2-arylpropionic acids and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using compounds of (R,S)-2-arylpropionic acids of the formula (Ia) , and their (R)- and (S)-isomers as inhibitors of neutrophile (PMN leukocytes) chemotaxis induced by IL-8. These compounds elicit unexpected ability to inhibit effectively IL-8-induced chemotaxis and degranulation of neutrophiles being without significant effect on activity of cyclooxygenases. These compounds can be used in treatment of such diseases as psoriasis, ulcerated colitis, melanoma, chronic obstructive pulmonary disease, bulla pemphigus, rheumatic arthritis, idiopathic fibrosis, glomerulonephritis, and for prophylaxis and treatment of damages induced by ischemia and reperfusion.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

9 cl, 3 tbl, 43 ex

 

The present invention relates to (R,S) 2-arylpropionic acids, their enantiomers (R) and (S) and containing pharmaceutical compositions, which are used for the prevention and treatment of tissue damage caused by increased accumulation polymorphically neutrophils (PMN leukocytes) in areas of inflammation.

Certain blood cells (macrophages, granulocytes, neutrophils, polymorphidae) respond to chemical stimuli (when stimulated by substances called chemokines) by migration in the direction of the concentration gradient stimulating agent, and this process is called chemotaxis. Main known stimulating agents or chemokines presents the decomposition products of complement C5a, some N-formylpiperidine resulting from the lysis of the surfaces of bacteria, or peptides synthetic origin, such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and, mainly, a variety of cytokines, including interleukin-8 (IL-8). Interleukin-8 is an endogenous chemotactic factor produced by most containing nucleus of cells, such as fibroblasts, macrophages, endothelial and epithelial cells exposed to TNF-α (tumor necrosis factor) incentives, interleukins IL-1α and IL-1β and lipopolysaccharides of bacterial walls (LPS), as well as those who nd neutrophils, exposed to the effects of LPS, or N-formilitary of bacterial origin (f-MLP). To the family of the specified chemotactic factor [also known as activating neutrophils factor (NAF), T-limfotsity chemotactic factor, monocytopenia neutrophil chemotactic factor (MDNCF)] belongs to a number of IL-8-like chemokines [GRO α, β, γ and NAP-2], which are associated with IL-8 receptors (Chang et al., J. Immunol., 148, 451, 1992). Neutrophils protect against bacterial infection due to the ability of these cells to migrate from the peripheral blood through endothelial connections and tissue matrix in the direction of the active areas (i.e. along the gradients of the concentration of the chemotactic factor), where they operate, attacking microorganisms, removing damaged cells and repairing tissue (M.A. Goucerot-Podicalo et al., Pathol. Biol (Paris), 44, 36, 1996).

In certain pathological conditions characterized by increased accumulation of neutrophils, more serious tissue damage at the site is associated with infiltration of polymorphonuclear cells. Was recently demonstrated the role of activated neutrophils in the determination of the damages, associated with post-ischemic reperfusion and hyperoxia lungs.

Experimental models [N. Sekido et al., Nature, 365, 654, 1993, and T. Matsumoto et al., Lab. Investig., 77, 119, 1997] and clinical studies [A has provocative effect et al., Recent Prog. Med., 85, 397, 194; G. Receipts et al., Atheroscl., 91, 1, 1991] demonstrated a direct correlation between cell damage and the degree of infiltration of PMN leukocytes, and IL-8 are the most specific and powerful activators. In patients with acute respiratory failure (ARDS) increased accumulation of neutrophils in the air ways and in lung fluids can have a good correlation with the concentration of the cytokine IL-8 (E.J. Miller et al., Am. Rev. Respir. Dis., 146, 437, 1992) and with the severity of pathology (Kurodowska et al., Immunol., 157, 2699, 1996). It was shown that treatment with anti-IL-8 antibody is effective in models of acute respiratory failure and pulmonary damage caused by the groove toxins (K. Yokoi et al.; Lab. Invest., 76, 375, 1997).

Was shown the specific role of IL-8 in the occurrence of lesions after post-ischemic reperfusion in patients with acute rupture of the myocardium (Y. Abe et al., Br. Heart J., 70, 132, 1993); the key role demonstrated IL-8 in oposredstvovanii damage associated with post-ischemic reperfusion, is also supported by the results obtained using anti-IL-8 antibodies in experimental models of focal cerebral ischemia in rabbits (T. Matsumoto et al., Lab. invest., 77, 119, 1997).

The biological activity of IL-8 is due to the interaction of interleukin CXCR1 and CXCR2 membrane receptors that belong to the family of seven transmembrane the receptors, expressed on the surface of human neutrophils and some types of T-cells (L. Xu et al., J.Leukocyte Biol., 57, 335, 1995).

Although it is known that CXCR1 activation plays a key role in IL-8-mediated the chemotaxis, it was recently suggested that CXCR2 activation 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 effect of IL-8 on the function of keratinocytes.

Indeed, it was shown that IL-8 are effective stimulators of proliferation of epidermal cells, and angiogenesis, both important aspects of psoriatic pathogenesis (A. Tuschil et al. J Invest Dermatol, 99, 294, 1992; Koch AE et al, Science, 258, 1798, 1992). In addition, IL-8 induce the expression of major histocompatibility complex II (MHC-II) a fragment of HLA-DR on cultured keratinocytes (L. Kemeny et al., Int Arch Allergy Immunol, 10, 351, 1995). Assume that the effect of CXCL8 on the function of keratinocytes mediated by CXCR2 activation. In accordance with this hypothesis, it was reported that CXCR2 is overly expressed in the affected skin of patients with psoriasis (R. Kulke et al., J. Invest. Dermatol, 110, 90, 1998).

In addition, it is proved that the pathophysiological role of IL-8 in the development and metastasis of melanoma may be mediated by CXCR2 activation.

The potential pathogenic role of IL-8 in the one melanoma does not depend on their chemotactic activity in human PMNs. Indeed, suggest that IL-8 acts as the main factor in the growth and metastasis of melanoma cells.

It was found that a significant number CXL8 is produced by melanoma cells, and it is known that cells in melanoma tumors Express immunoreactive CXCR2 receptor (L.R. Bryan et al., Am J Surg, 174, 507, 1997). It is known that IL-8 induces haptotactic migration and proliferation of melanoma cells (J.M. Wang et al., Biochem Biophys Res Commun, 169, 165, 1990).

Described in detail the potential pathogenic role of IL-8 in pulmonary diseases (lung syndrome acute respiratory failure, asthma, chronic pneumonia and cystic fibrosis) and especially in the pathogenesis of COPD (chronic obstructive pulmonary disease) through a scheme of CXCR2 receptors (D. WP Hay and H.M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

Were described phenylurea compounds that can selectively inhibit the binding of IL-8 receptor CXCR2 receptor (J.R. White et al., J. Biol. Chem., 273, 10095, 1998); the use of these compounds in the treatment of pathological conditions, oposredstvovanii interleukin-8, as claimed in WO 98/07418.

The study of the contribution of individual (S) and (R) enantiomers of Ketoprofen in anti-inflammatory activity of the racemate and their role in the modulation of chemokines demonstrated (P. Ghezzi et al., J. Exp. Pharm. Ther., 287, 969, 1998)that the two enantiomers and their salts with chiral and nacheral the different organic bases can inhibit dose-dependent manner chemotaxis and increase the intracellular concentration of ions of Ca 2+induced IL-8 in human PMN leukocytes (patent application U.S. 6069172). Then it was demonstrated (C. Bizzarri et al., Biochem. Pharmacol. 61, 1429, 2001), Ketoprofen participates in the activity of inhibiting the biological activity of IL-8 with other molecules belonging to the class of nonsteroidal anti-inflammatory agents (NSAID)such as flurbiprofen, ibuprofen, and indomethacin. Typical NSAID inhibition activity of the enzyme cyclo-oxygenase (COX) limits therapeutic use of these compounds in the context of treatment neutralization pathological conditions and inflammatory conditions such as psoriasis, idiopathic pulmonary fibrosis, acute respiratory failure, damage caused by reperfusion injury, and glomerulonephritis. Inhibition of prostaglandin synthesis, resulting from the activity of the enzyme cyclo-oxygenase, includes increased production of cytokines, which, like TNF-αplay a role in the amplification of unwanted proinflammatory effects of neutrophils.

Lower COX inhibitory efficiency (R) enantiomers NSAID belonging to the subclass phenylpropionic acids, compared with the efficiency of the (S) enantiomers assumes that the (R) enantiomers of Ketoprofen, flurbiprofen and ibuprofen can be potentially useful agents in the treatment of eutrophization pathologies. The fact that some of the (R) enantiomers are converted in vivo into the corresponding (S) enantiomers in the bodies of some species of animals and people, thereby showing COX inhibitory activity, is a serious restriction of the use of these compounds in the treatment of IL-8-oposredstvovanii pathologies. The above prerequisites explain the difficulties encountered in identifying the selectivity of IL-8 inhibitors belonging to the class 2-phenylpropionic acids.

It has been suggested that the chiral transformation of the R-enantiomers of 2-phenylpropionic acids associated with stereospecific formation of intermediate complex R-propenyl-CoA thioesters; it has been demonstrated that obtaining the derivative of the carboxyl function can avoid in vivo metabolic transformation without changing the efficiency of inhibition of IL-8. Studies of relationship between structure and activity conducted for a class of derivatives of 2-phenylpropionic acids, led to the discovery of new classes of effective and selective inhibitors of IL-8 biological activities suitable for in vivo administration. Amides R-2-arylpropionic acid and N-arylsulfonamides been disclosed as effective inhibitors of IL-8 induced chemotaxis of neutrophils and degranulation (WO 01/58852; WO 00/24710).

The authors found that selected subclasses of 2-allpro the ionov acids demonstrated an unexpected ability to inhibit IL-8-induced chemotaxis of neutrophils and degranulation without noticeable effect on the activity of cyclooxygenase. As R-and S-enantiomers (R,S)-2-arylpropionic acid, described below, does not really active in the inhibition of cyclooxygenase in the concentration range from 10-5up to 10-6M

In the present invention proposed (R,S)-2-arylpropionate acid of the formula (I) and (R)- and (S)-enantiomers:

and their pharmaceutically acceptable salt,

where

Ar represents a phenyl ring, substituted

group 3-(meta) position selected from linear or branched C1-C5-alkyl, C2-C5-alkenylphenol or C2-C5-alkenylphenol group, optionally substituted C1-C5-alkoxycarbonyl, substituted or unsubstituted phenyl, linear or branched C1-C5-hydroxyalkyl, arylhydroxylamine, or 3-(meta) linear or branched C1-C5is an alkyl group forms, together with the substituent in the ortho - or para-position of the benzene ring, saturated or unsaturated, substituted or unsubstituted basicaally; or

group 4-(para) position selected from C1-C5-acyloxy, substituted or unsubstituted benzoyloxy, C1-C5-acylamino, substituted or unsubstituted benzoylamine, C1-C5-sulfonyloxy, substituted or unsubstituted, benzosulfimide, C1 -C5-alkanesulfonyl, substituted or unsubstituted, benzosulfimide, C1-C5-alkanesulfonyl, substituted or unsubstituted benzosulfimide, C3-C6-cycloalkyl; 2-furil; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophene group or a C1-C8(alkanoyl, cycloalkenyl, arylalkyl)-C1-C5-alkylamino, for example, acetyl-N-methylamino, pivaloyl-N-etilenovomu; or

group 2-(ortho) position selected from substituted or unsubstituted arylmethyl, substituted or unsubstituted, aryloxy, substituted or unsubstituted, arylamino, where the substituents at the aryl groups are selected from C1-C4-alkyl, C1-C4-alkoxy, chlorine, fluorine and/or triptorelin group;

for use as inhibitors of IL-8 induced chemotaxis of human PMN.

The phenyl ring in the Ar group may be optionally substituted by other groups, such as C1-C5-alkyl or the group of halogen.

The term "substituted" in the above definition means substituted by a group selected from C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro, or cyano groups.

Preferred Ar in compounds of formula (I) are phenyl group, 3-substituted: isoprop-1 is the n-1-yl, the ethyl, isopropyl, Penta-2-EN-3-yl, Penta-3-yl, 1-phenylethylene-1-yl, α-methylbenzyl, α-hydroxybenzyl, α-hydroxyethyl, α-hydroxypropyl, bicyclic aryl patterns, such as 3-methylindol-5-yl, 3-methylindol-7-yl, 8-methyltetrahydro-2-yl, 5-methyltetrahydro-1-yl, and phenyl group, 4-substituted tripterocalyx, 2-propanesulfonate, benzylmalonate, benzosulfimide, 2'-ethylbenzophenone, 2'-chlorobenzenesulfonate, methanesulfonamido, triftormetilfullerenov, 2-propanesulfinamide, benzylmethylamine, benzosulfimide, 2'-ethylbenzylamine, aminocarbonylmethyl, 2'-chlorobenzenesulfonamide, triftormetilfullerenov, benzosulfimide, aminosulfonyl, aminosulfonyl; and the phenyl group of 2-substituted 2-(2,6-dichlorophenylamino)phenyl, 2-(2,6-dichlorophenylamino)-5-chlorophenyl, 2-(2,6-dichloro-3-methylphenylamine)phenyl, 2-(3-triptoreline)phenyl, 2-(2,6-dichlorophenoxy)phenyl, 2-(2-chlorophenoxy)phenyl, 2-(2,6-dichlorobenzyl)phenyl, 2-(2-Chlorobenzyl)phenyl.

Particularly preferred compounds of the present invention are:

(R,S) 2-[3'-(alpha-ethylpropyl)phenyl]propionic acid

(R) 2-[3'-(alpha-ethylpropyl)phenyl]propionic acid

(S) 2-[3'-(alpha-ethylpropyl)phenyl]propionic acid

2-[3'-(alpha-hydroxy is Teal)phenyl]propionic acid, and diastereoisomer

2-[3'-(alpha-hydroxypropyl)phenyl]propionic acid and its diastereoisomer

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

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

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

(R) 2-(4'-tripterocalyx)phenylpropionate acid

(S) 2-(4'-tripterocalyx)phenylpropionate acid

(R) 2-(4'-benzosulfimide)phenylpropionate acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(R) 2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionate acid

(S) 2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionate acid

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

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

(R) 2-(4'-benzylmalonate)phenylpropionate acid

(S) 2-(4'-benzylmalonate)phenylpropionate acid

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

(S) 2-(4'-aminosulfonyl)phenylpropionate acid

(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(S) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(R) 2-(4'-methanesulfonamido)phenylpropionate acid

(S) 2-(4'-methanesulfonamido)FeNi is propionic acid

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

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

(R) 2-(4'-benzosulfimide)phenylpropionate acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(R) 2-[4'-(2"-chloro)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-chloro)benzosulfimide]phenylpropionate acid

(R) 2-(4'-benzylmethylamine)phenylpropionate acid

(S) 2-(4'-benzylmethylamine)phenylpropionate acid

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

(S) 2-(4'-aminosulfonyl)phenylpropionate acid

(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(S) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(R) 2-(4'-benzosulfimide)phenylpropionate acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid

The next task of the present invention is to provide new compounds of the formula (Ia)

their (R)- and (S)-enantiomers and their pharmaceutically acceptable salts,

where Ar represents a phenyl ring substituted in the 4- (para) position with a group selected from C1-C5-sulfonyloxy, semese the aqueous or unsubstituted, benzosulfimide, C1-C5-alkanesulfonyl, substituted or unsubstituted, benzosulfimide, C1-C5-alkanesulfonyl, substituted or unsubstituted benzosulfimide.

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

The term "substituted" in the above definition means substituted by a group selected from C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro or cyano groups.

The most preferred compounds of formula Ia, as defined above, are:

(R) 2-(4'-tripterocalyx)phenylpropionate acid

(S) 2-(4'-tripterocalyx)phenylpropionate acid

(R) 2-(4'-benzosulfimide)phenylpropionate acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(R) 2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionate acid

(S) 2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionate acid

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

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

(R) 2-(4'-benzylmalonate)phenylpro the IP acid

(S) 2-(4'-benzylmalonate)phenylpropionate acid

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

(S) 2-(4'-aminosulfonyl)phenylpropionate acid

(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(S) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(R) 2-(4'-methanesulfonamido)phenylpropionate acid

(S) 2-(4'-methanesulfonamido)phenylpropionate acid

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

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

(R) 2-(4'-benzosulfimide)phenylpropionate acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

(R) 2-[4'-(2"-chloro)benzosulfimide]phenylpropionate acid

(S) 2-[4'-(2"-chloro)benzosulfimide]phenylpropionate acid

(R) 2-(4'-benzylmethylamine)phenylpropionate acid

(S) 2-(4'-benzylmethylamine)phenylpropionate acid

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

(S) 2-(4'-aminosulfonyl)phenylpropionate acid

(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(S) 2-(4'-triftormetilfullerenov)phenylpropionate acid

(R) 2-(4'-benzosulfimide)Fe is ylpropionic acid

(S) 2-(4'-benzosulfimide)phenylpropionate acid.

Compounds of the present invention do not affect the production of PGE2in murine macrophages stimulated by lipopolysaccharides (LPS, 1 μg/ml) in the whole concentration range from 10-5up to 10-6M, and thus devoid of any inhibitory activity against cyclooxygenase (COX). Due to the absence of COX inhibitory activity as R-and S-enantiomers of the described 2-phenylpropionic acid, the compounds of the present invention are the first 2-phenylpropionamide acids with characteristics required for therapeutic use in the treatment of pathologies associated with increased chemotaxis of neutrophils, and activation induced by IL-8. The expected metabolic chiral inversion of R-enantiomers of the present invention results in the corresponding S-enantiomers, which have R-enantiomers comparable characteristics from the standpoint of IL-8 efficiency and COX selectivity.

Compounds of the present invention of formula (I) are usually isolated in the form of their salts joining both organic and inorganic pharmaceutically acceptable bases.

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

3-(Meta) and 2-(ortho) substituted 2-and ylpropionic acid of the formula (I) and their enantiomers are disclosed in WO 01/58852 and in WO 00/24710

Acid of the formula I, as defined above, are obtained by alkylation of stannane polyamidine 2 phenylpropionic acid containing performancecontrol group in ortho - or meta - or para-position, as will be disclosed hereinafter.

The enantiomers of 2-arylpropionic acid of the formula (I) can be obtained in a regular and stereospecific synthesis: it is also known transformation of racemates in one of the enantiomers after transformation into 2-aryl-2-propylketone, as disclosed Larse RD et al., J. Am. Chem. Soc., 111, 7650, 1989 and Myers AG, ibidem, 119, 6496, 1997. Stereoselective synthesis of 2-arylpropionic acid refers mainly to the S-enantiomers, but they can be modified in such a way as to obtain the R-enantiomers, choosing a suitable chiral auxiliary agent. Arylalkylamine as substrates for the synthesis of α-arylalkenes acids disclosed, see for example Trost BM and JH Rigby, J. Org. Chem., 14, 2926, 1978; atilirovanie Meldrum acid disclosed, see JT Piney and RA Rowe, Tet. Lett., 21, 965, 1980; tartaric acid as a chiral auxiliary agent is disclosed, see Castaldi et al., J. Org. Chem., 52, 3019, 1987; α-hydrocyclone esters as chiral reagents disclosed, see RD Larsen et al., J. Am. Chem. Soc., 1ll, 7650, 1989 and cited herein U.S. patent 4940813.

The method of obtaining 2-(2-OH-phenyl)propionic acids and their esters disclosed in the Italian patent 128369. A common and effective way of getting the R-enantiomer (R,S)-2-(5-benzoyl-2-acetoxy)propionic acid and acids of the formula (Ia) is the transformation of these chlorides of carboxylic acids (anhydrides) in the corresponding prop-1-ketene when interacting with a tertiary amine, such as dimethylethylamine, with subsequent interaction of ketene with R(-)pantolactone with the production of esters of R-enantiomers of these acids with R-dihydro-3-hydroxy-4,4-dimethyl-2(3H)furan-2-one. The subsequent saponification of ester LiOH obtain the corresponding free acid.

A common way to obtain R-2-arylpropionic acids of the formula (Ia) include, for example, the implementation of the interaction of esters 4-hydroxyphenylpropionic acid or esters 4-aminophenylamino acid with the appropriate C1-C5-sulphonylchloride or benzosulfimide in the presence of a suitable organic or inorganic bases; or the interaction of esters 4-chloromethylphosphonic acids with the corresponding C1-C5-thiolate or sensationally in the presence of a suitable organic or inorganic base, which is disclosed in detail in the section "General method for the synthesis of (S)- and (R)-2-[(4'-aryl/alkylsulfonyl)phenyl]propionic acid of formula Ia and the last is in later sections. A typical way to obtain the compounds of formula (Ia) includes the engagement of hydroxyacrylates formula (Ia) mono - or polyamidine performancemonitoring to get performancenumber esters of the formula (IIb), where n is an integer from 1 to 9:

The compounds of formula (IIb) is subjected to rearrangement of Willgerodt in order to obtain, after esterification and methylation on the alpha carbon, arylpropionate derivatives of the formula (IIc), where n is an integer from 1 to 9, and R3represents C1-C4-alkyl or C2-C4alkenyl.

The compounds of formula (IIc) is subjected to interaction with the corresponding tributylstannyl formula Bu3SnR4where R4represents a linear or branched C2-C6-alkyl; linear or branched C2-C6alkenyl, or linear or branched C2-C6-quinil, unsubstituted or substituted aryl group, to obtain the corresponding (R,S)-2-arylpropionate formula (IId).

Alkeneamine or alkyline groups can be gidrirovanii under conditions of catalytic hydrogenation to obtain the corresponding saturated alkyl groups. The compounds of formula (IId) process the feed, using the method of deracemization, as has been disclosed above for the conversion of the corresponding acid chlorides in ketene, that is, when interacting with R(-)pantolactone and c followed by hydrolysis into pure R-enantiomer; the reaction of the intermediate ketene with chiral auxiliary S(+)-pantolactone receive the corresponding pure S-enantiomer.

Compounds of the present invention of formula (I) evaluated in vitro for their ability to inhibit chemotaxis polymorphically leukocytes (hereinafter referred PMN) and monocytes induced by fractions of IL-8 and GRO-α. For this purpose, to highlight PMN from heparinised human blood collected from healthy adult volunteers, mononucleate removed by precipitation of the dextran (in accordance with the method disclosed WJ. Ming et al., J. Immunol, 138, 1469, 1987), and red blood cells gipotonikam solution. Cell viability assessed by exclusion Trypanosoma blue, while the ratio of circulating polymorphonuclear appreciate using cytocentrifuge after dyeing Diff Quick.

Human recombinant IL-8 (Pepro Tech) is used as stimulating agents in the chemotaxis experiments, obtaining almost identical results: liofilizovannye protein is dissolved in a volume of HBSS containing 0.2% bovine albumin savoro the key (BSA), to get so original solution with a concentration of 10-5M, which is then diluted with HBSS to a concentration of 10-9M, for the analysis of chemotaxis.

During the analysis of chemotaxis (according to the method of W. Falket et al., J. Immunol. Methods, 33, 239, 1980) use filters that do not contain PVP, with a porosity of 5 μm and microcamera suitable for replication.

Compounds of the present invention of formula (I) evaluated at a concentration in the range from 10-6up to 10-10M; for this purpose they are added in the same concentration as in the bottom of the pores, and at the top of the pores of Microtimer. The ability of the compounds of the present invention of formula (I) to inhibit IL-8-induced chemotaxis of human monocytes is carried out in accordance with the method disclosed Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989).

As an example, the following table shows the results from inhibition (C=10-6M) for some representatives of the compounds in tests on IL-8-induced PMN to chemotaxis:

(S) 2-[3'-isopropylphenyl]propionic acid
ExampleName% inhibition (C=10-6M)
5(R,S) 2-[3'-isopropylphenyl]propionic acid51±12
10(S) 2-[3'-isopropylphenyl]propionic acid43±18
1450±9
7(R,S), (R,S) 2-[3'-(alpha-methyl-benzyl)phenyl]propionic acid54±4
16(R,S), (R,S) 2-[3'-(alpha-hydroxyethyl)phenyl]propionic acid57±6
18(R,S) 2-[(2'-(2",6"-dichlorophenyl)amino]phenyl propionic acid52±3
19(R) 2-[(2'-(2",6"-dichlorophenyl)amino]phenyl propionic acid46±14
20(S) 2-[(2'-(2",6"-dichlorophenyl)amino]phenyl propionic acid50+7
6(R,S) 2-[3'-(alpha-ethylpropyl)phenyl]propionic acid58+2
22(R,S) 2-[(2'-(2",6"-dichloro)phenoxy)phenyl]propionic acid41+9

The above compounds show moderate efficacy in the test for GRO-α induced the PMN chemotaxis, suggesting a selective effect on CXCR1 oposredstvovaniya schema.

Particularly preferred compounds of the present invention are the compounds of formula Ia, which show an additional property effective inhibiting GROα-induced PMN of chemotaxis; this activity allows therapeutic use of these the compounds associated with IL-8 pathologies, where CXCR2 scheme involved specifically or with CXCR1 signals.

In the following table shows the biological activity of compounds demonstrating high efficiency of inhibition of PMN chemotaxis induced both IL-8 and selective CXCR2 agonist GRO-α.

Presents some examples of selective GRO-α effective inhibitors.

Dual inhibitors of IL-8 and GRO-α induced biological activities are highly preferred from the point of view of interest in therapeutic applications, but the described compounds selectively acting on CXCR1, IL-8 receptor, or receptor CXCR2 GRO-α/IL-8 receptor, can find useful therapeutic use in the treatment of specific pathologies, as disclosed below.

The results of the biological activities against CXCR1 and CXCR2 receptors (% inhibition)
ExampleNameIL-8

c=10-8M
GRO-α

c=10-8M
24(R) 2-(4'-benzosulfimide)phenylpropionate acid49±1133±11+
25(R) 2-(4'-methanesulfonamido)phenylpropionate acid25±732±5
26(R) 2-[4'-(2"-propane)sulfonylamino]phenylpropionate acid54±1444±12
27(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid8±1040±14
28(R) 2-(4'-benzylmethylamine)phenylpropionate acid60±1024±8
29(R)2-[4'-(2"-chloro)benzosulfimide]phenyl propionic acid-2±1066±10
30(R) 2-[4'-(2"-ethyl)benzosulfimide] phenylpropionate acid44±1480±10
31(S) 2-[4'-aminosulfonyl)phenylpropionate acid55±102±5
32(R) 2-(4'-benzosulfimide)phenylpropionate acid28±1125±10
35(R) 2-[4'-(2"-propane)sulfonyloxy]phenylpropionate acid49±846±6
34(R) 2-(4'-tripterocalyx)phenylpropionate acid62±759±10
33(R) 2-(4'-benzylmalonate)phenylpropionate acid59±11 25±11
36(R) 2-[4'-(2"-chloro)benzosulfimide] phenylpropionate acid25±765±10
37(R) 2-[4'-(2"-ethyl)benzosulfimide]-phenylpropionate acid45±1370±10
38(R) 2-(4'-aminosulfonyl)phenylpropionate acid65±105±7
40(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid48+745±7
39(R) 2-(4'-benzosulfimide)phenylpropionate acid60±752+5

All compounds of the present invention show a high degree of selectivity in relation to inhibition of IL-8-induced chemotaxis compared with chemotaxis induced by C5a (10-9M) or f-MLP(10-8M).

The compounds of formula (I), assessed ex vivo in blood in toto (in General) in accordance with the procedure disclosed Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705, 1994, as it was discovered, is not fully effective as inhibitors of the enzyme cyclooxygenase (COX). In almost all cases, the compounds of formula (I) inhibit the production of PGE2induced in murine macrophages by stimulation with lipopolysaccharide (LPS, ug/ml) in the concentration range from 10 -5up to 10-7M. Inhibition of the production of PGE2that may be registered, in most cases, is at the limit of statistical significance and more often amounts to less than 15-20% of baseline values. Reduced efficiency of inhibition by CO is an advantage for therapeutic use the compounds of the present invention, since the inhibition of prostaglandin synthesis is an incentive for cells macrophages increased synthesis of TNF-α (induced by LPS or hydrogen peroxide), which are important mediators of the activation of neutrophils and incentives for the production of the cytokine interleukin-8.

From the point of view of the experimental evidence discussed above and the role of interleukin-8 (IL-8), and similar in ways, which include the activation and infiltration of neutrophils, the compounds of the present invention is particularly useful for the treatment of diseases, such as psoriasis (R. J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991). Other diseases that can be treated by the compounds of the present invention, are chronic intestinal inflammatory diseases, such as ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273, 1992) and melanoma, chronic obstructive pulmonary disease (COPD), bullous disease, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), ideoptions the th fibrosis (E. J. Miller, previously cited, and P. C. Carre et al., J. Clin. Invest., 88, 1882, 1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994) and the prevention and treatment of damages caused by ischemia and reperfusion.

Inhibition of the activation of CXCR1 and CXCR2 are suitable, as described in detail above, particularly in the treatment of chronic inflammatory pathologies (e.g., psoriasis), in which it is assumed that the activation of both IL-8 receptors plays a crucial pathophysiological role in the development of the disease.

Indeed, it is known that activation of CXCR1 is essential in IL-8-mediated the PMN chemotaxis (Hammond M et al., J. Immunol, 155,1428, 1995). On the other hand, suggest that activation of CXCR2 is essential for IL-8-mediated proliferation of epidermal cells and angiogenesis in patients with psoriasis (Kulke R, et al., J Invest Dermatol, 110, 90, 1998).

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

The next task of the present invention to provide compounds suitable for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and d is I the prevention and treatment of injuries, caused by ischemia and reperfusion, as well as the use of such compounds to obtain drugs for the treatment of the above diseases. Pharmaceutical compositions comprising the compound of the present invention and a suitable carrier, is also included in the scope of the present invention. Compounds of the present invention, together with commonly used adjuvant, carrier, diluent or excipient, can be prepared in the form of pharmaceutical compositions and their standard dosage forms, and as such, can be used in solid form, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all for oral administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) administration. Such pharmaceutical compositions and their standard dosage forms may include ingredients in conventional proportions, together with additional active compounds or principles, or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient corresponding to the assigned interval daily doses.

If acid of the present invention are used as medicines, they are about is a rule introduced in the form of pharmaceutical compositions. Such compositions can be obtained by a method well known to pharmacists, and they include at least one active connection.

Typically, compounds of the present invention is administered in a pharmaceutically effective amount. The number of real input connection is usually determined by the physician, taking into account the relevant circumstances, including the subject to the treatment condition, the chosen route of administration, the specific input connection, the age, weight and response of the individual patient, the severity of symptoms, etc.

The pharmaceutical compositions of the present invention can be administered in a number of ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended method of administration the compounds are preferably prepared either in the form of compositions for injection, or for oral administration.

Compositions for oral administration can be in the form of liquid solutions or suspensions, or in the form of powders. More often, however, these songs are presented in standard dosage forms to facilitate accurate dosing. The term "standard dosage forms" refers to physically discrete units suitable for use as a standard doses for humans and other mammals, and ka is the Mae dose contains a certain amount of the active ingredient, designed in such a way as to provide the desired therapeutic effect, together with a suitable pharmaceutical excipient. Typical standard dosage forms include pre-filled, measured ampoules or syringes with liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In the compositions of acidic compounds are usually smaller component (from about 0.1 to about 50 wt.%, or preferably from about 1 to about 40% weight %), and the rest consists of various fillers or carriers and auxiliary agents, facilitating the creation of the desired dosage form.

Liquid forms for oral administration may include appropriate water or not water carriers, buffers, suspendresume and dispersing agents, colorants, flavorings and other Liquid forms, including compositions for injection, described later, is always kept in the dark to avoid any catalytic action of light, such as the formation of gidroperekisi or peroxide.

Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, resin tragakant or gelatin; excipients such as starch or lactose, loosening agents such as alginic acid, Primogel, and corn starch; lubricating agents such as magnesium stearate; a sizing agents, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or agent, gives taste of orange.

Compositions for injection are usually based on a sterile saline solution for injection or phosphate buffer saline solution, or other medium for injection, known in the art. As mentioned above, a derivative of the acid of formula I in such compositions is typically in the range of from 0.05 to 10% by weight of the carrier for injection, etc. the average daily dose will depend on various factors such as the severity of the disease and the patient's condition (age, gender and weight). The magnitude of the dose usually ranges from 1 mg or more mg up to 1500 mg of the compounds of formula (I), optionally divided into several stages. You can also enter and higher doses, due to the low toxicity of the compounds of the present invention for extended periods of time.

The above-described components for compositions for oral administration or for injection are merely illustrative. Other materials, as well as processing methods, etc. are presented in part 8 "Remington''s Pharmaceutical Sciences Handbook", 18th Edition, 1990, Mack Publishing Company, Easton, Pennsylvania, which included Xu is for reference.

Compounds of the present invention can also enter in forms with delayed allocation or delivery systems of drugs with delayed allocation. Description of representative materials with delayed allocation can also be found in the materials listed above Remington''s Handbook.

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

When describing the compounds of the present invention of formula (I) to denote the absolute configuration of any chiral substituents that may be present in the substituent R' of the above compounds, indices (for example, R', S', S" and so on).

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

Materials and methods

General method of synthesis of 2-arylpropionic acids of formula I and their R-enantiomers

Under stirring, at room temperature and less humidity, 12.0 g of anhydrous K2CO3(86,2 mmol) are added to 80,0 mmol solution of (o,m,p)-hydroxyacetophenone (mono - or polishmaster on phenyl) in acetone (80 ml). The mixture is stirred for 30 minutes at room temperature. Then added dropwise a solution of performancemonitoring (15,5 ml, 861 mmol) in acetone (30 ml) and the mixture bales which belong under reflux for 2 hours. After cooling at room temperature, the solid part was filtered and the filtrate is evaporated to dryness. The residue is placed in EtOAc (100 ml). The organic solution was washed with a saturated solution of KHCO3(20 ml) and then saturated NaCl solution (20 ml). After drying over Na2SO4and solvent evaporation receive the corresponding ester performancelevel in the form of oil, sufficiently pure to be used in subsequent reactions with almost quantitative yield.

The mixture thus obtained complex ether acetophenone performancelevel a (80.0 mmol), sulfur (2,95 g, 92.0 mmol) and research (8,0 ml, 92.0 mmol) is refluxed for 6 hours. After cooling at room temperature the solution was poured into a mixture of ice and 6N HCl (40 ml). The mixture is extracted with CH2Cl2(2×50 ml); the organic extracts are dried over Na2SO4and the solvent is evaporated, obtaining the crude yellow oil, after chromatographic purification on silica gel (eluent: n-hexane/EtOAc 9:1) yields a corresponding morphodynamics in the form of a transparent oil (yield 73%).

The solution morphodynamics (58,0 mmol) in glacial acetic acid (25,0 ml) are added to 37% HCl (40 ml), and the mixture is then refluxed for 16 hours under refrigeration. After cooling at room temperature the round, the mixture is filtered from the precipitated sludge. After evaporation of the filtrate the residue was diluted with H2O (50 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with saturated NaCl solution (20 ml), dried over Na2SO4and evaporated under reduced pressure, receiving the oil from which the result of crystallization from n-hexane get (o,m,p) performancereport 2-phenylacetic acid in the form of solid crystals (yield 90-93%). In the subsequent esterification of concentrated H2SO4in hot absolute ethanol, the corresponding ethyl ester with almost quantitative yield. Small successive portions of a 60% suspension of sodium hydride in mineral oil (1.6 g; 66,7 mmol) is slowly added to a solution of ethyl (o,m,p)-performancesthanks-2-phenylacetate (about 25 mmol) in THF (50 ml), cooled to T=0,5°C. After 15 minutes, added dropwise methyliodide (of 1.88 ml, 30.2 mmol) and left to react at room temperature for 3.5 hours. The reaction is stopped by adding a saturated solution of NH4Cl (45 ml); the solvent is evaporated under reduced pressure and the aqueous phase extracted with CH2C12(3×50 ml); the combined organic extracts are washed with saturated NaCl solution (200 ml), dried over N2SO4and evaporated under reduced pressure, getting estato is, after chromatographic purification leads to the production of ethyl ether complex of the corresponding (o,m,p) performancesthanks-2-phenylpropionic acid in the form of a solid substance (yield 70%).

Based on the racemate of ester ethyl ethyl (o,m,p)-(nonatherosclerotic)-2-phenylpropionate get 2-arylpropionate acid of the formula I, in the interaction of these sulfonates with ORGANOTIN compounds in accordance with the methods disclosed T.N. Mitchell, Synthesis, 803, 1992, and K. Ritter, Synthesis, 735, 1993. In accordance with illustrated above receive the following connections:

Example 1

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

The above acid is obtained from ethyl 3'-performancesthanks-2-phenylpropionate (7,63 mmol)which is dissolved in N-ethylpyrrolidin (30 ml); the mixture of anhydrous LiCl (0,94 g is 22.9 mmol), triphenylarsine (90 mg; 0.3 mmol) and diallydimethylammonium (0,173 g; 0.15 mmol Pd). After 5 minutes at room temperature add tributyltinhydride (2.83 g; 8,55 mmol) and the solution stirred for 5 hours at T=90°C. After cooling the solution to room temperature the mixture is diluted with hexane and add a saturated solution of KF; after filtration and separation of the phases the organic phase is dried over Na2SO4evaporate the vacuum. The result of purification of the residue via flash chromatography receive 2-[3'-isopropylphenyl]ethylpropane (K. Ritter, Synthesis, 735, 1993, and Mitchell T. N., Synthesis, 803, 1992).

1N NaOH (5 ml) are added to a solution of ester in dioxane (5 ml)and the resulting solution was stirred at room temperature overnight. After evaporation of the organic solvent mixture is acidified to pH=2 using 2n HCl, until complete precipitation of the product, which is marked by filtration in the form of a solid white color.

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15(m, 1H); 7,05 (m, 2H); 5,02 (s, 2H); 3.75 to (m, 1H); of 2.34 (m, 1H); from 1.8 to 1.6 (m, 4H); a 1.45 (d, 3H, J=7 Hz); 0,78 (s, 3H).

Example 2

2-[3'-(alpha-ethylpropyl)phenyl]propionic acid

In accordance with the above method are specified acid, using as the source reagent tributyl-(α-ethyl)propanolol obtained by known methods (K. Ritter, Synthesis, 735, 1993, and Mitchell T. N., Synthesis, 803, 1992).

1H NMR (CDCl3): δ) 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H), and 5.5 (m, 1H); 3.75 to (m, 1H); 1,8-1,6 (q, 2H); of 1.45 (d, 3H, J=7 Hz); of 0.85 (d, 3H, J=7 Hz); 0,78 (t, 3H, J=7 Hz)

Example 3

3-[3'-(l"-styrenic)phenyl]propionic acid

In accordance with the above mentioned acid is obtained using as a starting reagent tributyl-α-Stereolove obtained in a known manner (K. Ritter, Synthesis, 735, 1993 the Mitchell T. N., Synthesis, 803, 1992).

1H NMR (CDCl3): δ) 11,0 (users, 1H, COOH); 7,38-7,13 (m, 9H); 3,95 (m, 2H); 3,81 (m, 1H); 1,72 (d, 3H, J=7 Hz)

Example 4

2-[3'-isobutylphenyl]propionic acid

In accordance with the above mentioned acid is obtained using as a starting reagent tributylstannyl obtained in a known manner (K. Ritter, Synthesis, 735, 1993, and Mitchell T. N., Synthesis, 803, 1992).

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H), and 5.5 (m, 1H); 3.75 to (m, 1H);of 1.45 (d, 3H, J=7 Hz); 1,45 (s, 3H); to 1.35 (s, 3H).

In the example discussed getting 2-[(3'-isopropyl)phenyl]propionic acid

Example 5

A mixture of 2-[3'-(isopropyl)phenyl]ethylpropane obtained by the method described above (1 g, 4.6 mmol), 95% ethanol (10 ml) and Pd/C 10% (100 mg) is subjected to catalytic hydrogenation at room temperature and atmospheric pressure until the disappearance of the original reagent (2 hours). The catalyst is filtered off on celite, and after evaporation of the filtrate get a clear oil (0,99 g; 4.5 mmol), which is hydrolized in a solution of KOH in ethanol (10 ml) at T=80°C for 2 hours. After cooling at room temperature the solvent is evaporated under reduced pressure; the residue is taken using EtOAc (20 ml) and extracted with N2About (3×10 ml); the aqueous phase is acidified to pH=2 using 2n HCl and extrage is comfort in a counter EtOAc (2× 10 ml); the organic extracts are combined and washed with saturated NaCl solution, dried over Na2SO4and evaporated under reduced pressure, obtaining 2-[(3'-isopropyl)phenyl]propionic acid (0.75 g; 3.6 mmol).

1H NMR (CDCl3): δ 10,5 (users, 1H, COOH); 7,15-was 7.08 (m, 4H); 3,55 (m, 1H); 2.91 in (m, 1H); of 1.45 (d, 3H, J=7 Hz); 1.26 in (d, 3H, J=7 Hz).

The same way we obtain the following connections:

Example 6

(R,S) 2-[3'-(alpha-ethylpropyl)phenyl]propionic acid

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H); 3.75 to (m, 1H); of 2.34 (m, 1H); from 1.8 to 1.6 (m, 4H); a 1.45 (d, 3H, J=7 Hz); 0,78 (t, 6H, J=7 Hz).

Example 7

(R,S) 3-[3'-(alpha-methyl)benzylethanolamine acid

1H NMR (CDCl3): δ 11,0 (users, 1H, COOH); 7,38-7,13 (m, 9H); 4,20 (m, 1H); of 3.78 (m, 1H); 1,72 (d, 3H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

Example 8

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

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H); of 3.78 (m, 1H); 2.50 each (d, 2H, J=7 Hz); 1,9 (m, 1H); of 1.45 (d, 3H, J=7 Hz); and 0.98 (d, 6H, J=7 Hz).

Example 9

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

In accordance with the above mentioned acid is obtained, using as initial reagents bromide cyclohexylglycine, commercial reagent and ethyl-3-performancesthanks-2-phenylpropionate.

1H NMR (CDCl3): δ 10,15 (users, 1H, COOH); and 7.1 (s, 1H); 7,25-7,35 (who, 3H); 3.75 to (q, 1H, J1=15 Hz, J2=7 Hz); 2,48 (d, 2H, J=7 Hz); 1.77 in is 1.70 (m, 4H); 1.60-to a 1.45 (d, 3H, J=7 Hz+m, 1H); 1.30 and 1.10 for (m, 4H); 1,08-of 0.90 (m, 2H).

Each of the racemates acid formula-Arb-C(CH3)H-CO2H turn then the R-enantiomer using the stereospecific receipt of ester R-pantolactone (through the intermediate ketene) in accordance with the methods disclosed A.G. Myers et al., J. Am. Chem. Associates, 119, 6496, 1997, and R.D. Larsen et al., J. Am. Chem. Associates, 111, 7650, 1989.

In this way receive the following connections:

Example 10

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

[α]D=-23(c=0.5; CH2C12)

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,15-7,10 (m, 4H); the 3.65 (m, 1H); 2,90 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 1.32 to (d, 3H, J=7 Hz).

Example 11

(R)-2-[3'-(l"-ethylpropyl)phenyl]propionic acid

[α]D=-29 (c=0.5; CH2C12)

1H NMR (CDCl3): δ of 10.25 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H); 3.75 to (m, 1H); of 2.34 (m, 1H); from 1.8 to 1.6 (m, 4H); a 1.45 (d, 3H, J=7 Hz); 0,78 (t, 6H, J=7 Hz).

Example 12

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

[α]D=-35 (c=0.5; CH2C12)

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,28 (m, 1H); to 7.15 (m, 1H); 7,05 (m, 2H); of 3.78 (m, 1H); 2.50 each (d, 2H, J= 7 Hz); 1,9 (m, 1H); of 1.45 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz).

Example 13

(R),(R',S')-3-[(3'-α-methyl)benzylphenol]propionic acid

[α]D=-9 (c=0.5; CH2C12)

1H NMR (CDCl3): δ 11,0 (users, 1H, COOH); 7,38-7,13 (m, 9H); 4,20 (m, 1H); of 3.78 (m, 1H); 1,72 (d, 3H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

As described above, but using S-pantolactone, exercise stereospecific getting S-enantiomers:

Example 14

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

[α]D=+24,2 (c=0.5; CH2C12)

1H NMR (CDCl3): δ 10,1 (users, 1H, COOH); 7,12-7,07 (m, 4H); to 3.64 (m, 1H); 2.91 in (m, 1H); of 1.45 (d, 3H, J=Hz); of 1.30 (d, 3H, J=7 Hz).

Example 15

(R),(R',S')-2-[(3'-α-hydroxybenzyl)phenyl]propionic acid

To a solution of R(-)Ketoprofen (0,254 g, 1 mmol) in ethanol (5 ml), add triethylamine (0.12 g; 1 mmol) and catalyst (Pd/C 5% 0.025 g); the mixture hydronaut at room temperature and atmospheric pressure for 3 hours. After removal of catalyst by filtration layer celite the filtrate is evaporated and the residue purified on a chromatographic column. The product is obtained in the form of a solid white color (yield 85%).

[α]D=-45,7 (c=l; CHCl3)

1H NMR (CDCl3): δ 7,41 of 7.3 (m, 3H); 7,31-7,14 (m, 6H); of 5.75 (s, 1H); was 4.02 (users, 1H, OH); 3,68 (kV, 1H, J=Hz); 1,4(d, 3H, J=7 Hz).

According to the method of example 15 and on the basis of (R,S)-2-[(3'-acetyl)phenyl]propionic acid have the following connections:

Example 16

(R,S),(R,S) 2-[3'-(alpha-hydroxyethyl)phenyl]propionic acid

1H NMR (CDCl3): δ 7,40-7,15 (who, 4H); of 4.90 (q, 1H, J=7 Hz); of 3.78 (q, 1H, J=7 Hz); of 1.55(m, 6H).

Example 17

(R),(R',S')-2-[3'-α-hydroxy-α-methylbenzyl)phenyl]propionic acid

To a solution of methyl ether complex R(-)Ketoprofen (0,269, 1 g) in ethyl ether (10 ml) was added a 3.0 M solution of methylmagnesium in ethyl ether (2 mmol); the resulting solution is refluxed for 2 hours. After cooling the mixture, the organic phase is washed with 5%solution of NaH2PO4(2×10 ml), dried over Na2SO4and evaporated in vacuum. The resulting residue is again dissolved in a mixture of 1:1 MeOH/1N NaOH (5 ml) and the solution stirred overnight. The organic solvent is removed in vacuum and the aqueous solution is acidified to pH=2; the resulting precipitate is filtered, washed with water. (R),(R',S')-2-[3'-α-hydroxy-α-methylbenzyl)phenyl]propionic acid is obtained in the form of white powder.

[α]D=-45,3 (c=l; CHCl3)

1H NMR (CDCl3): δ 7,41 of 7.3 (m, 3H); 7,31-7,14 (m, 6H); was 4.02 (users, 1H, OH); 3,68 (kV, 1H, J=7 Hz); 1,4 (d, 3H, J=7 Hz).

Receiving (R,S) 2-[2'-(2",6"-dichlorophenyl)aminophenylamino acid (Example 18) (R) 2-[2'-(2",6"-dichlorophenyl)aminophenylamino acid (Example 19) and (S) 2-[2'-(2",6"-dichlorophenyl]aminophenylamino acid (Example 20).

The compound obtained as racemic mixtures in accordance with the method Geigy, JR; patent UK 1132318 (30.10.1968). Optical is the resolution to obtain the compounds of examples 19 and 20 is carried out by saponification, using R(+)-N-methylbenzylamine by the way, opened in Arzneim. Forsch. 19' 96, 46:9 891-894 by Akguen et al.

Example 21

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

1. Methyl 2-bromophenylacetate

To a solution of 2-bromoferrocene acid (2 g; of 9.30 mmol) in methyl alcohol (10 ml) is added a catalytic amount of concentrated H2SO4(3 drops); the solvent is stirred at room temperature for 18 hours and then evaporated. The remaining oil is removed with ethyl ether (10 ml); then the organic phase is washed with H2O (3×10 ml), dried over Na2SO4and evaporated, getting 2,12 g methyl ether complex in the form of a clear oil. Yield: quantitative.

1H NMR (CDCl3): δ of 7.60 (d, 1H, J=7 Hz); 7,28-7,20 (m, 2H); 7,1-a 7.0 (m, 1H); and 3.8 (s, 2H), and 3.72(s, 3H).

2. Methyl 2-(2'-)brompheniramine

To a solution of Diisopropylamine (1,66 ml; and 11.8 mmol) in anhydrous THF (30 ml) in a stream of Ar and cooled to T=10°C, is added dropwise a solution of n-utility in n-hexane (1,6 M; 7,4 ml; and 11.8 mmol), and adding exercise, so that the temperature did not exceed 0°C. After complete addition, the mixture is stirred at T=-4°C for 30 minutes, then add methyl 2-bromophenylacetate (1.9 grams; 8,30 mmol) in anhydrous THF (8 ml). After complete addition, the mixture is stirred at room temperature for 1 hour. C is the mixture is again cooled to T=-2° C and add methyliodide (0,81 ml, 12.75 mmol). The mixture is stirred at room temperature for 2 hours until, until it fades the original product; THF is evaporated to dryness, the residue taken in CHCl3(10 ml) and ml washed with 1N HCl (3×10) and then saturated NaCl solution (2×10 ml). It is acidified Na2SO4and evaporated under reduced pressure, obtaining a dark red oily residue (1,95 g; 8,02 mmol) of sufficient purity that it can be used in the following stages. Yield 96%.

1H NMR (CDCl3): δ of 7.60 (d, 1H, J=7 Hz); 7,30-7,26 (m, 2H); 7,2-to 7.15 (m, 1H); 4.25 in (q, 1H, J=7 Hz); of 3.75 (s, 3H); of 1.75 (d, 3H, J=7 Hz).

3. Methyl 2-(2'-)benzylphosphonate

Powder zinc (2,412 g; 36,9 mmol) are loaded into the flask in an argon atmosphere. The flask was cooled to T=0-4°C in a bath with a mixture of ice/water and slowly added dropwise a solution of benzylbromide (2,109 g; 12.3 mmol) in anhydrous THF (10 ml). The mixture is stirred at the same temperature for 3 hours until, until it fades the original product. In parallel to another flask in an atmosphere of Ar download tetrakis(triphenylphosphine)palladium (410 g; 0.35 mmol) and methyl 2-(2'-bromophenyl)propionate (1,9 g; 7.8 mmol); add previously obtained ORGANOTIN solution, and when adding dropwise ends, the solution is refluxed for 18 hours. After cooling to room which temperature the mixture is diluted with 0.1 n HCl (10 ml), and add ethyl ether (15 ml); the mixture is shaken out, and it is divided into two phases, the aqueous phase is again extracted with ethyl ether (3×15 ml); the organic extracts are combined, washed with saturated solution of NaHCO3, dried over Na2SO4and evaporated under reduced pressure, obtaining the waxy residue, which after a thorough trituration with isopropyl ether during the night, and filtration in vacuum leads to the production of methyl 2-(2'-benzoylphenyl)propionate in the form of a solid white color (1.52 g; 6 mmol). Yield 77%.

1H NMR (CDCl3): δ 7,50-7,25 (m, 5H); from 7.24 to 7.15 (m, 2H); 7,10-7,05 (m, 2H); 4.25 in (q, 1H, J=Hz); 4,15 (s, 2H); of 3.75 (s, 3H); of 1.55 (d, 3H, J=7 Hz).

4. (R,S) 2-(2'-benzoylphenyl)propionic acid

Methyl 2-(2'-benzoylphenyl)propionate (1.5 g, 5.9 mmol) is dissolved in methyl alcohol (5 ml). To the solution was added 1M NaOH (7,1 ml) and the resulting solution was refluxed for 3 hours; then it was stirred at room temperature for about 18 hours. The alcohol is then evaporated under reduced pressure, the residue taken up with water; the pH value of the aqueous phase is brought to pH=l, using 1N HCl, and extracted with ethyl ether (3×5 ml). The combined organic extracts washed with saturated solution of NaHCO3, dried over Na2SO4and evaporated under reduced pressure, receiving (R,S) 2-(2'-benzoylphenyl)prop is about acid (1.06 g; was 4.42 mmol) in the form of a clear yellow oil. A yield of 75%.

1H NMR (CDCl3): δ 9,25 (users, 1H, COOH); 7,55-to 7.35 (m, 5H); from 7.24 to 7.15 (m, 2H); 7,10-7,05 (m, 2H); 4.25 in (square, 1H, J=7 Hz); 4,15 (s, 2H); 1.50 in (d, 3H, J=7 Hz).

The same way we obtain the following connections:

Example 22

(R,S) 2-[2'-[2"-chloro)benzyl]phenylpropionate acid

1H NMR (CDCl3): δ 10,0 (users, 1H, COOH); 7,40-7,35 (m, 1H); 7,34-7,25 (m, 3H); 7,20-to 7.15 (m, 2H); 7,10-7,00 (m, 1H); 6,95-to 6.80 (m, 1H); 4,20 (square, 1H, J=7 Hz); of 4.12 (s, 2H); of 1.53(d, 3H, J=7 Hz).

Example 23

(R,S) 2-[2'-(2",6"-dichloro)benzylethanolamine acid

1H NMR (CDCl3): δ of 9.55 (users, 1H, COOH); 7,40-7,30 (d, 2H, J=8 Hz); 7,27-to 7.15 (m, 4H); 6,70-6,60 (d, 1H, J=8 Hz); 4,27 (s, 2H); 4,15 (square, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

Example 24

Receiving (R,S) 2-(2'-phenoxy)phenylpropionic acid

1. Methyl 2-(2'-hydroxy)phenylpropionate

To a solution of 2-(2'-hydroxy)phenylpropionate acid (2 g; 12 mmol) (obtained is known in the literature) in methyl alcohol (10 ml) is added a catalytic amount of concentrated H2SO4(3 drops); the mixture is stirred at room temperature for 18 hours. The solvent is then evaporated and the obtained residue oil is taken in ethyl ether (10 ml); the organic phase is then washed with H2O (3×10 ml), dried over Na2SO4and evaporated, getting 2.17 g (12 mmol) of methyl complex ester as a clear oil. To the quantitative output.

1H NMR (CDCl3): δ 7,30-7,26 (m, 2H); 7,2-to 7.15 (m, 1H); 6.75 in (d, 1H, J=7 Hz); 5,55 (users, 1H, OH); 4,15 (kV, 1H, J=7 Hz); 3,70 (s, 3H); of 1.75 (d, 3H, J=7 Hz).

2. Methyl 2-[2'-(2"-chloro)phenoxy]phenylpropionate

Methyl 2-(2'-hydroxy)phenylpropionate (2 g; 11.1 mmol) dissolved in CHCl3(60 ml); successively added 2-Chlorfenvinphos acid (7,71 g; to 49.3 mmol), copper acetate (3,24 g; 17,82 mmol) and triethylamine (7.7 ml; 5,54 mmol). The resulting solution is refluxed for 24 hours until, until it fades the original product. After cooling to room temperature, the salt is filtered off on a layer of celite; the filtrate was washed with 2n HCl (3×50 ml) and saturated NaCl solution (2×35 ml); the organic phase is dried over Na2SO4and evaporated under reduced pressure, obtaining a dark oily residue, which was purified using flash chromatography (eluent CHCl3/CH3OH 9:1). Methyl 2-[2'-(2"-chloro)phenoxy]phenylpropionate (1,38 g; 5 mmol) was isolated as a clear oil. Yield 45%.

1H NMR (CDCl3): δ 7,45-7,22 (m, 4H); 7,15-was 7.08 (m, 2H); 7,05-to 6.95 (m, 2H); 6,92-to 6.88 (m, 1H); to 4.28 (q, 1H, J=7 Hz); 3,85 (s, 3H); of 1.65 (d, 3H, J=7 Hz).

3. (R,S) 2-[2'-(2"-chloro)phenoxy]phenylpropionate acid

Methyl 2-[2'-(2"-chloro)phenoxy]phenylpropionate (1.3 g; 4.7 mmol) dissolved in dioxane (15 ml). To the solution was added 1M NaOH (4,7 ml) and the solution stirred at room temperature for 1 hours. The solvent is evaporated under reduced pressure and the residue away with water; the pH value of the aqueous phase is brought to pH=1 with concentrated H2SO4and extracted with CHCl3(3×15 ml). The combined organic extracts washed with saturated solution of NaHCO3then a saturated solution of NaCl, dried over Na2SO4and evaporated under reduced pressure, receiving (R,S) 2-[2'-(2"-chloro)phenoxy]phenyl]propionic acid (1.18 g; 4.5 mmol) in a transparent waxy yellow substance. Yield 96%.

1H NMR (CDCl3): δ 7,45-7,22 (m, 4H); 7,15-was 7.08 (m, 2H); 7,05-to 6.95 (m, 2H); 6,92-to 6.88 (m, 1H); of 3.95 (q, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

The same way we obtain the following connections:

Example 25

(R,S) 2-[2'-(2",6"-dichloro)phenoxy]phenylpropionate acid

1H NMR (CDCl3): δ 9,40 (users, 1H, COOH); 7,40-7,30 (d, 2H, J=8 Hz); 7,27-to 7.15 (m, 4H); 6,70-6,60 (d, 1H, J=8 Hz); 3,90 (kV, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

Example 26

Getting 2-(3-methylindol-5-yl)propanoic acid

On the basis of 6-methoxy-l-indanone (commercial reagent) get the desired acid are known from the literature methods, in particular, 6-methoxy-l-indanone is subjected to Wittig reaction (yield 80%) ridom of triphenylmethylchloride, getting derived azomethine that using catalytic hydrogenation (H2/Pd 5%, P atmospheric; yield 95%) to restore the production of the CSOs of methylindenyl. The phenolic groups of the substrate, the processing BBr3are removed the protective group (yield >95%); the corresponding triplet receive as a result of processing the intermediate triftormetilfullerenov anhydride (yield 80%)received triplet subjected to reaction cross combinations (described earlier Stille reaction) with methyl 2-tributylstannyl. The reaction proceeds in good yield (40%), and the thus obtained intermediate compound, 2-methoxycarbonyl isopropane-2-yl, after catalytic hydrogenation to restore the double bond and saponification with KOH/EtOH in a well-known conditions, leads to the production of 2-(3-methylindol-5-yl)propanoic acid with high yields. Output 90%.

1H NMR (CDCl3): δ 7,15-7,05 (m, 3H); 3.75 to (m, 1H); 3.15 in (m, 1H); 2.95 and-2,70 (m, 2H); 2,32 (m, 1H); 1,78 is 1.58 (m, 1H); of 1.50 (d, 3H, J=7 Hz); of 1.35 (d, 3H, J=7 Hz).

A common way to obtain (S) and (R)-2-[(4'-aryl/alkylsulfonyl)phenyl]propionic acid of formula Ia

The separation of the two enantiomers of a commercial reagent, 2-(4'-nitrophenyl)propionic acid, is carried out by crystallization of the corresponding S-(-) or R-(+)-α-phenylethylamine salts in ethanol solution by the method disclosed in H. Akgun et al., Arzneim.-Forsch./Drug Res., 46(11), Nr.9, 891-894 (1996).

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

[α]D=+43,9°(c=2; absolute EtOH);

1H NMR (CDCl3 ): δ 8,15 (d, 2H, J=7 Hz); 7,47 (d, 2H, J=7 Hz); 3,95 (users, 1H, COOH); of 3.78 (m, 1H); of 1.52 (d, 3H, J=7 Hz).

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

[α]D=-43,5° (c=2; absolute EtOH);

1H NMR (CDCl3): δ to 8.12 (d, 2H, J=7 Hz); 7,49 (d, 2H, J=7 Hz); 3,90 (users, 1H, sooN); 3,81 (m, 1H); of 1.50 (d, 3H, J=7 Hz).

Methyl esters of 4'-nitrophenylamino acid

(R)-2-(4'-nitrophenyl)propionic acid (4 mmol) dissolved in methanol (40 ml) and added dropwise 96% H2SO4(0.5 ml). The resulting solution was left under stirring overnight. After evaporation of the solvent the oily residue is dissolved in diethyl ether and the organic phase is washed with a saturated solution of NaHCO3(C ml), dried over Na2SO4and evaporated under reduced pressure, obtaining the desired product in the form of oil pale yellow color.

Methyl ester of (R)-2-(4'-nitrophenyl)propionic acid

[α]D=-48,3°(c=2; absolute EtOH);

1H NMR (CDCl3): δ to 8.12 (d, 2H, J=7 Hz); 7,49 (d, 2H, J=7 Hz); of 3.75 (m, 1H); 3,70 (s, 3H); is 1.51(d, 3H, J=7 Hz).

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

[α]D=+49°(c=2; absolute EtOH);

1H NMR (CDCl3): δ 8,11 (d, 2H, J=7 Hz); 7,49 (d, 2H, J=7 Hz); of 3.78 (m, 1H); 3,68 (s, 3H); is 1.51 (d, 3H, J=7 Hz).

Methyl esters (S)- and (R)-2-(4'-AMINOPHENYL)propionic acid

Both connections get reset the pouring nitro on the way Ram S. et al., Tetrahedron Lett., 25, 3415 (1984) and A.G.M. Barrett et al., Tetrahedron Lett., 29, 5733 (1988).

Methyl ester (S)-2-(4'-AMINOPHENYL)propionic acid

[α]D=+16,5°(C=2; absolute EtOH);

1H NMR (CDCl3): δ a 7.85 (d, 2H, J=7 Hz); was 7.45 (d, 2H, J=7 Hz); 3,81 (m, 1H); to 3.67 (s, 3H); of 1.62(d, 3H, J=7 Hz).

Methyl ester of (R)-2-(4'-AMINOPHENYL]propionic acid

[α]D=-17,1°(c=2; absolute EtOH);

1H NMR (CDCl3): δ a 7.85 (d, 2H, J=7 Hz); was 7.45 (d, 2H, J=7 Hz); 3,81 (m, 1H); 3,66 (s, 3H); of 1.65 (d, 3H, J=7 Hz).

(R)-2-[(4'-aryl/alkylsulfonyl)phenyl]propionic acid

To a solution of the above methyl ether complex (R)-2-(4'-AMINOPHENYL)propionic acid (10 mmol) in acetone (20 ml) was added dry pyridine (15 mmol) or equivalent organic/inorganic base and arylsulfonyl (or alkylsulfonyl) chloride (10 mmol) and the resulting solution was left under stirring overnight. After evaporation of the solvent the oily residue is dissolved in CHCl3(30 ml) and the organic phase washed with water (3×30 ml), dried over Na2SO4and evaporated, obtaining the desired product in the form of pure solids after treatment at room temperature overnight in isopropyl ether and filtration of the precipitate in a vacuum.

To a solution of methyl ether complex (6 mmol) in CH3OH (25 ml) is added 2n NaOH (12 mmol) and the resulting mixture OST is collected under stirring over night at room temperature. CH3OH evaporated and the aqueous basic layer is acidified to pH=2 by adding dropwise 12 n HCl; add ethyl acetate, and the mixture is divided into two phases. The organic extracts washed again with water (3×20 ml), dried over Na2SO4and evaporated under reduced pressure, obtaining a product which is isolated in pure form as solids after treatment at room temperature overnight in n-hexane and filtration of the precipitate in a vacuum (yield 75%-100%).

In accordance with the above-described method are the following compounds:

Example 27

(R) 2-(4'-(benzosulfimide)phenylpropionate acid

[α]D=-56,5°(c=l; absolute EtOH);

1H NMR (CDCl3): δ 9,40 (users, 1H, SO2NH); of 7.70 (d, 2H, J=8 Hz); 7,30 (m, 3H); 7,05 (d, 2H, J=8 Hz); 6,92 (d, 2H, J=8 Hz); of 3.45 (q, 1H, J=7 Hz); 1,22 (d, 3H, J=Hz).

Example 28

(R) 2-(4'-methanesulfonamido)phenylpropionate acid

[α]D= -124,3° (C=l; absolute EtOH);

1H NMR (CDCl3): δ of 7.48 (users, 1H, SO2NH); to 7.35 (d, 2H, J=8 Hz); 7.18 in (d, 2H, J=8 Hz); 6,55 (users, 1H, SO2NH); of 3.80 (q, 1H, J=7 Hz); 3,00 (s, 3H); of 1.55 (d, 3H, J=7 Hz).

Example 29

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

[α]D=-110°(c=l; absolute EtOH);

1H NMR (CDCl3): δ 7,21 (d, 2H, J=8 Hz); 7,05 (d, 2H, J=8 Hz); 6,20 (users, 1H, SO2NH); the 3.65 (q, 1H, J=7 Hz); 3,23 (m, 1H); of 1.50 (d, 3H, J=7 Hz); 1.30 on d, 6H, J=7 Hz).

Example 30

(R) 2-(4'-triftormetilfullerenov)phenylpropionate acid

[α]D=-84,5° (c=l; absolute EtOH);

1H NMR (CDCl3): δ 7,25-7,05 (m, 4H); 7,00 (users, 1H, SO2NH); of 3.60 (q, 1H, J=7 Hz); of 1.41 (d, 3H, J=7 Hz).

Example 31

(R) 2-(4'-benzylmethylamine)phenylpropionate acid

[α]D=-47°(c=l; absolute EtOH);

1H NMR (CDCl3): δ 7,53 (m, 5H); 7,31 (d, 2H, J=7 Hz); 7,15 (users, 1H, SO2NH); 7,02 (d, 2H, J=7 Hz); the 4.65 (s, 2H); of 3.80 (m, 1H); of 1.55 (d, 3H, J=7 Hz).

Example 32

(R) 2-[4'-(2"-chloro)benzosulfimide]phenylpropionate acid

[α]D=-81,5° (c=l; absolute EtOH);

1H NMR (CDCl3): δ to 7.95 (d, 1H, J=8 Hz); 7,40 (m, 2H); 7,22 (m, 1H); 7,10 (m, 2H); to 6.95 (m, 2H+SO2NH); 3,55 (kV, 1H, J=7 Hz); of 1.35 (d, 3H, J=7 Hz).

Example 33

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

Getting 2-ethylbenzaldehyde

On the basis of commercial 2-ethylbenzoyl get related sulfonic acid according to the method, opened W.S. Trahanovsky, "Oxidation in Organic Chemistry", Vol. 5-D, 201-203 Academic Press, Inc., (London), 1982. As a result of processing sulfonic acid with excess thionyl chloride receive 2-ethylbenzonitrile, sufficiently pure for use in the condensation reaction with methyl ether complex R(-)-2-(4'-AMINOPHENYL)propionic acid.

[α]D=-95°(C=l; absolute EtOH);

1H NMR (CDCl3): δ of 9.30 (users, 1H, SO2NH); of 7.70 (d, 2H, J=8 Hz); 7,25 (m, 4H); was 7.08 (d, 2H, J=8 Hz); 3,41 (kV, 1H, J=7 Hz); 2,70 (q, 2H, J=8 Hz); of 1.42 (d, 3H, J=8 Hz); 1,22 (d, 3H, J=7 Hz).

Example 34

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

[α]D=-110°(c=l; absolute EtOH);

1H NMR (CDCl3): δ to 7.95 (d, 2H, J=8 Hz); 7,54 (users, 2H, NSO2NH2); 6,98 (m, 2H+ SO2NH2); 3,57 (kV, 1H, J=Hz); of 1.30 (d, 3H, J=7 Hz).

A common way to obtain (S)- and (R)-2-[(4'-aryl/alkylsulfonate)phenyl]propionic acid of formula Ia

The separation of the two enantiomers of commercial reagent 2-(4'-hydroxyphenyl)propionic acid is carried out by crystallization of the corresponding S(-) or R(+)-α-phenylethylamine salt in ethanol solution, as disclosed H. Akgun et al., Arzneim.-Forsch./Drug Res., 46(II), Nr.9, 891-894 (1996).

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

[α]D=+12°(c=2; absolute EtOH);

1H NMR (CDCl3): δ 7,31 (d, 2H, J=7 Hz); 7,05 (d, 2H, J=7 Hz); 6,25 (users, 1H, OH); of 3.80 (q, 1H, J=7 Hz); of 1.52 (d, 3H, J=7 Hz).

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

[α]D=-1,5°(c=2; absolute EtOH);

1H NMR (CDCl3): δ 7,30 (d, 2H, J=7 Hz); 7,07 (d, 2H, J=7 Hz); 6,35 (users, 1H, OH); of 3.75 (q, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Methyl esters of (R)- and (S)-2-(4'-hydroxyphenyl]-propionic acid

(2R)-2-(4'-hydroxyphenyl)propionic acid (4 mmol) of rest the accelerate in CH 3OH (40 ml) and added dropwise concentrated H2SO4(0.5 ml). The resulting solution was left under stirring overnight. After evaporation of the solvent the oily residue is dissolved in diethyl ether and the organic phase is washed with a saturated solution of NaHCO3(2×30 ml), dried over Na2SO4and evaporated under reduced pressure, obtaining the desired product in the form of oil pale yellow color.

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

[α]D=-78°(c=2; absolute EtOH);

1H NMR (CDCl3): δ to 7.32 (d, 2H, J=7 Hz); 7,10 (d, 2H, J=7 Hz); 6,40 (users, 1H, OH); 3,70 (m, 4H); of 1.53 (d, 3H, J=7 Hz).

(R) 2-[(4'-aryl/alkylsulfonate)phenyl]propionic acid

A mixture of the above methyl ether complex (2R)-2-(4'-hydroxyphenyl)propionic acid (2 mmol) and arylsulfonyl (or alkylsulfonyl)chloride (2 mmol) in dry pyridine (1 ml) or in the presence of equivalent organic/inorganic bases heated at T=60°C within 24 hours. After cooling to room temperature the reaction mixture was poured into 1 n HCl (5 ml) and the aqueous solution extracted with CH2Cl2(3×10 ml). The combined organic extracts washed in countercurrent c 1N NaOH (2×10 ml), dried over Na2SO4and evaporated under reduced pressure to give crude residue, to which a rather clean for to use it in the next stage (output 80-92%).

A mixture of crude methyl ether complex (of 1.85 mmol), glacial acetic acid (2.5 ml) and 37% HCl (0.5 ml) is refluxed for 18 hours. All the solvent is evaporated, the oily residue dissolved in CH2Cl2(5 ml) and the organic phase is washed with NaOH (2×5 ml) and water (2×10 ml), dried over Na2SO4and evaporated under reduced pressure, obtaining the pure (2R) aryl (or alkyl)sulfonylacetanilide acid with a quantitative yield.

In accordance with the above method are the following compounds:

Example 35

(R) 2-(4'-benzosulfimide)phenylpropionate acid

[α]D=-66,2°(c=l; absolute EtOH);

1H NMR (CDCl3): δ a 7.92 (d, 2H, J=7 Hz); of 7.70 (t, 1H, J=7 Hz); EUR 7.57 (t, 2H, J=7 Hz); of 7.25 (d, 2H, J=7 Hz); to 6.95 (d, 2H, J=7 Hz); of 3.75 (q, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Example 36

(R) 2-(4'-benzylmalonate)phenylpropionate acid

[α]D=-84,6°(c=l; absolute EtOH);

1H NMR (CDCl3): δ to 7.50 (m, 5H); 7,28 (d, 2H, J=7 Hz); 7,05 (d, 2H, J=7 Hz); a 4.53 (s, 2H); of 3.77 (m, 1H); of 1.52 (d, 3H, J=7 Hz).

Example 37

(R) 2-(4'-tripterocalyx)phenylpropionate acid

[α]D=-28/5° (c=l; CH3OH);

1H NMR (CDCl3): δ was 7.45 (d, 2H, J=7 Hz); 7,22 (d, 2H, J=7 Hz); 3,82 (kV, 1H, J=7 Hz); is 1.51 (d, 3H, J=7 Hz).

Example 38

(R) 2-[4'-(2"-propane)sulfanilic and]phenylpropionate acid

[α]D=-42,8° (c=l; CH3OH);

1H NMR (CDCl3): δ 7,41 (d, 2H, J=7 Hz); of 7.25 (d, 2H, J=7 Hz); 3,82 (kV, 1H, J=7 Hz); of 3.45 (d, 3H, J=7 Hz); of 1.52 (m, N).

Example 39

(R) 2-[4'-(2"-chloro)benzosulfimide)phenylpropionate acid

[α]D=-43° (c=l; absolute EtOH);

1H NMR (CDCl3): δ of 7.90 (d, 1H, J=8 Hz); 7,44 (m, 2H); 7,20 (m, 1H); for 7.12 (m, 2H); to 6.95 (d, 2H, J=8 Hz); 3,52 (kV, 1H, J=7 Hz); to 1.38 (d, 3H, J=7 Hz).

Example 40

(R) 2-[4'-(2"-ethyl)benzosulfimide]phenylpropionate acid

Getting 2-ethylbenzaldehyde

On the basis of commercial 2-ethylbenzoyl get related sulfonic acid according to the method, opened W.S. Trahanovsky, "Oxidation in Organic Chemistry", Vol. 5-D, 201-203 Academic Press, Inc., (London), 1982.

As a result of processing sulfonic acid with excess thionyl chloride receive 2-ethylbenzonitrile, sufficiently pure for use in the condensation reaction with (R)-methyl ether complex of 2-(4'-hydroxyphenyl)propionic acid.

[α]D=-104° (c=l; absolute EtOH);

1H NMR (CDCl3): δ 7,71 (d, 2H, J=8 Hz); 7,25 (m, 4H); for 7.12 (d, 2H, J=8 Hz); 3,44 (kV, 1H, J=7 Hz); a 2.71 (q, 2H, J=8 Hz); of 1.45 (d, 3H, J=8 Hz); of 1.20 (d, 3H, J=7 Hz).

Example 41

(R) 2-(4'-aminosulfonyl)phenylpropionate acid

[α]D=-91,5° (c=l; absolute EtOH);

1H NMR (CDCl3): δ to 7.95 (d, 2H, J=8 Hz); 7,84 (users, 2H, NSO2NH2); to 6.95 (d, 2H, J=8 Hz); 3,61 (who, 1H, J=HZ); to 1.35 (d, 3H, J=7 Hz).

The method of obtaining (S)- and (R)-2-(4'-aryl/alkylsulfonamides)propionic acids of formula Ia

Example 42

(R) 2-(4'-benzosulfimide)phenylpropionate acid

Specified in the header of the product is obtained in the multi-stage synthesis proceeding from commercially available (R)-2-phenylpropionic acid. In accordance with the method disclosed in EP 0889020 (Example 4), with good output receive (R)-2-[(4'-chloromethyl)phenyl]propionic acid. The above acid is transformed into methyl ester in the usual way and the ester is added to the cold mixture sensation/tert-piperonyl potassium/18-crown-6 (1:1,1:0.95) and, after the reaction over night, and normal processing (washing with water, drying over Na2SO4and evaporation of the solvent), allocate net derivative sensationalise and used in the next stage of oxidation. As a result of oxidation related to sulfone two equivalents of 3-chloroperoxybenzoic acid and final treatment with a mixture of NaOH/dioxane at room temperature to produce the desired product with a good final output (65%) from (R)-2-[(4'-chlorotrityl)phenyl]propionic acid).

[α]D=-125° (c=l; absolute EtOH);

1H NMR (CDCl3): δ of 7.90 (m, 2H); 7,44-7,20 (m, 3H); for 7.12 (d, 2H, J=8 Hz); to 6.95 (d, 2H, J=8 Hz); and 3.72 (s, 2H); 3,55 (kV, 1H, J=7 Hz); USD 1.43 (d, 3H, J=7 Hz).

Example 43

(R) 2-(4'-triptorelin lformer)phenylpropionate acid

In accordance with the method disclosed in U.S. patent 5245039 (14/09/1993), and based on methyl ether complex (R)-2-[(4'-chloromethyl)phenyl]propionic acid get related (R)-2-[(4'-thiomethyl)phenyl]propionic acid with high yield (85%). As a result of processing tialata (formed "in situ" 1 equivalent of tert-butoxide potassium) commercial triptoreline get derived cryptomaterial. Subsequent oxidation to the sulfone derivative (by treatment with 2 equivalents of 3-chloroperoxybenzoic acid) and final hydrolysis of ester a mixture of NaOH/dioxane at room temperature allows you to select the product with a fairly good yield (47%, from (R)-2-[(4'-chloromethyl)phenyl]propionic acid).

[α]D=-86°(c=l; absolute EtOH);

1H NMR (CDCl3): δ 7,14 (d, 2H, J=8 Hz); 7,02 (d, 2H, J=8 Hz); 3,85 (s, 2H); 3,51 (kV, 1H, J=7 Hz); to 1.48 (d, 3H, J=7 Hz).

A list of structures of examples

1. Compounds (R,S)-2-propionic acids of formula (Ia) and (R)- and (S)-enantiomers

and their pharmaceutically acceptable salt,

where Ar represents a phenyl ring substituted in the 4-(para) position with a group selected from C1-C5-sulfonyloxy, resumes the frame benzosulfimide or benzosulfimide, substituted group selected from C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro or cyano groups, C1-C5-alkanesulfonyl, unsubstituted, benzosulfimide or benzosulfimide substituted group selected from C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro, or cyano groups, C1-C5-alkanesulfonyl, unsubstituted benzosulfimide or benzosulfimide substituted group selected from C1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro or cyano groups.

2. Compounds according to claim 1, selected from

(R)2-(4'-tripterocalyx)phenylpropionic acid,

(S)2-(4'-tripterocalyx)phenylpropionic acid,

(R)2-(4'-benzosulfimide)phenylpropionic acid,

(S)2-(4'-benzosulfimide)phenylpropionic acid,

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

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

(R)2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionic acid,

(S)2-[4'-(2"-chloro)phenylsulfonyl]phenylpropionic acid,

(R)2-[4'-(2"-about the Academy)sulfonyloxy]phenylpropionic acid,

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

(R)2-(4'-benzylmalonate)phenylpropionic acid,

(S)2-(4'-benzylmalonate)phenylpropionic acid,

(R)2-(4'-aminosulfonyl)phenylpropionic acid,

(S)2-(4'-aminosulfonyl)phenylpropionic acid,

(R)2-(4'-triftormetilfullerenov)phenylpropionic acid,

(S)2-(4'-triftormetilfullerenov)phenylpropionic acid,

(R)2-(4'-methanesulfonamido)phenylpropionic acid,

(S)2-(4'-methanesulfonamido)phenylpropionic acid,

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

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

(R)2-(4'-benzosulfimide)phenylpropionic acid,

(S)2-(4'-benzosulfimide)phenylpropionic acid,

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

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

(R)2-[4'-(2"-chloro)benzosulfimide]phenylpropionic acid,

(S)2-[4'-(2"-chloro)benzosulfimide]phenylpropionic acid,

(R)2-(4'-benzylmethylamine)phenylpropionic acid,

(S)2-(4'-benzylmethylamine)phenylpropionic acid,

(R)2-(4'-aminosulfonyl)phenylpropionate sour is you,

(S)2-(4'-aminosulfonyl)phenylpropionic acid,

(R)2-(4'-triftormetilfullerenov)phenylpropionic acid,

(S)2-(4'-triftormetilfullerenov)phenylpropionic acid,

(R)2-(4'-benzosulfimide)phenylpropionic acid,

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

3. The compound according to any one of claims 1 and 2, suitable as pharmaceuticals.

4. The use of compounds according to any one of claims 1 and 2 to obtain a drug suitable for the treatment of diseases caused by chemotaxis of neutrophils induced by IL-8.

5. The use of compounds according to any one of claims 1 and 2 to obtain a drug suitable for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous bladderworts, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia or reperfusion.

6. Pharmaceutical composition having inhibitory activity against the chemotaxis of neutrophils induced IL-8 comprising a compound according to any one of claims 1 and 2 in a mixture with a suitable a carrier.

7. Method of preparing compounds according to claim 1, where Ar represents a C1-C5-sulfonyloxy or benzensulfonamidelor, enabling the th interaction of esters 4-hydroxyphenylpropionic acids with the corresponding 1-C5-sulphonylchloride or benzosulfimide in the presence of a suitable organic or inorganic bases.

8. Method of preparing compounds according to claim 1, where Ar represents a C1-C5-sulfonylamino or benzosulfimide, including the interaction of esters 4-aminophenylamino acids with the corresponding1-C5-sulphonylchloride or benzosulfimide in the presence of a suitable organic or inorganic bases.

9. Method of preparing compounds according to claim 1, where Ar represents a C1-C5-sulfonylmethane or benzosulfimide, including the interaction of esters 4-chloromethylene-propionic acid with the appropriate1-C5-thiolate or sensationally in the presence of a suitable organic or inorganic bases.



 

Same patents:

FIELD: organic chemistry, pharmacy, pharmacy.

SUBSTANCE: invention relates to novel compounds designated for delivery of active substances to tissues of the following formula: wherein values of radicals R1-R7 are determined in claim 1 of the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to compositions designated for delivery of active substances to tissues and containing: (A) active substance and (B) at least one compound designated for delivery of active substance to animal tissues of the formula: wherein values of radicals R1-R7 are determined in claims 3-5 of the invention claim. Also, proposed invention relates to a standard medicinal formulation designated for delivery of active substances to body tissues and to a method for preparing indicated compositions and administration of substances for their delivery to body tissues.

EFFECT: valuable properties of compounds.

23 cl, 11 tbl, 11 ex

The invention relates to methods for derivatives phenoxyalkanoic acid, namely 2,4-dichloroacetylene acid, which are used as herbicides for cereal crops

The invention relates to new intermediate products-compounds: (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-Piran-2-ONU, [3(R), 6(R)]-5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)propyl] -6-[1-(2-phenyl)ethyl] -6-propyl-2H-Piran-2-ONU, [3(R), 6(R)] -5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl] -6-[1-(2-phenyl)ethyl]-6-propyl-2H-Piran-2-ONU, as well as to improved methods of producing an intermediate product of the formula (CVI), where R1represents C1-C6alkyl, -CH2-CH2-фенилR1-1where R1-1represents H, where R2represents C1-C6alkyl, -CH2-CH2-фенилR1-1where R1-1represents N.

The invention relates to new bicyclic aromatic compounds of General formula (I) having the ability to bind RXRand pharmaceutical compositions based on them, which can be used in medicine, veterinary medicine and in cosmetics

The invention relates to new derivatives of benzofuran-2-ones of formula 1, where a value of substituents specified in paragraph (1 formulas that can be used as stabilizers for organic polymers susceptible to oxidative, thermal or induced light decay

The invention relates to a new process for the preparation of 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I)

OCOOH

(I) This connection is used for regulating the level of blood lipids

The invention relates to a method for producing new derivatives benzocycloheptene acids

The invention relates to new ligands X-receptor retinoic acid of the formula I, where R1- R7, R10X and communications, indicated by the dotted line have the meanings specified in the description

The invention relates to new aromatic carboxylic acid derivative of the formula (I) where R1radical of formula (a), R2- C2-8- alkanoyl, C2-8- alkyl, C2-8alkenyl, C2-8- quinil or OCH2R3or R1- the remainder of the formula (V), R2- C2-8-alkanoyl, C2-8alkenyl, C2-8- quinil or OCH2R3, R3- C1-6-alkyl, C2-6alkenyl or C2-6-quinil; R4-R9independently from each other hydrogen or C1-5- alkyl, or R8and R9together denote (CRaRb)n, Raand Rbis hydrogen or C1-5-alkyl, n = 1, 2, or 3, and R4- R7have the specified values, or R8and R9together denote (CRaRb)nand R4and R6together is methylene or ethylene which may be substituted by a hydroxyl group, and Ra, Rb, R5, R7and n have the above meanings; R10- carboxyl or C1-6-alkoxycarbonyl, and the dotted bond in the formula (a) is optional, and pharmaceutically acceptable salts of carboxylic acids of the formula I

The invention relates to a new polyene compounds of formula I, where R1- COR9; R2, R4, R6is hydrogen; R3, R5, R10, R11is hydrogen or lower alkyl; R7- cycloaliphatic radical or lower alkyl; R8- radical-O-CH2-OCH2-CH2-O-CH3or or11; R4and R6taken together may form with the adjacent benzene cycle naphthalene cycle; R9- O-R10as well as their salts and their optical and geometric isomers

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

The invention relates to organic chemistry, particularly to a method of obtaining 5,8-dihydroxy-2,3,6-trimetoksi-7-ethyl-1,4-naphthoquinone, which is an intermediate in the synthesis 2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone (echinochrome A), the beginning of the current cardioprotective and ophthalmic drug histogram
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