R-2-(aminoaryl)-propionic acid amides for using in prevention of leukocyte activation

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

 

This invention relates to Amida R-2-aminoalkylphosphonic acids and pharmaceutical compositions containing them, which can be used for preventing and inhibiting recruitment and activation of leukocytes and for the treatment of pathologies directly dependent on the specified activation.

PRIOR art

For many physiological processes requires that the cells were in close contact with other populations of cells and/or extracellular matrices. These processes of adhesion, however, necessary for the activation, migration, proliferation and differentiation of cells. Several families of cell adhesion molecules (ICA), which play a significant role in normal and pathophysiological processes that mediate cell-cell-matrix interaction.

The process of cell adhesion is essential for the activation of neutrophils, accompanied by release of cytokines, which include IL-8 and MCP-1, which allow the amplification of the inflammatory process (see: C.D. Huang et al., Chang Keng J. Hsueh, 22, 392, 1999; B.Walzog et al., FASEB J., 13, 1855, 1999).

Chemokines, in turn, differ in their effect on other cytokines cellular selectivity of their action: each of them regulates the migration and function of single cells in a specific way. Thus, while MSR influences and directs the movement of monocytes, IL-8 performs the crucial role of neutrophilic chemoreflexes factor.

This is confirmed by the presence of high concentrations of IL-8 in the areas of inflammation and in the surrounding liquid, quantified during many acute pathologies mediated by neutrophils, to prevent serious tissue damage and reduced infiltration of neutrophils observed after injection of antibodies to IL-8 in experiments on animal models which are shown dependent neutrophil pathology (see: Yang X.D., et al, J. Leukoc. Biol. 66, 401, 1999). Typical clinical situations where activation of neutrophils plays a predominant pathological role, are lesions that appear in the recovery of cerebral blood flow (Stanimirovic D. and K. Satoh, Brain Pathol., 10, 113, 2000) and result in ischemia and restore blood flow in the myocardium.

These observations confirmed the hypothesis that IL-8 is the main mediator of tissue damage caused by neutrophils, to such an extent that in this way it is possible to offer interleukin-8 as the optimal target for therapeutic intervention in dependent neutrophil pathologies (N. Mukaida et al., Inflammation Res. 47 (Suppl. 3) S151, 1998). For this reason, as an alternative use of anti-IL-8 antibody substances of low molecular weight could be of great interest is for the clinic to be extremely useful, moreover, these substances can be embedded in inter - and intracellular transmission system signal and to inhibit the migration of human neutrophils stimulated by IL-8 and similar substances (GRO-α,β,γ; ENA-78, NAP-2, GCP-2).

Currently, it is increasingly recognized that it becomes more clearly defines the role that the activation of some kinases and tyrosinekinase plays in the dynamics of the phenomenon dependent IL-8 chemotaxis.

For a long time it was assumed that the activation of some tyrosinekinase is the triggering event of the phenomenon of chemotaxis after that Yasui et al. (J. Immunol. 152, 5922, 1994) demonstrated that complete inhibition of chemotaxis of neutrophils (PMN) followed by suppression of the activity of these enzymes.

Recently discovered that a sharp decline in the chemotaxis of neutrophils caused near hemodynamically factors observed in genetically modified rats defective in the enzyme phosphoinositide-3-kinase (RK, Hirsch et al., Science, 287, 1049, 2000; Sasaki et al., Science, 287, 1040, 2000), allowed to characterize this enzyme as a leading kinase - primus movens sequential cascade of events and to establish itself in the assumption about the election and defining roles of enzymatic processes phosphorylation.

When the phenomenon of chemotaxis induced by interleukin-8 in neutrophils, in addition to FOS who inositide-3-kinase, equally important, apparently, plays Rock (rich in Proline of tyrosinekinase), the activation of which is essential for the development of related processes of cell adhesion. In turn, the activation process Ruk induced IL-8 in neutrophils is dependent on RC process, which, apparently, is localized in the cell membrane, designed for focal adhesion (Clark et al., 268, 233, 1995; Avraham et al., Blood, 88, 417, 1996) through direct contact with sitestructure proteins involved in the phenomenon of adhesion (for example, vinculin, α-actin etc).

Also in the light of recent discoveries believe that therapeutic potential of new molecules with low molecular weight, designed to prevent the phenomenon dependent IL-8 chemotaxis, increased by some suppressive activity against factors that cause adhesion, and/or antagonistic activity against some integrins, such as very late antigen 4 (VLA-4), LPAM-1, to block their binding with their ligands in order to practically prevent ab initio beginning of this cascade of events, beginning with the intracellular processes of adhesion, turn into activation of neutrophils.

Have recently been described N-arylsulfonamides and amides R-2-arylpropionic acid (WO 00/24710 and PCT/ER/01285 matched with the public), which are characterized by the selectivity of their suppressive activity stimulated IL-8 chemotaxis of human neutrophils. In the course of research aimed at the elucidation of the molecular mechanisms of action, it has been observed that they are very high (70-80% suppression), dose-dependent inhibitory activity against activity Ruk-tyrosine kinase concentrations, in the range from 10-7up to 10-8M, other than concentrations that are effective suppression-dependent IL-8 chemotaxis.

In addition, the activity of these amides and N-arylsulfonamides R-2-arylpropionic acids, apparently, is completely independent of their participation in the suppression (SOH-1 and/or MOR-2) - dependent cyclooxygenase inflammatory processes.

Accumulated data that inhibition of the synthesis of prostaglandins (PG) (S)-enantiomers of 2-arylpropionic acids and some 2-alloxysnada acids may for a long period to give a negative knee-jerk reaction on the dynamics of the dependent neutrophil inflammatory process, where the inhibition of PG synthesis and, therefore, PGE2 removes the factor of regulation of endogenous synthesis of TNF-α. Accordingly, when compared with the same IL-8 TNF-α may contribute, together with the cytokines IL-6 and IL-1 and adhesion molecules (Eselectin, ICAM-1 and C-reactive protein) deterioration of nature and the severity of the tissue damage during acute myocardial infarction (R.Pudil et al., Clin. Chim. Acta, 280, 127, 1999).

Description of the INVENTION

It was found that amides of (R)-2-phenylpropionic acids bearing nitrogen-containing substituents on the phenyl group, possess unexpected properties suppression induced IL-8 chemotaxis. Examples of such substituents are alkylamino or dialkylamino and nitrogen-containing heterocycles. The compounds of this invention exhibit enhanced solubility in water and is optimized pharmacokinetic properties compared with other inorganic salts, such as described in PCT/ER/01285.

Stereochemistry, electronic, polarization and spatial effects of the substituents at the nitrogen atom contribute to the modulation of the properties of suppression induced IL-8 chemotaxis.

DETAILED description of the INVENTION

In the following paragraphs provides definitions for the most important chemical groups that exist in the structures of the compounds according to this invention and intended for use throughout the description and in the claims, unless specified to the specific values of the broader definition.

"C1-C3-Alkyl" or "C1-C5-alkyl" refers to monovalent alkyl groups having from 1 to 3 or 1 to 5 carbon atoms. An example of the mi for these terms are such groups, as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

"C3-C7-Cycloalkyl" refers to cycloalkyl groups having from 3 to 7 carbon atoms. Examples for these terms are groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples3-C7-cycloalkyl-C1-C3-alkyl groups are cyclopropylmethyl or cyclopentylmethyl.

"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or polycondensation ring (e.g., naphthyl). Preferred arily include phenyl, biphenyl, naphthyl, phenanthrene and the like.

"Substituted or unsubstituted": unless otherwise indicated for a specific definition of a specific substituent, the above groups, like "alkyl", "cycloalkyl", "aryl" groups, etc. may be optionally substituted by 1 to 5 substituents selected from the group consisting of "C1-C3-alkyl", "C1-C3-alkylaryl", "C1-C3-alkylglycerol", primary, secondary or tertiary amino groups or Quaternary ammonium groups, "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl", "heteroa the La", carboxyl, cyano, halogen, hydroxy, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, dialkoxy, trihalomethyl and the like. In this invention the "substitution" means that included the situation where adjacent substituents are closing ring, in particular when this involves neighboring functional substituents, forming thus, for example, lactams, lactones, cyclic anhydrides or cycloalkanes, and acetals, thioacetals, amirali formed by the closure ring, for example, when trying to get the protective group.

"Pharmaceutically acceptable salts" refers to salts or complexes defined below, compounds of formula I, which retain the desired biological activity. Examples of such salts include, but are not limited to, salts of accession acids, 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, dikalova acid, pamula acid, alginic acid, polyglutamine acid, on calendulauda acid, naphthalenedisulfonic acid and polygalacturonase acid. These compounds can also be introduced in the form of pharmaceutically acceptable Quaternary salts known in the art. Examples of salts include organic bases, such as tromethamine, L-lysine, L-arginine, and the like.

This invention relates also to Amida (R)-enantiomers of 2-arylpropionic acids of the formula (1):

and their pharmaceutically acceptable salts, where

q is zero or an integer equal to 1;

Ph is fenelonov group associated with the group -(CH2)qIn position 2, 3 or 4 and optionally substituted in other positions by one or more Deputy, the same or different, selected from C1-C3-alkyl, halogen, C1-C3-alkoxy, hydroxy, SH, C1-C3-alkylthio, nitro, halogenoalkane.

And represents:

- N-C1-C5-alkylamino, N,N-C1-C5-dialkylamino, N-C1-C8-alkanoyl(cycloalkenyl, arylalkyl)-N-C1-C5-alkylamino;

is a saturated or unsaturated nitrogen-containing 5 to 7-membered heterocyclic ring;

- the remainder of the formula (2A):

where Rwithrepresents hydrogen, C1-C3-Ala is l or balance With 1-C3-alanovoy acids;

R represents:

- N; -SO2-CH3;1-C3the alkyl group of the formula-CH2-CH2-X-(CH2-CH2O)n-R, where R represents H, methyl, ethyl, isopropyl;

-CH2CO2R1where R1represents N or C1-C3; n is an integer from 0 to 5,

X represents O or S;

group of the formula (3)

-(CH2)m-F(3)

- where, when m is an integer from 2 to 3, f represents an unsubstituted or substituted phenylene, as stated above, 2-(1-methylpyrrolidinyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl or group-NRaRb, where each of Ra and Rb, identical or different, represent a1-C5is alkyl or hydroxyalkyl-(CH2)miIs HE, where mian integer from 2 to 3, or Ra and Rb together with the N atom to which they are linked, form a heterocyclic ring comprising from 3-7 members; when m is zero, f is selected from the group comprising 2 - or 4-pyridyl, 2 - or 4-pyrimidinyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 1-1,2,4-thiadiazolyl, 3-1,2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl, 2-1,3-thiazolidine, 2-1,3-thiazolyl, 3-isoxazolyl, dihydroisoxazole-4-yl, 5-methylisoxazol-4-yl, 2-imidazolyl,imidazol-4-yl-5-carboxamid, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazole, 7-azaindole-3-yl, indol-3-yl, 2 - or 3 - or 4-chinolin;

- balance α-amino acids selected from the group comprising alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, p-forfinally, tyrosine, biphenylene, 2'-methoxybiphenyl-alanine, tryptophan, 7-attrition, histidine, S-methylcysteine, carboxymethylcysteine, methionine, O-medicein, atillery, glycine, phenyl - or p-florfenicol;

- acid residue selected from the group including β-alanine, γ-aminobutyric, δ-aminovaleric, CIS-4-aminocyclohexane-carboxylic, TRANS-4-aminomethylenemalonate and 3-amino-1,5-pentadiene acid;

- the remainder of the formula (3A)

where In represents H; linear or branched C1-C5-alkyl; (CH2)ni-NH2; -(CH2)ni-NH-tert-butoxycarbonyl; -(CH2)ni-NH-benzyloxycarbonyl; (CH2)ni-CO2N, where nian integer between 1 and 3; benzyl; p-terbisil; p-phenylbenzyl; n-(2-methoxyphenyl)benzyl; CH2O-C2H5; -CH2-S-CH3; -CH2-S-CH2-CO2N; indolyl-3-methyl; 7-azaindole-3-methyl;

provided that when q is zero, R is SO2CH3and Ph represents a 3-chloro-1,4-phenylene, a is a group which, non-1-2,5-dihydropyrimidine.

Last connection, where a represents 1-2,5-dihydropyrimidine described in WO 00/24710.

Salts of compounds of formula (1) with pharmaceutically acceptable bases and acids are the next object of the present invention.

The Ph preferably is associated with the group (-CH2)q-And at position 3, or more preferably in position 4. The Ph preferably is 1,4-phenylene, unsubstituted or substituted in position 3, for example chlorine.

And preferably is N,N-dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino, N-acetyl-N-methylamino, N-pivaloyl-N-ethylamino or nitrogen-containing ring selected from 1-pyrrolidine, 1-2,5-dihydropyrimidine (or 1-3-pyrroline), 1-pyrrole, 1-piperidino, 1-piperazine derivatives of 4-unsubstituted or 4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzhydryl or phenyl)-4-research, 4-3 A 5-dimethylmorpholine, 4-thiomorpholine.

Examples 3-7-membered heterocyclic rings formed-NRaRbthe group include 4-morpholino, 1-piperidino, 1-piperazine derivatives and 4-substituted-1-piperazine (4-methyl, 4-benzyl, 4-2-phenylethyl).

Examples of compounds of this invention are:

R-N-2-[4-(pyrrolidin-1'-yl)were]propionylthiocholine;

R-N-2-[4-(4'-benzylpiperazine-1'-illuminometer)phenyl]propionylthiocholine;

(R,S')-2-[3'-chloro-4-(timoho the Jn-4-yl)phenyl]-N-(2-carboxyethyl)propionamide;

(R)-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-(2-methoxycarbonylethyl)propionamide;

(R,S')-2-[(3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-[1-(3,5-dimethylbenzenesulfonyl)ethyl-2-(3-indolyl)]propionamide;

(R,S')-2-[(3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-[1-(benzyloxycarbonyl)ethyl-2-(4'-forfinal)]propionamide;

R-2-[3-chloro-4-(3-pyrrolidin-1-yl)phenyl]propionamide;

(R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(N',N'-dimethylaminopropyl)propionamide;

(R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(bicarboxylic)propionamide;

R(-)-2-[3-chloro-4-(piperidine-1-yl)phenyl]-N-(2"-hydroxyethoxyethyl)propionamide;

(R)-2-(4-morpholinyl)-N-(4'-pyrimidinyl)propionamide;

(R)-2-[4-((N-ethyl-N-China-2'-ylmethylamino)methyl)phenyl]-N-(2'-allyloxycarbonyl)propionamide;

(R,R')-2-[3-chloro-4-(piperidine-1-yl)]-N-[1'-methyl-2'-(2"-hydroxyethoxy)ethyl]propionamide;

(R)-2-(4-morpholinyl)-N-(4'-pyrimidinyl)propionamide;

R-2-[4-((N-ethyl-N-China-2'-ylmethylamino)methyl)phenyl)]-N-(4'-pyridyl)propionamide;

R-2-[3-chloro-4-(pyrrolidin-1-yl)-phenyl)]-N-(2'-pyridyl)-propionamide;

R-2-[3-chloro-4-(3-pyrrolin-1-yl)-phenyl]-N-(4'-pyridyl)-propionamide;

R-2-[3-chloro-4-(1H-pyrrol-1-yl)-phenyl]-N-(4'-pyridyl)-propionamide;

R-2-[3-chloro-4-(morpholine-4-yl)-phenyl]-N-(1,3-thiazol-2-yl)-propionamide;

R-2-[4-(morpholine-4-illuminometer)-phenyl]-N-(pyrazin-2-yl)-propionamide;

R-2-[3-chloro-4-(3'-pyrrolin-1-yl)-phenyl]-N-(4'-pyrimidinyl)-propionamide;

R-2-[4-(Pyrrhus is lidin-1-ylmethyl)-phenyl]-N-(4'-pyridyl)propionamide;

R-2-[4-(3-pyrrolin-1-yl)-phenyl]-N-(4'-pyridylethyl)propionamide;

R-2-(4-piperidine-1-ylphenyl]-N-(1-imidazolyl)-propionamide;

R-2-[3-chloro-4-(pyrrolidin-1-yl)-phenyl]-N-(2'-pyridyl)-propionamide;

R-2-[3-chloro-4-(3-pyrrolin-1-yl)-phenyl]-N-(4'-pyridyl)-propionamide;

R-2-[3-chloro-4-(1H-pyrrol-1-yl)-phenyl]-N-(4'-pyridyl)-propionamide;

R-2-[3-chloro-4-(morpholine-4-yl)-phenyl]-N-(1,3-thiazol-2-yl)-propionamide;

R-2-[4-(morpholine-4-illuminometer)-phenyl]-N-(pyrazin-2-yl)-propionamide;

R-2-[3-chloro-4-(3'-pyrrolin-1-yl)-phenyl]-N-(4'-pyrimidinyl)propionamide;

R-2-[4-(pyrrolidin-1-ylmethyl)-phenyl]-N-(4'-pyridyl)-propionamide;

R-2-[4-(3'-pyrrolin-1-yl)-phenyl]-N-(4'-pyridylethyl)-propionamide;

R-2-[4-piperidine-1-ylphenyl]-N-(1-imidazolyl)-propionamide;

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)-phenyl]-propionylthiocholine;

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)-phenyl]-N-(2-carboxyethyl)propionamide;

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)-phenyl]-propionamide.

Especially preferred are compounds of formula (1), where fenelonov group Ph is unsubstituted 1-4-phenylene or p-3 monosubstituted or C-3,C-5 disubstituted-phenylene.

Preferred are also the compounds of formula (1), where R is an amino acid residue, such as glycine, aminomalonate, benzyl and p-forbindelsesanalyse, or the remaining one of monocarboxylic or dicarboxylic amino acid is so

Especially preferred are compounds of formula (1), where R is the residue of L-alanine, L-phenylalanine, L-p-pertanyaannya, L-methionine or L-p-(2'-methoxyphenyl)phenylalanine.

Preferred inorganic salts of formula (1) are those in which R represents H, a group-SO2-CH3, polyoxyethylene residue of the formula -(CH2-CH2-Oh)2-R, where R is H, methyl, ethyl, isopropyl or CH2-CO2R1where R1is N or C1-C3-alkyl.

Preferred inorganic salts of formula (1) are those in which R is a Deputy of the formula (3)

(CH2)m-F(3)

where, when m is an integer from 2 to 3, f is a key residue selected from the group: N,N-diethylamino, 4-morpholyl, 1-piperidyl, 1-(4-benzyl)piperazinil, 1-(4-diphenylmethyl)piperazinil, 1-(4-(4',4"-giftgiver)methyl)piperazinil, where m is zero, f is preferably heteroaryl residue, such as 2 - or 4-pyridyl, 2 - or 4-pyrimidinyl, 2-pyrazinyl, 2-1,3-thiazolyl, 2-1,3-thiazolidine, 2-imidazolyl, more preferably 4-pyridyl.

The compounds of this invention defined in the formula (1)obtained using well-known techniques involving the interaction of aktivirovani the second form of the acid of formula (4):

where And and (CH2)qabove, and at is the balance of activating a carboxyl group; with an amine of formula (5):

R-NH2(5)

in precensorship conditions in the presence, if desired, a molar excess of base. Examples of activated forms of the acids of formula (4, at=N) are the corresponding chlorides (al = Cl), imidazoline (at = 1-imidazole), esters with phenols, such as p-NITROPHENOL (at=pNO2-C6H4O-) or activated form, obtained by the reaction in the presence of 1-hydroxybenzotriazole (HOBT) or carbodiimide (such as cyclohexylcarbodiimide).

Primary amines have had the formula (5) R has the meaning indicated above.

The reaction of obtaining the amides of formula (1) is usually carried out at room temperature using conventional proton and aprotic solvents, preferably dehydrated by molecular sieves or mixtures thereof.

These solvents include esters such as ethyl acetate, methyl acetate, ethyl formate, NITRILES, such as acetonitrile, cyclic ethers such as dioxane, tetrahydrofuran, ethyl ether, sulfolan, amides, such as dimethylformamide, formamide; halogenated solvents, such as on Harmattan, aromatic hydrocarbons, such as toluene, chlorobenzene and heteroaromatic hydrocarbons, such as pyridine and picoline.

These reactions can be carried out in the presence of a base. Preferred inorganic bases are carbonates and bicarbonates of alkali and alkaline earth metals such as finely ground potassium carbonate, potassium bicarbonate and carbonates of magnesium and calcium.

If desired, the compounds of formula (1) can be converted into other compounds of formula (1) by removal of protecting groups and/or by selective hydrolysis of the groups of esters. Especially preferred ester group is allyl, tsepliaeva in highly selective conditions, for example, on the basis of the transfer of the allyl group in the molecule of the research, which in the presence of Pd(0) as catalyst acts as a migration tool N and as the nucleophilic acceptor in accordance with the process described in J. Org. Chem., 54, 751, 1989.

And finally, if desired, the compound of formula (1) can be converted into a salt using pharmaceutically acceptable acids or bases.

Examples of pharmaceutically acceptable acids include hydrochloric, sulfuric, nitric, phosphoric acid or mono - or polybasic organic acids such as acetic, benzoic, tartaric, citric, fumaric, small is new, Apple, almond, oxalic acid and malonic acid.

Examples of pharmaceutically acceptable salts are salts with cations of alkali and alkaline earth metals, preferably sodium and magnesium, and salts with organic bases, such as tromethamine, D-glucosamine, lysine, arginine, tetraethylammonium.

R-enantiomers of 2-(aminoaryl)propionic acid of the formula (4A)

(4A)

are well-known compounds, from which the corresponding S-enantiomers differ in that are not effective inhibitors cyclooxygenase enzymes.

From R-2-arylpropionic acids of the formula (4A), where q is equal to zero, especially preferred are the following:

R-2-[4-(2,5-dihydro-1H-pyrrol-1)-phenyl]propionic, R-2-[4-(1H-pyrrol-1)-phenyl]propionic, R-2-[4-(1H-pyrrolidin-1-yl)-phenyl]propionic, R-2-(4-piperidinophenyl]propionic, R-2-(4-morpholinyl]propionic, R-2-(4-thiomorpholine]propionic, R-2-[4-(4'-benzylpiperazine-1'-yl)-phenyl]propionic and 3-chloro-derivative, R-2-[4-(4'-benzhydrylpiperazine-1'-yl)-phenyl]propionic and her 3-chlorinated. All these acids are well known compounds and are obtained using well known methods. Basic guidance on the synthesis and optical resolution of these acids of the formula (4A; q=0) found in the U.S. patents US 3641040; US 399363; US 3997669 and US 4337264. More specifically described in these patents syntheses of derivatives of methyl and ethyl esters of 2-(4-AMINOPHENYL)propionic acid and 2-(3-chloro-4-AMINOPHENYL)propionic acid by reaction with a suitable α,ω-alkanol or alkene, variously substituted, is converted into the desired 1-azacycloheptan or cycloalken.

For example, in the following reaction scheme presents a method of obtaining used in the synthesis of esters of 2-(4-piperazine-1-ylphenyl)propionic acid of the formula (4b):

based on a complex ester of 2-(4-AMINOPHENYL)propionic acid by reaction with bis-(2-chloroethyl)amine of the formula (6), where R4is Vos,1-C3-alkyl, phenyl, benzyl, benzhydryl, 4,4'-diferensial.

From R-2-arylpropionic acids of the formula (4), where q is an integer equal to 1, especially preferred are the following:

R-2-[4-(2,5-dihydro-1H-pyrrol-1-methyl)phenyl]propionic, R-2-[4-(1H-pyrrol-1-methyl)phenyl]propionic, R-2-[4-(1H-pyrrolidin-1-methyl)phenyl]propionic, R-2-[4-(1H-pyrrolidin-3-one-1-ylmethyl)phenyl]propionic, R-2-[4-(piperidine-1-ylmethyl)phenyl]propionic, R-2-(4-piperidine-4-one-1-ylmethylene)propionic, R-2-(4-(morpholine-4-ylmethylene)propionic, 4-(thiomorpholine-4-ylmethyl)phenylpropionate, R-2-[4-(4'-benzylpiperazine-1'-ylmethyl)phenyl)propionic, R-2-[4-(4'-benzhydryl Azin-1'-ylmethyl)phenyl)propionic acid.

Receive them based on conversion of the tert-butyl ester 2-tolylpropan acid in the corresponding Br-methylpropane, which then transform into tert-butyl methyl ether acids of the formula (4A, q=1) by reaction with the desired amine of formula A-H (where a has the value stated above).

Allyl and benzyl ethers αor ω-amino acids are well known commercially available products, or they can be obtained using well-known methods; in obtaining allyl esters, see, for example, H. Waldmann and H. Kunz, Liebigs Ann. Chem., 1712, 1983, J. Org. Chem. 1989, already cited; in obtaining benzyl esters, see, for example, Mac Leod A.M. et al., J. Med. Chem., 37, 1269, 1994.

To assess pharmacological activity of some compounds of this invention of formula (1) used in vitro experiments on human neutrophils (herein below referred to as neutrophils, isolated from heparinised human blood, taken from consenting healthy adult subjects, by precipitation of the dextran according to the method described W.J. Ming et al., J. Immunol., 138, 1469, 1987. Each of the compounds under study, pre-incubated for 10 minutes at a temperature of 37°C. In the chemotaxis experiments, experiments aimed at quantifying what aktivnosti tyrosine kinase, and aimed at quantification of the levels of cytosolic CA2+used human recombinant interleukin-8 (rhIL-8, Pepro Tech): lyophilized protein was dissolved in (HBSS) SSR (balanced salt Hanks solution) at a concentration of 100 μg/ml and then diluted to concentrations of 10 ng/ml in chemotaxis experiments and up to 25-50 ng/ml when assessing intracellular changes of CA2+(for example, [CA2+]i) and up to 400 ng/ml in the evaluation of tyrosine kinase activity.

In the process of study of chemotaxis (W.Falket et al., J. Immunol. Methods, 33, 239, 1980) used the filters without PVP with 5 μm pores and microcamera suitable for implementation of replication. Compounds were evaluated in the concentration range from 10-6up to 10-10M using R(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide, ED50 which is equal to 10-9M, as a standard for comparison.

In addition, the compounds of this invention were able to inhibit induced IL-8 tyrosinekinase activity, as you know, decisive for the chemotaxis of neutrophils (Yasui et al., 1994, already cited). The above evaluation was performed using the method described by L'heureux et al., Blood, 85, 522, 1995. And finally, some of the compounds of this invention were able to inhibit the increase of ion concentration of intracellular CA2+caused by IL-8, and this assessment of the imp is applied on the experimental model, described Bizzarri et al, Blood, 86, 2388, 1995.

As established earlier, the compounds of this invention did not show the ability to inhibit the enzymes, when assessed ex vivo in blood in toto by the method described Patrignani et al, in J. Pharmacol. .. Ther., 271, 1705, 1994. In addition, in almost all cases, the compounds of this invention of formula (I) do not affect the production of PGE2induced in murine macrophages by stimulation with lipopolysaccharide (LPS, 1 μg/ml) at concentrations in the range from 10-5up to 10-7M Any suppression products PGE2that can be registered, is mostly at the limit of statistical significance and in most cases less than 15-20% of the base value.

It's a minor suppression of the synthesis of PGE2allows you to clearly differentiate the compounds of this invention of formula (1) from (S)-enantiomers of 2-arylpropionic acids and their amides, which, on the contrary, because of their pronounced suppression of the synthesis of PGE2create an incentive for some of murine macrophages to enhance the synthesis of TNF-α.

It is well known that increased synthesis of TNF-α enables activation of neutrophils and promotes their chemotaxis, as, in addition, the incentive synthesis of IL-8. The compounds of this invention of formula (I) do not show any effects on PG synthesis, then how is the overwhelming reality is for some of them in relation to the synthesis of TNF-α that is usually stimulated by LPS in macrophages, the inhibitory effect, which is also registered in respect of the synthesis of the same cytokine after stimulation N2About2.

Taking into account the experimental data discussed above, and the participation of IL-8 and its derivatives as the most important mediators and promoters infiltration of neutrophils such disorders as psoriasis (R.J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991), rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), ulcerative colitis (Y. R. Mahla et al., Clin. Sci., 82, 273, 1992), acute respiratory failure and idiopathic fibrosis (E.J. Miller, already cited, and P.C. Carré et al., J. Clin. Invest., 88, 1882, 1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994) and in preventing damage from ischemia and the resumption of blood flow, the compounds of this invention are believed particularly suitable for therapeutic purposes in these cases.

For this purpose, with the compounds of the present invention respectively produce pharmaceutical compositions using conventional techniques and excipients, such as described in "Remington''s Pharmaceutical Sciences Handbook", Mack Publishing, New York, 18° Ed., 1990.

The compositions of this invention can be administered intravenously in a bolus injection or orally in the form of capsules, tablets, syrup and dosage forms with controlled release, as well as the form of preparations for dermatological use (creams, lotions, sprayable preparations and ointments). The average daily dosage will depend on several factors, such as disease severity and patient data (age, gender and weight). The dose will vary generally from 1 or more mg to 1500 mg of the compounds of formula (1) per day, optionally divided into several varieties. Also due to the low toxicity of the compounds of the present invention it is possible to enter higher doses for extended periods of time.

The following examples illustrate the invention.

In the description of the absolute configuration of a single chiral substituents optionally present in the compounds of the present invention, the apexes (for example, R', S', S" and so on) will be used, as a rule, to specify the absolute configurations present in the substituent R, associated with the nitrogen atom of these compounds.

Examples of abbreviations are: THF for tetrahydrofuran, DMF for dimethylformamide, for AcOEt ethyl acetate, HOBT for 1-hydroxybenzotriazole, DC to dicyclohexylcarbodiimide.

Example 1

R-N-2-[4-(pyrrolidin-1'-yl)were]propionylthiocholine

N,N-dimethylaminopyridine (2.4 g, ˜ 0.02 mol), hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (of 3.73 g, ˜ 0.02 mol) and methanesulfonamide (1.85 g, 0.02 mol) are added in that order to a solution of 2-[(4-(pyrrole the n-1-yl)were]propionic acid (4 g, approximately 0.019 mol) in anhydrous CH2Cl2(30 ml). The mixture is left to mix overnight. The solvent is evaporated in vacuo, and the residue is treated with ethyl acetate (3 x 15 ml). The combined organic phases are washed with water to neutrality, dried with sodium sulfate and evaporated to dryness. The residue is purified on a column of silica gel to obtain 3.15 g of R-(N)-2-[4-(pyrrolidin-1'-yl)were]propionylthiocholine.

Example 2

R-N-2-[4-(4'-benzylpiperazine-1'-illuminometer)phenyl]-propionylthiocholine

Methanesulfonamide (2.3 g, 0,0243 mol) are added to a suspension of t-BuOK (2,73 g, 0,0244 mol) in anhydrous THF (30 ml). The mixture is stirred for 30 min at room temperature, then cooled at -25°With, then add a pre-cooled solution of imidazole R-2-[4-(4'-benzylpiperazine-1'-yl)aminomethylphenol)]propionic acid (of 5.45 g, ˜ 0.019 mol) in THF (10 ml). Stirring is continued at this temperature for 2 hours, then for 1 hour at 0°C. the Reaction mixture is neutralized by addition of 0.04 molar equivalent of a solution of ice Asón in THF. After separation by filtration of inorganic salts that have separated, the solvent is evaporated in vacuum and the oily residue partitioned between dichloromethane (30 ml) and a solution of 2.5% NaHCO3. The organic extracts are combined, washed with water, sushi is tons of sodium sulfate. After evaporation of the solvent and purification on a column of silica gel get 4,05 g R-N-2-[4-(4'-benzylpiperazine-1'-illuminometer)phenyl]propionylthiocholine.

Example 3

(R,S)-2-[3'-chloro-4-(thiomorpholine-4-yl)phenyl]-N-(2-carboxyethyl)propionamide

To a solution of R-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]propionic acid (6.4 g; ˜ 22,1 nmol) in DMF (20 ml), cooled to about T=0°add with stirring 3 g HOBT (22,2 mmol). After 15 minutes, add a mixture of methyl ester hydrochloride L-alanine (3.2 g; ˜ of 22.2 mmol) and triethylamine (3 ml) in DMF (5 ml); and, finally, add DCC successive portions only 5 g (24,24 mmol). The mixture was kept under stirring for two hours at T=0°and then at room temperature overnight. After removal by filtration of sediment dicyclohexylamine the filtrate is evaporated to small volume and distributed between ethyl acetate and a saturated solution of NaHCO3. The organic phases are combined and re-extracted with 2 N. N2SO4the acid extracts are combined add 2 N. NaOH to neutral reaction, and then extracted with AcOEt (50 ml). The organic phase is washed with 10% sodium sulphate solution (20 ml). After drying Na2SO4and evaporation of the solvent under reduced pressure to obtain a residue, which was suspended in hexane (60 ml) and provide the claim under stirring over night, which leads to the selection of a white crystalline precipitate consisting of (R,S')-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-(2-methoxycarbonylethyl)propionamide (4.9 g, ˜of 16.84 mmol). Add a solution of 2 g (6,87 mmol) of this compound in dioxane (9 ml) with an equal volume of 1 N. NaOH (9 ml) and kept under stirring at room temperature over night. After dilution with water and ice (130 ml) this mixture is acidified with 2 n H2SO4to a pH of 6-6 .5. The aqueous phase is extracted with CH2Cl2(4 x 20 ml); the organic extracts are combined, washed with saturated solution of NaCl (20 ml) and dried Na2SO4. After evaporation of the solvent under reduced pressure the residue crystallized from ethyl ether (30 ml), gives (R,S')-2-[3'-chloro-4-(thiomorpholine-4-yl)phenyl]-N-(2-carboxyethyl)propionamide (1.6 g, of 6.52 mmol).

By replacing the methyl ester of L-alanine methyl ester, glycine and 3.5-dimethylbenzyl ester of L-tryptophan benzyl ester of L-4-pertanyaannya in the procedure described above receive the following connections:

(R)-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-(2-methoxycarbonylmethyl)propionamide;

(R,S')-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-[1-(3,5-dimethylbenzenesulfonyl)-ethyl-2-(3-indolyl)]propionamide;

(R,S')-2-[3-chloro-4-(thiomorpholine-4-yl)phenyl]-N-[1-(benzyloxycarbonyl)ethyl-2-(4'-forfinal)]propionamide.

Example 4

R-2-[3-chloro-4-(3-pyrrolin-1-the l)phenyl]propionamide

A solution of R(-)-pirprofen (2 g, RS 9.69 mmol) in thionyl chloride (4 ml) is heated for 3 hours at the temperature of reflux distilled; after cooling to room temperature the solvent is evaporated under reduced pressure, the residue is treated with dioxane twice sequentially, and the solvent is evaporated in high vacuum to remove trace residues of thionyl chloride. The solution yellow oily residue R(-)-microfilaria hydrochloride (2.16 g; 9.6 mmol) in anhydrous acetonitrile (4 ml) was added dropwise to a solution of 28% NH4HE (10 ml), cooled to 0-5°With such a speed that the temperature of the mixture did not exceed +5°C. the Mixture is stirred for 1 h at room temperature to obtain after evaporation of the solvents the residue, which was dissolved in AcOEt (6 ml). After cooling allocated residue R-2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propionamide.

Example 5

(R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(N',N'-dimethylaminopropyl)propionamide

To a solution of (R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)]phenylpropionic acid (5 g, 20 mmol) in anhydrous CHCl3(20 ml), cooled to about T=0°with stirring HOBT (2.7 g; 20 mmol). After 15 min added dropwise a solution of 3-(dimethylamino)Propylamine (2,03 g; 20 mmol) in anhydrous CHCl3(5 ml); at the end of successive portions add DCC (4,13 g,20 mmol). When adding complete, the mixture is left under stirring for two hours at T=0°and then at room temperature overnight. After filtering off precipitated in the sediment of dicyclohexylamine the filtrate is diluted with dichloromethane (50 ml). The organic phase is washed with water (3 x 15 ml) and saturated NaCl solution (2 x 20 ml). After drying over Na2SO4evaporation of solvent gives a residue which is dissolved in anhydrous acetone (5 ml). Gaseous HCl is bubbled through the solution, the desired product precipitates in the form of cleaners containing hydrochloride salt in the form of white solids which are filtered and dried in vacuum at T=40°obtaining lower than the 5.37 g (16 mmol) of the hydrochloride of (R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(N',N'-dimethylaminopropyl)propionamide.

Example 6

(R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(bis-carboxymethyl)propionamide

To a solution of (R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)]phenylpropionic acid (5 g, 20 mmol) in anhydrous CHCl3(20 ml), cooled to about T=0°add with stirring a solution of HOBT (2.7 g; 20 mmol). After 15 min added dropwise a solution of hydrochloride diethylaminoacetate (to 4.23 g; 20 mmol) and triethylamine (2,78 ml, 20 mmol) in anhydrous CHCl3(5 ml); at the end of successive portions add DCC (4,13 g; 20 mmol). When adding end, the MCA is ü left under stirring for two hours at T=0° C and then at room temperature overnight. After filtering off precipitated in the sediment of dicyclohexylamine the filtrate is diluted with dichloromethane (50 ml), the organic phase is washed with water (3 x 15 ml) and saturated NaCl solution (2 x 20 ml). After drying Na2SO4and evaporation of the solvents to obtain the residue, which is purified flash chromatography (eluent CH2Cl2/CH3HE 95:5) to give the intermediate compound diethyl ester (4.9 g; 12 mmol).

To a solution of diethyl ether (4.5 g; 11 mmol) in anhydrous CH2Cl2(30 ml), cooled to T=-10°C, add a solution of 1M BBr3in CH2Cl2(12,36 ml) with stirring and with a syringe. The mixture is left at T=-10°With 1 hour and then at room temperature for 6 hours to complete the reaction. The mixture is then diluted with water (30 ml), the two phases are shaken and separated; the aqueous phase is extracted (2 x 15 ml) CH2Cl2. The organic extracts are combined and extracted with a saturated solution of NaHCO3(3 x 15 ml); the basic aqueous phase is then acidified to a pH of 6-6,5 monosubstituted saturated solution of sodium phosphate and protiwallergical CH2Cl2(3 x 15 ml). The combined organic extracts are washed with saturated NaCl, dried with Na2SO4and evaporated to obtain (R)-2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1)phenyl]-N-(the IP carboxymethyl)propionamide in the form of a glassy solid (1.75 g; of 4.95 mmol).

Example 7

R(-)-2-[3-chloro-4-(piperidine-1-yl)phenyl]-N-(2"-hydroxyethoxyethyl)propionamide

A solution of R-2-[3-chloro-4-(piperidine-1-yl)phenyl]propionyl chloride (9.5 mmol) in anhydrous acetonitrile (10 ml)obtained by the method of example 4, are added dropwise at room temperature to a solution of 2-(2-aminoethoxy)ethanol (0,97 ml, 9.7 mmol) and triethylamine (3 ml) in anhydrous CH2Cl2(15 ml). The reaction mixture was stirred over night at room temperature, then evaporated to dryness. The remainder collect a 5% solution of ethyl acetate and a 5% solution of potassium bicarbonate, washed with water and the organic phase is extracted with 2 N. sulfuric acid. The acid aqueous phase combine, add ice and the aqueous phase is alkalinized to pH 8 and again again extracted with AcOEt. These extracts are combined and washed with 10% solution of sodium sulfate. After drying Na2SO4and evaporation of the solvent under reduced pressure to obtain a residue, which was purified flash chromatography (eluent CH2Cl2/CH3HE 98:2) to produce in the form of a clear oil of 1.87 g of R(-)-2-[3-chloro-4-(piperidine-1-yl)phenyl]-N-(2"-hydroxyethoxyethyl)propionamide.

Example 8

Through the use of an amine selected from the group of p-methoxyaniline, (R)-1-methyl-2-(2'-hydroxyethoxy)ethylamine, methyl ester L-methionine, methyl ester L-2'-label is biphenylamine and ethyl-3-oxa-5-aminopentanoic in the procedure of the preceding example, received

R-2-[3-chloro-4-(piperidine-1-yl)]-N-(4-methoxyphenyl)propionamide;

(R,R')-2-[3-chloro-4-(piperidine-1-yl)]-N-[1'-methyl-2'-(2"-hydroxyethoxy)ethyl]propionamide;

(R,S')-2-[3-chloro-4-(piperidine-1-yl)]-N-[1-methoxycarbonyl-3-metaltipped]propionamide;

(R,S')-2-[3-chloro-4-(piperidine-1-yl)]-N-[1-methoxycarbonyl-2-(2'-methoxybiphenyl)ethyl)]propionamide;

R-2-[3-chloro-4-(piperidine-1-yl)]-N-[2-(ethoxycarbonylmethoxy)ethyl)]propionamide;

Example 9

(R)-2-(4-morpholinyl)-N-(4'-pyrimidinyl)propionamide

To a solution of (R)-2-(4-morpholinomethyl)propionic acid (5 g, of 21.3 mmol) in anhydrous ethyl acetate (20 ml) is added N,N'-carbonyldiimidazole (3.8 g; (LK 23 : 43 mmol) under stirring at room temperature. The mixture is stirred for three hours at room temperature and without the isolation of intermediate compounds imidazoline - add a solution of 4-aminopyrimidine (2,23 g; (LK 23 : 43 mmol) in anhydrous ethyl acetate (10 ml). Stirring at room temperature continued for 8 hours, then the organic phase is washed with 5% solution of NaHCO3(3 x 25 ml). The organic phase is extracted with 2 N. N2SO4(5 x 10 ml); the acidic aqueous phase is then alkalinized to pH 8.5-9 with NaOH and extracted with ethyl acetate (3 x 15 ml). The extracts are combined, washed with saturated NaCl solution (2 x 25 ml) and dried Na2SO4. After evaporation of the solvent under reduced pressure the get the crude residue, which purified flash chromatography to obtain (R)-2-(4-morpholinyl)-N-(4'-pyrimidinyl)propionamide in the form of a pure white solid (5.3 g; 17 mmol).

Example 10

R-2-[4-((N-ethyl-N-quinoline-2'-ylmethylamino)methyl)phenyl]-N-(2'-allyloxycarbonyl)propionamide

To a solution of R-2-[4-((N-ethyl-N-quinoline-2-ylmethylamino)-methyl)phenyl]propionic acid (0,47 g, about 1.2 mmol) in anhydrous ethyl acetate added to 1.1 molar equivalent of N,N'-carbonyldiimidazole at room temperature and under stirring. After 3 h at room temperature without the isolation of intermediate compounds propylimidazolium, add a solution of 1.1 molar equivalent of allyl ester of glycine in anhydrous AcOEt. Stirring is continued for 6 h at room temperature, then the reaction mixture was repeatedly washed with 5% sodium bicarbonate solution and water to neutrality. The organic phase is re-extracted with a 2N aqueous solution of N2SO4(5 x 8 ml) and water. The acidic aqueous extracts combine, alkalinized and again extracted with ethyl acetate. The combined organic phases are washed until neutral with a 10% solution of sodium sulfate and dried with anhydrous Na2SO4. After evaporation of the solvent receive R-2-[4-((N-ethyl-N-quinoline-2'-ylmethylamino)methyl)phenyl]-N-(2'-allyloxycarbonyl)propionamide.

Example 11

R-2-[4-((N-ethyl-N-quinoline-2-ylmethylamino)methyl)phenyl]-N-(4'-pyridyl)propionamide

A solution of (R)-2-[4-((N-ethyl-N-quinoline-2-ylmethylamino)-methyl)phenyl]propionic acid (4 g, about 12 mmol) in thionyl chloride (6.2 ml) is heated for 3 hours at the temperature of reflux distilled. After cooling to room temperature the solvent is evaporated under reduced pressure, the residue is treated successively twice with dioxane and the solvent is evaporated in high vacuum to remove trace residues of thionyl chloride. Oily residue, thus obtained, was dissolved in anhydrous CH2Cl2(10 ml).

The solution dropwise at room temperature are added to a solution of 4-aminopyridine (2.25 g; 24 mmol) in dichloromethane in the presence of excess triethylamine. The mixture is stirred over night at room temperature, then diluted with CH2Cl2(20 ml). The organic phase is washed with water (2 x 15 ml) and then saturated NaCl solution (15 ml). After drying in Na2SO4and evaporation of the solvents receive the product as a white solid (of 3.07 g; 7.8 mmol).

Example 12

Using the methods described in examples 10 and 11, R-2-(AMINOPHENYL)propionic acid of the formula (4A) is subjected to interaction with the heterocyclic amine selected from the group comprising: 2-aminopyridine, 4-aminopyridine, 4-AMI is pyrimidin, 2-aminopyrazine, 2-amino-1,3-thiazole, 2-(pyrid-4-yl)ethylamine, 2-(imidazol-1-yl)ethylamine, and get the following amides:

R-2-[3-chloro-4-(pyrrolidin-1-yl)phenyl)]-N-(2'-pyridyl)propionamide;

R-2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl)]-N-(4'-pyridyl)propionamide;

R-2-[3-chloro-4-(1H-pyrrol-1-yl)phenyl)]-N-(4'-pyridyl)propionamide;

R-2-[3-chloro-4-(morpholine-4-yl)phenyl)]-N-(1,3-thiazol-2-yl)-propionamide;

R-2-[4-(morpholine-4-illuminometer)phenyl]-N-(pyrazin-2-yl)-propionamide;

R-2-[3-chloro-4-(3'-pyrrolin-1-yl)phenyl]-N-(4'-pyrimidinyl)propionamide;

R-2-[4-(pyrrolidin-1-ylmethyl)phenyl)]-N-(4'-pyridyl)propionamide;

R-2-[4-(3-pyrrolin-1-yl)phenyl]-N-(4'-pyridylethyl)propionamide;

R-2-(4-piperidine-1-ylphenyl]-N-(1-imidazolyl)propionamide.

Example 13

Through the interaction of a solution of R-2-[3-chloro-4-(4'-benzylpiperazine-1-yl)phenyl]Propionaldehyde in dioxane with aqueous solution of N-methylamine in the Schotten's-Bauman get R-2-[3-chloro-4-(4'-benzylpiperazine-1-yl)phenyl]-N-methylpropionamide.

Receive:

A) a Mixture of 1.5 g of ethyl-2-(4-AMINOPHENYL)propionate, 2.3 g of bis(2-chloroethyl)benzylamine and N-ethyldiethanolamine (5 ml) in 25 ml of absolute ethanol is heated under reflux for 24 hours. The mixture was concentrated in vacuo to dryness, the product is raw, thus obtained, purified on a column of silica gel using CH2Cl2/Meon 98:2 as eluent, obtaining of 2.21 g of ethyl-2-[4-(4-b is silbereisen-1-yl)phenyl]propionate.

B) 22 g of tert-butyl-2-p-tolylpropan dissolved in 200 ml of CCl4and the solution is brought to boiling point. After the addition of 0.85 g of 1,1'-azo(biscyclopentadienyl)and add portions of 18.7 g of N-bromosuccinimide and temperature of reflux distilled maintained for 1 hour. The mixture is cooled to 0°and filtered With succinimide. When the concentration of the solution precipitates of 19.8 g of tert-butyl 2-(4-bromomethylphenyl)propionate.

According to the described method and on the basis of the corresponding tert-butyl-2-o-tolylpropan and tert-butyl-2-m-tolylpropan receive tert-butyl-2-(2-bromomethylphenyl)propionate and tert-butyl 2-(3-bromomethylphenyl)propionate.

(C) To a solution of 3-pyrroline (2,56 ml, 33.4 mmol) in anhydrous CH2Cl2(20 ml), maintained at room temperature, added dropwise a solution of tert-butyl 2-(4-bromomethylphenyl)propionate (5 g; of 16.7 mmol) in anhydrous CH2Cl2(10 ml). When the addition finished, the solution is brought to a temperature reflux distilled and aged at the same temperature for 12 hours to complete the reaction. After cooling to room temperature the mixture is diluted with equal volumes of 5%aqueous NaHCO3and CH2Cl2(25 ml), shaken and the two phases are separated; the organic phase is optionally washed with water (2 x 20 ml) and saturated NaCl solution (2 x 20 ml). After drying Na2SO4the issue is rivane solvent gives tert-butyl-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)phenyl]propionate as a pale yellow oil (4,25 g; 15,03 mmol).

Ester (4 g; 14.1 mmol) dissolved in anhydrous CH2Cl2(10 ml). The solution is cooled to T=0°and slowly added dropwise triperoxonane acid. When the dropwise addition finished, the mixture is left under stirring for 6 hours at room temperature. The reaction is stopped by evaporating the solvent to dryness and removing all the present solvents by evaporation with toluene (2 x 15 ml). The remaining oil is maintained with stirring in hexane-ethyl ether (1:1, 50 ml) over night. The formed precipitate is filtered off to obtain 2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)phenyl]propionic acid in the form of triptoreline, white solids (1,95 g; 8.6 mmol). Optical separation of the acid, thus obtained, is produced according to the method described in Arzneim. Forsch. Vol.46(II), 9, 891-894, 1996 to obtain R-pirprofen.

Example 14

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)phenyl]propionylthiocholine

Methanesulfonamide receive, based on the optically active acid (R), corresponding to example 2. Final purification of the product is achieved by flash chromatography (eluent CH2Cl2/CH3HE 98:2). The pure product is obtained in the form of a white solid.

Example 15

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)phenyl]-N-(2-carboxyethyl)propionamide

This am is d (R) optically active acid with L-alanine receive in accordance with example 3.

Final purification of the product is carried out by crystallization from ethyl ether.

Example 16

(R)-2-[4-(2,5-dihydro-1H-pyrrol-1-ylmethyl)phenyl]propionamide

The primary amide (R) optically active acid get in accordance with example 4.

Final purification of the product is carried out by crystallization from ethyl acetate.

1. Amides of (R)-enantiomers of 2-arylpropionic acids of the formula (1)

and their pharmaceutically acceptable salt,

where q is zero or an integer equal to 1;

Ph is fenelonov group associated with the group -(CH2)qIn position 2, 3 or 4, and optionally substituted in other positions by one or more Deputy, the same or different, selected from C1-C3-alkyl, halogen;

But a

- N-C1-C8- arylalkyl-N-C1-C5-alkylamino-group;

is a saturated or unsaturated nitrogen-containing 5 to 7-membered heterocyclic ring;

R represents

- N; -SO2-CH3;1-C3the alkyl group of the formula-CH2-CH2-X-(CH2-CH2O)n-R, where R is H, stands, ethyl, isopropyl;

-CH2CO2R1where R1represents H or is 1-C3; n is an integer from 0 to 5, X represents O;

- the remainder of the formula (3)

-(CH2)m-F (3)

where, when m is an integer from 2 to 3, f represents an unsubstituted or substituted phenylene, 2-(1-methylpyrrolidinyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl or group-NRaRb, where each of Ra and Rb, identical or different, represent a1-C5is alkyl or hydroxyalkyl-(CH2)miIs HE, where mian integer from 2 to 3, or Ra and Rb together with the N atom to which they are linked, form a heterocyclic ring containing from 3 to 7 members; when m is zero, f is selected from the group comprising 2 - or 4-pyridyl, 2 - or 4-pyrimidinyl, 2-pyrazinyl, 2-1,3-thiazolyl, indol-3-yl;

- the remainder of the formula (3A)

where In is a N;

provided that when q is zero, R is a-SO2CH3and Ph represents a 3-chloro-1,4-phenylene, a is a group other than 1-2,5-dihydropyrimidine.

2. The compound according to claim 1, where R represents H, -SO2-CH3, polyoxyethylene residue of the formula -(CH2-CH-O)2-R, where R represents H, methyl, ethyl, isopropyl; or CH2-CO2R1where R1represents N or C1- 3-alkyl.

3. The compound according to claim 1, where R is the Deputy of the formula (3)

-(CH2)m-F (3)

where, when m is an integer 2 or 3, f is the remnant of a base selected from the group comprising N,N-diethylamino, 4-morpholyl, 1-piperidyl, 1-(4-benzyl)piperazinil, 1-(4-diphenylmethyl)piperazinil, 1-(4-(4',4"-giftgiver)- methylpiperazine; whereas, when m is 0, f is preferably a heteroaryl residue, such as 2-or 4-pyridyl, 2 - or 4-pyrimidinyl, 2-pyrazinyl, 2-1,3-thiazolyl, 2-1,3-thiazolidine, 2-imidazolyl and, more preferably 4-pyridyl.

4. Compounds according to claims 1-3 for preventing the activation of leukocytes.

5. Compounds according to claim 4 for preventing the activation of leukocytes in the treatment of psoriasis, ulcerative colitis, glomerulonephritis, acute respiratory insufficiency, idiopathic fibrosis, rheumatoid arthritis.

6. Compounds according to claim 4 for preventing the activation of leukocytes in the prevention and treatment of damages caused by ischemia and reperfusion.

7. Pharmaceutical composition for preventing the activation of leukocytes containing compound according to any one of claims 1 to 3, and its pharmaceutically acceptable salt as an active substance in a mixture with a suitable carrier.

8. The way to obtain the amide of formula (1) according to any one of claims 1 to 3, including interaction act is vorovannogo acid derivative of the formula (4)

where and q are as defined in claim 1, and at is the balance of activating the carboxyl group, with an amine R-NH2where R represents a group that is defined in claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-pyridylalkylaminopyrazole represented by the following formula (1): wherein X represents C-halogen; R1 represents halogenalkyl group comprising from 1 to 4 carbon atoms with exception of perhalogenalkyl group; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom. Also, invention describes an agent used for control of insects comprising this derivative as an active component. Invention describes two methods for preparing compound of the formula 91). Compounds of the formula (1) are useful for control of insects in agriculture and for domestic animals.

EFFECT: improved preparing methods, valuable properties of compound and agent.

7 cl, 7 tbl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I):

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 6-alkyl-5-(2-isonicotinoylsulfohydrazoyl)uracil hydrochlorides of the general formula (I) wherein R means alkyl comprising 1-4 carbon atom. Compounds possess an anti-mycobacterial and an immunotropic activity and can be used as an immunomodulating agent and an anti-mycobacterial agents. Also, invention relates to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds.

4 cl, 10 tbl, 2 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase ring or aryl ring

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

FIELD: organic chemistry, biochemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dih-ydroxyhept-6-enoic acid crystalline salts wherein salt represents ammonium, methyl ammonium, ethyl ammonium, diethanol ammonium, tris-(hydroxymethyl)methyl ammonium, benzyl ammonium, 4-methoxybenzyl ammonium, lithium or magnesium salt possessing property of HMG CoA-reductase inhibitor. Also, invention relates to a pharmaceutical composition comprising crystalline salt in mixture with a pharmaceutically acceptable diluting agent or vehicle an to a method for preparing crystalline salt. Method involves addition of corresponding amine or a base to a solution of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(me-thylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-dihydro-xyhept-6-enoic acid in acetonitrile or ethyl acetate medium. The advantage of crystalline salts involves the possibility for enhancing purity and homogenicity of compounds, the possibility for re-crystallization and preparing the pure amorphous form and enhancing stability of the form.

EFFECT: improved preparing method.

15 cl, 9 dwg, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

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