2-arylpropynic acid derivatives and pharmaceutical compositions including them

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of (R)-2-arylpropionamides of general formula I, in which Ar is phenyl group, substituted in 3(meta) position by group R1, selected from: linear or branched C1-C8-alkanoyl, C3-C6- cycloalkanoyl, heteroarylcarbonyl, C1-C6-alkylaminocarbonyl, arylaminocarbonyl, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamino, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C6-aryloxycarbonyl, C1-C8-alkansulfonyl, arylsulfonyl, or 3,4-dihydro-1H-quinolyl-2-on; R is selected from: -H, OH; - heteroaryl group is selected from: pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole; - α or β carboxyl residue can consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted with other carboxyl (COOH) group; - residue with formula SO2Rd, in which Rd is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl or pyridyl, on condition that compounds of formula I are not the following compounds: (R)-2-(3-phenoxyphenyl)-propanoyl-phenylglycine; (R)-2-( phenoxyphenyl)-propanoyl-glycine; (R)-2-[(3'-acetyl)phenyl]-R-4''-pyrimidyl)propionamide. Invention also relates to method of obtaining formulaI compound and application of formula I compound for preparation of medications for treatment of diseases including C5a induced hemotaxis of human PMNs.

EFFECT: obtained are novel derivatives of (R)-2-arylpropionamide, possessing useful biological properties.

9 cl, 3 dwg, 2 tbl, 34 ex

 

Brief description of the invention

The present invention relates to new compounds useful for the inhibition of the chemotactic activation induced component C5a complement. These compounds are useful in the treatment of pathologies associated with chemotactic activation of neutrophils and monocytes induced component C5a complement. In particular, the compounds are useful in the treatment of sepsis, psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of lesions caused by ischemia and reperfusion.

The prior art to which the invention relates

Regarding immunological and infectious phenomena activation of the complement system mediates in amplification of the inflammatory response as through direct membrane action, and through the allocation of a series of peptide fragments, in General, known as anaphylatoxin obtained by enzymatic cleavage of C3, C4 and C5 component of complement. These peptides include C3a and C4a, both containing 77 amino acid residue; in turn, C5 convertase cleaves C5 component of complement, giving glycoprotein C5a, containing 74 amino acid residue.

C5a peptide fragment of complement was on Oprah Ellen as "the ultimate" Pro-inflammatory mediator, thanks to its chemotactic and inflammatory action. In fact, other inflammatory mediators, such as certain cytokines (such as IL-8, MCP-I and RANTES), vysokoselektivnye in relation to "self-attracted" cells (cells hemotoxicity attracting cells of the same species), while others, such as histamine and bradykinin, are weak chemotactic agents.

Proof of in vivo involvement of C5a in some pathological conditions, including ischemia/reperfusion injury, autoimmune dermatitis, membrane-idiopathic proliferative glomerulonephritis, irresponsiveness respiratory tract and chronic inflammatory diseases, respiratory distress syndrome and COPD, Alzheimer's disease, a form of rheumatoid arthritis in children (N.P. Gerard, Ann. Rev. Immunol., 12, 755, 1994).

In view of the neuro-inflammatory potential of C5a/C5a-desArg formed by as the local activation of complement and amyloid activation associated with astrocytic and microglial the chemotaxis and activation, directly induced by C5a, have been proposed inhibitors of compliment for the treatment of neurological diseases such as Alzheimer's disease (McGeer &McGeer P.L., Drugs, 55, 738, 1998).

In addition, control of the synthesis component of complement is regarded as a promising therapeutics the th goal for treatment of shock and prevent rejection in organ transplantation (multiple organ failure and hypertree rejection of the graft) (A.C. Issekutz et al., Int. J. Immunopharmacol, 12, 1, 1990; R. Inagi et at., Immunol. Lett., 27, 49, 1991). Recently it was reported that the method of inhibiting a component of complement was included to prevent damage to native and transplanted kidneys, taking into account the role of complement in the pathogenesis of chronic interstitial and acute glomerular kidney disease. (Sheerin N.S. & Sacks S.H., Curr. Opinion Nephrol. Hypert., 7, 395, 1998).

The characteristic accumulation of neutrophils occurs in acute and chronic pathological conditions, for example, in highly inflamed and resistant to therapy areas of psoriatic lesions. Neutrophils hemotoxicity are attracted and activated by the synergistic action of chemokines, IL-8 and Gro-α, secreted by stimulated keratinocytes, and C5a/C5a-desArg component produced with alternative ways of activation of complement (T. Terui et al., Exp. Dermatol., 9, 1, 2000)Nedavno we have described a new class of substances omega-aminoalkylated R-2-arylpropionic acids” as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells” (WO 02/068377). Specified new class includes compounds with a range from selective C5a inhibitors to dual C5a/IL-8 inhibitors.

In addition, Quaternary ammonium salts omega-aminoalkylation R-2-arylpropionic acids was reported as selective inhibitors of C5a inducir the bath chemotaxis of neutrophils and monocytes (WO 03/029187).

Recently we have described a new class of “2-arylpropionate” (WO 00/24710) and 2R-arylpropionate” (WO 02/58858), “2-arylpropionic acid (WO 03/043625) and 2-alloxane acid (WO 04/069782) as a strong and selective inhibitors induced CXCL8 of PMN chemotaxis of human rights. It was found that the compounds described in the above patent applications, inhibit CXCL8-induced chemotaxis polymorphonuclear (PMN) at concentrations in the range of 10-7M to 10-9M; for comparison, the compounds of the present invention does not inhibit C5a and f-MLP-induced PMN chemotaxis in the same concentration range.

Then, the authors describe a new class of omega-aminoalkylated R-2-arylpropionic acids as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells, indicated by anaphylatoxin C5a” (WO 02/068377). In this patent application, the authors reported that the omega amino group substitutes associated with N, is a key function (pharmacophoric point) for the presence of C5a inhibitory activity. It was found that some compounds corresponding to the invention, is able to inhibit both C5a and CXCL8 induced PMN chemotaxis flexible (from 2 to 4 atoms) spacer between the amino group and the primary balance. The key role of basic, positively charged parts for C5a inhibition confirmation is by the activity of the corresponding Quaternary ammonium salts, as described in (WO 03/029187).

Detailed description of the invention

At the present time, the authors were surprised to find a certain class of 2-R-arylpropionate and 2-R-arylpropionate that even in the absence of omega-aminoalkyl groups demonstrate a strong and selective inhibitory effect aimed at C5a-induced chemotaxis of PMN man.

Currently, the authors found that certain 2-R-arylpropionate and 2-R-arylpropionate with ACCEPTOR HYDROGEN bonds (atom/group), located in the well known position of the chemical space, show surprisingly powerful inhibitory effect aimed at C5a-induced chemotaxis of PMN man. Interestingly, these compounds are totally deprived CXCL8 inhibitory effect.

The concept of pharmacophore is defined as the combination of steric and electronic features in the group of biologically active compounds necessary for proper biological activity. In General, pharmacophore can be considered as a combination of steric and electronic features that is necessary to ensure certain interactions between biologically active compound and its biological target.

Calculated pharmacophor-model for inhibition of C5a is shown in Fig. 1. New pharmacophore-the hotel shares four of the five functions with the previous described pharmacophores, relevant CXCL8 inhibitors (WO 04/069782); four General functions (Options 1-4) are completely compatible in 3D chemical space.

Function 5, the corresponding additional Acceptor Hydrogen bonds characteristic of pharmacophore corresponding C5a inhibitors. The presence of scheme 5 is the reason for the high efficiency and the observed C5a/CXCL8 selectivity of the corresponding compounds. In fact, all the connections, it is appropriate pharmacophore model, shown in figure 1, lose their inhibitory effect against CXCL8.

Table 1 shows the set of selected examples of effective and selective CXCL8 inhibitors. Compounds devoid of additional group - acceptor hydrogen bonds, do not show any inhibitory activity against C5a (paragraphs, tables 1, 2 and 3).

Previously it was reported that amide derivatives and sulphonamide Ketoprofen (paragraphs, tables 4 and 5) are selective CXCL8 inhibitors with a slight inhibitory activity against C5a induced the chemotaxis of PMN.

Noteworthy is the fact that amide derivatives of Ketoprofen (paragraphs, tables 4 and 5) may work well under C5a-pharmacophore hypothesis from a geometrical point of view; in accordance with this observation, we observed moderate inhibitory activity at high concentration c=10 -6M) of the drug (table 1).

It is well known that carbonyl group of the benzophenone is extremely weak HYDROGEN bond ACCEPTOR due to the strong electron-withdrawing effect of the two phenyl groups; thus, the derivative of Ketoprofen does not satisfy pharmacophore hypothesis because the electronic properties of this group. Accordingly, the strengthening of the hydrogen-bond-acceptor characteristics of the groups in the field of 5 - ACCEPTOR HYDROGEN bonds in good agreement with the growth inhibitory potential against C5a (as examples see Examples 1-4 in Table 2) and at the same time, with the loss of inhibitory activity against CXCL8.

Compatible with model for selected compounds of this new class of C5a inhibitors shown in Fig. 2a and Fig. 2b.

The FORMATION of PHARMACOPHORE

The formation of pharmacophore was carried out using the software CatalystTMversion 4.7 (Molecular Simulations, Inc., San Diego, CA), which is intended to identify the basic configurations of the active molecules through their chemical functions. A configuration is a set of relative locations in 3D space, where each is associated with a function type. All compounds in the training series were characterized in terms of their chemical function is s, associate in 3D space. In addition, each chemical can be considered by the program as more than one function based on the identified similarity. For example, the aromatic ring can install as hydrophobic interactions and π-π interaction at the target site, and a different action refers to a variety of functions (HYDROPHOBIC,HYDROPHOBIC AROMATIC).

Functional group in the molecule may be associated with more than one function depending on its chemical and physical properties, and different functional groups may exhibit similar behavior when interacting with the target, thus reaching the same function.

Analysis of function definitions and function selection is a key step in the creation of pharmacophore hypothesis. It is well known that the most important forces involved in the recognition molecules are represented by electrostatic interactions, hydrogen bonds and hydrophobic interactions. The authors adopted the definition of individual functions, which include the chemical nature of the group to the possibility of the presence of valuable specific interactions responsible for the biological activity.

DEFINING FUNCTIONS

The HYDROGEN bond ACCEPTOR (HBA) (lipid)

The function of the hydrogen bond acceptor lipid selects the I of the following types of atoms and groups of atoms with available surface: nitrogen, oxygen or sulphur (except hypervalent), which have lone-pair and charge less than or equal to zero.

After consideration of the environment lipids all primary amines (primary, secondary and tertiary) are included in this definition. The hydrogen bond is characterized by a strictly direct interaction; this function is thus indirectly related to theoretical location of the appropriate donor of hydrogen. Three positions of the hydrogen bonds, for example in the case of the carbonyl group (acceptor): the first two in the direction of the (ideal) to the lone pairs and the third along the direction of the C=O connection.

The HYDROGEN bond DONOR (HBD)

The hydrogen bond donor is selected from the following types of atoms or groups of atoms with available surface:

sour hydroxyl, thiol, acetylene hydrogen and hydrogen at the nitrogen (except tetrazoles and trifluoromethyl sulfonamidnuyu hydrogen).

As a donor hydrogen bonds is not selected nitrogen, which could protonemata due to its high basicity.

HYDROPHOBIC (aliphatics, aromatics)

Hydrophobic function is defined as continuously connected set of atoms that are not located near charged or electronegative atoms, conformare, so that these atoms have available surface. The guide is Afonya groups include: phenyl, cycloalkyl, isopropyl and methyl.

However, it was necessary to distinguish between aromatic hydrophobic function and aliphatic in order to have good agreement with biological characteristics.

The model included only the aromatic atoms, then only aliphatic atoms.

Molecule involves configuration, unless she has a set of corresponding functions and specific conformation, such that its functions can be combined with the corresponding “ideal” positions. The set of functions can be considered compatible if each function is located within the boundaries of tolerance, which is located at a certain distance from the corresponding ideal point position.

Description of figures

Figure 1 graphically shows the five pharmacophoric features of the inhibitors of C5a. The following types of functions involved in pharmacophoric parts: three Hydrogen bond Acceptor, one Hydrophobic Aromatic and one Hydrophobic Aliphatic function. Appropriate (aromatic and aliphatic) hydrophobic functions are represented as spheres with a radius of 1.7 means that the Acceptor hydrogen bonds are represented by a vector function, including two spheres whose centers of mass are at a distance of 3.0 that is Smaller (1.7 km E radius) sphere determines the location of the atom acceptor hydrogen the Oh connection on the ligand, and a big sphere (2,3, E) determines the projected point of the hydrogen bond acceptor on the website of the receptor.

Figures 2a and 2b illustrate the compatibility of the selected arylpropionic derivatives corresponding to Formula I with pharmacophore model, shown in Fig. 1.

2a) is Represented by compounds corresponding to Formula I: (R)-2-[(2-aksakal-2-yl)phenyl]propionamide (example 14), (R)-2-(3-benzosulfimide)propionamide (example 19) and N-{(R)-2-[3-furan-2-carbonyl)]propionyl}methanesulfonamide (example 23)

2b) is Represented by compounds corresponding to Formula I: (R)-2-[3-(2-methoxyphenoxy)phenyl]propionamide (example 10); (R)-2-[3-(2-methoxybenzylamine)phenyl]propionamide (example 12); (R)-2-[3-(pyridine-2-ylamino)phenyl]propionamide (example 13).

COORDINATES

The absolute coordinates of the centers of mass of the spheres of each function in Fig. 1 below:

Common functions

Function 1

HYDROPHOBIC AROMATIC has Cartesian coordinates +2,588, +0,613, -1,940 respectively along the XYZ axes.

Function 2

HYDROPHOBIC ALIPHATIC has Cartesian coordinates +1,788, +2,693, +1,260 respectively along the XYZ axes.

Function 3

The PROJECTION POINT of ACCEPTOR HYDROGEN bonds has Cartesian coordinates -2,713, +2,333, +2,840 respectively along the XYZ axes.

The STARTING POINT of a HYDROGEN bond ACCEPTOR 1 has Cartesian coordinates -0,233, +0,936, +1,877 respectively along the XYZ axes.

Options the I 4

The PROJECTION POINT of the HYDROGEN bond ACCEPTOR 2 (optional) has Cartesian coordinates -5,013, -1,188, -0,400 respectively along the XYZ axes.

The STARTING POINT of a HYDROGEN bond ACCEPTOR 2 (optional) has Cartesian coordinates -2,688, -1,514, +1,472 respectively along the XYZ axes.

Function 5

The PROJECTION POINT of the HYDROGEN bond ACCEPTOR 3 has Cartesian coordinates -2,093, +3,893, +3,452 respectively along the XYZ axes.

The STARTING POINT of a HYDROGEN bond ACCEPTOR 3 has Cartesian coordinates -1,815, +1,640, +1,497 respectively along the XYZ axes.

The presence of features 1, 2, 3, 5 (HYDROPHOBIC ALIPHATIC, HYDROPHOBIC, AROMATIC, HYDROGEN bond ACCEPTOR 1, HYDROGEN bond ACCEPTOR 3) is necessary for biological C5a inhibitory activity of the corresponding class (connections).

Function 4 (ACCEPTOR HYDROGEN bonds 2) can be optionally presented by molecules of the specified class, but a second group of acceptor hydrogen bond is not essential.

Tolerance for all distances between the chemical functions was set to +0.5, and tolerance for geometric angles of ±20°.

The present invention relates to (R)-2-arylpropionate corresponding to the formula (I):

(I)

in which

Ar - e is about a phenyl group, substituted in the 3 (meta) position by a group R1choose from:

linear or branched C1-C8alkanoyl, C1-C6cycloalkenyl, heteroarylboronic, C1-C6-alkylaminocarbonyl, arylenecarborane, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamine, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C1-C6-aryloxyalkyl, C1-C8-alkanesulfonyl, arylsulfonyl, or if R1represented by the amino group, as defined above, R1forms a 5-7 membered cycle with a different substituent in the 4 position;

R is chosen from:

Is H, OH, C1-C5-alkyl, C3-C6-cycloalkyl, C2-C5-alkenyl, C1-C5-alkoxy;

- heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole;

α or β carboxialkilnuyu the remainder may consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C1-C6-phenylalkyl optionally substituted another carboxyl (COOH) group;

- balance formula SO2Rd, in which Rd is a C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6alkenyl, aryl, heteroaryl.

Preferred are those compounds according to dtweedie the invention, in which:

Ar is a phenyl group substituted in position 3 (meta) group R1choose from:

linear or branched C1-C8alkanoyl; 2-furil, 2-oxazolyl, 3-isoxazolyl, 2-benzoxazolyl, 3-benzisoxazole, 2-thiazolyl, 2-pyridyl; furancarboxylic; benzofuranyl; thiophencarboxylic; pyridylcarbonyl; benzylaminocarbonyl; C1-C6-acylamino; benzoylamine; aryloxy; arylamino, or R1forms coupled bicyclic system, selected from 3-4-dihydro-1H-chinolin-2-it, 1,3-dihydroindol-2-it, 1,3,4,5-tetrahydrobenzo[b]azepin-2-it;

R is chosen from:

Is H, OH, C1-C5-alkyl;

- 2-pyridyl, 2-thiazolyl; carboxialkilnuyu group may consist of straight or branched C1-C6-alkyl, C1-C6-phenylalkyl;

the remainder with the formula SO2Rd, in which Rd is a C1-C6-alkyl.

Examples of most preferred compounds of formula (I):

(R)-2-(3-isobutylphenyl)propionate,

(R)-2-(3-cyclopentanecarbonitrile)propionamide,

(R)-2-[(3-(furan-2-carbonyl)phenyl]propionamide,

(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]propionamide,

(R)-2-[(3-(thiazole-2-carbonyl)phenyl]propionamide,

(R)-2-[(3-(oxazol-2-carbonyl)phenyl]propionamide,

3-((R)-1-carbamoylethyl)-N-(2,6-dichlorophenyl)benzamide,

3-((R)-1-carbamoylethyl)-N-(2,6-dimetilfenil)benzamid,

3-((R)-1-carbamoylethyl)-N-(3-chloropyridin-2-yl)benzamid,

(R)-2-[3-(2-methoxyphenoxy)phenyl)propionamide,

(R)-2-[3-(2-chlorobenzylamino)phenyl]propionamide,

(R)-2-[3-(2-methoxybenzylamine)phenyl]propionamide,

(R)-2-[3-(pyridine-2-ylamino)phenyl]propionamide,

(R)-2-(3-oxazol-2-yl)phenyl]propionamide,

(R)-2-(3-furan-2-yl)phenyl]propionamide,

(R)-2-(oxo-1,2,3,4-tetrahydroquinolin-7-yl)propionamide,

(R)-2-(3-benzosulfimide)propionamide,

2-(3-acetylaminophenol)propionamide,

2-(3-benzoylamino)propionamide,

N-[(R)-2-(3-cyclopentanecarbonitrile)propionyl]methanesulfonamide,

N-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionyl}methanesulfonamide,

N-{(R)-2-[3-(5-methylfuran-2-carbonyl)phenyl]propionyl}methanesulfonamide,

N-{(R)-2-[(3-(thiophene-2-carbonyl)phenyl]propionyl}methanesulfonamide,

N-{(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]propionyl}methanesulfonamide,

N-{(R)-2-[(3-(oxazol-2-carbonyl)phenyl]propionyl}methanesulfonamide,

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-pyrid-2-ylpropionic,

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(2H-thiazol-2-yl)propionamide,

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide,

(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide,

(R)-2-(3-cyclopentanecarbonyl)-N-pyrid-3-ylpropionic,

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-hydroxypropionate,

(R)-2-[3-(thiazole-2-carbonyl)FeNi is]-N-hydroxypropionate,

2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}propionic acid,

2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}acetic acid.

Compounds corresponding to the invention, is an effective inhibitor of chemotaxis of human PMNs induced by C5a.

Thus, another objective of the present invention is the use of compounds of the formula (I)in the preparation of medicaments for the treatment of diseases, including C5a-induced PMNs chemotaxis of human rights.

To obtain compounds of the formula (I), used known methods of obtaining amides and arylsulfonamides (reaction Menshutkin); the corresponding carboxylic acid, in which Ar is defined above, to react with amines or sulfonamide of the formula RNH2where R is defined above, in the presence of normal activating the carboxyl group of reagents in accordance with the methods previously described in WO 01/58852; WO 00/24710 and WO 02/068377.

The compounds of formula (I), corresponding to the invention were tested in vitro for their ability to inhibit chemotaxis of polymorphonuclear leukocytes (below used to reduce PMNs) and monocytes induced C5a and C5a-desArg components of complement. To highlight PMNs from heparinised human blood collected from healthy adult volunteers, mononuclear cells (adnade the data cells) were separated by sedimentation on dextran (in accordance with the procedure described in W.J. Ming et al., J. Immunol., 138, 1469,1987), and red blood cells by hypotonic solution. Cell viability was calculated by the elimination method using Trypanosoma blue, while the ratio of circulating polymorphonuclear (polymorphonuclear cells) was estimated at cytocentrifuge after staining using Diff Quick (set for coloring).

Recombinant fraction C5a and C5a-desArg person (Sigma) were used as stimulating agents in the experiments with chemotaxis, giving almost identical results.

Dried C5a was dissolved in a volume of HBSS containing 0.2% bovine serum albumin BSA, in order thus to obtain a basic solution with a concentration of 10-5M for further dilution in HBSS to a concentration of 10-9M for chemotaxis experiments.

In experiments on the chemotaxis of PMNs were incubated with compounds of formula (I), corresponding to the invention, for 15' at 37°C in atmosphere containing 5% CO2. Chemotactic activity of C5a was evaluated on circulating polymorphonuclear person (PMNs) resuspending in HBSS to a concentration of 1.5×106PMNs in ml.

During chemotactic studies (in accordance with W. Falket et al., J. Immunol. Methods, 33, 239,1980used “PVP-free” (not containing pyridine) Phi is try with a porosity of 5 μm and microcamera suitable for this test.

The compounds of formula (I), corresponding to the invention was tested with a concentration lying between 10-7and 10-10M; that is, they were added at the same concentration as in the bottom hole and the top hole of microcamera. Holes in the lower part contained a solution of C5a or simple media, holes in the upper part contained a suspension of PMNs.

Inhibitory activity of C5a-induced chemotaxis through individual compounds of the invention of formula (I) was evaluated by incubation of microcamera for chemotaxis for 60 min at 37°C in atmosphere containing 5% CO2.

Evaluation of the ability of the compounds of the invention of formula (I) to inhibit C5a-induced chemotaxis of human monocytes was carried out in accordance with the method described by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989). Inhibitory activity of C5a-induced chemotaxis of individual compounds conforming to the invention, of the formula (I) in relation to human monocytes was evaluated at a concentration lying between 10-7and 10-10M by incubation of microcamera for chemotaxis for 120 min at 37°C in atmosphere containing 5% CO2.

As an example, the data of inhibition of PMN chemotaxis (concentration between 10-7and 10-8M) some typical examples of compounds suitable is relevant to the invention, are given in Table 2.

The compounds of formula (I) were assessed ex vivo in blood in toto in accordance with the procedure described Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705, 1994. In almost all cases, the compounds of formula (I) does not affect the formation of PGE2induced in mouse macrophages by stimulation with lipopolysaccharide (LPS, 1 μg/ml) at a concentration lying between 10-5and 10-7M. Inhibition of education PGE2mainly, in the limit of statistical significance and, in General, lower than 15-20% of the base value.

Thus, a further aim of the present invention is the use of compounds of the invention as pharmaceuticals.

In view of the experimental data discussed above and the role of the complement cascade, namely, its component C5a, in the process, which involves the activation and infiltration of neutrophils, compounds corresponding to the invention, practically useful in the treatment of diseases, such as psoriasis (R. J. Nicholoff et al., Am. J. Pathol., 138, 129,1991), bullous pemphigoid, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463,1981), chronic intestinal inflammatory diseases, such as ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273,1992), acute respiratory distress syndrome and idiopathic fibrosis (E. J. Miller, previously cited, and P. C. Carre et al., J. Clin. Invest., 88, 1882,991 ), cystic fibrosis, COPD, glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135,1994and prevention and treatment of damages caused by ischemia and reperfusion.

In addition, the compounds corresponding to the invention is particularly useful in the treatment of sepsis.

In vivo activity in the treatment of sepsis has been demonstrated, as set forth below:

Ligation of the cecum and puncture (CLP)

We used the sample murine polymicrobial sepsis and infected tissue (in accordance with the procedure described P. Villa et al., Journal of Endotoxin Research, 1997, 43 (3), 197-204), on the basis of surgically created diverticulum the caecum, which was then punctilobula to create extensive peritonitis.

Polymicrobial sepsis caused by legirovaniem the caecum and puncture (CLP)in mice leads to inflammation and pathological effects of infiltration by neutrophils lung syndrome respiratory disorders in adult (ARDS) and death.

After anesthesia, the mice were subjected to 1 cm laparotomy, and the cecum was isolated. Cecum was luigirules below the ileocecal valve (without obstruction), punctured on antimesenteric side of the needle 18 size, slightly crushed, to ensure that the hole is open, and then placed back into the abdominal cavity. The incision was closed and the mice were brought into consciousness by 1 ml of saline races the thief subcutaneously.

"Placebo"-operation (simulating surgery) was performed similarly, except that the intestine was not functionals. Antibiotics (gentamicin sulfate 3.2 mg/kg and clindamycin phosphate 40 mg/kg) was administered subcutaneously once daily for 3 days immediately after surgery. Survival was monitored twice a day for 10 days. Animals were selected randomly in the groups to which it was applied only to the media, or in groups, to which was applied the treatment, 8-15 individuals in the group.

Typical examples of the compounds of the present invention have demonstrated activity in the treatment of sepsis in the concentration range from 1 to 50 mg/kg

For this connection, corresponding to the invention, of the formula (I) are readily prepared in a pharmaceutical composition using conventional techniques and excipients, such as described in "Remington''s Pharmaceutical Sciences Handbook", MACK Publishing, New York, 18th ed.,1990.

Compounds corresponding to the invention can be applied by intravenous injection as a bolus, in the form of drugs applied to the skin (creams, lotions, sprays and ointments), by inhalation, and oral in the form of capsules, tablets, syrup, compositions with controlled release and such.

The average daily dose depends on several factors, such as the severity of Soboleva what I status, age, gender and weight of the patient. Dose, in General, will range from 1 to 1500 mg per day of the compounds of formula (I), optionally separated for repeated administration.

The following examples illustrate the invention.

Materials and methods

Amines of the formula RNH2used as reagents to obtain the compounds of formula (I)are known products, in General, commercially available or they can be obtained in accordance with the methods described in the literature.

Synthesis of 2-arylpropionic acids of the formula ϕ-Ar3-C(CH3)H-CO2H and R-enantiomers is described in International patent application WO 01/58852.

List of abbreviations: THF: tetrahydrofuran; EtOAc: Ethyl acetate; MeOH: methanol; EtOH: ethanol; DCC: 1,3-Dicyclohexylcarbodiimide; DCU: 1,3-Dicyclohexylmethane; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene.

Preparation of intermediates 2-arylpropionic acids

A. 2-[(3-chlorocarbonyl)phenyl]propionitrile

Commercially available 2-[(3-carboxy)phenyl]propionitrile (1.0 g, 5,70 mmol) was dissolved in SOCl2(5 ml) and the resulting solution was stirred at boiling for 3 hours After cooling to room temperature the mixture was evaporated under reduced pressure, which gave 2-[(3-chlorocarbonyl)phenyl]propionitrile in the form of a yellow oil with an almost quantitative yield.

Century 2-(3-AMINOPHENYL)is propionitrile

To a solution of 2-[(3-chlorocarbonyl)phenyl]propionitrile (2.5 g, of 14.25 mmol) in CH2Cl2(15 ml) was added tetrabutylammonium bromide (0.07 mmol)and the mixture was cooled to 0°C. Under vigorous stirring was added a solution of sodium azide (1,275 grams of 19.5 mmol) in H2O (5 ml) and the resulting mixture was stirred at 0°C for 2 hours the Resulting precipitate was filtered, the organic phase containing the corresponding acylated, washed with H2O (3×25 ml), dried over Na2SO4and used as is in the next stage. The organic solution was treated triperoxonane acid (21,38 mmol) and boiled for 48 hours after the reaction triperoxonane acid was evaporated under reduced pressure, the residue was diluted with CH2Cl2(50 ml), washed sequentially with saturated solution of NaHCO3(2×25 ml) and H2O (50 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained 2-[(3-triptoreline)phenyl]propionitrile.

A mixture of 2-[(3-triptoreline)phenyl]propionitrile (2.5 g, 9.25 mmol) and K2CO3(2.55 g, 17.6 mmol) in H2O/CH3OH (3:1) (50 ml) was heated at 60°C for 16 hours After cooling to room temperature and evaporation of methanol, the remaining aqueous phase was extracted with CH2Cl2(3×25 ml). The collected organic extracts were dried over Na2SO4 and evaporated under reduced pressure, which gave 2-(3-AMINOPHENYL)propionitrile in the form of a yellowish oil (1.2 g, 8,32 mmol). Yield 58%.

1H-NMR (CDCl3): δ was 7.08 (m, 1H); only 6.64 (m, 2H); to 6.57 (m, 1H); and 3.72 (q, 1H, J=7 Hz); 3,65 (USS, 2H, NH2); and 1.54 (d, 3H, J=7 Hz).

C. 2-(3-hydroxyphenyl)propionitrile

2-(3-AMINOPHENYL)propionitrile (1.0 g, of 6.75 mmol) suspended in water (12 ml), then with vigorous stirring was added dropwise H2SO4(1.5 ml, 27 mmol). After stirring for 20 min the mixture was cooled to 4°C, was added dropwise a solution of NaNO2(0,466 g of 6.75 mmol) in water (5 ml) and the resulting solution was stirred at boiling for 1 h, After cooling to room temperature, to the mixture was added ethyl acetate (10 ml), the crude product was extracted and the organic phase washed with water (3×10 ml) and brine (saturated NaCl solution in water) (3×10 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained 2-(3-hydroxyphenyl)propionitrile in the form of a yellow oil with an almost quantitative yield.

1H-NMR (CDCl3): δ 7,20 (d, 1H); to 6.88 (d, 1H, J=7 Hz) 6,80-6,72 (m, 2H); 4,90-4,60 (USS, 1H, OH); of 3.75 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

D. 2-(3-iodophenyl)propionitrile

2-(3-AMINOPHENYL)propionitrile (1.0 g, of 6.75 mmol), obtained as previously described, suspended in water (12 ml) and with stirring was added dropwise 37 HCl (1.6 ml, a 20.2 mmol). After 5 min the mixture was cooled to 4°C, was added dropwise NaNO2(0,466 g of 6.75 mmol)dissolved in water (5 ml)and the resulting solution was stirred for 20 minutes To a solution of the derived benzodiazepi chloride was added dropwise an aqueous solution (5 ml), KI (1.13 g, 6,76 mmol) at 4°C and the resulting mixture was stirred for 3 hours To the mixture was added EtOAc (15 ml), the crude product was extracted and washed with water [extract] (3×10 ml) and brine (3×10 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained 2-(3-iodophenyl)propionitrile in the form of a yellow oil (1.4 g, 5.4 mmol). Yield 80%.

1H-NMR (CDCl3): δ the 7.65 (d, 1H, J=7 Hz); 7,30-7,02 (m, 3H); of 3.80 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

General procedure for the optical purification of (R) enantiomers

Optical clearing of all racemic acids, obtained by the below described procedures were carried out according to the method described in Akgün, H.; et al., Arzneim.-Forsch./Drug Res. 1996, 46(II), 891-894, and using the most suitable chiral amines.

(R)-2-[3-(isobutyryl)phenyl]propionic acid(I)

The reaction was carried out in accordance with the following procedure, described in R. A. Grey, J. Org. Chem. 1984, 49, 2288-2289.

To a suspension of ZnCl2(0,390 g, to 2.85 mmol) in 5 ml dry THF at 0°C under nitrogen atmosphere was added commercially available Isopropylamine chloride (2M in Et2O, to 2.85 ml, 5,70 mmol). After p is remesiana for 20 min was added the catalyst (dppf)PdCl 2(1%, 0,057 mmol) and then was added dropwise a solution of 2-(chlorocarbonyl)phenylpropionitrile (5,72 mmol), prepared as described above in dry THF (5 ml). The mixture was stirred for 1 h at 0°C, then 3 h at room temperature. After cooling to 0°C was added 3N HCl (10 ml) and Et2O (30 ml). The aqueous layer was separated and the organic layer was washed sequentially with saturated solution of NaHCO3(2×30 ml) and brine (30 ml). After drying of Na2SO4and evaporation of the solvent under reduced pressure received product after flash chromatography (eluent n-hexane/EtOAc 95:5) gave 2-[3-(isobutyryl)phenyl]propionitrile in the form of a yellow oil (0,804 g, with 4.64 mmol). Yield 81%.

1H-NMR (CDCl3): δ 7,86 (s, 1H); 7,76 (d, 1H, J=7 Hz); 7,45-7,35 (m, 2H); of 3.84 (q, 1H, J=7 Hz); of 3.45 (m, 1H); by 1.68 (d, 3H, J=7 Hz); 1,1 (q, 6H, J=7 Hz).

To a solution of 2-[3-(isobutyryl)phenyl]propionitrile (0,93 g, to 4.62 mmol) in 10 ml of dioxane was added 37% HCl (10 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated, was added to the residue cold water (10 ml) and EtOAc (15 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to precipitate the acid. After deposition of 2-[3-(isobutyryl)phenyl]propionic acid was isolated by filtration pure product in the form of solid substances is TBA white (0,86 g, 3.95 mmol). Yield 85%.

[α]D25(c=1, EtOH): -38°;1H-NMR (CDCl3): δ 10,6 (USS, 1H, COOH); 7,86 (s, 1H); 7,76 (d, 1H, J=7 Hz); 7,45-7,35 (m, 2H); with 3.79 (q, 1H, J=7 Hz); of 3.45 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 1,1 (d, 6H, J=7 Hz).

In accordance with the same experimental procedure and using the appropriate commercial Grignard reagents as the source, were synthesized following connections:

(R)-2-[3-(cyclopentanecarbonyl)phenyl]propionic acid(II)

[α]D25(c=1, EtOH): -43°;1H-NMR (CDCl3): δ 7,86 (m, 1H); 7,79 (d, 1H, J=7 Hz); 7,52 (d, 1H, J=7 Hz); 7,37 (m, 1H); 3,82 (kV, 1H, J=7 Hz); 3,71 (m, 1H); 2,22 (m, 2H); for 2.01 (m, 3H); to 1.82 (m, 3H); was 1.58 (d, 3H, J=7 Hz).

(R)-2-[3-(oxazol-2-carbonyl)phenyl]propionic acid(III)

From the commercial reagent 2-(3-carboxy)phenylpropionitrile by following the procedures described in Harn, N. K. et al., Tetrahedron Letters, 1995, 36(52), 9453-9456, received 2-[3-(1,3-oxazol-2-ylcarbonyl)phenyl]propionic acid.

To a solution of oxazole (0.5 ml, 7.6 mmol) in 50 ml THF at -78°C under nitrogen atmosphere was added n-BuLi (of 1.6 M solution in hexane, to 4.7 ml of 7.60 mmol). After stirring for 20 min was added ZnCl2(2,071 g of 15.2 mmol), the mixture was brought to 0°C and stirred for 45 minutes and Then was added CuI (1.45 g, 7.6 mmol) and after 20 min was added dropwise a solution of 2-(chlorocarbonyl)phenylpropionitrile (15,2 mmol), obtained as described previously, in 10 ml of THF. The mixture was stirred for 2 hours the Organic phase is abbasli EtOAc and washed sequentially with saturated solution of NaHCO 3(2×50 ml) and brine (50 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure, the obtained residue, which after flash chromatography gave 2-[3-(oxazol-2-carbonyl)phenyl]propionitrile in the form of a yellow oil (1.27 g, 5,63 mmol). Yield 74%.

1H-NMR (CDCl3): δ 8,48 (m, 2H); of 7.70 (s, 1H); to 7.61 (d, 1H, J=7 Hz); 7,46 (t, 1H, J=7 Hz); 7,28 (s, 1H); 4,03 (kV, 1H, J=7 Hz); at 1.73 (d, 3H, J=7 Hz).

To a solution of 2-[3-(oxazol-2-carbonyl)phenyl]propionitrile (1 g, 4,43 mmol) in 10 ml of dioxane was added 37% HCl (10 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated, and was added to the residue cold water (10 ml) and EtOAc (15 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to precipitate the desired acid. After deposition, after filtration was obtained pure 2-[3-(oxazol-2-carbonyl)phenyl]propionic acid in the form of a solid white color (0.87 g, 3.54 mmol). Yield 80%.

[α]D25(c=1, EtOH): -43° (38%),1H-NMR (CDCl3): δ to 8.45 (m, 2H); of 7.90 (s, 1H); to 7.68 (d, 1H, J=7 Hz); 7,50 (t, 1H, J=7 Hz); 7,38 (s, 1H); 3,90 (kV, 1H, J=7 Hz); and 1.56 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using the thiazole as starting reagent was synthesized by the following connection:

(R)-2-[3-(thiazole-2-carbonyl)phenyl]impregnated the new acid (IV)

[α]D25(c=1, MeOH): -36°,1H-NMR (CDCl3): δ 8,44 (m, 2H); 8,10 (d, 1H, J=3 Hz); 7,73 (d, 1H, J=3 Hz); 7,63 (d, 1H, J=7 Hz); 7,51 (t, 1H, J=7 Hz); 3,90 (kV, 1H, J=7 Hz)and 1.60 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using furan as a source of reagent was synthesized by the following connection:

(R)-2-[3-(furan-2-carbonyl)phenyl]propionic acid(V)

[α]D25(c=1, MeOH): -41°,1H-NMR (CDCl3): δ 7,86 (m, 1H); of 7.82 (m, 1H, J=7 Hz); to 7.64 (s, 1H); 7,49 (m, 1H); 7,41 (m, 1H); 7,16 (d, 1H, J=7 Hz); 6,53 (m, 1H); with 3.79 (q, 1H, J=7 Hz); is 1.51 (d, 3H, J=7 Hz).

(R)-2-[3-(benzofuran-2-carbonyl)phenyl]propionic acid(VI)

From commercially available reagent 2-(3-carboxy)phenylpropionitrile by following the procedures described in Galli C., Synthesis, 1979, 303-304, was synthesized 2-[3-(benzofuran-2-carbonyl)phenyl]propionic acid.

To a solution of 2-(3-carboxy)phenylpropionitrile (1,03 g, 5,88 mmol) in 50 ml of dry acetonitrile under nitrogen atmosphere was added 2,3-benzofuran (1.65 ml, 14.7 mmol) and triperoxonane anhydride (3.3 ml, 23,52 mmol). The mixture was stirred 5 h the Solvent was evaporated under reduced pressure, the residue was diluted with CHCl3and washed successively with saturated solution of NaHCO3(2×50 ml) and brine (50 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure, the obtained residue, which after flash chromatographical 2-[3-(benzofuran-2-carbonyl)phenyl]propionitrile in the form of a yellow oil (1,05 g, is 3.82 mmol). Yield 65%.

1H-NMR (CDCl3): δ 8,04 (m, 2H); 7,76 (d, 1H, J=8 Hz); 7.68 per-rate of 7.54 (m, 5H); of 7.36 (m, 1H); 4,03 (kV, 1H, J=7 Hz); of 1.74 (d, 3H, J=7 Hz).

To a solution of 2-[3-(benzofuran-2-carbonyl)phenyl]propionitrile (1 g, 3.63 mmol) in 10 ml of dioxane was added 37% HCl (10 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated and added to a draught of cold water (10 ml) and CHCl3(15 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to pH=2 and an acidic phase was extracted with CHCl3(3×10 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure after filtration was obtained pure 2-[3-(benzofuran-2-carbonyl)phenyl]propionic acid as white powder (1.06 g, of 3.60 mmol). Quantitative output.

[α]D25(c=1, EtOH): -58° (35%),1H-NMR (CDCl3): δ of 7.82 (s, 1H); 7,72 (d, 1H, J=8 Hz); 7,51 (d, 1H, J=8 Hz); 7,42 (d, 2H, J=8 Hz); 7,28 (t, 2H, J=8 Hz); 7,11 (t, 1H, J=8 Hz); 6,38 (m, 1H); 4,23 (USS, 1H, COOH); the 3.65 (q, 1H, J=7 Hz); of 1.36 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using 2-methylfuran as a source of reagent, were synthesized following connections:

(R)-2-[3-(5-methylfuran-2-carbonyl)phenyl]propionic acid(VII)

[α]D25(c=1, MeOH): -72°,1H-NMR (CDCl3): δ 7,94 (m, 1H); 7,56 (m, 3H); ,10 (d, 1H, J=4 Hz); and 6.25 (d, 1H, J=4 Hz); of 3.85 (q, 1H, J=7 Hz); 2,52 (s, 3H); of 1.64 (d, 3H, J=7 Hz).

(R)-2-[3-(2,6-dichlorophenylamino)phenyl]propionic acid(VIII)

To a solution of commercial 2,6-dichloroaniline (1.4 g, 8,64 mmol) and pyridine (0,69 ml, 8,64 mmol) in 10 ml dry CH2Cl2at room temperature was added dropwise 2-[(3-chlorocarbonyl)phenyl]propionitrile (1,67 g, 8,64 mmol), prepared as described earlier. The mixture was stirred over night at room temperature. The reaction mixture was cooled to 0°C, was added 1N HCl and the organic phase is washed 1N HCl (2×10 ml). The organic layer was washed sequentially with saturated solution of NaHCO3(2×30 ml) and brine (30 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained pure 2-[3-(2,6-dichlorophenylamino)phenyl]propionitrile in the form of a yellow oil (1,929 g, 6.05 mmol), yield (70%).

1H-NMR (DMSO-d6): δ 10,4 (USS, 1H, CONH); 8,10-of 8.25 (m, 2H); 7,80-of 7.55 (m, 5H); was 4.02 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

To a solution of 2-[3-(2,6-dichlorophenylamino)phenyl]propionitrile (1,929 g, 6.05 mmol) in 15 ml of dioxane was added 37% HCl (8 ml). The mixture was stirred at 40°C overnight. After cooling to room temperature, the dioxane was evaporated, was added to the residue cold water (10 ml) and EtOAc (15 ml). The two phases were shaken and separated, the organic layer was extracted with 1N NaOH (2×5 ml). The collected primary aq is m extracts was added 37% HCl to precipitate the desired acid. After deposition, after filtration was obtained pure 2-[3-(2,6-dichlorophenylamino)phenyl]propionic acid as white solid (1,32 g, 3.93 mmol). Yield 40%.

[α]D25(c=1, EtOH): -32° (30%),1H-NMR (DMSO-d6): δ 10,4 (USS, 1H, CONH); 8,12 were 8.22 (m, 2H); 7,75-of 7.60 (m, 5H); of 3.95 (q, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

In accordance with the same experimental procedure and using the appropriate commercially available aniline derivatives were synthesized following connections:

(R)-2-[3-(2,6-dimethylphenylcarbamate)phenyl]propionic acid(IX)

[α]D25(c=1, EtOH): -32°,1H-NMR (DMSO-d6): δ 9,75 (USS, 1H, CONH); 8,00-of 7.90 (m, 2H); 7,60-7,40 (m, 3H); 7,10 (s, 2H); 3,70 (kV, 1H, J=7 Hz); of 2.15 (s, 6H, J=7 Hz); of 1.35 (d, 3H, J=7 Hz).

(R)-2-[3-(3-chloropyridin-2-ylcarbonyl)phenyl]propionic acid(X)

[α]D25(c=1, EtOH): -28°,1H-NMR (CDCl3): δ 8,70 (USS, 1H, CONH); to 8.20 (d, 1H, J=9 Hz); 7,80-to 7.68 (m, 3H); 7,40-to 7.18 (m, 3H); of 3.80 (q, 1H, J=7 Hz); was 1.58 (d, 3H, J=7 Hz).

(R)-2-{3-[(2-methoxy)phenoxy]phenyl}propionic acid(XI)

The reaction was carried out following the procedures described in D. A. Evans et al., Tetrahedron Letters, 1998, 39, 2937-2940.

To a solution of 2-(3-hydroxyphenyl)propionitrile (amount of 0.118 g, 0.80 mmol), prepared as previously described, in dry CH2Cl2(6 ml), was added molecular sieves (4E), CuOAc (0,145 mg, 0.80 mmol) and pyridine (0.33 ml, 4.0 mmol. After stirring for 20 min was added to commercially available 2-methoxyphenylalanine acid (0,243 g to 1.60 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was cooled to 0°C, was added 0,5N HCl and the organic phase was washed (3×10 ml), 0,5N HCl. After drying over Na2SO4and evaporation of the solvent under reduced pressure, the obtained residue, which after flash chromatography (eluting the mixture of n-hexane/EtOAc 9:1) gave 2-{3-[(2-metoxy)phenoxy)phenyl]propionitrile in the form of a yellowish oil (0.172 g, of 0.68 mmol). Yield 85%.

1H-NMR (CDCl3): δ 7,20-7,10 (m, 2H); 6,98-to 6.80 (m, 5H); 6,70 (d, 1H, J=7 Hz); of 3.75 (s, 3H); of 3.48 (q, 1H, J=7 Hz); of 1.45 (d, 3H, J=7 Hz).

To a solution of 2-{3-[(2-methoxy)phenoxy)phenyl]propionitrile (0.17 g, of 0.68 mmol) in 5 ml of dioxane was added 37% HCl (5 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated, was added to the residue cold water (10 ml) and ethyl acetate (10 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to precipitate the desired acid. After deposition, after filtration was obtained pure 2-{3-[(2-methoxy)phenoxy)phenyl]propionic acid in the form of a waxy substance white (0,166 g, 0.61 mmol). Output 90%.

[α]D25(c=1, EtOH): -41° (38%),1 H-NMR (CDCl3): δ 7,22 for 7.12 (m, 2H); 7,00-6,85 (m, 5H); 6,72 (d, 1H, J=7 Hz); of 3.75 (s, 3H); 3,55 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

(R)-2-[3-(2-chlorobenzylamino]phenyl]propionic acid(XII)

From 2-(3-amino)phenylpropionitrile and on the following described procedures (J. P. Wolfe et al., J. Am. Chem. Soc., 1996, 118, 7215-7216, J. P. Wolfe et al., Tet. Lett., 1997, 38, 6359-6362, J. P. Wolfe et al., J. Org. Chem., 2000, 65, 1144-1157, Ferreira, I. C. F. R. et al., Tetrahedron, 2003, 59, 975-981), was synthesized 2-[3-(2-chlorobenzylamino)phenyl]propionic acid.

A mixture of 2-bromochlorobenzene (of 0.58 ml, 5.5 mmol), 2-(3-amino)phenylpropionitrile (0,72 g, 5 mmol), Pd(OAc)2(3 mol.%), rac-BINAP (4 mol.%) and Cs2CO3(2.28 g, 7 mmol) in dry toluene (15 ml) was filled in an Ar atmosphere in provincewide the flask Slanka, and the mixture was heated at 100°C for 20 h After cooling to room temperature was added water (25 ml) and Et2O (25 ml). The phases were separated, and the aqueous phase was extracted with Et2O (2×10 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure, the obtained residue, which after flash chromatography gave 2-[3-(2-chlorobenzylamino)phenyl]propionitrile in the form of a colorless oil (0.64 g, 2.5 mmol). The yield is 50%.

1H-NMR (CDCl3): δ 7,22 (d, 1H, J=3 Hz); to 7.09 (m, 1H); 7,00 (m, 1H); 6,72 (m, 2H); only 6.64 (m, 2H); to 6.57 (m, 1H); 4,15 (USS, 1H, NH); of 3.75 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

To a solution of 2-[3-(2-chlorobenzylamino)phenyl]propionitrile (0.64 g, 2.5 mmol) in dioxane (10 ml) was added 37% HCl (2 ml). CME is ü stirred at 70°C for 4 hours After cooling to room temperature, the dioxane was evaporated, and was added to the residue cold water (10 ml). The aqueous phase is neutralized 2N NaOH and was extracted with (3×10 ml) CHCl3. After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained pure 2-[3-(2-chlorobenzylamino)phenyl]propionic acid as white powder slightly (0,67 g, 2.45 mmol). Exit 98%.

[α]D25(c=1, MeOH): -42° (30%),1H-NMR (DMSO-d6): δ 7,22 (d, 1H, J=3 Hz); to 7.09 (m, 1H); 7,05 (m, 1H); 6,72 (m, 2H); only 6.64 (m, 2H); to 6.57 (m, 1H); 4,15 (USS, 1H, NH); of 3.85 (q, 1H, J=7 Hz); of 1.62 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using commercially available 2-bromoanisole as a source of reagent, the following compounds was synthesized:

(R)-2-[3-(2-methoxybenzylamine]phenyl]propionic acid(XIII)

[α]D25(c=1, MeOH): -27°,1H-NMR (DMSO-d6): δ 7,52 (d, 1H, J=7 Hz); 7,25 (m, 1H); was 7.08 (m, 1H); to 6.80 (m, 2H); 6,62 (m, 2H); 6,50 (m, 1H); 4,15 (USS, 1H, NH); of 3.80 (s, 3H); and 3.72 (q, 1H, J=7 Hz); of 1.52 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using commercially available 2-bromopyridin as a source of reagent, the following compound was obtained:

(R)-2-[3-(2-pyridin-2-ylamino]phenyl]propionic acid(XIV)

[α]D25(c=1, MeOH): -31°,1H-NMR (DMSO-d6): δ 8,15 (USS, 1H, CONH); to 7.50 (m, 1H); 7,15-6,98 (m, 3H) 6,90 (m, 1H); PC 6.82 (m, 2H); 6.75 in (m, 1H); 3,55 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

(R)-2-(3-oxazol-2-ylphenyl)propionic acid(XV)

The reaction was carried out following the procedure described in A. Suzuki et al., Syn. Commun. 1981, 11, 513-519.

To a solution of 2-(3-iodophenyl)propionitrile (0.6 g, of 2.33 mmol) in dry THF (10 ml)were successively added in a nitrogen atmosphere Pd(PPh3)4(4% mol, 0.108 mg) and Na2CO3(0,493 g of 4.66 mmol). After stirring for 20 min was added commercially available 1,3-oxazol-2-Bronevoy acid (0,289 g, 2.56 mmol). The reaction mixture is boiled for 4 hours After cooling to room temperature, THF was evaporated under reduced pressure, EtOAc (10 ml) was added to the crude product, the organic phase is washed with water (3×10 ml) and brine (3×10 ml). After drying over Na2SO4and evaporation of the solvent was obtained residue, which after flash chromatography (eluting the mixture of n-hexane/EtOAc 8:2) gave 2-(3-oxazol-2-ylphenyl)propionitrile in the form of a yellow oil (0,360 g, 1.82 mmol). Yield 78%.

1H-NMR (CDCl3): δ of 8.09 (s, 1H); 7,98-to 7.93 (m, 1H); of 7.70 (s, 1H); was 7.45 (m, 2H); to 7.25 (s, 1H); of 3.85 (q, 1H, J=7 Hz); was 1.58 (d, 3H, J=7 Hz).

To a solution of 2-(3-oxazol-2-ylphenyl)propionitrile (0,360 g, 1.82 mmol) in 5 ml of dioxane was added 37% HCl (5 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated and added to the remainder of the cold water (10 ml) and EtOAc (10 ml). Two f the PS were shaken and separated, and the organic phase was extracted with 1N NaOH (2×5 ml). The mixture was acidified to pH=1 2N HCl, the crude product was extracted with CH2Cl2(3×10 ml). The collected organic extracts were dried over Na2SO4after evaporation of the solvent under reduced pressure was obtained pure 2-(3-oxazol-2-ylphenyl)propionic acid as a colourless oil (0,360 g of 1.66 mmol). Yield 92%.

[α]D25(c=1, EtOH): -33° (38%),1H-NMR (CDCl3): δ 8,07 (s, 1H); 7,95-of 7.90 (m, 1H); of 7.70 (s, 1H); 7,44 (m, 2H); 7.23 percent (s, 1H); 3,82 (kV, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

In accordance with the same experimental procedures, and using 2-Farnborough acid as starting reagent was synthesized by the following connection:

(R)-2-(3-furan-2-ylphenyl)propionic acid(XVI)

[α]D25(c=1, EtOH): -32°,1H-NMR (CDCl3): δ 7.68 per-7,58 (m, 2H); of 7.48 (s, 1H); 7,35-7,25 (m, 2H); of 6.68 (d, 1H, J=4 Hz); 6.48 in (DD, 1H, J1=4 Hz, J2=2 Hz); of 3.80 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

(R)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]propionic acid(XVII)

To a solution of 2-(3-AMINOPHENYL)propionitrile (0,500 g, to 3.38 mmol), prepared as described earlier, in CH2Cl2(8 ml) was added a solution of Et3N (0,515 ml, 3.72 mmol) and 3-chloropropionyl) chloride (0,355 ml, 3.72 mmol) in CH2Cl2(4 ml). The reaction mixture was stirred at boiling for 5 hours After cooling to room temperature the mixture RA is bavili CH 2Cl2(10 ml), the organic phase is washed KH2PO4buffer solution (pH=5) (3×10 ml) and brine (2×10 ml). After drying over Na2SO4and evaporation of the solvent under reduced pressure was obtained pure 2-[3-(3-chloropropylamine)phenyl]propionitrile in the form of a colorless oil (0,654 g, 2.77 mmol). Yield 82%.

1H-NMR (CDCl3): δ 8,00 (USS, 1H, CONH); 7,50-7,46 (m, 2H); 7,20 (m, 1H); 7,05 (d, 1H, J=7 Hz); of 3.95 (q, 1H, J=7 Hz); of 3.75 (m, 2H); 2.50 each (m, 2H)and 1.60 (d, 3H, J=7 Hz).

To a solution of 2-[3-(3-chloropropylamine)phenyl]propionitrile (0,654 g, 2.77 mmol) in CH2Cl2(8 ml) at 0°C was added in portions AlCl3(1.10 g, 8,31 mmol). The reaction mixture was stirred for 5 minutes, then boiled under reflux for 8 hours After cooling to 0°C the mixture was washed with 6N HCl solution (3×10 ml), water (3×10 ml) and brine (2×10 ml). After drying over Na2SO4and evaporation of the solvent was obtained a crude residue, which after flash chromatography (eluting the mixture of n-hexane/EtOAc 85:15) gave 2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]propionitrile in the form of a yellow oil (0,345 g, 1,72 mmol). Yield 62%.

1H-NMR (CDCl3): δ 8,00 (USS, 1H, CONH); 7,46 (s, 1H); 7.18 in (d, 1H, J=7 Hz); 7,05 (d, 1H, J=7 Hz); 3,90 (kV, 1H, J=7 Hz); 2,90 (m, 2H); of 2.56 (m, 2H); was 1.58 (d, 3H, J=7 Hz).

To a solution of 2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]propionitrile (0,345 g, 1,72 mmol) in 5 ml of dioxane was added 37% HCl (5 ml). The mixture was stirred at 40°C during the night. Polioksidony to room temperature, the dioxane was evaporated, was added to the residue cold water (10 ml) and EtOAc (15 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to precipitate the desired acid. After deposition, after filtration was obtained pure 2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]propionic acid in the form of a solid white color (0,293 g of 1.34 mmol). Yield 78%.

[α]D25(c=1, EtOH): -40° (35%),1H-NMR (CDCl3): δ 8,02 (USS, 1H, CONH); 7,46 (s, 1H); 7.18 in (d, 1H, J=7 Hz); 7,05 (d, 1H, J=7 Hz); 3,86 (kV, 1H, J=7 Hz); 2,90 (m, 2H); of 2.56 (m, 2H); of 1.55 (d, 3H, J=7 Hz).

(R)-2-[3-(benzazolyl))phenyl]propionic acid(XVIII)

The reaction was carried out following the procedure described in H. Suzuki et al., Tetrahedron Letters 1995, 36, 6239-6242.

To a solution of 2-(3-iodophenyl)propionitrile (0.6 g, of 2.33 mmol) in DMF (8 ml) was added under nitrogen atmosphere CuI (0,658 g of 3.45 mmol) and commercially available sodium salt of benzosulfimide acid (0,612 g, 3.73 mmol). The mixture was stirred 6 h at 110°C. the Conversion was monitored by TLC (thin layer chromatography, TLC). After cooling to room temperature, water (15 ml) and Et2O (12 ml) was added to the solution, the organic phase was separated, washed with brine (3×10 ml) and dried over Na2SO4. Removal (evaporation) of the solvent under reduced pressure gave an oily residue, which was purified chromatographically, is using n-hexane/EtOAc 9:1) to highlight 2-[3-benzazolyl)phenyl]propionitrile in the form of a yellowish oil (0,38 g, of 1.40 mmol). Yield 60%.

1H-NMR (CDCl3): δ 7,98 to 7.75 (m, 4H); 7,60-to 7.35 (m, 5H); 3,55 (kV, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

To a solution of 2-[3-benzazolyl)phenyl]propionitrile (0,38 g of 1.40 mmol) in 5 ml of dioxane was added 37% HCl (5 ml). The mixture was stirred at 70°C for 4 h After cooling to room temperature, the dioxane was evaporated and added to the remainder of the cold water (10 ml) and ethyl acetate (10 ml). The two phases were shaken and separated, the organic phase was extracted with 1N NaOH (2×5 ml). To the collected basic aqueous extracts were added 37% HCl to precipitate the desired acid. After deposition, after filtration was obtained pure 2-[3-benzazolyl)phenyl]propionic acid in the form of a solid white color (0,324 g, 1.12 mmol). Yield 80%.

[α]D25(c=1, EtOH): -29°,1H-NMR (CDCl3): δ of 7.96 to 7.75 (m, 4H); 7,62-7,38 (m, 5H); 3,50 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Synthesis of amides of formula (I)

Example 1

(R)-2-[3-(isobutyryl)phenyl]propionamide

(R)-2-(3-isobutylphenyl)propionic acid (I) (0,61 g, 2,78 mmol) was dissolved in SOCl2(5 ml) and the resulting solution was stirred while boiling 3 hours After cooling to room temperature the mixture was evaporated under reduced pressure; the crude acylchlorides was dissolved in dry THF (5 ml) and cooled to 0-5°C. Dry ammonia gas was in excess is passed through the mixture under vigorous stirring. Conversion is definitely the Lyali TLC; after complete disappearance of the original reagent, the solvent was evaporated under reduced pressure, the residue was diluted with CHCl3(10 ml) and water (10 ml); the two phases were shaken and separated, the organic phase is washed with saturated solution of NaHCO3(3×10 ml) and water (2×10 ml), dried over Na2SO4and was evaporated in vacuo, which gave pure (R)-2-(3-isobutylphenyl)propionate (0.56 g, 2.58 mmol) as a colourless oil. Yield 93%.

[α]D25(c=1, EtOH): -35°,1H-NMR (CDCl3): δ of 7.90 (s, 1H); 7,86 (d, 1H, J=7 Hz); 7,52 was 7.45 (m, 2H); 5,50 (USS, 2H, CONH2); of 3.80 (q, 1H, J=7 Hz); of 3.45 (m, 1H); of 1.50 (d, 3H, J=7 Hz); 1,1 (d, 6H, J=7 Hz).

In accordance with the same experimental procedure and using the appropriate 2-arylpropionate acid, described above, as the initial reagents were synthesized following connections:

Example 2

(R)-2-[3-(cyclopentanecarbonyl)phenyl]propionamide

[α]D25(c=1, EtOH): -28°,1H-NMR (CDCl3): δ 7,86 (s, 1H); 7,76 (d, 1H, J=7 Hz); 7,45-7,35 (m, 2H); ceiling of 5.60-5,50 (USS, 2H, CONH2); of 3.75 (q, 1H, J=7 Hz); 3,70 (m, 1H); of 2.23 (m, 2H); 2.05 is (m, 3H); of 1.85 (m, 3H); of 1.45 (d, 3H, J=7 Hz).

Example 3

(R)-2-[(3-(furan-2-carbonyl)phenyl]propionamide

[α]D25(c=1, MeOH): -41°,1H-NMR (CDCl3): δ 8,10 (d, 1H, J=3 Hz); 7,86 (m, 1H); of 7.82 (d, 1H, J=7 Hz); to 7.64 (s, 1H); 7,49 (m, 2H); 7,41 (m, 1H); 5,80 (USS, 2H, CONH2); with 3.79 (q, 1H, J=7 Hz); of 1.41 (d, 3H, J=7 Hz).

Example 4

(R)2-[3-(2-benzofuran-2-carbonyl)phenyl]propionamide

[α]D25(c=1, EtOH): -48°C,1H-NMR (CDCl3): δ 8.30 to (s, 1H); 8,15 (d, 1H, J=8 Hz); 7,51 (d, 1H, J=8 Hz); 7,42 (d, 2H, J=8 Hz); 7,28 (t, 2H, J=8 Hz); 7,11 (t, 2H, J=8 Hz); 5.25-inch (USS, 2H, CONH2); the 3.65 (q, 1H, J=7 Hz); of 1.36 (d, 3H, J=7 Hz).

Example 5

(R)-2-[3-(thiazol-2-ylcarbonyl)phenyl]propionamide

[α]D25(c=1, MeOH): -30°,1H-NMR (CDCl3): δ 8,40 (m, 2H); 8,08 (d, 1H, J=3 Hz); of 7.75 (d, 1H, J=3 Hz); 7,63 (d, 1H, J=7 Hz); 7,51 (t, 1H, J=7 Hz); 5,55 (USS, 2H, CONH2); 3,88 (kV, 1H, J=7 Hz); and 1.63 (d, 3H, J=7 Hz).

Example 6

(R)-2-[3-(1,3-oxazol-2-ylcarbonyl)phenyl]propionamide

[α]D25(c=1, EtOH): -39°,1H-NMR (CDCl3): δ to 8.45 (m, 2H); of 7.90 (s, 1H); to 7.68 (d, 1H, J=7 Hz); 7,50 (t, 1H, J=7 Hz); 7,38 (s, 1H); 5,66 (USS, 2H, CONH2); 3,90 (kV, 1H, J=7 Hz); and 1.56 (d, 3H, J=7 Hz).

Example 7

3-((R)-1-carbamoylethyl)-N-(2,6-dichlorophenyl)benzamide

[α]D25(c=1, EtOH): -27°,1H-NMR (DMSO-d6): δ 10,4 (USS, 1H, CONH); by 8.22-to 8.12 (m, 2H); 7,75-of 7.60 (m, 5H); 6,60 (USS, 2H, CONH2); of 3.95 (q, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Example 8

3-((R)-1-carbamoylethyl)-N-(2,6-dimetilfenil)benzamid

[α]D25(c=1, EtOH): -34°C,1H-NMR (DMSO-d6): δ 9,75 (USS, 1H, CONH); 8,00-of 7.90 (m, 2H); 7,60-7,40 (m, 3H); 7,10 (s, 2H); 5,80 (USS, 2H, CONH2); 3,70 (kV, 1H, J=7 Hz); of 2.15 (s, 6H, J=7 Hz); of 1.35 (d, 3H, J=7 Hz).

Example 9

3-((R)-1-carbamoylethyl)-N-(3-chloropyridin-2-yl)benzamid

[α]D25(c=1, EtOH): -30°,1H-NMR (CDCl3): δ 8,70 (USS 1H, CONH); to 8.20 (d, 1H, J=9 Hz); 7,80-to 7.68 (m, 3H); 7,40-to 7.18 (m, 3H); 6,12 (USS, 2H, CONH2); of 3.80 (q, 1H, J=7 Hz); was 1.58 (d, 3H, J=7 Hz).

Example 10

(R)-2-[3-(2-methoxyphenoxy)phenyl]propionamide

[α]D25(c=1, EtOH): -38°,1H-NMR (CDCl3): δ 7,22 for 7.12 (m, 2H); 7,00-6,85 (m, 5H); 6,72 (d, 1H, J=7 Hz); 5,50-5,20 (USS, 2H, CONH2); of 3.75 (s, 3H); 3,55 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Example 11

(R)-2-[3-(2-chlorobenzylamino)phenyl]propionamide

[α]D25(c=1, MeOH): -37°,1H-NMR (DMSO-d6): δ 7,22 (d, 1H, J=3 Hz); to 7.09 (m, 1H); 7,05 (m, 1H); 6,72 (m, 2H); only 6.64 (m, 2H); to 6.57 (m, 1H); ceiling of 5.60 to 5.35 (USS, 2H, CONH2); 4,15 (USS, 1H, NH); of 3.85 (q, 1H, J=7 Hz); of 1.62 (d, 3H, J=7 Hz).

Example 12

(R)-2-[3-(2-methoxybenzylamine)phenyl]propionamide

[α]D25(c=1, MeOH): -31°,1H-NMR (DMSO-d6): δ 7,50 (d, 1H, J=7 Hz); 7,28 (m, 1H); 7,10 (m, 1H); is 6.78 (m, 2H); 6,60 (m, 2H); 6,50 (m, 1H); 5,58 (USS, 2H, CONH2); 4,15 (USS, 1H, NH); of 3.80 (s, 3H); 3,70 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Example 13

(R)-2-[3-(pyridine-2-ylamino)phenyl]propionamide

[α]D25(c=1, MeOH): -36°,1H-NMR (DMSO-d6): δ 8,15 (USS, 1H, CONH); to 7.50 (m, 1H); 7,15-6,98 (m, 3H); to 6.88 (m, 1H); PC 6.82 (m, 2H); 6.75 in (m, 1H); 5,58-5,38 (USS, 2H, CONH2); to 3.58 (q, 1H, J=7 Hz); of 1.52 (d, 3H, J=7 Hz).

Example 14

(R)-2-(3-oxazol-2-yl)phenyl]propionamide

[α]D25(c=1, EtOH): -29°,1H-NMR (CDCl3): δ 8,00 (s, 1H); 7.95 is-a 7.92 (m, 1H); 7,68 (s, 1H); 7,42 (m, 2H); 7,20 (s, 1H); 5,20 (USS, 2H, CONH2); 3,60(kV, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz).

Example 15

(R)-2-(3-furan-2-yl)phenyl]propionamide

[α]D25(c=1, EtOH): -36°,1H-NMR (CDCl3): δ 7.68 per-7,58 (m, 2H); of 7.48 (s, 1H); 7,35-7,25 (m, 2H); 6,70 (d, 1H, J=4 Hz); 6,50 (DD, 1H, J1=4 Hz, J2=2 Hz); 5,35 (USS, 2H, CONH2); the 3.65 (q, 1H, J=7 Hz); was 1.58 (d, 3H, J=7 Hz).

Example 16

(R)-2-(oxo-1,2,3,4-tetrahydroquinolin-7-yl)propionamide

[α]D25(c=1, EtOH): -43°1H-NMR (CDCl3): δ 8,00 (USS, 1H, CONH); 7,46 (s, 1H); 7.18 in (d, 1H, J=7 Hz); 7,05 (d, 1H, J=7 Hz); 5,70-5,58 (USS, 2H, CONH2); 3,90 (kV, 1H, J=7 Hz); 2,90 (m, 2H); of 2.56 (m, 2H); was 1.58 (d, 3H, J=7 Hz).

Example 17

(R)-2-(3-benzosulfimide)propionamide

[α]D25(c=1, EtOH): -36°,1H-NMR (CDCl3): δ of 7.96 to 7.75 (m, 4H); 7,62-7,38 (m, 5H); 5,65 (USS, 2H, CONH2); 3,50 (kV, 1H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

Example 18

2-(3-acetylamino)phenylpropionamide

To a solution of 2-(3-amino)phenylpropionamide (0.2 g, of 1.26 mmol) (prepared from 2-(3-amino)phenylpropionitrile, as described in Erdelmeier I. et al., J. Org. Chem., 2000, 65, 8152-8157) in 10 ml dry CH2Cl2was added triethylamine (0,19 ml of 1.39 mmol) and acetylchloride (90 μl, of 1.26 mmol). The mixture was mixed at room temperature for 4 h, washed with water (H2O (3×15 ml) and dried over Na2SO4.After evaporation of the solvent under reduced pressure, the obtained residue, after purification by flash chromatography who gave 2-(3-acetylamino)phenylpropionamide in the form of a clear oil (0,202 g, 1.01 mmol). Yield 80%.

1H-NMR (CDCl3): δ 8,59 (USS, 1H, CONH); 7,46 (m, 2H); then 7.20 (t, 1H, J=8 Hz); 6,97 (d, 1H, J=8 Hz); 5,55 (USS, 2H, CONH2); of 3.53 (q, 1H, J=7 Hz); of 2.09 (s, 3H); USD 1.43 (d, 3H, J=7 Hz).

According to the same experimental procedure and using benzoyl chloride as the starting reagent was synthesized by the following connection:

Example 19

2-(3-benzoylamino)phenylpropionamide

1H-NMR (CDCl3): δ 8,59 (USS, 1H, CONH); 8,15 (m, 2H); a 7.62 (m, 1H); was 7.45 (m, 2H); 7,40 (m, 2H); 7,22 (t, 1H, J=8 Hz); 6,94 (d, 1H, J=8 Hz); 5,55 (USS, 2H, CONH2); of 3.53 (q, 1H, J=7 Hz); USD 1.43 (d, 3H, J=7 Hz).

Example 20

N-[(R)-2-(3-cyclopentanecarbonitrile)propionyl]methanesulfonamide

The reaction was carried out as described in Uehling D.E. et al., J. Med. Chem., 2002, 45(3), 567-583.

1,1'-Carbonyldiimidazole (0.5 g, a 3.06 mmol) was added to a solution of (R)-2-[3-cyclopentenyl)phenyl]propionic acid (II) (0.68 g, 2,78 mmol) in dry CH2Cl2(8 ml) and the resulting mixture was stirred at room temperature for 90 minutes was Added methanesulfonamide (0.26 g, 2,78 mmol) and DBU (of 0.43 ml, 2,78 mmol), the mixture was stirred further for 16 h at room temperature. The organic phase was washed 0,5N HCl (2×10 ml), 5% NaH2PO4(3×10 ml) and water (2×10 ml). After drying of Na2SO4the solvent was evaporated in vacuum and the crude product was purified flash chromatography (eluting the mixture of CH2Cl2/MeOH 95:5) of Pure N-[(R)-2-(3-cyclopentanecarbonitrile)propionyl]methanesulfonamide 22 was isolated as a colourless oil (0,67 g, of 2.09 mmol). Yield 79%.

[α]D25(c=1, EtOH): -48°C,1H-NMR (CDCl3): δ 7,80 (m, 2H); 7,42 (m, 2H); 3,68 (m, 2H); 3.15 in (s, 3H); of 1.88 (m, 4H); of 1.62 (m, 4H); USD 1.43 (d, 3H, J=7 Hz).

In accordance with the same experimental procedure and using the appropriate above arylpropionate acid, were synthesized following connections:

Example 21

N-{[(R)-2-[3-(furan-2-carbonyl)phenyl]propionyl}methanesulfonamide

[α]D25(c=1, EtOH): -23,5°.1H-NMR (CDCl3): δ to 7.95 (m, 1H); a 7.85 (s, 1H); 7,71 (s, 1H); to 7.50 (m, 2H); 7,28 (d, 1H, J=2 Hz); 6,60 (d, 1H, J=2 Hz); 3,82 (kV, 1H, J=7 Hz); 3,20 (s, 3H); of 1.55 (d, 3H, J=7 Hz).

Example 22

N-{[(R)-2-[3-(5-methylfuran-2-carbonyl)phenyl]propionyl}methanesulfonamide

[α]D25(c=1, EtOH): -15°,1H-NMR (CDCl3): δ to 7.95 (m, 1H); to 7.84 (m, 2H); of 7.48 (USS, 1H+CONH); 7,10 (d, 1H, J=2 Hz); 6,21 (d, 1H, J=2 Hz); of 3.80 (q, 1H, J=7 Hz); of 3.25 (s, 3H); to 2.42 (s, 3H)and 1.60 (d, 3H, J=7 Hz).

Example 23

N-{[(R)-2-[3-(thiophene-2-carbonyl)phenyl]propionyl}methanesulfonamide

[α]D25(c=1, EtOH): -37°,1H-NMR (CDCl3): δ 7,80 (m, 1H); 7,71 (m, 2H); 7,58 (m, 1H); 7,40 (m, 2H); 7,10 (m, 1H); 3.75 to (q, 1H, J=7 Hz); 3,18 (s, 3H); and 1.54 (d, 3H, J=7 Hz).

Example 24

N-{[(R)-2-[3-(benzofuran-2-carbonyl)phenyl]propionyl}methanesulfonamide

[α]D25(c=1, EtOH): -62,5°,1H-NMR (CDCl3): δ with 8.05 (m, 1H); to 7.95 (s, 1H); to 7.75 (m, 1H); of 7.69 (m, 1H); at 7.55 (m, 4H); 7,30 (m, 1H); of 3.85 (q, 1H, J=7 Hz); 3,29 (s, 3H); of 1.65 (d, 3H, J=7 Hz).

Example 25

N-[(R)-2-[3-(oxazol-2-cabonyl)phenyl]propionyl}methanesulfonamide

[α]D25(c=1, EtOH): -83°,1H-NMR (CDCl3): δ 8,48 (m, 1H); 8,35 (s, 1H); 8,05 (USS, 1H, CONH); to 7.95 (s, 1H); 7,66 (m, 2H); 7,40 (s, 1H); 3,82 (kV, 1H, J=7 Hz); of 3.25 (s, 3H)and 1.60 (d, 3H, J=7 Hz).

Example 26

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-pyrid-2-ylpropionic

Thionyl chloride (0.2 ml, 2.7 mmol) was added to a solution of (R)-2-[3-(2-furan-2-carbonyl)phenyl]propionic acid (V) (0,065 g, 0.27 mmol) in dry CH2Cl2(5 ml)and the resulting solution was boiled for 2 hours After cooling to room temperature, toluene and thionyl chloride were removed by evaporation in vacuo and the residue was dissolved in CH2Cl2(2 ml); 2-aminopyridine (0.05 g, 0.54 mmol) was added and the solution was stirred over night at room temperature. The organic solution was washed with water (2×10 ml), after drying of Na2SO4the solvent was removed by evaporation in vacuo, the crude product was purified chromatographically on silica gel (eluting the mixture of n-hexane/EtOAc 8:2)gave pure 28 as a colourless oil (0.07 g, 0.22 mmol). Yield 80%.

[α]D25(c or=0.6, MeOH): -69°,1H-NMR (CDCl3): δ by 8.22 (m, 2H); 8,00 (s, 1H); 7,88 (m, 2H); 7,80 (USS, 1H, CONH); of 7.70 (s, 2H); to 7.61 (m, 1H); 7,52 (m, 1H); 7,00 (m, 1H); 6,62 (m, 1H); 3,82 (kV, 1H, J=7 Hz); of 1.65 (d, 3H, J=7 Hz).

For the same experimental technique, and using the appropriate 2-arylpropionate acid and amine were synthesized following connections:

Example 27

(R)-2-[(furan-2-carbonyl)phenyl]-N-(2H-thiazol-2-yl)propionamide

[α]D25(c=0.5, MeOH): -7°,1H-NMR (CDCl3): δ with 8.05 (s, 1H); of 7.90 (m, 1H); of 7.75 (s, 1H); 7,60 (m, 1H); 7,52 (m, 2H); 7,22 (d, 1H, J=2 Hz); 7,02 (d, 1H, J=2 Hz); of 6.68 (d, 1H, J=2 Hz); of 3.95 (q, 1H, J=7 Hz); 1.70 to (d, 3H, J=7 Hz).

Example 28

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide

Reagent-Amin - 2-amino-4-cryptomaterial received, as described in M. Moazzam et al., Indian J. Chem., 1988, 27B(11), 1051-1053.

[α]D25(c or=0.6, MeOH): -11°,1H-NMR (CDCl3): δ 9,35 (USS, 1H, CONH); to 7.95 (m, 2H); of 7.75 (s, 1H); 7,58-7,39 (m, 2H); 7,30 (s, 1H); to 7.25 (s, 1H); 6,55 (s, 1H); 3.96 points (q, 1H, J=7 Hz); of 1.65 (d, 3H, J=7 Hz).

For the same experimental technique, and using arylpropionic acid VI and amine - 2-amino-4-cryptomaterial, the following compound was obtained:

Example 29

(R)-2-[3-(benzofuran-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide

[α]D25(c=1, EtOH): -55°,1H-NMR (CDCl3): δ cent to 8.85 (USS, 1H, CONH); 8,15 (m, 1H); with 8.05 (s, 1H); for 7.78 (d, 1H, J=7 Hz); the 7.65 7,58 (m, 5H); 7,40 (s, 1H); to 7.35 (t, 1H, J=7 Hz); of 4.05 (q, 1H, J=7 Hz); of 1.80 (d, 3H, J=7 Hz).

For the same experimental technique, and using arylpropionic acid II and the amine - 2-aminopyridine was synthesized by the following connection:

Example 30

(R)-2-(3-cyclopentanecarbonyl)-N-pyridin-2-ylpropionic

[α]D25(c=1, EtOH): -55°,1H-NMR (CDCl3): δ 8,70 (USS, 1H, CONH); 8,10 (s, 1H); 7,98 (d, 1H, J=3 Hz); to 7.84 (m, 1H); 7,80 (d, 1H, J=Hz); was 7.45 (d, 1H, J=7 Hz); 7,37 (m, 1H); 7,10 (d, 1H, J=3 Hz); to 6.95 (m, 1H); 3.75 to (q, 1H, J=7 Hz); 3,70 (m, 1H); 2,20 (s, 2H); 2.0 (m, 3H); of 1.80 (m, 3H); of 1.55 (d, 3H, J=7 Hz).

Example 31

(R)-2-[3-(furan-2-carbonyl)phenyl]-N-hydroxypropionate

Thionyl chloride (1.6 ml, 27 mmol) was added to a solution of (R)-2-[3-(2-furanol)phenyl]propionic acid (V) (0,53 g of 2.15 mmol) in dry toluene (10 ml)and the resulting solution was boiled for 3 hours After cooling to room temperature, toluene and thionyl chloride were removed by evaporation in vacuo, the residue was dissolved in dry CH2Cl2(30 ml) and bury to a solution of hydroxylamine hydrochloric acid (0,179 g, 2.57 mmol) and triethylamine (of 0.71 ml, 5,14 mmol) in dry CH2Cl2(10 ml). The resulting solution was stirred overnight at room temperature. The organic solution was diluted with 1N HCl (20 ml), after separation of the phases the organic phase was washed with water (2×20 ml). After drying of Na2SO4the solvent was evaporated in vacuum and the crude product was purified chromatography (eluting the mixture of CHCl3/CH3OH 95:5)gave pure 33 in the form of a yellowish oil (0.65 g, of 2.53 mmol). Yield 85%.

[α]D25(c=1, MeOH): -44°,1H-NMR (CDCl3): δ a 7.92 (m, 2H); of 7.75 (s, 1H); EUR 7.57 (m, 1H); to 7.50 (t, 1H, J=7 Hz); of 7.25 (d, 1H, J=2 Hz); is 6.61 (m, 1H); of 3.85 (q, 1H, J=7 Hz); 1,95 (USS, 1H, NHOH); of 1.62 (d, 3H, J=7 Hz).

For the same experimental technique, and using arylpropionic acid IV, it was Shin who ezerovo the following connection:

Example 32

(R)-2-[3-(thiazole-2-carbonyl)phenyl]-N-hydroxypropionate

[α]D25(c=1, MeOH): -28°,1H-NMR (CDCl3): δ 8,44 (m, 2H); to 8.12 (d, 1H, J=3 Hz); 7,73 (d, 1H, J=2 Hz); the 7.65 (d, 1H, J=7 Hz); 7,50 (t, 1H, J=7 Hz); a 3.87 (q, 1H, J=7 Hz); 1,90 (USS, 1H, NHOH); to 1.70 (d, 3H, J=7 Hz).

Example 33

2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}propionic acid

To a solution of (R)-2-[3-(2-furanol)phenyl]propionic acid (V) (2 g, 8.2 mmol) in dioxane (5 ml) was added thionyl chloride (0,92 ml, 12.3 mmol), the resulting solution was boiled for 3 hours After cooling to room temperature the solvent was evaporated, the crude acylchlorides was dissolved in DMF (5 ml) at 0°C, DCC (1,69 g, 8.2 mmol) and HOBT (1.01 g, 7.5 mmol) was added under stirring. After 30 min a solution of methyl ester of D,L-allingitalia (1.08 g, 7.5 mmol) and triethylamine (1,01 ml) in DMF (2 ml) was added. The resulting mixture was stirred for 2 h at 0°C and overnight at room temperature. Usageprice DCU was filtered; the filtrate was diluted with EtOAc (15 ml), the organic phase is washed with 10% citric acid buffer (2×10 ml), a saturated solution of NaHCO3(2×10 ml) and then brine (10 ml). After drying of Na2SO4the solvent was evaporated, which gave the crude product, which was suspended in n-hexane (20 ml) and was stirred over night at room temperature. Methyl ester 2-[(R)-2-[3-(furan-2-carbonyl)Fe is Il]propionamido]propionic acid was isolated by filtration in the form of a white powder (1.66 g, 5.7 mmol). Yield 69%. To a solution of the obtained methyl ester in dioxane (3 ml) was added 1N NaOH (5.7 ml), the mixture was stirred over night at room temperature. A mixture of ice/water (40 ml) was added, the mixture was acidified with concentrated H2SO4to pH 2. The aqueous phase was extracted with CH2Cl2(4×15 ml), the collected organic extracts were washed with brine (15 ml), drained Na2SO4and evaporated in vacuo gave an oily residue. 37 was isolated by crystallization from diethyl ether (10 ml) in a solid white color (0,72 g, 2.28 mmol). Yield 40%.

[α]D25(c=1, MeOH): -21°,1H-NMR (CDCl3) δ 7,86 (m, 1H), 7,80 (d, 1H, J=7 Hz), to 7.64 (s, 1H); 7,47 (m, 1H); 7,35 (m, 1H); 7,16 (d, 1H, J=7 Hz); 6,53 (m, 1H); 5,95 (USS, 1H, CONH); 4,50 (kV, 1H, J=7 Hz); the 3.65 (q, 1H, J=7 Hz); of 1.53 (d, 3H, J=7 Hz), of 1.35 (d, 3H, J=7 Hz).

For the same experimental technique, and using methyl ester of glyceraldehyde was synthesized by the following connection:

Example 34

2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}acetic acid

[α]D25(c=1, MeOH): -13,5°C,1H-NMR (CDCl3) δ 7,80 (m, 1H), 7,82 (d, 1H, J=7 Hz), to 7.64 (s, 1H); 7,47 (m, 1H); 7,33 (m, 1H); to 7.15 (d, 1H, J=7 Hz); 6,51 (m, 1H); 5,90 (USS, 1H, CONH); of 4.05 (s, 2H); 3,61 (kV, 1H, J=7 Hz); of 1.53 (d, 3H, J=7 Hz).

Table 1
Connections that do not have active is part of (inhibitory), aimed at PMNs C5a-induced chemotaxis
Chemical nameStructureIL-8 (10-8M)C5a (10-6M)
(R)-2-(4-isobutylphenyl)propionate57±12-
N-[(R)-2-(4-isobutylphenyl) propionyl]methanesulfonamide65±5-
(R)-2-(3-isopropylphenyl)propionamide60±5-
(R)-2-(3-benzoylphenyl)propionate37±730±2
N-[(R)-2-(3-benzoylphenyl) propionyl]methanesulfonamide38±520±5

Table 2
Compounds with activity is, (inhibitory) aimed at PMNs C5a-induced chemotaxis
No.StructureChemical name% inhibition of C5a-induced PMN migration
1(R)-2-(3-isobutylphenyl)propionate50±7a
2(R)-2-(3-cyclopentanecarbonitrile)propionamide59±16a
3(R)-2-[(3-(furan-2-carbonyl)phenyl]propionamide65±6a
4(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]propionamide55±7b
5(R)-2-[(3-(thiazole-2-carbonyl)phenyl] propionamide31±7b
6 (R)-2-[(3-(oxazol-2-carbonyl)phenyl]propionamide26±6b
73-((R)-1-carbamoylethyl)-N-(2,6-dichlorophenyl)benzamide57±8a
83-((R)-1-carbamoylethyl)-N-(2,6-dimetilfenil)benzamid65±10a
93-((R)-1-carbamoylethyl)-N-(3-chloropyridin-2-yl)benzamid40±2a
10(R)-2-[3-(2-methoxyphenoxy)phenyl]propionamide55±6b
11(R)-2-[3-(2-chlorobenzylamino)phenyl]propionamide42±5a
12(R)-2-[3-(2-methoxybenzylamine)phenyl]propionamide60±8a
13(R)-2-[3-(pyridine-2-ylamino)phenyl]propionamide38±3a
14(R)-2-(3-oxazol-2-yl)phenyl]propionamide63±9a
15(R)-2-(3-furan-2-yl)phenyl]propionamide41±7a
16(R)-2-(oxo-1,2,3,4-tetrahydroquinolin-7-yl)propionamide45±10b
17(R)-2-(3-benzosulfimide)propionamide54±7a
182-(3-acetylaminophenol)propionamide83±2a
192-(3-benzoylamino)about ionamin 34±11a
20(R)-2-(3-cyclopentanecarbonitrile) propionyl]methanesulfonamide22±2a
21N-{(R)-2-[3-(furan-2-carbonyl)phenyl] propionyl}methanesulfonamide61±15b
22N-{(R)-2-[3-(5-methylfuran-2-carbonyl)phenyl] propionyl}methanesulfonamide53±6b
23N-{(R)-2-[(3-(thiophene-2-carbonyl)phenyl] propionyl}methanesulfonamide37±11a
24N-{(R)-2-[(3-(benzofuran-2-carbonyl)phenyl] propionyl}methanesulfonamide53±5
25N-{(R)-2-[(3-(oxazol-2-carbonyl)phenyl] propionyl}methanesulfonamide 38±8a
26(R)-2-[3-(furan-2-carbonyl)phenyl]-N-pyrid-2-ylpropionic45±9b
27(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(2H-thiazol-2-yl)propionamide60±5b
28(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide49±9b
29(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide40±12a
30(R)-2-(3-cyclopentanecarbonyl)-N-pyrid-2-ylpropionic51±5b
31(R)-2-[3-(furan-2-carbonyl)phenyl]-N-hydroxypropionate70±5b
32(R)-2-[3-(thiazole-2-carbonyl)phenyl]-N-hydroxypropionate30±2b
332-{(R)-2-[3-(furan-2-carbonyl)phenyl]-propionamide}propionic acid40±5a
342-{(R)-2-[3-(furan-2-carbonyl)phenyl]-propionamide}acetic acid51±7a
adrug concentration: 10-7M
bdrug concentration: 10-8M

1. (R)-2-arylpropionate with the General formula (I)

in which Ar is a phenyl group substituted in the 3 (meta)position by a group R1choose from:
linear or branched C1-C8alkanoyl,3-C6cycloalkenyl, heteroarylboronic, C1-C6-alkylaminocarbonyl, arylenecarborane,1-C6-alkylamino,1-C6-acylamino, arylamino, benzoylamine, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl,6-ailextoro the sludge, C1-C8-alkanesulfonyl, arylsulfonyl, or 3,4-dihydro-1H-chinolin-2-he;
R is selected from H, HE;
heteroaryl group selected from pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole;
α or β carboxialkilnuyu the remainder may consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted another carboxyl (COOH) group;
the remainder with the formula SO2Rd, in which Rd is a C1-C6-alkyl, C3-C6-cycloalkyl,2-C6alkenyl or pyridyl,
provided that the compounds of formula (I) are the following compounds:
(R)-2-(3-phenoxyphenyl)-propanol-phenylglycine;
(R)-2-(3-phenoxyphenyl)-propanol-glycine;
(R)-2-[(3'-acetyl)phenyl]-N-(4"-pyrimidyl)propionamide.

2. Compounds according to claim 1, in which
Ar is a phenyl group substituted in position 3 (meta)group R1choose from:
linear or branched C1-C8alkanoyl; 2-furil, 2-oxazolyl, 3-isoxazolyl, 2-benzoxazolyl, 3-benzisoxazole, 2-thiazolyl, 2-pyridyl; furancarboxylic; benzofuranyl; thiophencarboxylic; pyridylcarbonyl; C1-C6-acylamino; benzoylamine; aryloxy; arylamino, or 3,4-dihydro-1H-chinolin-2-he;
R is selected from H, HE; 2-pyridyl, 2-thiazolyl;
carboxialkilnuyu group can octoate from a straight or branched C 1-C6-alkyl;
the remainder with the formula SO2Rd, in which Rd is a C1-C6-alkyl.

3. Compounds according to claim 1 or 2, selected from:
(R)-2-(3-isobutylphenyl)propionamide,
(R)-2-(3-cyclopentanecarbonitrile)propionamide,
(R)-2-[(3-(furan-2-carbonyl)phenyl]propionamide,
(R)-2-[(3-(thiazole-2-carbonyl)phenyl]propionamide,
(R)-2-[(3-(oxazol-2-carbonyl)phenyl]propionamide,
(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]propionamide,
3-((R)-1-carbamoylethyl)-N-(2,6-dichlorophenyl)benzamide,
3-((R)-1-carbamoylethyl)-N-(2,6-dimetilfenil)benzamide,
3-((R)-1-carbamoylethyl)-N-(3-chloropyridin-2-yl)benzamide,
(R)-2-[3-(2-methoxyphenoxy)phenyl)propionamide,
(R)-2-[3-(2-chlorobenzylamino)phenyl]propionamide,
(R)-2-[3-(2-methoxybenzylamine)phenyl]propionamide,
(R)-2-[3-(pyridine-2-ylamino)phenyl]propionamide,
(R)-2-(3-oxazol-2-yl)phenyl]propionamide,
(R)-2-[(3-furan-2-yl)phenyl]propionamide,
(R)-2-(oxo-1,2,3,4-tetrahydroquinolin-7-yl)propionamide,
(R)-2-(3-benzosulfimide)propionamide,
2-(3-acetylaminophenol)propionamide,
2-(3-benzoylamino)propionamide,
N-[(R)-2-(3-cyclopentanecarbonitrile)propionyl]methanesulfonamide,
N-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionyl}methanesulfonamide,
N-{(R)-2-[3-(5-methylfuran-2-carbonyl)phenyl]propionyl}methanesulfonamide,
N-{(R)-2-[(3-(thiophene-2-carbonyl)phenyl]propionyl}methanesulfonamide,
N-{(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]p is opional)methanesulfonamide,
N-{(R)-2-[(3-(oxazol-2-carbonyl)phenyl]propionyl}methanesulfonamide,
(R)-2-[3-(furan-2-carbonyl)phenyl]-N-pyrid-2-ylpropionic,
(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(2H-thiazol-2-yl)propionamide,
(R)-2-[3-(furan-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide,
(R)-2-[(3-(benzofuran-2-carbonyl)phenyl]-N-(4-trifluoromethyl-2H-thiazol-2-yl)propionamide,
(R)-2-(3-cyclopentanecarbonyl)-N-pyrid-3-ylpropionic,
(R)-2-[3-(furan-2-carbonyl)phenyl]-N-hydroxypropylamino,
(R)-2-[3-(thiazole-2-carbonyl)phenyl]-N-hydroxypropylamino,
2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}propionic acid,
2-{(R)-2-[3-(furan-2-carbonyl)phenyl]propionamide}acetic acid.

4. The method of obtaining compounds of formula (I) according to claim 1, comprising the reaction of compounds of formula (II)

in which Ar is a phenyl group substituted in the 3 (meta)position by R1in which R1similar to that described in claim 1, with an amine of the formula other, where R is the same as in item 1.

5. Compounds according to any one of claims 1 and 2 for use as drugs, inhibiting Sa induced PNM migration.

6. Compounds according to claim 3 for use as drugs, inhibiting Sa induced PNM migration.

7. The use of compounds according to claims 1-3 for the preparation of medicaments for the treatment of diseases, including Sa induced chemo is Aksis human PMNs.

8. The use of compounds according to any one of claims 1 to 3 for the preparation of medicaments for the treatment of sepsis.

9. The use of compounds according to any one of claims 1 to 3 for the preparation of medicaments for the treatment of psoriasis, bladderworts, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, COPD, glomerulonephritis and in the prevention and treatment of lesions caused by ischemia and reperfusion.



 

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< / BR>
where Ar is phenyl which may be unsubstituted or substituted one, two or three substituents independently chosen among Cl, Br, F, -OMe, NO2, CF3C1-4lower alkyl, -NMe2, -NEt2, -SCH3, -NHCOCH3; 2-thienyl, 2-furyl; 3-pyridyl; 4-pyridyl or 3-indolyl; R-OCH2R1where R1choose from a number of-CH= CME2The CME=CH2-The CCH; provided that when Ar is a phenyl,4-alkylphenyl, 4-methoxyphenyl or 3,4-acid, R can be any except 3-methyl-2-butenyloxy
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The invention relates to a new connection - 3-(5-ethoxycarbonylphenyl)-2,4-pentanedione formula 1

< / BR>
which exhibits the property of activator germination of wheat seeds and has growth-stimulating effects primarily on the root system of seedlings and its performance surpasses similar in structure and action

-diketones and ketoesters" target="_blank">

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining-dicarbonyl derivatives of adamantane General formula

< / BR>
where R=CH3:R1=CH3OC2H5; R=C6H5: R1=OC2H5C6H5, CF2H

R=CF3:R1=C6H5n-C6H4C1

< / BR>
< / BR>
which are the products for the synthesis of biologically active substances

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EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

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