(r)-2-arylpropionic acid omega-aminoalkylamides as inhibitors of polymorphonuclear and mononuclear cell hemotaxis, method for their preparing and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

18 cl, 3 tbl, 23 ex

 

The present invention relates to omega-aminoalkylated (R)-2-arylpropionic acids as inhibitors of chemotaxis of polymorphonuclear and mononuclear cells. In particular, the invention relates to C5a-induced chemotaxis of polymorphonuclear leukocytes and monocytes used in the treatment of pathological disorders, including psoriasis, rheumatoid arthritis and disruption caused by ischemia and reperfusion.

Animal studies have shown that some aminoacylase ester and amide prodrugs of racemic ibuprofen and naproxen, in particular some N-(3-diethylaminopropyl)amides have significantly higher analgesic and anti-inflammatory activity than the parent compound, even if they are weak inhibitors of prostaglandin synthesis in vitro. Also found that all of these prodrugs, except glycinamide, much less irritate the stomach lining than their predecessors - free acid. (Shanbhag VR et al., J. Pharm. Sci., 81, 149, 1992, and references cited 8-19).

Pittodrie [(±)-2-(3-benzoylphenyl)-N-(4-methyl-2-pyridinyl)propionamide] and antileishmanial (also called guadalevin air collaterlized, Eufans) are additional examples of non-steroidal anti-inflammatory (NSAI) prodrugs, finding rassmatrivaemoi therapeutic use. Moderate anti-inflammatory activity, minor side effects, and good gastrointestinal tolerance detected for a number of N-[2-(1-piperidinyl)propyl]amides some NSAI-prodrugs, such as racemic ibuprofen, indomethacin, n-chlorbenzene acid, acetylsalicylic acid, diacetylhydrazine acid and adamantane-1-carboxylic acid (Nawladonski F. and Reewuski, Pol. J. Chem., 52, 1805, 1978). Other amides of racemic 2-arylpropionic acids described in S. Biniecki et al., [PL 114050 (31. 01. 1981)], H. Akguen et al., [Arzneim-Forsch., 46, 891, 1986] and G. L. Levitt et al., [Russ. J. Org. Chem., 34, 346, 1998].

Anti-inflammatory and obezbolivaushee activity in vivo, comparable with similar activity predecessors, free acids, and sometimes large, together with the reduced number of cases of gastric lesions detected for some N-3-[(1-piperidinyl)propyl]amides of racemic Ketoprofen and flurbiprofen and for some reason manniche obtained by the interaction of their amides with formaldehyde and secondary amines such as morpholine, piperidine, dicyclohexylamine, dimethylamine, diethylamine, dibenzylamine and dibutylamine (N. Kawathekar et al, Indian J. Pharm. Sci., 60, 346, 1998).

In international patent application WO 00/40088 recently it was reported that a simple conversion to amide derivative 2-akriluksusnoy and/or 2-arylpropionic acid sufficient to convert selective COX1 inhibitor in COX-2-selective inhibitor, which explains the low degradability of these amides in the stomach, long considered only NSAI-prodrugs.

Previously it was found that the inhibition of the enzyme cyclooxygenase peculiar to the S-enantiomer of 2-arylpropionic acid, which is connected with the part R CoA-tiefer undergoing the bioconversion of "in vivo". Therefore, a weak correlation between enzyme inhibition in vitro and anesthetic actions in vivo detected for some R,S-2-arylpropionic acids (Brune K. et al., Experientia, 47, 257, 1991), caused an assumption that may be involved alternative mechanisms, such as inhibition of transcription kB-nuclear transcription factor (NF-kB) and/or inhibition of chemotaxis of neutrophils induced by interleukin-8 (IL-8).

R-enantiomers of flurbiprofen, Ketoprofen, naproxen, tiaprofenic and fenoprofen, in fact, described in WO 00/40088 as inhibitors of the activation of the transcription factor NF-kB and claimed for use in the treatment of NF-kB-dependent diseases (asthma, swelling, shock, Crohn's disease and ulcerative colitis, atherosclerosis, and so on). IL-8 is an important mediator of inflammation, and it is shown that it is effective chemotactic/cellular activator of polymorphonuclear neutrophils and basophils (PMNs) and T-lymphocytes. Cellular sources of IL-8 vklyuchayuthie, PMNs, endothelial cells, epithelial cells and keratinocytes, when stimulated by factors such as lipopolysaccharide, IL-1 and TNF-a. On the other hand, found that C5a fragment of complement, in addition to what is a direct mediator of inflammation, induces as a synthesis of IL-8, and high release of IL-8 from monocytes. The amount of IL-8, isolated from C5a-activated monocytes in the mononuclear cells of peripheral blood, 1000-fold exceeds the amount of IL-8 released from comparable numbers of PMNs in such conditions. Therefore, IL-8 released from C5a-activated monocytes may play a significant role in the development and prolongation of cell infiltration and activation at sites of infection, inflammation or tissue damage (Ember J.A. et al., Am. J. Pathol., 144, 393, 1994).

In response to immunological and infectious events activation of the complement system mediates amplification of the inflammatory response through a direct action on the membrane, and by the release of a number of peptide fragments, commonly known as anaphylatoxin generated by enzymatic cleavage of C3-, C4 - and C5 - fractions of complement. Such peptides include C3a, C4a, both built of 77 amino acids, in turn, C5-convertase splits a fraction of complement C5, giving glycoprotein C5a of 74 amino acids. Anaphylatoxin participate in the rasprostranenie inflammatory process by interacting with the individual cell components; common features include cellular release of vasoactive amines and lysosomal enzymes, reduction of smooth muscle and increased vascular permeability. In addition, C5a induces chemotaxis and aggregation of neutrophils, stimulates the release of leukotrienes and oxidized by reactive oxygen species, induces the transcription of IL-1 in macrophages and the production of antibodies.

C5a is a peptide fragment of complement called "full" Pro-inflammatory mediator. In contrast, other inflammatory mediators, such as selective cytokines (IL-8, MCP-1 and RANTES, for example) are highly selective with respect to samaritians cells, whereas histamine and bradykinin are only a weak chemotactic agents. Convincing evidence indicates the involvement of C5a, in vivo, in some pathological conditions, including ischemia/reperfusion injury, autoimmune dermatitis, membranosa-idiopathic proliferative glomerulonephritis, hypersensitivity of the respiratory tract, and chronic inflammatory diseases such as ARDS and COPD, Alzheimer's disease Steele (N.P. Gerard, Ann. Rev. Immunol., 12, 755, 1994).

In connection with narrowspectrum potential C5a/C5a-desArg created as a local production of complement fixation and activation of the amyloid associated with chemotaxis of astrocytes and microglia, and activation directly edstone called C5a, inhibitors of complement can be proposed for the treatment of neurological diseases such as Alzheimer's disease (McGeer &McGeer P.L., Drugs, 55, 738, 1998).

It is therefore considered that the regulation of local synthesis of fractions of complement creates a high therapeutic potential for the treatment of shock and prevent rejection (rejection associated with multiple damage, and Verhoture graft rejection) (A.C. Issekutz et al., Int. J. Immunopharmacol, 12, 1, 1990; R. Inagi et at., Immunol. Lett., 27, 49, 1991). Later it was reported that with regard to the involvement of complement in the pathogenesis of chronic interstitial and acute glomerular renal disorders, inhibition of fractions of complement leads to the prevention of damage to natural and transplanted kidneys (Sheerin N.S. & Sacks S.H., Curr. Opinion Nephrol. Hypert., 7, 395, 1998).

Research based on genetic engineering and molecular biology have led to the cloning of complementary receptors (CRs) and the production of CRs-agonists and antagonists. Recombinant soluble receptor CR1 (sCRl), which blocks the enzymes that activate C3 and C5, identified as a potential agent for suppression of C activation in ischemic/reperfusion violation (Weisman H.F. et al., Science, 239, 146, 1990; Pemberton M. et al., J. Immunol., 150, 5104, 1993).

It is reported that the cyclic peptide F-[OPdChWR] prevents the binding of C5a with what eception CD38 on PMNs and inhibits C5a-dependent chemotaxis and the production of cytokines by macrophages, and neutropenia induced in rats by stimulation of C5a and LPS (Short A. et al., Br. J. Pharmacol., 126, 551, 1999; Haynes D.R. et al., Biochem. Pharmacol., 60, 729, 2000). It is reported that as CGS 27913, C5aR antagonist, and its dimer CGS 32359, inhibit, in vitro, C5a-binding to membranes of neutrophils, intracellular mobilization of Ca2+the release of lysozyme, chemotaxis of neutrophils and edema of the skin in rabbits (Pellas T.C. et al., J. Immunol., 160, 5616, 1998)Nakonec, selection from a library of bacteriophages using the method of "phage display" led to the isolation of specific C5aR antagonist capable of reducing an inflammatory response in diseases mediated by immune complexes, and during ischemia and reperfusion disorders (Heller T. et al., J. Immunol., 163, 985, 1999).

Despite therapeutic potential of only two of the above C5a antagonists are active in vivo; moreover, therapeutic application of these antagonists is limited due to their peptide (Pellas T.C., P. Wennogle, Curr. Pharm. Des., 10, 737, 1999).

Characterized by accumulation of neutrophils can be observed in certain pathological disorders, such as on highly inflamed and not amenable to therapeutic treatment areas of psoriatic lesions. Neutrophils hemotoxicity are attracted and activated due to the synergistic action of chemokines, IL-8 and Gro-a released-stimulated keratinocytes, and fraction C5a/C5a-desArg, prod is ciremai by alternative activation of complementary ways (T. Terui et al., Exp. Dermatol., 9, 1, 2000). In addition, in many cases it is desirable to combine the inhibition of chemotaxis induced by C5a, and inhibition of chemotaxis induced by IL-8, with one tool.

Also received ones antagonists fractions of complement, for example, substituted-4,6-diaminopyridine. In particular, it is found that [N,N"-bis-(4-amino-2-methyl-6-chinolin)]urea and [6-N-2-chlorocinnamoyl)-4,6-diamino-2-methylinosine] are selective antagonists C5R, IC50vary from 3.3 to 12 µg/ml (Lanza T.J. et al., J. Med. Chem., 35, 252, 1992).

Recently, it was reported that some inhibitors semipretioase [namestamil (FUT 175) and some analogues are inhibitors as activation of complement, and the production of C3a/C5a (N. Ueda et al., Inflammation Res. 49, 42, 2000).

In U.S. patent 6069172 reported the use of pharmaceutical compositions of the ammonium salt of R(-)-Ketoprofen for inhibition of chemotaxis of neutrophils induced by IL-8.

WO 00/24710 describes N-arylsulfonamides R(-)-2-arylpropionic acid as inhibitors of IL-8-dependent chemotaxis of polymorphonuclear leukocytes.

Two recently submitted a patent application [WO 01/58852 and WO 01/79189] describe some R-2-arylpropionate and R-2-(AMINOPHENYL)propionamide, useful for preventing activation of leukocytes induced by IL-8.

The crust is asimi applicants recently discovered, that it is a purely formal restoration of the heteroaromatic cycle some R-2-aryl-N-(pyridinyl)propionamido causes a noticeable loss of activity (1 or 2 logarithmic order) in the ability to inhibit PMN chemotaxis of neutrophils induced by IL-8. Unexpectedly it was found that the related R-2-aryl-N-(piperidinyl)propionamide are effective inhibitors of PMN chemotaxis of leukocytes and monocytes induced by fraction C5a complement.

These unexpected findings are based on a new family of omega-aminoalkylation R-2-arylpropionic acid, can inhibit chemotactic activity induced by C5a and other chemotactic proteins whose biological activity associated with activation of receptor 7-membered domain (7-TD), homologous to the C5a receptor (e.g., C3a receptor and receptor CXCR2; Neote, K. et al., Cell, 72, 415, 1993; Tornetta M.A., J. Immunol., 158,5277, 1997).

The present invention relates to a new class of omega-aminoalkylation R-2-arylpropionic acids and containing pharmaceutical compositions. The position of the "omega" in the alkyl chain means most remote carbon atom counting from the N atom of amide group to which is attached the specified alkyl. Such amides are useful for the inhibition of the chemotactic activation induced by C5a and other chemotactic proteins whose biological is aktivnosti associated with activation of receptors 7-membered domains (7-TD) homologous to the C5a receptor. In particular, such amides are useful for the inhibition of the chemotactic activation of polymorphonuclear leukocytes, monocytes and T-lymphocytes induced by C5a fraction of complement, and for the treatment of pathological disorders associated with the specified activation.

The following paragraphs identify secreted chemical structures that build the connection according to the invention is proposed for use for the purpose of uniformity in the description and the attached items, if not given a precise definition, we use a broader definition.

The term "alkyl" means a monovalent alkyl group having preferably 1-6 carbon atoms. Examples of these terms are groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

"Aryl" means an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single cycle (e.g., phenyl) or multiple condensed cycles (e.g., naphthyl). Preferred aryl includes phenyl, diphenyl, naphthyl, phenanthrene and the like.

"Alkenyl" means alkeneamine group, preferably having 2-5 carbon atoms and one or more sections alkenylphenol unsaturation. Preferred alkeneamine groups include ethynyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2and the WMD similar.

"Alkylen", "albaniles", akinyan" means the group disubstituted with both ends. Preferred groups include methylene, ethylene, propylene and the like.

"Substituted or unsubstituted": unless otherwise noted, a separate Deputy for the above groups, such as the group "alkyl", "alkenyl", "aryl" and so on, may not necessarily be substituted by 1-5 substituents selected from group "C1-C6-alkyl", "C1-C6-alkylaryl", "C1-C6-alkylglycerol", "C2-C6alkenyl", primary, secondary or tertiary amino group or Quaternary ammonium group, "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl", "heteroaryl", carboxyl, cyano, halogen, hydroxy, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, dialkoxy, trihalomethyl and the like. It is understood that in the scope of the invention specified "substitution" also includes cases where adjacent substituents are closing cycle, particularly when involved vicinal (adjacent) functional substituents, forming thus, for example, lactams, lactones, cyclic anhydrides or cycloalkanes, and acetals, thioacetals, amirali obtained by closing the loop, for example, to form a protective group.

The term "pharmaceutically acceptable salt" relative to the tsya to salts or complexes of the following compounds of formula I, retains the desired biological activity. Examples of such salts include, but are not in the order restrictions, acid additive salts formed with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamula acid, alginic acid, polyglutamine acid, naphthalenesulfonate acid, naphthalenedisulfonic acid and polygalacturonase acid.

Examples of salts include salts of accession, formed with inorganic bases such as sodium hydroxide, and organic bases, such as tromethamine, L-lysine, L-arginine, and the like.

The present invention is compounds of (R)-2-arylpropionate formula (I),

where

Ar denotes a substituted or unsubstituted aryl group;

R is hydrogen, C1-C4-alkyl, C2-C4alkenyl, C2-C4-quinil, optionally substituted by a group of CO2R3where R3means ogorodili linear or branched C 1-C6is an alkyl group, or a linear or branched C2-C6-alkenylphenol group;

X means:

linear or branched C1-C6-alkylene, C4-C6-albaniles, C4-C6-akinyan, optionally substituted by a group of CO2R3or CONHR group4where R4means hydrogen, linear or branched C2-C6-alkyl, or a group OR3where R3accept above values;

(CH2)m-B-(CH2)ngroup, optionally substituted by a group of CO2R3or CONHR4taking the above values, where B stands for an oxygen atom or sulfur, m is zero or an integer of 2-3, and n means an integer of 2-3; or B means a group CO, SO or CONH, m means an integer of 1-3 and n means an integer of 2-3;

or X together with the nitrogen atom omega-amino group, with which it is associated, and with a group R1forms a non-aromatic nitrogen-containing 3-7 membered heterocyclic, monocyclic or polycyclic nucleus, in which the nitrogen atom has a Deputy Rc, where Rc denotes hydrogen, C1-C4-alkyl, C1-C4-hydroxyalkyl,1-C4-acyl, substituted or unsubstituted phenyl, diphenylmethyl; R1and R2independently selected from the group comprising: hydrogen, optionally interrupted by O atom or S if any or branched C 1-C6-alkyl, C3-C7-cycloalkyl, C3-C6alkenyl, C3-C6-quinil, aryl-C1-C3-alkyl, hydroxy-C2-C3-alkyl;

or R1and R2together with the N atom to which they are bound, form a nitrogen-containing 3-7-membered heterocyclic nucleus of the formula (II)

where Y represents a simple bond, CH2, O, S or a group N-Rc, receiving the above-mentioned values, and p is an integer of 0-3;

or R1accept above values, R2means a group of the formula (III):

where Rameans hydrogen and Rbmeans hydrogen, hydroxy, C1-C4-alkyl or the group NRdRewhere each of Rdand Reindependently means hydrogen, C1-C4-alkyl or phenyl;

or Raand Rbtogether with the nitrogen atom to which they are bound, form a 5-7-membered heterocyclic nucleus, monocyclic or condensed with a benzene nucleus, a pyridine or pyrimidine;

provided that when Ar means 4-diphenyl residue and X represents ethylene or propylene residue, R1and R2are not ethyl;

provided that when Ar means 4-(2-fluoro)diphenyl residue, and X is substituted CO2H a butylene group, Raand Rbare not bodoro the ohms;

and with the additional proviso that when Ar denotes phenyl and X is butylene, R1and R2together cant spell N-(2-methoxyphenyl)piperazine.

In addition, the present invention is also the compounds (R)-2-arylpropionate formula (I)

where

Ar denotes a substituted or unsubstituted aryl group;

R is hydrogen, C1-C4-alkyl, C2-C4alkenyl, C2-C4-quinil, optionally substituted by a group of CO2R3where R3means hydrogen or linear or branched C1-C6is an alkyl group, or a linear or branched C2-C6-alkenylphenol group;

X means:

linear or branched C1-C6-alkylene, C4-C6-albaniles, C4-C6-akinyan, optionally substituted by a group of CO2R3or CONHR group4where R4means hydrogen, linear or branched C2-C6-alkyl, or a group OR3where R3accept above values;

(CH2)m-B-(CH2)ngroup, optionally substituted by a group of CO2R3or CONHR4taking the above values, where B stands for an oxygen atom or sulfur, m is zero or an integer of 2-3, and n means an integer of 2-3; or B refers to the group C, SO or CONH, m means an integer of 1-3 and n means an integer of 2-3;

or X together with the nitrogen atom omega-amino group, with which it is associated, and with a group R1forms a non-aromatic nitrogen-containing 3-7 membered heterocyclic, monocyclic or polycyclic nucleus, in which the nitrogen atom has a Deputy Rc, where Rc denotes hydrogen, C1-C4-alkyl, C1-C4-hydroxyalkyl,1-C4-acyl, substituted or unsubstituted phenyl, diphenylmethyl;

R1and R2independently selected from the group comprising: hydrogen, optionally interrupted by O atom or S linear or branched C1-C6-alkyl, C3-C7-cycloalkyl, C3-C6alkenyl, C3-C6-quinil, aryl-C1-C3-alkyl, hydroxy-C2-C3-alkyl;

or R1and R2together with the N atom to which they are attached, form a 3-7-membered nitrogen-containing heterocyclic nucleus of the formula (II)

where Y represents a simple bond, CH2, O, S or a group N-Rc, receiving the above-mentioned values, and p is an integer of 0-3;

or R1accept above values, R2means a group of the formula (III):

where Rameans hydrogen and Rbmeans hydrogen, hydroxy, C1-C4-alkyl or the group NR dRewhere each of Rdand Reindependently means hydrogen, C1-C4-alkyl or phenyl; or Raand Rbtogether with the nitrogen atom to which they are bound, form a 5-7-membered heterocyclic nucleus, monocyclic or condensed with a benzene nucleus, a pyridine or pyrimidine;

as inhibitors of C5a-induced chemotaxis of polymorphonuclear leukocytes and monocytes.

Pharmaceutically acceptable salts of compounds of formula (I) are also included in the scope of the present invention.

Examples of aryl groups preferably include:

a) Ara- mono - or polyamidine aryl group or a group of the most common currently used in therapeutic applications containing heterocyclic ring 2-arylpropionic acids selected from the group comprising: alminoprofen, benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, loxoprofen, naproxen, pirprofen and his degidro - dihydro - derivatives, pranoprofen, suprofen, tiaprofenic acid, zaltoprofen;

b) arylhydroxylamine group of the formula (IVa)obtained by reduction of pinocarvone 2-arylpropionic acids selected from the group comprising: Ketoprofen, carprofen, tiaprofenic acid, in the form of individual (S',R) and/or (R',R) diastereoisomer, is in the form of diastereomeric mixture,

where in the case when Ar2means phenyl, Ar1selected from the group comprising phenyl and Tien-2-yl, and when Ar1means phenyl, Ar2selected from the group comprising phenyl, 4-thienyl, pyridyl,

c) aryl of formula (IVb):

φ-Arb(IVb),

where Arbmeans phenyl, mono - and polyamidine optionally substituted hydroxy, mercapto, C1-C3-alkoxy, C1-C3-alkylthio, chlorine, fluorine, trifluoromethyl, nitro, amino, optionally substituted C1-C7-acylamino; and φ means hydrogen; linear or branched C1-C5-alkyl, C2-C5-alkanniny or C2-C5-alkynylaryl balance, (optionally substituted)1-C3-alkoxycarbonyl, substituted or unsubstituted phenyl, 2-, 3 - or 4-pyridium, quinoline-2-silt; C3-C6-cycloalkyl group; 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophene or a residue of formula (IVc)

A-(CH2)q- (IVc),

where A denotes the1-C5-dialkylamino,1-C8(alkanoyl, cycloalkenyl, arylalkyl)-C1-C5-alkylamino, for example dimethylamino, diethylamino, methyl-N-ethylamino, acetyl-N-methylamino, pivaloyl-N-ethylamino; nitrogen-containing 5 to 7-membered monocycle, optionally containing one or two double bonds and obazatelno containing an additional heteroatom, separated by at least 2 carbon atoms from the N atom, so as to form, for example, group: 1-pyrrolidino, 2.5-dihydropyrrol-1-yl, 1-pyrrole, 1-piperidino, 1-piperazine derivatives of 4-unsubstituted or 4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzhydryl or phenyl), 4-morpholino, 4-3,5-dimethylmorpholine, 4-thiomorpholine; or alternatively, a residue of formula (IVd)

where Rg denotes hydrogen, C1-C3-alkyl or the residue With1-C3-alanovoy acid; q is zero or an integer of 1

d) 2-(phenylamino)phenyl of formula (IVe):

where P1and P2indicate that the two phenyl groups may be substituted independently by one or more1-C4-alkyl groups, With1-C3-alkoxygroup, chlorine, fluorine and/or trifluoromethyl.

Preferred compounds in accordance with the invention are compounds in which:

R means hydrogen,

X means:

linear alkylene, optionally substituted on the C1group-CO2R3taking the above values; linear alkylene, optionally substituted on the C1group-CONHR4where R4means-OH; 2-Butylin, CIS-2-butylen, TRANS-2-butylen; 3-oxapentane, 3-typestyles, 3-oxohexyl, 3-tigecyclin; (CH2)m-CO-NH-(CH2) -where each of m and n independently denotes an integer of 2-3; (CHR')-CONH-(CH2)nwhere n denotes an integer of 2-3, and R' denotes methyl, an absolute configuration R or S;

or X together with the N atom omega-amino group forms a nitrogen-containing cycloaliphatic nucleus, preferably 1-methyl-piperidine-4-yl or 1.5-tropan-3-yl.

The preferred compounds are those in which NR1R2means the group of NH2, dimethylamino, diethylamino, diisopropylamino, 1-piperidinyl, 4-morpholyl, 4-thiomorpholine, or R1and R2together form a residue of guanidine, aminoguanidine, hydroxyguanidine, 2-amino-3,4,5,6-tetrahydropyrimidine, 2-amino-3,5-dihydroimidazole.

Examples of particularly preferred aryl groups include:

4-isobutylphenyl, 4-cyclohexylmethanol, 4-(2-methyl)allylphenol, 3-phenoxyphenyl, 3-benzoylphenyl, 3-acetylphenyl, individual diastereoisomers (R) (S) and a mixture of diastereomers (R,S)selected from the group comprising: 3-C6H5-CH(OH)-phenyl, 3-CH3-CH(OH)-phenyl, 5-C6H5-CH(OH)-thienyl, 4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl, 5-benzoylation-2-yl, 4-canolfan, 3-nicotinoyl, 2-fluoro-4-phenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-acetoxyphenyl and 5-benzoyl-2-hydroxyphenyl.

Particularly preferred aryl groups of formula (IVb) are phenyl groups, 3-substituted isoprop-1 is the n-1-yl, the isopropyl, Penta-2-EN-3-yl; Penta-3-yl; 1-phenylethylene-1-yl; α-methylbenzyl.

Particularly preferred Allami formula (IVc) are 4-(pyrrolidin-1-yl)were, 3-chloro-4-(pyrrolidin-1-yl)were, 3-chloro-4-(2,5-dihydro-1-H-pyrrol-1-yl)were, 3-chloro-4-(thiomorpholine-4-yl)phenyl; 3-chloro-4-(piperidine-1-yl)phenyl, 4-((N-ethyl-N-quinoline-2 ylmethylamino)methyl)phenyl, 3-chloro-4-(morpholine-4-yl)phenyl.

Particularly preferred Allami formula (IVe) are 2-(2,6-dichlorophenylamino)phenyl; 2-(2,6-dichlorophenylamino)-5-chlorophenyl; 2-(2,6-dichloro-3-methylphenylamine)phenyl; 2-(3-triptoreline)phenyl.

Particularly preferred compounds according to the invention are:

(R)-2-[(4-isobutyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(4-dimethylaminomethyl)propionohydroxamic;

(R)-2-[(4-isobutyl)phenyl]-N-(3-N-morpholinopropan)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(2-dimethylaminoethyl)propionamide;

(R)-2-[(4-isobutyl)phenyl)propionyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]propionamide;

(R)-N-(Exo-8-methyl-8-Aza-bicyclo[3,2,1]Oct-3-yl)-2-[(4-isobutylphenyl)propionate;

(R)-2-[(4-isobutyl)phenyl]-N-(3-N-thiomorpholine)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[4-(N'-methyl)piperidinyl]propionohydroxamic;

(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-2-dimethylaminoethyl)propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-[(-carboxy-4-piperidine-1-yl)butyl]propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-4-aminobutyl)propionamide;

(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)aminocarbonylmethyl]propionohydroxamic;

2-(2,6-dichlorophenylamino)phenyl-N-(3-dimethylaminopropyl)propionamide;

(R),(R',S')-3-[3-(α-methyl)benzyl]phenyl-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(3-isopropyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[3-(Penta-3-yl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(3-guanidine)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[(3-hydroxyguanidine)propyl]propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[(3-aminoguanidine)propyl]propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[3-(2-amino-2-imidazolyl)propyl]propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[N-methyl-N-(2-hydroxyethyl)aminoethoxy]propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-[1-carboxy-5-aminopentyl]propionamide.

Obtaining compounds of formula (I) can be carried out by known techniques, such as the interaction of the activated form R-2-arylpropionic acid of formula (V) with an amine of formula (VI) in the absence of racemization, preferably in the presence of molar excess reasons:

where

AT means balance, activates carboxypropyl. Examples of activated forms of 2-arylpropionic acid of formula (V AT=OH) are chlorides (AT=Cl) imidazolidin (AT=1-imidazole), esters of phenols, such as p-NITROPHENOL (AT=p-NO2-C6H4O-), or activated form, obtained by the interaction in the presence of 1-hydroxybenzotriazole (HOBZ) or carbodiimide, such as dicyclohexylcarbodiimide.

Ar, R, X, R1and R2take the values from the above groups, optionally protected, where necessary.

The interaction of the activated form 2-arylpropionic acid of formula (V) with a protected amine of formula (VI) is usually performed at room temperature using standard proton or aprotic solvents and/or mixtures thereof, preferably anhydrous solvents such as methyl acetate, ethyl acetate, ethyl formate, NITRILES, such as acetonitrile, linear or cyclic ethers, such as diethyl ether, sulfolane, dioxane, tetrahydrofuran, amides such as dimethylformamide, formamide, halogenated solvents such as dichloromethane, aromatic hydrocarbons such as toluene, chlorobenzene, or heteroaromatic hydrocarbons such as pyridine and picoline. The interaction can be performed in the presence of a base; preferred inorganic bases are carbonates and bicarbonates of alkali and alkaline earth metals, such as, for example, finely ground potassium carbonate, potassium bicarbonate and magnesium carbonate or calcium. Received protected amides can be converted into amides of formula (I) by cleavage of the protective groups and any ester groups that may be present. Particularly preferred complex ester of this type is difficult allyl ether, which can be removed in a strictly selected conditions, for example, through the transfer of the allyl group to the molecule of the research, which in the presence of Pd(0) as catalyst acts as a carrier of H and as the nucleophilic acceptor, according to the method described in J. Org. Chem., 54, 751 1989.

Amides of formula (I), where R2means a group of the formula (III)can be obtained by the interaction of primary and secondary amines of the formula (I) with isothiourea or the corresponding salts isothiourea formula (IIIa)

where Alk means1-C3-alkyl and Raand Rbagree to the above values.

Getting hydroxyisoleucine formula (IIIa), where Randmeans OH and Rbmeans H, described in Bernd Clement, Arch. Pharm. (Wheineim) 319, 968 (1986); other compounds of formula (IIIa) are known compounds or may be obtained by conventional methods of alkylation in the basic environment of their linear and/or cyclic thiocarbamides and thiosemicarbazides. The compounds of formula (IIIa) was isolated as salts isothiourea and specified with the and can be subjected to interaction with amines of the formula Ie according to the method, described in Bodansky, M. et al., J. Am. Chem. Soc., 86, 4452, 1964. Alternatively, the excess solvent, such as ethyl acetate (AcOEt), is added to aqueous solution or suspension of the salt isothiourea formula (IIIa) and with vigorous stirring, the salt is neutralized by adding an equivalent of the basic solution (NaOH h, potassium carbonate n), obtaining the appropriate isothiourea.

Amides of formula (Ia)

where Ar1, Ar2, X, R, R1and R2take the above values, can be subjected to interact financebanking group, which leads to diastereomeric pair R',S'-alcohols, which are not necessarily shared by fractionated crystallization and/or preparative chromatography, getting individual diastereomers of the formula (Ib):

To denote the absolute configuration S' most polar diastereoisomer.

The compounds of formula (I) can be converted into pharmaceutically acceptable salts by forming a salt present in the structure of basic and acidic groups by using, respectively, a pharmaceutically acceptable acids or bases. Examples of pharmaceutically acceptable salts of the bases are salts of alkaline and alkaline-earth metals, preferably lithium, sodium and magnesium, or organic bases, such is how tromethamine, D-glucosamine, lysine, arginine.

The compounds of formula (I) are usually isolated in the form of additive salts, both organic and inorganic pharmaceutically acceptable acids. Examples of such acids are: hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, propionic, maleic, and succinic, malonic and methansulfonate, D and L-tartaric acid.

R-enantiomers of 2-arylpropionic acids of the formula (Va):

where Ar accepts the above values are weak inhibitors of cyclooxygenase and are generally known compounds.

Acid of the formula (Vb):

where φ and Arbtake the above values are obtained by alkylation of stannane polyamidine 2 phenylpropionic acid carrier in Orta-, meta - or paraprotein performancecontrol group, as described below.

The compounds of formula (Vb) are described in international patent application WO 01/58852.

In particular, 2-[3'-isopropyl)phenyl]propionic,

2-[3'-(α-methyl)benzyl)phenyl]propionic and

2-[3'-(3-isopentyl)phenyl]propionic acid are preferred precursors of amides of formula (I).

Each 2-arylpropionic acid may be obtained General and stereospecific synthesis or conversion of the racemate is in one of the individual enantiomers after transformation into 2-aryl-2-propylketone, as described Larse R.D. et al., J. Am. Chem. Soc., 111, 7650, 1989 and A.G. Myers, ibid, 119, 6496, 1997. Stereoselective synthesis of 2-arylpropionic acids are usually sent on the S-enantiomers, but can be easily modified in order to obtain the R-enantiomers by choosing a suitable chiral auxiliary agent. The use of arylalkylamines as reagents in the synthesis of α-arylalkenes acids are described, for example, B.M. Trost and J. H. Rigby, J. Org. Chem., 14, 2926, 1978; atilirovanie acids Meldrum'a described in J.T. Piney and R.A. Rowe, Tetrah. Lett., 21, 965, 1980; the use of tartaric acid as a chiral auxiliary agent in G. Castaldi et al., J. Org. Chem., 52, 3019, 1987; complex α-hydroxyamino as chiral reagents reported in R.D. Larsen et al., J. Am. Chem. Soc., 111, 7650, 1989 and U.S. 4.940.813, and these links.

The method of obtaining 2-(2-OH-phenyl)propionic acids and their esters described in the patent of Italy No. 1283649. A proven and effective way of obtaining R-enantiomer (R,S)-2-(5-benzoyl-2-acetoxy)propionic acid and acids of the formula (Vb), described above, is conversion of the acid chlorides of these prop-1-ketonovyh acids by reacting with a tertiary amine, such as dimethylethylamine, subsequent interaction with R(-)-pantolactone that leads to esters of R-enantiomers of these acids with R-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furan-2-one. Subsequent saponification of Slonov the ester with LiOH gives the corresponding free acid.

A common way to obtain R(-)-2-arylpropionic acids of the formula (Vb) includes the interaction of hydroxyacrylates formula (Vc), mono - or polyamidine, performancemonitoring, leading to performancelevel esters of the formula (Vd), where n means an integer from 1-9.

The compounds of formula (Vd) is subjected to rearrangement Willgerodt'a, after receiving the esterification and methylation on the alpha carbon arylpropionate derivatives of the formula (Ve), where n means an integer of 1-9 and R3means1-C4-alkyl or C2-C4alkenyl.

The compounds of formula (Ve) is subjected to interaction with the corresponding tributylstannyl formula Bu3SnR5where R5means a linear or branched C1-C6-alkyl, linear or branched C2-C6alkenyl or linear or branched C2-C6-quinil, unsubstituted or substituted aryl group to give the corresponding (R,S)-2-arylpropionate formula (Vf).

Alchemilla or Alchemilla groups can be gidrirovanny under conditions of catalytic hydrogenation, resulting in the corresponding saturated alkyl groups. The compounds of formula (Vf) is subjected to the process of deracemization, as described above, the state is interested in converting the corresponding acid chlorides of the acids in ketene, which by interaction with R(-)-pantolactone and subsequent hydrolysis turned into pure R-enantiomers.

Amines of formula (VI) are known products, mostly manufactured, or can be obtained by known methods. Synthesis of 4-dialkylamino-2-butenylamine and from CIS - and TRANS-4-dialkylamino-2-butenylamine described in R. Dalhome et al., J. Med. Chem., 9, 843, 1966 and T. Singh et al. ibid, 12, 368, 1969, respectively.

α-Amino acid with the amino group of the formula-NR1'R2'that is associated with a terminal carbon atom, receive by known methods, based on-hydroxy-α-amino acids, carboxy - and amino groups are protected. Alcohol group is converted into a bromide by reacting with triphenylphosphine and CBr4(RG Weiss et al., J. Org. Chem. 36, 403, 1971, and M. Kang., ibid, 64, 5528, 1966), followed by the interaction of the thus obtained of the halide with at least 2M excess of the desired amine (e.g. dimethylamine, piperidine). Suitable industrial substrates for these purposes are serine, homoserine: the above homologues get from α-amino acids protected With1and amino groups, free carboxypropyl which selectively reduced to the alcohol by recovery in THF at room temperature with an excess of DIBORANE.

The present image is eenie relates to compounds of formula (I), which is the R-enantiomers of 2-arylpropionic, suitable as pharmaceuticals.

Compounds according to the invention of formula (I) evaluated in vitro for their ability to inhibit chemotaxis of polymorphonuclear leukocytes (hereafter labeled PMNs) and monocytes induced by fractions of C5a and C5a-desArg complement. With this purpose, to highlight PMNs from heparinised human blood taken from healthy adult volunteers, mononuclear cells is removed by deposition on dextran (according to the methodology described in W.J. Ming et al., J. Immunol., 138, 1469, 1987), and red blood cells with a hypotonic solution. Cell viability assessed by exclusion using Trypanosoma blue, while the proportion of PMNs appreciate cytocentrifuged after staining with Diff-Quick.

Faction hr C5a and hrC5a-desArg (Sigma) is used as stimulating agents in the experiments on chemotaxis, obtaining almost identical results.

Liofilizovannye C5a is dissolved in a volume of HBSS containing 0.2% BSA to obtain a basic solution with a concentration of 10-5M, subject to dilution HBSS to a concentration of 10-9M, for the analysis of chemotaxis. In experiments on the chemotaxis of PMNs incubated with the compounds according to the invention of formula (I) for 15 minutes at 37°C in atmosphere containing 5% CO2.

Chemotactic activity of C5a appreciate circul the dominant polymorphonuclear (PMNs) man, resuspending in HBSS at a concentration of 1.5×106PMNs in ml.

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

Compounds of the present invention of formula (I) assess if the concentration range from 10-6up to 10-10M; to this end they are added at the same concentration in the lower and upper porous part of microcamera. Holes in the lower part contain the solution C5a or simple media, holes in the upper part contain a suspension in PMNs.

Inhibition of C5a-induced chemotactic activity of individual compounds of the present invention of formula (I) evaluate, incubare a micro-camera for chemotaxis for 60 min at 37°C and in an atmosphere containing 5% CO2. The ability of the compounds according to the invention of formula (I) to inhibit C5a-induced chemotaxis of human monocytes carried out according to the above method (Van Damme J. et al., Eur. J. Immunol., 19, 2367, 1989). Inhibition of C5a-induced chemotactic activity of individual compounds of the present invention of formula (I) in relation to human monocytes evaluated in the concentration range from 10-6up to 10-10M, incubare a micro-camera for chemotaxis for 120 min at 37°C in the atmosphere, the soda is containing 5% CO 2.

Compounds according to the invention can also be assessed on their ability to inhibit IL-8-induced chemotaxis of PMNs man. For this purpose, use of recombinant interleukin-8 person (rhIL-8, Pepro Tech): liofilizovannye protein dissolved in HBSS (balanced salt solution Khanka) at a concentration of 100 μg/ml and then diluted to a concentration of 10 ng/ml in experiments on chemotaxis. R(-)-2-[(4'-isobutyl)phenyl]propionylcarnitine (ED50=10-9M), described in WO 00/24710 use as a reference.

The results for inhibition of chemotaxis induced by C5a and IL-8, are shown in table 1. The results show that different patterns of amide groups may lead to different selectivity of the compounds of the present invention.

The selected series of compounds is dual inhibitors that inhibit chemotaxis induced as C5a and IL-8, others are selective inhibitors of chemotaxis induced by C5a. For example, N-(1-methylpiperid-4-yl)amides, β-Tropicamide, N-(H2N-alkyl)amides of the formula (I) are selective inhibitors of C5a-induced chemotaxis of PMN and monocytes in a concentration range from 10-6up to 10-8M. All these compounds exhibit weak activity as inhibitors of interleukin-8-induced chemotaxis in the same interval concentric the th.

The selected number of compounds according to the invention is also able to inhibit interleukin-8-induced chemotaxis of PMN-leukocytes and T lymphocytes in addition to the C5a-induced the chemotaxis of PMN-leukocytes and monocytes in a concentration range from 10-6up to 10-8M. In particular, the compounds of formula (I), where R1and R2different from hydrogen, exhibit inhibitory activity against C5a-induced chemotaxis and IL-8-induced chemotaxis. Both activity inherent in the compounds, in which the distance between the tips of the basic nitrogen and the amide nitrogen is 2-4 atom, with the optimal value of n=3. It was found that when such a structural skeleton of the compounds according to the invention have a dual role, inhibitors of C5a-induced chemotaxis and IL-8-induced chemotaxis.

It was found that the compounds of formula (I), evaluated ex vivo in whole blood by the method described in Patrignani et al., J. Pharmacol. .. Ther., 271, 1705, 1994, it is not effective as inhibitors of COX enzymes.

In almost all cases, the compounds of formula (I) inhibit the production of PGE2induced in macrophages of mice by stimulation with lipopolysaccharide (LPS, 1 μg/ml) in the concentration range from 10-6up to 10-7M. Inhibition of the production of PGE2that may be registered, for the most part is is within a statistical error and often is below 15-20% of the initial level.

Taking into account discussed above experimental data and the role of activation of complement, C5a-faction in pathological disorders such as psoriasis (R.J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991), bladderwort and pemphigoid, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), chronic inflammatory diseases of the bowel, such as ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273, 1992), acute respiratory distress syndrome, cystic fibrosis and idiopathic fibrosis (E. J. Miller, the previous link, and P. C. Carry et al., J. Clin. Invest., 88, 1882, 1991), chronic obstructive pulmonary disease (COPD), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994), as well as in the prevention and treatment of disorders caused by ischemia or reperfusion, the compounds of the present invention are represented particularly useful to achieve these therapeutic goals.

Thus, the present invention relates to compounds of formula (I)suitable for the treatment of diseases, including psoriasis, hand, foot and pemphigoid, rheumatoid arthritis, chronic inflammatory diseases of the gut including ulcerative colitis, acute respiratory distress syndrome, systemic and idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary violation, glomerulonephritis and in the prevention and treatment of disorders caused by and is the Accademia and reperfusion.

The invention also concerns the use of compounds of formula (I) in the industrial production of medicinal products for the treatment and prevention of these disorders. Compounds according to the invention together with commonly used assistive device, carrier, diluent or excipient can be represented in the form of pharmaceutical compositions and their standard dosages, and in this form can be used in the form of solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all for oral use, or in the form of sterile solutions for injection for parenteral (including subcutaneous) use. Such pharmaceutical compositions and dosage forms may include ingredients in conventional proportions, with or without additional active compounds or active beginning of the medicinal substance, and such dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended for the use of the intended range of doses.

When used as pharmaceuticals amides of the present invention is usually administered in the form of pharmaceutical compositions. So the e composition can be obtained well-known in the field of pharmacy ways and include, at least one active connection. Typically, compounds of the present invention is administered in a pharmaceutically effective amount. Really enter the number of connections is usually determined by the attending physician taking into account the relevant circumstances, including requiring treatment condition, the chosen route of administration, the specific input connection, the age, weight and response of the particular patient, the severity of the symptoms observed in the patient, and the like.

The pharmaceutical compositions according to the invention can be introduced in various ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended method of delivery of the compound is preferably formulated in the form of compositions, intended either for injection, or for oral administration. Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. However, most of the songs are in the dosed medicinal forms, which contributes to precise dosing. The term "dosage form" refers to physically discrete units suitable as single doses to the patient, which is the person or other mammal, each unit is and contains a predetermined amount of the active ingredient, designed depending on the desired therapeutic action, together with a suitable pharmaceutical excipient. Typical dosage forms include pre-filled and measured ampoules or syringes containing liquid composition, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions amide compound is usually not the main mass component (from about 0.1 to 50 mass%, or preferably from 1 to 40 mass %), while the rest consists of various solvents or fillers and processing AIDS helpful for forming the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous solvent with a buffer, suspendresume and dispersing agents, dyes, korrigentami and the like. Liquid form, comprising the following composition for injection, usually stored in the absence of light to avoid catalytic action of light, such as the formation of hydroperoxide or peroxide. Solid forms may include, for example, any of the following ingredients, or close to them by nature connections: binder, such as microcrystalline cellulose, gum tragakant or gelatin; an excipient, such as cu is hmal or lactose, dispersing agent, such as alginic acid, primogel or corn starch; lubricating substance, such as magnesium stearate; a means for sliding, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a corrective tool, such as peppermint, methyl salicylate or orange flavoring.

Compositions for injection are usually based on suitable for injection sterile physiological solution or containing phosphate buffer saline solution, or other known in the field suitable for injection media. As mentioned above, the amide derivative of the formula (I) in such compositions is typically not the main mass component, often contained in the range of 0.05-10 mass %, the rest is a suitable injection medium, and the like. The average daily dose is determined by several factors, such as severity of disease and patient characteristics (age, gender and weight). The dose is usually vary from 1 mg or more mg to 1500 mg of the compounds of formula (I) per day, not necessarily sharing it for multiple injections. Higher doses can also enter due to the low toxicity of the compounds according to the invention over a long period of time.

The above-described components for oral input or the intended drainhole compositions are only typical examples. Additional materials and processing methods described in section 8 "Remington''s Pharmaceutical Sciences Handbook", 18thEdition, 1990, Mack Publishing Company, Easton, Pennsylvania, is incorporated herein by reference.

Compounds according to this invention can be introduced in the form of a delayed-release or drug-delivery systems by slow release. Description typical materials for slow release can also be found in the materials included in Remington''s Handbook, see above.

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

When describing the compounds according to the invention of formula (I) is conventionally taken to indicate the absolute configuration of any additional chiral substituents optionally present in the structure of these compounds, signs of a stroke (for example, R', S', S", etc.).

Examples of abbreviations: AcOH is acetic acid, AcOEt - acetic acid ethyl ester, BOC - N-tert-butoxycarbonyl-, DCC - dicyclohexylcarbodiimide, DCU - dicyclohexylcarbodimide, DMF - dimethylformamide (DMF), EtOH - ethanol, Et2O - diethyl ether, HOBZ - 1-hydroxybenzotriazol, hr - hour (h), hrs - hours (h), MeOH is methanol, r.t. - room temperature (room temperature), THF - tetrahydrofuran (THF), Z - N-benzyloxycarbonyl.

P is operativnye examples:

Intermediate compounds used in the examples below, obtained by the following methods.

1-Amino-4-dimethylaminoborane

The dimethylamine hydrochloride (1.2 g; 12.5 mmol) and after 1 h, 4-bromotryptamine (3.5 g; 12.4 mmol) are added to a suspension of K2CO3(4.3 g; 31 mmol) in acetone (5 ml) at 25°C; after which the suspension is heated to the boiling temperature under reflux overnight. After cooling to room temperature the mixture is filtered and evaporated to dryness; flash chromatography on silica gel residual oils (eluent CHCL3/CH3OH 8:2) gives N-(4-dimethylaminomethyl)phthalimide in the form of a white solid (2.2 g; to 8.94 mmol).

A solution of the compounds in EtOH is treated with 35% aqueous hydrazine (0.45 ml), heated to boiling point under reflux until the disappearance of all starting reagents (˜2 h), filtered and evaporated to dryness. The final crystallization from a mixture of CH2Cl2/CH3OH (98:2) gives 0,85 g (7,32 mmol; yield 82%) of 1-amino-4-dimethylaminoborane in the form of a white solid.

1H-NMR (CDCl3): δ to 7.75 (m, 2H); the 7.65 (m, 2H); 2,72 (m, 2H); 2,35 (t, 2H, J=7 Hz); 2.23 to (C, 6N); to 1.75 (m, 2H); 1,56 (USS, 2H, NH2); to 1.48 (m, 2H).

1-Amino-4-methylaminomethyl

Party 1-amino-4-methylaminomethyl receive the above method, using methylamine instead of dimethylamine.

1-(3-what aminopropyl)thiomorpholine:

A solution of 3-BOC-aminopropionic (of 3.07 g; 12.9 mmol) and thiomorpholine (2,6 ml; and 25.8 mmol) in CH2Cl2(25 ml) is heated to the boiling temperature under reflux for 24 hours the Mixture is cooled to room temperature, filtered, washed with water (2×50 ml), dried over Na2SO4and evaporated to dryness in a vacuum. Purification with flash chromatography on silica gel (eluent CHCl3/CH3OH 9:1) gives 1-(3-BOC-aminopropyl)thiomorpholine (3.1 g; 11,96 mmol) as a clear oil.

Cleavage of the protective group is carried out by dissolving 1.4 g (5.4 mmol) of the compounds in 3n aqueous HCl (6 ml) at room temperature; after 18 h, the solution after alkalizing the addition of an aqueous 2n NaOH to achieve pH 8 extracted with CH2Cl2(2×10 ml). The combined extracts dried over Na2SO4and evaporated to dryness, obtaining 1-(3-aminopropyl)thiomorpholine in the form of a clear oil (0,63 g; of 3.96 mmol).

1H-NMR (CDCl3): δ to 7.75 (m, 2H); the 7.65 (m, 2H); 2,72 (m, 2H); 2,35 (t, 2H, J=7 Hz); 2.23 to (C, 6N); to 1.75 (m, 2H); 1,56 (USS, 2H, NH2); to 1.48 (m, 2H).

1-(3-Aminopropyl)-4-methylpiperazine (highlighted in the form of a hydrochloric salt)

1H-NMR (D2O): δ of 3.75 (m, 7H); to 3.45 (m, 3H); 3.15 in (m, 2H); 3,05 (m, 4H); of 2.20 (m, 2H)

receive the same method, using 4-methylpiperazin instead thiomorpholine.

1-(3-Aminopropyl)piperidine

1H-NMR (CDCl3): δ2,85 (t, 2H, J=8 Hz); of 2.45 (m, 6N); 1,90 (USS, 2H, NH2); 1,8-of 1.62 (m, 6N); of 1.55 (m, 2H)

receive the same method, using piperidine instead thiomorpholine.

1-BOC-propane-1,3-diamine

An aqueous solution (5 ml) NaN3(1.4 g; 21.5 mmol) and 2-3 drops of Aliquat 336 add to the mix a solution of 3-BOC-aminopropionic (5 g, 21.5 mmol) in toluene (10 ml); the mixture is heated to boiling point under reflux for 4 hours After cooling to room temperature, the organic phase is separated, dried over Na2SO4and evaporated to dryness in a vacuum, getting the 3-BOC-aminopropylene (3.75 g; and 18.3 mmol) as a clear oil (yield 85%).

A solution of triphenylphosphine (4.8 g; and 18.3 mmol) in THF (15 ml) is added dropwise to a stirred solution of the above azide in THF (30 ml)/H2O (0.3 ml; and 18.3 mmol); the stirring is continued for 24 h at room temperature. After removal of the solvent to dryness in vacuo the residue absorb a certain amount of EtOH, to select a white precipitate of triphenylphosphine oxide by stirring for 6 h at room temperature. Finally EtOH is removed to dryness under reduced pressure, getting up 3.22 g (18 mmol) of 1-BOC-propane-1,3-diamine as a pale yellow oil.

1H-NMR (CDCl3): δ 4,90 (USS, 1H, CONH); of 3.25 (m, 2H); to 2.85 (t, 2H, J=7 Hz); of 1.75 (t, 2H, J=7 Hz); 1,60 (USS, 2H, NH2); of 1.55 (s, N).

3-(BOC-methylamino)Propylamine

Received the t in the above method, using 3-(BOC-methylamino)propyl bromide.

Methyl-(S)-2-amino-3-dimethylaminopropionic

2M solution of dimethylamine in THF (2.5 ml) is added dropwise to a stirred solution of methyl-(S)-2-BOC-amino-3-bromopropionate (0.45 g; of 1.42 mmol) (R.G. Weiss et al., J. Org. Chem, 36, 403, 1971; M. Kang et al., ibid., 61, 5528, 1996) in anhydrous THF (10 ml) at 25°C. the Mixture is stirred over night at room temperature and evaporated to dryness in a vacuum. The residue is partitioned between Et2O (30 ml) and water 0,5N NaOH (2×5 ml); the ether extracts are combined, washed with saturated salt solution, dried over Na2SO4and evaporated to dryness, obtaining 0.34 g (1,22 mmol) methyl-(S)-2-amino-3-dimethylaminopropionic in the form of a light yellow oil.

1H-NMR (CDCl3): δ was 7.45 (m, 5H); 5,73 (USS, 1H, CONH); further 5.15 (s, 2H); 4,32 (m, 1H); is 3.82 (s, 3H); to 2.75 (m, 2H); 2,22 (C, 6N).

Stir the solution specified complicated methyl ester (0.34 g; 1,22 mmol) in acetonitrile (12 ml) is treated with trimethylsilylimidazole (of 0.21 ml of 1.46 mmol) at room temperature; after 3 h, the mixture was quenched by adding MeOH (0,24 ml; 5.9 mmol), and evaporated in vacuum to dryness. The remainder absorb Et2O (2×10 ml); the ether extracts are re-extracted using 30% aqueous AcOH (2×5 ml), collected, alkalinized to pH 8 and extracted with CH2Cl2(2×10 ml). The in dichloromethane extracts are combined, dried over Na2SO4, evaporated to dryness, p is the best 0.16 g (1.1 mmol) of methyl(S)-2-amino-3-dimethylaminopropionic.

1H-NMR (CDCl3): δ 4,32 (m, 1H); is 3.82 (s, 3H); 3.24 in (USS, 2H, NH2); to 2.75 (m, 2H); 2,22 (C, 6N).

Methyl-(S)-2-amino-5-(piperidine-1-yl)pentanoate

With stirring and external cooling, keeping the reaction temperature in the range of 20-25°C, of 0.03 molar equivalent of 1N solution of B2H6(DIBORANE) in THF is added to 0,01M to a solution of 1-hemimetabola ether (S)-2-BOC-amino-1,5-pentadienoic acid in THF (15 ml); after 2 h, the excess DIBORANE destroy the careful addition of water. After concentration to a small volume in vacuo, the solution was diluted with AcOEt (25 ml). The organic phase is washed with 5% aqueous NaHCO3saturated salt solution and water until neutral, dried over Na2SO4and evaporated to dryness.

The crude residue methyl-(S)-2-BOC-amino-5-hydroxydecanoate is treated with triphenylphosphine and CBr4give crude sample of methyl(S)-2-BOC-amino-5-bromopentanoate.

The interaction of the latter compound with piperidine in THF leads to methyl-(S)-2-BOC-amino-5-(piperidine-1-yl)pentanoate that when processed triperoxonane acid in dichloromethane gives the bis-trifenatate salt of methyl(S)-2-amino-5-(piperidine-1-yl)pentanoate.

1H-NMR (CDCl3): δ 4,32 (m, 1H); is 3.82 (s, 3H); of 3.54 (m, 1H); to 2.85 (t, 2H, J=7 Hz); of 2.45 (m, 6N); δ 1,85 (USS, 2H, NH2); δ 1,75-1,6 (m, 6N); δ 1,5(m, 2H).

Hydrochloride 5-BOC-ornithinolytica ether

<> Maintaining the reaction temperature in the range of 0-5°C due to external cooling, solid 2-Z,5-BOC-ornithine (1 g, 2.7 mmol; industrially produced reagent) and, after 15 min, methyliodide (0,34 ml, 5.4 mmol) is added to a stirred suspension crushed to a fine powder K2CO3(0,38 g; 2.7 mmol) in dry DMF (20 ml). The mixture is stirred an additional hour at 0-5°C and at room temperature for 1 h, then diluted with EtOAc (40 ml) and filtered. The clear solution was washed with water (40 ml) and saturated salt solution (3×30 ml); dried over Na2SO4and evaporated to dryness. Subsequent purification with flash chromatography on silica gel (eluent CHCl3/CH3OH 8:2) gives 2-Z,5-BOC-initimately ester (0.8 g; 2.1 mmol).

Hydrolytic cleavage of the Z-protective group (performed by the method of J. Meienhofer et. al, Tetrahedron. Lett., 3259, 1974) gives the hydrochloride of 5-BOC-ornithinolytica ester (0.73 g; 2.0 mmol) as a white solid.

1H-NMR (CDCl3): δ 9,25 (USS, 3H, NH3+); 5,40 (USS, 1H, CONH); however, 4.40 (m, 1H); and 3.8 (s, 3H); 3,0 (m, 2H); 1.8 m (m, 4H); 1,4 (, N).

Exo-8-methyl-8-azabicyclo[3,2,1]Octan-3-amine (β-1H,5H-troponin)

The sample receive from tropinona by the method Burks J.E. et al., Org. Proc. Res. Dev., 1, 198, 1997.

4-(N,N-Dimethylamino)aniline

4-Nitroaniline (1,83 g; 13,24 mmol) is added in portions to a cooled (T=+4° (C) formic acid(3 ml; 66,2 mmol). Add formaldehyde (37 wt.% the solution in water; 2,72 ml; 29,13 mmol) and the resulting mixture heated to the boiling temperature under reflux for 24 hours After cooling to room temperature, add 6N HCl (2.2 ml) and the resulting precipitate filtered. The filtrate is diluted with 1N NaOH (5 ml) and extracted with CH2Cl2(3×20 ml); the collected organic extracts are dried over Na2SO4and evaporated in vacuum, obtaining a solid residue, which after treatment with a mixture of diisopropyl ether/acetone 1:1 and filtering gives 4-nitro-N,N-dimethylaniline as a yellow powder (1.65 g; to 9.93 mmol). Iron powder (2,145 g; to 38.3 mmol) and 37% HCl (28 ml) suspended in 96% ethyl alcohol (35 ml) and the mixture is heated to boiling point under reflux for 30 minutes; finally, add 4-nitro-N,N-dimethylaniline (0.64 g; of 3.84 mmol) and the mixture is left to warm up to the boiling point under reflux and with stirring for 2 hours, the Hot mixture is filtered through a loose layer of celite and after cooling to room temperature, the filtrate evaporated in vacuum. Oily residue was diluted with CH2Cl2(25 ml) and washed with 1N NaOH (3×25 ml), dried over Na2SO4and evaporated in vacuum, obtaining 4-(N,N-dimethylamino)aniline as a light yellow oil (0,44 g; 3,26 mmol).

1H-NMR (CDCl3): δ 7,10 (d, 2H, J8 Hz); 6,60 (d, 2H, J=8 Hz); 3,55 (USS, 2H, NH2); to 2.25 (s, 6N).

By the same method receive a 4-(N,N-dimethylaminomethyl)aniline as a light yellow oil.

1H-NMR (CDCl3): δ for 7.12 (d, 2H, J=8 Hz); only 6.64 (d, 2H, J=8 Hz); 3,50 (USS, 2H, NH2); or 3.28 (s, 2H); 2,25 (C, 6N).

N,N-Dimethylbutan-2-Indiamen

Propylbromide (1.3 ml, of 17.4 mmol) dissolved in DMF (30 ml) and add cliffline (3.4 g; 18.4 mmol). The mixture is heated to boiling point under reflux for 5 hours After cooling to room temperature the mixture is diluted with diethyl ether, washed with water (3×50 ml), dried over Na2SO4and evaporated in vacuum, obtaining N-propargylamine in the form of a white solid (3.15 g; 17 mmol).

N-Propargylamine (0.64 g; 3.4 mmol) dissolved in 1,4-dioxane (20 ml), then added dimethylamine (8.5 ml; 17 mmol), copper chloride(I) (0.35 g) and paraformaldehyde (1 g). The solution is heated to boiling point under reflux for 3 hours After cooling to room temperature the precipitate is filtered and the filtrate evaporated in vacuum, obtaining a green oily residue which is then dissolved in CH2Cl2and washed with a saturated solution of NaHCO3(2×30 ml) and water (2×30 ml). The organic phase is dried over Na2SO4and evaporated in vacuum. The crude product is purified by treatment with diethyl ether, produces the N-phthalimido-N',N'-dimethylbutan-2-yl-1,4-diamine as a pale yellow solid (0.5 g; 2.05 mmol).

A suspension of N-phthalimido-N',N'-dimethylbutan-2-yl-1,4-diamine (0.5 g, 2.05 mmol) in ethanol (10 ml) is treated with hydrazinehydrate (98 μl; 2 mmol) and the mixture is heated to boiling point under reflux overnight. After cooling to room temperature the precipitate is filtered and the filtrate evaporated in vacuo; the crude residue is treated with acetone at room temperature, receiving after removing the formed precipitate pure product N,N-dimethylbutan-2-yl-1,4-diamine as a red oil (0.2 g; 1.78 mmol).

1H-NMR (CDCl3): δ to 3.52 (m, 2H); with 3.27 (m, 2H); 2,35 (C, 6N); 1,90-1,65 (USS, 2H, NH2).

2-(Aminooxy)-N-methyl-N-(2-hydroxyethyl)]ethylamine

a) (Z-Aminooxy)acetic acid

Maintaining a reaction temperature of about 0-5°C due to external cooling, benzylchloride (1,41 ml, 10 mmol) and aqueous 4n NaOH (2,23 ml) dropwise and sequentially added to the solution in aqueous 2n NaOH (5 ml) of 2.18 g (10 mmol) of hemihydrated of carboxymethylamino [(industrially produced reagent) also called hydrochloride (aminooxy)acetic acid]. Stirring is continued for 15 minutes, then remove any organic impurities with Et2O (2×15 ml); then add crushed ice and podkashlivanija to pH 2 with 37% HCl receive the solid product which was filtered, washed with chilled water and dried the vacuum at T=40° C, receiving 2,62 g (8.2 mmol) of (Z-aminooxy)acetic acid.

b) 2-(Z-aminooxy)-N-methyl-N-(2-hydroxyethyl)ndimethylacetamide

Thionyl chloride (0,78 ml, 9 mmol) is added to a stirred solution of (Z-aminooxy)acetic acid (2,62 g, 8.2 mmol) in MeOH (10 ml). The mixture was incubated over night at room temperature, after receiving a conventional solvent evaporation in high vacuum the crude sample (Z-aminoxy)acetylchloride. Without any additional purification solution of the compounds in CH2Cl2(10 ml) is added dropwise at room temperature in a mixed solution of 2-methylaminoethanol (of 1.44 ml, 18 mmol) in CH2Cl2(5 ml); after 18 h, the reaction mixture is diluted with aqueous 1N HCl (15 ml). The organic phase is separated; washed with water (2×15 ml), dried over Na2SO4and evaporated, obtaining 2-(Z-aminooxy)-N-methyl-N-(2-hydroxyethyl)ndimethylacetamide (2.64 g, 7 mmol) as a clear oil.

c) 2-(Z-Aminooxy)-N-methyl-N-(2-hydroxyethyl)ethylamine

Selective reduction with DIBORANE 2-(Z-aminooxy)-N-methyl-N-(2-hydroxyethyl)ndimethylacetamide carried out by the method of Brown a (J. Am. Chem. Soc. 86, 3566, 1964 and J. Org. Chem., 38, 912, 1973), obtaining 2.1 g (5.8 mmol) of 2-(Z-aminooxy)-N-methyl-N-(2-hydroxyethyl)ethylamine in the form of oil.

d) 2-(Aminooxy)-N-methyl-N-(2-hydroxyethyl)ethylamine

Splitting benzyloxycarbonyl by hydrogenolysis is carried out in presets is under ammonium formate according to the method Makowski (Liebigs Ann. Chem., 1457, 1985), get 2-(aminooxy)-N-methyl-N-(2-hydroxyethyl)ethylamine (1.06 g, with 4.64 mmol) as a clear oil.1H-NMR (CDCl3): δ 5,28 (USS, 2H, ONH2); of 4.67 (t, 2H, J=7 Hz); 3.40 in (m, 2H); to 2.75 (t, 2H, J=7 Hz); 2,42 (t, 2H, J=7 Hz); of 2.21 (s, 3H); 1.8 m (USS, 1H, OH).

2-Arylpropionate formula V (General method).

The solution was 72.8 mmol 2-arylpropionic acid of the formula V [for example, (R)-2-(4-isobutylphenyl)propionic acid, (R)(-)-ibuprofen, for 72.8 mmol] thionyl chloride (37.5 ml) is heated to the boiling temperature under reflux for 3 hours the Mixture is cooled to room temperature and the excess reagent is evaporated to dryness in a vacuum; then twice in a row, add a small amount of anhydrous dioxane and evaporated to dryness in a high vacuum to remove any residual traces of thionyl chloride. The final oily residue use in subsequent interactions.

IR (film) cm-1: 1800 (ClC=0)

(S)-2-(4-Isobutylphenyl)]-N-(3-dimethylaminopropyl)propionohydroxamic

Applying the previous technique (S)(+)-ibuprofen (reagent Fluka'a) is transformed into the corresponding propionate, the treatment of which 3-dimethylaminopropylamine by the method of example 1 allows you to get a sample of (S)-2-(4-isobutylphenyl)]-N-(3-dimethylaminopropyl)propionohydroxamic, TPL 97-98°C [α]D=+27 (c=1; CH3OH).

1H-NMR (D2 O): δ 7,45-7,21 (m, 4H); 3.75 to (q, 1H, J1=7 Hz, J2=7 Hz); 3.45 points is 3.15 (m, 2H); 2.95 and (t, 2H, J=8 Hz); 2,85 (C, 6N); 2,52 (d, 2H, J=7 Hz); to 1.98 (m, 1H); to 1.47 (d, 3H, J=7 Hz); of 0.90 (d, 6N, J=7 Hz).

Example 1

(R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionohydroxamic

When the outer cooling, keeping the reaction temperature below 40°C, a solution of (R)-2-(4-isobutylphenyl)Propionaldehyde (16,35 g; for 72.8 mmol) in CH2Cl2(10 ml) is added slowly to a stirred solution of 3-dimethylaminopropylamine (19 ml, 152 mmol). After keeping overnight at room temperature, the reaction mixture was diluted with water (100 ml), the organic phase is separated, washed with water (50 ml) and dried over Na2SO4. After removal of the solvent under reduced pressure to obtain 20 g (of 68.8 mmol) of crude (R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide in the form of a light yellow oil.

Stir the solution part of the above amide (58 mmol) in isopropyl alcohol (200 ml) is treated with an aqueous 37% HCl (6 ml), slowly adding at room temperature; after 2 h, the reaction mixture is evaporated to dryness under reduced pressure. Traces of residual water is removed by azeotropic distillation in vacuum, adding a small amount of anhydrous isopropyl alcohol. The final crystallization from AcOEt (300 ml) allocates a white powder, which is filtered, washed with dry AcOEt and the shat for 24 h under vacuum at T=40° C, obtain 18 g (55 mmol) of (R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionohydroxamic.

TPL 95-98°C,

[α]D=-26 (c=1,6; CH3OH).

1H-NMR (D2O): δ of 7.5 to 7.2 (m, 4H); 3.75 to (q, 1H, J1=7 Hz, J2=7 Hz); 3.45 points is 3.15 (m, 2H); 3,05 (t, 2H, J=8 Hz); 2,80 (d, 6N, J=4.5 Hz); to 2.55 (d, 2H, J=7 Hz); 1,95 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 0,93 (d, 6N, J=7 Hz).

Example 2

Using 2-diethylaminoethylamine and 4-dimethylaminobutyric instead of 3 dimethylpropylene in the method of example 1, have the following connections:

(R)-2-(4-isobutylphenyl)-N-(2-dimethylaminoethyl)propionamide·HCl

TPL 90-93°C; [α]D=-16 (c=1; CH3OH).

1H-NMR (CDCl3): δ 12,25 (USS, 1H, NH+); 7,82 (USS, 1H, CONH); was 7.45 (d, 2H, J=8 Hz); 7,05 (d, 2H, J=8 Hz); of 3.85 (m, 2H); 3,70 (m, 1H); 3,10 (m, 2H); 2,80 (s, 3H); to 2.75 (s, 3H); to 2.55 (d, 2H, J=7 Hz); of 1.97 (m, 1H); of 1.65 (d, 3H, J=7 Hz); and 0.98 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-(4-dimethylaminomethyl)propionamide·HCl

TPL 95-97°C; [α]D=-16 (c=0,52; CH3OH).

1H-NMR (CDCl3): δ to 7.25 (d, 2H, J=8 Hz); 7,10 (d, 2H, J=8 Hz); 6,18 (USS, 1H, CONH); of 3.60 (q, 1H, J1=7 Hz, J2=7 Hz); 3.25 to 3.15 in (m, 2H); 2.95 and (m, 2H); 2,75 (C, 6N); of 2.45 (d, 2H, J=7 Hz); of 1.85 (m, 1H); of 1.65 (m, 4H); to 1.48 (d, 3H, J=7 Hz); 0,93 (d, 6N, J=7 Hz).

Example 3

(R)-2-(4-isobutylphenyl)-N-2-(N-morpholinylmethyl)propionamide·HCl

Using 1-aminoacylation in the method of example 1, get crude (R)-2-(4-isobutylphenyl)-N-[2-(1-morpholinyl)ethyl]propionamide 4,2n acetylchloride in absolute EtOH (3 ml) is added dropwise to a stirred solution of the indicated amide (0,416 g, 1.3 mmol) in absolute EtOH (5 ml). The mixture is stirred an additional 2 h at room temperature, then remove the solvents under reduced pressure. The remainder absorb ethyl ether, highlighting 0.39 g (1.1 mmol) of (R)-2-(4-isobutylphenyl)-N-[2-(1-morpholinyl)ethyl]propionohydroxamic in the form of a white solid, which was filtered and washed with the same solvent.

TPL 123-125°C; [α]D=-36,3 (c=0.5; CH3OH).

1H-NMR (CDCl3): δ 12,55 (USS, 1H, NH+); 7,80 (USS, 1H, CONH); was 7.45 (d, 2H, J=8 Hz), 7,05 (d, 2H, J=8 Hz); 4.25 in (m, 2H); 3,95 (m, 1H); 3,70 (m, 4H); to 3.41 (m, 1H); 3,05 (m, 3H); to 2.75 (m, 2H); of 2.45 (d, 2H, J=7 Hz); of 1.97 (m, 1H); 1,65 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

Example 4

Using the method according to example 3 of the following amines selected from the group including: 1-(3-aminopropyl)morpholine, 1-(3-aminopropyl)-4-thiomorpholine, 1-(2-amino-ethyl)piperazine-4-methyl, 1-(3-aminopropyl)piperazine-4-methyl, 1-(3-aminopropyl)piperidine and Exo-8-methyl-8-Aza-bicyclo[3,2,1]-octane-3-amine instead of 1-(3-aminopropyl)the research gives: (R)-2-(4-isobutylphenyl)-N-3-(N-morpholinylmethyl)propionamide·HCl

TPL 90-93°C

[α]D=-22,6 (c=0.5; CH3OH).

1H-NMR (CDCl3): δ 12,55 (USS, 1H, NH+); 7,80 (USS, 1H, CONH); was 7.45 (d, 2H, J=8 Hz), 7,05 (d, 2H, J=8 Hz); 4.25 in (m, 2H); 3,95 (m, 1H); 3,70 (m, 4H); to 3.41 (m, 1H); 3,05 (m, 3H); to 2.75 (m, 2H); of 2.45 (d, 2H, J=7 Hz); of 2.15 (m, 2H); of 1.97 (m, 1H); of 1.65 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-3-(N-t is morpholinopropan)propionamide· HCl

TPL 70-73°C; [α]D=-23 (c=0.5; CH3OH).

1H-NMR (D2O): δ 8,15 (USS, 1H, CONH); 7,40 (m, 4H), 3,82 (kV, 1H, J=7 Hz); the 3.65 (m, 2H); to 3.41 (m, 1H); of 3.25 (m, 1H); 3.15 and is 2.80 (m, 8H); of 2.45 (d, 2H, J=7 Hz); 1,95 (m, 3H); of 1.55 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-[2-(4-methylpiperazin-1-yl)ethyl]propionohydroxamic

TPL above 240°C; [α]D=-33,7 (c=0.5; CH3OH).

1H-NMR (DMSO-d6): δ to 7.15 (m, 4H); of 4.45 (m, 1H); 4,13 (m, 2H), to 3.02 (m, 3H); to 2.75 (m, 4H); of 2.38 (d, 2H, J=7 Hz); of 1.85 (m, 1H); of 1.30 (d, 3H, J=7 Hz); 0,81 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-[3-(4-methylpiperazin-1-yl)propyl]propionamide-bis-hydrochloride

TPL 216-220°C; [α]D=20.5 and (c=0.5; CH3OH).

1H-NMR (D2O): δ 7,25 (m, 4H); 3.75 to (m, 1H); 3,55 (m, 8H), of 3.25 (m, 2H); 3.15 in (m, 1H); 3,00 (s, 3H); 2,48 (d, 2H, J=7 Hz); 1,95 (m, 3H); of 1.45 (d, 3H, J=7 Hz); of 0.90 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-[3-(1-piperidinyl)propyl]propionohydroxamic

TPL 76-80°C; [α]D=-29(c=0.5; CH3OH).

1H-NMR (CDCl3): δ 11,4 (USS, 1H, NH+); was 7.45 (d, 2H, J=8 Hz); 7,35 (USS, 1H, CONH); 7,05 (d, 2H, J=8 Hz), 3,85 (kV, 1H, J=7 Hz); of 3.45 (m, 4H); to 2.75 (m, 2H); 2,52 (m, 4H); to 2.25 (m, 2H); is 2.05 (m, 2H); of 1.97 (m, 3H)and 1.60 (d, 3H, J=7 Hz); 0,97 (d, 6N, J=7 Hz).

(R)-2-(4-isobutylphenyl)-N-[Exo-8-methyl-8-Aza-bicyclo[3.2.1.]-Oct-3-yl)propionohydroxamic

TPL 72-75°C; [α]D=-3,3 (c=0.5; CH3OH).

1H-NMR (CDCl3): δ to 7.15 (d, 2H, J=8 Hz), 7,05 (d, 2H, J=8 Hz); 6,15 (USS, 1H, CONH); 4,34 (m, 1H); 3.75 to (m, 2H); 3,4 (kV, 1H, J=7 Hz); of 2.72 (s, 3H); 2,60-of 2.38 (m, 4H); 2,30-to 1.98 (m, 6N); to 1.98 (m, 2H); of 1.45 (d, 3H, J=7 Hz); 0,9 (d, 6N, J=7 Hz).

Example 5

(R)-2-(4-isobutylphenyl)-N-[3-aminopropyl)propionohydroxamic

A solution of 3-BOC-aminopropylene (3,22 g; 18 mmol) in CH2Cl2(10 ml) is added dropwise to a stirred suspension of (R) - (-)-ibuprofen (3 g; 17.5 mmol), DCC (3.8 g; 18 mmol) and HOBZ (2.8 g; 18 mmol) in CH2Cl2(50 ml) at 25°C. Stirring is continued for 18 h at room temperature; after removal of the DCU by filtration of the reaction mixture is evaporated to dryness in a vacuum. The remaining oil absorb several times with acetonitrile, and finally the collected extracts are filtered, evaporated to dryness, obtaining the crude sample of (R)-2-(4-isobutylphenyl)-N-3-(BOC-aminopropyl)propionamide, which crystallized from hot MeOH (50 ml)to give 3.4 g (a 9.25 mmol, yield 53%) of pure (R)-2-(4-isobutylphenyl)-N-(3-aminopropyl)propionamide upon cooling to T=+4°C for 18 hours

The suspension of the compounds in 10 ml of aqueous 3n HCl was stirred at room temperature for 48 h, obtaining (R)-2-(4-isobutylphenyl)-N-3-(aminopropyl)propionohydroxamic (1,9 g; 6.3 mmol);

TPL 160-163°C;

[α]D=-31 (c=0.5; CH3OH).

1H-NMR (CDCl3): δ 8,2 (USS, 1H, NH3+); to 7.18 (d, 2H, J=8 Hz); 7,05 (d, 2H, J=8 Hz), 6,83 (USS, 1H, CONH); the 3.65 (q, 1H, J=7 Hz); 3,30 (m, 2H); 3,00 (m, 2H); 2.40 a (d, 2H, J=7 Hz); 1,95-of 1.74 (m, 3H); of 1.45 (d, 3H, J=7 Hz); 092 (d, 6N, J=7 Hz).

Example 6

(R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionohydroxamic

The ammonium formate (15,4 g; 240 mmol) and 10% Pd/C (3,14 g; 29 mmol) are added to a solution of 1-methyl-4-piperidone (3,26 ml; of 26.5 mmol) in aqueous methanol (80 ml, CH3OH/H2O 9:1); the mixture is stirred for 24 h at room temperature, the catalyst was removed by filtration through celite and evaporated to dryness under reduced pressure, obtaining a light yellow residue of 1-methyl-4-aminopiperidine. Adding drops of 37% HCl (4.6 ml) to a stirred solution of the specified amine in EtOH (50 ml) leads to the release of the white precipitate of 1-methyl-4-aminopiperidine, which is filtered off after 18 h, after cooling for 18 h to T=+4°C. Finally, an aqueous solution of the hydrochloride is treated with excess 0.1 n NaOH (≈ 10 ml), extracted with CH2Cl2(3×10 ml). After standard processing, the solvent is evaporated to dryness, obtaining pure 1-methyl-4-aminopiperidine (1.4 g; 12.4 mmol).

1H-NMR (CDCl3): δ to 2.85 (m, 2H); of 2.58 (m, 1H); of 2.25 (s, 3H), a 2.01 (m, 2H); of 1.85 (m, 2H); 1,63 (USS, 2H, NH2); to 1.47 (m, 2H).

At room temperature a solution of (R)-2-(4-isobutylphenyl)Propionaldehyde (1.12 g; 5 mmol) in CH2Cl2(20 ml) is slowly added dropwise to a solution of 1-methyl-4-aminopiperidine (1.1 g; 10 mmol) in CH2Cl2(10 ml). After 3 h, the reaction mixture is again diluted with CH2Clsub> 2(10 ml), washed with 1N HCl (25 ml) and saturated salt solution, dried over Na2SO4getting after evaporation to dryness of the solvent (R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionohydroxamic in the form of a glassy solid (1.2 g; 3.5 mmol).

[α]D=-11 (c=0.5; CH3OH).

1H-NMR (D2O): δ 7,28 (m, 5H); 3,95 (m, 1H); 3.75 to (q, 1H, J=7 Hz), of 3.54 (m, 2H); 3.15 in (m, 2H); 2,90 (s, 3H); 2,53 (d, 2H, J=7 Hz); 2,28-2,05 (m, 2H); 1,95-of 1.65 (m, 4H); a 1.45 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

Example 7

Sodium salt of (R),(S)-2-(4-isobutylphenyl)-N-(1-carboxy-2-dimethylaminoethyl)propionamide

A solution of (S)-methyl-3-dimethylamino-2-aminopropanoic (0.16 g; 1.1 mmol) in CH2Cl2(2 ml) is added dropwise to a stirred suspension of (R) - (-)-ibuprofen (0,23 g; 1.1 mmol), DCC (0,23 g; 1.1 mmol) and HOBZ (0.17 g; 1.1 mmol) in CH2Cl2(5 ml) at room temperature. Stirring is continued for 18 h at room temperature; after removal of the DCU removal by filtration, the reaction mixture is evaporated to dryness in a vacuum. The residue is repeatedly absorb acetonitrile; then the collected extracts filtered and evaporated to dryness in a vacuum. Subsequent purification with flash chromatography on silica gel (eluent CH2Cl2/CH3OH 95:5) gives 0.3 g (0.88 mmol) of methyl(S),(R)-3-dimethylamino-2-[2-(4-isobutylphenyl)propionyl]aminopropanoic (yield 80%) as a clear oil.

Paramashiva the initial solution of the specified complex ester (0.3 g; 0.88 mmol) in dioxane (2 ml) is treated with a stoichiometric amount of water n NaOH (0,88 ml) and incubated for 18 h at room temperature, then diluted with chilled water (20 ml). The frozen solution lyophilized getting 0,307 g (0.88 mmol) of sodium salt of (R),(S)-2-(4-isobutylphenyl)-N-(1-carboxy-2-dimethylaminoethyl)propionamide in the form of a white solid.

TPL above 240°C;

[α]D=-25 (c=0.5; CH3OH)

1H-NMR (CDCl3): δ 7,35 (m, 4H); 6,25 (USS, 1H, CONH); 4.72 in (m, 1H); of 3.60 (m, 1H); of 2.51 (d, 2H, J=7 Hz), 2,30 (d, 2H, J=7 Hz); 2,22 (m, 6N); of 1.55 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

Example 8

Sodium salt of (R),(S)-2-(4-isobutylphenyl)-N-(1-carboxy-2-piperidine-1-yl-butyl)propionamide and (R),(S)-2-(4-isobutylphenyl)-N-(1-etoxycarbonyl-2-piperidine-1-yl-butyl)propionamide

Get, using (S)-methyl-5-(piperidine-1-yl)-2-aminopentanoic in the method of example 7 instead of (S)-methyl-3-dimethylamino-2-aminopropanoic.

Example 9

R-2-[(4'-isobutylphenyl]-N-[2-(dimethylaminoethyl)aminocarbonylmethyl]propionohydroxamic

HOBZ (0,607 g; 4,49 mmol) is added to a stirred solution of (R) - (-)-ibuprofen (1.01 g; 4.9 mmol) in DMF (4 ml) at T=0°C and left to mix for 30 minutes Then add the mixture of N-(3-dimethylaminopropyl)glycinebetaine (0.64 g; 4,47 mmol) in DMF (8 ml) and triethylamine (0.6 ml; of 4.45 mmol), and add, in small portions N,N-dice logicalgroove (1 g; is 4.85 mmol). The mixture is stirred for 2 h at T=0°C and then 18 h at room temperature. After filtering DCU large part of the DMF is removed by distillation under reduced pressure. The remainder absorb water and extracted with Et2O (3×25 ml); the organic extracts are combined, dried over Na2SO4and evaporated under reduced pressure, obtaining a clear oil (1 g; of 3.43 mmol). Then a solution of the obtained compound in dioxane (3.5 ml) is treated with 1N NaOH (3.5 ml), stirred for 24 h at room temperature, diluted with water (10 ml) and then podkalyvayut 2n HCl and extracted with CH2Cl2(3×10 ml).

Then the organic extracts are combined, dried over Na2SO4and evaporated under reduced pressure, obtaining R-2-[(4'-isobutyl)phenyl]-N-[2-(dimethylaminoethyl)aminocarbonylmethyl]propionohydroxamic (0.68 g; 2.04 mmol) as a pale yellow oil.

[α]D=-25 (c=0.5; CH3OH).

1H-NMR (CDCl3): δ from 7.24 (m, 2H); 7,10 (m, 2H); 6,10 (USS, 1H, CONH), 3,55 (m, 1H); 3,30 (m, 2H); of 2.45 (d, 2H, J=7 Hz); 2,35 (m, 2H); to 2.18 (s, 6N); of 1.85 (m, 1H); of 1.52 (d, 3H, J=7 Hz); of 0.90 (d, 6N, J=7 Hz).

Example 10

(R)-2-[2-(2,6-dichlorophenylamino)phenyl]-N-3-(dimethylaminopropyl)propionamide

A suspension of (R)-2-[2-(2,6-dichlorophenylamino)]phenyl]propionic acid (0.15 g; 0.48 mmol), DCC (0,173 g; 0.84 mmol) and HOBZ (0.075 g; 0,56 mmol) in CH2Cl2(6 ml) is stirred for 4 h at room temperature; then d is billaut dropwise a solution of 3-(dimethylamino)Propylamine (0.06 ml; 0.48 mmol) in CH2Cl2(5 ml). Stirring is continued for 18 h at room temperature, then separated DCU is filtered and the solvent is removed under reduced pressure. The residue twice absorb the acetonitrile extracts combine, filtered to remove traces of DCU and evaporated under reduced pressure. Purification with flash chromatography (eluent CH2Cl2/CH3OH 95:5) gives (R)-2-[2-(2,6-dichlorophenylamino)phenyl]-N-3-(dimethylaminopropyl)propionamide (0,141 g; 0.36 mmol; 75%yield) as a clear oil.

[α]D=-30 (c=1; CH3OH).

1H-NMR (D2O): δ 7,38 (m, 4H); to 7.15 (m, 1H); 7,05 (m, 1H), 6,60 (m, 1H+CONH); of 4.25 (DD, 2H, J1=7 Hz, J2=3 Hz); 3,30 (m, 2H); 2,35 (m, 2H); 2,10 (C, 6N); of 1.65 (m, 2H); of 1.65 (d, 3H, J=7 Hz).

Example 11

The following amides get, using (R),(R',S')-2-[3-(α-hydroxybenzyl)phenyl]propionic acid, 2-[3'-(α-hydroxyethyl)phenyl]propionic acid and (R),(R',S')-2-[3'-(α-hydroxy,α-methylbenzyl)phenyl]propionic acid as starting material instead of (R)-2-[2-(2,6-dichlorophenylamino)]phenyl]propionic acid in the method of example 10.

(R),(R',S')-2-[3-(α-hydroxybenzyl)phenyl]-N-3-(dimethylaminopropyl)propionamide in the form of a colorless oil.

[α]D=-24 (c=1; CH3OH).

1H-NMR (CDCl3): δ 7,41 of 7.3 (m, 3H); 7,31-7,14 (m, 6N); of 5.75 (s, 1H), was 4.02 (USS, 1H, HE); and 3.31 (m, 2H); of 2.38 (t, 2H, J=8 Hz); 2,15 (C, 6N); 1.75 m, 2H); 3,68 (kV, 1H, J=7 Hz); 1,4 (d, 3H, J=7 Hz).

(R),(R',S')-2-[3-(α-hydroxy,α-methylbenzyl)phenyl]-N-3-(dimethylaminopropyl)propionamide in the form of a colorless oil.

[α]D=-28 (c=1; CH3OH).

1H-NMR (CDCl3): δ 7,41 of 7.3 (m, 3H); 7,31-7,14 (m, 6N); was 4.02 (USS, 1H, HE), and 3.31 (m, 2H) of 2.38 (t, 2H, J=8 Hz); 2,15 (C, 6N); to 1.75 (m, 2H); 3,68 (kV, 1H, J=7 Hz); 1,4 (d, 3H, J=7 Hz).

(R),(R',S')-2-[3-(α-hydroxyethyl)phenyl]-(3-dimethylaminopropyl)propionamide

1H-NMR (DMSO-d6): δ 8,12 (USS, 1H, CONH); 7,31 (s, 1H), 7,25-7,10 (m, 3H); 5,1 (USS, 1H, HE); the 4.7 (m, 1H); 3,62 (m, 1H); 3,10 (m, 2H); 2.91 in (m, 2H); 3,65 (C, 6N); at 1.73 (m, 2H); of 1.30 (m, 6N).

Example 12

(R),(R',S')-2-[3'-(α-methylbenzyl)phenyl]-N-3-(dimethylaminopropyl)propionamide in the form of a light yellow oil (1.2 g; to 3.52 mmol).

[α]D=-30(c=1; CH3OH)

1H-NMR (CDCl3): δ 7,38-7,13 (m, N); 6,60 (USS, 1H, CONH); 4,20 (m, 1H), 3,78 (m, 1H); with 3.27 (m, 2H); 2,30 (m, 2H); 2,12 (C, 6N); 1,72 (d, 3H, J=7 Hz); of 1.65 (m, 2H); of 1.55 (d, 3H, J=7 Hz) are obtained using the method of example 1 (R),(R',S')2-[3-(α-methylbenzyl)phenyl]propionate instead of (R)-(2-(4-isobutylphenyl)propionitrile.

Alternative use of (R)-2-(3-isopropylphenyl)Propionaldehyde, (R)-2-(3-isobutylphenyl), (R)-2-[3-(styren-1-yl)phenyl]propionitrile, (R)-2-[3'-(Penta-3-yl)phenyl]Propionaldehyde in the method of example 1 gives:

(R)-2-(3-isopropylphenyl)-N-3-(dimethylaminopropyl)propionamide

1H-NMR (CDCl3): δ 7,21 (m, 4H); 6,95 (USS, 1H, CONH); of 3.53(m, 1H), 3,30 (m, 2H); 2,90 (m, 1H); is 2.37 (m, 2H); 2,15 (C, 6N); of 1.65 (d, 3H, J=7 Hz); of 1.23 (d, 3H, J=7 Hz).

(R)-2-(3-isobutylphenyl)-N-3-(dimethylaminopropyl)propionamide

[α]D=-30 (c=1; CH3OH).

1H-NMR (CDCl3): δ 7,21-7,13 (m, 4H); 6,85 (USS, 1H, CONH); of 3.53 (m, 1H), 3,25 (m, 2H); 2,48 (d, 2H, J=7 Hz); 2,30 (t, 2H, J=7 Hz); 2,09 (C, 6N); 1,9 (m, 1H); of 1.55 (m, 2H); of 1.45 (d, 3H, J=7 Hz); of 0.95 (d, 3H, J=7 Hz).

(R)-2-[3-(styren-1-yl)phenyl]-N-3-(dimethylaminopropyl)propionamide

[α]D=-31 (c=1; CH3OH).

1H-NMR (CDCl3): δ 7,8-7,13 (m, N); 6,95 (USS, 1H, CONH); 5,0 (s, 2H), 3,53 (m, 1H); 3,30 (m, 2H); is 2.37 (m, 2H); 2,15 (C, 6N).

(R)-2-[3'-(Penta-3-yl)phenyl]-N-3-(dimethylaminopropyl)propionamide

[α]D=-28(c=1; CH3OH).

1H-NMR (CDCl3): δ 7,25 (m, 3H); for 7.12 (m, 1H); 7,08 (USS, 1H, CONH); the 3.65 (m, 1H), 3,5-3,13 (m, 2H); to 2.75 (m, 2H); to 2.55 (s, 6N); 2,35 (m, 1H); 1,95 (m, 2H); to 1.70 (m, 2H); was 1.58 (m, 2H); 1.50 in (d, 3H, J=7 Hz); 0,76 (t, 6N, J=7 Hz).

(R)-2-[(3-benzoyl)phenyl]-N-(3-diethylaminopropyl)propionamide:

[α]D=-11,5 (c=3; CH3OH)

1H-NMR (CDCl3): δ 7,8 (m, 3H); 7,70-of 7.55 (m, 3H); 7,50-7,28 (m, 3H), 7,25 (USS, 1H, CONH); of 3.75 (m, 1H); 3,50-3,20 (m, 2H); 3,3,15 is 2.80 (m, 6N); is 2.05 (m, 2H); of 1.65 (d, 3H, J=7 Hz); 1.70 to 1,53 (m, 3H); 1,50-of 1.45 (m, 3H).

(R)-2-[(3-benzoyl)phenyl]-N-(3-dimethylaminopropyl)propionamide

[α]D=-20(c=1; CH3OH)

1H-NMR (CDCl3): δ 7,88 for 7.78 (m, 3H); 7,75-7,58 (m, 3H); 7,55-7,46 (m, 3H), 7,25 (d, 1H, CONH); 3,62 (m, 1H); or 3.28 (m, 2H); 2,35 (m, 2H); 2,12 (C, 6N); 1,68-of 1.53 (m, 5H).

Example 13

(R)-2-(4-isobutylphenyl)-N-3-(gua is itinerrary)propionohydroxamic

(R)-2-[(4-isobutylphenyl)-N-3-(aminopropyl)propionohydroxamic in example 5 turn into a free amine and treated with isothiouronium according to the method of M. Bodanszky et al, (J. Am. Chem. Soc., 86, 4452, 1964), obtaining (R)-2-(4-isobutylphenyl)-N-3-(guanidinium)propionohydroxamic.

TPL 142-146°C; [α]D=-24 (c=1 CH3OH).

1H-NMR (D2O): δ to 7.2 (d, 2H, J=8 Hz), and 7.1 (d, 2H, J=8 Hz); 6.8 cm (USS, 1H, CONH); 3,6 (kV, 1H, J=7 Hz); 3,55 (m, 2H); 2.95 and (m, 2H); 2,4 (d, 2H, J=7 Hz); 2,0-1,8 (m, 3H), and 1.5 (d, 3H, J=7 Hz); 0,9 (d, 6N, J=7 Hz).

An alternative application of the same methodology hydrochloric salt of methyl ester of N-hydroxycarbamide acid and methyl ester of N-aminocarnitine acid gives:

(R)-2-(4-isobutylphenyl)-N-[3-(hydroxyguanidine)propyl]propionamide·HCl

(R)-2-(4-isobutylphenyl)-N-[3-(aminoguanidine)propyl]propionamide·HCl

Example 14

(R)-2-(4-isobutylphenyl)-N-[3-(imidazolin-2-yl)-aminopropyl]propionamide

(R)-2-[(4-Isobutylphenyl)-N-3-(aminopropyl)propionohydroxamic (see, example 5) turn into a free amine and treated with 2-methylthio-2-imidazolylidene (industrial reagent) according to the above method Bodanszky (J. Am. Chem. Soc., 86, 4452, 1964), obtaining (R)-2-(4'-isobutylphenyl)-N-[3-(imidazolin-2-yl)aminopropyl]propionamide.

TPL 155-168°C; [α]D=-15 (c=1 CH3OH).

1H-NMR (D2O): δ to 7.2 (d, 2H,J=8 is C); and 7.1 (d, 2H, J=8 Hz); 6.8 cm (USS, 1H, CONH); 3,6 (kV, 1H, J=7 Hz), 3,55 (m, 2H); 3.40 in (s, 4H); 2,90 (m, 2H); 2,35 (d, 2H, J=7 Hz); 2,0-1,8 (m, 3H); of 1.55 (d, 3H, J=7 Hz); 1.0 in (d, 6N, J=7 Hz).

Using 2-methylthiopyrimidine in the above method gives: (R) 2-(4-isobutylphenyl)-N-[3-(tetrahydropyrimidin-2-yl)aminopropylphosphonic.

1H-NMR (D2O): δ to 7.2 (d, 2H, J=8 Hz); and 7.1 (d, 2H, J=8 Hz); 6.8 cm (USS, 1H, CONH); 3,6 (kV, 1H, J=7 Hz), 3,55 (m, 2H); 3.40 in (s, 4H); 2,90 (m, 2H); 2,35 (d, 2H, J=7 Hz); 2,0-1,8 (m, 5H); of 1.55 (d, 3H, J=7 Hz); 1.0 in (d, 6N, J=7 Hz).

Example 15

(R),(S')-2-(4-isobutylphenyl)-N-[(1-carboxy-4-amino)butyl]propionamide

A solution of (R)-2-(4-isobutylphenyl)Propionaldehyde (0.54 g; 2,42 mmol) in CH2Cl2(10 ml) is slowly added dropwise to a suspension of the hydrochloride of 5-BOC-ornithinolytica ether (0,69 g; 2,42 mmol) and triethylamine (0.68 ml; 4,84 mmol) in CH2Cl2at 25°C. the Mixture is left to mix overnight at room temperature, then diluted with water (10 ml). The organic phase is separated and washed with saturated solution of NaHCO3(10 ml), dried over Na2SO4and evaporated, to give crude product, which was purified flash chromatography (eluent CHCl3/CH3OH 9:1)to give methyl ester (R),(S)-2-(4-isobutylphenyl)propionyl(5-BOC-ornithine in the form of a clear oil (0.6 g; 1.4 mmol). Processing the specified connection 3n HCl (8 ml) for 18 h at room temperature with subsequent evaporation of the of astorias gives (R),(S')-2-(4-isobutylphenyl)-N-[(1-methoxycarbonyl-4-amino)butyl]propionohydroxamic (0,41 g, 1.25 mmol).

To a solution of the specified hydrochloride in dioxane is added at room temperature, 4n NaOH (of 0.625 ml; 2.5 mmol), the mixture is stirred overnight and evaporated to dryness under reduced pressure. The remainder absorb EtOAc (15 ml); the organic phase is washed with saturated NaCl solution (2×15 ml) and dried over Na2SO4. Evaporation AcOEt gives (R),(S')-2-(4-isobutylphenyl)-N-[(1-carboxy-4-amino)butyl]propionamide in the form of a white solid,

TPL above 240°C;

[α]D=-29 (c=0.5; CH3OH).

1H-NMR (DMSO-d6): δ and 7.3 (d, 2H); δ and 7.1 (d, 2H); 6,25 (USS, 1H, CONH); 4,20 (m, 1H); 3,70 (m, 1H), 3,50 (m, 2H); 2,5 (d, 2H); 1,9 (m, 1H); 1.8 m (m, 4H); 1,6 (d, 3H); of 0.95 (d, 6N, J=7 Hz).

(R),(S')-2-(4'-isobutylphenyl)-N-(1-carboxy-5-aminopentyl)propionohydroxamic

Receive, using the appropriate derivative (L)-lysine instead of a derivative of ornithine.

[α]D=-28,3 (c=1; CH3OH)

1H-NMR (DMSO-d6): δ br12.62 (USS, 1H, COOH); of 8.25 (d, 1H, CONH, J=8 Hz), of 7.75 (d, 3H, NH3+); to 7.25 (d, 2H, J=8 Hz); 7,06 (d, 2H, J=8 Hz); 4,15 (m, 1H); 3,70 (m, 1H); 2.63 in (m, 2H); of 2.38 (d, 2H, J=7 Hz); 1,92-2,78 (m, 1H); 1.70 to to 1.38 (m, 4H); to 1.35 (d, 3H, J=7 Hz); of 1.20 (m, 2H); to 0.92 (d, 6N, J=7 Hz).

Example 16

(R)-2-(4-isobutylphenyl)-N-[(N'-methyl,N'-2-hydroxyethyl)aminoethoxy]propionamide

A solution of (R)-2-(4-isobutylphenyl)Propionaldehyde (0,42 g; 1,875 mmol) in CH2Cl2(10 ml) is slowly added dropwise to a solution of 0.85 g (3.75 mmol)of 2-(aminooxy)-N-methyl-N-(2-hydroxyethyl)ethylamine in CH 2Cl2(10 ml) at 25°C. the Mixture is allowed to mix at room temperature for 3 h and then diluted with H2O (10 ml). Two phases are then shaken and the organic phase is separated, washed with water (5 ml), dried over Na2SO4and evaporated, getting 0,59 g (1,43 mmol) of (R)-2-(4-isobutylphenyl)-N-2-[(N'-methyl,N'-2-hydroxyethyl)aminoethoxy]propionamide in the form of oil.

[α]D=-35 (c=1; CH3OH).

1H-NMR (CDCl3): δ 7,25 (m, 4H); 6,15 (USS, 1H, CONH); of 4.67 (t, 2H, J=7 Hz), 3,40 (m, 2H); to 2.75 (t, 2H, J=7 Hz); to 2.55 (d, 2H, J=7 Hz); 2,35 (USS, 1H, HE); to 2.42 (t, 2H, J=7 Hz); of 2.21 (s, 3H); 1,95 (m, 1H); of 1.53 (d, 3H, J=7 Hz); 1,00 (d, 6N, J=7 Hz).

Example 17

R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butynyl]propionamide

R(-)-ibuprofen (0.34 g; of 1.65 mmol) dissolved in dry CH2Cl2; add DCC (0,37 g; 1.8 mmol) and HOBZ (0.24 g; 1.78 mmol) and the solution is kept at room temperature under stirring for 3 hours the solution was added N,N-dimethylbutan-2-yl-1,4-diamine (0.2 g; 1.78 mmol)dissolved in dry CH2Cl2(2 ml)and the resulting mixture is stirred over night. After 18 h DCU was filtered and the filtrate is diluted with CH2Cl2and washed with a saturated solution of NaHCO3(2×10 ml), water (2×10 ml) and saturated salt solution, dried over Na2SO4and evaporated in vacuum, obtaining red oily crude residue. Subsequent purification with flash chromatography gives R(-)-2-[(4'-is tbutyl)phenyl]-N-[4-(dimethylamino)-2-butynyl]propionamide in the form of a yellow oil (0,347; 1,155 mmol).

[α]D=+4,4 (c=0.5; CH3OH)

1H-NMR (CDCl3): δ 7,15-7,10 (m, 2H); 7,09-7,05 (m, 2H); 5,45 (USS, 1H, CONH); of 4.05 (m, 2H), 3,55 (m, 1H); 3.15 in (s, 2H); 2,47 (d, 2H, J=7 Hz); 2,22 (C, 6N); of 1.85 (m, 1H); to 1.48 (d, 3H, J=7 Hz); of 0.91 (d, 6N, J=7 Hz).

Example 18

R-Z-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butenyl]propionamide

R-2-[(4'-isobutyl)phenyl]-N-[4-dimethylamino-2-butynyl]propionamide in example 17 (0.08 g; 0.27 mmol) dissolved in absolute EtOH (5 ml) and add 5% palladium on calcium carbonate (catalyst Lindlar'a; 0.08 g). The mixture hydronaut at atmospheric pressure and room temperature for 2 h, then filtered through a loose layer of celite. A dense precipitate on the filter is very washed with EtOH, the filtrate is evaporated in vacuum, obtaining pure R-Z-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butenyl]propionamide in the form of a light yellow oil (0.07 g; 0.23 mmol).

[α]D=-26,5 (c=1,1; CH3OH)

1H-NMR (CDCl3): δ 7,20 for 7.12 (d, 2H, J=8 Hz), 7,10-7,05 (d, 2H, J=8 Hz); 5,95 (USS, 1H, CONH); 5,67-of 5.55 (m, 2H); 3,93-of 3.85 (m, 2H); 5,02 (m, 1H); 3,05 (d, 2H, J=8 Hz); 2,47 (d, 2H, J=7 Hz); 2,25 (C, 6N); 1,93 (m, 1H); of 1.55 (d, 3H, J=7 Hz); of 0.95 (d, 6N, J=7 Hz).

Example 19

R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylaminomethyl)phenyl]propionamide

R(-)-Ibuprofen (0.31 g; 1.5 mmol) is dissolved in thionyl chloride (5 ml) and the solution heated to boiling point under reflux for 90 minutes. The complete disappearance of the original carboxylic acid control Studio strobe, flash the Ute on IR; after cooling to room temperature, and separating the solvent additions 1,4-dioxane oily residue was diluted with dry DMF (5 ml) and added dropwise to a stirred solution of 4-(N,N-dimethylaminomethyl)aniline (0.27 g; 1.8 mmol) in dry DMF (3 ml) at room temperature. The mixed solution is kept during the night; the solvent is evaporated in vacuo and the residue purified flash chromatography, receiving R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylaminomethyl)phenyl]propionamide in the form of a light yellow oil (0,406 g; 1.2 mmol).

[α]D=-98 (c=1; CH3OH)

1H-NMR (CDCl3): δ 7,40-to 7.18 (m, N); of 3.75 (m, 1H); 3,47 (s, 2H); 2.50 each (d, 2H, J=7 Hz); 2,17 (C, 6N); 1,95 (m, 1H); and 1.56 (d, 3H, J=7 Hz); 0,94 (d, 6N, J=7 Hz).

Following the same methodology, receive R-2-[4-isobutyl)phenyl]-N-[4-(dimethylamino)phenyl]propionamide.

[α]D=-131 (c=0,25; CH3OH)

1H-NMR (CDCl3): δ 7,28-7,25 (m, 4H); 7,22-to 7.15 (m, 2H); 6,83-6,79 (USS, 1H, CONH); 6.73 x-6,65 (m, 2H), and 3.72 (m, 1H); 2,80 (C, 6N); 2,48 (d, 2H, J=7 Hz); of 1.85 (m, 1H); of 1.52 (d, 3H, J=7 Hz); 0,97 (d, 6N, J=7 Hz).

Table 1
ExampleStructure% Inhibition of IL-8-induced (10 ng/ml) chemotaxis of PMNs% Inhibition Sa-induced (1 ng/ml) chemotaxis of PMNs
(R),(S')-2-(4'-isobutylphenyl)-N-(1-carboxy-5-aminopentyl)propion Megadroid 10-8M

5±8
10-5M

49±3
Sodium salt of (S'),(R)-2-(4-isobutylphenyl)-N-[1-carboxy-4-(1-piperidinyl)butyl]propionamide56±933±15
(R)-2-(4-isobutylphenyl)-N-(2-dimethylaminoethyl)propionohydroxamic56±1362±12
(R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionohydroxamic51±1565±14
(R)-2-(4-isobutylphenyl)-N-(3-aminopropyl)propionohydroxamic2±784±8
(R)-2-(4-isobutylphenyl)-N-(4-dimethylaminomethyl)propionohydroxamic34±655±8
(R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionohydroxamic4±948±8
(R)-2-(4-isobutylphenyl)-N-(Exo-8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)propionohydroxamic 3±857±6
(R)-2-(4-isobutylphenyl)-N-3-(N-morpholinylmethyl)propionohydroxamic55±1224±11
(R)-2-(4-isobutylphenyl)-N-3-(1-piperidinylmethyl)propionohydroxamic46±876±6
(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminocarbonylmethyl] propionohydroxamic31±668±4
(R)-2-(3-isopropylphenyl)-N-3-(dimethylaminopropyl)propionamide48±2

(C=10-6M)
42±18
(R)-2-(3-isopropylphenyl)-N-3-(dimethylaminopropyl)propionamide5±642±18
(R)-2-(3-benzoylphenyl)-N-3-(dimethylaminopropyl)propionamide53±856±2
(R)-2-[2-(2,6-dichlorophenylamino)phenyl]-N-3-(dimethylaminopropyl)propionamide58±5

(C=10-6M)
41±2
(R)-2-[2-(2,6-di is hlorfeniramina)phenyl]-N-3-(dimethylaminopropyl)propionamide 1±1341±2

Experimental data in vivo in models of hypersensitivity reactions of the delayed type (RGST) and liver damage as a result of ischemia/reperfusion (I/R)

(R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionamide, (R)-2-(4-bromophenyl)-N-(1-methylpiperidin-4-yl)propionamide and (R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)-propionamide investigated in various animal models against damage RGST and I/R. These models are respectively the representatives of inflammatory diseases such as psoriasis and liver damage in the result of postischemic reperfusion.

Experimental example 1

(R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionamide investigated in the mouse model RGST using two different Aptana (DNFB-fluoro-2,4-dinitrobenzene and oxazole1,2) at a dose of 30 mg/kg (treatment: subcutaneously for 8 h prior to the introduction; for 30 minutes before injection; after 8 h, 16 h after injection of the substance causing disease).

The effectiveness of the model GST was estimated as 24 h after injection provoking substances methylpyrrolidinyl method (LRO), the assessment of the weight of the ear mouse and oedema (extramaze fluid Evans blue). Moreover, (R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionamide tested in a rat model of I/R 3the liver, with two different doses of 13 mg/kg and 6.5 mg/kg (treatment: subcutaneously for 12 h before ischemia; intravenous 5 before reperfusion and subcutaneously 2 h after reperfusion), as will be shown below.

Effectiveness against I/R liver injury was assessed by measuring the infiltration polymorphically neutrophils (PMN) liver (MPO study and calculation histological PMN) and evaluation of hepatocellular necrosis (levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in the serum). Results efficiency (R)-2-(4-isobutylphenyl)-N-(1-methylpiperidin-4-yl)propionamide on the above models are shown in Table 2.

Experimental example 2

(R)-2-(4-bromophenyl)-N-(1-methylpiperidin-4-yl)propionamide researched on the described experimental model RGST at a dose of 30 mg/kg (treatment: subcutaneously for 8 h prior to the introduction; for 30 minutes before injection; after 8 h, 16 h after injection of the substance causing disease), using as Aptana DNFB. It was found that (R)-2-(4-bromophenyl)-N-(1-methylpiperidin-4-yl)propionamide effective in preventing PMN infiltration (-50% MPO levels) and in reducing the increased weight of the ear (-30%).

Experimental example 3

(R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide tested in a rat model of I/R3liver in two different doses of 13 mg/kg, 6.5 mg/kg (treatment: subcutaneously for 12 hours before Isami is, intravenous 5 before reperfusion, subcutaneously 2 h after reperfusion). The results of the experiments are presented in Table 3.

Table 2
DTH - DNFB1DTH-oxazoleI/R3liver
Eden (extramaze Evans blue): -50%

The weight of the ear: -40%

The LRO: -70%
Eden (extramaze Evans blue): -70%

The weight of the ear: -50%

The LRO: -80%
(1 hour of ischemia and 6 h of reperfusion)
DoseALTASTLROPMNs/hpf
13 (mg/kg)-80%-63%-36%-67%
6.5 (mg/kg)-70%-68%-30%
(1 hour ischemia/12 h reperfusion)
13 (mg/kg)-52%-40%-29%-33%
6.5 (mg/kg)-50%-50%-17%

Table 3
I/R liver (1 hour ischemia/6 hour reperfusion)
DoseASTPMNs/hpf
13 (mg/kg)-56%-40%-40%
6.5 (mg/kg)-76%-70%
(1 hour ischemia/12 h reperfusion)
13 (mg/kg)-20%-47%
6.5 (mg/kg)-60%-70%-30%

Links:

1) Dilulio NA et al. Groα-mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity. 1999. Eur J Immunol 29, 3485-3495.

2) Grabbe S et al. Beta2 integrins are required for skin homing of primed T cells but not for priming naive T cells. 2002. J Clin Invest 109, 183-192.

3) Bertini et. al 2004, PNAS, 101, 11791-11796.

Example pharmaceutical compositions.

The preparation for injection

In the solution containing 100 g of the compound obtained in example 8, 5 g of dinitrigenoxide in 3 l of double-distilled water was adjusted to pH 6.5 using 2n hydrochloric acid, the solution is sterile filtered, poured into glass containers for preparations for injection, lyophilizer in sterile sterile conditions and sealed. Each glass container of medicine for injection contains 5 mg of biologically active substances.

Tablets

A mixture of 1 kg of biologically active substance (compound of example 10), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of stearate is Agnes thoroughly mixed and pressed into tablets so each tablet contains 10 mg of biologically active substances.

1. Omega-aminoethylamide (R)-2-arylpropionic acid of the formula (I)

and their pharmaceutically acceptable salt,

where Ar denotes phenyl, substituted by a group selected from isobutyl, benzoyl, isopropyl styrene, penttila, (2,6-dichlorophenyl)amino, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl;

R means hydrogen;

X means:

linear C1-C6-alkylen,4-C6-albaniles,4-C6-akinyan, optionally substituted by a group of CO2R3where R3denotes hydrogen;

(CH2)m-B-(CH2)ngroup, where In denotes an oxygen atom, m is zero and n means an integer of 2; or means a group CONH, m means an integer 1, and n means an integer 2;

or X together with the nitrogen atom omega-amino group, with which it is associated, and with a group R1forms a non-aromatic nitrogen-containing 6-membered heterocyclic, monocyclic nucleus, in which the nitrogen atom has a Deputy Rc, where Rc means1-C4-alkyl, or X is phenyl or phenylmethylene group;

R1and R2independently selected from the group comprising: hydrogen, Lina is hydrated With 1-C4-alkyl, hydroxy-C2-C3-alkyl;

or R1and R2together with the N atom to which they are bound, form a nitrogen-containing 6-membered heterocyclic nucleus of the formula (II)

where Y represents CH2, O, S or a group N-Rc, receiving the above-mentioned values, and p denotes an integer of 2;

or R1accept above values, R2means a group of the formula (III)

where Rameans hydrogen and Rbmeans hydrogen;

or Raand Rbtogether with the nitrogen atom to which they are attached, form a 5-6-membered heterocyclic nucleus, monocyclic the kernel.

2. Compounds according to claim 1, where Ar is chosen from the group comprising 4-isobutylphenyl, 3-benzoylphenyl.

3. Compounds according to claim 1, where Ar denotes phenyl, 3-substituted by groups selected from the group comprising isopropyl, Penta-3-yl, α-methylbenzyl.

4. Compounds according to claim 1, where Ar is 2-(2,6-dichlorophenylamino)phenyl.

5. Compounds according to any one of claims 1 to 4, where R is hydrogen, X is a linear alkylene, optionally substituted C1group - CO2R3taking the above value; or X, together with the N atom omega-amino group forms a nitrogen-containing cycloaliphatic nucleus selected from 1-methyl-PIP is ridin-4-yl or 1.5-tropan-3-yl.

6. Compounds according to any one of claims 1 to 5, where NR1R2means the group of NH2, dimethylamino, diethylamino, diisopropylamino, 1-piperidinyl, 4-morpholyl, 4-thiomorpholine, or R1and R2together form a residue of guanidine, aminoguanidine, hydroxyguanidine, 2-amino-3,4,5,6-tetrahydropyrimidine.

7. Compounds according to any one of claims 1 to 6, selected from the group including:

(R)-2-[(4-isobutyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(4-dimethylaminomethyl)propionamide hydrochloride;

(R)-2-[(4-isobutyl)phenyl]-N-(3-N-morpholinopropan)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(2-dimethylaminoethyl)propionamide;

(R)-2-[(4-isobutyl)phenyl)propionyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]propionamide;

(R)-N-(Exo-8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-2-[(4-isobutylphenyl)propionate;

(R)-2-[(4-isobutyl)phenyl]-N-(3-N-thiomorpholine)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[4-(N'-methyl)piperidinyl]propionamide hydrochloride;

(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-2-dimethylaminoethyl)propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-[(1-carboxy-4-piperidine-1-yl)butyl]propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-4-aminobutyl)propionamide;

(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)amino-carbonylmethyl]propionamide hydrochloride;

2-(2,6-dichlorophenyl the Mino)phenyl-N-(3-dimethylaminopropyl)propionamide;

(R),(R',S')-3-[3-(α-methyl)benzyl]phenyl-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(3-isopropyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[3-(Penta-3-yl)phenyl]-N-(3-dimethylaminopropyl)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-(3-guanidine)propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[(3-hydroxyguanidine)propyl]-propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[(3-aminoguanidine)propyl]-propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[3-(2-amino-2-imidazolyl)propyl]-propionamide;

(R)-2-[(4-isobutyl)phenyl]-N-[N-methyl-N-(2-hydroxyethyl)-aminoethoxy]propionamide;

(R),(S')-2-[(4-isobutyl)phenyl]-N-[1-carboxy-5-aminopentyl]-propionamide.

8. Compounds according to claim 7, selected from the group comprising (R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide hydrochloride.

9. Compounds according to claim 7, selected from the group comprising (R)-2-(4-isobutylphenyl)-N-3-(1-piperidinylmethyl)-propionamide hydrochloride.

10. Compounds according to any one of claims 1 to 6, where R1and R2mean group other than hydrogen.

11. Connection of claim 10, where x is the linear C2-C4-alkylen.

12. Omega-aminoethylamide (R)-2-arylpropionic acid according to claim 1, suitable as drugs having inhibitory activity against both Sa-induced chemotaxis of polymorphonuclear leukocytes and monocyte is in, and induced interleukin-8 chemotaxis of polymorphonuclear leukocytes.

13. Omega-aminoethylamide (R)-2-arylpropionic acid PP and 11 are suitable as inhibitors Sa-induced chemotaxis of polymorphonuclear leukocytes and monocytes and induced interleukin-8 chemotaxis of polymorphonuclear leukocytes.

14. The method of obtaining omega-aminoalkylation (R)-2-arylpropionic acid of the formula (I) according to claim 1

where Ar, X, R, R1and R2take the values specified in claim 1, including the interaction of the activated form R-2-arylpropionic acid of formula (V) with an amine of formula (VI)

where AT denotes the residue activates carboxypropyl R-2-arylpropionic acids;

provided that Ar is not substituted by a residue of dihydropyrrole.

15. Inhibitors Sa-induced chemotaxis of polymorphonuclear leukocytes and monocytes, representing the connection of omega-aminoethylamide (R)-2-arylpropionic acid of the formula (I)

and their pharmaceutically acceptable salt,

where Ar denotes phenyl, substituted by a group selected from isobutyl, benzoyl, isopropyl styrene, penttila, (2,6-dichlorophenyl)amino, α-hydroxyethyl, α-hydroxybenzyl, α-mative the ZIL and α -hydroxy-α-methylbenzyl;

R means hydrogen;

X is the linear C1-C6-alkylen,4-C6-albaniles,4-C6-akinyan, optionally substituted by a group of CO2R3where R3denotes hydrogen; (CH2)m- (CH2)ngroup, where In denotes an oxygen atom, m is zero and n means an integer of 2; or means a group CONH, m means an integer 1, and n means an integer 2;

or X together with the nitrogen atom omega-amino group, with which it is associated, and with a group R1forms a non-aromatic nitrogen-containing 6-membered heterocyclic, monocyclic nucleus, in which the nitrogen atom has a Deputy Rc, where Rc means1-C4-alkyl, or X is phenyl or phenylmethylene group;

R1and R2independently selected from the group comprising: hydrogen, linear C1-C4-alkyl, hydroxy-C2-C3-alkyl;

or R1and R2together with the N atom to which they are bound, form a nitrogen-containing 6-membered heterocyclic nucleus of the formula (II)

where Y represents CH2, O, S or a group N-Rc, receiving the above-mentioned values, and p denotes an integer of 2;

or R1accept above values, R2means the group of four who uly (III)

where Rameans hydrogen and Rbmeans hydrogen;

or Raand Rbtogether with the nitrogen atom to which they are attached, form a 5-6-membered heterocyclic, monocyclic the kernel.

16. Inhibitors indicated in paragraph 15 are suitable for the treatment of psoriasis, bladderworts and pemphigoid, rheumatoid arthritis, chronic inflammatory bowel pathologies, including ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary disorders, glomerulonephritis.

17. Inhibitors indicated in paragraph 15, for use for the prevention and treatment of disorders caused by ischemia and reperfusion.

18. Pharmaceutical composition having inhibitory activity against the chemotaxis of polymorphonuclear leukocytes and monocytes containing compound according to any one of claims 1 to 11 and 15 in a mixture with a suitable carrier.



 

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< / BR>
where R1, R2, R3, R4, R5and "n" and "m" have the following meanings:

R1, R2denote hydrogen, linear or branched (C1-C8)-alkyl;

(C3-C8-cycloalkyl as cyclohexyl; phenyl, which can be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano group, nitro group, trifluoromethyl or acylamino group; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and a phenyl ring, which may be single or twofold substituted stands, methoxy group, halogen, nitro group, cyano group or acylamino-group;

< / BR>
denotes a morpholine or piperidine which may be substituted by one or twice (C1-C2)-alkyl group or a group

< / BR>
where R6may denote H, NHCО2CH2CH3;

R3does

< / BR>
represents piperidine or morpholine

n = 1-5;

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< / BR>
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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

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EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

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< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

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< / BR>
where a IS-O-CmH2m-X1-

or denotes the formula (II)

,

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or formula (III)

< / BR>
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< / BR>
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The invention relates to new compounds with a structure similar to the structure of the 15-doxicillin
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