WO1994018165A1

WO1994018165A1 - Sulfonamide compounds as opioid k-receptor agonists

Info

Publication number: WO1994018165A1
Application number: PCT/JP1994/000118
Authority: WO
Inventors: Mamoru Uchiyama
Original assignee: Pfizer Inc.; Pfizer Pharmaceuticals Inc.
Priority date: 1993-02-12
Filing date: 1994-01-28
Publication date: 1994-08-18

Abstract

Compounds having chemical formula (I): wherein R1 is hydrogen, hydroxy, C¿1?-C6alkoxy, tri(C1-C6alkyl)silyloxy or acyloxy; R?2 is C¿1-C6alkyl; and Ar is optionally substituted aryl. The compounds and their pharmaceutcally acceptable salts have excellent activity as opioid λ-receptor agonists. They are useful for the treatment and prevention of pain, asthma, scabis, psoriasis vulgaris or inflammation, especially pain, in mammalian subjects, e.g., human subjects.

Description

SULFONAMIDE COMPOUNDS AS OPIOID K-RECEPTOR AGONISTS

Technical Field This invention relates to novel sulfonamide compounds and their pharmaceutically acceptable salts, and to pharmaceutical compositions for the treatment of pain, asthma, scabies, psoriasis vulgaris, inflammation, in a mammalian subject, especially a human subject.

Background Art Previously the analgesics, such as morphine, were therapeutically used but their usage was strictly limited because of their side effects such as drug dependency. Thus the analgesics with high usefulness and no drug dependency have been desired. On the other hand, a lot of pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors. Especially the discovery of the subtype of opioid receptor such as μ, 6, K at a peripheral nerve in a variety species including human 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 K-receptor agonist from the action based on μ-receptor agonist has been tried. Recently κ-selective agonists are 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 applied to clinical trial (Med. Res. Rev., 12, 525 (1992)). Even using selective K-receptor agonists, when high doses are adopted, side effects such as hallucination, sedation are observed. Therefore the search for excellent analgesics, which have selectively efficacy at peripheral nerve together with high therapeutic coefficient, has been pursued.

The object of the present invention is to provide the novel sulfon∑imide compounds with peripheral nerve selective analgesic activity. These sulfonamides show strong K- receptor agonist activity but weak μ-receptor agonist activity. Another object of the present invention is to provide the pharmaceutical composition containing the novel sulfonamide compounds for pain, asthma, scabies, psoriasis vulgaris, inflammation, the treatment of congestive heart failure or hypertension, in a maπ-malian subject, especially a human subject. In consideration of the above, the inventors made an effort in order to create novel analgesics with high therapeutic coefficient.

Brief Disclosure of the Invention The present invention provides novel sulfonamide compounds of the formula I:

(D and the pharmaceutically acceptable salts thereof, wherein R¹ is hydrogen, hydroxy, C_j-C₆ alkoxy, tri(C₁-C₆ alkyl)silyloxy or acyloxy; R² is C_rC₆ alkyl; and

Ar is optionally-sustituted aryl.

The compounds of the formula I show pharmacological activity as K receptors agonists in mammals, including humans. Therefore they are useful as analgesic agents in niammals, including humans. Accordingly, this invention also provides pharmaceutics compositions, useful for treating or preventing pain in a mammalian subject, especially a human subject, which comprise a compound of the formula I and a pharmaceutically-acceptable carrier or diluent. Yet further, this invention provides a method for treating or preventing pain in a mammalian subject, especially a human subject, which comprises administering to said mammalian subject an analgesically-effective amount of a compound of the formula I.

Detailed Disclosure of the Invention In this specification, the term "alkyl" is used to mean straight or branched hydrocarbon chain radicals including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like; the term "alkoxy" is used to mean -OR (R is alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like; the term "acyl" is used to mean C₂-C₆ alkanoyl, benzoyl or benzoyl having one substitutent selected from C-^ alkyl, C_j-C₆ alkoxy, C₂-C₆ alkenyl, C fluorinated alkyl (such as fluoromethyl, difluoromethyl or trifluoromethyl), benzyl, pyridylmethyl, halogen (i.e., fluorine, chlorine, bromine or iodine), hydroxy, carboxy, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, C₂-C₆ alkanoyloxy, C₂-C₆ alkanoylthio, C₂-C₍₅ alkanoylamino, carbamoyl, cyano, nitro, mono (C_j-C₆ alkyl)amino, d - alkyl)amino, amino, C C₆ alkylsulfonylamino, mercapto, C_j- alkylthio, C_j- alkylsulfinyl, C---C₆ alkylsulfonyl, phenyl and phenoxy; the term "optionally-substituted aryl" is used to mean aromatic radicals such as phenyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl, and their ring-fused derivatives (e.g., benzo-fused derivatives), optionally substituted by at least one substituent selected from - alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₁-C₆ fluorinated alkyl (such as fluoromethyl, difluoromethyl or trifluoromethyl), benzyl, pyridylmethyl, halogen (i.e., fluorine, chlorine, bromine or iodine), hydroxy, carboxy, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkanoyl, C₂-C₆ alkanoyloxy, C₂-C₆ alkanoylthio, C₂-C₆ alkanoylamino, carbamoyl, cyano, nitro, mono (C_j- - ) alkylamino, di(C₁-C₆) alkylamino, amino, C_j- alkylsulfonylamino, mercapto, C^ alkylthio, C_j-Cg alkylsulfinyl, - alkylsulfonyl, phenyl, phenoxy and the like.

However, preferred optionally-substituted aryl groups are phenyl, naphthyl, mono- substituted phenyl and mono-substituted naphthyl, wherein the substituent is selected from C_j-C₆ alkyl, C₁-C₆ alkoxy, halosubstituted (C--C₆) -alkyl, halosubstituted (C C₆) alkoxy, C--C₆ alkylsulfonyl, nitro, di (C_j-C₆) alkylamino, mono(C₁-C₆) alkylamino monoacylamino, mono (C_j^ ) alkylsulfonylamino and amino.

A preferred group of compounds of this invention consists of the compounds of formula I, wherein R¹ is hydrogen or hydroxy; R² is methyl; and Ar is phenyl, naphthyl or substituted phenyl wherein the substituent is 2-chloro, 2-iodo, 2-nitro, 2-amino, 2- dimethylamino, 2-acetylamino, 2-methansulfonylamino, 3-bromo, 3-methoxy, 3-chloro, 4- chloro, 4-fluoro, 4-methyl, 4-nitro, 4-trifluoromethyl, 4-cyano, 4-methoxyc.arbonyl, 4- meth-insulfonyl, 4-trifluoromethoxy, 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 2,6-dichloro 3,4-dichloro, 3,5-dichloro, 3,4-difluoro, 3,5-difluoro or 2,3,6-trichloro. Preferred individual compounds of the invention are N-2-(3-hydroxypyrrolidin- 1 -yl)- 1 -phenylethyl-N-methyl-(3,4- dichlorophenyl)methanesulfonamide;

N-[2-(3-hydroxypyrrolidin- 1-yl)- l-phenylethyl]-N-methyl (2,3- dichlorophenyl)methanesulfonamide;

N- [2-(3-hydroxypyrrolidin- 1-yl)- 1 -phenylethyl]-N-methyl (2,4- dichlorophenyl)methanesulfonamide; N-[2-(3-hydroxypyrrolidin-l-yl)-l-phenylethyl]-N-methyl (3,4- difluorophenyl)memanesulfonamide;

N-[2-(3-hydroxypyrrolidin-l-yl)-l-phenylethyl]-N-methyl-(4- methylphenyl)methanesulfonamide; and

N-[2-(3-hydroxypyrrolidin- 1-yl)- l-phenylethyl]-N-methyl-(4- trifluoromethylphenyl)methanesulfonamide.

The sulfonamide compounds of the present invention can be used in the form of the inorganic salts with acid such as hydrochloric acid, hydrobromic acid, sulfonic acid, nitric acid, phosphoric acid and the like and the organic salts with acid such as acetic acid, formic acid, benzoic acid, oxalic acid, succinic acid, fumaric acid, citric acid, alkylsulfonic acid. The sulfonamide compounds of this invention possess at least one asymmetric center and they are capable of occurring in various isomeric forms. The present invention includes all such forms within its scope. The individual isomers can be obtained by methods well known to those skilled in the art, e.g., by fractional crystallization, asymmetric synthesis and the like. Hence, when those skilled in the a . rt use the compounds of this invention, they may choose any desired isomers such as optical isomers or diastereomers, or mixtures thereof.

The following standard methods well known to those skilled in the art can be used in order to obtain the compounds of the present invention.

For example, as shown in Equation 1, they can be synthesized by reacting the secondary amine (A) with the sulfonyl chloride (B) in an adequate solvent. A base such as triethylamine, pyridine, lutidine or potassium carbonate can be added to the reaction, if desired. Equation 1

^<A) "»

A solvent which does not react with the reactants or product is preferable. Dichloromethane, tetrahydrofuran (THF), dimemylfoιτnaπ-ide (DMF), toluene are examples of such a solvent. The base per se is also used as a solvent. Temperatures from room temperature to the reflux temperature of the solvent can be used, but the preferable range is from 15 to 100 °C. The progress of the reaction is easily monitored with thin-layer chromatography (TLC). The reaction time is in general from few minutes to several hours. The secondary amine (A) can be synthesized in accordance with the method in the literature (A. Barber et al., Naunyn-Schmled. Arch. Pharm., 345 (Suppl.): Abst 456 and EP 260041), while the sulfonyl chloride (B) is either commercially available or it can be obtained in the similar manner to the method in the following literature. Halogen substitution reaction of sulfonic acid salt: P. D. Bartlett and L. H. Knox, Org. Synth. Col. Vol. V, 196 (1973); reaction of sulfinic acid with halogen: F. Asinger, P. Laue and B. Fell, Chem. Ber., 100, 1696 (1967); reaction of Grignard agent with sulfuryl chloride: S. N. Bhattacharaya, C. Eaborn and D. R. M. Walton, J. Chem. Soc. C, 1265 (1968); halogenation reaction of thiol derivative: I. B. Douglass and T. B. Johnson, J. Amer. Chem. Soc, 60, 1486 (1938) and F. Cortes, Org. Synth. Col. Vol. π, 564 (1943).

On the other hand, as shown in Equation 2, the sulfonamide I can be synthesized by condensation of the secondary amine (A) with the sulfonic acid (C) in an adequate solvent. A well known reagent for peptide synthesis such as 1,3-dicyclohexylcarbodiimide, diethyl azodicarboxylate - triphenylphosphine, diphenylphosphoryl azide (J. Amer. Chem. Soc, 94, 6203 (1972)) can be used as a condensing agent in this reaction. Also in this reaction the activation of sulfonic acid part by 1-hydroxybenzotriazol can be carried out in advance if desired (Chem. Ber., 103, 788, 2024 (1970), J. Amer. Chem. Soc, 93, 6318 (1971) and Helv. Chim. Acta, 56, 717 (1973)). Equation 2

A solvent in this reaction which does not react with the reactants or product is preferable. Dichloromethane, THF, DMF and toluene are examples of such a solvent. Temperatures from room temperature to the reflux temperature of the solvent can be used, but the preferable range is from 15 to 100 °C. The progress of the reaction is easily monitored with TLC. The reaction time is in general from few minutes to several hours.

The compounds of this invention can be isolated from the reaction mixture and purified with the well known method to those skilled the in the art, e.g., recrystallization and column chromatographic separation. The measurement of the binding capacities and affinities in vitro of the compounds of the present invention at μ, δ and κ-receptor site are measured by using membrane suspensions from guinea-pig brain sample according to A. L. Regina et al.'s method (J. Recept. Res., 12, 171-180 (1992)). The compounds of the present invention showed the excellent IC₅₀ values at κ-receptor. For example, the κ-affinity range of values of the compounds of Examples 1 and 2 was 1.4 nM-1.3 μM and μ- affinity range was more than hundred times weaker than κ-range. The analgesic activity in vivo was estimated by S. Hunskaar et al.'s formaline test described in J. Neurosci. Methods, 14, 69-76 (1985). The compounds of the present invention had a good ED₅₀ values. For example, the range of values of the compounds in Examples 1 and 2 is 0.1-10 g/kg (i. p.). On the other hand, the sedative effect of the compounds of the present invention, which is thought of as a side effect of opioid analgesic, was measured using the rat rotor rod test (W. T. Kinnard JR. and C. J. Carr, J. Pharmac exp. Therap., 121, 354 (1957)). Surprisingly, the compounds of the present invention are significantly less active as sedatives than EMD- 60400 (A. Barber et al., Naunyn-Schmled. Arch. Pharmacol., 345 (Suppl.): Abst 456). As mentioned above, the compounds of the present invention have excellent selective

K-agonist activity and in addition reduced the side effects such as sedative effect.

Consequently the novel sulfonamide compounds of formula (I) and their pharmaceutically acceptable salts are useful for treatment of the diseases based on K- receptor e.g., pain, asthma, scabies, psoriasis vulgaris, inflammation, congestive heart failure or hypertension in a variety of π-ammalian species including man. In general, for the alleviation of pain in a human subject, these compounds or pharmaceutically acceptable salts may be administered in doses ranging from 0.2 to 500 mg per day, preferably from 1 mg to 300 mg per day, in single or divided doses. Variations will occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.

The novel sulfonamide compounds or pharmaceutically acceptable salts of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents either orally, parenterally or topically 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, troches, 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, sterile aqueous media, various non- toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds or pharmaceutically acceptable salts of this invention are present in such dosage forms at concenu-ation levels ranging from 5 to 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellu'ose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic 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 gelatin capsules. Preferred materials in this connection 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 may be combined with various sweetening or flavoring 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 adπiinistration, solutions of the sulfonamide compounds or pharmaceutically acceptable salts 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 if necessary, and the liquid diluent first rendered isotonic. 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 or pharmaceutically acceptable salts of the present invention topically to an affected part such as 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 The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific det-iils of these examples. Melting points were taken with a Yanako micro melting point apparatus and uncorrected. Optical rotations were measured on a JASCO DJJP-370 digital po-^rimeter in a 10 cm cell. IR spectra were obtained on a Shimadzu J-R-470 infrared spectrophotometer. All NMR spectra were measured in CDC1₃ by a JEOL NMR spectrometer (JNM-GX270, 270 MHz for ^!H, 67.5 MHz for ¹³C) unless otherwise indicated and peak positions are expressed in parts per million (ppm) down field from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

Example 1 Preparation of_. N-2-(3-hvdroxypyrrolidin- 1-vD- l-phenylethyl-N-methyl-(3,4- dichlorophen vDmethanesu lfonamide (i) 3,4-Dichlorobenzyl bromide

After 3,4-dichlorobenzyl alcohol (5.0 g) and HBr water (16 ml) in dioxane (30 ml) was stirred at 80 °C for 5 hours, the mixture was poured onto saturated sodium chloride solution (150 ml). The solution was extracted three times with each 50 ml of ethyl acetate. The combined organic layer was washed with saturated NaHCO₃ and saturated sodium chloride, successively and dried. Concentrating the residue gave the light brown oil (8.44 g, quant.) ¹H NMR δ 7.48 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.22 (dd, J = 2.2, 8.2 Hz, 1H), 4.41 (s, 2H). J-R (film) 1560, 1469, 1439, 1397, 1260, 1225, 1133, 1034, 899, 819, 705, 688, 632 cm-¹.

(ii) Sodium 3,4-dichlorobenzylsulfonate

The mixture of 3,4-dichlorobenzyl bromide (8.44 g), sodium sulfite (3.55 g), and tetrabutylammonium bromide (95 mg)in water (25 ml) was stirred at 95 °C for 16 hours. After cooling the precipitate was collected by filtration, washed with acetone, ethyl acetate and ether, successively, and dried to give the title compound (5.0 g, 75 %). IR (film) 1560, 1439, 1397, 1260, 1225, 1133, 1034. ¹H NMR [(CD₃)₂SO] δ 7.54 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 1.9, 8.1 Hz, 1H), 3.74 (s, 2H). (iii) 3,4-Dichlorobenzylsulfonyl chloride After the mixture of sodium 3,4-dichlorobenzylsulfonate and phosphorous pentachloride was stirred a 80 °C for 1.5 hours, the resulting oily suspension was poured onto ice-water. Then the mixture was extracted with dichloromethane (260 ml). The extract was washed with saturated NaHC0₃ solution and saturated sodium chloride, successively and dried over MgS0₄ to give the product (3.74g, 91 %). mp 48-59 C. IR (film) 1471, 1169 cm-l. H NMR δ 7.59 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 2.2, 8.5 Hz, 1H), 4.80 (s, 2H).

(iv) N-Benzyloxycarbonyl-(S)-phenylglycyl-3-(S)-hydroxypyrrolidine Diethylphosphonyl cyanide (7.67 g) and N-methylmorpholine (4.57 g) was added dropwise successively to a mixture of 3-(S)-pyrrolidinol (3.28 g) and N-benzyloxycarbonyl- (S)-phenylglycine (10.74 g) in DMF (45 ml) at room temperature. The reaction mixture was stirred for 20 hours. The mixture was poured onto a mixture of water, ether, ethyl acetate and hexane. The separated organic layer was washed with saturated NaHCO₃ solution, diluted HC1 solution and saturated sodium chloride solution, successively, dried over MgSO₄ and concentrated. The resulting crude product was chromatographed on a silica gel column eluting methanol : dichloromethane = 1:50-1:3 to give the product (8.08 g, 61 %). IR (film) 3410, 1721, 1639 cm-^l. 1H NMR δ 7.45-7.25 (m, 10H), 6.31 (Hike, J = 7.7 Hz, 1H), 5.39, 5.35 ( two d's, J = 7.7, 8.1 Hz, 1H), 5.15-4.95 (m, 2H), 4.50-4.43 (m, 1H), 3.8- 3.0 (m, 4H), 2.0-1.7 (m, 3H). N-t-butyloxyc^bonyl-(S)-phenylglycyl-3-(S)-hydroxypyrrolidine was prepared in a similar manner to the above by using N-t-butyloxycarbonyl-(S)-phenylglycine and can be used for synthesis as a starting material in example 1 (v).

[α]_D ²⁵ = 121.8° (MeOH, c = 1.00). LR (nujol) 3380, 1705, 1670, 1640 cm-ⁱ. H NMR rotamer mixture δ 7.41-7.30 (m, 5H), 5.99 (br d, J = 8.1 Hz, 0.5H), 5.95 (br d, J = 8.1 Hz, 0.5H), 5.37 (br d, J = 8.1 Hz, 0.5 H), 5.33 (br d, J = 8.1 Hz, 0.5H), 4.50-4.38 (m, 1H), 3.80- 3.65 (m, 2H), 3.62-3.50 (m, 0.5H), 3.46 (dd, J = 4.4, 13.2 Hz, 0.5H), 3.30-3.22 (m, 0.5H), 3.11 (br d, J = 12.1,. 0.5H), 2.06-1.84 (m, 2H), 1.81 (br s, 1H), 1.41 (s, 4.5H), 1.40 (s, 4.5H). (v) N-[2-(3-(S)-t-Butyldimethylsilyloxypyrrolidin- 1-yl)- l-(S)-phenylethyl]-N-methyl- (3,4-dichlorophenyl) methanesulfonamide

The product obtained in (iv)(709 mg) in THF (10 ml) solution was added dropwise to the mixture of LiAlH₄ in THF at room temperature with stirring. After starring for three hours at 80 °C, the reaction mixture was cooled down to the room temperature. The reaction was quenched by adding the mixture of Na₂SO₄*10H₂O. The precipitated salt was filtered off and washed with dichloromethane. The filtrate was concentrated azeotropically with toluene and acetonitrile and the residual crude product has a following J-R spectrum. IR (film) 3350, 1674, 1471, 1463, 1252, 1100, 905, 837, 775, 700, 665 cπr . Then a mixture of imidazole (817 mg), t-butyldimehylsilyl chloride (905 mg) in DMF (5 ml) was added to the crude product .and the reaction mixture was stirred at room temperature for three hours. The reaction was quenched by adding a saturated NaHC0₃ solution. The mixture was poured onto a mixture of ether, ethyl acetate and hexane. The separated organic layer was washed with saturated sodium chloride solution, dried over MgS0₄ and concentrated. The resulting product was adapted the next reaction without further purification. A small amount of the resulting crude product was chromatographed on a silica gel column eluting a mixture of methanol and dichloromethane to give the analytical pure product. IR (film) 3350, 1472, 1439, 1253, 1105, 905, 836, 775, 701 cm-**. -Η NMR δ 7.4-7.2 (m, 5H), 4.44- 4.32 (m, IH), 3.56 (dd, J = 4.4, 11.0 Hz, IH), 3.00 (dd, J = 6.4, 9.5 Hz, IH), 2.82-2.68 (m, 2H), 2.57 (dt, J = 4.8, 8.1 Hz, IH), 2.38-2.32 (m, 2H), 2.29 (s, 3H), 2.16 (brs, IH), 2.12- 2.00 (m, IH), 1.72-1.60 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).

The sulfonyl chloride (623 mg) obtained in the above (iii) and 4- dimethylaminopyridine (586 mg) was added to a solution of the crude product obtained above. After stirring for 16 hours at room temperature, the reaction mixture was partitioned between saturated sodium chloride solution and dichloromethane. The organic layer was dried over MgS04, concentrated and chromatographed on a silica gel column eluting with ethyl acetate : hexane = 1:40-1:30 to give the analytical pure product (819 mg, 73 %). -^→U NMR δ 7.5-7.2 (m, 8H), 5.32 (dd, J = 2.0, 10.8 Hz, IH), 4.45-4.35 (m, IH), 4.40 (AB quartet, J = 13.6 Hz, 2H), 3.35 (t, J = 12.0 Hz, IH), 3.25-3.15 (m, IH), 2.7-2.6 (m, 2H), 2.5- 2.35 (m, 4H), 2.25-2.1 (m, IH), 1.85-1.70 (m, IH), 0.81 (s, 9H), 0.01, -0.01 (two's, 6H). IR (film) 1470, 1330, 1250, 1140, 1030, 940, 835, 780, 700, 590 cm-¹.

(vi) N-[2-(3-(S)-hydroxypyrrolidin-l-yl)-l-(S)-phenylethyl]-N-meLbyl-(3,4- dichlorophenyl) methanesulfonamide 1M THF solution of tetrabutylammonium fluoride (2.52 ml) was added to a THF solution of the product (704 mg) obtained in (v) (10 ml) at room temperature. After stirring for one hour, the mixture was poured onto a saturated sodium chloride solution (50 ml). The mixture was extracted three times with ethyl acetate. The combined organic layer was dried over MgS0₄, concentrated and chromatographed on a silica gel column eluting with methanol : dichloromethane = 1:50- 1:30) to give the titled compound (550 mg, 99 %). IR (KBr) 3450, 1469, 1398, 1325, 1138, 934, 912, 827, 776, 729, 702, 590 cm-¹. Η NMR δ 7.4-7.3, 7.2-7.14 (m, 8H), 5.20 (dd, J = 4.0, 11.4 Hz, IH), 4.35 (m, IH), 4.31, 4.23 (two d's, J = 13.6 Hz, 2H), 3.36-3.24 (m, 2H), 2.84-2.70 (m, 2H), 2.65 (dd, J = 4.0, 12.8 Hz, IH), 2.50-2.38 (s, 4H), 2.30-2.10 (m, 2H), 1.90-1.70 (m, IH). The free base product in (vi) was converted quantitatively to the hydrochloride salt by treating 4M HC1 in ethyl acetate solution. IR (KBr) 3450, 1470, 1335, 1160, 930, 780, 710, 590 cm-¹. Anal. Calcd for C₂₀H₂₄N₂C1₂O₃S*HCM/2H₂O: C, 49.14; H, 5.36; N, 5.73; S, 6.56; Cl, 21.76: Found: C, 49.18; H, 5.62; N, 5.68; S, 6.35; Cl, 21.39.

Example 2 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin- 1-vIV HS)-ρhenylethvπ-N-methvI-(4- fluorophenvpmethanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from 3,4- dichlorobenzyl bromide and N-[2-(3-(S)-t-butyldimethylsilyloxypyrrolidin-l-yl)-l-(S phenylethyl]-N-methylamine. IR (film) 3450, 1325 cm-¹. Η NMR δ 7.35-7.15 (m, 7H), 7.02-6.96 (m, 2H), 5.18 (dd, J = 4.4, 11.0 Hz, IH), 4.35-4.20 (m, IH), 4.27 (s, 2H), 3.35- 3.20 (m, 2H), 2.80-2.72 (m, 2H), 2.67 (dd, J = 4.4, 12.5 Hz, IH), 2.48 (s, 3H), 2.50-2.14 (m, 3H), 1.85-1.75 (m, IH).

Example 3 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)-phenylethvn-N-methyl-(2- nitrophenvDmethanesulfonamide

The title compound was synthesizeu in a manner similar to that of Example 1 from (2- nitrophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxypyrrolidin-l- yl)-l-(S)-phenylethyl]-N-methylamine. W NMR δ 7.98 (dd, J = 1.8, 8.1 Hz, IH), 7.62- 7.48 (m, 3H), 7.37-7.18 (m, 5H), 5.19 (dd, J = 4.4, 11.0 Hz, IH), 4.94 (d, J = 13.6 Hz, IH), 4.83 (d, J = 13.9 Hz, IH), 4.32 (brs, IH), 3.34-3.25 (m, 2H), 2.80-2.66 (m, 3H), 2.64 (s, 3H), 2.40-2.10 (m, 3H), 1.87-1.75 (m, IH). IR (film) 3450, 1530, 1355, 1330 cm"¹.

Example 4 Preparation of N-l^"2-(3-(S)-hvdroxypyrrolidin- 1-vD- l-(S)-phenylethyl1-N-methvI-(2- aminophenvDmethanesulfonamide

The title compound was synthesized by catalytic hydrogenation of N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin- 1-yl)- l-(S)-phenylethyl-N-methy-(2- nitrophenyl)metanesulfonamide in Example 3 as an intermediate using 10 % palladium carbon in ethanol according to the usal way, followed by deprotecting t- butyldimethylsilyloxy group in a manner similar to that of (vi). IR (film) 3450, 3370, 1325 cm-¹, NMR δ 7.38-7.25 (m, 5H), 7.13 (dt, J = 1.5, 7.7 Hz, IH), 7.01 (d, J = 7.7 Hz, IH), 6.78-6.72 (m, 2H), 5.34 (dd, J = 3.7, 11.0 Hz, IH), 4.63 (d, J = 13.9 Hz, IH), 4.30 (d, J = 13.6 Hz, IH), 4.35-4.27 (m, IH), 3.39-3.31 (m, 2H), 2.81 (br d, J = 9.9 Hz, IH), 2.72-2.64 (m, 2H), 2.54 (s, 3H), 2.30-2.16 (m, 2H), 1.90-1.75 (m, IH).

Example 5 Preparation of N-r2-(3-(S)-hvdroxypyrτolidin-l-yl)-l-(S)-phenylethvIl-N-methyl r2-(N',N'- dimethylamino)phenyll-methanesulfonamide

The title compound was synthesized by dimethylation of N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin- 1 -yl)- 1 -(S)-phenylethyl-N-methy-(2- aminophenyl)methanesulfonamide in Example 4 as an intermediate according to the A. G. Giumanini's method (Synthesis, 1980, 743), followed by deprotecting t- butyldimethylsilyloxy group in a manner similar to that of (vi). IR (film) 3450, 1325 cm-¹. NMR δ 7.63 (br d, J = 6.6 Hz, IH), 7.39-7.33 (m, IH), 7.21-7.12 (m, 5H), 6.85-6.82 (m, 2H), 5.05 (dd, J = 4.8, 11.0 Hz, IH), 4.76 (d, J = 13.9 Hz, IH), 4.36 (d, J = 13.6 Hz, IH), 4.25-4.17 ⁽ _ IH), 3.35-3.28 (m, IH), 3.18 (dd, J = 11.0, 12.2 Hz, IH), 2.80 (br d, J = 9.2 Hz, IH), 2.72-2.59 (m, 2H), 2.61 (s, 3H), 2.45 (s, 6H), 2.23-2.06 (m, 3H), 1.85-1.75 (m, IH). Example 6

Preparation of N-r2-(3-(S)-hvdroxypyrrolidin- 1-yl)- l-(S)-phenylethyn-N-methyI-(3,4- difluorophenvDmethanesulfonamide hydrochloride.

The title compound was synthesized in a manner similar to that of Example 1 from (3,4-difluorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylarnine. IR (film) 3450, 1330 cm-¹. ⁱH NMR (free base) δ 7.38-7.00 (m, 8H), 5.21 (dd, J = 4.4, 11.4 Hz, IH), 4.35- 4.30 (m, IH), 4.31 (d, J = 13.9 Hz, IH), 4.24 (d, J = 13.9 Hz, IH), 3.33-3.27 (m, IH), 3.30 (dd, J = 11.4, 13.2 Hz, IH), 2.81-2.72 (m, 2H), 2.66 (dd, J = 4.4, 13.2 Hz, IH), 2.49 (s, 3H), 2.40-2.13 (m, 3H), 1.87-1.74 (m, IH). Example 7

Preparation of N-r2-(3-(S)-hvdroxypyrroIidin-l-yl)-l-(S)-phenylethvn-N-methyl-(3,5- difluorophenyPmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (3,5- difluorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (film) 3450, 1320, 1120 cm"¹. Η NMR (free base) δ 7.39-7.29 (m, 3H), 7.23-7.19 (m, 2H), 6.89-6.74 (m, 3H), 5.23 (dd, J =4.0, 11.4 Hz, IH), 4.38 -4.33 (m, IH), 4.35 (d, J = 13.6 Hz, IH), 4.27 (d, J = 13.6Hz, IH), 3.35-3.25 (m, IH), 3.31(dd, J = 11.4, 12.8 Hz, IH), 2.81-2.73 (m, 2H), 2.66 (dd, J = 4.0, 12.8 Hz, IH), 2.50 (s, 3H), 2.50-2.15 (m, 3H), 1.87-1.75 (m, IH). Example 8

Preparation of N- f 2-(3-(S)-hydroxypyrrolidin- 1 - ylV 1 -(S)-phen yleth yl.-N-meth yl-(2- acetylaminophenvDmethanesulfonamide hydrochloride

The title compound was synthesized by acetylation of N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl-N-methy-(2- aminophenyl)methanesulfonamide in Example 4 as an intermediate with acetic anhydride in pyridine, followed by deprotecting t-butyldimethylsilyloxy group in a manner similar to that of (vi). IR (Nujol) 3350, 1675,1320, 1130 cm-¹. W NMR (free base) 8.78 (br.s, IH), 7.79 (br.d, J = 7.7Hz, IH), 7.40-7.29 (m, 4H), 7.26-7.15 (m, 2H), 7.10-6.99 (m, 2H), 5.24 (dd, J =4.4, 11.4 Hz, IH), 4.45 (d, J = 13.9 Hz, IH), 4.35-4.30 (m, IH), 4.33 (d, J = 13.9Hz, IH), 3.31-3.23 (m, IH), 3.31(dd, J = 11.4, 12.8 Hz, IH), 2.78 (d, J = 2.9Hz, 2H), 2.71 (dd, J = 4.4, 12.8 Hz, IH), 2.55 (s, 3H), 2.35-2.13 (m, 3H), 2.21( s, 3H), 1.85-1.75 (m, IH).

Example 9 Preparation of N- r2-(3-(S -hvdroxypyrrolidin- 1 -yl)- 1 -(S)-phenylethyl1-N-methyl-(2- methanesulfonylaminophenyl)-methanesulfonamide hvdrochloride

The title compound was synthesized by treatment of N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl-N-methy-(2- aminophenyl)methanesulfonamide in Example 4 as an intermediate with methane sulfonic anhydride, followed by deprotecting t-butyldimethylsilyloxy group in a manner similar to that of (vi). IR (Nujol) 3550, 3250, 1320, 1310, 1140, 1125 cm-¹. Η NMR (free base) δ 7.51 (dd, J = 1.1, 8.1Hz, IH), 7.40-7.18 (m, 9H), 5.23 (dd, J =3.7, 11.7 Hz, IH), 4.76 (d, J = 13.9 Hz, IH), 4.40-4.32 (m, IH), 4.30 (d, J = 14.3Hz, IH), 3.37 (dd, J = 11.7, 12.8Hz, IH), 3.25-3.17 (m, IH), 3.10 (s, 3H), 2.83-2.73 (m, 2H), 2.66 (s, 3H), 2.65 (dd, J = 3.7, 12.8Hz, IH), 2.35-2.11 (m, 3H), 1.88-1.77 (m, IH).

Example 10 Preparation of N-[2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)-phenylethvn-N-methyl-(4- cvanophenyp-methanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (4- cyanophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (film) 3500, 2230, 1330, 1130 cm^*1. ^lU NMR (free base) δ 7.60 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 7.39-7.31 (m, 3H), 7.20-7.13 (m, 2H), 5.21 (dd, J =4.0, 11.4 Hz, IH), 4.46 (d, J = 13.5 Hz, IH), 4.37-4.31 (m, IH), 4.34 (d, J = 13.5Hz, IH), 3.32 (dd, J = 11.7, 12.8Hz, IH), 3.36-3.30 (m, IH), 2.82 (br.d, J = 9.5Hz, IH), 2.74 (dd, J = 4.4, 9.9Hz, IH), 2.66 (dd, J = 4.0, 12.8Hz, IH), 2.52 (s, 3H), 2.28- 2.15 (m, 3H), 1.88-1.75 (m, IH).

Example 11 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(^'S)-phenvIethvn-N-methyl-(4- methoxycarbonylphenvD-methanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (4- methoxycarbonylphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (film) 3500 1720, 1330, 1115 cm-¹. -Η NMR (free base) δ 7.97 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.4Hz 2H), 7.32-7.29 (m, 3H), 7.18-7.13 (m, 2H), 5.20 (dd, J =4.4, 11.0 Hz, IH), 4.40 (d, J = 13.9 Hz, IH), 4.37-4.28 (m, IH), 4.34 (d, J = 13.9Hz, IH), 3.92 (s, 3H), 3.32-3.23 (m, 2H), 2.80- 2.71 (m, 2H), 2.67 (dd, J = 4.4, 12.8Hz, IH), 2.47 (s, 3H), 2.55-2.35 (m, IH), 2.29-2.12 (m 2H), 1.87-1.74 (m, IH). Example 12

Preparation of N-f2-(3-(S)-hvdroxypyrrolidin- 1-yl)- l-(S)-phenylethyn-N-methyl- phenylmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from phenylmethanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin-l-yl)-l- (S)-phenylethyl]-N-methylamine. IR (KBr) 3350, 1330, 1155, 1125 cm-¹. W NMR (free base) δ 7.35-7.20 (m, 8H), 7.18-7.08 (m, 2H), 5.18 (dd, J = 4.4, 10.8 Hz, IH), 4.30 (s, 2H) 4.29(brs, IH), 3.35-3.20 (m, 2H), 2.80-2.68 (m, 3H), 2.48 (s, 3H), 2.30-2.10 (m, 2H), 1.85- 1.70 (m, 2H).

Example 13 Preparation of N-r2-(3-fS)-hvdroxypyrrolidin- l-yl)-HS)-ρhenylethyl .-N-methyl-(3- bromophenvDmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (3- bromophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (KBr) 3350, 1330, 1155, 1125 cm-¹. Η NMR (free base) δ 7.55-7.15 (m, 9H), 5.21 (dd, J = 4.4, 11.4 Hz, IH), 4.35 (brs, IH), 4.28 (s, 2H), 3.35-3.20 (m, 2H), 2.80-2.72 (m, 2H), 2.68 (dd, J = 4.4, 12.8 Hz, IH), 2.47 (s, 3H), 2.35-2.10 (m, 3H), 1.87-1.75 (m, IH). Example 14

Preparation of N- r2-(3-(S)-hydroxypyrrolidin- 1 -yl)- 1 -(S)-phen yIethyn-N-methyl-(4- methylphenvDmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (4- methylphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (KBr) 3350, 1330, 1155, 1125 cm"¹. -Η NMR (free base) δ 7.38-7.25 (m, 4H), 7.20-7.05 (m, 5H), 5.17 (dd, J = 4.8, 10.6 Hz, IH), 4.28 (brs, IH), 4.25 (s, 2H), 3.35-3.15 (m, 2H), 2.80-2.64 (m, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.30-2.10 (m, 2H), 1.90-1.70 (m, IH), 1.65 (brs, IH).

Example 15 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin- 1-ylV l-fS)-phenylethvn-N-methyl-2- naphthylmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from 2- naphthylmethanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin-l-yl)- l-(S)-phenylethyl]-N-methylamine. mp : 235.3-236.1 °C. IR (KBr) 3350, 1340, 1155, 1125 cm-¹. ⁱH NMR (free base) δ 7.90-7.70 (m, 3H), 7.65-7.42 (m, 4H), 7.30-7.22 (m, IH), 7.16 (t, J = 7.3 Hz, 2H), 7.04 (d, J = 7.7 Hz, 2H), 5.17 (dd, J = 4.8, 10.6 Hz, IH), 4.46 (s, 2H), 4.29 (brs, IH), 3.35-3.14 (m, 2H), 2.82-2.63 (m, 3H), 2.46 (s, 3H), 2.30-2.10 (m, 2H), 1.90- 1.55 (m, 2H).

Example 16 Preparation of N- r2-r3-(S)-hvdroxypyrrolidin- 1 -vi)- 1 -(S)-phenylethvn-N-methvH2- iodophenvDmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (2- iodophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin-l- yl)-l-(S)-phenylethyl]-N-methylamine. mp: 191.7-192.5 °C. [a]_O ²⁵ = +66.0° (MeOH, c=1.0). IR (KBr) 3250, 1330, 1155, 1125 cm-¹. *H NMR (free base) δ 7.87 ( , J =l.lHz, IH), 7.84 (d, J = 1.1Hz, IH), 7.40-7.23 (m, 4H), 7.18-7.10 (m, 2H), 7.08-7.00 (m, IH), 5.16 (dd, J = 4.9, 10.8 Hz, IH), 4.55 (d, J = 14.3Hz, IH), 4.49 (d, J = 13.9Hz, IH), 4.27 (brs, IH), 3.35-3.18 (m, 2H), 2.80-2.65 (m, 3H), 2.72 (s, 3H), 2.25-2.14 (m, 2H), 1.85-1.70 (m, IH), 1.60 (brs, IH).

Example 17 Preparation of N-F2-(3-(S)-hydroxypyrrolidin- 1-yl)- l-(S)-phenylethvH-N-methyl-C4- nitrophenvDmethanesulfonamide hydrochloride The title compound was synthesized in a manner similar to that of Example 1 from (4- nitrophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin-l- yl)-l-(S)-phenylethyl]-N-methylamine. IR (KBr) 3350, 1525, 1350, 1320, 1155, 1125 cm-¹. NMR (free base) δ 8.16 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.37-7.30 (m, 3H), 7.28-7.15 (m, 2H), 5.23 (dd, J = 4.0, 11.4 Hz, IH), 4.51 (d, J = 13.6 Hz, IH), 4.39 (d, J = 13.6 Hz, IH), 4.37 (brs, IH), 3.40-3.25 (m, 2H), 2.90-2.75 (m, 2H), 2.67 (dd, J = 4.2, 13.0 Hz, IH), 2.53 (s, 3H), 2.30-2.10 (m, 3H), 1.90-1.75 (m, IH).

Example 18 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin-l-yl)-l-(S)-phenylethyll-N-methyl-(4- trifluoromethylphenyD-methanesulfonamide hydrochloride The title compound was synthesized in a manner similar to that of Example 1 from (4- trifluoromethylphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-

Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. ER (KBr) 3350, 1325, 1160, 1125 cm-¹. -Η NMR (free base) δ 7.58 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.35-7.28 (m, 3H), 7.18-7.05 (m, 2H), 5.18 (dd, J = 4.2, 11.2 Hz, IH), 4.42 (d, J = 13.9 Hz, IH), 4.34 (d, J = 13.6 Hz, IH), 4.33 (brs, IH), 3.39-3.20 (m, 2H), 2.88-2.64 (m,

3H), 2.52 (s, 3H), 2.36 (brs, IH), 2.30-2.10 (m, 2H), 1.90-1.75 (m, IH).

Example 19 Preparation of N-r2-(3-(S)-hvdroxypyrroIidin-l-vI)-l-(S)-phenylethvn-N-methyl-(3- methoxyphenvDmethanesulfonamide hydrochloride

The title compound was synthesized in a manner similar to that of Example 1 from (3- methoxyphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. IR (KBr) 3350, 1330, 1155, 1125 cm-¹. *H NMR (free base) δ 7.38-7.20 (m, 4H), 7.18-7.10 (m, 2H), 6.92- 6.80 (m, 3H), 5.19 (dd, J = 4.8, 11.0 Hz, IH), 4.30 (brs, IH), 4.28 (s, 2H), 3.75 (s, 3H), 3.35-3.20 (m, 2H), 2.85-2.65 (m, 3H), 2.49 (s, 3H), 2.30-2.10 (m, 2H), 1.90-1.60 (m, 2H).

Example 20 Preparation of N-r2-(3-(S)-(t-butyldimethylsilyloxy)pyrroIidin- 1-yl)- l-(S)-phenylethyIl-N- methyl-(2-chlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (2- chlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine.

(2-Chlorophenyl)methanesulfonyl chloride IR (film) 1375, 1171, 1055, 1038 cm-¹. W NMR δ 7.63-7.25 (m, 4H), 5.12 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl-(2- chlorophenyl)methanesulfonamide

IR (KBr) 1330, 1259, 1148, 1031 cm"¹. -»H NMR δ 7.60-7.55 (m, IH), 7.46-7.28 (m, 8H), 5.33 (dd, J = 4.4, 10.8 Hz, IH), 4.83 (d, J = 13.9 Hz, IH), 4.56 (d, J = 13.9 Hz, IH), 4.44- 4.36 (m, IH), 3.28 (dd, J = 10.6, 12.8 Hz, IH), 3.16-3.02 (m, 2H), 2.80 (dd, J = 4.4, 12.8 Hz, IH), 2.71 (s, 3H), 2.60-2.50 (m, 2H), 2.23-2.08 (m, IH), 1.84-1.70 (m, IH), 0.83 (s, 9H), 0.02, 0.00 (two's, 6H).

Example 21 Preparation of N-r2-(3-(S)-(t-butvIdimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethvn-N- methyl-(3-chlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (3- chlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- l-yl)-l-(S)-phenylethyl]-N-methylamine. (3-Chlorophenyl)methanesulfonyl chloride IR (film) 1374, 1168, 1035 cm"¹. Η NMR δ 7.50-7.26 (m, 4H), 4.83 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl-(3- chlorophenyl)methanesulfonamide IR (film) 1472, 1329, 1254, 1139, 1035 cm-¹. iH NMR δ 7.43-7.25 (m, 9H), 5.34 (dd, J = 3.7, 11.4 Hz, IH), 4.47 (AB quartet, J = 13.6 Hz, 2H), 4.44-4.35 (m, IH), 3.33 (dd, J = 11.7, 12.5 Hz, IH), 3.23-3.12 (m, IH), 2.98 (dd, J = 5.7, 9.9 Hz, IH), 2.72-2.60 (m, 2H), 2.53-2.42 (m, IH), 2.38 (s, 3H), 2.23-2.10 (m, IH), 1.84-1.70 (m, IH), 0.80 (s, 9H), -0.01, - 0.02 (two's, 6H). Example 22

Preparation of N-r2-(3-(S)-(t-butvIdimethyIsiIyloxy)pyrrolidin- 1-yl)- l-(S)-phenylethyll-N- methyl-(4-chlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (4- chlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t-butyldimethylsilyloxy)pyrrolidin- 1-yl)- l-(S)-phenylethyl]-N-methylamine.

(4-Chlorophenyl)methanesulfonyl chloride IR (film) 1490,1359, 1151 cm-¹. W NMR δ 7.42 (brs, 4H), 4.83 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl-(4- chlorophenyl)methanesulfonamide IR (KBr) 1325, 1137, 1030 cm"¹. Η NMR δ 7.4-7.3 (m, 9H), 5.35 (dd, J = 3.1, 11.4 Hz, IH), 4.50 (AB quartet, J = 13.6 Hz, 2H), 4.45-4.35 (m, IH), 3.38 (t, J = 12.5 Hz, IH), 3.28- 3.18 (m, IH), 2.94 (dd, J = 5.5, 9.9 Hz, IH), 2.6 (dt, J = 3.1, 12.9 Hz, 2H), 2.50-2.37 (m, 4H), 2.25-2.10 (m, IH), 1.85-1.70 (m, IH), 0.80 (s, 9H), -0.01 (s, 6H).

Example 23 Preparation of N-r2-(3-(S)-(t-butyldimethylsilyloxy)pyrrolidin-l-ylH-(S)-phenylethyl1-N- methyl-(2,3-dichlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (2,3-dichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine.

(2,3-Dichlorophenyl)methanesulfonyl chloride IR (film) 1428, 1372, 1167, 1035 cm"¹. Η NMR δ 7.60 (dd, J = 1.5, 7.7 H/, IH), 7.52 (dd, J = 1.5, 7.7 Hz, IH), 7.32 (t, J = 7.7 Hz, IH), 5.16 (s, 2H). N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl-

(2,3-dichlorophenyl)methanesulfonamide

IR (film) 1426, 1330, 1254, 1140, 1035 cm-¹. ⁱH NMR δ 7.46 (dd, J = 1.6, 7.7 Hz, IH), 7.43 (dd, J = 1.6, 7.7 Hz, IH), 7.36-7.28 (m, 5H), 7.19 (t, J = 7.7 Hz, IH), 5.30 (dd, J = 4.0, 11.0 Hz, IH), 4.87 (d, J = 13.6 Hz, IH), 4.58 (d, J = 13.6 Hz, IH), 4.40-4.32 (m, IH), 3.35 (dd, J = 11.0, 13.2 Hz, IH), 3.10 (q like, J = 6.2 Hz, IH), 2.99 (dd, J = 5.5, 9.5 Hz, IH), 2.74 (dd, J = 4.0, 13.2 Hz, IH), 2.68 (s, 3H), 2.54 (dd, J = 1.6, 9.5 Hz, IH), 2.50-2.40 (m, IH), 2.18 -2.03 (m, IH), 1.80-1.67 (m, 2H), 0.77 (s, 9H), -0.03, -0.05 (two's, 6H).

Example 24 Preparation of N-r2-(3-(S)-(t-butyldimethvIsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N- methyl-(2,4-dichlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (2,4-dichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. (2,4-Dichlorophenyl)methanesulfonyl chloride IR (film) 1475, 1378, 1170 cm-¹. Η NMR δ 7.57-7.52 (m, 2H), 7.44-7.38 (m, IH), 5.07 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl- (2,4-dichlorophenyl)methanesulfonamide

IR (film) 1473, 1331, 1249, 1140, 1035 cm-¹. Η NMR δ 7.48 (d, J = 8.4 Hz, IH), 7.43 (d, J = 2.2 Hz, IH), 7.36-7.28 (m, 5H), 7.24 (dd, J = 2.2, 8.4 Hz, IH), 5.29 (dd, J = 4.0, 11.4 Hz, IH), 4.77 (d, J = 13.8 Hz, IH), 4.48 (d, J = 13.8 Hz, IH), 4.40-4.32 (m, IH), 3.29 (dd, J = 11.4, 12.8 Hz, IH), 3.10 (q like, J = 6.6 Hz, IH), 2.97 (dd, J = 5.5, 9.5 Hz, IH), 2.72 (dd, J = 4.0, 12.8 Hz, IH), 2.66 (s, 3H), 2.56 (dd, J = 1.6, 9.5 Hz, IH), 2.50-2.40 (m, IH), 2.20- 2.02 (m, IH), 1.82-1.68 (m, 2H), 0.79 (s, 9H), -0.02, -0.04 (two's, 6H).

Example 25

Preparation of N-r2-(3-(S)-(t-butyldimethylsilvloxy)pyπOlidin- 1-yl)- l-fSVphenylethyll-N- methyl-(2,6-dichlorophenyl)methanesulfonamide The title compound was synthesized in a manner similar to that of Example 1 from

(2,6-dichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine.

(2,6-Dichlorophenyl)methanesulfonyl chloride

IR (film) 1439, 1378, 1213, 1173, 1131, 1094 cm-¹. Η NMR δ 7.46 (d, J = 9.2 Hz, IH), 7.45 (d, J = 6.6 Hz, IH), 7.36 (dd, J = 6.6, 9.2 Hz, IH), 5.44 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl-

(2,6-dichlorophenyl)methanesulfonamide

IR (KBr) 1436, 1331, 1139, 1038 cm-¹. Η NMR δ 7.42-7.28 (m, 7H), 7.19 (dd, J = 7.3, 8.8

Hz, IH), 5.35 (dd, J = 3.7, 11.4 Hz, IH), 4.98 (d, J = 14.1 Hz, IH), 4.74 (d, J = 14.1 Hz, IH), 4.43-4.33 (m, IH), 3.35 (dd, J = 11.4, 12.8 Hz, IH), 3.15 (q like, J = 6.6 Hz, IH), 3.07

(dd, J = 5.9, 9.5 Hz, IH), 2.78 (s, 3H), 2.74 (dd, J = 3.7, 12.8 Hz, IH), 2.58-2.43 (m, 2H),

2.20-2.04 (m, IH), 1.86-1.76 (m, 2H), 0.78 (s, 9H), -0.01, -0.04 (two's, 6H).

Example 26

Preparation of N-r2-(3-(S)-(t-butyldimethylsilyloxy)pyrrolidin- 1-yl)- l-(S)-phenylethyll-N- methyI-(3,5-dichlorophenyl)methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from

(3,5-dichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin- 1 -yl)- 1 -(S)-phenylethyl]-N-methylamine.

(3,5-Dichlorophenyl)methanesulfonyl chloride IR (KBr) 1365, 1174 cm-¹. ⁱH NMR δ 7.49 (t, J = 1.8 Hz, IH), 7.39 (d, J = 1.8 Hz, 2H),

4.79 (s, 2H).

(3,5-dichlorophenyl)methanesulfonamide IR (KBr) 1323, 1136, 1033 cm-¹. Η NMR δ 7.36-7.26 (m, 8H), 5.31 (dd, J = 3.7, 11.0 Hz, IH), 4.52 (d, J = 13.6 Hz, IH), 4.38 (d, J = 13.6 Hz, IH), 4.44-4.34 (m, IH), 3.30 (dd, J = 11.0, 12.8 Hz, lhj, 3.22-3.10 (m, IH), 2.70-2.60 (m, 2H), 2.48-2.36 (m, IH), 2.41 (s, 3H), 2.22-2.08 (m, IH), 1.84-1.70 (m, 2H), 0.81 (s, 9H), 0.00, -0.02 (two's, 6H). Example 27

Preparation of N-[2-(3-(S)-(t-butyldimethylsilyloxy)pyrrolidin-l-yl)- l-(S)-phenylethyll-N- methyl-(2,5-dichlorophenyl)-methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (2,5-dichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin- 1-yl)- 1 -(S)-phenylethyl]-N-methylamine. (2,5-Dichlorophenyl)methanesulfonyl chloride IR (KBr) 1472, 1362, 1170, 1150 cm-¹. ⁱH NMR δ 7.60 (d, J = 2.2 Hz, IH), 7.43 (d, J = 8.8 Hz, IH), 7.40 (dd, J = 2.2, 8.8 Hz, IH), 5.06 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl- (2,5-dichlorophenyl)methanesulfonamide

J-R (KBr) 1471, 1332, 1253, 1140 cm-¹. -Η NMR δ 7.59 (d, J = 2.2 Hz, IH), 7.38-7.29 (m, 6H), 7.23 (dd, J = 2.2, 8.4 Hz, IH), 5.34 (dd, J = 3.7, 11.4 Hz, IH), 4.82 (d, J = 13.5 Hz, IH), 4.53 (d, J = 13.5 Hz, IH), 4.42-4.53 (m, IH), 3.33 (dd, J = 11.4, 13.0 Hz, IH), 3.17 ( q like, J = 6.0 Hz, IH), 2.97 (dd, J = 4.0, 9.5 Hz, IH), 2.71 (dd, J = 3.7, 13.0 Hz, IH), 2.64-2.56 (m, 4H), 2.50-2.40 (m, IH), 2.21-2.06 (m, IH), 1.82-1.68 (m, 2H), 0.78 (s, 9H), -0.03, -0.04 (two's, 6H).

Example 28 Preparation of N-r2-(3-(S)-(t-butyldimethylsilyIoxy)pyrrolidin-l-yl)-l-(S)-phenylethvn-N- methvI-(2,3,6-trichlorophenyl)-methanesulfonamide The title compound was synthesized in a manner similar to Example 1 from (2,3,6- trichlorophenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. (2,3,6-Trichlorophenyl)methanesulfonyl chloride IR (film) 1440, 1382, 1189 cm-i. H NMR δ 7.54 (d, J = 8.8 Hz, IH), 7.41 (d, J = 8.8 Hz, IH), 5.47 (s, 2H).

N-[2-(3-(S)-(t-Butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methyl- (2,3,6-trichlorophenyl)methanesulfonamide IR (KBr) 1435, 1328, 1140, 1039 cm-¹. Η NMR δ 7.39 (d, J = 8.8 Hz, IH), 7.38-7.34 (m, 5H), 7.30 (d, J = 8.8 Hz, IH), 5.35 (dd, J = 3.7, 11.4 Hz, IH), 5.05 (d, J = 14.3 Hz, IH), 4.78 (d, J = 14.3 Hz, IH), 4.44-4.36 (m, IH), 3.35 (dd, J = 11.4, 13.2 Hz, IH), 3.19 (q like, J = 6.6 Hz, IH), 3.02 (dd, J = 5.5, 9.5 Hz, IH), 2.79 (s, 3H), 2.73 (dd, J = 3.7, 13.2 Hz, IH), 2.58 (dd, J = 1.6, 9.5 Hz, IH), 2.50-2.40 (m, IH), 2.20-2.04 (m, IH), 1.86-1.74 (m, 2H), 0.77 (s, 9H), -0.02, -0.04 (two's, 6H).

Example 29 Preparation of N-r2-(3-(S)-hvdroxypyrroIidin- 1-yl)- l-(S)-phenylethyll-N-methyl-(4- methanesulfonylphenvD-methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (4- methanesulfonylphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin- 1 -yl)- 1 -(S)-phenylethyl]-N-methylamine. N-[2-(3-(S)-hydroxypyrrolidin- 1-yl)- l-(S)-phenylethyl]-N-methyl-(4- methanesulfonylphenyl)methanesulfonamide

IR (KBr) 3320, 1330, 1300, 1150 cm-¹. Η NMR δ 7.90 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.40-7.18 (m, 5H), 5.24 (dd, J = 4.2, 11.4 Hz, IH), 4.53 (d, J = 13.6 Hz, IH), 4.36 (d, J = 13.6 Hz, IH), 4.40-4.30 (m, IH), 3.40-3.28 (m, 2H), 3.06 (s, 3H), 2.86-2.75 (m, 2H), 2.70 (dd, J = 4.2, 13.0 Hz, IH), 2.56 (s, 3H), 2.35-2.15 (m, 2H), 1.90-1.55 (m, 2H).

Example 30 Preparation of N-r2-(3-(S)-hvdroxypyrrolidin-l-vI)-l-(S)-phenylethyll-N-methyl-(4- trifluoromethoxyphenvD-methanesulfonamide

The title compound was synthesized in a manner similar to that of Example 1 from (4- methanesulfonylphenyl)methanesulfonyl chloride and N-[2-(3-(S)-t- butyldimethylsilyloxy)pyrrolidin-l-yl)-l-(S)-phenylethyl]-N-methylamine. N-[2-(3-(S)-hydroxypyrrolidin- 1-yl)- l-(S)-phenylethyl]-N-methyl-(4- trifluoromethoxyphenyl)methanesulfonamide

IR (KBr) 3330, 2960, 1510, 1460, 1335, 1265, 122C, 1200, 1160, 930 cm-¹. -Η NMR δ 7.40- 7.25 (m, 5H), 7.20-7.10 (m, 4H), 5.19 (dd, J = 4.4, 11.0 Hz, IH), 4.35 (d, J = 13.9 Hz, IH), 4.28 (d, J = 13.6 Hz, IH), 4.40-4.25 (m, IH), 3.36-3.15 (m, 2H), 2.85-2.62 (m, 3H), 2.51 (s, 3H), 2.28-2.10 (m, 2H), 1.90-1.55 (m, 2H).

The compounds and their pharmaceutically acceptable salts have excellent activity as opioid K-receptor agonists. They are useful for the treatment and prevention of pain, asthma, scabies, psoriasis vulgaris or inflammation, especially pain, in mammalian subjects, e. g., human subjects.

Claims

18165 -26- Clai s

(1) A compound having the chemical formula (I)

R ²

(D and the pharmaceutically-acceptable salts thereof, wherein R¹ is hydrogen, hydroxy, C_j- alkoxy, tri(C_j-C₆ alkyl)silyloxy or acyloxy;

R² is C_rC₆ alkyl; and

4Ar is optionally-substituted aryl.

(2) A compound according to claim 1, in which Ar is phenyl, naphthyl, mono-substituted phenyl or mono-substituted naphthyl, wherein the substituent is selected from C_j-C₆ alkyl

C_rC₆ alkoxy, halosubstituted (C**-C₆) alkyl, halosubstituted (C C₆) alkoxy, C_rC₆ alkylsulfonyl, nitro, di (C₁-C₆) alkylamino, mono(C_j-C₆) alkylamino monoacylamino, mono (Cj-Cg) alkylsulfonylamino and amino.

(3) A compound according to claim 2, in which R¹ is hydrogen or hydroxy; R² is methyl. (4) A compound according to claim 3, in which Ar is phenyl, naphthyl or substituted phenyl wherein the substituent is 2-chloro, 2-iodo, 2-nitro, 2-amino, 2-dimethylamino, 2- acetylamino, 2-methansulfonylamino, 3-bromo, 3-methoxy, 3-chloro, 4-chloro, 4-fluoro, 4- methyl, 4-nitro, 4-trifluoromethyl, 4-cyano, 4-methoxycarbonyl, 4-meth.ansulfonyl, 4- trifluoromethoxy, 2,3-dichloro, 2,4-dichloro, 2,5-dichloro, 2,6-dichloro, 3,4-dichloro, 3,5- dichloro, 3,

4-difluoro, 3,

5-difluoro or 2,3,6-trichloro. (5) A compound according to claim 4, in which R¹ is hydroxy; and

Ar is substituted phenyl wherein the substituent is 4-methyl, 4-trifluoromethyl, 2,3- dichloro, 2,4-dichloro, 3,4-dichloro or 2,3,

6-trichloro. (6) A compound or its pharmaceutically acceptable salt according to any one of claims 1 to 5 in which the carbon atom (Cl) is S-configuration or R-configuration.

(7) A pharmaceutical composition for the treatment or prevention of pain in a mammalian subject which is characterized by comprising a compound according to any one of claims 1 to 5 together with a pharmaceutically inert carrier.

(8) A pharmaceutical composition for the treatment or prevention of asthma, scabies, psoriasis vulgaris or inflammation in a mammalian subject, which is characterized by comprising a compound according to any one of claims 1 to 5 together with a pharmaceutically inert carrier.

(9) A method of treating or preventing pain, asthma, scabies, psoriasis vulgaris or inflammation in a mammalian subject, which comprises administering to said subject an effective amount of a compound according to claim 1.

(10) A process for preparing a compound according to claim 1, which comprises reacting a compound of the formula

with ArCH₂S0₃H in the presence of condensing agent or ArCH₂SO₂Cl.