HK1075014B - 2-aryl-propionic acids and pharmaceutical compositions containing them - Google Patents

Description

2-aryl-propionic acids and pharmaceutical compositions containing them

Technical Field

The present invention relates to (R, S) 2-aryl-propionic acids, their single enantiomers (R) and (S), and pharmaceutical compositions containing them, useful for the prevention and treatment of tissue damage caused by the acute recruitment of polymorphonuclear neutrophils (PMN leukocytes) at the site 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 or synthetic peptides produced by bacterial surface lysis, such as formyl-methionyl-leucyl-phenylalanine (f-MLP), and primarily various cytokines, including interleukin-8 (IL-8). Interleukin-8 is an endogenous chemokine produced by most nucleated cells, such as fibroblasts, macrophages, endothelial cells and epithelial cells, which are affected by TNF-alpha (tumor necrosis factor) stimulators, the interleukins IL-1 alpha and IL-1 beta and bacterial parietal Lipopolysaccharides (LPS), and the same class of neutrophils exposed to lipopolysaccharides or N-formyl-peptides (F-MLP) derived from bacteria. A series of IL-8 chemokines that bind to the IL-8 receptor (GRO α, β, γ, and NAP-2) belong to this family of endogenous chemokines (also known as Neutrophil Activating Factors (NAF), T-lymphotactin, monocyte-derived neutrophil chemokines) (Chang et al, J.Immunol., 148, 451, 1992). Neutrophils are the first line of defense against bacterial infection because these cells have the ability to migrate from peripheral blood via endothelial junctions and tissue matrix to sites of action (i.e. migration along a chemokine concentration gradient) where their action is to attack microorganisms, clear damaged cells and repair tissue (m.a. goukert-Podicalo et al, pathol. biol (Paris), 44, 36, 1996).

In some pathological states characterized by acute recruitment of neutrophils, more localized tissue damage is associated with neutrophil infiltration. Recently, the role of neutrophil activation in determining post-ischemic reperfusion and hyperoxia-related damage in the lungs has been generally demonstrated. Experimental models [ n.sekido et al, Nature, 365, 654, 1993and t.matsumoto et al, lab.investig., 77, 119, 1997] and clinical studies [ a Mazzone et al, Recent prog.med., 85, 397, 1994; receipts et al, atheroscl, 91, 1, 1991 have shown that cell damage is directly related to the degree of PMN leukocyte infiltration, with IL-8 being the most specific and strongest activator. Acute neutrophil recruitment in the airways and lung water of patients with Acute Respiratory Distress Syndrome (ARDS) may be closely related to the concentration of the chemokine IL-8 (e.j.miller et al, am.rev.respir.dis., 146, 437, 1992) and the severity of the pathology (Kurodowska et al, immunol., 157, 2699, 1996). It has been found that the treatment of acute respiratory insufficiency and lung injury models caused by endotoxemia with IL-8 antibodies is effective (K.Yokoi et al; Lab.invent., 76, 375, 1997).

It has been found that IL-8 has a specific effect on causing injury in patients with acute myocardial infarction after post-ischemic reperfusion (Y.Abe et al, Br.Heart J., 70, 132, 1993); the effect obtained with anti-IL-8 antibodies in experimental models of rabbit focal cerebral ischemia also demonstrated that IL-8 plays a key role in mediating post-ischemic reperfusion-related injury (t. matsumoto et al, lab. invent., 77, 119, 1997).

The biological activity of IL-8 is mediated by the interaction of this interleukin with CXCR1 and CXCR2 membrane receptors belonging to seven transmembrane receptor families expressed on the surface of human neutrophils and certain classes of T cells (L.xu et al, J.Leukocyte biol., 57, 335, 1995).

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 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 production 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). In addition, IL-8 induces the expression of part of the major histocompatibility complex II (MHC-II) molecule HLA-DR on cultured keratinocytes (L. Kemneny et al, Int Arch Allergy Immunol, 10, 351, 1995). The effects of CXCL8 on keratinocyte function may be mediated by activation of CXCR 2. Consistent with this hypothesis, CXCR2 has been reported to be overexpressed in the skin of epithelial lesions in patients with psoriasis (r. kulke et al, j. invest. dermotol, 110, 90, 1998).

Furthermore, there is continuing evidence that the pathophysiological role of IL-8 in melanoma progression and metastasis is mediated by activation of CXCR 2.

The potential pathogenic role of IL-8 in cutaneous melanoma is independent of its chemotactic activity on human PMNs. Indeed, the role of IL-8 may be an autocrine growth and transfer factor for melanoma cells.

Melanoma cells have been found to produce consistent amounts of CXCL8, and are known to express the immunoreactive CXCR2 receptor (l.r.bryan et al, Am J Surg, 174, 507, 1997). IL-8 is known to induce the chemotactic migration and proliferation of melanoma cells (J.M.Wang et al, biochem Biophys Res Commun, 169, 165, 1990).

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 extensively described (D.WP Hay and H.M. Sarau., Current Opinion in pharmacology 2001, 1: 242-.

Phenylurea-based compounds are described which selectively antagonize the binding of IL-8 to the CXCR2 receptor (j.r. white et al, j.biol.chem., 273, 10095, 1998); WO 98/07418 claims the use of these compounds in the treatment of interleukin-8 mediated pathologies.

In a study evaluating 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, 1998), it has been demonstrated that two enantiomers with chiral and achiral organic bases and their salts inhibit IL-8 in humans dose-dependentlyPMN leukocyte-induced Ca²⁺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 had the same activity 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 damage caused by glomerulonephritis. Inhibition of prostaglandin synthesis resulting from action on cyclooxygenase involves increasing cytokine production, which, like TNF- α, plays a role in augmenting the undesirable pro-inflammatory effects of neutrophils.

The (R) enantiomer of NSAIDs belonging to the phenylpropionic subclass has a lower potency in inhibiting COX compared to the (S) enantiomer, and for this reason it has been suggested that the (R) enantiomer of ketoprofen, flurbiprofen and ibuprofen may be a potentially useful agent for the treatment of neutrophilic granulocytic pathologies. The conversion of some of the (R) enantiomers to the corresponding (S) enantiomers in vivo in certain animal species and humans, thereby restoring COX inhibitory activity, greatly limits the utility of these compounds in the treatment of IL-8 mediated pathologies.

The points mentioned above explain the difficulties currently encountered in identifying selective IL-8 inhibitors belonging to the 2-phenylpropanoid class.

It has been proposed that the chiral transition of the R enantiomer of 2-phenylpropionic acid is due to the stereospecificity of the intermediate R-lofoyl-CoA thioester formation; it was thus demonstrated that derivatization of the carboxyl function can avoid metabolic switching "in vivo" without affecting the inhibitory potency of IL-8.

Structural activity correlation studies on the class of 2-phenylpropionic acid derivatives have allowed the identification of several new classes of potent and selective inhibitors of IL-8 bioactivity that are suitable for "in vivo" administration. R-2-arylpropionic acid amides and N-acylsulfonamides are described as potent inhibitors of IL-8-induced neutrophil chemotaxis and degranulation (WO 01/58852; WO 00/24710).

Disclosure of Invention

We have found that selected subsets of 2-aryl-propionic acids have a very good ability to effectively inhibit IL-8-induced neutrophil chemotaxis and degranulation without any significant effect on cyclooxygenase activity.

The two R and S enantiomers of (R, S) -2-aryl-propionic acids are described below at 10^-5To 10^-6The concentration range of M has virtually no cyclooxygenase-inhibiting activity.

The present invention therefore provides (R, S) -2-aryl-propionic acids of general formula (I), their (R) and (S) single enantiomers, and pharmaceutically acceptable salts thereof, useful as inhibitors of IL-8-induced chemotaxis of human PMNs.

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

ar is a benzene ring substituted with the following groups,

-a group in position 3 (meta), said group being selected from the group consisting of C₁-C₅Linear or branched C optionally substituted by alkoxycarbonyl₁-C₅Alkyl radical, C₂-C₅-alkenyl or C₂-C₅Alkinyl, substituted or unsubstituted phenyl, straight or branched C₁-C₅Hydroxyalkyl, aryl-hydroxymethyl, or straight or branched C in the 3 (meta) position₁-C₅The alkyl group, together with the substituent at the para-or ortho-position and the benzene ring, forms a saturated or unsaturated, substituted or unsubstituted bicyclic aryl group; or

-a group in the 4 position (ortho), said group being selected from C₁-C₅-acyloxy, substituted or unsubstituted benzoyloxyBase, C₁-C₅-acylamino, substituted or unsubstituted benzoylamino, C₁-C₅-sulfonyloxy, substituted or unsubstituted phenylsulfonyloxy, C₁-C₅Alkanesulfonylamino, substituted or unsubstituted benzenesulfonylamino, C₁-C₅Alkanesulfonylmethyl, substituted or unsubstituted benzenesulfonylmethyl, C₃-C₆-a cycloalkyl group; 2-furyl; 3-tetrahydrofuranyl; 2-thiophenyl; 2-tetrahydrothiophenyl or C₁-C₈(alkanoyl, cycloalkanoyl, aralkanoyl) -C₁-C₅Alkylamino, such as acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino; or

-a group in position 2 (para), said group being selected from substituted or unsubstituted arylmethyl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylamino, wherein the substituents on the aryl group are selected from C₁-C₄Alkyl radical, C₁-C₄-alkoxy, chloro, fluoro and/or trifluoromethyl.

The benzene ring on the Ar group may be substituted by other groups such as C₁-C₅-alkyl or halogen groups are optionally substituted.

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.

Preferred Ar in the compounds of formula (I) is phenyl substituted in the 3-position by isopropyln-1-en-1-yl, ethyl, isopropyl, pent-2-en-3-yl, pent-3-yl, 1-phenyl-ethen-1-yl, α -methylbenzyl, α -hydroxybenzyl, α -hydroxyethyl, α -hydroxypropyl or bicyclic aryl structures, for example 3-methyl-indan-5-yl, 3-methyl-indan-7-yl, 8-methyl-tetrahydrocinn-2-yl, 5-methyl-tetrahydrocinn-1-yl, the 4-position by trifluoromethanesulfonyloxy, 2-propanesulfonyloxy, phenylmethylsulfonyloxy, Phenylsulfonyloxy, 2 '-ethylphenylsulfonyloxy, 2' -chlorobenzenesulfonyloxy, methanesulfonylamino, trifluoromethanesulfonylamino, 2-propanesulfonylamino, phenylmethylsulfonylamino, phenylsulfonylamino, 2 '-ethylphenylsulfonylamino, aminosulfonylmethyl, 2' -chlorobenzenesulfonylamino, trifluoromethanesulfonylmethyl, phenylsulfonylmethyl, aminosulfonyloxy, aminosulfonylamino phenyl, and the 2-position substituted by 2- (2, 6-dichloro-phenylamino) -phenyl, 2- (2, 6-dichloro-phenyl-amino) -5-chloro-phenyl, 2- (2, 6-dichloro-3-methyl-phenyl-amino) -phenyl, 2- (3-trifluoromethyl-phenyl-amino) -phenyl, phenyl-sulfonyl, phenyl, 2- (2, 6-dichloro-phenoxy) -phenyl, 2- (2-chloro-phenoxy) -phenyl, 2- (2, 6-dichloro-benzyl) -phenyl, 2- (2-chloro-benzyl) -phenyl substituted phenyl.

Particularly preferred compounds of the invention are:

(R, S)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

(R)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

(S)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

2- [ 3' - (alpha-dihydroxy-ethyl) phenyl ] propionic acid and single diastereoisomer thereof

2- [ 3' - (alpha-dihydroxy-propyl) phenyl ] propionic acid and single diastereoisomer thereof

(R, S)2- [ 3' -isopropylidene ] propionic acid

(R)2- [ 3' -isopropylidene ] propionic acid

(S)2- [ 3' -isopropylidene ] propionic acid

(R)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(R)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(S)2- [4 '(2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(R)2- (4' -aminosulfonyloxy) phenylpropionic acid

(S)2- (4' -aminosulfonyloxy) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(R)2- (4' -Methanesulphonylamino) phenylpropionic acid

(S)2- (4' -Methanesulphonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylsulfonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(S)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(R)2- (4' -aminosulfonylamino) phenylpropionic acid

(S)2- (4' -aminosulfonylamino) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(R)2- (4' -phenylsulfonylmethyl) phenylpropionic acid

(S)2- (4' -phenylsulfonylmethyl) phenylpropionic acid.

Another object of the present invention is to provide novel compounds represented by the general formula (Ia), their (R) and (S) single enantiomers and pharmaceutically acceptable salts thereof,

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

ar is phenyl substituted in the 4 position (ortho position) by a group selected from C₁-C₅-sulfonyloxy, substituted or unsubstituted phenylsulfonyloxy, C₁-C₅Alkanesulfonylamino, substituted or unsubstituted benzenesulfonylamino, C₁-C₅-an alkanesulfonylmethyl group, a substituted or unsubstituted benzenesulfonylmethyl group.

The phenyl ring on the Ar group in formula (Ia) may be substituted by other groups such as C₁-C₅-alkyl or halogen groups are optionally substituted.

The term "taking" as used in the above definitionSubstituted is selected from C₁-C₅Alkyl, halogen, hydroxy, C₁-C₅Alkoxy, amino, C₁-C₅-alkylamino, nitro or cyano.

Particularly preferred compounds of the formula (Ia) are the following compounds:

(R)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(R)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(S)2- [4 '(2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(R)2- (4' -aminosulfonyloxy) phenylpropionic acid

(S)2- (4' -aminosulfonyloxy) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(R)2- (4' -Methanesulphonylamino) phenylpropionic acid

(S)2- (4' -Methanesulphonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylsulfonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(S)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(R)2- (4' -aminosulfonylamino) phenylpropionic acid

(S)2- (4' -aminosulfonylamino) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(R)2- (4' -phenylsulfonylmethyl) phenylpropionic acid

(S)2- (4' -phenylsulfonylmethyl) phenylpropionic acid.

Compounds of the invention are described in 10^-5To 10^-6The concentration range does not prevent lipopolysaccharide (1 microgram/ml) from stimulating mouse macrophage to produce PGE₂And thus lack any inhibitory activity against Cyclooxygenase (COX).

Since the R and S enantiomers of 2-phenylpropionic acid do not possess COX inhibitory activity, the compound of the invention is the first example of 2-phenylpropionic acid with the necessary characteristics for therapeutic use, useful in the treatment of IL-8 induced acute neutrophil chemotaxis and activation-related pathologies. The R-enantiomer of the invention is subjected to expected metabolic chiral conversion to obtain the corresponding S enantiomer, and the IL-8 potency and COX selectivity of the S enantiomer are equivalent to those of the R enantiomer.

In general, the compounds of formula (I) of the present invention are isolated as addition salts with pharmaceutically acceptable organic and inorganic bases. These bases are, for example: sodium hydroxide, potassium hydroxide, calcium hydroxide, (D, L) -lysine, L-lysine, tromethamine.

WO 01/58852 and WO 00/24710 describe 2-arylpropionic acids substituted in the 3 (meta) and 2 (para) positions of the general formula (I) and the enantiomers thereof.

The stannane reaction of the polysubstituted 2-phenyl-propionic acids bearing perfluorobutanesulfonate groups in the para or meta or ortho position is carried out according to the method described hereinafter to give the acids of general formula (I) as defined above.

The various 2-arylpropionic acids were prepared by a completely and stereospecific synthesis as described by Larsen r.d. et al (j.am. chem.soc., 111, 7650, 1989) and myersa.g. (ibidem, 119, 6496, 1997), i.e. the racemate was converted into one of the single enantiomers after conversion to 2-aryl-2-propyl-enone. The stereospecific synthesis of 2-arylpropionic acids involves mainly the S enantiomer, but the R enantiomer is easily obtained by modification thereof by appropriate choice of chiral auxiliary. For example, synthesis of α -arylalkanoic acids using arylalkyl ketones as reactants is described in b.m.trost and j.h.rigby (j.org.chem., 14, 2926, 1978), for arylation of Meldrum acid (Meldrum acid), see j.t.piney and r.a.rowe (tetra.lett., 21, 965, 1980); regarding the use of tartaric acid as a chiral auxiliary, see g.castaldi et al (j.org.chem.52, 3019, 1987); for the use of alpha-hydroxy esters as chiral auxiliaries, reference is made to r.d. larsen et al (j.am. chem. so., 111, 7650, 1989) and US4,940,813 and the literature cited therein.

Italian patent No. 1,283,649 describes a process for the preparation of 2- (2-hydroxy-phenyl) -propionic acid and esters thereof. An established efficient process for the preparation of (R, S) -2- (5-benzoyl-2-acetoxy) -propionic acid and the R enantiomer of the acid of general formula (Ia) comprises reacting the chloride of the carboxylic acid with a triamine, e.g. dimethylethylamine, to convert it to the corresponding propan-1-enone, which in turn is reacted with R (-) pantolactone to give the ester of the R enantiomer of the acid with R-dihydro-3-hydroxy-4, 4-dimethyl-2 (3H) -furan 2-one. The ester is then saponified with lithium hydroxide to produce the corresponding free acid.

For example, one general method for preparing R-2-arylpropionic acids of formula (Ia) involves reacting a 4-hydroxy-phenylpropionate or a 4-aminophenylpropionate with the corresponding C in the presence of a suitable organic or inorganic base₁-C₅-sulfonyl chloride or benzenesulfonyl chloride reaction; or 4-chloromethylphenylpropionic acid ester with the corresponding C in the presence of a suitable organic or inorganic base₁-C₅Thiolate or thiophenolate, detailed procedure for the synthesis of (S) and (R) -2- [ (4' -aryl/alkylsulfonylamino) phenyl ] of general formula (Ia)]General procedure for propionic acid "section and following section.

In general, the preparation of compounds of formula (Ia) involves reacting a perfluorobutanesulfonyl fluoride, represented by formula (IIa), mono-or poly-substituted hydroxyaryl ketone to form a perfluorobutanesulfonic acid ester, represented by formula (IIb), wherein n is an integer from 1 to 9.

After esterification and methylation of the carbon atom in the alpha position, subjecting the compound of formula (IIb) to Willgenod rearrangement to produce an arylpropionic acid derivative of formula (IIc), wherein n is an integer from 1 to 9 and R is₃Is represented by C₁-C₄Alkyl or C₂-C₄An alkenyl group.

A compound of the formula (IIc) and a compound of the formula Bu₃SnR₄A suitable tributylstannane reaction of formula (I), wherein R₄Is unsubstituted or substituted by aryl, straight-chain or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl or straight-chain or branched C₂-C₆Alkynyl to give the corresponding (R, S) -2-arylpropionic acid ester represented by the general formula (IId).

Under the condition of catalytic hydrogenation, the alkenyl or alkynyl can be subjected to hydrogenation reaction to obtain the corresponding saturated alkyl. As mentioned above, the compounds of formula (IId) are racemized, the corresponding acid chlorides are converted into ketenes, which are then reacted with R (-) -pantoic lactone and hydrolyzed to the pure R enantiomer. The ketene intermediate reacts with chiral auxiliary S (+) -pantoic acid lactone to generate corresponding pure S enantiomer.

The ability of the compounds of general formula (I) of the invention to inhibit polymorphonuclear leukocyte (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 percentage of circulating polymorphonuclear in the cell centrifugation products was estimated after staining with DiffQuinck.

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).

As an example, the inhibition data for some representative compounds in the IL-8 induced PMN chemotaxis assay (C ═ 10) are listed in the table below^-6M)：

Examples	Name (R)	Percent inhibition (C ═ 10)M)
			5	(R, S)2- [ 3' -isopropylidene phenyl]Propionic acid	51±12
10	(R)2- [ 3' -isopropylidene ] phenyl]Propionic acid	43±18
			14	(S)2- [ 3' -isopropylidene ] phenyl]Propionic acid	50±9
7	(R, S), (R, S)2- [ 3' - (alpha-methyl-benzyl) phenyl]Propionic acid	54±4
			16	(R, S), (R, S)2- [ 3' - (alpha-dihydroxy-ethyl) phenyl]Propionic acid	57±6
18	(R, S)2- [ (2 ' - (2 ', 6 ' -dichlorophenyl) amino group]Phenylpropionic acids	52±3
			19	(R)2- [ (2 ' - (2 ', 6 ' -dichlorophenyl) amino group]Phenylpropionic acids	46±14
20	(S)2- [ (2 ' - (2 ', 6 ' -dichlorophenyl) amino group]Phenylpropionic acids	50±7
			6	(R, S)2- [ 3' - (alpha-ethyl-propyl) phenyl]Propionic acid	58±2
22	(R, S)2- [ (2 ' - (2 ', 6 ' -dichloro) phenoxy) phenyl]Propionic acid	41±9

The compounds listed above were moderately potent in the GRO-alpha induced PMN chemotaxis assay, suggesting a selective effect on the CXCR1 mediated pathway.

Particularly preferred compounds of the invention are compounds of formula (Ia) which have the additional property of effectively inhibiting GRO- α induced PMN chemotaxis; this activity makes these compounds therapeutically useful for IL-18 related pathologies that involve CXCR2 pathways specifically or in combination with CXCR1 signaling.

The following table lists compounds whose biological activity has a high potency for inhibiting PMN chemotaxis induced by IL-8 or the selective CXCR2 agonist GRO-. alpha.

Examples of some selective potent inhibitors of GRO- α are included in the table.

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 either the CXCR1IL-8 receptor or the CXCR2 GRO-alpha/IL-8 receptor may be useful in the treatment of certain pathologies described below.

	Biological activity data (percentage inhibition) of CXCR1 and CXCR2 receptors
				Examples	Name (R)	IL-8(c＝10M)	GRO-α(c＝10M)
24	(R)2- (4' -phenylsulfonylamino) phenylpropionic acid	49±11	33±11
				25	(R)2- (4' -Methanesulphonylamino) phenylpropionic acid	25±7	32±5
26	(R)2- [ 4' - (2 "-propane) sulfonylamino]Phenylpropionic acids	54±14	44±12
				27	(R)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid	8±10	40±14
28	(R)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid	60±10	24±8
				29	(R)2- [ 4' - (2 "-chloro) benzenesulfonylamino group]Phenylpropionic acids	-2±10	66±10
30	(R)2- [ 4' - (2 "-ethyl) benzenesulfonylamino group]Phenylpropionic acids	44±14	80±10
				31	(R)2- (4' -aminosulfonylamino) phenylpropionic acid	55±10	2±5
32	(R)2- (4' -phenylsulfonyloxy) phenylpropionic acid	28±11	25±10
				35	(R)2- [ 4' - (2 "-propane) sulfonyloxy group]Phenylpropionic acids	49±8	46±6
34	(R)2- (4' -trifluoromethanesulfonyloxy)) Phenylpropionic acids	62±7	59±10
				33	(R)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid	59±11	25±11
36	(R)2- [ 4' - (2 "-chloro) benzenesulfonyloxy]Phenylpropionic acids	25±7	65±10
				37	(R)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy]Phenylpropionic acids	45±13	70±10
38	(R)2- (4' -aminosulfonyloxy) phenylpropionic acid	65±10	57±7
				40	(R)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid	48±7	45±7
39	(R)2- (4' -phenylsulfonylmethyl) phenylpropionic acid	60±7	52±5

It has been demonstrated that compared to C5a (10)^-9M) or f-MLP (10)^-8M), all compounds of the invention have a high selectivity for inhibition of IL-8-induced chemotaxis.

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

In most cases, 10^-5To 10^-7The compounds of formula (I) in the M concentration range do not interfere with the stimulation of mouse macrophages by lipopolysaccharide (LPS, 1. mu.g/ml) to induce PGE production₂. 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 inhibiting prostaglandin synthesis is a macrophage stimulator enhancing TNF-alpha synthesis (induced by LPS or hydrogen peroxide), an important mediator of neutrophil activation, and a stimulator of cytokine IL-8 production.

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 injury 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 compounds for the treatment of psoriasis, ulcerative colitis, melanoma, Chronic Obstructive Pulmonary Disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and the prevention and treatment of injury caused by ischemia and reperfusion, and the use of these compounds in the manufacture of medicaments for the treatment of the above-mentioned diseases. 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: a binder 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 described above, the acid derivative represented by the general formula (I) in these compositions is 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.

In describing the compounds of the general formula (I) of this invention, the absolute configuration of any chiral substituent present in the substituent R ' of the compound is indicated by the common convention for the starting symbol (e.g., R ', S ', S ", etc.).

Abbreviations: THF represents tetrahydrofuran, DMF represents dimethylformamide, AcOEt represents ethyl acetate, HOBZ represents 1-hydroxybenzotriazole, and DCC represents dicyclohexylcarbodiimide.

Detailed Description

Materials and methods

General synthesis method of 2-aryl propionic acid and R enantiomer thereof represented by general formula I

12.0 g of anhydrous potassium carbonate (86.2mmol) were added, with stirring at room temperature and complete drying, to an 80.0mmol solution of (p, m, o) -hydroxyacetophenone (mono-or polysubstituted on the phenyl) in acetone (80 ml). The mixture was stirred at room temperature for 30 minutes. A solution of perfluorobutanesulfonyl fluoride (15.5 mL, 86.1mmol) in acetone (30 mL) was then added dropwise and the mixture refluxed for 2 hours. After cooling at room temperature, the solid was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (100 ml). The organic solution was washed with a saturated solution of potassium bicarbonate (20 ml) followed by a saturated solution of sodium chloride (20 ml). After drying over sodium sulfate and evaporation of the solvent, the corresponding perfluorobutanesulfonyl ester was obtained in a practically quantitative yield in the form of an oil, pure enough to be used in the next reaction.

A mixture of the resulting acetophenone perfluorobutanesulfonyl ester (80.0mmol), sulfur (2.95 g, 92.0mmol) and morpholine (8.0 mL, 92.0mmol) was refluxed for 6 hours. After cooling at room temperature, the solution was poured into a mixture of ice and 6N hydrochloric acid (40 ml). Extraction with dichloromethane (2 × 50 ml); the organic extracts were dried over sodium sulfate and the solvent evaporated to give crude butter which, after purification by silica gel chromatography (eluent n-hexane/ethyl acetate 9: 1), gave the corresponding morpholine as a clear oil (73% yield).

A solution of morpholine amide (58.0mmol) in glacial acetic acid (25.0 mL) was added to 37% hydrochloric acid (40 mL) and stirred under reflux for 16 h. After cooling at room temperature, the mixture was filtered and the precipitate was isolated. After evaporation of the filtrate, the residue was diluted with water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The organic extracts were combined, washed with a saturated solution of sodium chloride (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give an oil which crystallized from n-hexane to give the (p, m, o) -perfluorobutanesulfonate salt of 2-phenyl-propionic acid as a solid crystal (yield 90-93%). And then carrying out esterification reaction with concentrated sulfuric acid in heated absolute ethyl alcohol to generate corresponding ethyl ester with actual quantitative yield. To a solution of (p, m, o) -perfluorobutanesulfonyloxy-2-phenyl-acetic acid ethyl ester (e.g. 25mmol) in tetrahydrofuran (50 ml) cooled to 0.5 ℃ was slowly added 60% sodium hydride in small portions with a suspension of mineral oil (co-weight 0.6 g, 66.7 mmol). After 15 minutes, methyl iodide (1.88 ml; 30.2mmol) was added dropwise and the reaction was carried out at room temperature for 3.5 hours. Adding saturated ammonium chloride solution (40 ml) to stop the reaction; the solvent was evaporated under reduced pressure and the aqueous phase was extracted with dichloromethane (3 × 50 ml); the organic extracts were combined, washed with saturated sodium chloride solution (200 ml), dried over sodium sulfate and evaporated under reduced pressure to give a residue which, after purification by chromatography, gave the corresponding ethyl ester of (p, m, o) -perfluorobutanesulfonyloxy-2-phenyl-propionic acid as a solid (yield 70%).

Starting from ethyl (p, m, o) - (nonafluorobutanesulfonyloxy) -2-phenyl-propionate, the sulfonate salt was reacted with an organostannane to prepare the 2-aryl-propionic acid racemate represented by general formula I, according to the methods described by Mitchell T.N (Synthesis, 803, 1992) and Ritter K (Synthesis, 735, 1993).

The following compounds were prepared according to the above procedure:

example 1

2- [ 3' - (isopropylidene) phenyl]Propionic acid

The title acid was synthesized starting from ethyl 3' -perfluorobutanesulfonyloxy-2-phenylpropionate (7.63mmol) dissolved in N-ethylpyrrolidone (30 mL); to the mixture was added anhydrous lithium chloride (0.94 g, 22.9mmol), triphenylarsine (90 mg, 0.3mmol), and dipalladium tribenzylacetone (0.173 g, 0.15mmol of palladium). After standing at room temperature for 5 minutes, tributylisopropenyltin (2.83 g, 8.55mmol) was added and the solution was stirred at 90 ℃ for 5 hours. After the solution is cooled to room temperature, diluting the mixture with hexane, and adding a saturated solution of potassium fluoride; after filtration and separation of the two phases, the organic phase is dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography to give ethyl 2- [ 3' -isopropenylphenyl ] propionate (RitterK., Synthesis, 735, 1993and Mitchell T.N., Synthesis, 803, 1992).

To a solution of the ester in dioxane (5 ml) was added 1N sodium hydroxide (5 ml) and the solution was stirred at room temperature overnight. After evaporation of the organic solvent, the mixture was acidified with 2N hydrochloric acid to pH 2 until complete precipitation of the product, which was isolated by filtration as a white solid.

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；5.02(s，2H)；3.75(m，1H)；2.34(m，1H)；1.8-1.6(m，4H)；1.45(d，3H，J＝7Hz)；0.78(s，3H)。

Example 2

2- [ 3' - (alpha-ethyl-propenyl) phenyl]Propionic acid

The title acid was synthesized by reference to the above procedure starting from tributyl- (. alpha. -ethyl) propenyltin synthesized according to known methods (Ritter K., Synthesis, 735, 1993and Mitchell T.N., Synthesis, 803, 1992).

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；5.5(m，1H)；3.75(m，1H)；1.8-1.6(q，2H)；1.45(d，3H，J＝7Hz)；0.85(d，3H，J＝7Hz)；0.78(t，3H，J＝7Hz)。

Example 3

3- [ 3' - (1 "-styryl) phenyl]Propionic acid

The title acid was synthesized by reference to the above procedure starting from tributyl- (. alpha. -styryltin) synthesized according to known methods (Ritter K., Synthesis, 735, 1993and Mitchell T.N., Synthesis, 803, 1992).

¹H-NMR(CDCl₃)：δ11.0(bs，1H，COOH)；7.38-7.13(m，9H)；3.95(m，2H)；3.81(m，1H)；1.72(d，3H，J＝7Hz)。

Example 4

2- [ 3' -isobutenyl-phenyl]Propionic acid

The title acid was synthesized by reference to the above procedure starting from tributyl-isobutenyltin synthesized according to known methods (Ritter K., Synthesis, 735, 1993and Mitchell T.N., Synthesis, 803, 1992).

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；5.5(m，1H)；3.75(m，1H)；1.45(d，3H，J＝7Hz)；1.45(s，3H)；1.35(s，3H)。

Example 5

This embodiment discloses2- [ (3' -isopropyl) phenyl group]Propionic acidAnd (4) preparing.

A mixture of ethyl 2- [ 3' - (isopropylidene) phenyl ] propionate (1 g, 4.6mmol) obtained by the above-mentioned method, 95% ethanol (10 ml) and 10% palladium on charcoal (100 mg) was subjected to catalytic hydrogenation at room temperature under atmospheric pressure until the starting reagent disappeared (2 hours). The catalyst was filtered off with celite and after evaporation of the filtrate a clear oil (0.99 g, 4.5mmol) was obtained which was hydrolysed in a 1N solution of potassium hydroxide in ethanol (10 ml) at 80 ℃ for 2 hours. After cooling at room temperature, the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (20 ml) and extracted with water (3 × 10 ml); the aqueous phase was acidified to pH 2 with 2N hydrochloric acid and back-extracted with ethyl acetate (2 × 10 ml); the organic extracts were combined, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure to give 2- [ (3' -isopropyl) phenyl ] propanoic acid (0.75 g, 3.6 mmol).

¹H-NMR(CDCl₃)：δ10.5(bs，1H，COOH)；7.15-7.08(m，4H)；3.55(m，1H)；2.91(m，1H)；1.45(d，3H，J＝7Hz)；1.26(d，3H，J＝7Hz)。

The following compounds were prepared according to the same procedure:

example 6

(R, S)2- [ 3' - (alpha-ethyl-propyl) phenyl]Propionic acid

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；3.75(m，1H)；2.34(m，1H)；1.8-1.6(m，4H)；1.45(d，3H，J＝7Hz)；0.78(t，6H，J＝7Hz)。

Example 7

(R, S)3- [ 3' - (alpha-methyl) benzyl-phenyl]Propionic acid

¹H-NMR(CDCl₃)：δ11.0(bs，1H，COOH)；7.38-7.13(m，9H)；4.20(m，1H)；3.78(m，1H)；1.72(d，3H，J＝7Hz)；1.55(d，3H，J＝7Hz)。

Example 8

(R, S)2- [ 3' -isobutylphenyl]Propionic acid

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；3.78(m，1H)；2.50(d，2H，J＝7Hz)；1.9(m，1H)；1.45(d，3H，J＝7Hz)；0.98(d，6H，J＝7Hz)。

Example 9

(R, S)2- [ (3' -cyclohexylmethyl) phenyl]Propionic acid

The title acid was synthesized according to the procedure described above starting from cyclohexylmethylzinc bromide, the commercially available reagent and ethyl 3-perfluorobutanesulfonyloxy-2-phenylpropionate.

¹H-NMR(CDCl₃)：δ10.15(bs，1H，COOH)；7.1(s，1H)；7.25-7.35(m，3H，)；3.75(q，1H，J₁＝15Hz，J₂＝7Hz)；2.48(d，2H，J＝7Hz)；1.77-1.70(m，4H)；1.60-1.45(d，3H，J＝7Hz+m，1H)；1.30-1.10(m，4H)；1.08-0.90(m，2H)。

The corresponding esters were prepared stereospecifically with R-pantolactone (via the enone intermediate) according to the methods described by Myers a.g. et al (j.am.chem.associates, 119, 6496, 1997) and larsenr.d. et al (j.am.chem.associates, 111, 76501989), and the general formula phi-Ar was prepared_b-C(CH₃)H-CO₂Each racemate of the acid represented by H is converted to the R enantiomer.

The following compounds were prepared according to this method:

example 10

(R) -2- [ (3' -isopropyl) phenyl group]-propionic acid

[α]_D＝-23(c＝0.5；CH₂Cl₂)

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.15-7.10(m，4H)；3.65(m，1H)；2.90(m，1H)；1.45(d，3H，J＝7Hz)；1.32(d，3H，J＝7Hz)。

Example 11

(R) -2- [ 3' - (1 "-ethyl-propyl) phenyl]Propionic acid

[α]_D＝-29(c＝0.5；CH₂Cl₂)

¹H-NMR(CDCl₃)：δ10.25(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；3.75(m，1H)；2.34(m，1H)；1.8-1.6(m，4H)；1.45(d，3H，J＝7Hz)；0.78(t，6H，J＝7Hz)。

Example 12

(R)2- [ 3' -isobutylphenyl group]Propionic acid

[α]_D＝-35(c＝0.5；CH₂Cl₂)

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；3.78(m，1H)；2.50(d，2H，J＝7Hz)；1.9(m，1H)；1.45(d，3H，J＝7Hz)；0.98(d，6H，J＝7Hz)。

Example 13

(R), (R ', S ') -3- [ (3 ' -alpha-methyl) phenylmethyl phenyl]Propionic acid

[α]_D＝-49(c＝0.5；CH₂Cl₂)

¹H-NMR(CDCl₃)：δ11.0(bs，1H，COOH)；7.38-7.13(m，9H)；4.20(m，1H)；3.78(m，1H)；1.72(d，3H，J＝7Hz)；1.55(d，3H，J＝7Hz)。

The S enantiomer was prepared stereoscopically in the same manner as above, but using S-pantolactone:

example 14

(S) -2- [ (3' -isopropyl) phenyl group]-propionic acid

[α]_D＝+24.2(c＝0.5；CH₂Cl₂)

¹H-NMR(CDCl₃)：δ10.1(bs，1H，COOH)；7.12-7.07(m，4H)；3.64(m，1H)；2.91(m，1H)；1.45(d，3H，J＝7Hz)；1.30(d，3H，J＝7Hz)。

Example 15

(R)，(R′，S′))-2-[(3′-α-hydroxybenzyl) phenyl]Propionic acid

To a solution of R (-) ketoprofen (0.254 g, 1mmol) in ethanol (5 ml) was added triethylamine (0.12 g, 1mmol) and catalyst (5% palladium on charcoal, 0.025 g); the mixture was subjected to hydrogenation reaction at room temperature and atmospheric pressure for 3 hours. After filtering off the catalyst on a celite pad, the filtrate is evaporated and the residue is purified with a chromatography column. The product was obtained as a white solid (yield 85%).

[α]_D＝-45.7(c＝1；CHCl₃)

¹H-NMR(CDCl₃)：δ7，41-7.3(m，3H)；7.31-7.14(m，6H)；5.75(s，1H)；4.02(bs，1H，OH)；3.68(q，1H，J＝7Hz)；1.4(d，3H，J＝7Hz)。

With reference to the procedure of example 15, starting from (R, S) -2- [ (3' -acetyl) phenyl ] -propionic acid, the following compounds were prepared:

example 16

(R, S), (R, S)2- [ 3' - (alpha-hydroxy-ethyl) phenyl]Propionic acid

¹H-NMR(CDCl₃)：δ7，40-7.15(m，4H)；4.90(q，1H，J＝7Hz)；3.78(q，1H，J＝7Hz)；1.55(m，6H)。

Example 17

(R), (R ', S ') -2- [3 ' -alpha-hydroxy-alpha-methylbenzyl]Phenyl radical]Propionic acid

To a solution of the methyl ester of R (-) -ketoprofen (0.269 g, 1mmol) in diethyl ether (10 mL) was added a 3.0M solution of methylmagnesium bromide in diethyl ether (2 mmol); the resulting solution was refluxed for 2 hours. After the mixture had cooled, the organic phase was washed with 5% sodium dihydrogen phosphate solution (2X 10ml), dried over sodium sulfate and evaporated in vacuo. The resulting residue was redissolved in a methanol/1N sodium hydroxide 1: 1 mixture (5 ml) and the solution was stirred overnight. The organic solvent was removed in vacuo and the aqueous solution was acidified to pH 2; the precipitate formed is filtered off and washed with water. To give (R), (R ', S ') -2- [3 ' - α -hydroxy- α -methylbenzyl ] phenyl ] propionic acid as a white powder.

[α]_D＝-45.3(c＝1；CHCl₃)

¹H-NMR(CDCl₃)：δ7，41-7.3(m，3H)；7.31-7.14(m，6H)；4.02(bs，1H，OH)；3.68(q，1H，J＝7Hz)；1.4(d，3H，J＝7Hz)。

(R, S)2- [2 '- (2', 6 '-dichlorophenyl) aminophenylpropionic acid (example 18), (R)2- [ 2' - (2 ', 6' -dichlorobenzene Yl) Aminophenylpropionic acid (example 19) and (S)2- [2 ' - (2 ', 6 ' -dichlorophenyl) Aminophenylpropionic acid (example) Example 20) preparation of

According to Geigy, JR; british patent 1.132.318(30.10.1968) discloses the preparation of the compound of example 18 as a racemic mixture. Optical resolution with R (+) -N-methylbenzylamine was carried out by the method disclosed by Akguen et al (Arzneim. Forsch. 19' 96, 46: 9891-894) to give the compounds of examples 19 and 20.

Example 21

Preparation of (R, S) - (2- (3' -benzyl) phenylpropionic acid

1.2-bromophenylacetic acid methyl ester

To a solution of 2-bromophenylacetic acid (2 g, 9.30mmol) in methanol (10 ml) was added a catalytic amount of concentrated sulfuric acid (3 drops); the solvent was stirred at room temperature for 18 hours and then evaporated. The residual oil was dissolved in diethyl ether (10 ml); the organic phase was washed with water (3X 10ml), dried over sodium sulphate and evaporated to give 2.12 g of methyl ester as a clear oil.

The yield is as follows: quantification of

¹H-NMR(CDCl₃)：δ7.60(d，1H，J＝7Hz)；7.28-7.20(m，2H)；7.1-7.0(m，1H)；3.8(s，2H)；3.72(s，3H)。

2.2- (2' -) bromophenyl propionic acid methyl ester

To a solution of diisopropylamine (1.66 ml, 11.8mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise a solution of n-butyllithium in n-hexane (1.6M, 7.4 ml, 11.8mmol) under argon vapor and cooling to-10 ℃; the addition is carried out at a temperature not higher than 0 ℃. After the addition was complete, the mixture was stirred at-4 ℃ for 30 minutes, and methyl 2-bromophenylacetate (1.9 g, 8.30mmol) in dry tetrahydrofuran (8 ml) was added. When the addition was complete, the mixture was stirred at room temperature for 1 hour. The mixture was cooled to-2 ℃ and methyl iodide (0.81 ml, 12.75mmol) was added. The resulting mixture was stirred at room temperature for 2 hours until the starting product disappeared; the tetrahydrofuran was evaporated to dryness and the residue was dissolved in chloroform (10 ml) and washed with 1N hydrochloric acid (3 × 10ml) followed by a saturated solution of sodium chloride (2 × 10 ml). Drying over sodium sulphate and evaporation under reduced pressure gave a dark red oily residue (1.95 g, 8.02mmol) of sufficient purity to be used in the next step.

The yield is as follows: 96 percent

¹H-NMR(CDCl₃)：δ7.60(d，1H，J＝7Hz)；7.30-7.26(m，2H)；7.2-7.15(m，1H)；4.25(q，1H，J＝7Hz)；3.75(s，3H)；1.75(d，3H，J＝7Hz)。

3.2- (2' -) Phenylmethylphenylpropionic acid methyl ester

Zinc powder (2.412 g, 36.9mmol) was charged in a flask under an argon atmosphere. The flask was cooled to 0-4 ℃ with an ice/water bath and a solution of benzyl bromide (2.109 g, 12.3mmol) in dry tetrahydrofuran (10 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 3 hours until the disappearance of the starting product. Also, tetrakis (triphenylphosphine) palladium (410 g, 0.35mmol) and methyl 2- (2' -bromophenyl) propionate (1.9 g, 7.8mmol) were charged in another flask under an argon atmosphere, the previously obtained organotin solution was dropped, and after the dropping, the solution was heated to reflux temperature and held for 18 hours. After cooling at room temperature, the mixture was diluted with 0.1N hydrochloric acid (10 ml) and diethyl ether (15 ml) was added; the phases were separated by shaking and the aqueous phase was extracted again with ether (3X 15 ml); the organic phases were combined, washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate and evaporated under reduced pressure to give a waxy residue which, after trituration with isopropyl ether overnight and vacuum filtration, gave methyl 2- (2' -) phenylmethylphenylpropionate (1.52 g 6mmol) as a white solid.

The yield is as follows: 77 percent

¹H-NMR(CDCl₃)：δ7.50-7.25(m，5H)；7.24-7.15(m，2H)；7.10-7.05(m，2H)；4.25(q，1H，J＝7Hz)；4.15(s，2H)；3.75(s，3H)；1.55(d，3H，J＝7Hz)。

(R, S)2- (2' -phenylmethyl phenyl) propanoic acid

Methyl 2- (2' -phenylmethylphenyl) propanoate (1.5 g, 5.9mmol) was dissolved in methanol (5 ml). To this solution was added 1M sodium hydroxide solution (7.1 ml), and the resulting solution was refluxed for 3 hours; and stirred at room temperature for 18 hours. Then, methanol was evaporated under reduced pressure and the residue was dissolved in water; the aqueous phase was adjusted to pH 1 with 1N salt and extracted with ether (3 × 15 ml). The organic extracts were combined, washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate and evaporated under reduced pressure to give (R, S)2- (2' -phenylmethyl) propionic acid (1.06 g, 4.42mmol), a clear butter.

The yield is as follows: 75 percent of

¹H-NMR(CDCl₃)：δ9.25(bs，1H，COOH)；7.55-7.35(m，5H)；7.24-7.15(m，2H)；7.10-7.05(m，2H)；4.25(q，1H，J＝7Hz)；4.15(s，2H)；1.50(d，3H，J＝7Hz)。

The following compounds were prepared according to the same procedure:

example 22

(R, S)2- [ 2' - (2 "-chloro) benzyl]Phenylpropionic acids

¹H-NMR(CDCl₃)：δ10.0(bs，1H，COOH)；7.40-7.35(m，1H)；7.34-7.25(m，3H)；7.20-7.15(m，2H)；7.10-7.00(m，1H)；6.95-6.80(m，1H)；4.20(q，1H，J＝7Hz)；4.12(s，2H)；1.53(d，3H，J＝7Hz)。

Example 23

(R, S)2- [2 ' - (2 ', 6 ' -dichloro) benzyl]Phenylpropionic acids

¹H-NMR(CDCl₃)：δ9.55(bs，1H，COOH)；7.40-7.30(d，2H，J＝8Hz)；7.27-7.15(m，4H)；6.70-6.60(d，1H，J＝8Hz)；4.27(s，2H)；4.15(q，1H，J＝7Hz)；1.55(d，3H，J＝7Hz)。

Example 24

Preparation of (R, S) - (2- (2' -phenoxy) phenylpropionic acid

1.2- (2' -hydroxy) phenylpropionic acid methyl ester

To a solution of 2- (2' -hydroxy) phenylacetic acid (2 g, 12mmol), prepared as described in the literature, in methanol (10 ml) was added a catalytic amount of concentrated sulfuric acid (3 drops); the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residual oil was dissolved in ether (10 ml); the organic phase was washed with water (3X 10ml), dried over sodium sulphate and evaporated to give 2.17 g (12mmol) of methyl ester as a clear oil.

The yield is as follows: quantification of

¹H-NMR(CDCl₃)：δ7.30-7.26(m，2H)；7.2-7.15(m，1H)；6.75(d，1H，J＝7Hz)；5.55(bs，1H，OH)；4.15(q，1H，J＝7Hz)；3.70(s，3H)；1.75(d，3H，J＝7Hz)。

2.2- [ 2' - (2 "-chloro) -phenoxy ] phenylpropionic acid methyl ester

Methyl 2- (2' -hydroxy) phenylpropionate (2 g, 11.1mmol) was dissolved in chloroform (60 ml); 2-Chlorophenylboronic acid (7.71 g, 49.3mmol), copper acetate (3.24 g, 17.82mmol) and triethylamine (7.71 ml, 5.54mmol) were added successively. The resulting solution was refluxed for 24 hours until disappearance of the starting product. After cooling at room temperature, the salts were filtered off on a celite cake; the filtrate was washed with 2N hydrochloric acid (3 × 50 ml) and saturated sodium chloride solution (2 × 35 ml); the organic phase was dried over sodium sulfate and evaporated under reduced pressure to give a dark oily residue which was purified by flash chromatography (chloroform/methanol 9: 1 eluent). Methyl 2- [ 2' - (2 "-chloro) phenoxy ] phenylpropionate (1.38 g, 5mmol) was recovered as a clear oil.

The yield is as follows: 45 percent of

¹H-NMR(CDCl₃)：δ7.45-7.22(m，4H)；7.15-7.08(m，2H)；7.05-6.95(m，2H)；6.92-6.88(m，1H)；4.28(q，1H，J＝7Hz)；3.85(s，3H)；1.65(d，3H，J＝7Hz)。

(R, S)2- [ 2' - (2 "-chloro) phenoxy ] phenylpropionic acid

Methyl 2- [ 2' - (2 "-chloro) phenoxy ] phenylpropionate (1.3 g, 4.7mmol) was dissolved in dioxane (15 mL). To the solution was added 1M sodium hydroxide (4.7 ml), and the solution was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was dissolved with water; the aqueous phase was adjusted to pH 1 with concentrated sulfuric acid and extracted with chloroform (3 × 15 ml). The organic extracts were combined, washed with a saturated solution of sodium bicarbonate followed by a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure to give (R, S)2- [ 2' - (2 "-chloro) phenoxy ] phenylpropionic acid (1.18 g, 4.5mmol) as a clear yellow waxy solid.

The yield is as follows: 96 percent

¹H-NMR(CDCl₃)：δ7.45-7.22(m，4H)；7.15-7.08(m，2H)；7.05-6.95(m，2H)；6.92-6.88(m，1H)；3.95(q，1H，J＝7Hz)；1.50(d，3H，J＝7Hz)。

The following compounds were prepared according to the same procedure:

example 25

(R.S)2- [2 ' - (2 ', 6 ' -dichloro) phenoxy]Phenylpropionic acids

¹H-NMR(CDCl₃)：δ9.40(bs，1H，COOH)；7.40-7.30(d，2H，J＝8Hz)；7.27-7.15(m，4H)；6.70-6.60(d，1H，J＝8Hz)；3.90(q，1H，J＝7Hz)；1.55(d，3H，J＝7Hz)。

Example 26

Preparation of 2- (3-methylindan-5-yl) propionic acid

The desired acid was synthesized according to the literature using 6-methoxy-1-indanone (a commercially available reagent) as the starting material. Specifically, 6-methoxy-1-indanone and triphenylphosphine bromide are subjected to a Wittig reaction (yield is 80%) to generate a methylene derivative, and the methylene derivative is reduced to a methyl indanoyl derivative through hydrogenation catalysis (hydrogen/palladium is 5%, atmospheric pressure; yield is 95%). Treating the substrate with boron tribromide to remove phenol group protection (the yield is more than 95%); this intermediate was processed with trifluoromethanesulfonic anhydride to give the corresponding trifluoromethanesulfonate salt (yield 80%), which was cross-coupled with methyl 2-tributylstannate alkyl acrylate (formerly known as the Stille reaction). The reaction has high yield (40%) and can produce 2- (3-methyl indan-5-yl) propionic acid in high yield after catalytic hydrogenation reduction of double bond and saponification reaction with potassium hydroxide/ethanol under known conditions.

The yield is as follows: 90 percent of

¹H-NMR(CDCl₃): δ 7.15-7.05(m, 3H); 3.75(m, 1H); 3.15(m, 1H); 2.95-2.70(m, 2H); 2.32(m, 1H); 1.78-1.58(m, 1H); 1.50(d, 3H, J ═ 7 Hz); 1.35(d, 3H, J ═ 7 Hz). Synthesis of (S) and (R) -2- [ (4' -aryl/alkylsulfonylamino) phenyl of the general formula Ia]General procedure for propionic acid

The separation of the two enantiomers of the commercially available reagent 2- (4' -nitrophenyl) propionic acid was obtained by crystallization of the corresponding S- (-) or R- (+) -alpha-phenylethylammonium salt in ethanol solution according to the method described by Akgun H.et al (Arzneim. -Forsch./Dmg Res., 46(II), Nr.9, 891-.

(S) -2- (4' -nitrophenyl) propionic acid

[α]_D43.9 ° (c 2; absolute ethanol);

¹H-NMR(CDCl₃)：δ8.15(d，2H，J＝7Hz)；7.47(d，2H，J＝7Hz)；3.95(bs，1H，COOH)；3.78(m，1H)；1.52(d，3H，J＝7Hz)。

(R) -2- (4' -nitrophenyl) propionic acid

[α]_D-43.5 ° (c-2; absolute ethanol);

¹H-NMR(CDCl₃)：δ8.12(d，2H，J＝7Hz)；7.49(d，2H，J＝7Hz)；3.90(bs，1H，COOH)；3.81(m，1H)；1.50(d，3H，J＝7Hz)。

4' -Nitrophenylpropionic acid methyl ester

(R) -2- (4' -nitrophenyl) propionic acid (4mmol) was dissolved in methanol (40 mL) and 96% sulfuric acid (0.5 mL) was added dropwise. The resulting solution was stirred overnight. After evaporation of the solvent, the oily residue is dissolved in diethyl ether, the organic phase is washed with a saturated solution of sodium bicarbonate (2 × 30 ml), dried over sodium sulfate and evaporated under reduced pressure to give the desired product, a pale yellow oil.

(R) -2- (4' -Nitrophenyl) propionic acid methyl ester

[α]_D-48.3 ° (c-2; absolute ethanol);

¹H-NMR(CDCl₃)：δ8.12(d，2H，J＝7Hz)；7.49(d，2H，J＝7Hz)；3.75(m，1H)；3.70(s，3H)；1.51(d，3H，J＝7Hz)。

(S) -2- (4' -Nitrophenyl)) Propionic acid methyl ester

[α]_D-49 ° (c-2; absolute ethanol);

¹H-NMR(CDCl₃)：δ8.11(d，2H，J＝7Hz)；7.49(d，2H，J＝7Hz)；3.78(m，1H)；3.68(s，3H)；1.51(d，3H，J＝7Hz)。

(S) and (R) -methyl 2- (4' -aminophenyl) propionate

Both compounds are prepared by reducing the nitro group as described by Ram s. et al (Tetrahedron lett., 25, 3415(1984)) and Barrett a.g.m. et al (Tetrahedron lett., 29, 5733 (1988)).

(S) -2- (4' -aminophenyl) propionic acid methyl ester

[α]_D16.5 ° (c 2; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.85(d，2H，J＝7Hz)；7.45(d，2H，J＝7Hz)；3.81(m，1H)；3.67(s，3H)；1.62(d，3H，J＝7Hz)。

(R) -2- (4' -amino) propionic acid methyl ester

[α]_D-17.1 ° (c ═ 2; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.85(d，2H，J＝7Hz)；7.45(d，2H，J＝7Hz)；3.81(m，1H)；3.66(s，3H)；1.65(d，3H，J＝7Hz)。

(R) -2- [ (4' -aryl/alkylsulfonylamino) phenyl]Propionic acid

To a solution of the above methyl (R) -2- (4' -aminophenyl) propionate (10mmol) in acetone (20 mL) was added dry pyridine (15mmol) or equivalent organic/inorganic base and arylsulfonyl chloride (or alkylsulfonyl chloride) (10mmol), and the resulting solution was stirred overnight. After evaporation of the solvent, the oily residue is dissolved in chloroform (30 ml), the organic phase is washed with water (3 × 30 ml), dried over sodium sulfate, evaporated, treated overnight with room temperature isopropyl ether and the precipitate is filtered off in vacuo to give the desired pure product as a solid.

To a solution of methyl ester (6mmol) in chloroform (25 ml) was added 2N sodium hydroxide (12mmol) and the resulting mixture was stirred at room temperature overnight. Evaporating methanol, and dripping 12N hydrochloric acid to acidify the aqueous alkaline layer to pH 2; ethyl acetate was added and the two phases were separated. The organic extracts were washed back with water (3X 20 ml), dried over sodium sulfate, evaporated under reduced pressure, treated overnight with n-hexane at room temperature and the precipitate was filtered off in vacuo to give the desired pure product as a solid (yield 75% -100%).

The following compounds were synthesized according to the above procedure:

example 27

(R)2- (4' - (benzenesulfonylamino) phenylpropionic acid

[α]_D-56.5 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ9.40(bs，1H，SO₂NH)；7.70(d，2H，J＝8Hz)；7.30(m，3H)；7.05(d，2H，J＝8Hz)；6.92(d，2H，J＝8Hz)；3.45(q，1H，J＝7Hz)；1.22(d，3H，J＝7Hz)。

example 28

(R)2- (4' -Methanesulphonylamino) phenylpropionic acid

[α]_D-124.3 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.48(bs，1H，SO₂NH)；7.35(d，2H，J＝8Hz)；7.18(d，2H，J＝8Hz)；6.55(bs，1H，SO₂NH)；3.80(q，1H，J＝7Hz)；3.00(s，3H)；1.55(d，3H，J＝7Hz)。

example 29

(R)2- [ 4' - (2 "-propane) sulfonylamino]Phenylpropionic acids

[α]_D-110 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.21(d，2H，J＝8Hz)；7.05(d，2H，J＝8Hz)；6.20(bs，1H，SO₂NH)；3.65(q，1H，J＝7Hz)；3.23(m，1H)；1.50(d，3H，J＝7Hz)；1.30(d，6H，J＝7Hz)。

example 30

(R)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

[α]_D-84.5 ° (c-1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.25-7.05(m，4H)；7.00(bs，1H，SO₂NH)；3.60(q，1H，J＝7Hz)；1.41(d，3H，J＝7Hz)。

example 31

(R)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

[α]_D-47 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.53(m，5H)；7.31(d，2H，J＝7Hz)；7.15(bs，1H，SO₂NH)；7.02(d，2H，J＝7Hz)；4.65(s，2H)；3.80(m，1H)；1.55(d，3H，J＝7Hz)。

example 32

(R)2- [ 4' - (2 "-chloro) benzenesulfonylamino group]Phenylpropionic acids

[α]_D-81.5 ° (c-1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.95(d，1H，J＝8Hz)；7.40(m，2H)；7.22(m，1H)；7.10(m，2H)；6.95(m，2H+SO₂NH)；3.55(q，1H，J＝7Hz)；1.35(d，3H，J＝7Hz)。

example 33

(R)2- [ 4' - (2 "-ethyl) benzenesulfonylamino group]Phenylpropionic acids

Preparation of 2-ethyl benzene sulfonyl chloride

The corresponding sulfonic acids were prepared as described by Trhanovavsky W.S. according to the method described ("Oxidation of organic chemistry", Vol.5-D, 201-203, college publishers, London, 1982) using commercially available 2-ethylbenzenethiol as starting material. The sulfonic acid is treated with excess thionyl chloride to give 2-ethylbenzenesulfonyl chloride of purity suitable for the condensation reaction of R (-) -2- (4' -aminophenyl) methyl propionate.

[α]_D-95 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ9.30(bs，1H，SO₂NH)；7.70(d，2H，J＝8Hz)；7.25(m，4H)；7.08(d，2H，J＝8Hz)；3.41(q，1H，J＝7Hz)；2.70(q，2H，J＝8Hz)；1.42(d，3H，J＝8Hz)；1.22(d，3H，J＝7Hz)。

example 34

(R)2- (4' -aminosulfonylamino) phenylpropionic acid

[α]_D-110 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.95(d，2H，J＝8Hz)；7.54(bs，2H，NSO₂NH ₂)；6.98(m，2H+SO₂NH)；3.57(q，1H，J＝7Hz)；1.30(d，3H，J＝7Hz)。

general procedure for the Synthesis of (S) and (R) -2- [ (4' -aryl/alkylsulfonyloxy) phenyl ] propanoic acids of general formula Ia

The separation of the two enantiomers of the commercially available reagent 2- (4' -hydroxyphenyl) propionic acid was obtained by crystallization of the corresponding S- (-) or R- (+) -alpha-phenylethylammonium salt in ethanol solution according to the method described by Akgun H.et al (Arzneim. -Forsch./Dmg Res., 46(II), Nr.9, 891-.

(S) -2- (4' -hydroxyphenyl) propionic acid

[α]_D12 ° (c ═ 2; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.31(d，2H，J＝7Hz)；7.05(d，2H，J＝7Hz)；6.25(bs，1H，OH)；3.80(q，1H，J＝7Hz)；1.52(d，3H，J＝7Hz)。

(R) -2- (4' -hydroxyphenyl) propionic acid

[α]_D12.5 ° (c 2; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.30(d，2H，J＝7Hz)；7.07(d，2H，J＝7Hz)；6.35(bs，1H，OH)；3.75(q，1H，J＝7Hz)；1.50(d，3H，J＝7Hz)。

(R) and (S) -methyl 2- (4' -hydroxyphenyl) propionate

(2R) -2- (4' -hydroxyphenyl) propionic acid (4mmol) was dissolved in methanol (40 ml), and concentrated sulfuric acid (0.5 ml) was added dropwise. The resulting solution was stirred overnight. After evaporation of the solvent, the oily residue is dissolved in diethyl ether, the organic phase is washed with a saturated solution of sodium bicarbonate (2 × 30 ml), dried over sodium sulfate and evaporated under reduced pressure to give the desired product, a pale yellow oil.

(R) methyl 2- (4' -hydroxyphenyl) propionate

[α]_D-78 ° (c-2; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.32(d，2H，J＝7Hz)；7.10(d，2H，J＝7Hz)；6.40(bs，1H，OH)；3.70(m，4H)；1.53(d，3H，J＝7Hz)。

(R)2- [ (4' -aryl/alkylsulfonyloxy) phenyl]Propionic acid

A mixture of methyl (2R) -2- (4' -hydroxyphenyl) propionate (2mmol) above with arylsulfonyl chloride (or alkylsulfonyl chloride) (2mmol) and dried pyridine (1 mL) or equivalent organic/inorganic base was heated at 60 ℃ for 24 hours. After cooling at room temperature, the reaction mixture was poured into 1N hydrochloric acid (5 ml) and the aqueous solution was extracted with dichloromethane (3 × 10 ml). The organic extracts were collected, washed back with 1N sodium hydroxide (2X 10ml), dried over sodium sulfate and evaporated under reduced pressure to give a crude residue which was used in the next step in purity (80-92% yield).

A mixture of crude methyl ester (1.85mmol), glacial acetic acid (2.5 mL) and 37% hydrochloric acid (0.5 mL) was refluxed for 18 hours. All solvents were evaporated, the oily residue was dissolved in dichloromethane (5 ml), the organic phase was washed with 1N sodium hydroxide (2 × 5 ml) and water (2 × 10ml), dried over sodium sulfate and evaporated under reduced pressure to give pure (2R) aryl (or alkyl) sulfonyloxyphenylpropionic acid in quantitative yield.

The following compounds were synthesized according to the above procedure:

example 35

(R)2- (4' - (phenylsulfonyloxy) phenylpropionic acid

[α]_D-66.2 ° (c-1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.92(d，2H，J＝7Hz)；7.70(t，1H，J＝7Hz)；7.57(t，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；6.95(d，2H，J＝7Hz)；3.75(q，1H，J＝7Hz)；1.50(d，3H，J＝7Hz)。

example 36

(R)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

[α]_D-84.6 ° (c-1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.50(m，5H)；7.28(d，2H，J＝7Hz)；7.05(d，2H，J＝7Hz)；4.53(s，2H)；3.77(m，1H)；1.52(d，3H，J＝7Hz)。

example 37

(R) 2-4' -trifluoromethanesulfonyloxy) phenylpropionic acid

[α]_D-28.5 ° (c-1; methanol);

¹H-NMR(CDCl₃)：δ7.45(d，2H，J＝7Hz)；7.22(d，2H，J＝7Hz)；3.82(q，1H，J＝7Hz)；1.51(d，3H，J＝7Hz)。

example 38

(R)2- [ 4' - (2 "-propane) sulfonyloxy group]Phenylpropionic acids

[α]_D-42.8 ° (c ═ 1; methanol);

¹H-NMR(CDCl₃)：δ7.41(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；3.82(q，1H，J＝7Hz)；3.45(q，1H，J＝7Hz)；1.52(m，9H)。

example 39

(R)2- [ 4' - (2 "-chloro) -benzenesulfonyloxy]Phenylpropionic acids

[α]_D-43 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.90(d，1H，J＝8Hz)；7.44(m，2H)；7.20(m，1H)；7.12(m，2H)；6.95(d，2H，J＝8Hz)；3.52(q，1H，J＝7Hz)；1.38(d，3H，J＝7Hz)。

example 40

(R)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy]Phenylpropionic acids

Preparation of 2-ethyl benzene sulfonyl chloride

The sulfonic acid was prepared from commercially available 2-ethylbenzenethiol as a starting material by the method described in Trhanovavsky W.S. (Vol.5-D, 201-203, academic Press, London, 1982). The sulfonic acid is treated with excess thionyl chloride to give 2-ethylbenzenesulfonyl chloride of purity suitable for the condensation reaction of R (-) -2- (4' -hydroxyphenyl) propionic acid methyl ester.

[α]_D-104 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.71(d，2H，J＝8Hz)；7.25(m，4H)；7.12(d，2H，J＝8Hz)；3.44(q，1H，J＝7Hz)；2.71(q，2H，J＝8Hz)；1.45(d，3H，J＝8Hz)；1.20(d，3H，J＝7Hz)。

EXAMPLE 41

(R)2- (4' -aminosulfonyloxy) phenylpropionic acid

[α]_D-91.5 ° (c-1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.95(d，2H，J＝8Hz)；7.84(bs，2H，NSO₂NH ₂)；6.95(d，2H，J＝8Hz)；3.61(q，1H，J＝7Hz)；1.35(d，3H，J＝7Hz)。

general procedure for the Synthesis of (S) and (R) -2- [ (4' -aryl/alkylsulfonylmethyl) phenyl ] propionic acid of the general formula Ia

Example 42

(R)2- (4' -phenylsulfonylmethyl) phenylpropionic acid

The title product was prepared by a multistep synthesis starting from commercially available (R) -2-phenylpropionic acid. (R) -2- [ (4' -chloromethyl) phenyl ] propanoic acid is prepared in good yield by reference to the procedure described in example 4 of European patent EP 0889020. The acid was converted to the methyl ester by conventional means, the ester was added to the cooled mixture of benzenethiol/potassium tert-butoxide/18-crown-6 (1: 1.1: 0.95), reacted overnight and after customary work-up (washing with water, drying over sodium sulfate, evaporation of the solvent), the pure benzenethiomethyl derivative was isolated and used in the next oxidation step. The desired product can be isolated in a better final yield (65% yield starting from (R) -2- [ (4' -chloromethyl) phenyl ] propionic acid) by oxidizing the relevant sulfone with 2 equivalents of 3-chloroperbenzoic acid and working up with sodium hydroxide/dioxane at room temperature.

[α]_D-125 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.90(m，2H)；7.44-7.20(m，3H)；7.12(d，2H，J＝8Hz)；6.95(d，2H，J＝8Hz)；3.72(s，2H)；3.55(q，1H，J＝7Hz)；1.43(d，3H，J＝7Hz)。

example 43

(R)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

Starting from methyl (R) -2- [ (4 '-chloromethyl) phenyl ] propanoate, the procedure described in U.S. Pat. No. 3, 5,245,039(14/09/1993) gave the relevant (R) -2- [ (4' -thiomethyl) phenyl ] propanoic acid in very high yields (85%). Treatment of the thiolate with commercially available iodotrifluoromethane (generated "in situ" with 1 equivalent of potassium tert-butoxide) affords the trifluoromethanesulfonyl derivative. The sulfone derivative is then oxidized (treated with 2 equivalents of 3-chloroperbenzoic acid) and the resulting ester is hydrolyzed with sodium hydroxide/dioxane at room temperature, allowing the desired product to be isolated in good final yield (47% yield starting from (R) -2- [ (4' -chloromethyl) phenyl ] propionic acid).

[α]_D-86 ° (c ═ 1; absolute ethanol);

¹H-NMR(CDCl₃)：δ7.14(d，2H，J＝8Hz)；7.02(d，2H，J＝8Hz)；3.85(s，2H)；3.51(q，1H，J＝7Hz)；1.48(d，3H，J＝7Hz)。

the structures of the example compounds are listed below.

Claims (10)

1. Use of (R, S) -2-aryl-propionic acid compounds of formula (I) and their (R) and (S) enantiomers, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease, bullous pemphigoid, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of injury caused by ischemia and reperfusion:

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

ar is a benzene ring substituted with the following groups,

-a group in position 3 selected from C₁-C₅Linear or branched C optionally substituted by alkoxycarbonyl₁-C₅Alkyl radical, C₂-C₅-alkenyl or C₂-C₅Alkinyl, substituted or unsubstituted phenyl, straight or branched C₁-C₅Hydroxyalkyl, aryl-hydroxymethyl, or straight or branched C in position 3₁-C₅The alkyl group, together with the substituent at the para-or ortho-position and the benzene ring, forms a saturated or unsaturated, substituted or unsubstituted bicyclic aryl group; or

-a group in position 4 selected from C₁-C₅-acyloxy, substituted or unsubstituted benzoyloxy, C₁-C₅-acylamino, substituted or unsubstituted benzoylamino, C₁-C₅-sulfonyloxy, substituted or unsubstituted phenylsulfonyloxy, C₁-C₅Alkanesulfonylamino, substituted or unsubstituted benzenesulfonylamino, C₁-C₅Alkanesulfonylmethyl, substituted or unsubstituted benzenesulfonylmethyl, C₃-C₆-a cycloalkyl group; 2-furyl; 3-tetrahydrofuranyl; 2-thiophenyl; 2-tetrahydrothiophenyl or C₁-C₈(alkanoyl, cycloalkanoyl, aralkanoyl) -C₁-C₅Alkylamino, such as acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino; or

-a group in position 2 selected from substituted or unsubstituted arylmethyl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylamino, wherein the substituents on the aryl group are selected from C₁-C₄Alkyl radical, C₁-C₄-alkoxy, chloro, fluoro and/or trifluoromethyl.

2. The use of claim 1, wherein: ar is a benzene ring substituted in position 3 with a group selected from the group consisting of isopropyl-1-en-1-yl, ethyl, isopropyl, pent-2-en-3-yl, pent-3-yl, 1-phenyl-ethen-1-yl,. alpha. -methylbenzyl,. alpha. -hydroxybenzyl,. alpha. -hydroxyethyl,. alpha. -hydroxypropyl, bicyclic aryl structures such as 3-methyl-indan-5-yl, 3-methyl-indan-7-yl, 8-methyl-tetrahydronaphthalen-2-yl, 5-methyl-tetrahydronaphthalen-1-yl;

or Ar is a benzene ring substituted in the 4-position with a group selected from the group consisting of trifluoromethanesulfonyloxy, 2-propanesulfonyloxy, phenylmethylsulfonyloxy, benzenesulfonyloxy, 2 '-ethylbenzenesulfonyloxy, 2' -chlorobenzenesulfonyloxy, methanesulfonylamino, trifluoromethanesulfonylamino, 2-propanesulfonylamino, phenylmethylsulfonylamino, benzenesulfonylamino, 2 '-ethylphenylsulfonylamino, aminosulfonylmethyl, 2' -chlorobenzenesulfonylamino, trifluoromethanesulfonylmethyl, benzenesulfonylmethyl, aminosulfonyloxy, aminosulfonylamino;

or Ar is a benzene ring substituted in the 2-position with a group selected from 2- (2, 6-dichloro-phenylamino) -phenyl, 2- (2, 6-dichloro-phenyl-amino) -5-chloro-phenyl, 2- (2, 6-dichloro-3-methyl-phenyl-amino) -phenyl, 2- (3-trifluoromethyl-phenyl-amino) -phenyl, 2- (2, 6-dichloro-phenoxy) -phenyl, 2- (2-chloro-phenoxy) -phenyl, 2- (2, 6-dichloro-benzyl) -phenyl, 2- (2-chloro-benzyl) -phenyl.

3. Use according to claim 1 or 2, characterized in that: the compound is selected from:

(R, S)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

(R)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

(S)2- [ 3' - (alpha-ethyl-propyl) phenyl ] propanoic acid

2- [ 3' - (alpha-dihydroxy-ethyl) phenyl ] propionic acid and single diastereoisomer thereof

2- [ 3' - (alpha-dihydroxy-propyl) phenyl ] propionic acid and single diastereoisomer thereof

(R, S)2- [ 3' -isopropylidene ] propionic acid

(R)2- [ 3' -isopropylidene ] propionic acid

(S)2- [ 3' -isopropylidene ] propionic acid

4.(R, S) -2-aryl-propionic acid compounds represented by the general formula (Ia), their (R) and (S) single enantiomers and pharmaceutically acceptable salts thereof,

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

ar is a benzene ring substituted in the 4-position by a group selected from C₁-C₅-sulfonyloxy, substituted or unsubstituted phenylsulfonyloxy, C₁-C₅Alkanesulfonylamino, substituted or unsubstituted benzenesulfonylamino, C₁-C₅-an alkanesulfonylmethyl group, a substituted or unsubstituted benzenesulfonylmethyl group.

5. The compound of claim 4, wherein: the compound is selected from:

(R)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonyloxy) phenylpropionic acid

(R)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylsulfonyloxy) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonyloxy ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(S)2- [4 '(2' -chloro) phenylsulfonyloxy ] phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonyloxy ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonyloxy) phenylpropionic acid

(R)2- (4' -aminosulfonyloxy) phenylpropionic acid

(S)2- (4' -aminosulfonyloxy) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylamino) phenylpropionic acid

(R)2- (4' -Methanesulphonylamino) phenylpropionic acid

(S)2- (4' -Methanesulphonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-propane) sulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylsulfonylamino) phenylpropionic acid

(R)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(S)2- [ 4' - (2 "-ethyl) benzenesulfonylamino ] phenylpropionic acid

(R)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(S)2- [4 '- (2' -chloro) benzenesulfonylamino ] phenylpropionic acid

(R)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(S)2- (4' -phenylmethylsulfonylamino) phenylpropionic acid

(R)2- (4' -aminosulfonylamino) phenylpropionic acid

(S)2- (4' -aminosulfonylamino) phenylpropionic acid

(R)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(S)2- (4' -trifluoromethanesulfonylmethyl) phenylpropionic acid

(R)2- (4' -phenylsulfonylmethyl) phenylpropionic acid

(S)2- (4' -phenylsulfonylmethyl) phenylpropionic acid.

6. A process for preparing a compound as claimed in claim 4, wherein Ar is C₁-C₅-a sulfonyloxyphenyl or phenylsulfonyloxyphenyl group characterized in that: the process comprises reacting a 4-hydroxy-phenyl propanoate with the corresponding C in the presence of a suitable organic or inorganic base₁-C₅-sulfonyl chloride or benzenesulfonyl chloride.

7. A process for preparing a compound as claimed in claim 4, wherein Ar isIs C₁-C₅-a sulphonylaminophenyl or benzenesulphonylaminophenyl group, characterized in that: the process comprises reacting a 4-aminophenylpropionate ester with the corresponding C in the presence of a suitable organic or inorganic base₁-C₅-sulfonyl chloride or benzenesulfonyl chloride.

8. A process for preparing a compound as claimed in claim 4, wherein Ar is C₁-C₅-a sulfonylmethylphenyl or phenylsulfonylmethylphenyl group characterized in that: the process comprises reacting 4-chloromethylphenylpropionic acid ester with the corresponding C in the presence of a suitable organic or inorganic base₁-C₅Thiolates or thiophenolates.

9. Use of a compound according to claim 4 or 5 for the preparation of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease, bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of injury caused by ischemia and reperfusion.

10. A pharmaceutical composition comprising a compound as claimed in claim 4 or 5 and a suitable carrier therefor.