether/hexane to give 1.04g (80%) of pale yellow powder, mp 1 18 - 120 °C .

'H NMR (270MHz, CDC1 ₃ ) δ 7.44 ( I H , d, J = 1 .8Hz), 7.37 - 7.24 (6H, m, including

IH, d, J = 8.4Hz at 7.36ppm), 7. 17 ( I H, dd, J = 1 .8, 8.4Hz), 5.56 (IH, dd, J = 5.9, 10.3Hz), 3.90 ( IH , d, J = 14.3Hz), 3.70 (IH, d, J = 13.9Hz), 3.31 (IH, dd,

J = 10.6, 12.5Hz), 2.73 (I H, dd, J = 5.9, 12.5Hz), 2.60 - 2.45 (4H, m), 1.80 - 1.55

(4H, ).

IR(CH ₂ C1 ₂ ) : 3450, 1650cm ¹ .

MS m/z: 394 (MX2, 0.48), 392(M ⁺ , 1. 1), 21 1 (4.8), 173(3. 1), 149(12.9), 132(12.8), 99(28.8), 84( 100).

925mg of this crystalline was dissolved in CH ₂ C1 ₂ (10ml). To this solution was added HC1 gas saturated ether ( 10ml) at room temperature. The mixture solution was concentrated to give a white crystalline, which was collected by filtration and washed with ether to afford 971 mg of HCI salt as white powder. mp 161 - 162 °C .

[a] _D = + 1 19.8(c = 0.884, MeOH).

Anal. Calcd for C,„H ₂ ,C1 ₂ N _? O ₂ - HCI-0.5H,O : C, 54.75 ; 5.51 ; N, 6.38

Found : C, 54.96 ; H, 5.49 ; N , 6.44.

Example 3

2-(3.4-Dichlorophenyl)-N-mctho\v-N-π-(S)-phenyl-2-(l-pyrrol idinyl)ethyllncetamide

A mixture of 2-( ,4-Dιchlorophenyl)-N-hydroxy-N-[l-(S)-phenyl-2-(l- pyrrolιdιnyl)ethyl]acetamιde (598mg, 15mmoI), tetrabutylammonium hydrogen sulfate(lθmg), NaOH 50% aqueous solution (1ml), and lodomethane (0.12ml, 2mmol) in toluene (4ml) was stirred at room temperature for 3h The mixture was extracted with ethyl acetate (20m! x 2) The extract combined was washed with brine, dned (Na ₂ SO ₄ ) and concentrated to afford 106g of brown viscous oil, which was punfied by column chromatography (silica gel 60g, CH ₂ Cl ₂ /MeOH: 20/1) to give 304mg (49.8%) of yellow viscous oil 'H NMR (270MHz, CDCI ₃ ) δ 741 - 7.26 (7H, m), 7.09 (IH, dd, J = 1.8, 8.1Hz),

5.70- 5.60 (IH, m), 383 (IH, d, J = 154Hz), 365 (IH, d, J = 15.4Hz), 3.50 (3H, s), 3.50 (IH, dd, J = 99, 125Hz), 275 - 257 (3H, , including IH, dd, J = 4.8, 12.5Hz at 260ppm), 255 - 240 (2H, m), 170 (4H, m) IR(neat) : 1670cm ' 304mg of this crystalline was dissolved in MeOH (5ml). To this solution was added HCl gas saturated ether (5ml) at room temperature. The mixture solution was concentrated to give a white crystalline, which was collected by filtration and washed with ether to afford 277mg of HCl salt as white powder mp 165-166 °C Anal Calcd tor C _. „H,,CI ₂ N,Oj HCl 05H ₂ O : C, 5570 ; 579; N, 6.19

Found : C, 5553 , H, 580 , N, 619

Example 4 N-Hvdroxy-N-π-(5)-nhenyl-2-(l-Dyrrolidinyl)ethvn-2-(2.3.6- trichlorophenvPncetnmide This was prepared from (5)- l-(2-0-benzylhydroxyIamιno-2- phenylethy pyrrolidine in 68% yield according to a procedure similar to that described in Examples 2 and 3 mp 217-218.5 °C (HCl salt)

Η NMR (270MHz, free amine, CDCI ₃ ) δ 7.44 - 7.20 (8H, m), 5.61 (IH, dd, J = 5.9, 106Hz), 4.36 (IH, d, J = 16.9Hz), 426 (IH, d, J = 17.2Hz), 3.40 (IH, dd,

J = 10.6, 12.5Hz), 2.80 (IH, del, J = 5.9, 12.5Hz), 2.76 - 2.55 (4H, m), 1.90- 1.70 (4H, m).

IR(neat, free amine) : 1650cm ^'1 .

Anal. Calcd for C ₂₀ H ₂₁ Cl ₃ N ₂ O ₂ -HCl-0.5H ₂ O : C, 50.76 ; 4.90; N, 5.92 Found : C, 50.58 ; H, 4.65 ; N, 5.83.

Example 5 N-Hvdroxy-N-π-(5)-Dhenyl-2-(l-Dyrrolidinyl)ethvn-2-(4- trifUioromethylohenvPacetnmide

This was prepared from (5)- l-(2-0-benzylhydroxylamino-2- phenylethyl)pyrrolidine in 66.6% yield according to a procedure similar to that described in Examples 2 and 3. mp 172.8-177 °C (HCl salt)

'H NMR (270MHz, free amine, CDC1 ) δ 7.55 (2H, d, J = 8.4Hz), 7.45 (2H, d, J

= 8.1Hz), 7.40 - 7.20 (6H, ), 5.57 (IH, dd, J = 5.9, 10.3Hz), 4.00 (IH, d, J = 13.9Hz), 3.81 (IH, d, J = 13.9Hz), 3.30 (IH, dd, I = 10.6, 12.5Hz), 2.71 (IH, dd,

J = 5.9, 12.5Hz), 2.60 - 2.40 (4H, m), 1.80 - 1.50 (4H, m).

IR(neat, free amine) : 3150, 1650cm ^"1 .

Anal. Calcd for C _2I H ₂₃ F ₃ N ₂ 0 ₂ -HC1-H ₂ 0 : C, 56.44 ; 5.86; N, 6.27

Found : C, 56.16 ; H, 5.77 ; N, 6.76.

Example 6

N-Hvdroxy-2-(l-naphthyl)-N-[l-(. ^< D-Phenyl-2-(l-pyrrolidinyl)ethvnncetnmide

This was prepared from (5)-l-(2-(9-benzylhydroxylamino-2- phenylethy pyrrolidine in 65.1% yield according to a procedure similar to that described in Examples 2 and 3. mp 81.0- 83.5 °C (HCl salt)

'H NMR (270MHz, free amine, CDC1 ₃ ) δ 7.55 - 7.20 (13H, m), 5.59 (IH, dd, J = 5.9, 10.3Hz), 4.43 (IH, d, J = 14.7Hz), 4.10 (IH, d, J = 15.0Hz), 3.31 (IH, dd, J = 11.0, 12.1 Hz), 2.65 (IH, del, J = 5.9, 12.5Hz), 2.55 -2.35 (4H, m), 1.60- 1.35 (4H, ).

IR(neat, free amine) : 3150, 1650cm'.

Anal. Calcd for C ₂₄ H _?ή N ₂ 0 ₂ HCI- 1.2H ₂ 0 : C, 66.64 ; 6.85; N, 6.48

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

Example 7 N-Hvdro y-N-ri-(S)-ρhenyl-2-(l-Dyrroliclinyl)ethyll-2-(2,4.6- trimethylphenvPncetnmide

This was prepared from (S)- 1 -(2-(?-benzylhydroxylamino-2- phenylethy pyrrolidine in 58.9% yield according to a procedure similar to that described in Examples 2 and 3. mp 186 - 187.2 °C (HCl salt).

Η NMR (270MHz, free amine, CDC1 ₃ ) δ 7.42 - 7.24 (6H, m), 6.82 (2H, s), 5.70 - 5.55 (IH, m), 3.86 (2H, br.s), 3.38 (IH, dd, J = 10.6, 12.1Hz), 2.74 (IH, dd, J = 5.9, 12.5Hz), 2.70 - 2.55 (4H, m), 2.22 (9H, s), 1.85 - 1.75 (4H, m). IR(neat, free amine) : 3220, 1640cm ^'1 . Anal. Calcd for C ₂₃ H ₃₀ N ₂ 0 ₂ -HC1 1.3H ₂ 0 : C, 64.79 ; 7.94; N, 6.57

Found : C, 64.51 ; H, 7.48 ; N, 6.31.

Example 8 N-Hvdroxy-2-(4-p ridyl)-N-fl-(S)-phenyl-2-(l-pyrrolidinyl)ethvnncetnmide

This was prepared from (5)- l-(2-<?-benzylhydroxylamino-2- phenylethyOpyrrolidine in 67.9% yield according to a procedure similar to that described in Examples 2 and 3.

'H NMR (270MHz, free amine, CDCN) δ 8.46 (2H, d, J = 5.9Hz), 7.40- 7.18 (8H, m), 5.61 (IH, dd, J = 5.5, 10.6Hz), 3.91 (IH, d, J = 14.3Hz), 3.77 (IH, d, J = 13.9Hz), 3.33 (IH, dd, J = 11.0, 12.1Hz), 2.68 (IH, dd, J = 5.5, 12.5Hz), 2.57 - 2.40 (4H, m), 1.80 - 1.55 (4H, m).

IR(neat, free amine) : 1640cm ¹ .

Example 9 2-(BenzorAlfιιraιι-4-yl)-N-h ^y diO\y-N'-fl- ⁽ ^-phenyl-2-(l-pyriOlidinyl)ethyllacetamide

This was prepared from (5)- 1 -(2-0-benzylhydroxylamino-2- phenylethyl)pyrrolιdιne in 735% yield according to a procedure similar to that described in Examples 2 and 3

Η NMR (270MHz, CDCI ₃ ) δ 759 (IH. d, J = 18Hz), 7.45 - 7.20 (9H, m), 6.98 (IH, br.s), 558 (IH, dd, J = 59, 10.6Hz), 424 (IH, d, J = 13.6Hz), 3.91 (IH, d,

J = 13.6Hz), 3.28 (IH, dd, J = 113, 117Hz), 260 (IH, dd, J = 5.9, 12.5Hz), 2.45 - 2.30 (4H, m), 1.60 - 1.30 (4H, m). IR(neat, free amine) . 1650cm '

Preparation 2 l,4-Diiodo-2-(S)-(tet nhvdropyranylo\v)butane

To a stirred solution of (5)-(-)-l,2,4-butanetπol (10.61g, O.lmol) in pyridine (100ml) was added p-toluenesulfonyl chloride (38.13g, 0.2mol) by portions at 0 °C. After 2h stirring, the reaction mixture was poured into 10% HCl aqueous solution including ice and acidified to pH2 The mixture was extracted with ethyl acetate (150ml x 3) The extract combined was washed with brine, dried (Na ₂ SO ₄ ), and concentrated to give 42.88s of colorless oil A mixture of this crude ditosylate (42.88g, 0 lmol) and Nal( 4497g, 03mol) in acetone (300ml) was refluxed with stirring for 5h The solid precipitated was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with Na ₂ S ₂ O ₃ aqueous solution and brine. After dry (Na ₂ S0 ₄ ), the solvent was evaporated and the residue was purified by column chromatography (silica gel 250g, hexane/ethyl acetate: 10/1) to afford 24.81g of colorless oil A mixture of this oil (24.81g, 76.1mmol), 3,4- dihydro-2H-pyran (219ml, 024mol), and pyπdinium p-toluenesulfonate (125mg) in CH ₂ C1 ₂ (100ml) was stirred at room temperature for 12h The reaction mixture was diluted with CH ₂ CI ₂ (100ml), washed with NaHC0 ₃ aqueous solution, and dried

(Na ₂ S0 ₄ ). Evaporation of the solvent gave 33.56g of pale yellow oil, which was purified by column chromato-graphy (silica gel 250g, hexane/ethyl acetate: 20/1) to afford 28.75g (701 % for 3 steps) of colorless oil ΗNMR (270MHZ, CDCI,) δ 4.80 - 4.75 (IH, m), 4.02 -3.85 (IH, m), 3.70-3.17 (6H, m), 2.27 - 201 (2H, m), 190 - 155 (6H, m).

Preparation 3 2-(/?)-Phenyl-2-(3-(.S -tetrπhvclropyrπnyloxypyrrolidin-l-yl)ethanol

A suspension mixture of 1 ,4-diiodo-2-(5)-(tetrahydropyranyloxy)-butane (12.50g, 30mmol), ?-(-)-phenylglycinol (3.43g, 25mmol), and K ₂ CO ₃ (6.91g, 50mmol) in ethanol (50ml) was refluxed with stirring for 6h. The white solid was removed by filtration and the filtrate was concentrated. The residue was diluted with NaHCO ₃ aqueous solution (30ml) and extracted with CH ₂ C1 ₂ (20ml x 3). After dry (Na ₂ SO ₄ ), the solvent was evaporated to give 9.54g of clear yellow oil, which was purified by column chromatography (silica gel 150g, CH _: CI,/MeOH: 20/1) to afford 7.22g (99%) of colorless viscous oil.

Η NMR (270MHz, CDCI,) δ 7.37 - 7.27 (5H, m), 4.61 - 4.51 (IH, m), 4.40 - 4.28 (IH, m), 3.91 - 3.75 (3H, m), 3.55 - 3.42 (2H, m), 2.92 - 2.72 (IH, m), 2.70 - 2.57 (2H, m), 2.55 - 2.25 (2H, m), 2.20 - 1.95 (IH, m), 1.93 - 1.60 (3H, m), 1.60 - 1.45 (4H, m). IR(neat) : 3450cm ^'1 .

Preparation 4 l-(S)-Phenyl- -tetrahvdropyranylo'v-2-(3-(5)-tetrahvdropyranyloxypyrrolidi n-l- vPethylamine

This was prepared from 2-(?)-phenyl-2-(3-(S)-tetrahydro-pyranyloxypyrrolidin- l-yl)ethanol and O-tetrahydropyranyl-hydroxylamine (R.N.Warrener and E.N.Cain,

Angew. Chem. Int. Edit. 1966, 5, 511) in 42.5% yield as a brown oil according to a procedure similar to that described in Preparation 1.

Η NMR (270MHz, CDCI ₃ ) δ 7.45 - 7.25 (5H, m), 6.51 (IH, br.s), 4.80 - 4.73 (IH, ), 4.65 -4.55 (IH, in), 4.45 -4.33 (IH, m), 4.28 -4.15 (IH, m), 4.00-3.75 (2H, m), 3.70 - 2.55 (9H, m), 2.30 - 2.05 (IH, m), 1.90 - 1.35 (12H, m).

Example 10 2-(3.4-Dichlorophenyl)-N-tetrnhydropyrnnyloxy-N-f2-(3-(5)- tetrahydroDyrnnyloxypyrrolidin-l-vP-l-(S)-phenylethyllacetam ide

This was prepared from l-(5)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)- tetrahydropyranyloxypyrrolidin-l-yDethylamine and 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brown viscous oil according to a procedure similar to that described in Example 1. 'H NMR (270MHz, CDCI,) δ 7.43 - 7.15 (7.4H, m), 6.98 - 6.91 (0.6H, ), 5.69

(0.4H, dd, J=4.0, 11.0Hz), 5.58 (0.6H , dd, J=4.8, 11.4Hz), 5.35 - 5.20 (IH, m), 4.65-4.53 (IH, m),4.41 -4.21 (IH, m), 4.15 - 3.80 (4H, m), 3.68 - 3.10 (4H, m), 3.03 - 2.80 (2H, m), 2.70 - 2.35 (3H, m), 2.20 - 1.10 (13H, m). IR(neat) : 1660cm ^'1 .

Example 11

2-(3.4-Dichlorophenyl)-N-hvdroxy-N-[2-(3-(5)-hvdroxypyrro lidin-l-yl)-l-(S)- phenylethyllacetamide

A mixture of 2-(3,4-Dichlorophenyl)-N-tetrahydropyranyloxy-N-[2-(3-(S)- tetrahydropyranyloxypyrrolidin- 1 -yl)- 1 -(5yphenylethyl]acetamide (1.13g, 1.96mmol) and HCl gas saturated MeOH (4ml) in MeOH (20ml) was stirred at room temperature for 7h. The solvent was evaporated. The residue was basified with saturated NaHCO ₃ aqueous solution, extracted with CH _? C1 ₂ , and dried (Na ₂ S0 ₄ ). Evaporation of the solvent gave 0.80g of brown viscous oil, which was crystallized by adding ether and scratching. The crystalline was collected by filtration and washed with ether to afford 377mg(47.1 %) of white powder. mp98.5 -99.5°C.

'H NMR (270MHz, CDC1,) δ 7.45 - 7.20 (7H, ), 7.14 (IH, dd, J= 1.8, 9.9Hz), 5.62 (IH, dd, J=5.5, 11.0Hz).5.00 - 3.00 (2H, almost flat br.s), 4.35 - 4.25 (IH, m), 3.85 (IH, d, J = 14.3 Hz), 3.73 (IH, d, J = 13.9Hz), 3.38 (IH, dd, J = 11.0, 12.5 Hz), 2.95 (IH, dt, J=5.l.8.8 Hz), 2.73 (IH, d, J = 10.6Hz), 2.65 (IH, dd, J=5.5,

12.5Hz), 2.51 (IH, dd, J=5.5, 10.6Hz), 2.40 - 2.27 (IH, m), 2.22 - 2.07 (IH, m), 1.65 - 1.50 (IH, m). IR(Nujol) : 3070, 1640cm'. MS m/z: 412(MX4, 10.3), 410(MX2, 85.7), 408(M ⁺ , 100), 304(8.6), 149(50.2), 114(22.7), 112(24.2).

[α]„ = +102.9(c= 0.516, MeOH).

HCl salt: mp 65.5-67.0 °C.

Anal. Calcd for C,„H ₂ ,CUN,O,-HCI-0.5H,O : C, 52.82 ; H, 5.32; N, 6.16.

Found : C, 53.09 ; H, 5.29 ; N, 6.17.

Preparation 5

(/?)-(-)-2-(4-FlnorophenvPglvcinol

This was prepared from 4-fluoro-D-a-phenylgIycine in 88% yield according to the procedure of D.A.Evans (Organic Synthesis, 68, 77).

Η NMR (270MHz, CDC1 δ 7.30 (2H, dd, J =5.5, 8.4Hz), 7.03 (2H, t, J = 8.4Hz), 4.05 (IH, dd, J=4.4, 8.1Hz), 3.71 (IH, dd, J=4.4, 10.6Hz), 3.53 (IH, dd, J = 8.4,

10.6Hz), 2.19 (3H, br.s). lR(KBr) : 3350, 3280cm ¹ .

Preparation 6 2-rR)-(4-Flιιorophenyl)-2-(3-(.S -tetrahvdropyranyloxypyrrolidin-l-yl)ethanol This was prepared from (/?J-(-)-2-(4-fluorophenyl)glycinol in 68.8% yield according to a procedure similar to that described in Preparation 3. Η NMR (270MHz, CDC1 ₃ ) δ 7.31-7.26 (2H, m), 7.03 (2H, dd, J = 8.4, 8.8Hz), 4.65- 4.51 (IH, m), 4.40-4.27 (IH, m), 3.90-3.75 (3H, m), 3.55-3.40 (2H, m), 2.90-2.70 (IH, m), 2.70-2.50 (2H, m), 2.50-2.35 (IH, m), 2.30-1.95 (2H, m), 1.95-1.60 (3H, ), 1.60-1.45 (4H, m). lR(neat) : 3450cm ¹ .

Example 12 2-(3.4-DichlorophenvP-N-fl-(S)-(4-ππoiOphenyl)ethyl-2-(3-( S)-hvdroxypyrrolidin-l- This was prepared from 2-(/?)-(4-fluorophenyI)-2-(3-(S)-tetrahydropyranyl- oxypyrrolidin-l-yl)ethanol and 3,4-dichlorophenylacetic acid in 52.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDCI,) δ 7.41 - 7.26 (4H, m), 7.12 (IH, dd, J = 1.8, 8.1Hz),

6.99 (2H, dd, J = 8.4, 8.8Hz), 5.60 (IH, dd, J = 5.1, 11.0Hz), 4.35 - 4.25 (1H, m), 3.82 (IH, d, J = 13.9Hz), 3.72 (IH, d, J = 14.3Hz), 3.71 (IH, s), 3.58 (IH, s), 3.35 (IH, dd, J=11.7, 12.1Hz), 3.00 - 2.90 (IH, m), 2.73 (IH, br.d, J = 11.0Hz), 2.58 (IH, dd, J = 5.1, 12.5Hz), 2.51 (IH, dd, J = 5.5, 10.6Hz), 2.37-2.10 (2H, m), 1.65- 1.55 (IH, m). lR(neat) : 3200, 1640cm ^'1 . MS m/z: 426(M ⁺ ). HCl salt: amo hous solid.

Anal. Calcd for C ₂₀ H ₂ ,Cl ₂ FN ₂ O ₁ -HCl-0.7H ₂ O : C, 50.43 ; H, 4.95; N, 5.88. Found : C, 50.80 ; H, 4.96 ; N, 5.45.

Example 13 2-(4-Bromophenyl)-N-hvdroxy-N-f2-(3-(S)-hvdroxypyrrolidin-l- yl)-l-(5)- phenylethyllacetamide

Thiswaspreparedfrom2-(?)-phenyl-2-(3-( )-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 4-bromophenylacetic acid in 44.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDC1 δ 7.50- 7.14 (9H, m), 5.61 (IH, dd, J = 5.1, 11.0Hz),

4.28-4.22 (IH, m), 3.90 (IH, l, J = 13.6Hz), 3.70 (IH, d, J = 13.9Hz), 3.33 (IH, dd,

J = 11.0, 12.5Hz), 2.92-2.82 (IH, m), 2.72-2.64 (2H, m), 2.50 (IH, dd, J = 5.5, 10.6Hz), 2.38-2.28(1H, m), 2.20 (2H, br.s), 2.16-2.01 (IH, m), 1.60-1.50 (IH, m). lR(neat) : 3200, 1630cm ¹ .

MS m/z: 418(M ⁺ ).

HCl salt: amorphous solid.

Anal. Calcd for C _2o H ₂₃ BrN ₂ O ₃ -HC10.5H ₂ O : 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-hvclroxy-N-I2-(3-(S)-hvclroxypyrrolidin- l-yl)-1-(S)- phenylethyllncetamide

Thiswaspreparedfrom2-(?)-phenyl-2-(3-(5)-tetrahydropyrany loxypyrrolidin-l-

yl)ethanol and 3-bromophenylacetic acid in 29.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDC1 _. δ 7.51-7.15 (9H, m), 5.62 (IH, dd, J = 5.5, 11.0Hz), 4.28-4.20 (IH, m), 3.94 (IH, d, J = 13.9Hz), 3.70 (IH, d, J = 13.6Hz), 3.35 (IH, dd, J = 11.4, 12.5Hz), 2.92-2.83 (IH, m), 2.70-2.62 (2H, m), 2.51 (IH, dd, J=5.1,

10.6Hz), 2.42 (2H, br.s), 2.38-2.28 (1 H, m), 2.18-2.03 (IH, m), 1.60-1.46 (IH, m). lR(neat) : 3200, 1630cm ^'1 . MS m/z: 418(M ⁺ ). HCl salt: amorphous solid. Anal. Calcd for C ₂₀ H ₂₃ BrN,O ₃ -HCI-H ₂ O : C, 50.70 ; H, 5.53; N, 5.91.

Found : C, 50.57 ; H, 5.58 ; N, 5.90.

Example 15 2-(4-Flιιorophenyl)-N-hvdroxy-N-[2-(3-(5)-hvdroxypyrrolidi n-l-yl)-l-(5)- phenylethyllncetamide This wasprepared from 2-(?)-phenyl-2-(3-( )-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 4-fluorophenylacetic acid in 23.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDC1 ₃ ) δ 7.40-7.22 (7H, m), 7.10-6.95 (2H,m), 5.67-5.61 (IH, m), 4.34-4.22 (IH, m), 3.92 (IH, d, J=13.6Hz), 3.73 (IH, d, J=13.9Hz), 3.36 (IH, dd, J=10.6, 12.5Hz), 2.96-2.86 (IH, m), 2.76-2.62 (2H, m), 2.58-2.48 (IH, m),

2.40-2.28 (IH, m), 2.24-1.70 (3H, m), 1.64-1.48 (IH, m). lR(neat) : 3400, 1630cm ^'1 . MS m/z: 358(M ⁺ ). HCl salt: amorphous solid. Anal. Calcd for C ₂₍₁ H ₂₁ FN ₂ O ₃ -HCl-0.4H ₃ O : C, 59.74 ; H, 6.22; N, 6.97.

Found : C, 59.81 ; H, 6.43 ; N, 6.88.

Example 16 2-(3.4-Dimethoxypheιιyl)-N- vdroxy-N-f2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)- phenylethvPncetnmide

This asprepared from 2-(?)-pheny l-2-(3-(5)-tetrahydropyranyloxypyrrolidin-l- yOethanol and 3,4-dimeihoxyphenylacetic acid in 10.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. 'H NMR (270MHz, CDC1 ₃ ) δ 7.40-7.22 (5H, m).6.95-6.78 (3H, m), 5.70-5.60 (IH, m), 4.25-4.15 (IH, m), 3.91 (IH, d, J = 13.9Hz), 3.88 (3H, s), 3.87 (3H, s), 3.68

(IH, d, J=13.9Hz), 3.33 (IH, dd, J= 11.4,11.7Hz), 2.90-2.78 (IH, m), 2.74-2.60 (2H, m),2.47(lH,dd, J=5.1, 10.6Hz), 2.34-2.20 (IH, m), 2.14-1.98 (IH, m), 1.90 (2H, br.s), 1.50-1.36 (IH. m). lR(neat) : 3400, 1640cm ¹ . MS m/z: 400(M ⁺ ).

HCl salt: amorphous solid.

Anal. Calcd for C ₂₂ H ₂ ,N,0,-HC1-2.7H ₂ 0 : C, 54.42 ; H, 7.14; N, 5.77.

Found : C, 54.31 ; H, 6.77 ; N.5.92.

Example 17 N-Hvdro\v-N-r2-(3-(S)-hvdroxyoyrrolidin-l-yl)-l-(5)-Dhenylet hyll-2-(3- trifluoromethylphenvPacetnmi e

This was prepared fro m2-(/?)-pheny 1 -2-(3-(S)-tetrahydropy ranyloxypyrrolidin-1- yOethanol and 3-trifluoromethylphenylacetic acid in 18.9% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. 'H NMR (270MHz, CDC1 ) δ 7.60-7.26 (9H, m), 5.75-5.65 (IH, m), 4.35-4.25 (IH, m), 3.99 (IH, d, J=14.3Hz), 3.86 (IH, d, J = 14.3Hz), 3.54-3.38 (IH, m), 3.04-2.94 (IH, m), 2.84-2.40 (6H, m), 2.20-2.06 (IH, m), 1.70-1.55 (IH, m). lR(neat) : 3350, 1630cm ^'1 . MS m/z: 408(M + H) ⁺ . HCl salt: amorphous solid.

Anal. Calcd for C _2l H ₂₃ F ₃ N _? OvHCH .9H ₂ 0 : C, 54.70 ; H, 5.64; N, 6.08. Found : C, 54.83 ; H, 5.97 ; N, 6.21 .

Example 18 N-Hvdroxy-N-r2-(3-(S)-hv oxynyrrolidin-l-yl)-l-(5)-Dhenylethyll-2-(4-

trifluoromethylnhcnvPacct amide

Thiswaspreparedfrom2-(?)-phenyl-2-(3-( ^' )-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 4-triπuoromethylphenylacetic acid in 35.4% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. ^l H NMR (270MHz, CDCI ₃ ) δ 7.56 (2H, d, J = 8.IHz), 7.44 (2H, d, J = 8.1Hz), 7.33-

7.26 (5H, ), 5.65 (IH, dd, J=5.9, 11.0Hz), 4.35 - 4.20 (IH, m), 3.99 (IH, d, J = 14.3Hz), 3.85 (lH,d,J= 13.9Hz), 3.41 (IH, dd, J = 12.1, 12.5Hz), 3.00-2.90 (IH, m), 2.82-2.02 (7H, m), 1.64-1.50 (IH, m). lR(neat) : 3100, 1650cm ¹ . MS m/z: 408(M ⁺ ).

HCl salt: mp 142.5-144.2 °C

Anal. Calcd for C ₂ ,H ₂ F ₃ N ₂ 0 ₃ -HC!X2H ₂ 0 : C, 56.24 ; H, 5.48; N, 6.25.

Found : C, 56.27 ; H, 5.61 ; N, 6.08.

Example 19 2-(4-Biphenyl)-N-hvdro\v- -f2-(3-( )-hvdro\ypyrrolidin-1-yl)-l-(S)- phenylethvπacetamide

This wasprepared fro nι2-(/?)-phenyl-2-(3-(5)-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 4-biphenylacetιc acid in 38.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. 'H NMR (270MHz, CDCI ₃ ) δ 7.60-7.26 (14H, m), 5.66 (IH, dd, J=5.1, 11.0Hz),

4.20-4.14 (IH. m), 4.04 (IH, d, J = 13.6Hz), 3.76(1H, d, J = 13.2Hz), 3.35 (IH, dd, J=10.3, 13.6Hz), 2.90-2.80 (IH, m), 2.73-2.63 (2H, m), 2.55-2.45 (IH, m), 2.35- 2.22 (IH, m), 2.10-1.96 (IH, m), 1.90 (2H, br.s), 1.50-1.35 (IH, m). MS m/z: 417(M + H) ⁺ . HCl salt: mp 163.8-165.5 °C

Anal. Calcd for C _ή H _?s N ₂ O ₁ HC10.5H ₂ O : C, 67.60 ; H, 6.55; N, 6.06. Found : C.67.77 ; H, 6.42 ; N.5.76.

Ex mple 20 N-Hvdroxy-N-r2-(3-(5)-hvclroxynyrrolidin-l-yl)-l-(S)-D enylcthv11-2-(4-

nit rophenvPaeet amide

This wasprepared from 2-(?)-phenyl -2-(3-(5)-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 4-nitrophenylacetιc acid in 11.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDCU,) δ 8.14 (2H, d, J = 8.8Hz), 7.44 (2H, d, J = 8.8Hz), 7.35-

7.16 (5H, m), 5.74 (IH, dd, J=4.8, 10.3Hz), 4.46-4.38 (IH, m), 4.03 (IH, d, J = 15.0Hz), 3.96 (IH, cl, J = 15.0Hz), 3.64-3.50 (IH, m), 3.20-3.10 (IH, m), 2.96 (IH, br.d, J = 10.3Hz), 2.90-2.74 (3H, m),2.66(2H, br.s), 2.30-2.16 (IH, m), 1.84- 1.70 (IH, m). lR(neat) : 3400, 1630cm ¹ .

MS m/z: 385(M ⁺ ). HCl salt: amoφhous solid.

Anal. Calcd for C,„H ₂₁ N-,O,-HCH.5H_O : C, 53.5! ; H, 6.06; N, 9.36. Found : C, 53.71 ; H, 6.01 ; N, 9.11 .

Example 21

N-Hvdroxy-N-r2-(3-(5)-hvdro\VDyrrolidin-l-yl)-l-(5)-nheny lethyll-2-(3- nitrophenvPacetamide

This wasprepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-l- yOethanol and 3-nitrophenylacetic acid in 11.6%) yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCI δ 8.17-8.08 (2H, m), 7.66-7.20 (7H, m), 5.64 (IH, dd, J=5.9, 11.0Hz), 4.38-4.30 (IH, m), 4.03 (IH, d, J=14.7Hz), 3.90 (IH, d, J = 14.3Hz), 3.50-3.38 (IH, m), 3.06-2.94 (IH, m), 2.84-2.70 (2H, m), 2.66-2.56 (IH, m), 2.50-2.32 (IH, m), 2.20-2.04 (IH, m), 1.96 (2H, br.s), 1.70-1.50 (IH, m). MS m/z: 386(M + HX

HCl salt: mp 154.3-155.5 °C.

Anal. Calcd for C,„H ₂₁ N,Os-HCI-0.3H ₂ O : C, 56.22 ; H, 5.80; N, 9.83.

Found : C, 56.29 ; H, 5.80 ; N, 9.55.

Example 22

2-(4-ChloroDhcnv0-N-hv(lroxy-N-r2-(3-(S)-hvdroxyDyrrolidin-l -yl)-l-(S)- phenylethvnacetamide

This wasprepared from 2 -(?)-pheny 1-2 -(3-(S)-tetrahydropyranyloxypyrrolidin-l- yOethanol and 4-chlorophenylacetic acid in 49.4% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDC1 ₃ ) δ 7.40-7.20 (9H, m), 5.65 (IH, dd, J = 5.1, 11.0Hz), 5.00-3.30 (2H, wide spread br.s), 4.35-4.25 (IH, m), 3.86 (IH, d, J = 13.9Hz), 3.74 (IH, d, J = 13.9Hz), 3.40 (IH. del. X11.7, 12.1Hz), 3.02-2.90 (IH, m), 2.75 (IH, br.d, J= 10.6Hz), 2.61 (IH, dd. J=5.1, 12.5Hz), 2.51 (IH, dd, J = 5.1, 10.3Hz), 2.40-2.25 (IH, m), 2.23-2.08 (IH, m). 1.65-1.50 (IH, ). lR(neat) : 3400, 1630cm ^'1 . MS m/z: 374(M + ). HCl salt: mp 146.5-147.3 °C. Anal. Calcd for C _2u H ₂₃ ClN ₂ O,HC10.3H ₂ O : C, 57.64 ; H, 5.95; N, 6.72. Found : C, 57.87 ; H, 5.88 ; N, 6.78.

Example 23 2-(3-Chlorophenyl)-N-hvdroxy-N-I2-(3-(S)-hvdroxypyrrolidin-l -yl)-l-(5)- phenylethyllacetnmide

This wasprepared from 2-(?)-phenyl-2-(3-(_T)-tetrahydropyranyloxypyrrolidin- 1- yOethanol and 3-chlorophenylacetic acid in 29.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCN) δ 7.34-7.20 (9H, m), 5.75-5.62 (IH, m), 4.35-4.25 (IH, m), 3.94 (IH. d, J=13.9Hz). 3.74 (IH, d, J=13.9Hz), 3.45 (IH, dd, J=9.5,

12.1Hz), 3.05-2.92 (IH, m), 2.80 (IH, br.d, J = 10.6Hz), 2.77-2.30 (3H, m), 3.80- 2.30 (2H, almost flat peak), 2.23-2.06 (IH, m), 1.68-1.54 (IH, m). lR(neat) : 3350, 1630cm ^'1 .

MS m/z: 374(M ⁺ ).

HCl salt: mp 113.2-114.3 °C.

Anal. Calcd for C^H^CIN HCI O^HO : C, 57.40 ; H, 5.97; N, 6.69. Found : C, 57.79 ; H, 5.84 ; N, 6.74.

Example 24 2-(2-ChloroDhenyl)-N-h\(l o\\-N-r2-(3-(S)-hvdro\voyrrolidin-l-yl)-l-(S - phenylethyllaeet amide

This wasprepared from 2 -(/?)-phenγl -2-(3-( )-tetrahydropyranyloxypyrrohdιn-l- yOethanol and 2-chlorophenylacetιc acid in 312% yield according to a procedure similar to that described in Pieparation 4, Examples 10 and 11. 'H NMR (270MHz, CDC1 ₃ ) δ 745-7 16 (9H, m), 5.85-570 (IH, m), 4.44 -4.34 (IH, m),4.14(lH,d, J = 161Hz), 391 (IH, d, J = 161Hz), 368-3.48 (IH, m), 3.24-3.10 (IH, m), 298- 240 (6H, m) 234-218 (IH, m), 186-170(1H, m). lR(neat) 3400, 1640cm ¹

MS m/z- 374(M ⁺ ) HCl salt mp 146 °C

Anal Calcd for C,„H ₂₁ CIN ₂ O ₁ HCl H ₂ 0 C, 5595 , H, 6.10; N, 6.52. Found C, 5618 , H, 600 , N, 655

Example 25

N-Hvdroxy- -r2-(3-(S)-hvdrox Dvι-rolidin-l-yl)-l-(S -ohenylethvn-2-(2.3.5- trichlorophenx Pacetamide

Thiswaspreparedfrom2-(.?)-phenyl-2-(3-(5)-tetrahydropyran yloxypyrrohdin-l- yl)ethanol and 2,3,5-tπchlorophenylacetιc acid in 516% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDC1 ₃ ) δ 745-726 (6H, m), 714 (IH, d, J=2.2Hz), 5.70 (IH, dd, J=4.8, 110Hz), 448-430 (IH, m), 420-300 (2H, wide spread br.s), 4.06 (IH, d, J= 165Hz), 390 (IH, d, J = 161Hz), 350 (IH, dd, J = ll 4, 12.1Hz), 3.20-310 (IH, m), 286 (IH, br d, J = 103Hz), 275-260 (2H, m), 255-2.35 (IH, m), 2.35- 2.20 (IH, m), 185-170 (IH m) lR(neat) ^• 3400, 1640cm ' MS m/z 444(M ⁺ ) HCl salt amorphous solid Anal. Calcd tor C _ill H ₂₁ CI ₃ N ₂ 0 ₁ HCl H ₂ 0 C, 48.21 ; H, 4.86; N, 5.62. Found : C, 4856 , H, 5 17 , NX 40

Example 26 N-Hvdroxy-N-r2-(3-(S)-hvdroxyπyrrolidin-l-yl)-l-(S)-nhenyle thyll-2-(2.4.6- trichlorophenvPacetainide

This wasprepared from 2 -(?)-phenyl -2 _: (3-(5 tetrahydropyranyloxypyrrolidin-l- yOethanol and 2,4,6-trichlorophenylacetic acid in 14.0% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDC1 ₃ ) δ 7.50-7.26 (7H, m), 5.60 (IH, dd, J=4.8, 11.4Hz),

4.47-4.38 (IH, m),4.19(2H, s), 3.49 (IH, dd, J = 11.7, 12.1Hz), 3.25-3.10 (IH, m),

2.84 (IH, br.d, J=9.5Hz), 2.75-2.60 (2H, m), 2.50-2.35 (2H, m), 2.35-2.20 (2H, m), 1.90-1.70 (IH, m). lR(KBr) : 3450, 1640cm- 1.

MS m/z: 442(M + ).

HCl salt:amorphous solid.

Anal. Calcd for C ₂₀ H ₂₁ Cl N ₂ O ₃ -HCl-0.2H ₂ O : C, 49.65 ; H, 4.67; N, 5.79. Found : C, 49.42 ; H, 4.39 ; N.5.96.

Example 27 N-Hvdroxy-N-[2-(3-(S)-hvdro\voyrroliclin-l-yl)-l-(S)-nhenyle thvn-2-(2.4.6- trimethylphenvPacetamide

Thiswaspreparedfrom2-(?)-phenyl-2-(3-( )-tetrahydropyranyloxypyrrolidin-l- yl)ethanol and 2,4,6-trimethylphenylacetic acid in 67.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCN) δ 7.45-7.25 (5H, m), 6.81 (2H, s), 5.80-5.65 (IH, m),

4.40-4.30(lH, m), 3.86 (2H. s), 3.49 (IH, dl, J=11.7, 13.2Hz), 3.20-3.10 (IH, m),

2.80 (IH, br.d, J = 10.3Hz), 2.65-2.50 (2H, m), 2.35-2.25 (3H, m), 2.23 (3H, s), 2.18 (6H, s), 1.90-1.65 (IH, m), 1.65-1.50 (IH, m).

IR(neat) : 3250, 1630cm ^'1 .

MS m/z: 382(M ⁺ ).

HCl salt:amorphous solid.

Anal. Calcd for C ₂₃ H _1ll N ₂ O,-HC10.2H2O : C, 64.01 ; H, 7.57; N, 6.49. Found : C, 64.08 ; H, 7.85 ; N, 6.61 .

Example 28 2-(2.3-DichloroDheιιyl)- -hvdroxy-N-12-(3- ⁽ S ⁾ -hvdroxypyrrolidin-l-yl)-l-(S)- phenylethyllacet amide

This wasprepared from 2-(?)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-l- yOethanol and 2,3-dichlorophenylacetιc acid in 56% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDC1 ₃ ) δ 7.50-7.05 (8H, m), 5.69 (IH, dd, J = 5.1, 11.4Hz), 5.00

- 3.00 (2H, almost flat br.s), 4.45-4.35 (IH, m), 4.10(1H, d, J = 16.1Hz), 3.92 (IH, d, J= 16.1Hz), 3.48 (IH, dd, XII.7, 12.1Hz), 3.20-3.10 (IH, m), 2.82 (IH, d, J = 10.3Hz), 2.70-2.55 (2H, m), 2.45-2.20 (2H, m), 1.80-1.70 (IH, m). lR(neat) : 3200, 1640cm ¹ .

MS m/z: 408(M + ).

HCl salt: mp 155.3-158.1 °C.

Anal. Calcd for C ₂₀ H ₂₂ C1 ₂ N ₂ 0 ₃ -HC1 : C, 53.89 ; H, 5.20; N, 6.28. Found : C, 53.72 ; H, 5.24 ; N, 6.16.

Example 29 2-f2.4-Dichloronhenyl)-N-hvdroxy-N-12-(3-(5)-hvdroxyDyrrolid in-l-yl)-l-(5)- phenylethyllπcetamide

This wasprepared from2-(/?)-phenyl-2-(3-( )-tetrahydropyranyloxypyrrolidin- 1- yOethanol and 2,4-dichlorophenylacetic acid in 71.9% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDCI δ 7.45-7.15 (8H, m), 5.69 (IH, dd, J = 5.1, 11.4Hz),

6.50-4.50 (2H, almost flat br.s), 4.35-4.25 (IH, m), 4.00 (IH, d, J= 16.1Hz), 3.86

(IH, d, J = 16.1Hz), 3.47 (IH, dd, JX1.7, 12.1Hz), 3.20-3.10 (IH, m), 2.83 (IH, d, J=10.6Hz),2.61 (2H, dd, J=5.5, 12.1Hz), 2.45-2.20 (2H, m), 1.80-1.65 (IH, m). lR(neat) : 3200, 1635cm ¹ .

MS m/z: 408(M ⁺ ).

HCl salt: mp 149-151.5 °C.

Anal. Calcd for C ₂₍ ,H, ₂ CI ₂ N ₂ O HCI 0.2H ₂ O : C, 53.46 ; H, 5.25; N, 6.23. Found : C, 53.46 ; H, 5.19 ; N, 6.19.

Example 30 2-(2.5-DichloroDhenyl)- -h ^y droxy-N-r2- ⁽ 3-(5 ⁾ -hvdroxypyrrolidin-l-yl)-l-(S)- phenylethyllacet amide

This wasprepared from -(?)-phenyl-2-(3-( )-tetrahydropyranyloxypγrrolidin-l- yOethanol and 2,5-dichlorophenylacetic acid in 56.3% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCI ₃ ) δ 7.45-7.15 (8H, m), 5.69 (IH, dd, J = 5.1, 11.0Hz),

5.60-4.50 (2H, almost flat br.s), 4.35-4.25 (IH, m), 4.03 (IH, d, J= 16.1Hz), 3.86

(IH, d, J= 16.1Hz), 3.47 (IH, t, J=11.7Hz), 3.20-3.10 (IH, m), 2.82 (IH, d, J = 10.6Hz), 2.63 (2H, dd, J=5.1, 12.1Hz), 2.45-2.20 (2H, m), 1.85-1.70 (IH, m). lR(neat) : 3200, 1635cm ¹ .

MS m/z: 408(MX

HCl salt: 157.5-158.2 °C.

Anal. Calcd for C ₂₍₁ H ₂₂ CI N ₂ O ₃ HC10.2H ₂ O : C, 53.46 ; H, 5.25; N, 6.23. Found : C, 53.35 ; H, 5.21 ; N, 6.14.

Prep ation 7 2-(3-(S)-Mcthoxymethyloxypyrroliclin-l-vP-2-(?)-phenylethano l

To a stirred solution of (S)-(-)-butanetriol (10.61g, O.lmol) in pyridine (50ml) was added p-toluenesulfonyl chloride (38.13g, 0.2mo!) by portions at 0 °C (ice bath). After lh stirring, the reaction mixture was poured into c-HCl aqueous solution including ice and acidified to pH2. The mixture was extracted with ethyl acetate (100ml x 3). The extract combined was washed with brine, dried (NaSO ₄ ), and concentrated to give 36.22g of pale brown clear oil. To a stirred solution of this crude ditosylate (36.22g) and meth lal(50 ml) in CH ₃ C1 ₂ (50ml) was added P ₂ 0 ₅ (20g). After lh stirring, another !0g of P ₂ Os was added to the reaction mixture. After 2h stirring, the CH ₂ CI ₂ layer was separated. Residual dark brown solid was washed with CH ₂ C1 ₂ . The combined CH ₂ C1 ₂ layer was washed with NaHCO ₃ aqueous solution, dried (Na ₂ SO ₄ ), and concentrated to give 38.5 I g of brown viscous oil. A mixture of this oil (38.5 lg, 84mmol), (?)-(-)-2-phenylglycinol (10.97g, δOmmol), and triethylamine (23mmol, lόOmmol) in ethanol (40ml) was retluxed with stirring for 15h. The solvent

was evaporated and the residue was dissolved in CH ₂ C1 ₂ (200ml), washed with NaHC0 ₃ aqueous solution and brine, dried (Na ₂ S0 ₄ ), and concentrated to give 28.43g of brown viscous oil. This oil was purified by column chromatography(silica gel 200g, CHjC /methanol: 40/1 to 20/1) to afford 9.74g (48.4%) of clear brown viscous oil. 'H NMR (270MHz. CDCI ₃ ) ύ ⁷ .40 - 7.25 (5H, m), 4.62 (IH, d, J = 7.0Hz), 4.58 (IH, d, J = 6.6Hz), 4.26 - 4.18 (IH, m).3.92 (IH, d, J=6.2, ll.OHz), 3.82 (IH, dd, J = 5.5, ll.OHz), 3.54 (2H, t, J=5.9Hz), 3.33 (3H, s), 2.93 (IH, br.s), 2.85 - 2.66 (3H, m), 2.56 - 2.47 (IH, m), 2.16 - 2.02 (IH, m), 1.88 - 1.77 (IH, m).

Example 31 2-(2.6-DichloroDhenvn-N-hvdro\v-N-r2-(3-(5)-hvdroxyDyrrolidi n-l-yl)-l-(S)- phenylethyllacetamide

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolidin-l-yl)-2-(?)- phenylethanol and 2,6-dichlorophenylacetic acid in 47.2% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. 'H NMR (270MHz, CDC1 ₃ ) δ 750-7.25 (7H, m), 7.20-7.10 (IH, m), 5.71 (IH, dd,

J=5.1, 11.4Hz), 5.40-3.70 (2H, almost flat br.s), 4.50-4.40 (IH, m), 4.25 (2H, s), 3.50 (IH, dd, J = 11.0, 12.5Hz).3.28-3.15 (IH, m), 2.87 (IH, d, J = 10.3Hz), 2.75- 2.55 (2H, m), 2.50-2.25 (2H, m), 1.90-1.70 (IH, m). lR(KBr) : 3400, 1640cm '. MS m/z: 408(M ⁺ ).

HCl salt: mp 95.5-96.8 °C.

Anal. Calcd for C ₂₍ ,H ₂₂ CI ₂ N ₂ O ₃ ΗC10.5H ₂ O : C, 52.82 ; H, 5.32; N, 6.16.

Found : C, 52.61 ; H.5.13 ; N, 6.10.

Example 32 2-(3.5-Dichlorophenyl)-N-hvdroxy-N-12-(3-(5)-hydroxypyrrolid in-l-vP-l-(S)- phenylethvπacctamide

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolidin-l-yl)-2-(/?)- phenylethanol and 3,5-dichlorophenylacetic acid in 47.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDCI,) δ 7.45-7.15 (8H, m), 5.63 (IH, dd, J = 5.5, ll.OHz), 4.50-3.00 (2H, almost flat br.s), 4.40-4.28 (IH, m), 3.87 (IH, d, J= 14.3Hz), 3.71 (IH, d, J= 14.3Hz), 3.39 (IH, dd, J = 11.4, 12.1 Hz), 3.05-2.95(lH, m), 2.74 (IH, d, J = 11.0Hz), 2.65 (IH, dd, J=5.5, 12.5Hz), 2.54 (IH, dd, J = 5.5, 10.6Hz), 2.45-2.30 (IH, m), 2.25-2.10 (IH, m), 1.70-1.55 (IH, m). lR(neat) : 3350, 1650cnr'. MS m/z: 408(M ⁺ ). HCl salt: amorphous solid.

Anal. Calcd for C ₂₀ H ₂₂ Cl ₂ N ₂ CγHCI-2H ₂ O : C, 49.86 ; H, 5.65; N, 5.81. Found : C, 49.49 ; H, 5.53 ; N, 5.59.

Example 33 N-Hvdroxy-N-r2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(5)-phenylet hyll-2-(2.3.6- trichlorophenvPacetamide

This was prepared from 2-(3-(5 methoxymethyloxypyrrolidin-l-yl)-2-(fl)- phenylethanol and 2,3,6-trichlorophenylacetic acid in 46.7% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCI ₃ ) δ 7.45-7.20 (7H, m), 5.69 (IH, dd, J=4.8, ll.OHz),

5.00-3.50 (2H, almost Hat br.s), 4.50-4.40 (IH, m),4.29 (2H, s), 3.49 (IH, t,

J = 11.7Hz), 3.25-3.15 (IH, m), 2.85 (IH, d, J = 10.3Hz), 2.70-2.60 (2H, m), 2.45- 2.20 (2H, m), 1.90-1.70 (IH, m). lR(KBr) : 3400, 1640cm'.

MS m/z: 442(M ⁺ ).

HCl salt: mp 102-103 °C.

Anal. Calcd for C ₂₁₎ H ₂₁ C1 ₃ N ₂ 0, HC1-H ₂ 0 : C, 48.21 ; H, 4.86; N, 5.62. Found : C, 48.40 ; H, 4.64 ; N, 5.52.

Example 34 2-(Benzoftiruran-4-yl)-N-hvdroxy-N-f2-(3-(5)-hvdroxypyrrolid in-l-yl)-l-(5)- phenylethyllacetnmide

This was prepared from 2-(3-(S)-methoxymethyloxypyrrolidin-l-yl)-2-(?)-

phenylethanol and 4-benzo[b]furanacetιc acid in 57.5% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDC1,) δ 7.64 (IH, d, J=2.2Hz), 7.50-7.25 (7H, m), 7.14 (IH, d, J = 7.3Hz), 6.84 (IH, dd, J=07.2.2Hz), 5.61 (IH, dd, J=5.5, 11.4Hz), 4.24 (lH,d, J=13.6Hz), 4.05-3.95 (IH, m), 391 (IH, d, J = 13.2Hz), 3.31 (IH, dd,

J = 11.7, 12.1Hz), 275-265 (IH, m), 263-2.50 (2H, m), 2.30 (IH, dd, J=5.1, 10.3Hz), 2.20-2.10 (IH, m), 200-185 (IH, m). lR(neat) : 3400, 1635cm ' MS m/z: 380(M ⁺ ). HCl salt: amorphous solid.

Anal. Calcd for C ₂₂ H _2J N ₂ CyHCl 1 1H ₂ 0. C, 60.51 ; H, 6.28; N, 6.41 . Found : C, 60.31 ; H, 598 ; N.6.47

Example 35 N-Hvdroxy-N-r2-(3-(S)-hvdro\vpyrrolidin-l-yl)-l-(S)-phenylet hyl1-2-(l-tetralon-6- vPacetamide

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolidin-l-yl)-2-(7?)- phenylethanol and (l-tctralon-6-yl)acetιc acid in 59.4% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDC1 ₃ ) 796 (IH, d, J=8.1Hz), 7.40-7.18 (7H, m), 5.66 (IH, dd, J=5.5, ll.OHz), 4.30-4.20 (IH, m), 3.94 (IH, d, J = 14.3Hz), 3.81 (IH, d,

J=13.9Hz), 3.80-2.00 (2H, almost flat br.s), 3.40 (IH, dd, J = 11.7, 12.1Hz), 3.00-

2.85 (3H, m), 2.80-2.50 (5H, m), 2.45-2.30 (IH, m), 2.20-2.05 (3H, m), 1.65-1.50

(IH, m). lR(neat) : 3400, 1680. 1640cm ¹ MS m/z: 408(M ⁺ )

HCl salt: amorphous solid.

Anal. Calcd for C ₂ ,H ₂ N ₂ 0,-HCI l.2H ₂ 0. C, 61.78 ; H, 6.78; N, 6.00.

Found : C, 61.60 ; H, 6.59 ; N, 6.35.

Example 36

2-(3.4-Dimethylphenyl)-N-hvdroχv-N-r2-(3-(5)-hvdroxypyrroli din-l-yl)-l-(5)- phenylethyllacetamide

This was prepared from 2-(3-(S)-methoxymethyloxypyrrohdιn-l-yl)-2-(/?)- phenylethanol and 3,4-dιmethylphenylacetιc acid in 66.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'H NMR (270MHz, CDCI ₃ ) δ 745-725 (5H, m), 7.20-7.00 (3H, m), 5.66 (IH, dd, J = 5.1, 11.4Hz), 4.25-4 10 (IH, m), 3.87 (IH, d, J=13.9Hz), 3.67 (IH, d, J = 13.9Hz), 3.37 (IH, dd, J = ll 7, 121Hz), 3.00-2.85 (IH, m), 2.71 (IH, d, J = 99Hz), 2.55 (IH, dd, J=55, 125Hz), 242 (IH, dd, J = 5.1, 9.9Hz), 2.35-2.05 (9H, m, including each 3H, s, at 222 and 2.21ppm), 1.80-1.35 (2H, m). lR(neat) .3350, 1630cm ' MS m/z: 368(M ⁺ ) HCl salt: amo hous solid. Anal. Calcd for C ₂₂ H _2S N ₂ 0,-HC1 1.8H ₂ 0 : C, 60.42 ; H, 7.51; N, 6.41. Found : C, 6051 ; H, 7.71 , N, 6.29

Example 37 2-(3.4-Dichlo ophenyl)- -hvdroxy-N-[2-(3-(5)-hvdroxypyrroli in-l-yl)-l-(/?)- phenylethyllncetnmide

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolιdιn-l-yl)-2-(5)- phenylethanol and 3,4-dιchlorophenylacetιc acid in 32.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

'HNMR (270MHZ, CDC1 ₃ ) δ 745-7.25 (7H, m),7.13(lH, dd, J = 1.5, 8.1Hz), 5.61

(IH, dd, J=5.5, 106Hz), 5.00-3.90 (2H, almost flat br.s), 4.45-4.35 (IH, m), 3.85

(IH, d, J = 14.7Hz), 377 (IH, d, J=14.3Hz), 3.37 (IH, dd, J = 11.0, 12.5Hz), 2.89 (IH, dd, J=4.7, 84Hz), 280-2.60 (3H, m), 2.45-2.35 (IH, m), 2.15-2.00 (IH, m),

1.80-1.65 (IH, m). lR(KBr) : 3450, 3250, 1650c ¹ .

MS m/z: 408(M ⁺ ). mp 125.5-126.0 °C. [α]D = -95.4 ° (c = 0.218, methanol)

Anal. Calcd for C _2U H 1 ₂ N _? 0, _: c, 58.69 ; H, 5.42; N, 6.84. Found : C, 58.51 ; H, 5.42 ; N.6.70.

Example 38 2-(3.4-Difhιorophenv0-N-hvdroxy-N-r2-(3-(S)-hvdroxypyrrolid in-l-yl)-l-(S- phenylethyllacet ami e

This was prepared from 2-(3-(5 ^' )-methoxymethyloxypyrrolidin-l-yl)-2-(/?)- phenylethanol and 3,4-ditluorophenylacetιc acid in 53.6% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDCI ₃ ) δ 7.40-7.25 (5H, m), 7.18-6.95 (3H, m), 5.65 (IH, dd, J = 5.5, 11.4Hz), 5.00-3.90 (2H, almost flat br.s), 4.35-4.25 (IH, m), 3.82 (IH, d,

J=14.3Hz), 3.74 (IH, d, J = 14.3Hz), 3.40 (IH, dd, J = 10.6, 13.2Hz), 2.95 (IH, dt, j=4.4, 8.8Hz), 2.75 (IH, d, J = 10.6Hz), 2.61 (IH, dd, J=5.1, 12.5Hz), 2.51 (IH, dd, J=5.5, 10.6Hz).2.40-2.10 (2H, m), 1.70-1.50 (IH, m). lR(neat) : 3350, 3250, 1630cm ^'1 . MS m/z: 376(M ⁺ ).

HCl salt : amorphous solid.

Anal. Calcd for CXXF.N 'HCl-O.SH^O : C, 56.94 ; H, 5.73; N, 6.64.

Found : C, 57.21 ; H, 6.07 ; N, 6.63.

Example 39 2-(Benzof_)lthiophen-4-vn-N-hvdroxy-N-r2-(3-(S)-hvdroxypyrro lidin-l-vP-l-(S)- phenylethyllaeetamidc

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolidin-l-yl)-2-(/)- phenylethanol and (benzo[/]thiophen-4-yl)acetιc acid in 48.8% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDC1,) δ 7.79 (IH, d, J=7.7Hz), 7.66 (IH, d, J = 5.5Hz), 7.50-

7.20 (8H, m), 5.60 (IH, dd, J = 5.5, 11.4Hz), 4.60-3.20 (2H, almost flat br.s), 4.32 (IH, d, J= 13.6Hz), 4.0! (IH, d, J=l3.6Hz), 4.00-3.90 (IH, m), 3.30 (IH, dd, J=11.7, 12.1Hz), 2.70-2.45 (3H, m), 2.28 (IH, dd, J=5.1, 10.3Hz), 2.20-2.10 (IH, m), 1.95-1.80 (IH, m), 1.20-1.05 (IH, m).

lR(neat) : 3400, 3200, 1630cm ¹ . MS m/z: 396(M ⁺ ). HCl salt : amorphous solid.

Anal. Calcd for C ₂₂ H ₂₄ N ₂ O ₃ SΗC10.5H ₂ O : C, 59.79 ; H, 5.93; N, 6.34. Found : C, 59.85 ; H.6.09 ; N, 6.27.

Example 40 N-Hvdroxy-N-r2-(3-(S)-lιvdroxypyrrolidin-l-yl)-l-(5)-phenyl ethvn-2-(3.4- methylenedioxyphenvPacet amide

This was prepared from 2-(3-(5)-methoxymethyloxypyrrolidin-l-yl)-2-(/?)- phenylethanol and 3,4-methylenedioxyphenylacetic acid in 59.7% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11.

Η NMR (270MHz, CDC1) δ 7.45-7.25 (5H, m), 6.85-6.70 (3H, m),5.92 (2H, s),

5.66 (IH, dd, J=5.5, 11.4Hz), 4.50-3.30 (2H, almost flat br.s), 4.30-4.20 (IH, m),

3.86(1H, d,J = 13.6Hz), 3.64 (I H,d,J= 13.9Hz), 3.39(1 H,t,J = 12.1Hz), 3.05-2.95 (IH, m), 2.72 (IH, d, J = 10.3Hz).2.59 (IH, dd, J = 5.5, 12.5Hz), 2.48 (IH, dd,

J=5.5, 10.3Hz), 2.35-2.10 (2H, m), 1.65-1.50 (IH, m). lR(neat) : 3400, 3250, 1630cm ¹ .

MS m/z: 384(M ⁺ ).

HCl salt : amorphous solid. Anal. Calcd for C _2l H ₂₄ N,OyHCI-1.4H ₂ O _: C, 56.54 ; H, 6.28; N, 6.28.

Found : C, 56.74 ; H, 6.38 ; N, 5.89.

Example 41 2-(3.5-Difluorophenyl)-N-hvd oxy- -r2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)- phenylethyllacetamidc This was prepared from 2-(3-(5 ^* )-methoxymethyloxypyrrolidin-l-yl)-2-(?)- phenylethanol and 3,4-difluorophenylacetic acid in 40.0% yield according to a procedure similar to that described in Preparation 4, Examples 10 and 11. Η NMR (270MHz, CDCI ₃ ) δ 7.40-7.25 (5H, m), 6.82 (2H, d, J = 8.1Hz), 6.72-6.64 (IH, m), 5.65 (IH, dd, J=5.1, ll.OHz), 5.30-4.20 (2H, almost flat br.s), 4.40-4.30

(IH, m), 3.86 (IH, d, J = 143Hz), 374 (IH, d, J = 143Hz), 3.41 (IH, dd, J = 11.7, 12.1Hz), 3.10-2.95 (IH, m), 276(lH,d, J=106Hz),261 (IH, dd, J = 5.1 , 12.5Hz), 2.52 (IH, dd, J=55, 106Hz), 240-2 10 (2H, m), 1.70-155 (IH, m). lR(neat) : 3350, 3200, 1630cm ¹ MS m/z: 376(M ⁺ ).

HCl salt ^• amorphous solid

Anal. Calcd for C _2n H ₂₂ F ₂ N ₂ 0 ₃ HCl 05H,O C, 5694 , H, 5.73; N, 6.64.

Found : C, 5701 ; H, 5.93 , N.645

Preparation 8 l-Benzyl-3-(?)-tetrahvdiOpyranyloxypyrrolidine

To a stirred solution of (?)-( + )-l-benzyl-3-pyrrolιdιnol (5.00g, 28mmol) and D-camphor-10-sulfonιcacιd (697g, 30mmol) in CH ₂ Cl ₂ (10ml) was added 3,4-dihydro- 2H-pyran (20ml) at rt and the reaction mixture was stirred for 14h (in most cases, the reaction was completed after exothermic reaction subsided). The reaction mixture was diluted with CH ₂ C1 ₂ (100ml), washed with saturated NaHC0 ₃ aqueous solution, dried

(Na ₂ SO), and concentrated to give brown oil This was purified by column chromatography(sιlιca gel 200g, CH C! ₂ /MeOH:40/l as eluent) to give 8.78g (97.6%) of desired compound as brown oil Η NMR (270MHz, CDC1 ₃ ) δ 7.34-7.22 (5H, m), 4.61 (0.5H, dd, J=2.9, 4.4Hz), 4.54 (0.5H, dd, 1=2.9, 4.4Hz), 4.42-4.31 (IH, m), 3.90-3.79 (IH, m), 3.67 (IH, d,

J = 12.8Hz), 3.59 (05H, d. J = 128Hz), 358 (05H, d, J = 12.8Hz), 3.50-3.40 (IH, m), 2.88 (0.5H, dl, J = 66, 103Hz), 274-2.45 (35H, m), 2.25-2.05 (IH, m), 1.95- 1.45 (7H, m)

Preparation 9 3-(/?)-TetrnhvdropyraιiyloxypyriOlidine

Amixtureof ^, -benzyl-3-(?)-tetrahydropyranyloxypyrrolιdιne(8.78g, 27.3mmol) and Pearlman's catalyst (3.50g) m MeOH (100ml) was stirred under hydrogen atmosphere at rt for 4h After removal of the catalyst by Celite filtration, the filtrate was concentrated to give 5.74g of clear light brown oil. This was used for the next

reaction without purification.

Η NMR (270MHz, CDC1,) δ 4.62 ( 1 H, br.s), 4.45-4.30 (IH, m), 3.90-3.80 (IH, m), 3.55-3.45 (IH, m), 3.20-2.80 (5H, m), 2.00-1.40 (8H, m).

Preparation 10 l-(S)-Phenyl-2-(3-(/?)-tetι-ahvdiOpyrnnyloxypyrrolidin-l-yl )ethanol and 2-(/?)-

Phenyl-2-(3-(/?)-tetrahvdropyranyloxypyrrolidin-l-yl)etha nol

A mixture of 3-(?)-tetrahydropyranyloxypyrrolidine (1.43g, 8.32 mmol) and (5)-(-)-styrene oxide (l.OOg, 8.32mmol) in EtOH (10ml) was refluxed with stirring for lh. Evaporation of the solvent gave 3.098g of brown oil, which was purified by column chromatography(silica gel:100g, CH ₂ CI ₂ /MeOH:40/l to 15/1 as eluent) to afford 1.68g (69.3%) of clear light brown oil as about 2 to 1 mixture of title compounds in which l-(S)-phenyl-2-(3-(R)-tetrahydro-pyranyloxypyrrolidin-l-yl)e thanol was main. Η NMR (270MHz, CDCl _. ,) δ 7.40-7.24 (5H, m), 4.72 and 4.68 (total 0.67H, app.each d, J=2.6Hz, OCHO), 4.63-4.55 (lH.m, PhCHOH and OCHO), 4.43-4.25

(lH,m,OCHCHN), 3.89-3.81 (1.67H,m), 3.52-3.46 (1.33H, m), 2.88-2.47 (5.33H, m), 2.15-1.90 (2H, m), 1.86-1.66 (3H, m), 1.58-1.51 (4H, m).

Example 42 2-(3.4-DichlorophenvP-N-π-(.S)-phenyl-2-(3-(j ^t ?)-tetrnhvdropyranyloxypyrτolidin-l- vPethyll-N-tetrahvdropyranyloxyacetamide

To a stirred solution of I-(5)-phenyl-2-(3-(/?)-tetrahydropyranyloxypyrrolidin-l- yOethanol (1.67g, 5.73mmol) and Et N (0.96ml, 6.88mmol) in CH ₂ C1 ₂ (20ml) was added dropwise mesyl chloride (0.53ml, 6.88mmol) at 0 °C. The reaction mixture was stirred at rt for 16h. The reaction mixture was washed with saturated NaHCO ₃ aqueous solution and brine, dried(Na ₂ S0 ₄ ), and concentrated to give 2.02g of brown oil. This oil was used for next reaction without purification. Η NMR (270MHz, CDC1 ₃ ) δ 7.42-7.30 (5H, m), 4.94 (IH, dd, J=5.9, 8.1Hz, PhCHCI), 4.60 and 4.52 (total I H, each m, OCHO), 4.35-4.31 (IH, m, OCHCH ₂ N),

3.88-3.82 (IH, m), 3.48-3.45 (IH, m), 3.25-3.17 (IH, m), 3.02-2.69 (3H, m), 2.66- 2.50 (3H, m), 1.88-1.67 (3H, m), 1.56-1.51 (4H, m).

A mixture of crude chloride derivative (2.02g, 5.73mmol) and 0-(tetra- hydropyranyOhydroxylamine (0.806g, 6.88mmol) in EtOH (10ml) was refluxed with stirring for 0.5h. The reaction mixture was concentrated, diluted with CH ₂ C1 ₂ (30ml), washed with saturated NaHCO-, aqueous solution and brine, dned (Na ₂ SO ₄ ), and concentrated to give 2.59g of brown oil. This oil was used for the next reaction without purification.

A mixture of the above crude amine derivative (2.59g, 5.73mmol), 3,4- dichlorophenylacetic acid (1 41g, 6.88mmol), and l-ethyl-3-(3- dimethylaminopropyOcarbodumicle hydrochlonde (abbreviated as WSC, 1.32g, 6.88mmol) in CH ₂ Cl ₂ (15ml) was stirred at rt for 0.5h. The reaction mixture was washed with saturated NaHCO, aqueous solution and brine, dried (Na ₂ S0 ₄ ), and concentrated to give 4.12g of brown oil. This oil was purified by column chromatography (silica gehlOOg. CH ₂ Cl ₂ /MeOH:50/l to 40/1 as eluent) to give

2.22g(67.1%) of pale yellow oil.

Example 43 2-(3,4-Diehlorophenyl)-N-hv(l oxy-N-[2-(3-(/?)-hvdroxypyrrolidin-l-yl)-l-(S)- phenylethyllacetamide A mixture of above amide derivative (2.20g, 3.81mmol) and HCl gas containing MeOH (10ml) was stirred at rt for lh. The reaction mixture was concentrated, basified with NH, aqueous solution, and extracted with CH ₂ C1 ₂ (30ml). The extract was washed with brine, dried (Na ₂ S0 ₄ ), and concentrated to give light brown powder. This was collected by filtration and washed with hexane to afford 1.117g (71.6%) of light brown powder.

Η NMR (270MHz, CDC1,) δ 7.41-7.28 (7H, m), 7.13 (IH, dd, J =1.8, 8.4Hz), 5.61 (IH, dd, J = 5.5, 10.6Hz), 4.50-3.50 (2H, almost flat br.s), 4.40-4.35 (IH, m), 3.84 (IH, d, J = 14.7Hz), 3.77 (IH, d, J = 14.3Hz), 3.38 (IH, dd, J = 11.0, 12.1Hz), 2.94- 2.85 (IH, m), 2.74-2.63 (3H, m), 2.44-2.35 (IH, m), 2.15-2.01 (IH, m), 1.80-1.65 (IH, m).lR(KBr) : 3250, 1650cm ¹

MS m/z : 408(M ⁺ )

HCl salt : amorphous solid.

Anal. Calcd for C ₂₀ H ₂₂ CI ₂ N,0 HC 0.8H ₂ O: C.52.20; H, 5.39; N, 6.09. Found: C,

52.22; H, 5.39; N.6.12.

Example 44

2-(3.4-DichlorophenvP-N-hvdroxy-N-r2-(3-(/?)-hvdroxypyrro lidin-l-yl)-l -(/?)- phenylethyllacetnmide

This was prepared from 3-(/?)-tetrahydropyranyloxypyrrolidine and (/?)-( + )- styrene oxide in 33.3% yield according to the procedure similar to that described in Examples 3 to 5.

Η NMR (270MHz, CDC1 ₃ ) δ 7.38 (IH, d, J = 8.4Hz), 7.36-7.25 (6H, m), 7.13 (IH, dd, J =1.8, 8.1Hz), 5.64 (IH, dd, J=5.1, ll.OHz), 5.00-3.50 (2H, almost flat br.s), 4.35-4.25 (IH, m), 3.84 (IH, d, J=14.3Hz), 3.73 (IH, d, J = 13.2Hz), 3.40 (IH, dd, J=11.4, 12.5Hz), 3.05-2.95 (IH, m), 2.74 (IH, br.d, J=10.3Hz), 2.62 (IH, dd, J = 5.1, 12.5Hz), 2.51 (IH, dd, J=5.5, 10.6Hz), 2.40-2.25 (IH, m), 2.25-2.10 (IH, m), 1.70-1.55 (IH, m). lR(KBr) : 3400, 3200, 1640cm ¹ . MS m/z : 408(M ⁺ ) HCl salt : amorphous solid Anal. Calcd for C _2l) H _2? Cl N ₂ O ₃ HCI 0.5H ₂ O: C52.82; H, 5.32; N, 6.16. Found: C,

52.71; H, 5.59; N, 6.15.

Preparation 11 (S)-l-(3-Methylphcnyl)-1.2-ethanediol

A mixture of 3-methylstyrene (1.69ml, 12.7mmoI), and AD-mix-α (17.78g, 12.7mmol) in water (65ml) and /-BuOH (65ml) was stirred at 0 °C for 3.5h. To this reaction mixture was added Na ₂ SO, (20g) and the mixture was stirred at rt for lh. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried (Na ₂ SO ₄ ), and concentrated to give 2.07g of light brown oil, which was purified by column chromaiography (silica gel: 1 lOg, ethyl acetate/hexane:3/2) to afford

1.89g(98%) of desired product as light brown oil.

Η NMR (270MHz, CDCI,) δ 7.24 (IH, dd, J=7.3, 7.7Hz), 7.19-7.09 (3H, m), 4.77 (IH, dd, J = 3.7, 8.1Hz), 3.74 (IH, dd, J =3.7, 11.4Hz), 3.65 (IH, dd, J = 8.1, 11.4Hz), 2.82 (IH, br.s).2.35 (3H, s), 1.77 (IH, br.s).

Preparation 12

(5)-l-(3-MethylphenvP-1.2-ethanediol 2-tosylnte

To a stirred solution of (5 ^* )-!-(3-methylphenyl)-l,2-ethanediol (1.78g, 11.7mmol) in pyπdine (35m!) was added p-toluenesulfonyl chloride (2.46g, 12.9mmol), and 4-dimethylamιnopyridine (1.58g, 12.9mmol) at 0 °C and the reaction mixture was stirred at 0 °C to rt for 17h. The reaction mixture was acidified with 6N

HCl aqueous solution and extracted with CH ₂ C1 ₂ . The extract was washed with water and brine, dried (Na _? S0 ₄ ), and concentrated to give 3.02g of yellow oil, which was purified by column chromatography (silica gel: lOOg, ethyl acetate/hexane:l/9 to 1/3) to afford 2.63g (73%) of desired product as light yellow oil. Its optical purity was 97% ee by HPLC employing a chiral stationary phase (chiral pak AS, Daicel Chemical

Industries, eluted with n-hexane/EtOH:98/2; detection time: 55min for (/?)-isomer 59min for ( )-isomer).

Η NMR (270MHz, CDC1-,) δ 7.77 (2H, d, J = 8.4Hz), 7.33 (2H, d, J = 8.1Hz), 7.22 (IH, dd, J = 7.7, 8.1 Hz), 7.15-7.05 (3H, m), 4.94 (IH, ddd, J = 2.9, 2.9, 8.4Hz), 4.15 (IH, dd, J = 2.9, 10.3Hz), 4.04 (IH, dd, J = 8.4, 10.3Hz), 2.54 (IH, br.d, J = 2.9Hz),

2.45 (3H, s), 2.33 (3H, s), 1.58 (3H, s).

Preparation 13 2-(3-(S)-MethoxymethyloxypyriOli(lin-l-yl)-l-(.S-(3-methylph enyl)-ethanol and 2-(3- (S)-methoxymethyloxypyrrolid ^' m-l-vP-2-(/?)-(3-methylphenvPethanol A mixture of (5)-l-(3-methylpheny!)-l ,2-ethanediol 2-tosylate (2.63g,

8.59mmol), (5)-3-methoxymelhyloxypyrroIidine (1.24g, 9.45mmol), and K ₂ CO ₃ (1.31g, 9.45mmol) in ethanol (25ml) was refiuxed with stirring for2h. After removal of the solvent by evaporation, the residue was diluted with water and extracted with CH ₂ C1 ₂ . The extract was washed with brine, dried (Na ₂ S0), and concentrated to give

2.1 lg of brown oil, which was purified by column chromatography (silica gel: 1 lOg, CH ₂ Cl ₂ /MeOH: 15/1 to 10/1) to afford 1.72g (76%) of 3 to 2 mixture of desired products as a light brown oil. Η NMR (270MHz, CDC1 δ 7.26-7.05 (4H, m), 4.68 (0.6H, dd, J = 2.9, 10.6Hz, PhCHOH), 4.67 (0.6H, d, J=7.0Hz. OCH ₂ O), 4.63 (0.6H, d, J = 6.6Hz, OCH ₂ 0),

4.62 (0.4H, d, J = 7.0Hz, OCH 0). 4.59 (0.4H, d, J = 7.0Hz, OCH ₂ 0), 4.34-4.24 (0.6H, , OCHCH ₂ N), 4.24-4.16 (0.4H, m, OCHCH ₂ N ), 3.88 (0.4H, dd, J=6.2, 10.6Hz, CHCH ₂ OH), 3.79 (0.4H. dd, J=5.8, ll.OHz, CHCH ₂ OH), 3.47 (0.4H, dd, J = 5.8, 6.2Hz, NCHPh), 3.38 (1.8H, s), 3.33 (1.2H, s), 3.05-2.92 (1.2H, m), 2.82- 2.40 (4H, m), 2.35 (3H, s), 2.25-1.50 (3H, m).

Example 45 2-(3.4-Dichlorophenyl)- -r2-(3-(5)-mcthoxymethyloxypyrrolidin-l-yl)-l-(S)-(3- methylphenyl)ethyll-N-tetrπhv(lropyranyloxyacetamide

This was prepared from a mixture of 2-(3-(i -methoxymethyloxypyrrolidin-l- yl)-l-(S)-(3-methylphenyl)ethanol and 2-(3-(5)-methoxymethyloxypyrτolidin-l-yl)-2-(/?)-

(3-methylphenyl)ethanol in 60% yield according to the procedure similar to that described in Example 4.

Η NMR (270MHz. CDC1 ₃ ) δ 7.39 (0.5H, d, J = 1.8Hz), 7.35 (0.5H, d, J = 8.4Hz), 7.27-7.02 (5.5H, m), 6.96 (0.5H. dl, J = 1.8, 8.4Hz), 5.65 (0.5H, dd, J=5.1, 11.4Hz, PhCHN), 5.52 (0.5H, dd, J=4.8,l 1.0Hz, PhCHN), 5.30-5.20 (IH, m,

NOCHO), 4.64 (0.5H, d, J = 6.6Hz, OCH ₂ 0), 4.63 (0.5H, d, J = 7.0Hz, OCH ₂ 0), 4.61 (0.5H, d, J=6.6Hz, OCH.O), 4.60 (0.5H, d, J = 6.6Hz, OCH ₂ 0), 4.30-4.20 (0.5H, m, OCHCH ₂ N), 4.20-4.10 (0.5H. m, OCHCH ₂ N), 4.06-3.85 (3H, m), 3.56- 3.36 (1.5H, m), 3.35 (1.5H. s. OM_e).3.34 (1.5H, s, OMe), 3.24-3.10 (0.5H, m), 3.01-2.80 (2H, m), 2.66-2.40 (3H, m), 2.34 (I.5H, s), 2.28 (1.5H, s), 2.15-1.15 (8H, m).

Example 46 2-(3.4-DichlorophenyP-N-hyclroxy-N-r2-(3-(S)-hydroχypyrroli din-l-yl)-l-(S)-(3- methylphenvPelhylliUTtamide

This was prepared from2-(3.4-dichlorophenyl)-N-[2-(3-( )-methoxymethyloxy- pyrrolidin-l-yl)-l-(5 ^' )-(3-methylphenyl)ethyl]-N-tetrahydropyranyloxyacetami dein77% yield according to the procedure similar to that described in Example 5 NMR (270MHz, CDCIO δ 7.42-7.05 (7H, m).5.59 (IH, dd, J=5.1, ll.OHz, PhCHN), 4.35-4.25 (IH, m, CHOH), 3.85 ( I H, d, J= 14.3Hz, COCH ₂ Ph), 3.74 (IH, d, J= 15.8Hz, COCXPh). 3.50-2.50 (2H, almost fiat br.s, OHx2), 3.38 (IH, dd, J = 11.7, 12.1Hz), 3.00-2.90 (IH, ), 2.73 (lH.br.d, J=10.6Hz), 2.62 (IH, dd, J=5.1, 12.5Hz), 2.53 (IH, del, J =5.5, 10.6Hz), 2.40-2.25 (4H, m, including 3H, s at 2.30ppm), 2.23-2.07 (IH, m), 1.65-1.55 (IH, m). lR(neat) : 3350, 1650cm ^'1 .

MS m/z : 422(M ⁺ ) HCl salt : amorphous solid

Anal. Calcd for C,,H- ₄ Cl ₃ N,O,- HCl- 1.5H ₂ 0: C, 51.81; H, 5.80; N, 5.75. Found: C, 51.85; H, 5.72; N, 5.47.

Example 47

N-π-(5)-(4-Chloronhenvn-2-(3-(S -hvdroxypyrrolidin-l-yl)ethyll-2-(3.4- dichloroph en vP-N-hvdroxyacet amide

This was prepared from 4-chlorostyrene and 3-(5)-methoxymethyloxypyrrolidine in 12% overall yield according to a procedure similar to that described in Examples 7 to 11.

Η NMR (270MHz, CDC1 ₃ ) δ 7.40 (IH, d, J=2.2Hz), 7.36 (IH, d, J = 8.4Hz), 7.30- 7.20 (4H, m), 7.14 (IH, dd, J=2.2, 8.1Hz), 5.58 (IH, dd, J=5.1, ll.OHz, PhCHN), 5.00-3.00 (2H, almost fiat br.s, OHx2), 4.35-4.25 (IH, m, CHOH), 3.85 (IH, d, J = 14.3Hz, COCXPh), 3.72 ( I H, d, J = 13.9Hz, COCH ₂ Ph), 3.33 (IH, t, J= 11.7Hz), 3.00-2.85 (IH, in), 2.74 (lH.br.d, J = l0.3Hz), 2.65 (IH, dd, J = 5.1, 12.5Hz), 2.60-

2.45 (IH, m), 2.45-2.25 (IH, m), 2.25-2.05 (IH, ), 1.70-1.50 (IH, m). HCl salt : amorphous solid lR(KBr) : 3400, 3100, 1650cm ^'1 . MS m/z : 443(M + H)\ Anal. Calcd for C _2(l H _ι Cl,N ₂ O ₁ -HC10.7H ₂ O: C48.74; H, 4.79; N, 5.68. Found: C,

49.15; H, 5.21; N, 5.58.

Example 48 2-(3,4-DichlorophenvP-N-hv ro'v-N-f2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)-(4- methoxyphenvPelhvπacel mide and 2-(3,4-cliehlorophenyl)-N-hvdroxy-N-f2-(3-(S)- hvdroxypyrrolidin-l-yP-I-f/?)-(4-melhoxypheιιvP-ethyllacet amide

This was prepared from 4-methoxystyrene and 3-(5)- methoxymethyloxypyrrolidine in 5.2% overall yield according to a procedure similar to that described in Examples 7 to 11 In this case racemization occurred at 1 -position to afford the title compounds dunng the following reactions (mesylation, addition of THPONH ₂ , and acylation).

Η NMR (270MHz, CDCU) δ 7.40-7.26 (4H, m), 7.12 (0.5H, dd, J = 2.2, 8.4Hz), 7.11 (0.5H,dd, J=2.6, 8.4Hz), 6.84 (2H, d, J = 8.4Hz), 5.70-5.60 (IH, m, PhCHN), 4.50-4.40 (0.5H, m, CHOH), 4.50-300 (2H, almost flat br.s, OHx2), 4.40-4.30 (0.5H, m, CHOH), 3.84 (IH, d, J = 14.3Hz, COCH ₂ Ph), 3.79 (3H, s), 3.73 (IH, d, J = 14.7Hz, COCH ₂ Ph), 3.65-3.40 (IH, m), 3.15-3.00 (IH, m), 2.90-2.40 (4H, m),

2.30-2.10 (IH, m), 1.90-1.78 (0.5H, m), 1.78-1.60 (0.5H, m). HCl salt : amorphous solid lR(KBr) : 3400, 3150, 1650cm ' MS m/z : 438(M ⁺ ) Anal. Calcd for C _2! H ₂₄ CI ₂ N ₂ 0, HC12.5H ₂ 0. C,48.43; H, 5.81; N, 5.38. Found: C,

48.21; H, 5.75; N, 5.35.

Example 49 2-(3.4-DichlorophenvP-N-|-ιvdiO\v-N-r2-(3-(S)-hvdroxypyrrol idin-l-yl)-l-(S)-(4- trifl oromcthylphcπvPethyllncct amide This was prepared from 4-trillιιoromethylstyrene and 3-(S)-methoxymethyloxy- pyrrolidine in 25.3% overall yield according to a procedure similar to that described in Examples 7 to 11.

'H NMR (270MHz, CDCI ₃ ) δ 7.60-7.35 (6H, m), 7.20-7.10 (IH, m), 5.65 (IH, dd, J=5.5, ll.OHz, PhCHN), 4.40-4.30 (IH, m, CHOH), 3.90 (IH, d, J = l3.9Hz,

COCHjPh), 3.73 (IH, d, J = 12.5Hz, COCH,Ph), 3.34 (IH, dd, J = 11.0, 12.5Hz), 3.00-2.90 (IH, m), 2.75-2.65 (2H,m), 2.54 (lH,dd, J = 5.1, 10.6Hz), 2.50-2.00 (4H, m), 1.70-1.55 (IH, m). lR(neat) : 3400, 3250, 1635cm ¹ . MS m/z : 476(M ⁺ )

HCl salt : amorphous solid

Anal. Calcd for C _l H ₂ ,Cl ₂ FN ₂ O HCl-2H ₂ 0: C,45.88; H, 4.77; N, 5.10. Found: C,

45.90; H, 4.83; N, 4.71.

Preparation 14 (S)-l-(4-MethylphenvP-1.2-ethanediol 2-tosylate

This was prepared from 4-methylstyrene in 75% overall yield according to a procedure similar to that described in Examples 7 and 8. Optical purity was 98.3% ee by HPLC analysis. ^l H NMR (270MHz, CDC1 ₃ ) δ 7.77 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.4Hz), 7.20 (2H, d, J = 8.1Hz), 7.14(2H, d, J =8.1 Hz), 5..00-4.90 (IH, m), 4.13 (IH, dd, J = 3.3,

10.3Hz), 4.03 (IH, d, J = 8.4, 10.3Hz), 2.49 (IH, d, J=2.9Hz), 2.45 (3H, s), 1.57 (3H, s).

Preparation 15 (5)-4-Methylstyrene oxide Amιxtureof(5)-!-(4-methylphenyl)-l ,2-ethanediol2-tosylate(4.13g, 13.5mmol) and 50% NaOH aqueous solution (5ml) in THF (25ml) was stirred at rt for lh and at 50 °C for 2h. After cooling αown to rt, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried(NaS0 ₄ ), and concentrated to give 1.59g(88%) of desired compound as pale brown oil. This oil was used for next reaction without purification.

Η NMR (270MHz, CDCI3) δ 7.20-7.10 (4H, m), 3.83 (IH, dd, J = 2.6, 4.0Hz), 3.13 (IH, dd, J=4.0, 5.5Hz), 2.80 (IH, dd, J =2.6,5.5Hz), 2.34 (3H, s).

Preparation 16

2-(3-(S)-Metho'vmethyloχyi)vn()li(lin-l-yl)-l-(S)-(4-methyl phenyl)-ethanol and 2-(3- (S)-methoxymelhyloxypyrrolidin-l-yl)-2-(?)-(4-methylphenyl)e thanol

A mixture of ( 4-methylstyrene oxide (159g, 11.9mmol) and 3-(5 methoxymethyloxypyrrolidine (1.55g, 1 I 9ιnmol) in isopropanol (25ml) was refluxed for 7h. The solvent was evaporated and the residue was purified by column chromatography(sιlιca gel: 150g, CH ₂ Cl/MeOH.50/1 to 15/1) to give 2.39g (76%) of desired products as a pale brown oil This was 3 to 2 mixture of title compounds. 'H NMR (270MHz. CDC1 δ 726 (12H, d, J = 81Hz), 7.21-7.10 (2.8H, m), 4.75- 4.55 (2.6H, m, including 06H, d, J=66Hz at 466ppm, 0.6H, d, J = 7.0Hz at 4.63ppm, 0.4H, d, J=7.0Hz at 462ppm, 04H, d, J=7.0Hz at 458ppm), 4.35-4.23

(0.6H, m, OCHCH ₂ N), 4.23-4.15 (0.4H, m, OCHCH ₂ N ), 3.87 (0.4H, dd, J = 6.2, 10.6Hz, CHCH ₂ OH), 3.77 (04H, dd, J=5.9, 10.6Hz, CHCH ₂ OH), 3.49 (0.4H, dd, J=5.9, 6.2Hz, NCHPh), 338 (I 8H, s), 333 (1.2H, s), 3.05-2.90 (1.2H, m), 2.80- 2.40 (5H, m), 234 (3H, s), 225-2.00 (lH.m), 195-1.75 (IH, m).

Example 50

2-(3.4-DichlorophenvP-N-hvdro\v-N-r2-(3-(5)-hvdroxypyrrol idin-l-yl)-l-(S)-(4- methylphenvPethyllncetamide

This was prepared from 2-(3-( )-metho\ymethyloxypyrrolidιn-l-yl)-l-( )-(4- methylpheny ethanol and 2-(3-(5)-methoxymethyloxypyrrolιdin-l-yl)-2-(/?)-(4- methylphenyOethanol in 29.5% overall yield according to a procedure similar to that described in Examples 10 and 11

Η NMR (270MHz, CDC1 ₃ ) δ 7.40-7.30 (2H, m), 7.23 (2H, app.d, J = 8.1Hz), 7.11

(3H, app.d, J=7.7Hz), 564 (IH, del, J=5 1, 114Hz, PhCHN), 5.00-3.00 (2H. almost fiat br.s, OHx2), 440-4.30 (IH, m, CHOH), 3.84 (IH, d, J = 14.7Hz, COCH ₂ Ph), 3.73 (IH, d, J=l4.3Hz, COCH,Ph).3.46 (IH, dd, J = 11.4, 12.1Hz),

3.10-295 (IH, m).2.83(IH,bι d, J= 11.0Hz), 275-2.40 (3H, m), 2.32 (3H, s), 2.25-

2.10 (IH, m), 1.75-1.60 (IH, m)

HCl salt : amorphous solid

MS m/z : 422(M ⁺ ) lR(KBr) : 3420, 3180, 1650cm ¹ .

Anal. Calcd for C,,H ₂ C N_A-HC1-0.5H ₂ O: C.53.80; H, 5.59; N, 5.98. Found: C, 53.51; H, 5.67; N, 6.04

Preparation 17 (S)-l-(3-MethoxymethyloxyphenvP-1.2-ethanediol This was prepared from 3-ιnethoxymethyloxystyrene (prepared by methoxymethylation of 3-hydroxystyrene in a standard manner) in quantitative yield according to a procedure similar to that described in Example 7. Η NMR (270MHz, CDCI,) δ725 (IH, dd, J=77, 8.1Hz), 7.03 (IH, d, J = 1.8Hz), 6.98-6.92 (2H, m), 5.15 (2H. s, OCHAMe), 4.74 (IH, dd, J = 3.3, 8.1Hz, ArCHOH), 371 (IH, br.d, J=9.9Hz. CHCHAH), 3.65-3.55 (2H, m, including IH, dd, J=8.1, 11.0Hz at 361 ppm, CHCH ₂ OH), 3.44 (3H, s, OCH ₂ OM_e ), 3.14 (IH, br.s, OH).

Preparation 18 (S)-l-(3-MethoxymethyloxyphenvP-1.2-ethnnediol 2-tosylate This was prepared from (5)-l-(3-methoxymethyloxyphenyl)-l,2-ethanediol in

64% yield according to a procedure similar to that described in Example 8. Its optical purity was 96%ee by HPLC.

'H NMR (270MHz, CDC1 ₃ ) δ 777 (2H, d, J = 8.4Hz), 7.34 (2H, d, J = 8.1Hz), 7.25 (IH, dd, J=7.7, 8.4Hz), 7.00-6.92 (3H, m), 5.15 (2H, s), 4.95 (IH, ddd, J=3.3, 3.3, 8.4Hz, ArCHOH), 4.15 (lH.dd, J =3.3, 103Hz, CHCH ₂ OTs), 4.03 (IH, dd, J = 8.4,

10.3Hz, CHCH ₂ OTs), 3.46 (3H, s, OCH ₂ OMe), 2.65 (IH, d, J = 3.3Hz, ArCHOH). 2.45 (3H, s, PhMe).

Example 51 2-(3.4-Dichlorophenyl)-N-fl-(S)-(3-methoxymethyloχyphenyl)- 2-(3-(5)- tetrahvdropyranyloxypyrrolidin-l-vPethvn-N-tetrahvdropyranyl oxy-acetamide

This was prepared from (5)-l-(3-methoxymethyloxyphenyl)-l,2-ethanediol 2- tosylate in 52% overall yield according to the procedure similar to that described in Examples 9 and 10

NMR (270MHz, CDCI,) δ 7.42-6.91 (7H, m), 5.65 (0.5H, dd, J = 3.3, 9.9Hz, PhCHN), 5.54 (0.5H. dd. J=4.4, ll.OHz, PhCHN), 5.35-5.25 (IH, m, NOCHO), 5.19 (0.5H, d, J = 6.6Hz. OCH.O).5.15 (0.5H, d, J = 6.6Hz, OCH ₂ 0), 5.14 (0.5H, d, J = 7.0Hz, OCH.O). 5.10 (0.5H, d, J = 7.0Hz, OCH ₂ 0), 4.65-4.55 (IH, m, CHOCHO), 4.40-4.30 (0.5H, m, OCHCHX), 4.30-4.20 (0.5H, m, OCHCH ₂ N), 4.10-

3.85 (4H, m, including 0.5H, , J = 16.5Hz at 4.06ppm, 0.5H, d, J = 16.5Hz at 3.92ppm, and IH, sat 3.92ppm. COCH,Ph), 3.68-3.15 (6H, m, including each 1.5H, s, at 3.47 and 3.46ppm, OM_e), 3.02-2.80 (2H, m), 2.66-2.35 (3H, m), 2.20-1.15 (14H, m).

Example 52

2-(3.4-Dichlorophenyl)-\-hvdroxy-N-π-(5)-(3-hvdroxypheny l)-2-(3-(5)- hvdroxypyrrolidin-l-yl)ethvnacel amide

This was prepared from 2-(3,4-dichlorophenyl)-N-[l-(5)-(3- methoxy methyloxy phenyl )-2- ( -(S)-tet rah yd ropy ranyloxypyrrol idin-l-yl)ethy 1]-N- tetrahydropyranyloxvacetamide in 46% yield according to the procedure similar to that described in Example I I.

'H NMR (270MHz, CDCI, and DMSOd _ή ) δ 7.56 (IH, s, PhOH), 7.40 (IH, d, J=1.8Hz), 7.37 (IH, d, J = 8.4Hz), 7.17 (IH, dd, J=1.8, 8.1Hz), 7.11 (IH, dd, J = 7.7, 8.1Hz), 6.90-6.70 (3H, m), 5.56 (IH, dd, J=5.1, 10.6Hz, PhCHN), 4.30- 4.20 (IH, m, CHOH), 3.90 (IH. d, J=15.0Hz, COCH ₂ Ph), 3.74 (IH, d, J = 14.5Hz,

COCF Ph), 4.50-2.50 (2H, almost fiat br.s, OHx2), 3.32 (IH, dd, J = 11.4, 11.7Hz), 3.00-2.85 (IH, m), 2.75-2.55 (3H. m, including IH, dd, J=5.1, ll.OHz), 2.40-2.30 (IH, m), 2.15-2.00 (IH, m), 1.80-1.60 (IH. m). lR(KBr) : 3350, 3200, 1630cm ¹ . MS m/z : 424(M ⁺ )

Free amine : mp 151.6-153.1 °C

Anal. Calcd for C ₂ , _l H„Cl,NA _l .7H,O: 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 the Examples 1 to 52 are summarized in the following tables.

TABLE

(T)

Ex.# Ar R X