HK1089431B

HK1089431B - Sulfonic acids, their derivatives and pharmaceutical compositions containing them

Info

Publication number: HK1089431B
Application number: HK06111286.4A
Authority: HK
Inventors: M‧阿莱格蒂; A‧阿拉米尼; M‧C‧切斯塔; R‧贝尔蒂尼; C‧比萨里; F‧科洛塔
Original assignee: Dompé Farmaceutici S.P.A.
Priority date: 2003-03-14
Filing date: 2004-03-11
Publication date: 2008-08-15

Description

Sulfonic acids, derivatives thereof and pharmaceutical compositions containing them

Technical Field

The present invention relates to sulfonic acids and derivatives thereof and pharmaceutical compositions containing the same, which are useful for preventing and treating tissue damage caused by malignant accumulation of polymorphonuclear neutrophils (PMN leukocytes) at sites of inflammation.

Background

Specific blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear cells) respond to a chemical stimulus (when stimulated with a substance called a chemokine) by migrating along the concentration gradient of the stimulus through a process called chemotaxis. Representative of the major known stimulators or chemokines are the breakdown products of complement C5a, some N-formyl peptides produced by bacterial surface lysis or from synthetic peptides, such as formyl-methionyl-leucyl-phenylalanine (f-MLP), mainly various cytokines including interleukin-8 (IL-8, also known as CXCL 8). Interleukin-8 is an endogenous chemokine produced by most nucleated cells, such as fibroblasts and macrophages.

In some pathological conditions characterized by malignant accumulation of neutrophils, more severe tissue damage at the site is associated with neutrophil infiltration. Recently, a role for neutrophil activation in determining post-ischemic reperfusion and hyperoxia-related damage in the lung has been generally demonstrated.

The biological activity of IL-8 is mediated by the interaction of this interleukin with CXCR1 and CXCR2 membrane receptors belonging to a family of seven transmembrane receptors expressed on the surface of human neutrophils and certain classes of T cells (L Xu et al, J.Leukocyte biol., 57, 335, 1995). Some selective ligands are known that are able to discriminate CXCR1 from CXCR2, where GRO-a is an example of a CXCR2 selective chemokine.

Although activation of CXCR1 is known to play an important role in IL-8 mediated chemotaxis, it has recently been suggested that activation of CXCR2 may also play a pathophysiological role in chronic inflammatory diseases such as psoriasis. Indeed, the pathophysiological role of IL-8 in psoriasis is also supported by the effect of IL-8 on keratinocyte function.

There is evidence in fact that IL-8 is a potent stimulator of epithelial cell proliferation and angiogenesis, which are two important aspects of the pathogenesis of psoriasis (A. Tuschil et al, J Invest Dermatol, 99, 294, 1992; Koch AE et al, Science, 258, 1798, 1992).

Furthermore, there is continuing evidence that the pathophysiological role of IL-8 in melanoma progression and metastasis is mediated by activation of CXCR2 (l.r.bryan et al, Am J Surg, 174, 507, 1997).

The potential pathogenic role of IL-8 in pulmonary diseases (lung injury, acute respiratory distress syndrome, asthma, chronic pneumonia and cystic fibrosis), particularly in the pathogenesis of chronic obstructive pulmonary disease, via the CXCR2 receptor channel has been widely described (D.WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1: 242-.

In investigating the contribution of ketoprofen (S) and (R) single enantiomers to their racemate anti-inflammatory activity and their role in cytokine modulation (p.ghezzi et al, j.exp.pharm.ther., 287, 969, 19)98) It has been demonstrated that both enantiomers and their salts with chiral and achiral organic bases inhibit IL-8 induced Ca in human PMN leukocytes in a dose-dependent manner²⁺Chemotaxis and elevation of the intracellular concentration of ions (patent application US6,069,172). Later, it was also demonstrated (c.bizzarri et al, biochem. pharmacol.61, 1429, 2001) that ketoprofen has the same properties of inhibiting IL-8 bioactivity as other molecules belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs), such as flurbiprofen, ibuprofen and indomethacin. The classic Cyclooxygenase (COX) inhibitory activity of NSAIDs limits the therapeutic utility of these compounds in neutrophil-dependent pathologies and inflammatory diseases, such as psoriasis, idiopathic pulmonary fibrosis, acute respiratory failure, reperfusion and injury caused by glomerulonephritis. Inhibition of prostaglandin synthesis by action on cyclooxygenase involves an increase in cytokine production, which, like TNF- α, plays a role in augmenting the undesirable proinflammatory effects of neutrophils.

Several new classes of potent and selective inhibitors of IL-8 bioactivity have been discovered that are suitable for "in vivo" administration. R-2-arylpropionic acid amides and N-acylsulfonamides are described as potent inhibitors of IL-8-induced chemotaxis and degranulation of neutrophils (WO 01/58852; WO 00/24710). Furthermore, the novel R and S-2-phenylpropionic acids have recently been identified as potent IL-8 inhibitors, completely free of undesirable COX inhibitory effects (PCT/EP 02/12939).

Disclosure of Invention

We have found that a class of sulfonic acids and derivatives thereof has the ability to effectively inhibit IL-8-induced chemotaxis and degranulation of neutrophils.

Accordingly, the present invention provides sulfonic acids and derivatives represented by the general formula (I):

and the use of a pharmaceutically acceptable salt thereof,

in the formula (I), the compound is shown in the specification,

ar is phenyl substituted with 1 to 3 substituents independently selected from halogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxyl, C₁-C₄-acyloxy, phenoxy, cyano, nitro, amino, C₁-C₄-acylamino, halo-C₁-C₃-alkyl, halo-C₁-C₃-alkoxy, benzoyl, or Ar is a substituted or unsubstituted 5-6 membered heteroaromatic ring;

x represents-CH₂-or-CH (CH)₃) -a group, or an E-configured alkenyl group of formula (II) wherein R' is H or CH₃；

Y is selected from O (oxygen) and NH; and is

-when Y is O (oxygen), R is H (hydrogen);

-when Y is NH, R is selected from the group consisting of:

-H、C₁-C₅alkyl radical, C₁-C₅-cycloalkyl, C₁-C₅-alkenyl, C₁-C₅-an acyl group;

-general formula-CH₂-CH₂-Z-(CH₂-CH₂O) nR ', wherein R' is H or C₁-C₅-alkyl, n is an integer from 0 to 2, Z is oxygen or sulphur;

-general formula- (CH)₂) n-NRaRb wherein n is an integer of 0 to 5, and Ra and Rb, which may be the same or different, are each C₁-C₆Alkyl radical, C₁-C₆-alkenyl, or, alternativelyAlternatively, Ra and Rb, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring represented by the general formula (III),

wherein W represents a single bond, CH₂O, S, N-Rc, Rc being H, C₁-C₆-alkyl or C₁-C₆-an alkyl-phenyl group,

use in the manufacture of a medicament for inhibiting IL-8-induced chemotaxis of human PMNs.

The term "substituted" as used in the above definitions means with a substituent selected from C₁-C₅Alkyl, halogen, hydroxy, C₁-C₅Alkoxy, amino, C₁-C₅-alkylamino, nitro or cyano.

Ar is a substituted phenyl group selected from the group consisting of 3 '-benzoylphenyl, 3' - (4-chloro-benzoyl) -phenyl, 3 '- (4-methyl-benzoyl) -phenyl, 3' -acetyl-phenyl, 3 '-propionyl-phenyl, 3' -isobutyryl-phenyl, 4 '-trifluoromethanesulfonyloxy-phenyl, 4' -benzenesulfonyloxy-phenyl, 4 '-trifluoromethanesulfonylamino-phenyl, 4' -benzenesulfonylamino-phenyl, 4 '-benzenesulfonylmethyl-phenyl, 4' -acetoxyphenyl, 4 '-propionyloxy-phenyl, 4' -benzoyloxy-phenyl, 4 '-acetylamino-phenyl, 4' -acetyl-benzoyl, and, 4 '-propionylamino-phenyl, 4' -benzoylamino-phenyl or is a heteroaromatic ring selected from pyridine, pyrrole, thiophene, furan, indole.

When Y is NH, the preferred R group is

-H、C₁-C₅Alkyl radical, C₁-C₅An acyl group;

-general formula-CH₂-CH₂-O-(CH₂-CH₂O) R 'wherein R' is H or C₁-C₅-an alkyl group;

-general formula- (CH)₂) N-NRaRb wherein N is an integer of 2 to 3, preferably 3, and the group NRaRb is N, N-dimethylamine, N-diethylamine, 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, 1- (4-methyl) piperazinyl.

The present invention also provides novel sulfonic acids and derivative compounds of formula (I) as defined above selected from:

1- (4-isobutylphenyl) ethanesulfonic acid

1- [4- (1-oxo-2-isoindolinyl) phenyl ] ethanesulfonic acid

2- (4-phenylsulfonyloxy) ethanesulfonic acid

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonic acid

2- (3-benzoylphenyl) ethanesulfonic acid

2- (3-isopropylphenyl) ethanesulfonic acid.

E-2- (4-isobutylphenyl) ethenesulfonic acid

E-2- (3-benzoylphenyl) ethenesulfonic acid

E-2- (4-methylsulfonylaminophenyl) ethenesulfonic acid

E-2- (4-trifluoromethylsulfonyloxyphenyl) ethenesulfonic acid

E-2- (4-isobutylphenyl) ethenesulfonamide

E-2- (3-benzoylphenyl) ethenesulfonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethenesulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethenesulfonamide

E-2- (4-isobutylphenyl) ethene-N- (N, N-dimethylaminopropyl) sulphonamide

E-2- (3-benzoylphenyl) ethylene-N- (N, N-dimethylaminopropyl) sulphonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N- (N, N-dimethylaminopropyl) sulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N- (N, N-dimethylaminopropyl) sulphonamide

E-2- (4-isobutylphenyl) ethylene-N-methylsulfonamide

E-2- (3-benzoylphenyl) ethylene-N-methylsulfonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N-methylsulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N-methylsulfonamide

E-2- (4-isobutylphenyl) ethylene-N- (2' -methoxyethyl) sulfonamide

E-2- (3-benzoylphenyl) ethylene-N- (2' -methoxyethyl) sulfonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N- (2' -methoxyethyl) sulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N- (2' -methoxyethyl) sulfonamide

(1-methyl-5-isobutyryl group(s) (s))isobutirryl) Pyrrolyl) -1-methanesulfonamides

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonamide

1- (4-isobutylphenyl) ethanesulfonamide

1- (3-isopropylphenyl) ethanesulfonamide

1- (4-isobutylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- (3-benzoylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- [4- (methylsulfonylamino) phenyl ] ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- (4-isobutylphenyl) ethane-N- (2-methoxyethyl) sulfonamide

1- (3-benzoylphenyl) ethane-N- (2-methoxyethyl) sulfonamide

1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N- (2-methoxyethyl) sulfonamide

1- [4- (methylsulfonylamino) phenyl ] ethane-N- (2-methoxyethyl) sulfonamide

1- (4-isobutylphenyl) ethane-N-methylsulfonamide

1- (3-benzoylphenyl) ethane-N-methylsulfonamide

1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N-methylsulfonamide

1- [4- (methylsulfonylamino) phenyl ] ethane-N-methylsulfonamide

1- [ 4-isobutylphenyl ] ethane-N-acetylsulphonamide

E-2- (3-benzoylphenyl) -2-methyl-ethenesulfonamide

E-2- (3-isopropylphenyl) -2-methyl-ethenesulfonamide

E-2- (4-isobutylphenyl) -2-methyl-ethenesulfonamide

And pharmaceutically acceptable salts thereof.

Preferably, the salt is a sodium salt.

The ethanesulfonamide described above is a chiral compound, and the present invention provides a racemate and (+) and (-) single enantiomers.

When the compounds of general formula (I) according to the invention carry acidic or basic groups, they are generally isolated in the form of their addition salts with pharmaceutically acceptable organic and inorganic acids or bases.

Examples of such acids are selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, citric acid.

Examples of such bases are selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, (D, L) -lysine, L-lysine, tromethamine.

Compounds of formula (I) wherein YR is OH can be prepared by reacting a corresponding compound of formula (IV) (wherein J is H or COCH)₃) With a suitable oxidizing agent (e.g. H)₂O₂HClO and a peroxy acid, preferably m-chloroperbenzoic acid).

In the general formula (I), Y is NH and X is-CH₂The compounds of (A) can be prepared by reacting the corresponding sulfonyl halides (e.g. sulfonyl chlorides) with 1 or 2 equivalents of a compound of the formula NH₂The amine represented by R is prepared by reacting in the presence of a suitable organic or inorganic base, if necessary.

In the general formula (I), Y is NH, X is-CH (CH)₃The compound of (a) can be prepared by: the thiol of the corresponding formula (IV) is reacted with a suitable N-bromoimide, for example N-bromophthalimide (Bromofetimide), followed by oxidation of the sulfur atom and deprotection of the sulfonamide derivative, as described in the examples below.

Compounds of the formula (I) in which Y is NH and X is a radical of the formula (II) can be prepared by reacting the corresponding sulfonyl halides, for example sulfonyl chlorides, with a radical of the formula NH₂The amine represented by R is reactedAnd (4) preparing.

The compounds of the invention are particularly useful as inhibitors of IL-8-induced chemotaxis of human PMNs.

It is another object of the present invention to provide the above novel sulfonic acids and derivative compounds, which are useful as pharmaceuticals.

The ability of the compounds of formula (I) to inhibit polymorphonuclear leukocytes (hereinafter PMN) and monocyte chemotaxis induced by IL-8 and GRO-. alpha.fragments was assessed "in vitro". To this end, heparinized human blood was drawn from healthy adult volunteers, PMNs were isolated from the blood, monocytes were removed by dextran sedimentation (following the procedure disclosed by w.j.ming et al, j.immunol., 138, 1469, 1987), and red blood cells were removed by treatment with hypotonic solution. Cell viability was calculated by trypan blue exclusion and the percent circulating polymorphonuclear in the cell centrifugation products was estimated after staining with DiffQuick.

The same results were actually obtained in chemotaxis assays using human recombinant IL-8(Pepro Tech) as stimulator: dissolving lyophilized protein in HBSS containing 0.2% Bovine Serum Albumin (BSA) to obtain 10^-5Mother liquor of M, diluted to 10 with HBSS^-9M was used for chemotaxis assays.

During the chemotaxis assay (according to w.falkett et al, j.immunol.methods, 33, 239, 1980), a PVP-free filter with a pore size of 5 μm was used, with a microchamber suitable for carrying out the same assay.

The estimated concentration range of the compounds of the general formula (I) according to the invention is 10^-6To 10^-10M, therefore, they were added to the lower and upper wells of the microchamber at the same concentration. The ability of the compounds of general formula (I) of the invention to inhibit IL-8-induced chemotaxis of human monocytes was assessed as described above (Van Damme J. et al, Eur. J. Immunol., 19, 2367, 1989).

Table 2 lists the biological results of some representative compounds in the IL-8 induced PMN chemotaxis assay (inhibition data, C ═ 10)^-8M)

Particular preference is given to using compounds of the formula (I) in which the Ar group is 3 '-benzoylphenyl, 3' - (4-chloro-benzoyl) -phenyl, 3 '- (4-methyl-benzoyl) -phenyl, 3' -acetyl-phenyl, 3 '-propionyl-phenyl, 3' -isobutyryl-phenyl, 4 '-trifluoromethanesulfonyloxy-phenyl, 4' -benzenesulfonyloxy-phenyl, 4 '-trifluoromethanesulfonylamino-phenyl, 4' -benzenesulfonylamino-phenyl, 4 '-benzenesulfonylmethyl-phenyl, 4' -acetoxyphenyl, 4 '-propionyloxy-phenyl, 4' -benzoyloxy-phenyl, 4 ' -acetylamino-phenyl, 4 ' -propionylamino-phenyl, 4 ' -benzoylamino-phenyl, which compounds have the additional property of effectively inhibiting GRO-alpha induced PMN chemotaxis; this property may make these compounds therapeutically useful for IL-18 related pathologies that are involved specifically in the CXCR2 pathway or in combination with CXCR1 signaling.

While dual inhibitors of IL-8 and GRO-alpha-induced biological activity are preferred for therapeutic applications of interest, such compounds that act selectively on the CXCR1 IL-8 receptor or the CXCR2GRO-/IL-8 receptor may be useful in the treatment of certain pathologies described below.

The compounds of general formula (I) were evaluated in vitro completely in blood using the procedure described by Patrignani et al (j. pharmacol. expert. ther., 271, 1705, 1994), and as a result they were found to be completely ineffective as inhibitors of the Cyclooxygenase (COX) enzyme.

In most cases, the compounds of the formula (I) are present in an amount of 10^-5To 10^-7The M concentration range does not interfere with the stimulation of mouse macrophage by lipopolysaccharide (LPS, 1 microgram/ml) to induce PGE₂. Recordable pair PGE₂The resulting inhibition is usually below the limit of statistical significance and generally does not exceed 15-20% of the basal value. The reduced efficiency of COX inhibition is an advantage of the compounds of the invention in therapeutic applications, as much as inhibition of prostaglandin synthesis, a stimulus for macrophage stimulation (LPS or hydrogen peroxide induction), enhances TNF-alpha, an important mediator of neutrophil activation, and a stimulus for cytokine IL-8 productionAnd (4) exciting the plant.

In view of the experimental results discussed above and the role of interleukin-8 (IL-8) and its homologues in the processes involved in neutrophil activation and infiltration, the compounds of the present invention are particularly useful in the treatment of certain diseases, such as psoriasis (r.j. nicholoff et al, am.j. pathol., 138, 129, 1991). Other diseases that can be treated with the compounds of the invention are chronic intestinal inflammatory pathologies such as ulcerative colitis (y.r. mahida et al, clin.sci., 82, 273, 1992) and melanoma, acute respiratory distress syndrome, bullous pemphigoid, rheumatoid arthritis (m.selz et al, j.clin.invest., 87, 463, 1981), idiopathic fibrosis (e.j.miller and p.c.carrre et al, cited above, j.clin.invest., 88, 1882, 1991), glomerulonephritis (t.wada et al, j.exp.med., 180, 1135, 1994) and the prevention and treatment of damage caused by ischemia and reperfusion.

Inhibitors of activation of CXCR1 and CXCR2 are useful for the applications described above, in particular for the treatment of chronic inflammatory pathologies (e.g. psoriasis), where activation of both IL-8 receptors is considered to have an important pathophysiological role for the progression of the disease.

It is in fact well known that activation of CXCR1 is essential for IL-8 mediated chemotaxis of PMNs (Hammond M et al, J Immunol, 155, 1428, 1995). On the other hand, activation of CXCR2 is known to be essential for IL-8 mediated epithelial cell proliferation and angiogenesis in psoriatic patients (Kulke R et al, J Invest dermotol, 110, 90, 1998).

In addition, CXCR2 selective antagonists are particularly useful in the treatment of important pulmonary diseases, such as chronic obstructive pulmonary disease (D.WP Hay and H.M.Sarau., Current Opinion in Pharmacology 2001, 1: 242-247).

It is therefore a further object of the present invention to provide the use of compounds of general formula (I) for the preparation of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, Chronic Obstructive Pulmonary Disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and for the prevention and treatment of injury caused by ischemia and reperfusion, and the use of these compounds. Pharmaceutical compositions containing a compound of the invention and a suitable carrier therefor are also within the scope of the invention.

The compounds of the present invention, together with adjuvants, carriers, diluents or excipients conventionally employed, may be presented in virtually any form for preparing pharmaceutical compositions and unit dosage forms thereof, whether solid, such as tablets or filled capsules, or liquid, such as solutions, suspensions, emulsions, elixirs or filled capsules thereof, all of which may be administered orally or parenterally (including subcutaneously) in the form of sterile injectable solutions. These pharmaceutical compositions and unit dosage forms thereof may comprise the ingredients in conventional proportions, with or without the addition of the active compound or active ingredient, and the unit dosage forms may also contain any suitable effective amount of the active ingredient commensurate with the dosage to be taken per day.

When the acid of the present invention is used as a medicament, it is generally administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner known per se in the pharmaceutical art and comprise at least one active compound. Typically, the amount of a compound of the invention administered is a pharmaceutically effective amount. The actual amount of the compound to be administered will, however, generally be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the route of delivery chosen, the compounds are preferably formulated as injectable solutions or oral compositions. Oral compositions may be prepared as bulk solutions or suspensions or bulk powders. However, it is most common to formulate compositions in unit dosage form to facilitate accurate dosage calculation. The term "unit dosage form" refers to a unit dosage of matter suitable for human beings and other mammals, each unit containing a pre-calculated predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include ampoules or syringes pre-filled and pre-measured of liquid compositions or solid compositions such as pills, tablets, capsules and the like. In these compositions, the acid compound is often a minor component (from about 0.1% to about 50% by weight, preferably from about 1% to about 40% by weight), with the remainder being various excipients or carriers and processing aids to aid in forming the desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle and buffer, suspending and dispersing agent, coloring agent, flavoring agent, and the like. Liquid forms, including the injection compositions mentioned below, are generally stored in a dark environment to avoid any catalytic effects, such as the formation of hydrogen peroxide or peroxides, when exposed to light. The solid form may include, for example, any of the following or a compound having similar properties: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, for example, alginates, xanthan gum or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; or a flavoring agent, such as a mint, salicylate, or orange flavoring agent.

Injectable compositions are generally based on the injection of sterile saline or phosphate buffered saline or other injection vehicles known in the art. As mentioned above, the acid derivative represented by the general formula (I) in these compositions is generally a minor component, and the weight thereof is often between 0.05 and 10%, and the remainder is an injection carrier or the like. The average daily dose depends on many factors, such as the severity of the disease and the condition of the patient (age, sex, body weight). The daily dose of the compounds of formula (I) is usually not fixed and may be administered in divided doses from 1 mg or a few mg up to 1500 mg, optionally in multiple doses. Higher doses can be administered due to the low toxicity of the compounds of the invention when taken over a long period of time.

The above ingredients of the oral or injectable compositions are merely representative. Other materials or processing techniques, etc., are described and incorporated herein by reference (Mack Press, Pennsylvania, Remingto's pharmaceutical series Handbook, eighth part, 18 th edition, 1990).

Administration of the compounds of the present invention may be in sustained release form or via a sustained release drug delivery system. Representative sustained release materials are also described in the references Remingto's Pharmaceutical Seiences handbook cited above.

The present invention is illustrated in detail by the following examples, which should not be construed as limiting the scope of the present invention.

Detailed Description

example 1

General formula R-Ar-C (CH) ₃ )H-SO ₃ Aryl methanesulfonic acid, 1-aryl ethanesulfonic acid and related enantiomers thereof represented by H General synthetic method of

To a cooled (T ═ 0-4 ℃) solution of substituted benzene (17mmol) and acetyl chloride (18mmol) in dry dichloromethane (25mL) was added portionwise AlCl with vigorous stirring₃(18 mmol). The ice bath was removed and the solution was refluxed until the starting material apparently disappeared completely (2-3 hours). After cooling at room temperature, the mixture was poured into a cooled 2N hydrochloric acid solution and stirred for 30 minutes. The acid solution was transferred to another funnel and extracted with dichloromethane (3X 20 mL). The organic extracts were collected, washed with saturated sodium chloride solution (2X 25mL), dried over sodium sulfate and evaporated in vacuo to give pure arylacetophenone (14.45-16.15mmol) in high yield (85-95%).

To a solution of arylacetophenone (11.5mmol) in methanol (40mL) was added sodium borohydride (17.2mmol) portionwise with stirring. The mixture was refluxed until complete disappearance of the starting material (3 hours). After cooling at room temperature, 1M HCl was added to the mixture and the methanol was distilled off. The aqueous phase was extracted with ethyl acetate (3X 15mL), and the organic extracts were collected, washed with saturated sodium chloride solution (2X 25mL), dried over sodium sulfate, and evaporated in vacuo to give pure 1-arylethanol (yield about 75%).

To a solution of 1-arylethanol (4.5mmol) in dry chloroform (10mL) was added thioacetic acid (5.39mmol) and zinc iodide (2.24mmol) with stirring. The reaction mixture was refluxed for 3 hours; after cooling at room temperature, the mixture was diluted with water (15mL) and transferred to another funnel. The two phases were separated by shaking. The organic phase was washed with a saturated solution of sodium bicarbonate (3X 20mL) followed by a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo to give pure 1-arylethylthioacetate (yield about 80%).

A solution of 1-arylethylthioacetate (0.91mmol) in glacial acetic acid (2mL) was stirred at 60 ℃ and 30% H was added dropwise₂O₂(4.56 mmol); the resulting solution was stirred at 60 ℃ for 24 hours and then azeotropically distilled with toluene to remove acetic acid. After dilution of the residue with water (5mL), neutralization with 1N NaOH, washing with diethyl ether (2X 15mL) and lyophilization, the racemic mixture of the sodium salt of 1-arylethanesulfonic acid was obtained as a white solid (yield about 90%).

Optical resolution

Racemic 1-Arylethanesulfonic acid sodium salt was filtered on a column packed with Amberlite IR-120 resin (H + form) and the eluent was water to give the product as a viscous oil. The two isomers can be separated by recrystallization of the corresponding (+) or (-) alpha-phenylethylammonium salt from ethanol solution according to the optical resolution of arylpropionic acids disclosed by Akguen et al (Arzneim. -Forsch./Drug Res., 46(II), Nr.9, 891-894 (1996)). The pure enantiomer isolated was the sodium salt.

Following the above procedure, the following compounds were prepared:

(-) -1- (4-isobutylphenyl) ethanesulfonic acid sodium salt (1)

This compound was synthesized using commercially available isobutylbenzene as a starting material.

[α]D＝-35(c＝1；H₂O)

¹H-NMR(DMSO-d₆)：δ7.25(d，2H，J＝7Hz)；7.05(d，2H，J＝7Hz)；3.62(m，1H)；2.37(d，2H，J＝7Hz)；1.86(m，1H)；1.40(d，3H，J＝7Hz)；0.91(d，6H，J＝7Hz)。

(+) -1- (4-isobutylphenyl) ethanesulfonic acid sodium salt (2)

[α]_D＝+34.5(c＝1；H₂O)

¹H-NMR(DMSO-d₆)：δ7.25(d，2H，J＝7Hz)；7.08(d，2H，J＝7Hz)；3.62(m，1H)；2.37(d，2H，J＝7Hz)；1.86(m，1H)；1.42(d，3H，J＝7Hz)；0.90(d，6H，J＝7Hz)。

(-) -1- [4- (1-oxo-2-isoindolinyl) phenyl ] ethanesulfonic acid sodium salt (3)

The compound was synthesized according to the above method using intermediate 4- (1-oxo-2-isoindolinyl) acetophenone as starting material. The intermediates used were prepared from the commercially available reagents benzaldehyde and 4-aminoacetophenone, according to Ichiro, T.et al (Heterocycles 43: 11, 2343-2346 (1996)).

[α]_D＝-52.4(c＝1；H₂O)

¹H-NMR(DMSO-d₆)：δ7.68(m，3H)；7.35(m，3H)；7.15(d，2H，J＝7Hz)；4.68(s，2H)；3.65(q，1H，J1＝7Hz，J2＝3Hz)；1.28(d，3H，J＝7Hz)。

(+) -1- [4- (1-oxo-2-isoindolinyl) phenyl ] ethanesulfonic acid sodium salt (4)

The compound was synthesized according to the above method using intermediate 4- (1-oxo-2-isoindolinyl) acetophenone as starting material. The intermediates used were prepared from the commercially available reagents benzaldehyde and 4-aminoacetophenone according to Ichiro, T.et al (Heterocycles 43: 11, 2343-2346 (1996)).

[α]_D＝+50(c＝1；H₂O)

¹H-NMR(DMSO-d₆)：δ7.708(m，3H)；7.35(m，3H)；7.18(d，2H，J＝7Hz)；4.68(s，2H)；3.65(q，1H，J1＝7Hz，J2＝3Hz)；1.30(d，3H，J＝7Hz)。

(-) -2- (4-Phenylsulfonyloxy) ethanesulfonic acid sodium salt (5)

The compound was synthesized according to the above method using the intermediate 4-benzenesulfonyloxyacetophenone as the starting material. The intermediates used were prepared from the commercially available reagent 4-hydroxyacetophenone according to known experimental methods.

[α]_D＝-47.5(c＝1；H₂O)

¹H-NMR(D₂O)：δ7.90(d，2H，J＝7Hz)；7.70(t，1H，J＝7Hz)；7.55(t，2H，J＝7Hz)；7.32(d，2H，J＝7Hz)；6.95(d，2H，J＝7Hz)；3.64(m，1H)；1.41(d，3H，J＝7Hz)。

(+) -2- (4-Phenylsulfonyloxy) ethanesulfonic acid sodium salt (6)

[α]_D＝+49(c＝1；H₂O)

¹H-NMR(D₂O)：δ7.93(d，2H，J＝7Hz)；7.70(t，1H，J＝7Hz)；7.55(t，2H，J＝7Hz)；7.32(d，2H，J＝7Hz)；6.91(d，2H，J＝7Hz)；3.67(m，1H)；1.41(d，3H，J＝7Hz)。

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonic acid sodium salt (7)

This compound was synthesized by Friedel crafts acylation of commercially available reagent methyl 1-methyl-2-pyrrolidineacetate as a starting material with acetyl chloride to give (1-methyl-5-acetylpyrrolyl) -1-methylacetate. The ester group is then hydrolyzed. The relevant sodium (1-methyl-5-acetylpyrrolyl) -1-methanesulphonate salt was obtained according to the experimental procedure described in WO 02/0704095.

¹H-NMR(DMSO-d₆)：δ7.5(s，1H)；6.18(s，1H)；3.60(s，3H)；3.51(s，2H)；2.10(s，3H)。

(±) -2- (3-benzoylphenyl) ethanesulfonic acid sodium salt (8)

This compound was synthesized by Friedel Crafts acylation of commercially available reagent 3- (1-cyanoethyl) benzoic acid as a starting material with benzene to give 2- (3' -benzoylphenyl) propionitrile. The ester group is then hydrolyzed. The relevant sodium salt of 2- (3' -benzoylphenyl) ethanesulfonic acid was obtained according to the experimental procedure described in WO 02/0704095.

¹H-NMR(D₂O)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；3.62(m，1H)；1.40(d，3H，J＝7Hz)。

(±) -2- (3-isopropylphenyl) ethanesulfonic acid sodium salt (9)

The compound is synthesized by using a commercial reagent 3- (1-cyanoethyl) acetophenone as a starting material, and reducing methylene by a known method through a Wittig reaction to obtain 2- (3-isopropylphenyl) propionitrile. The relevant sodium salt of 2- (3-isopropylphenyl) ethanesulfonic acid was obtained according to the experimental procedure described in WO 02/0704095.

¹H-NMR(D₂O)：δ7.30(m，2H)；7.10(m，2H)；3.92(m，1H)；3.63(m，1H)；1.42(d，3H，J＝7Hz)；1.25(d，6H，J＝8Hz)。

example 2

Preparation of E-arylethenesulfonic acid (sodium salt)

Aryl ethanesulfonic acid was dissolved in thionyl chloride (5mL) and the resulting solution was refluxed overnight. After cooling at room temperature, thionyl chloride was evaporated in vacuo and the crude aryl ethanesulfonyl chloride was diluted with dry THF (5mL) and cooled in an ice water bath at 0 ℃; 1N aqueous NaOH (0.64mmol) was added at 4 deg.C; the ice-water bath was removed and the reaction mixture was allowed to stand still for about 1 hour and the temperature was raised to room temperature to precipitate a white solid. The organic sodium salt was vacuum filtered, washed with THF, and dried in a vacuum oven at 40 deg.C to give pure E-aryl vinyl sulfonic acid sodium salt (0.32-0.51mmol) as a white powder (50-80% yield).

Following the above procedure, the following compounds were prepared:

e-2- (4-isobutylphenyl) ethenesulfonic acid sodium salt (10)

¹H-NMR(D₂O)：δ7.60(d，1H，J＝8Hz)；7.55-7.32(m，4H)；7.05(d，1H，J＝14Hz)；2.62(m，2H)；1.90(m，1H)；0.97(d，6H，J＝7Hz)。

E-2- (3-benzoylphenyl) ethenesulfonic acid sodium salt (11)

¹H-NMR(D₂O)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.65(d，1H，J＝8Hz)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；7.00(d，1H，J＝14Hz)。

E-2- (4-Methylsulfonylaminophenyl) ethenesulfonic acid sodium salt (12)

¹H-NMR(DMSO-d₆)：δ7.60(d，1H，J＝8Hz)；7.35(d，2H，J＝8Hz)；7.20(d，2H，J＝8Hz)；7.07(d，1H，J＝14Hz)；6.51(bs，1H，SO2NH)；3.00(s，3H)。

E-2- (4-Trifluoromethanesulfonyloxyphenyl) ethenesulfonic acid sodium salt (13)

¹H-NMR(CDCl₃)：δ7.62(d，1H，J＝8Hz)；7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；7.05(d，1H，J＝14Hz)。

Practice ofExample 3

General synthetic method of E-aryl vinyl sulfonamide

Aryl ethanesulfonic acid (0.64mmol) was dissolved in thionyl chloride (5mL) and the resulting solution was refluxed overnight. After cooling at room temperature, thionyl chloride was evaporated in vacuo and the crude aryl ethanesulfonyl chloride was diluted with dry THF (5mL) and cooled in an ice water bath at 0 ℃; the selected amine (1.28mmol) was added dropwise. The ice-water bath was removed and the reaction mixture was allowed to stand until the temperature rose to room temperature. After complete disappearance of the starting reagent, the solvent was evaporated in vacuo and chloroform (10mL) and water (10mL) were added to the residue; the phases were separated by shaking and the organic phase was washed with water (3X 15mL), dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by flash chromatography to isolate pure E/Z-arylethenesulfonamide (0.32-0.51mmol) as a colorless oil (50-80% yield).

The following compound was prepared according to the above procedure using ammonia (0.5M, 1, 4-dioxane as solvent):

e-2- (4-isobutylphenyl) ethenesulfonamide (14)

¹H-NMR(CDCl₃)：δ7.55(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；6.88(d，1H，J＝14Hz)；4.75(bs，2H，SO₂NH₂)；2.55(d，2H，J＝7Hz)；1.94(m，1H)；1.02(d，6H，J＝7Hz)。

E-2- (3-benzoylphenyl) ethenesulfonamide (15)

¹H-NMR(CDCl₃)：δ7.80(d，2H，J＝7Hz)；7.72(s，1H)；7.62(d，1H，J＝8Hz)；7.52(d，1H，J＝14Hz)；7.50(m，2H)；7.30(m，3H)；6.88(d，1H，J＝14Hz)；4.75(bs，2H，SO₂NH₂)。

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethenesulfonamide (16)

¹H-NMR(CDCl₃)：δ7.60(d，1H，J＝8Hz)；7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；7.10(d，1H，J＝14Hz)；4.85(bs，2H，SO₂NH₂)。

E-2- [4- (methylsulfonylamino) phenyl ] ethenesulfonamide (17)

¹H-NMR(CDCl₃)：δ7.55(d，1H，J＝14Hz)；7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.90(d，1H，J＝14Hz)；6.45(bs，1H，SO₂NH)；4.80(bs，2H，SO₂NH₂)；2.98(s，3H)。

Following the above procedure, the amine used was 3- (dimethylamino) propylamine, the following compound was prepared:

e-2- (4-isobutylphenyl) ethen- (N, N-dimethylaminopropyl) sulphonamide (18)

¹H-NMR(CDCl₃)：δ7.45(m，3H)；7.20(d，2H，J＝7Hz)；6.70(d，1H，J＝14Hz)；6.40(bs，1H，SO₂NH)；3.18(m，2H)；2.55(m，4H)；2.30(s，6H)；1.92(m，1H)；1.75(m，2H)；0.97(d，6H，J＝7Hz)。

E-2- (3-benzoylphenyl) ethylene-N- (N, N-dimethylaminopropyl) sulfonamide (19)

¹H-NMR(CDCl₃)：δ7.82(d，2H，J＝7Hz)；7.74(s，1H)；7.60(d，1H，J＝8Hz)；7.50(d，1H，J＝14Hz)；7.45(m，2H)；7.26(m，3H)；6.70(d，1H，J＝14Hz)；6.45(bs，1H，SO₂NH)；3.15(m.，2H)；2.50(m，4H)；2.35(s，6H)。

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene- (N, N-dimethylaminopropyl) sulfonamide (20)

¹H-NMR(CDCl₃)：δ7.62(d，1H，J＝14Hz)；7.48(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；7.00(d，1H，J＝14Hz)；6.50(bs，1H，SO₂NH)；3.17(m.，2H)；2.48(m，4H)；2.35(s，6H)。

E-2- [4- (methylsulfonylamino) phenyl ] ethylene- (N, N-dimethylaminopropyl) sulfonamide (21)

¹H-NMR(CDCl₃)：δ7.57(d，1H，J＝14Hz)；7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.75(d，1H，J＝14Hz)；6.50(bs，2H，SO₂NH)；3.15(m，2H)；2.98(s，3H)；2.50(m，4H)；2.40(s，6H)。

Following the above procedure, the amine used was methylamine (2M, solvent THF), the following compound was prepared:

e-2- (4-isobutylphenyl) ethylene-N-methylsulfonamide (22)

¹H-NMR(CDCl₃)：δ7.55(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；6.88(d，1H，J＝14Hz)；4.80(bs，1H，SO₂NH)；2.75(d，3H，J＝4Hz)；2.55(d，2H，J＝7Hz)；1.95(m，1H)；1.04(d，6H，J＝7Hz)。

E-2- (3-benzoylphenyl) ethylene-N-methylsulfonamide (23)

¹H-NMR(CDCl³)：δ7.81(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝8Hz)；7.55(d，1H，J＝14Hz)；7.45(m，2H)；7.30(m，3H)；6.90(d，1H，J＝14Hz)；4.60(bs，1H，SO₂NH)；2.70(d，3H，J＝4Hz)。

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N-methylsulfonamide (24)

¹H-NMR(CDCl₃)：δ7.60(d，1H，J＝8Hz)；7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；7.10(d，1H，J＝14Hz)；4.85(bs，1H，SO₂NH)；2.70(d，3H，J＝4Hz)。

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N-methylsulfonamide (25)

¹H-NMR(CDCl₃)：δ7.56(d，1H，J＝14Hz)；7.35(d，2H，J＝8Hz)；7.20(d，2H，J＝8Hz)；6.92(d，1H，J＝14Hz)；6.50(bs，1H，SO₂NH)；4.70(bs，1H，SO₂NH)；3.00(s，3H)，2.75(d，3H，J＝4Hz)。

Following the above procedure, the amine used was 2-methoxyethylamine, and the following compound was prepared:

e-2- (4-isobutylphenyl) ethylene-N- (2-methoxyethyl) sulfonamide (26)

¹H-NMR(CDCl₃)：δ7.57(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.20(d，2H，J＝7Hz)；6.90(d，1H，J＝14Hz)；4.80(bs，1H，SO₂NH)；3.74(m，2H)；3.55(m，2H)；3.45(s，3H)；2.52(d，2H，J＝7Hz)；1.95(m，1H)；1.05(d，6H，J＝7Hz)。

E-2- (3-benzoylphenyl) ethylene-N- (2-methoxyethyl) sulfonamide (27)

¹H-NMR(CDCl₃)：δ7.80(d，2H，J＝7Hz)；7.72(s，1H)；7.62(d，1H，J＝8Hz)；7.55(d，1H，J＝14Hz)；7.40(m，2H)；7.30(m，3H)；6.95(d，1H，J＝14Hz)；4.62(bs，1H，SO₂NH)；3.75(m，2H)；3.50(m，2H)；3.40(s，3H)。

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N- (2-methoxyethyl) sulfonamide (28)

¹H-NMR(CDCl₃)：δ7.62(d，1H，J＝8Hz)；7.50(d，2H，J＝7Hz)；7.30(d，2H，J＝7Hz)；7.15(d，1H，J＝14Hz)；4.80(bs，1H，SO₂NH)；3.77(m，2H)；3.52(m，2H)；3.40(s，3H)。

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N- (2-methoxyethyl) sulfonamide (29)

¹H-NMR(CDCl₃)：δ7.58(d，1H，J＝14Hz)；7.35(d，2H，J＝8Hz)；7.25(d，2H，J＝8Hz)；6.90(d，1H，J＝14Hz)；6.52(bs，1H，SO₂NH)；4.75(bs，1H，SO₂NH)；3.70(m，2H)；3.50(m，2H)；3.40(s，3H)；3.05(s，3H)。

Example 4

General synthetic method of aryl methanesulfonamide

(1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonamide (30)

This compound was synthesized by Friedel Crafts acylation of commercially available reagent methyl 1-methyl-2-pyrrolidineacetate as a starting material with isobutyryl chloride to give (1-methyl-5-isobutyrylpyrrolyl) -1-methylacetate. The ester group is then hydrolyzed. The relevant sodium salt of (1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonic acid was obtained according to the experimental procedure described in WO 02/0704095.

(1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonic acid sodium salt (0.64mmol) was dissolved in thionyl chloride (5mL), and the resulting solution was refluxed overnight. After cooling at room temperature, thionyl chloride was evaporated in vacuo and crude (1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonyl chloride was diluted with dry THF (5mL) and cooled in an ice-water bath at 0 ℃; an aqueous ammonia solution (1.28mmol) was added dropwise thereto. The ice-water bath was removed and the reaction mixture was allowed to stand until the temperature rose to room temperature. After complete disappearance of the starting reagent, the solvent was evaporated in vacuo and chloroform (10mL) and water (10mL) were added to the residue; the phases were separated by shaking and the organic phase was washed with water (3X 15mL), dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by flash chromatography to isolate pure (1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonamide (0.60mmol) as a yellow oil (93% yield).

¹H-NMR(DMSO-d₆)：δ7.5(s，1H)；6.18(s，1H)；4.65(bs，2H，SO₂NH₂)；3.60(s，3H)；3.51(s，2H)；3.38(m，1H)；1.25(d，6H，J＝8Hz)。

Following the procedure described above, using (1-methyl-5-acetylpyrrolyl) -1-methanesulfonic acid, sodium salt (7) (prepared according to the general synthetic procedure for aryl methanesulfonic acid described above), the following compound was prepared:

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonamide (31)

¹H-NMR(DMSO-d₆)：δ7.5(s，1H)；6.18(s，1H)；4.40(bs，2H，SO₂NH₂)；3.60(s，3H)；3.51(s，2H)；2.10(s，3H)。

Enantioselective synthesis of (+) and (-) enantiomers of Compounds 32 and 33

The (+) and (-) enantiomers of 1- (4-isobutylphenyl) ethanesulfonamide were synthesized enantioselectively according to the method of Davis F.A. et al (J.org.chem., 58, 4890-4896, (1993)). The process comprises subjecting N-sulfonylcamphorimine, prepared from 4-isobutylbenzylsulfonamide (27) and N, N-diisopropyl- (1S) - (+) -10-camphorsulfonamide or N, N-diisopropyl- (1R) - (-) -10-camphorsulfonamide, to a diastereoselective C-methylation reaction. Acid hydrolysis of the diastereomers gave the desired compounds, both as clear oils.

(-) -1- (4-isobutylphenyl) ethanesulfonamide (32)

[α]D＝-8.5(c＝1.2；CHCl₃)

¹H-NMR(CDCl₃)：δ7.30(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.25(m，1H+bs SONH₂)；2.45(d，2H，J＝7Hz)；1.87(m，4H)；0.97(d，6H，J＝7Hz)。

(+) -1- (4-isobutylphenyl) ethanesulfonamide (33)

[α]_D＝+15(c＝1；CHCl₃)

Example 5

Replacement synthesis of arylethanesulfonamides

Synthesis of (+) -1- (3-isopropylphenyl) ethanesulfonamide (34)

The title compound was synthesized by starting with the commercially available reagent 3- (1-cyanoethyl) benzoic acid, which was subjected to the procedures described by Kindler k. et al (chem. be., 99, 226(1966)) and Kindler k. et al (liebig ann. chem., 26, 707(1967)) to give intermediate 3-isopropylbenzoic acid. Reduction of the benzyl alcohol derivative with LiAlH4 followed by treatment of the alcohol with thioacetic acid gives the intermediate ethyl thioacetate. The thiol derivative is then subjected to hydrolysis according to the method described by Corey e.j. et al (tet.lett., 33, 4099 (1992)).

To a suspension of 3-isopropylbenzylthiol (3.85 g; 23.2mmol) and potassium tert-butoxide (2.6 g; 23.2mmol) in dichloromethane (15mL) was added 18-crown-6 (0.6 g; 2.3 mmol). Stirring was carried out at a temperature in the range of 0 ℃ to 4 ℃ for 15 minutes, and N-bromo-phthalimide (5.24 g; 23.2mmol) was added. After the addition, the ice-water bath was removed and the solution was stirred at room temperature for 1 hour; the organic phase was washed with water (3X 15mL), dried over sodium sulfate and evaporated in vacuo to give an oily residue which was purified by flash chromatography to give 3-isopropylbenzylthiophthalimide (6.05 g; 18.56mmol) as a pale yellow oil (80% yield). The methylation reaction was then carried out as described by Davis F.A. et al (J.org.chem., 58, 4890-4896, (1993)) to give racemic 1- (3-isopropylphenyl) ethylthiophthalimide. Oxidation with 3-chloroperbenzoic acid (2 equivalents) and treatment with hydrazine to cleave the phthalimido group in a manner well known in the art gave the final product, 1- (3-isopropylphenyl) ethanesulfonamide (31).

¹H-NMR(CDCl₃)：δ7.28(m，2H)；7.05(m，2H)；4.40(bs，2H，SO₂NH₂)；3.90(m，1H)；3.65(m，1H)；1.35(d，3H，J＝7Hz)；1.20(d，6H，J＝8Hz)。

The corresponding 1-arylethanesulfonamides (prepared as described above) were alkylated under phase transfer conditions using 3-dimethylaminopropyl chloride as the alkylating agent according to the methods described by Gajda T. et al (Synthesis, 1005(1981)) and Burke P.O. et al (Synthesis, 935 (1985)). The following compounds were prepared:

(±) -1- (4-isobutylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulfonamide (35)

¹H-NMR(CDCl₃)：δ7.32(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.26(m，1H)；4.10(bs，1H，SONH)；3.18(m，2H)；2.55(m，4H)；2.45(d，2H，J＝7Hz)；2.40(s，6H)；1.85(m，4H)；1.00(d，6H，J＝7Hz)。

(±) -1- (3-benzoylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulfonamide (36)

¹H-NMR(CDCl₃)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；4.35(bs，1H，SO₂NH)；3.62(m，1H)；3.18(m，2H)；2.55(m，4H)；2.40(s，6H)；1.30(d，3H，J＝7Hz)。

(±) -1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N- (N, N-dimethylaminopropyl) sulfonamide (37)

¹H-NMR(CDCl₃)：δ7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；4.30(bs，1H，SO₂NH)；3.85(m，1H)；3.20(m，2H)；2.60(m，4H)；2.45(s，6H)；1.25(d，3H，J＝7Hz)。

(±)1- [4- (methylsulfonylamino) phenyl ] ethane-N- (N, N-dimethylaminopropyl) sulfonamide (38)

¹H-NMR(CDCl₃)：δ7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.45(bs，1H，SO2NH)；4.80(bs，1H，SO₂NH)；3.82(m，1H)；3.25(m，2H)；2.98(s，3H)；2.65(m，4H)；2.45(s，6H)；1.05(d，3H，J＝7Hz)。

The corresponding 1-arylethanesulfonamides (prepared as described above) were alkylated under phase transfer conditions using 2-bromoethyl methyl ether as the alkylating agent as described by Gajda T. et al (Synthesis, 1005(1981)) and Burke PO. et al (Synthesis, 935 (1985)). The following compounds were prepared:

(±) -1- (4-isobutylphenyl) ethane-N- (2-methoxyethyl) sulfonamide (39)

¹H-NMR(CDCl₃)：δ7.30(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.25(m，1H)；4.80(bs，1H，SO₂NH)；3.74(m，2H)；3.55(m，2H)；3.45(s，3H)；2.45(d，2H，J＝7Hz)；1.87(m，1H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。

(±) -1- (3-benzoylphenyl) ethane-N- (2-methoxyethyl) sulfonamide (40)

¹H-NMR(CDCl₃)：δ7.82(d，2H，J＝7Hz)；7.75(s，1H)；7.62(d，1H，J＝7Hz)；7.55(m，2H)；7.30(m，3H)；4.25(bs，1H，SO₂NH)；3.75(m，2H)；3.60(m，1H)；3.55(m，2H)；3.48(s，3H)；1.55(d，3H，J＝7Hz)。

(±) -1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N- (2-methoxyethyl) sulfonamide (41)

¹H-NMR(CDCl₃)：δ7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；4.30(bs，1H，SO₂NH)；3.85(m，1H)；3.60(m，2H)；3.55(m，2H)；3.48(s，3H)；1.35(d，3H，J＝7Hz)。

(±) -1- [4- (methylsulfonylamino) phenyl ] ethane-N- (2-methoxyethyl) sulfonamide (42)

¹H-NMR(CDCl₃)：δ7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；6.45(bs，1H，SO₂NH)；4.32(bs，1H，SO₂NH)；3.85(m，1H)；3.62(m，2H)；3.55(m，2H)；3.48(s，3H)；3.00(s，3H)；1.35(d，3H，J＝7Hz)。

The corresponding 1-arylethanesulfonamides (prepared as described above) were monoalkylated using diazomethane as alkylating agent according to the methods described by Muller E.et al (Liebigs Ann. chem., 623, 34(1959)) and Saegusa T. et al (Lett., 6131 (1966)). The following compounds were prepared:

(±) -1- (4-isobutylphenyl) ethane-N-methylsulfonamide (43)

¹H-NMR(CDCl₃)：δ7.25(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.80(bs，1H，SO₂NH)；4.20(m，1H)；2.70(d，3H，J＝4Hz)；2.45(d，2H，J＝7Hz)；1.87(m，1H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。

(±) -1- (3-benzoylphenyl) ethane-N-methylsulfonamide (44)

¹H-NMR(CDCl₃)：δ7.82(d，2H，J＝7Hz)；7.75(s，1H)；7.62(d，1H，J＝7Hz)；7.55(m，2H)；7.30(m，3H)；4.25(bs，1H，SO₂NH)；4.15(m，1H)；2.70(d，3H，J＝4Hz)；1.55(d，3H，J＝7Hz)。

(±) -1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N-methylsulfonamide (45)

¹H-NMR(CDCl₃)：δ7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；4.10(bs，1H，SO₂NH)；3.80(m，1H)；2.75(d，3H，J＝4Hz)；1.20(d，3H，J＝7Hz)。

(±) -1- [4- (methylsulfonylamino) phenyl ] ethane-N-methylsulfonamide (46)

¹H-NMR(CDCl₃)：δ7.50(d，2H，J＝7Hz)；7.27(d，2H，J＝7Hz)；6.50(bs，1H，SO₂NH)；4.30(bs，1H，SO₂NH)；3.90(m，1H)；3.05(s，3H)；2.70(d，3H，J＝4Hz)；1.32(d，3H，J＝7Hz)。

(±) -1- (4-isobutylphenyl) ethane-N-acetylsulfonamide (47)

This compound was synthesized by acylation of the corresponding 1- (4-isobutylphenyl) ethanesulfonamide with acetyl chloride as described above.

¹H-NMR(CDCl₃)：δ7.28(d，2H，J＝7Hz)；7.20(d，2H，J＝7Hz)；4.82(bs，1H，SO₂NH)；4.30(m，1H)；2.45(d，2H，J＝7Hz)；1.85(m，1H)；1.80(s，3H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。

Example 6

General synthetic method of E/Z2-aryl-2-methylethenesulfonamide

A solution of the appropriate arylacetophenone (20mmol) (prepared according to the general synthesis method for 1-arylethanesulfonic acid described above) in 10mL of tert-butyl alcohol was added dropwise over 20 minutes to a commercially available ylide, iodomethylenetriphenylphosphorane (25mmol), and the resulting mixture was stirred at room temperature for 4 hours while maintaining the reaction temperature below 25 ℃. At the end of the reaction, the mixture is shaken well with 50ml pentane and 50ml water, filtered and the two layers are separated. The aqueous layer was extracted with pentane (3X 50ml), dried over sodium sulphate and purified by flash chromatography to give pure 2- (aryl) iodopropene (E/Z isomer mixture) (yield about 70%). Carbonyl compounds were subjected to the Wittig olefination reaction described above, according to the method described by Sotaro Miyano et al (ball. chem. soc. j., 1197, 52 (1979)).

2- (aryl) propylene iodide (2mmol) was dissolved in acetonitrile (5mL) and added to a solution of potassium thioacetate (4mmol) in acetonitrile (2mL) at room temperature; the reaction mixture was stirred for 4 hours. The mixture was quenched with water and extracted with ethyl acetate; the phases were separated and the organic phase was dried, filtered and concentrated to give 2-arylpropenethioacetate (E/Z isomer mixture) (almost quantitative yield).

Stirring of 2-aryl-2-methylethyl ether at 60 deg.CA solution of alkenylthioacetate (1.00mmol) in glacial acetic acid (2mL) was added dropwise with 30% H₂O₂(4.56 mmol); the resulting solution was stirred at 60 ℃ for 24 hours, and then, acetic acid was removed by azeotropic distillation with toluene. The residue was diluted with water (5mL), neutralized with 1N NaOH, washed with diethyl ether (2X 15mL), and lyophilized to give 2-aryl-2-methylethenesulfonic acid, sodium salt (E/Z isomer mixture) as a white solid (yield about 90%).

E/Z2-aryl-2-methylethenesulfonamide was prepared according to the general synthetic procedure for E-arylethenesulfonamide described above to give E/Z-2-aryl-2-methyl-ethenesulfonamide (0.75-0.85mmol) (85-95% yield) as a colorless oil.

Following the above procedure, the following compounds were synthesized:

e-2- (3-benzoylphenyl) -2-methylethenesulfonamide (48)

¹H-NMR(CDCl₃)：δ7.75(m，3H)；7.62(m，2H)；7.53(m，4H)；6.15(d，1H，J＝1.4Hz)，5.96(d，1H，J＝1.3Hz)；4.38(bs，2H，SONH₂)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)。

E-2- (3-isopropylphenyl) -2-methylethenesulfonamide (49)

¹H-NMR(CDCl₃)：δ7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；6.15(d，1H，J＝1.4Hz)，5.96(d，1H，J＝1.3Hz)；4.38(bs，2H，SONH₂)；3.15(m，1H)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)；1.25(d，6H，J＝7Hz)。

E-2- (4-isobutylphenyl) -2-methylethenesulfonamide (50)

¹H-NMR(CDCl₃)：δ7.32(d，2H，J＝7Hz)；7.23(d，2H，J＝7Hz)；6.15(q，1H，J＝1.4Hz)；5.96(q，1H，J＝1.3Hz)；4.35(bs，2H，SONH₂)；2.45(d，2H，J＝7Hz)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)；1.88(m，1H)；0.97(d，6H，J＝7Hz)。

Table 1 lists some compound names and structures of examples 1-6.

TABLE 1

TABLE 2

Inhibition of IL-8(100ng/mL) induced chemotaxis of human PMN (%)

^*Test concentration of compound c 10^-7

Claims

1. The sulfonic acid and derivative compounds shown in the general formula (I) and the pharmaceutically acceptable salts thereof, in the preparation of the drugs for inhibiting the chemotaxis of human polymorphonuclear neutrophils induced by IL-8,

in the general formula (I), Ar is phenyl, pyridine, pyrrole or indole which is unsubstituted or substituted by 1 to 3 substituents which are independentIs selected from C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄-acyloxy, phenoxy, amino, C₁-C₄-acylamino, halo-C₁-C₃-alkyl, halo-C₁-C₃-alkoxy, benzoyl;

Y is selected from O and NH; and is

-when Y is O, R is H; and

-when Y is NH, R is selected from the group consisting of: H. c₁-C₅Alkyl radical, C₁-C₅-cycloalkyl, C₁-C₅-an acyl group; general formula-CH₂-CH₂-Z-(CH₂-CH₂O) nR ', wherein R' is H or C₁-C₅-alkyl, n is an integer from 0 to 2, Z is oxygen; general formula one (CH)₂) n-NRaRb wherein n is an integer of 0 to 5, and Ra and Rb, which may be the same or different, are each C₁-C₆-an alkyl group.

2. Use according to claim 1, characterized in that: ar is a substituted phenyl group selected from the group consisting of 3 '-benzoylphenyl, 3' - (4-chloro-benzoyl) -phenyl, 3 '- (4-methyl-benzoyl) -phenyl, 3' -acetyl-phenyl, 3 '-propionyl-phenyl, 3' -isobutyryl-phenyl, 4 '-trifluoromethanesulfonyloxy-phenyl, 4' -benzenesulfonyloxy-phenyl, 4 '-trifluoromethanesulfonylamino-phenyl, 4' -benzenesulfonylamino-phenyl, 4 '-benzenesulfonylmethyl-phenyl, 4' -acetoxyphenyl, 4 '-propionyloxy-phenyl, 4' -benzoyloxy-phenyl, 4 '-acetylamino-phenyl, 4' -acetyl-benzoyl, and, 4 '-propionylamino-phenyl, 4' -benzoylamino-phenyl.

3. Use according to claim 1, characterized in that: YR is OH.

4. Use according to claim 1, characterized in that: y is NH, R is:

H、C₁-C₅alkyl radical, C₁-C₅An acyl group;

general formula-CH₂-CH₂-O-(CH₂-CH₂O) R 'wherein R' is H or C₁-C₅-an alkyl group;

general formula- (CH)₂-) N-NRaRb where N is an integer of 2 or 3 and the group NRaRb is N, N-dimethylamine, N-diethylamine.

5. Use according to claim 4, characterized in that: n is 3.

6. Sulfonic acid and derivative compounds of general formula (I) according to claim 1, selected from the following compounds:

1- (4-isobutylphenyl) ethanesulfonic acid

1- [4- (1-oxo-2-isoindolinyl) phenyl ] ethanesulfonic acid

2- (4-phenylsulfonyloxy) ethanesulfonic acid

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonic acid

2- (3-benzoylphenyl) ethanesulfonic acid

2- (3-isopropylphenyl) ethanesulfonic acid

E-2- (4-isobutylphenyl) ethenesulfonic acid

E-2- (3-benzoylphenyl) ethenesulfonic acid

E-2- (4-methylsulfonylaminophenyl) ethenesulfonic acid

E-2- (4-trifluoromethylsulfonyloxyphenyl) ethenesulfonic acid

E-2- (4-isobutylphenyl) ethenesulfonamide

E-2- (3-benzoylphenyl) ethenesulfonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethenesulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethenesulfonamide

E-2- (4-isobutylphenyl) ethene-N- (N, N-dimethylaminopropyl) sulphonamide

E-2- (3-benzoylphenyl) ethylene-N- (N, N-dimethylaminopropyl) sulphonamide

E-2- (4-isobutylphenyl) ethylene-N-methylsulfonamide

E-2- (3-benzoylphenyl) ethylene-N-methylsulfonamide

E-2- [4- (trifluoromethanesulfonyloxy) phenyl ] ethylene-N-methylsulfonamide

E-2- [4- (methylsulfonylamino) phenyl ] ethylene-N-methylsulfonamide

E-2- (4-isobutylphenyl) ethylene-N- (2' -methoxyethyl) sulfonamide

E-2- (3-benzoylphenyl) ethylene-N- (2' -methoxyethyl) sulfonamide

(1-methyl-5-isobutyrylpyrrolyl) -1-methanesulfonamide

(1-methyl-5-acetylpyrrolyl) -1-methanesulfonamide

1- (4-isobutylphenyl) ethanesulfonamide

1- (3-isopropylphenyl) ethanesulfonamide

1- (4-isobutylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- (3-benzoylphenyl) ethane-N- (N, N-dimethylaminopropyl) sulphonamide

1- (4-isobutylphenyl) ethane-N- (2-methoxyethyl) sulfonamide

1- (3-benzoylphenyl) ethane-N- (2-methoxyethyl) sulfonamide

1- [4- (methylsulfonylamino) phenyl ] ethane-N- (2-methoxyethyl) sulfonamide

1- (4-isobutylphenyl) ethane-N-methylsulfonamide

1- (3-benzoylphenyl) ethane-N-methylsulfonamide

1- [4- (trifluoromethanesulfonyloxy) phenyl ] ethane-N-methylsulfonamide

1- [4- (methylsulfonylamino) phenyl ] ethane-N-methylsulfonamide

1- [ 4-isobutylphenyl ] ethane-N-acetylsulphonamide

E-2- (3-benzoylphenyl) -2-methyl-ethenesulfonamide

E-2- (3-isopropylphenyl) -2-methyl-ethenesulfonamide

E-2- (4-isobutylphenyl) -2-methyl-ethenesulfonamide

And pharmaceutically acceptable salts thereof.

7. The compound of claim 6, wherein: the compound is the respective ethanesulfonamide compound and is the (-) or (+) single enantiomer of the respective ethanesulfonamide compound.

8. The process for the preparation of the compounds of formula (I) wherein YR is OH according to claim 6 or 7, wherein: the process comprises reacting an intermediate compound of formula (IV),

wherein J is H or COCH₃，

With a suitable oxidizing agent.

9. The method of claim 8, wherein the oxidizing agent is a peroxyacid.

10. The method of claim 8, wherein the oxidizing agent is selected from H₂O₂HClO or m-chloroperbenzoic acid.

11. The compound of claim 6 or 7, wherein Y is NH and X is-CH₂-or a process for the preparation of a compound of vinyl group of E configuration of formula (II),

the method is characterized in that: the process comprises reacting the corresponding sulfonyl halide with 1 or 2 equivalents of a compound of the formula NH₂And (3) reacting the amine shown as R.

12. The method of claim 11, wherein the sulfonyl halide is a sulfonyl chloride.

13. The compound of claim 6 or 7, wherein Y is NH, X is-CH (CH)₃A process for producing the compound of (1), characterized in that: the process comprises reacting an intermediate compound of formula (IV),

wherein J is H or COCH₃，

Reaction with a suitable N-bromoimide, reoxidation of the sulfur atom, and subsequent deprotection of the sulfonamide derivative.

14. The method of claim 13, wherein the N-bromoimide is N-bromophthalimide.

15. A pharmaceutical composition characterized by: the pharmaceutical composition comprises a compound according to claim 6 or 7 and a suitable carrier therefor.

16. Use according to any one of claims 1 to 4, characterized in that: can be used for preparing medicines for treating psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease, bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and preventing and treating injury caused by ischemia and reperfusion.