N-(2-arylpropionyl)sulfonamides and pharmaceutical preparation comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

 

The present invention relates to N-(2-arylpropionic)sulfonamides and pharmaceutical preparations on their basis used for the prevention and treatment of lesions of the tissues by promoting the recruitment of polymorphonuclear neutrophils (PMN leukocytes in inflammation.

The chemotaxis is called cell-mediated response, which causes the migration of specific blood cells (macrophages, granulocytes, polymorphonuclear neutrophils) concentration gradient stimulating agent, which follows the chemical stimulus (chemotaxonomy). The most typical chemotaxonomy are cleavage products of complement Sa, some N-formulate formed by lysis of the bacterial surface, or synthetic nature, such as formyl-methionyl-leucyl-phenylalanine (f-MLP), and mainly a number of cytokines, attributed to interleukin IL-8. Interleukin IL-8 is an endogenous chemotactic factor secreted by a majority containing the nucleus of cells (fibroblasts, macrophages, endothelial and epithelial cells) in response to the processing of TNF-a (tumor necrosis factor, interleukins IL-la and IL-lfi and wall lipopolysaccharides of bacterial cells (LPS), as well as the actual neutrophils when they are exposed to LPS and N-formylation bacterial origin (fMPL peptides). This chemotactic factor [also known as factor activation of neutrophils (NAF), a chemotactic factor for T cells, produced by monocytes chemotactic factor for neutrophils (MDNCF)] adjusts the number of IL-8-like chemokines [GROa, fi, V, and NAP-2], which are associated with the IL-8 receptor (Chanq et al., J. Immunol., 148, 451, 1992).

Neutrophils under the influence of chemotactic factors undergo changes predisposing to migration and activation form, which ends with the degranulation reaction, oxygen uptake and generation of reactive oxygen species.

All of these events that occur within a few seconds after impact chemotaxins on neutrophils, biochemically characterized by a transient increase in the intracellular CA ion level2+, ions of Na+and camp with consequent changes in membrane potential. The increase was due to chemotaxonomy intracellular ion concentrations of CA2+accompanied by the activation of G proteins, phospholipase C and A2and the arachidonic acid cascade with formation of the products of cyclooxygenase and lipoxygenase (see L.rvath in the Regulation of neutrophil chemotaxis, Ann. Reports in Med. Chem., page 233-235, vol.24, 1992, and the references therein). Neutrophils are the earliest protection against bacterial infections due to their ability to easily migrate from the peripheral blood through the junction of endothelia and intercellular substance or tissue sections, where they have a specific action, i.e. destroy microbes, remove damaged cells and stimulate tissue regeneration (.A.Goucerot-Podlcalo et al., Pathol. Biol. (Paris), 44, 36, 1996).

In specific pathological conditions characterized by increased recruitment of neutrophils, favorable essentially regenerating health effect is neutralized by increased tissue damage, which slows down the healing process and in the most severe cases, leads to death of the patient.

Recently, unexpected convincing data support the hypothesis that lesions during ischemia and reperfusion and gipertoksicheskaya the lung damage associated with the presence of activated neutrophils and that the defeat of the cells depends on the activation. This has been proven in experimental models [N.Sekido et al., Nature, 365, 654, 1993, and .Matsumoto et al., Lab. Investig., 11, 119, 1997] and clinico-pathological studies in humans [.Mazzone et al., Recent Prog. Med., 85, 397, 1994; ..Fisher and H.J.Meiselmann, Thromb. Res., 74 (Suppl.1), S21-S34, 1994; G.Ricevuti et al., Atheroscl., 91, 1, 1991], based on which damage cells directly and strictly linked to the degree and distribution of infiltration. PMN leukocytes, and more often it is assumed that the cytokine IL-8 is the most specific and powerful activator. In the pathogenesis of such conditions among different activating neutrophil chemotactic f is Ktorov, such as Sa, PAF, LTB4, which mediate the direct migration of these neutrophils, IL-8 may play an important role also in the fact that its production by mononuclear phagocytes may mediate the migration of other cells of inflammation and secreting IL-8 again, and by inducing its workings nearby immune cells [..Metiko et al., J Clin. Invest, 90, 791 (1992)].

In patients affected by acute respiratory distress (ARDS), increased presence of neutrophils in the Airways and in the lung fluids (which characterizes the disease) significantly correlated with a high concentration of cytokine. On the other hand, the concentration of NAP-1/IL-8 present in the lung alemneh fluids of these patients, consistent with the optimum concentrations required for induction of chemotaxis of neutrophils (.J.Miller et al., Am. Rev. Respir. Dis., 146, 437, 1992); in conclusion, clearly there is a strong correlation between mortality and high concentrations of IL-8 in alveolar fluids (A.Kurdowska et al., J. Immunol., 157, 2699, 1996).

In this context, particularly significant are the results obtained using ant-IL-8 antibodies that can neutralize the effects of cytokines in models of acute respiratory failure and endotoxaemia damage to the lungs by intratracheal injection of small doses of the inactivated nahrawan the m Streptococcus pyogenes (OK-432) (Cuoco et al., Lab. Invest., 16, 375, 1997).

In patients affected by acute myocardial infarction, within 22 hours after it started, it was shown a significant increase in IL-8 in serum (13-1100 ng/l). This increase can play a pivotal role in the development of myocardial damage due to high stimulating effect of the cytokine on neutrophils and their role in tissue damage (Y.Abe et al., Br.Heart J., 70, 132, 1993), which is in clinical development case ischemia obviously depends largely on the process of reperfusion than the time duration of ischemia.

Recently it was proved that the effect of anti-IL-8 antibodies reduces Eden brain and the distribution of the damaged area on the model of reperfusion in temporary focal ischemia in the rabbit brain (.Matsumoto et al., Lab. Invest., 77, 119, 1997). A significant increase in IL-8 in brain tissue observed in this model suggests that local production of IL-8 in perfoirmance tissues and the presence of activated neutrophils in the walls of blood vessels determine the degree of tissue damage.

It is believed that receptor interaction between neutrophil and chemotactic agent is critical for chemotaxis; IL-8 participates in it through two different receptors (CXCR1 and CXCR2)present on the surface of human neutrophils and some T cells is Ah (L. Xu et al., J.Leukocyte Biol., 57, 335, 1995). This can be proved by using N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea, which selectively inhibits the binding of IL-8 with the membrane receptor for neutrophil CXCR2 with IC5022 nm (J.R.White et al., J. Biol. Chem., 273, 10095, 1998). The consequence is blocking chemotaxis of human neutrophils stimulated by IL-8 (1 nm) and GROa (10 nm) with similar values IC50(20-60 nm) [but not in the case of chemotaxis stimulated component of complement Sa in the concentration range from 50 to 330 nm], and not delay the mobilization of intracellular ions Ca2+induced IL-8 or optimal concentrations LIB4, the same human neutrophils.

Using vinylmation in the treatment of interleukin-8(IL-8)-mediated pathologies was recently claimed in the invention WO 98/07418 (28.02.1998).

In the course of research aimed at identifying the contribution of individual enantiomers (S) and (R) Ketoprofen give in anti-inflammatory activity of the racemate, and their role in modulation of cytokines (.Ghezzi et al., J. Exp. Pharm. Ther., 1998 in press), surprisingly it was found that the salts of the individual enantiomers with chiral or organization of the achiral organic bases, depending on the dose inhibited the increase in intracellular concentration of ions of Ca2+([Ca2+]i)induced IL-8 PMN leukocytes (application for vyd the Chu patent Italy No. MI 98A000146 (28.01.1998), owned by the present applicant). One competitive research with ions of La (lanthanum) showed that the effects of inhibition of these salts response of neutrophils to IL-8 was neither a consequence of receptor interaction or weak expression of a number of receptors IL-8, and the result of the election block the effect of cations Ca2+in a quantity sufficient to prevent the course of events, typical caused by cytokine activation of the neutrophil: chemotaxis and degranulation of neutrophils (with the release of elastase, cathepsin and other enzymes). Moreover, the single enantiomers inhibit chemotaxis and increased [Ca2+]iinduced Sa and fMLP, albeit less efficiently.

The main difference between the two enantiomers is lower efficiency (at least 10-100 times) enantiomer (R) as the inhibitor WITH the enzyme.

Therefore, compared with the enantiomer (S) enantiomer (R) has a weaker inhibitory activity against prostaglandin synthesis, which, in turn, exert inhibitory and regulatory action in relation to the release of cytokines, which, like TNF-a, reinforce the value of proinflammatory effects typical of neutrophils. As a consequence, the enantiomer (S) is less than a therapeutically effective is applied in the treatment of neutrophil-related disorders and inflammatory conditions, such as psoriasis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, reperfusion injury, and glomerulonephritis.

Now it was found that N-arylsulfonamides 2-arylpropionic acids are effective inhibitors of chemotaxis and degranulation of neutrophils induced by IL-8. Similar properties have also been proved for R(2)-[(4-isobutyl)phenyl]propionamide (described in W.H.Pirke and J.Me Cune, J.Chromatography, 469, 67, 1989). Therefore, the invention also relates to their use in the treatment of neutrophil-dependent pathologies.

More specifically the present invention refers to new N-(2-arylpropionic)sulfonamides of General formula (1)

in which R2is an aryl group, R is a linear or branched C1-C16is an alkyl group, triptorelin, tsiklogeksilnogo, ortho-Tolley, 3-peredelnoj 2-pyridylamine, para-cianfanelli, para-aminophenylalanine,

3-cyan-1-through 4-aminobutyl group, alkoxyamine CH3-(CH2ni-(OCH2CH2)mi-group where niis 0 or 1 and mian integer from 1 to 3, or P1P2N-CH2-CH2-group where P1and P2independently are hydrogen, C1-C3-alkyl, benzyloxycarbonyl, α -, β - the do γ -pyridineboronic, carboxyaniline or carboalkoxylation, or P1and R2together with the nitrogen atom to which they are bound, form phtalimide, piperidinyl, morpholinyl balance;

R’ is hydrogen or linear or branched C1-C3is an alkyl group, preferably hydrogen.

"Aryl group" preferably means a phenyl group, optionally substituted by 1-3 substituents, which are identical or different, chosen from halogen atoms, With1-C4-alkyl, C1-C4-CNS, hydroxyl, C1-C7-Allexinno, ceanography, nitro, amino, C1-C3-acylamino, halogen-C1-C3-alkyl, halogen-C1-C3-alkoxygroup, bentilee group or aryl radical known anti-inflammatory 2-arylpropionic acids such as ibuprofen, Ketoprofen, naproxen, suprofen, carprofen, pirprofen, fenoprofen.

Preferred aryl residues 2-arylpropionic acids are 4-isobutylphenyl, 3-benzoylphenyl, 5-benzoyl-2-acetoxyphenyl, 3-phenoxyphenyl, 5-benzoylation-2-yl, 4-canolfan, 1-oxo-2-isoindolyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl, 6-methoxy-β -naphthyl, 5-benzoyl-2-thiophenyl, 1-hydroxyphenyl or a residue of the formula

in which a is benzyl, benzoline or N-hydroxymethylamino, 1-hydroxyphenyl-1-methyl group, b is hydrogen, hydroxy-group, C1-C3-alloctype or amino group.

R2preferably is aryl residue known anti-inflammatory 2-arylpropionic acid, as described above.

Especially preferred values of PR2 are 4-(2-methylpropyl " phenyl, 3-phenoxyphenyl, 2-[4-(1-oxo-2-isoindolyl)phenyl]5-benzoylation-2-yl, 4-canolfan.

C1-C3-alloctype is preferably acetyl group; a linear or branched C1-C16-alkyl group is preferably methyl, hexeline, Godzilla or hexadecimally group; C1-C3-alkyl group is preferably methyl group.

Particularly preferred compounds according to the invention of formula (1) are those in which the methyl group is configured R.

Compounds according to the invention can be obtained using methods such as interaction in an inert solvent equimolecular quantities of acids of the formula (2)

in which R2’ has the same meaning as R2or is a group which can be converted to R2by-the Oia any protective groups,

with equimolecular quantities sulfonamida formula (3)

in which R and R’ have the above values,

in the presence of equimolecular number and/or a slight excess of condensing agent such as a carbodiimide (such as dicyclohexylcarbodiimide), soluble carbodiimide (such as hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide) or 1,1’-carbonyldiimidazole and counter-base selected from the group comprising triethylamine, 4-(N,N-dimethylamino)pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.

Alternatively, such an effective process is in the interaction of the sulfonamide anion of the formula (3’)

in which R has the above significance,

in an inert solvent with a suitable reactive form of the acids of formula (2); acid chlorides of the formula (2) are the most preferred reactive forms in the preparation of chiral N-arylsulfonamides according to the invention, in order to avoid the difficulties associated with the partial racemization that can occur during the interaction of sulphonylchloride formula (4) with the amide anion of formula (5)

In the case when R2’ in the compounds obtained in accordance with the laws the AI with the above methods, represents benzoyloxy group specified benzoline group could lead to various compounds of formula (1) by known reactions oximo or by reduction of the carbonyl group through alcohol to hydrocarbon (benzyl) when the absorption of one or two equivalents of hydrogen in the presence of a suitable catalyst.

N-Arylsulfonamides compounds of formula (1) is a group, enough acid for the formation of salts of addition, the strong and medium bases, such as L-lysine, L-arginine, tromethamine or chiral amines such as ephedrine, cinchonine, cinchonidine and so on, thereby providing the optical separation of these sulfonamides on their individual enantiomers (R) and (S). Various chromatographic methods, not necessarily in chiral media (see, for example, W.H.Pirkle and J.McCune, cited above), such as TLC or different methods of column chromatography, can be used for the purification and separation of enantiomers and diastereomers, optical purity which is measured using the R-(-)-2-[(4’-isobutyl)phenyl]propionamide as a reference.

The acid chlorides alkylsulfonates, arylsulfonate or heteroarylboronic acids and their amides are known commercially available and convenient for obtaining compounds. So, for example, the Le conversion polyoxyethylenated alcohol of the formula CH 3-(CH2)ni-(OCH2CH2)ni-OH (where niand mihave the above values into the respective tozilaty or halides (X=CL, Br or I), the interaction of the latter with an excess of thiourea gives the corresponding salt isothiourea: CH3-CH2)ni-(OCH2CH2)min-S-(C=NH)-NH2·HX, which is directly converted into the corresponding sulphonylchloride: N3-(CH2)ni-(OCH2CH2)min-SO2Cl by chlorination at room temperature, and then into the corresponding sulfonamides (J..Sprague and ..Johnson, J. Am. Chem. Soc., 59, 1837, 1937).

2-Alkylbenzenesulfonate formulas P1P2-N-CH2-CH2-SO2NH2where P1and R2are C1-C3-alkyl group or, as described above, form a ring with the nitrogen atom, are known compounds or can be obtained using known methods. For the synthesis of amides of taurine (see, for example. Miller et al., J. Am. Chem. Soc., 62, 2099, 1940, and .Mcllwain, J. Chem. Soc., 75, 1941, as the main method of obtaining 2-dialkylbenzosulphonates, A. Le Berre and .Porte, Bull. Soc. Chim. (France), 11-602, 1978 describes the addition of secondary amines (dimethylamine, piperidine or research) to ethylenesulphonic [CH2=CH-SO2NH2], the synthesis of which is described in A.S.Matlack, J. Org. Chem., 23, 729, 1958,and cited in the references.

It is known that the sulfonamides of the formula (3) and sulphonylchloride formula (4) are compounds which can be obtained using well known methods.

2-Arylpropionate acid of the formula (2) are well known compounds that are used as analgesics and anti-inflammatory drugs. There are several procedures for getting them as individual enantiomers, and racemates. There are a lot of effective methods for optical separation of racemates. Enantioselective synthesis usually refers to the (S) enantiomers arylpropionic acids, but they can also be modified to obtain (R) enantiomers by appropriate selection of reagents (chiral assistants), for example, to use alkylalcohol as substrates for α -arylalkenes acids (see ..Trost and J.H.Rigby, J. Org. Chem., 14, 2936, 1978; for α -arilirovaniya acid Meldrum. J.T.Piney and .A.Rowe, Tetrah. lett., 21, 965, 1980; to use tartaroo acid as chiral assistant G.Castaldi et al., J. Org. Chem., 52, 3018, 1987; α -hydroxyamino as chiral reagents R.D.Larsen et al., J. Am. him. Soc. 111, 7650, 1989, and US 4940813 and cited in these references).

In more detail, arrowie acid of the formula (2), in which R2is 3-benzoyl-2-hydroxyphenylazo or 3-benzoyl-2-AMINOPHENYL the OIC group, are known compounds. The retrieval method described in the application for the grant of a patent Italy 1283649 (23.04.1998), owned by the present applicant.

Specific examples of the compounds of the invention are: R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide and its salt of L(+)-lysine;

R(-)-N-2-[(3-benzoylphenyl)propionyl]methanesulfonamide;

R(-)-N-(2-[3-(1ε -hydroxy-1ε -phenyl)methyl]propionyl)methanesulfonamide;

R(-)-N-methyl,N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide;

R(-)-N-[2-(3-benzoylphenyl)propionyl]methanesulfonamide;

(±)N-[2-(5’-benzoyl-2’-acetoxyphenyl)propionyl]methanesulfonamide;

hydrochloride R(-)-N-2-[(4-isobutylphenyl)propionyl]-2-aminoethylamide;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-palmitoylethanolamide;

amide R(-)-N-[2-(3-benzoylphenyl)propionyl],N’-carbobenzoxy;

amide R(-)-N-[2-(3-phenoxyphenyl)propionyl],N’-carbobenzoxy;

amide R(-)-N-[2-[4-(1-oxo-2-isoindoline]propionyl],N’-carbobenzoxy;

N-[2-(5-benzoylation-2-yl)propionyl]-(2-carbobenzoxy)econsultant;

N-[2-(4-canolfan)propionyl]-(2-carbobenzoxy)econsultant;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2-carbobenzoxy)econsultant;

R(-)-N-[2-(3-benzoylphenyl)propionyl]-(2-amino)econsultant;

R(-)-N-[2-(3-phenoxyphenyl)propionyl]-(2-amino)econsultant;

-[2-(5-benzoylation-2-yl)propionyl]-(2-amino)econsultant;

N-[2-(4-canolfan)propionyl]-(2-amino)econsultant;

R(-)-N-[2-(4-isobutylphenyl)propionyl]cyclohexylsulfamic;

R(-)-N-[2-(4-isobutylphenyl)propionyl]dodecylsulfonate;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-steam-cyanobenzenesulfonyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3-cyano-1-propanesulfonate;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-methoxybenzenesulfonamide;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxaheptyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxoanthracene;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxymethylene;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxadecyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]cyclohexylsulfamic;

R(-)-N-[2-(4-isobutylphenyl)propionyl]dodecylsulfonate;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-steam-cyanobenzenesulfonyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3-cyano-1-propanesulfonate;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-methoxybenzenesulfonamide;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxaheptyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxoanthracene;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxymethylene;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxadecyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-dimethylbenzenesulfonamide;

R(-)-N-[2-(4-of butylphenyl)propionyl]-2-(piperidine-1-yl)ethylsulfonyl;

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-(morpholine-4-yl)ethylsulfonyl.

Compounds according to the invention was studied using PMN cells derived sedimentation on the dextran heparinized blood from healthy volunteers; mononuclear cells were removed by Ficoll/Hypaque, whereas the erythrocytes were removed by hypotonic treatment solutions. The viability of PMN leukocytes was counted by exclusion Turk and Trifanova blue, while the share containing the kernel of RM-cells in cytocentrifuge was assessed by staining Diff Quinck (W.J.Ming et al., J. Imnunol., 138, 1469, 1987).

In each of the below described tests in vitro PMN were incubated with the compounds according to the invention for 10 minutes at a temperature of 37° C.

In tests on chemotaxis and tests to determine the level of ions of Ca2+in the cytosol of recombinant IL-8 person (Ergo Tech.) used as a stimulating agent: lyophilized protein was dissolved in HBSS (balanced salt Hanks solution) at a concentration of 100 ng/ml and used after dilution in HBSS at a concentration of 10 ng/ml in tests on chemotaxis and at a concentration of 25-50 ng/ml when determining cellular modifications [Ca2+]i.

In tests on chemotaxis used (in accordance W.Falket et al., J. Immunol. Metods, 33, 239, 1980) PVP filters with 5 mm porosity and the Plexiglas micro camera capable of 48 repeat the. The micro-camera consists of a piece of plexiglass containing 48 cells with a capacity of 25 [ml each, and equipped with a cover, which on its reverse side contains 48 then arranged so that when the cover is closed and bolted to the underlying part in the micro-camera created compartments with a capacity of 50 µl.

Equal concentrations of the test compounds were placed at the top of the cell containing the PMN suspension, and at the bottom of the cell, which contained the media, optional added IL-8 (or other stimulating agent).

As an example, R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide (DF 1681), depending on the dose inhibited chemotaxis induced IL-8 (10 ng/ml)in the concentration range from 10-6up to 10-11M. Presented as the mean + S.D. of three independent experiments results, expressed as the number of migrated PMN shown in Fig. 1 in the form of histograms.

(S) - (+)-N-2-[(4-Isobutylphenyl)propionyl]methanesulfonamide and R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide mattered IC50in the range of 10-7up to 10-8M

Presented on Fig. 2 results confirm the fact that the compounds according to the invention selectively inhibit IL-8-induced chemotaxis instead of chemotaxis induced CA (10-9M) or f-MLP (10-8M), at least for the range of the concentration of the Nations DF 1681 from 10 -6up to 10-7M [presented as the mean + S.D. of three independent tests results are expressed as the number of migrated PMN].

Changes in [CA2+]iin the cytosol was determined in an experimental model described C.Bizzarri et al. (Blood, 86, 2388, 1995), using slides containing stuck PMN added 1 μ M Fura-2AM to assess changes in [Ca2+]iin real-time. In turn PMN cytocentrifuged resuspendable in medium RPMI 1640 with 5% FCS (fetal bovine serum) at a concentration of 3× 106/ml and then were placed on a round glass slides with a diameter of 25 mm, which were placed in the incubator for 30 minutes at a temperature of 37° C. After three consecutive otmivaniya BSS (balanced salt solution) to remove unattached cells, all adherent cells further incubated for up to 4 hours before adding Fura-2-AM.

As an example, the results obtained with R(-)-N-2-[3-(benzoylphenyl)propionyl]methanesulfonamide (DF 1661) and R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide (DF 1681) using PMNs of cells from three different donors are shown in table 1. These leukocytes were found close to IL-8 (50 ng/ml) when in response to a stimulus [Ca2+]iwas higher than the control level, 34% (normalized to 00).

Table 1
IL-8 (50 ng/ml)254±23 (n=20)
DF 1661 (10-6M) + IL-8 (50 ng/ml)184+16 (n=10)
DF 1681 (10-6M) + IL-8 (50 ng/ml)159+16 (n=10)

Answers, expressed in % compared to control values [CA2+]iequal to the average value of the responding cells and include the average error of measurement (SEM); n = number of repetitions. During these tests, the percentage neotmetilsia cells differed in different groups: 30% in the group that was affected only IL-8, 40% in the group, which previously worked DF 1661, and 70% in the group, which previously worked DF 1681.

N-2-Arylpropionate according to the invention of formula (1) characterized by their ability to inhibit in vitro PMN chemotaxis of human leukocytes stimulated by interleukin 8, see table 2. Arylsulfonamides of the invention, depending on the dose inhibit PMN chemotaxis of human leukocytes, with the value of the IC50(dose inhibiting effect by 50%) in the concentration range from 10-7up to 10-9M with a remarkable level of selectivity and specificity to IL-8-induced chemotaxis. Concentrations above one or two orders of magnitude is required for inhibition of in vitro chemotaxis, the Indus is new other chemotactic factors: Sa, formylpiperidine bacterial and synthetic nature (f-LMP). The specificity of the compounds of the invention proved by the fact that they inhibit stimulated IL-8 increase in human PMN intracellular concentration [Ca2+]iwhose increase is associated with activation of PMNL [J.H.Liu et al., J.Infect. Dis., 166, 1089 (1992)].

Regardless of the absolute structure of the methyl group of compounds according to the invention does not significantly affect the products and prostaglandins. In fact, in LPS-stimulated macrophages of mice (1 mg/ml) shows that the compounds according to the invention (in the concentration range from 10-5up to 10-7M) inhibit the production of PGE2usually less than is statistically significant, and never higher than 10-15% of the control values.

It is not relevant inhibition of the synthesis of PGE2is useful as compounds according to the invention, in contrast to some 2-arylpropionic acids, in the case of macrophages mice (LPS stimulated) are not appropriate incentives to enhance the synthesis of TNFα which in turn enhances activation and chemotaxis of neutrophils and synthesis of IL-8. These effects (neusilin synthesis of TNF-α ) also affected in the case of the synthesis of TNFα stimulated by hydrogen peroxide.

Taking into account these experimental data and the fact that interleukin 8 (IL-8)and its analogues are involved in the process of infiltration by neutrophils in pathologies such as psoriasis (B.J.Nickoloff et al., Am.J.Pathol., 138, 129, 1991), rheumatoid arthritis (M.Selz et al., J.Clin. Invest. 87, 463, 1991), ulcerative colitis (Y.R.Mahkla et al., Clin. Sci., 82, 273, 1992), respiratory distress syndrome in adults (ARDS) and idiopathic fibrosis (Rstage et al., J. Clin. Invest., 88, 1802, 1991, and E.J.Miller et al., Am. Rev. Respir. Dis. cited above), glomerulonephritis (.Wada et al., J. Exp. Med., 180, 1135, 1994), the compounds according to the invention can be used in the treatment of these pathologies.

For these therapeutic purposes the compounds according to the invention is conveniently represented in the pharmaceutical compositions using conventional techniques and excipients, such as described in "Remington''s Pharmaceutical Sciences Handbook", Mack Publishing Co., New York, 18thEd, 1990.

The composition of the invention can be administered intramuscularly, intravenously, in the form of balls, dermatological preparations (creams, lotions, sprays and ointments), as well as orally in the form of capsules, tablets, syrups, compositions with controlled release and the like.

The average daily dosage depends on various factors such as the severity of the disease and the condition of the patient (age, gender and weight). The dose usually ranges from 1 or more milligrams to 1500 mg daily connections, optional split to multiple injections. Higher dosage also may be introduced due to the low toxicity of the compounds according to the invention, even La long course of treatment.

The following examples illustrate more the invention.

OBTAIN

The method used to obtain alkylsulfonamides, arylalkylamines, geteroarilsulfoksidu and alkoksimyetilfosfinov formula CH3-(CH3)ni-(OCH2-CH2)mi-SO2NH2where niis zero or 1 and mian integer from 1 to 3, is carried out, as described J.M.Sprague and ..Jonson J.A.C.S., 59,. 1837, 1937, and .Miller et al., back, 62, 2099 (1940).

So, for example, hydrochloride 2-amoxicillinonline obtained by interaction of 2-amoxicillina with a small molar excess of thiourea in alcohol distillation with reflux. When bubbling CL2in the salt solution, cooled to about 25° is highlighted yellow oily mass, which was dissolved in ethyl ether and dried over sodium sulfate. The solvent is evaporated to obtain 2-ataxiatelangiectasia, which is added slowly to a solution of ammonium hydroxide to obtain 2-ethoxyethylene, which, if required, crystallized from dilute alcohol or purified by the method of column chromatography. Using the above process to prepare the following compounds:

2-methoxybenzenesulfonamide;

2-(2-methoxyethoxy)econsultant or 3,6-dioxaheptyl;

<> (2 ethoxyethoxy)econsultant or 3,6-dioxoanthracene;

3,6,9-trioxadecyl;

3,6,9-trioxadecyl.

EXAMPLE 1

The MAIN METHODS for the preparation of N-ARYLSULFONAMIDES

A) by reacting the carboxylic acid of the formula (2) with anion sulfonamida formula (3)

R(-)-N-[2-(4-isobutyl)propionyl]methanesulfonamide

a) Obtaining the carboxylic acid of the formula (2)

A suspension of R(-)-2-(4-isobutyl)propionic acid (R-ibuprofen, 4 g, 0019 mol) in thionyl chloride (7.4 ml) was distilled under reflux for 4 hours, then left to cool at room temperature. The excess thionyl chloride is evaporated in vacuum. Residues of thionyl chloride was removed by washing twice the rest mass of a few drops of dry dioxane and the solvent evaporated in vacuum. of 4.66 g (0.019 mol) R(-)-2-(4-isobutyl)propionitrile received in the form of a yellow oil, which was dissolved in a few milliliters of anhydrous tetrahydrofuran (THF).

b) obtaining anion sulfonamida

Methanesulfonamide (2.3 g, 0,0243 mol) was added to a suspension of tert-butoxide potassium (2,73 g, 0,244 mol) in anhydrous THF (28 ml); the mixture was stirred for 30 minutes at room temperature. After this was added R(-)-2-(4-isobutyl)propionate (of 4.66 g, 0.019 mol) under stirring and left the reaction mixture is mixed in accordance with the s-night at room temperature.

Selected inorganic salt was filtered, the solvent evaporated in vacuum and the oily residue was distributed between CH2Cl2(30 ml) and a saturated solution of phosphate monolatry. The organic phase is washed with water (2× 10 ml) and the aqueous phase was extracted with CH2Cl2(2× 10 ml). The combined organic extracts were dried over Na2SO4and the solvent evaporated, and then to a solution of the oily residue in anhydrous methanol (10 ml) was added two microcapsules of concentrated sulfuric acid to atrificial in methyl ether any traces of unreacted R(-)-2-(4-isobutyl)propionic acid. The mixture was stirred over night at room temperature, the solvent is carefully evaporated in vacuo, the residue was distributed between water (10 ml) and methylene chloride (25 ml). The aqueous phase was discarded and the organic phase was extracted with a saturated solution Panso3(2× 20 ml). The main phases were combined, acidified with concentrated Hcl and was extracted with CH2Cl2(3× 15 ml). After the usual washing until neutral pH values the combined organic extracts were dried over Na2SO4and the solvent evaporated in vacuum to obtain 1.86 g (0,0066 mol) R(-)-N-[2-(4-isobutyl)propionyl]methanesulfonamide; TPL 103-105° C (decomp.); [α ]D=-68° (C=1; CH HE); NMR (DMSO-d6): δ and 7.3 (d, 2H, J=8 Hz); to 7.09 (d, 2H, J=7 Hz); 3.42 points (kV, 1H, J=8 Hz); 2,8 (s, 3H); of 2.45 (d, 2H, J=7 Hz); of 1.55 (m, 1H); 1,3 (d, 3H, J=8 Hz); of 0.95 (d, 6N, J=7 Hz).

In) direct condensation of the acid of formula (2) with a sulfonamide of the formula (3) in the presence of a condensing agent

N,N-Dimethylaminopyridine (2,363 g, 0,0194 mol), hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (3,721 g, 0,0194 mol) and methanesulfonamide (1,845 g, 0,0194 mol) were added sequentially to a solution of R-(-)-ibuprofen (4 g, 0,0194 mol) in anhydrous CH2Cl2(30 ml); the mixture was left to mix overnight. The solvent is evaporated, the residue mylevel with ethyl acetate (40 ml) and the combined organic phases were washed with water (15 ml) and 20% aqueous citric acid solution (2× 10 ml) and dried over Na2SO4then the solvent is evaporated to obtain 2.2 g (0,0076 mol) R(-)-N-[2-(4-isobutylphenyl]methanesulfonamide in the form of a white solid, TPL 103-105° C (decomp.); [α ]D=-68° (C=1; CH3IT).

EXAMPLE 2

Using the procedures described in example 1, were prepared the following compounds.

S(+)-N-[2-(4-isobutyl)propionyl]methanesulfonamide:

TPL 109-111° C (decomp.); [α ]D=+73° (C=1; CH3HE);1H-NMR (CDCl3): δ 7,65 (users, 1H, NH); a 7.2 to 7.0 (m, 4H); the 3.65 (q, 1H, J=8 Hz); of 3.25 (s, 3H); 2,5 (d, 2H, J=7 Hz); of 1.85 (m, 1H), and 1.5 (d, 3H, J=8 Hz); of 0.95 (d, 6N, J=7 Hz).

R(-)-N-[2-(3-benzoylphenyl)p is opional]methanesulfonamide:

pale jeltova oil; [α ]D=-73° (C=1; CH3HE);1H-NMR (Dl3): δ 8,25 (users, 1H, NH), 7,80-7,35 (m, N), 3,80 (kV, J=7 Hz, 1H), 3,21 (s, 3H), of 1.55 (d, J=7 Hz, 3H).

S(+)-N-[2-(3-benzoylphenyl)propionyl]methanesulfonamide:

pale yellow oil; [α ]D=+67° (C=1; CH3HE);1H-NMR (Dl3): δ 8,5 (users, 1H, NH), 7,9 was 7.45 (m, N in), 3.75 (q, J=7 Hz, 1H), 3,21 (s, 3H), of 1.55 (d, J=7 Hz, 3H).

S(+)-N-[2-(2-fluoro-4-biphenylyl)propionyl]methanesulfonamide:

TPL 130-132°; [α ]D=+44° (C=1; CH3HE);1H-NMR (Dl3): δ 7,8 (users, 1H, NH); 7,50-7,30 (m, 5H); 7,05-of 6.90 (m, 3H); the 3.65 (q, 1H, J=7 Hz); 3,20 (s, 3H); 1.50 in (d, 3H, J=7 Hz).

R(-)-N-[2-(2-fluoro-4-biphenylyl)propionyl]methanesulfonamide:

TPL 106-108°; [α ]D=-42° (C=1; CH3HE);1H-NMR (Dl3): δ 7,9 (users, 1H, NH); 7,50-7,30 (m, 5H); 7,10-to 6.95 (m, 3H); the 3.65 (q, 1H, J=7 Hz); 3,20 (s, 3H); 1.50 in (d, 3H, J=7 Hz).

EXAMPLE 3

R(-)-N-Methyl,N-[2-(4-isobutyl)propionyl]methanesulfonamide N-arylsulfonamides are sufficiently acidic substances, giving, after reaction with diazoalkanes, N-acyl-N-alkylsulfonamides due process, described hereafter.

A solution of R(-)-N-[2-(4-isobutyl)propionyl]methanesulfonamide (0.3 g, 0.0001 mol) in dry ethyl ether, cooled in an ice bath (T=4° (C)was added dropwise to 0,67-called solution diazomethane in ethyl ether until a steady yellow. Excess di is smetana was destroyed by adding to the cooled solution a few drops of glacial acetic acid. The solution was kept at room temperature and the solvent evaporated. The residue was again dissolved in toluene and evaporated in vacuum to remove residues of acetic acid. The oily residue was purified by the method of column chromatography (n-hexane/CH2CL2, 7:3) to obtain the R(-)-N-methyl-[2-(4-isobutyl)propionyl]methanesulfonamide (0.24 g, 0,00076 mol) as a colourless oil, [α ]D=-60° (C=1; CH3HE);1H-NMR (CDCl3): δ 7,2-to 7.09 (m, 4H); 4,15 (kV, 1H, J=8 Hz); 3,2 (s, 3H); 2,9 (s, 3H); of 2.45 (d, 2H, J=7 Hz); of 1.75 (m, 1H); to 1.35 (d, 3H, J=8 Hz); of 0.95 (d, 6N, J=7 Hz).

The same compound can be prepared according to the procedure of example 1, using equimolar amounts of N-methylmethanesulfonamide instead of methanesulfonamide.

EXAMPLE 4

R(-)-N-[2([3-(1ε -hydroxy-1ε -phenyl)methyl]phenyl)propionyl]methanesulfonamide

To a solution of 0.5 g of N-(R(-)-2-[3-(benzoylphenyl)propionyl])methanesulfonamide in ethanol was added 0.05 ml of triethylamine and a catalytic amount of 5% palladium on active carbon and kept in an atmosphere of hydrogen until absorption of one molar equivalent of gas. The catalyst was filtered through celite and the eluate was evaporated to dryness. The residue was distributed between ethyl ether and 5% aqueous solution Pan2RHO4and the organic phase gave 0.4 g of R(-)-N-[2([3-(1ε -hydroxy-1ε -phenyl)methyl]phenyl)impregnated the Nile]methanesulfonamide.

EXAMPLE 5

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

To a solution of 0.5 g of N-(R(-)-2-[3-(benzoylphenyl)propionyl])methanesulfonamide in ethanol was added 0.05 ml of triethylamine and a catalytic amount of 5% palladium on active carbon and kept in an atmosphere of hydrogen until absorption of at least two molar equivalents of gas. The catalyst was filtered through celite and the eluate was evaporated to dryness. The residue was distributed between ethyl ether and 5% aqueous solution Pan2RHO4and the organic phase gave 0.4 g of R(-)-N-2[3-biphenyl)propionyl]methanesulfonamide.

EXAMPLE 6

(±)N-2-[(5’-Benzoyl-2’-acetoxyphenyl)propionyl]methanesulfonamide

To a solution of 6 g (+)4-acetoxy-3-(1’-methyl-2’-propen-1-yl)benzophenone in CH2Cl2(125 ml) was added an equivalent volume of water was added successively with vigorous stirring glacial acetic acid (12 ml), Aliquat 336 (0, 37 g) and, in small portions, potassium permanganate to a total of 9.5 g (to 0.060 mol). The mixture was kept under stirring for 20 hours at room temperature until complete disappearance of the starting product. The reaction mixture is provided by adding an aqueous solution of sodium metabisulfite (7.2 g in H2O, 15 ml), then added CH2Cl2(10 ml) and separated phases. The organic phase was washed with saturated saline (2× 25 ml) and dried in the Na 2SO4the solvent is evaporated under vacuum to obtain 6.2 g (±)2-(5’-benoil-2’-acetoxyphenyl)propionic acid good purity in the form of an oily liquid. HPLC N2O/CH3SP t=0 60 40, t=12 0 100, t=15 0 100. Bondapak C18 20 cm, 1=254 nm, room temperature, 5.5 minutes), TLC (CH2CL2/CH3HE 9:1) Rf=0,2;1H-NMR (CDCl3): δ to 7.95 (s, 1H); a 7.85 (DD, 2H, J’=7 Hz); of 7.75 (DD, 1H, J’=-7 Hz); 7,6 (m, 1H); 7,45 (7, 2H, J=7 Hz); of 7.25 (s, 1H); from 3.9 (q, 1H, J=8 Hz); 2,35 (s, 3H), and 1.5 (d, 3H, J=8 Hz).

Using this connection in the process of example 1 was received (+)N-2-[(5’-benzoyl-2’-acetoxyphenyl)propionyl]methanesulfonamide.

EXAMPLE 7

L(±)-lysine salt of R(-)-N-[2-(4-isobutyl)propionyl]methanesulfonamide

To a solution of L(+)-lysine (129 mg; 0.88 mmol) in water (1.3 ml) was added a solution of R(-)-N-[2-(4-isobutylphenyl]methanesulfonamide (250 mg; 0.88 mmol) in 1 ml of methanol. The solvent is evaporated and the residual mass was brought ethyl ether (5 ml) and was stirred over night at room temperature. Crystallin, highly hygroscopic selected material was rapidly filtered under nitrogen atmosphere, washed on the filter with anhydrous ethyl ether and dried under vacuum at 50° C for 2 hours to obtain 360 mg L(+)-lysine salt of R(-)-N-[2-(4-isobutyl)propionyl]methanesulfonamide in the form of a pale yellow powder. [α ]D=- 17, 3C° (C=1,15; CH3HE);1H-NMR (D2O): δ7,30 (DD, 4H, J=8 Hz), of 3.77 (t, 1H, J=7 Hz), the 3.65 (q, 1H, J=7 Hz), 3,05 (m, 5H), 2,52 (d, 2H, J=7 Hz), with 1.92 (m, 2H), of 1.75 (m, 2H) 1,50 (m, 3H), of 1.40 (d, 3H, J=7 Hz), 0,90 (6N, d, J=7 Hz).

EXAMPLE 8

R(-)-2-[(4’-Isobutyl)phenyl]propionamide

Using the procedure of example 1 28% aqueous solution of NH4OH instead of sulfonamide-anion, in accordance with the process described here, to prepare amides of acids of the formula (2). A solution of 1 g of R(-)-2[4-isobutylphenyl]Propionaldehyde in dry acetonitrile (1.5 ml) was added dropwise to cooled to 0-5° With 28% solution of NH4HE (3 ml) at such a rate that the temperature of the reaction mixture did not exceed +5° C. the Mixture was left to mix for 1 hour at room temperature, the solvents evaporated under reduced pressure to obtain residue, which was dissolved in ethyl acetate (5 ml). The solution was cooled to 0-4° With the purpose to separate the white crystalline precipitate (1,218 g; to 5.93 mmol) of R(-)-2-[(4’-isobutyl)phenyl]propionamide, which was filtered and dried under vacuum, TPL 125-127°; [α ]D=-28° (c=1; CH3HE);1H-NMR (CDCl3): δ 7,2-7,05 (m, 4H); 5,25 (users, 2H, NH3); 3,6 (kV, J=8 Hz, 1H), 2,5 (m, 2H), and 1.9 (m, 1H), 1.55V (d, J=8 Hz, 3H), of 0.93 (d, J=7 Hz, 6N).

EXAMPLE 9

Hydrochloride R(-)N-[2-(4-isobutyl)propionyl]-(2-amino)ethylsulfonyl

Following the method described by R. Winterbottom et al., J. Am. Chem. Soc., 69, 1393-1401 (1947), with 21.4 g of phthalic anhydride (0,145 mol) was added suspensie taurine (17 g, 0,137 mol) and potassium acetate (14.2 g, 0,145 mol) in glacial acetic acid (48 ml), heated under reflux. Heating was continued with the aim of complete dissolution of the reagents (2.5 hours); after cooling to 0-5° With the resulting precipitate, isolated by filtration, washed with glacial acetic acid and absolute alcohol, dried in air and under vacuum (50° (C) obtaining and 31.2 g of potassium salt of 2-phthalimidomalonate acid [TPL >300°;1H-NMR (D2O) δ : a 7.85 (m, 4H), of 4.05 (t, 3H, J=8 Hz), of 3.25 (t, 2H, J=8 Hz). To a dry method azeotropically distillation suspension of 5 g of salt in benzene (50 ml) was added 2,56 g pentachloride phosphorus (0.015 mol) and distilled under reflux for 1 hour. Then add a second aliquot of pentachloride phosphorus (2,56 g, 0.015 mol). The mixture was distilled under reflux in the course of the next 90 minutes, then the solvent and the reagents are evaporated under vacuum and under reduced pressure. The mixture was distilled under reflux for subsequent 1,30 hours; cooled to room temperature and evaporated the solvent under reduced pressure. The residue was placed in 30 g of powdered ice with the formation of high-purity solid was filtered, washed with water and dried) 2-palmitoylethanolamide (3,71 g; TPL=158-159° C).

28% ammonia solution (15,5 ml) in acetonitrile (15 ml) was added dropwise to a solution of 2-palmitoylethanolamide cooled to 0-4° With acetonitrile (30 ml), the mixture stirred for 30 seconds at 0-4° C, the solvent evaporated and the residual mass was added to hot water in order to separate the precipitate of 2-palmitoylethanolamide (0.8 g) [TPL=206-209°;1NMR (DMSO-d6): δ to 7.95 (m, 4H), 7,15 (users, 2H, NH2), of 4.05 (t, 3H, J=8 Hz), at 3.35 (t, 2H, J=8 Hz)].

0.75 g (0,00295 mol) of the compound was added in terms of inert gas to a suspension of tert-butoxide potassium (0,331 g, 0,00295 mol) in anhydrous THF (7 ml); the mixture was stirred for 1 hour, then to it was added a solution of R(-)2-(4-isobutylphenyl)propionitrile [freshly prepared by the reaction of 0.47 g of the acid (0,00227 mol) thionyl chloride] in anhydrous THF (2 ml). The mixture was kept under stirring at room temperature for 24 hours; the solid residue was filtered, the solution was evaporated to dryness and the residue is divided between water and ethyl acetate. The combined organic phases were washed with water (2× 25 ml) and saturated brine (25 ml) and dried over. Na2SO4as usual, the solvent evaporated under vacuum to obtain an oily residue, which was purified by the method of flash chromatography (eluent CH2Cl2/CH3OH 98:2) to yield a clear oil 06 g of N-[R(-)2-(4-isobutylphenyl)propionyl]-2-palmitoylethanolamide. 1H-NMR (Dl3): δ with 8.05 (m, 4H), to 7.15 (m, 4H), 7,05 (users, 1H, NH), of 4.05 (t, 3H, J=8 Hz), at 3.35 (m, 3H), 2,50 (d, 2H, J=7 Hz), with 1.92 (m, 1H), 1,20 (d, 3H, J=8 Hz), of 0.95 (d, 6N, J=7 Hz).

A solution of the compound (0.5 g, 1.12 mmol) in ethanol (4 ml) was added 85% of the hydrate. hydrazine (0.4 ml) was distilled under reflux for 1 hour. After evaporation of the solvent under vacuum, dilution with water and acidification 2 N. hydrochloric acid falicitated was isolated by filtration. The eluate was evaporated to dryness obtaining of 0.332 g of the hydrochloride R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2-amino)acanaloniidae, also called hydrochloride R(-)N-[2-(4-isobutylphenyl)propionyl]touristulanude.

EXAMPLE 10

Using the method according to example 9 N’-carbobenzoxy received in accordance with .Mcllwain, J. Chem. Soc, 75, 1941, and chloride 2-arylpropionic acid selected from the group comprising R(-)2-(3-benzoylphenyl)propionic, R(-)2-(3-phenoxyphenyl)propionic, R(-)2-[4-(1-oxo-2-isoindolyl)phenyl]propionic, 2-(5-benzoylation-2-yl)propionic, 2-(4-canolfan)propionic and R(-)-2-(4-isobutylphenyl)propionic acid, were obtained the following compounds, respectively:

R(-)-N-[2-(3-benzoylphenyl)propionyl]-(2-carbobenzoxy)econsultant

1H-NMR (CDCl3): δ 8,40 (user. s, 1H, CONHSO2); of 7.90-7,20 (m, 14N); 5,50 (user. s, 1H, OCONH); 5,20 (s, 2H); of 3.80 (q, 1H, J=7 Hz); 3.40 in (t, 2H, J=7 Hz); of 3.25 (m, 2H); of 1.55 (d, 3H, J=7 Hz; R(-)-N-[2-(3-phenoxyphenyl)propionyl]-(2-carbobenzoxy)econsultant

1H-NMR (CDCl3): δ 8,28 (user. s, 1H, CONHSO2); 7,95-7,25 (m, 14N); the 5.45 (user. s, 1H, OCONH); the 5.25 (s, 2H); of 3.85 (q, 1H, J=7 Hz); 3.42 points (t, 2H, J=7 Hz); of 3.25 (m, 2H); was 1.58 (d, 3H, J=7 Hz);

R(-)-N-[2-[4-(l-oxo-2-isoindolyl)phenyl)propionyl]-(2-carbobenzoxy)econsultant

1H-NMR (Dl3): δ 8,35 (user. s, 1H, CONHSO2); the 7.85-to 7.15 (m, 13H); 5,48 (user. s, 1H, OCONH); 5,20 (s, 2H); 4,20 (s, 2H); 3,90 (kV, 1H, J=7 Hz); of 3.45 (t, 2H, J=7 Hz); 3,30 (m, 2H); of 1.55 (d, 3H, J=7 Hz);

N-[2-(5-benzoylation-2-yl)propionyl]-(2-carbobenzoxy)econsultant

1H-NMR (Dl3): δ of 7.90 (DD, 2H, J=7 Hz); 7,65-7,20 (m, N); 7,05 (d, 1H, J=4 Hz); 5,55 (user. s, 1H, OCONH); 5,20 (s, 2H); 4,10 (kV, 1H, J=7 Hz); of 3.48 (t, 2H, J=7 Hz); at 3.35 (m, 2H); 1,75 (user. s, 1H, CONHSO2); to 1.70 (d, 3H, J=7 Hz);

N-{2-[4-(2-thienoyl)phenyl]propionyl}-(2-carbobenzoxy)econsultant

1H-NMR (Dl3): δ 7,80-7,20 (m, 11N); 7,05 (DD, 1H, J=4 Hz); 5.40 to (user. s, 1H, OCONH); by 5.18 (s, 2H); 3.75 to (q, 1H, J=7 Hz); of 3.45 (t, 2H, J=7 Hz); 3,30 (m, 2H); 1.55V (user. s, 1H, CONHS2); a 1.50 (d, 3H, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2-carbobenzoxy)econsultant

1H-NMR (DMSO-d6): δ : 11,90 (user. s, 1H, CONHSO2); 7,40-7,10 (m, N); 5,35 (user. s, 1H, OCONH); of 5.05 (s, 2H); 3.75 to 3.50 for each (m, 5H); of 2.45 (d, 2H, J=7 Hz); of 1.85 (m, 1H); of 1.50 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

EXAMPLE 11

A suspension of 2 g of R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2-carbobenzoxy)Athens is lonarid and 0.1 g of palladium mobile in a mixture of water (20 ml), methanol (20 ml) and acetic acid (6 ml) was stirred in hydrogen atmosphere; emissions of carbon dioxide was stopped after half an hour. The suspension was filtered to remove palladium, the solvent evaporated in vacuum. The residue was placed in vacuum in the presence of NaOH. To a solution of the residue in ethanol (5 ml) was affected by a saturated solution of Hcl in ethanol to highlight hydrochloride R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2-amino)acanaloniidae, which was collected by filtration.

Using a similar method carbonintensity in example 10, were obtained the following compounds in the form of hydrochloride:

R(-)-N-[2-(3-benzoylphenyl)propionyl]-(2-amino)econsultant

1H-NMR (Dl3): δ of 7.90-7,20 (m, N); 6,05 (user. s, 1H, CONHSO2); 4,78 (user. s, 2H, NH2); of 3.78 (m, 2H); to 3.58 (q, 1H, J=7 Hz); 3,20 (t, 2H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz);

R(-)-N-[2-(3-phenoxyphenyl)propionyl]-(2-amino)econsultant;

R(-)-N-[2-[4-(1-oxo-2-isoindolyl)phenyl]propionyl]-(2-amino)econsultant

1H-NMR (CDCl3): δ a 7.85-to 7.15 (m, 8H); 6,10 (user. s, 1H, CONHSO2); 4,90 (user. s, 2H, NH2); 4,20 (s, 2H); 3.75 to (m, 2H); 3,55 (kV, 1H, J=7 Hz); 3,18 (t, 2H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz);

N-[2-(5-benzoylation-2-yl)propionyl]-(2-amino)econsultant

1H-NMR (CDCl3): δ of 7.90 (DD, 2H, J=7 Hz); the 7.65 7,40 (m, 4H); 7,05 (d, 1H, J=4 Hz); 6,10 (user. s, 1H, CONHSO2); 5,00 (user. s, 2H, NH2); 4,10 (kV, 1H, J= Hz); of 3.80 (m, 2H); of 3.25 (t, 2H, J=7 Hz); 1.70 to (d, 3H, J=7 Hz);

N-{2-[4-(2-thienoyl)phenyl]propionyl}-(2-amino)econsultant

1H-NMR (CDCl3): δ 7,80-7,20 (m, 6N); 7,05 (DD, 1H, J=4 Hz); between 6.08 (user. s, 1H, CONHSO2); 4,80 (user. s, 2H, NH2); of 3.85 (m, 2H); 3.75 to (q, 1H, J=7 Hz); of 3.25 (t, 2H, J=7 Hz); 1.50 in (d, 3H, J=7 Hz).

EXAMPLE 12

Using the method according to example 1 of the sulfonamide selected from the group comprising cyclohexylsulfamic, hexylsilane, dodecylsulfonate or hexadecylsulfate, partialattributedeletionlist, 3-cyano-1-propanesulfonate, 2-methoxybenzenesulfonamide, 3,6-dioxaheptyl, 3,6-dioxothiazolidine, 3,6,9-trioxadecyl and 3,6,9-trioxadecyl received the following connections:

R(-)-N-[2-(4-isobutylphenyl)propionyl]cyclohexylsulfamic

1H-NMR (CDCl3): δ then 7.20 (d, 2H, J=7 Hz); 7,05 (d, 2H, J=7 Hz); between 6.08 (user. s, 1H, CONHS2); 3,90 (kV, 1H, J=7 Hz); 3.15 in (m, 1H); 2.50 each (d, 2H, J=7 Hz); 2,30-2,05 (m, 4H); of 1.84 (m, 1H); of 1.55 (d, 3H, J=7 Hz); 1,49-of 1.39 (m, 6N); of 0.95 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]hexylsilane

1H-NMR (Dl3): δ to 7.25 (d, 2H, J=7 Hz); 7,10 (d, 2H, J=7 Hz); 6,05 (user. s, 1H, CONHS2); of 3.85 (q, 1H, J=7 Hz); 3.40 in (t, 2H, J=7 Hz); 2,48 (d, 2H, J=7 Hz); 1,89 (m, 1H); of 1.64 (m, 2H); of 1.55 (d, 3H, J=7 Hz); 1,39 of 1.28 (m, 6N); of 1.05 and 0.98 (m, N);

R(-)-N-[2-(4-isobutylphenyl)propionyl]dodecylsulfonate

1H-NMR (Dl3): δ 7,28 (d, 2H, J=7 Hz); was 7.08 (d, 2H,J=7 Hz); 6,00 (user. s, 1H, CONHSO2); is 3.82 (q, 1H, J=7 Hz); to 3.38 (t, 2H, J=7 Hz); 2.50 each (d, 2H, J=7 Hz); of 1.88 (m, 1H); of 1.62 (m, 2H); of 1.52 (d, 3H, J=7 Hz); 1,34 of 1.28 (m, N); of 1.05 and 0.98 (m, N);

R(-)-N-[2-(4-isobutylphenyl)propionyl]hexadecylsulfate

1H-NMR (Dl3): δ 7,28 (d, 2H, J=7 Hz); was 7.08 (d, 2H, J=7 Hz); 6,00 (user. s, 1H, CONHS2); is 3.82 (q, 1H, J=7 Hz); to 3.38 (t, 2H, J=7 Hz); 2.50 each (d, 2H, J=7 Hz); 1,90 (m, 1H)and 1.60 (m, 2H); of 1.53 (d, 3H, J=7 Hz); 1,34 of 1.28 (m, N); of 1.05 and 0.98 (m, N);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-steam-cyanobenzenesulfonyl

1H-NMR (Dl3): δ 7,45-7,05 (m, 8H); 6,15 (user. s, 1H, CONHSO2); the 4.65 (s, 2H); 3,98 (kV, 1H, J=7 Hz); of 2.51 (d, 2H, J=7 Hz); 1,90 (m, 1H); of 1.55 (d, 3H, J=7 Hz); of 1.05 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3-cyano-1-propanesulfonate

1H-NMR (Dl3): δ then 7.20 (d, 2H, J=7 Hz); 7,10 (d, 2H, J=7 Hz); 6,15 (user. s, 1H, CONHS2); of 3.85 (q, 1H, J=7 Hz); 3.40 in (t, 2H, J=7 Hz); 2,50-to 2.42 (m, 6N); of 1.84 (m, 1H); of 1.55 (d, 3H, J=7 Hz); 1,00 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-methoxybenzenesulfonamide

1H-NMR (Dl3): δ 7,28 (d, 2H, J=7 Hz); for 7.12 (d, 2H, J=7 Hz); 6,05 (user. s, 1H, CONHS2); 4,00 (kV, 1H, J=7 Hz); 3,70-to 3.58 (m, 4H); or 3.28 (s, 3H); 2.50 each (d, 2H, J=7 Hz); 1,89 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxaheptyl

1H-NMR (CDCl3): δ 7,15-7,05 (m, 4H); 6,15 (user. s, 1H, CONHSO2); of 3.95 (q, 1H, J=7 Hz); of 3.69 (t, 2H, J=7 Hz); 3,01-to 2.85 (m, 6N); 2,50 (d, 2H, J=7 Hz); 2,10 (s, 3H); 1,89 (m, 1H); of 1.55 (d, 3H, J7 Hz); of 1.02 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6-dioxoanthracene

1H-NMR (CDCl3): δ 7,15-7,05 (m, 4H); 6,12 (user. s, 1H, CONHSO2); to 3.92 (q, 1H, J=7 Hz); 3,70 (t, 2H, J=7 Hz); 2.95 and-2,70 (m, 8H); 2,50 (d, 2H, J=7 Hz); 1,90 (m, 1H); of 1.50 (d, 3H, J=7 Hz); 1,10-1,00 (m, N);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxymethylene

1H-NMR (CDCl3): δ 7,15-7,05 (m, 4H); 6,05 (user. s, 1H, CONHSO2); 3,90 (kV, 1H, J=7 Hz); 3,71 (t, 2H, J=7 Hz); 3,01 is 2.80 (m, 10H); 2,49 (d, 2H, J=7 Hz); 2,10 (s, 3H); 1,89 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-3,6,9-trioxadecyl

1H-NMR (Dl3): δ 7,15-7,05 (m, 4H); 6,02 (user. s, 1H, CONHSO2); the 3.89 (q, 1H, J=7 Hz); 3,88 (t, 2H, J=7 Hz); 2,98-2,69 (m, N); 2,48 (d, 2H, J=7 Hz); of 1.88 (m, 1H); of 1.50 (d, 3H, J=7 Hz); 1,08-0,98 (m, N).

Optionally, in cases where the solution of one of cyanocarbonimidate selected from R(-)-N-[2-(4-isobutylphenyl)propionyl]-para-cyanobenzenesulfonyl and R(-)-N-[2-(4-isobutylphenyl)propionyl]-3-cyano-1-propanesulfinamide, was first made in ethanol containing gaseous Hcl, in the presence of platinum oxide were hydrochloride the following sulfonamides:

R(-)-N-[2-(4-isobutylphenyl)propionyl]-steam-aminomethyl-phenylmethanesulfonyl

1H-NMR (Dl3): δ 7,35-7,05 (m, 8H); 5,98 (user. s, 1H, CONHSO2); and 5.30 (s, 2H); 4,12 (user. s, 2H, NH2); to 3.92 (q, 1H, J=7 Hz); 3,82 (s, 2H); 2.49 USD (d, 2H, J=7 Hz); 1,89 (m, 1 is); of 1.45 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-4-amino-1-butanesulfinamide

1H-NMR (Dl3): δ to 7.25 (d, 2H, J=7 Hz); 7,10 (d, 2H, J=7 Hz); 5,95 (user. s, 1H, CONHS2); 4,82 (user. s, 2H, NH2); the 3.89 (q, 1H, J=7 Hz); 3,68 (t, 2H, J=7 Hz); 3,10 (m, 2H); 2,48 (d, 2H, J=7 Hz); 1,89 by 1.68 (m, 5H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz).

EXAMPLE 13

Using the method according to example 1 of the sulfonamide selected from the group comprising 2-dimethylbenzenesulfonamide, 2-(piperidine-1-yl)ethylsulfonyl and 2-(morpholine-4-yl)ethylsulfonyl received:

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-dimethylbenzenesulfonamide

1H-NMR (CDCl3): δ to 7.25 (d, 2H, J=7 Hz); 7,10 (d, 2H, J=7 Hz); 5,98 (user. s, 1H, CONHSO2); of 3.85 (q, 1H, J=7 Hz); 3,68 (t, 2H, J=7 Hz); 3,30 (t, 2H, J=7 Hz); 2,48 (d, 2H, J=7 Hz); 2,12 (C, 6N); 1,89 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-(piperidine-1-yl)ethylsulfonyl

1H-NMR (CDCl3); δ 7,28 (d, 2H, J=7 Hz); for 7.12 (d, 2H, J=7 Hz); 5,80 (user. s, 1H, CONHS2); 3,90 (kV, 1H, J=7 Hz); 3,55-of 3.32 (m, 4H); to 2.75 (m, 4H); of 2.45 (d, 2H, J=7 Hz); 1,90-to 1.60 (m, 7H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-2-(morpholine-4-yl)ethylsulfonyl

1H-NMR (Dl3): δ 7,28 (d, 2H, J=7 Hz); for 7.12 (d, 2H, J=7 Hz); 5,80, (OSiR. s, 1H, CONHS2); the 3.89 (q, 1H, J=7 Hz); 3,80 of 3.56 (m, 6N); 3,01 is 2.75 (m, 6N); of 2.45 (d, 2H, J=7 Hz); 1,89 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz).

EXAMPLE 14

Used is the method of example 1 R(-)-2-(3-benzoylphenyl)propionitrile and sulfonamide, selected from the group comprising triftormetilfullerenov, ortho-tolilsulfonil, 3-pyridinesulfonamide and 4-pyridinesulfonamide received the following connections.

R(-)-N-[2-(3-benzoylphenyl)propionyl]triftormetilfullerenov

1H-NMR (DMSO-d6): δ 11,90 (user. s, 1H, CONHS2); 7,70-7,38 (m, N); the 3.65 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz);

R(-)-N-[2-(3-benzoylphenyl)propionyl]-ortho-tolilsulfonil

1H-NMR (CDCl3): δ a 7.85-to 7.15 (m, 13H); 6,18 (user. s, 1H, CONHS2); of 3.95 (q, 1H, J=7 Hz); of 2.20 (s, 3H); of 1.55 (d, 3H, J=7 Hz);

R(-)-N-[2-(3-benzoylphenyl)propionyl]-(3-pyridyl)sulfonamide

1H-NMR (CDCl3): δ 8,50-to 8.40 (m, 2H); 7,75-7,25 (m, 11N); 6,10 (user. s, 1H, CONHS2); of 4.05 (q, 1H, J=7 Hz); of 1.55 (d, 3H, J=7 Hz);

R(-)-N-[2-(3-benzoylphenyl)propionyl]-2(4-pyridyl)econsultant

1H-NMR (CDCl3): δ 8,49 (d, 2H, J=7 Hz); 7,80-7,30 (m, 11N); 6,05 (user. s, 1H, CONHS2); of 3.85 (q, 1H, J=7 Hz); 3,10-to 2.85 (m, 4H); of 1.55 (d, 3H, J=7 Hz).

EXAMPLE 15

To a solution of 0.35 g of R(-)-N-[2-(3-benzoylphenyl)propionyl]triftormetilfullerenov in 5 ml of pyridine was added 0.11 g of hydroxylamine hydrochloride. The mixture was left to interact at room temperature for 12 hours, then the solution villeval dropwise 40 ml of 2 N. H2SO4. The resulting precipitate was extracted with ethyl acetate (3× 8 ml). The organic phases were combined, washed with water until neutral value is pH, was dried over sodium sulfate and evaporated to dryness to obtain 0.36 g of the oxime R(-)-(Z,E)-N-[2-(3-benzoylphenyl)propionyl]triftormetilfullerenov.

Using the above method, the R(-)-N-[2-(3-benzoylphenyl)propionyl]methanesulfonamide, got oxime R(-)-(Z,E)-N-[2-(3-benzoylphenyl)propionyl]methanesulfonamide.

EXAMPLE 16

R(-)2-(4’-Isobutylphenyl-(2"-N-nicotianamine)econsultant

A solution of nicotinic acid (0.565 g, 4.6 mmol) in thionyl chloride (3,07 ml of 42.3 mmol) was boiled under reflux for 3 hours and cooled to room temperature to give, after drying in vacuum, nicotinanilide in the form of a pale yellow solid (0.65 g). The mixture obtained nicotinanilide (0.64 g, to 4.52 mmol) in N,N-dimethylformamide (DMF, 1 ml) was added dropwise to a solution of R(-)2-(4’-isobutyl)phenylpropionyl(2’-amino)acanaloniidae (0.6 g, 1.92 mmol) and triethylamine (1 ml) in DMF (10 ml). The resulting mixture was stirred for 24 hours at room temperature. DMF is evaporated under vacuum; the crude residue was purified by the method of column chromatography (eluent: l3/CH3HE/cyclohexane/NH4HE 60:14:24:2) to obtain the R(-)2-(4’-isobutyl)phenylpropionyl-(2’-N-nicotianamine)acanaloniidae, [α ]D=-10,7° (C=0,15; EtOH), as a colourless oil (0.56 g; of 1.34 mmol), MM=417,53, MS=m/z 418,5 (ES)1; TLC (l3/CH3HE/cyclo is exan/NH 4HE 60:14:24:2) Rf=0,4;1H-NMR (CD3D): δ ppm of 9.2 and 9.0 (users, 1H, NH); 8,7-8,5 (users 1H, NH); and 8.4 (d, 1H, J=8 Hz); 7,9 (m, 1H); of 7.5 to 7.4 (m, 1H); to 7.35 (s, 1H); to 7.25 (d, 2H, J=8 Hz); 7,05 (d, 2H, J=8 Hz); 3,8-3,5 (m, 5H); 2,5 (l, 2H, J=7 Hz); 1,95-1,8 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 0,9 (d, 6N, J=7 Hz).

Using the above method isonicotinoyl and Pikalyovo acid instead of nicotinic acid were obtained the following compounds.

R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2’-N-isonicotinamide)econsultant

1H-NMR (Dl3): δ to 8.45 (d, 2H, J=7 Hz); 7,50-7,28 (d, 6N); 6,05 (user. s, 1H, CONH); 5,90 (user. s, 1H, CONHSO2); the 3.89 (q, 1H, J=7 Hz); 3.45 points-of 3.25 (m, 4H); of 2.45 (d, 2H, J=7 Hz); 1,89 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz);

R(-)-N-[2-(4-isobutylphenyl)propionyl]-(2’-N-picolylamine)econsultant

1H-NMR (Dl3): δ to 8.45 (d, 1H, J=7 Hz); 7,50-7,28 (m, 7H); 6,03 (user. s, 1H, CONH); 5,94 (user. s, 1H, CONHS2); to 3.92 (q, 1H, J=7 Hz); 3,40 is 3.15 (m, 4H); 2,43 (d, 2H, J=7 Hz); 1,90 (m, 1H); of 1.55 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz).

EXAMPLE 17

R(-)2-(4’-Isobutyl)phenylpropionyl-(2’-N-carboxyaniline)econsultant

The solution ethylchloroformiate (0,62 g, to 4.52 mmol) in DMF (1 ml) was added dropwise to a stirred solution of R(-)2-(4’-isobutyl)phenylpropionyl-(2’-amino)acanaloniidae (0.6 g, 1.92 mmol) and triethylamine (1 ml) in DMF (10 ml). The resulting mixture was stirred for 24 hours at room temperature. DMF is evaporated under vacuum, neocide the hydrated residue was diluted with water and was extracted with diethyl ether (3× 10 ml). The combined organic extracts were washed with water (2× 15 ml) and saturated saline (20 ml), dried over Na2SO4and evaporated in vacuum to obtain R(-)2-(4'-isobutylphenyl-(2"-N-ETHYLACETYLENE)acanalonia in the form of a colorless oil (0.51 g, 1.25 mmol).

To a solution of the above R(-)2-(4’-isobutyl)phenylpropionyl-(2’-N-ETHYLACETYLENE)acanaloniidae (0.5 g, 1,22 mmol) in dioxane (1,55 ml) was added 1 N. NaOH (1,55 ml) and was stirred over night at room temperature. The dioxane was removed in vacuo, then water-soluble residue was diluted with water, was added 4 N. N2SO4to pH=2; the aqueous phase was extracted with dichloromethane (4× 15 ml); the combined organic extracts were washed with water (2× 15 ml) and saturated brine (15 ml), dried over PA2SO4and evaporated in vacuum to obtain R(-)2-(4’-isobutyl)phenylpropionyl-(2’-N-carboxyaniline)acanalonia in the form of a colorless oil (0,426 g, 1.1 mmol); TLC (CHCl3/CH3OH/H2O 65:25:4) Rf=0,5; [α ]D=-60° (C=1; CH3HE);1H-NMR (CD3OD): δ ppm 10,55-10,0 (users, 1H, COOH); to 7.25 (d, 2H, J=8 Hz); 7,05 (d, 2H, J=8 Hz); 3,8-3,5 (m, 5H); 2,5 (d, 2H, J=7 Hz); 1,95-1,8 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 0,9 (d, 6N, J=7 Hz).

EXAMPLE 18

R(-)2-(4’-Isobutyl)phenylpropionyl-(2’-N-benzyloxycarbonylamino)econsultant

Tau is Jn (1 g, 8 mmol) was dissolved in 2 N. NaOH (4.3 ml) and after cooling in an ice bath was also added 4 N. NaOH (2,14 ml) and the solution benzyloxycarbonylamino (3,27 ml, 8 mmol) in toluene (3 ml). After the addition the mixture was left to mix at a temperature of 0-5° C for 1 hour. The reaction was stopped by addition of diethyl ether. The mixture was processed and the phases were separated. The aqueous phase was cooled to 0-5° and added 37% Hcl to pH=2. The acid phase was extracted with ethyl acetate (3× 10 ml) and the combined organic extracts were washed with water (2× 15 ml) and saturated brine (15 ml), dried over Na2SO4and evaporated in vacuo to obtain 2-(N-benzyloxycarbonylamino)econsultancy acid in the form of the crude product, purified by rubbing the powder in diethyl ether to obtain the pure product as white solid (1,46 g, 5,64 mmol, yield of 70.5%).

2-(N-Benzyloxycarbonylamino)econsultancy acid (0.6 g, 2,31 mmol) suspended in dry toluene (6 ml) was added PCl5(0.65 g, 3.11 mmol). The mixture was boiled under reflux for 2 hours until complete dissolution of the reagents. After cooling at room temperature the solvent is evaporated in vacuum to obtain crude 2-(N-benzyloxycarbonylamino)acanaloniidae, pure enough for the next stage.

accidenly 2-(N-benzyloxycarbonylamino)acanaloniidae was dissolved in acetonitrile (10 ml). The resulting solution was cooled in an ice bath was added dropwise a solution of 28% NH4OH (5 ml) and acetonitrile (5 ml) in a 1:1 ratio. After stirring for 30 seconds, the solvents evaporated in vacuo and the crude residue was recrystallized in methanol to obtain 2-(N-benzyloxycarbonylamino)acanalonia in the form of a white powder (0.51 g, a 1.96 mmol).

R(-)Ibuprofen (0.32 g, 1.55 mmol) was dissolved in dry dichloromethane (7.5 ml) and to it was added N,N-dimethylaminopyridine (0,19 g, 1.55 mmol) and dicyclohexylcarbodiimide (0.32 g, 1.7 mmol); the mixture was left to mix for 30 seconds. Then added 2-(N-benzyloxycarbonylamino) econsultant (0.4 g, 1.55 mmol) and the mixture was left to mix overnight. The precipitation of N,N-dicyclohexylamine was filtered and the filtrate evaporated in vacuo to obtain the crude residue diluted with acetonitrile, the second portion of N,N-dicyclohexylamine was filtered and the filtrate after evaporation of the solvent was diluted with dichloromethane. The organic phase was washed 2 N. Hcl (2× 10 ml), saturated brine (15 ml), dried over Na2SO4and evaporated in vacuum to obtain R(-)2-(4’-isobutyl)phenylpropionyl-(2’-N-benzyloxycarbonylamino)acanalonia in the form of a white powder (0,44 g, 0.98 mmol); TPL=107-109° C; TLC (CH2CL /CH3HE 98:2) Rf=0,2; [α ]D=-47,4° (C=1; EtOH);1H-NMR (Dl3): δ ppm 7,45-7,30 (m, 5H); 7,25-7,05 (m, 5H, NH); 5,4-5,3 (users, 1H, NH); to 5.1 (s, 2H); 3.75 to 3.5mm (m, 5H); of 2.45 (d, 2H, J=7 Hz); 1,95-1,8 (m, 1H), and 1.5 (d, 3H, J=7 Hz); 0,9 (d, 6N, J=7 Hz).

1. N-(2-Arylpropionic)sulfonamides of formula 1

where R2represents phenyl or thiophenyl, optionally substituted from 1 to 3 substituents, independently selected from halogen, C1-C4-alkyl, phenyl, phenoxy, benzyl, benzoyl,1-C7-acyloxy, 2-thienoyl or 1-oxo-2-isoindolyl;

R represents a linear or branched C1-C16-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cianfanelli, p-aminomethylphenol, 3-cyano-1-propyl, alkoxyethanol group SN3-(CH2)ni-(OCH2CH2)mi-where niand miindependently is an integer from 1 to 3, or a group P1P2N-CH2-CH2-where P1and R2are independently H, C1-C3-alkyl, benzyloxycarbonyl, α-, βor γ-iridocorneal, carboxyterminal or carboalkoxylation, or P1and R2together with the nitrogen atom to which they are attached, form morpholino;

R’ represents the or linear or branched C 1-C3-alkyl, or their salts with strong and medium bases.

2. Compounds according to claim 1 where R’ represents hydrogen.

3. Compounds according to claim 1 or 2, in which R2selected from 4-isobutylphenyl, 3-benzoylphenyl, 5-benzoyl-2-acetoxyphenyl, 3-phenoxyphenyl, 1-oxo-2-isoindoline or residue of the formula

in which a represents a benzyl or benzoyl, represents hydrogen or C1-C3-acyloxy.

4. Compounds according to any one of the above points, in which the asymmetric carbon atom is replaced by stands, has the absolute configuration R.

5. The compound according to claim 1, which represents the R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide or its salt with L(+)-lysine.

6. The compound according to claim 1, which represents the R(-)-N-2-[3-(benzoylphenyl)propionyl]methanesulfonamide.

7. The compound according to any one of claims 1 to 6 for use as a drug for prevention or treatment of tissue lesions associated with chemotaxis and degranulation of neutrophils induced by interleukin-8.

8. The compound according to any one of claims 1 to 6 to obtain drugs having inhibitory activity against induced interleukin-8 chemotaxis and degranulation of neutrophils.

9. The compound of claim 8 to obtain medicinal cf is DSTV for the treatment of psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory failure, idiopathic fibrosis, chloromelanite.

10. The compound of claim 8 or 9, which represents the R(-)-N-2-[(4-isobutylphenyl)propionyl]methanesulfonamide or its salt with L(+)-lysine.

11. Pharmaceutical composition having inhibitory activity against induced interleukin-8 chemotaxis and degranulation of neutrophils containing as active ingredient a compound according to any one of claims 1 to 6 in a mixture with a suitable carrier.

12. A method of obtaining a compound according to any one of claims 1 to 6, including interaction in an inert solvent equimolar amounts of the acid of formula (2)

where R2’ has the same values as the group R2specified in claim 1, with equimolar amounts of sulfonamida formula (3):

where R and R’ are specified in claim 1 values, in the presence of a condensing agent.

13. A method of obtaining a compound according to any one of claims 1 to 6, including the interaction of sulfadimidine formula (3’)

where R and R’ have the meanings indicated in claim 1, in an inert solvent with an acid chloride of the acid of formula (2)

where R2' has the values listed in item 12.



 

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< / BR>
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The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

The invention relates to new unsaturated derivatives of hydroximino acid formula

< / BR>
where R1means phenyl, optionally substituted by 1-3 substituents selected from the group comprising FROM1-2alkoxygroup, halogen, or represents a 6-membered unsaturated heterocyclic group containing one nitrogen atom as a heteroatom, and R2means hydrogen or R1together with R2form5-7-cycloalkyl group, Y represents hydrogen, a hydroxy-group,3-22-alkanoyloxy, X means halogen, a hydroxy-group or amino group, R3represents a group of formula-NR4R5where R4and R5mean independently from each other hydrogen, C1-5is an alkyl group, or R4and R5form with the adjacent nitrogen atom a 5 - or 6-membered saturated heterocyclic group which may contain an oxygen atom and may be condensed with a benzene ring, in addition, its geometrical and/or optical isomers and/or pharmaceutically acceptable acid salt additive
The invention relates to chemical-pharmaceutical industry, specifically to an improved method for producing 1-(parachlorophenyl)-4-(2-oxyethyl)-piperazine by the interaction of 1-(2-oxyethyl)piperazine with parachlorobenzotrifluoride when heated in toluene or acetone at a molar ratio of reactants is 1:(0.5 to 2), followed by separation of the target product by concentrating the reaction solution under low pressure, treatment with diluted hydrochloric acid, extraction with benzene twice with intermediate alkalinization of the aqueous layer, washing with water, and re-concentration at low pressure drop

The invention relates to the field of medicine and relates to farbkomposition for inhibition of metalloproteinases containing sulfonated amino acid derivatives, and new sulfonated amino acid derivatives

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains steroid as active principle, in particular 11-β,16-α,17-α,21-tetrahydroxy-9-α-fluoro-1,4-pregnadiene-3,20-dione or pharmaceutically acceptable salt thereof and special-destination additives including microcrystalline cellulose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

3 cl, 1 tbl

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.

EFFECT: higher efficiency of application.

42 cl, 39 ex

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