(r)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of (R)-2-arylpropionamide of the formula (I): , wherein Ar means aryl of the formula (IIIb): F-Arb wherein Arb means phenyl mono- or poly-substituted with the following groups: chlorine, fluorine atom; F means hydrogen atom, linear or branched (C1-C5)-alkyl residue, benzoyl, 2,6-dichlorophenylamino-, 2,6-dichloro-3-methylphenylamino-group; R means hydrogen atom, (C1-C4)-alkyl; X means linear or branched (C1-C6)-alkylene optionally substituted with the group -CO2R4 wherein R4 means hydrogen atom or linear or branched (C1-C6)-alkyl group, phenyl or phenylmethylene group; R1, R2 and R3 mean independently linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C6)-alkenyl, aryl, aryl-(C1-C3)-alkyl, or R1 and R2 in common with nitrogen atom (N) to which they are attached form nitrogen-containing 6-membered heterocyclic ring of the formula (II) , and R3 has values indicated above independently wherein in the formula (II) Y means a simple bond, methylene group, oxygen atom, nitrogen atom or sulfur atom; p means a whole number 2; Z- means a pharmaceutically acceptable counterion of quaternary ammonium salts. Also, invention relates to using compound of the formula (I) in treatment of psoriasis, pemphigus and pemphigoid, rheumatic arthritis, intestine chronic inflammatory pathology including ulcerous colitis, acute respiratory distress-syndrome, idiopathic fibrosis, mucoviscidosis, pulmonary chronic obstructive disease and glomerulonephritis, and also for prophylaxis and treatment of injure caused by ischemia and reprefusion. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to chemotaxis of polymorphonuclear leukocytes and monocytes induced by complement C5a fractions and comprising compound of the formula (I) in mixture with a suitable carrier. Also, invention relates to a method for synthesis of compounds of (R)-2-arylpropionamide of the formula (I) that involves interaction of amides of the formula (IV) given in the invention description with compounds of the formula R3Zwherein Z means a leaving group, such as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate. Invention provides synthesis of (R)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts used for inhibition of chemotaxis activation induced by the C5a complement component.

EFFECT: valuable properties of compounds and pharmaceutical compositions.

17 cl, 1 tbl, 6 ex

 

Introduction and background to the creation of inventions

This invention relates to compounds applicable in the inhibition of chemotactic activation induced component Sa of complement and other chemotactic proteins (chemokines), which exert their effects through activation of receptor 7-transmembrane domain (7-TM). These compounds are Quaternary ammonium salts of R-2-arylpropionate applicable in the treatment of pathologies dependent chemotactic activation of neutrophils and monocytes induced component Sa complement. In particular, the compounds according to the invention is applicable in the treatment of psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, glomerulonephritis and in the prevention of the destruction caused by ischemia and reperfusion.

Detailed description of the invention

This invention relates to (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 CO2R4where R4means hydrogen, or linear or branched C1-C6is an alkyl group, or LINENO is or branched C 2-C6-alkenylphenol group;

X means:

linear or branched C1-C6-alkylene, C4-C6-albaniles, C4-C6-akinyan, optionally substituted by a group of CO2R4or CONHR group5where R5means hydrogen, linear or branched C2-C6-alkyl or a group OR4where R4defined above;

phenyl or a group of phenylmethylene formula:

group (CH2)m-B-(CH2)n, optionally substituted by a group of CO2R4or CONHR5as defined above, where In denotes an oxygen atom or sulfur, m denotes zero or an integer from 2 to 3, and n means an integer from 2 to 3; or means a group of CO, SO or CONH, m means an integer from 1 to 3, and n means an integer from 2 to 3;

or X together with the nitrogen atom to which it is attached, and with a group R1forms a nitrogen-containing 3-7 membered heterocyclic monocyclic or polycyclic ring;

R1, R2and R3means independently linear or branched C1-C6-alkyl, optionally substituted by oxygen atom or sulfur, C3-C7cycloalkyl, C3-C6alkenyl, C3-C6-quinil, aryl, aryl-C1-C3-alkyl, hydroxy-C2-C3is an alkyl group;

or R1The R 2together with the N atom to which they are attached, form a nitrogen-containing 3-7 membered heterocyclic ring of formula (II) and R3independently has a value as specified above.

In the General formula (II)

Y represents a simple bond, a methylene group, oxygen atom, nitrogen atom or sulfur atom,

p means an integer from 0 to 3;

Z means the standard anions used as counterions of Quaternary ammonium salts that are pharmaceutically acceptable, such as, for example, halide ions Cl-I-, Br-the sulfate anion or anions, derived from sulfonic acids, such as methanesulfonate or p-toluensulfonate.

In the compounds of General formula (I) aryl group Ar is preferably selected from such as

a) mono - or polyamidine aryl group Arathe most common (±)2-arylpropionic acids in therapeutic application currently: alminoprofen, benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, loxoprofen, R-naproxen, pirprofen, and their degidro and dihydrobromide, pranoprofen, suprofen, tiaprofenic acid, zaltoprofen;

b) aryl-hydroxymethyl-aryl group of formula (IIIa) in a mixture of diastereoisomers and separate GeoStereo is the Windows,

where, when Ar2means phenyl, Ar1selected from the group consisting of phenyl and Tien-2-yl, and when Ar1means phenyl, Ar2selected from the group consisting of phenyl, 4-tanila, pyridyl;

C) aryl of formula (IIIb):

where:

Arbmeans phenyl, mono - or politeley groups: hydroxy, mercapto, C1-C3-alkoxy, C1-C3-alkylthio, chlorine, fluorine, trifluoromethyl, nitro, amino, optionally substituted C1-C7-acylamino;

Φ means hydrogen; linear or branched residue C1-C5-alkyl, C2-C5-alkenyl or C2-C5-quinil, optionally substituted C1-C3-alkoxycarbonyl, substituted or unsubstituted phenyl, 2-, 3 - or 4-pyridium, quinoline-2-silt; C3-C6-cycloalkyl; 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophene or C1-C8(alkanoyl, cycloalkenyl, arylalkyl)-C1-C5-alkylamino, for example, acetyl-N-methylamino, pivaloyl-N-ethylamino;

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

where the substituents R1and R2mean that the two phenyl groups are substituents, namely, each independently mono - or polyamidine groups C1-C4-alkyl, C1C 3-alkoxy, chlorine, fluorine and/or trifluoromethyl.

Preferred compounds according to the invention are the following, where

R means hydrogen;

X means

- linear C1-C6-alkylen, preferably C2-C4, optionally substituted C1group-CO2R4as defined above;

- linear C1-C6-alkylene, optionally substituted C1group-CONHR5where R5means IT;

- 2-Butylin, CIS-2-butylen, TRANS-2-butylen;

- 3-oxapentane, 3-typestyles, 3-oxohexyl, 3-tigecyclin;

- (CH2)m-CO-NH-(CH2)nwhere m and n each independently represent an integer from 2 to 3;

- (CHR')-CONH-(CH2)nwhere n denotes an integer from 2 to 3 and R' denotes methyl, an absolute configuration of R or S;

is phenyl or a group of phenylmethylene formula:

or X together with N-atom forms azacycloheptane ring, preferably 1 methylpiperidin-4-yl or 1.5-tropan-3-yl.

Preferred compounds are also those in which the group NR1R2R3means the group of ammonium, triethylamine, N-methyl-N,N-diethylamine, N-methyl-N,N-Diisopropylamine, N-cyclohexylmethyl-N,N-dimethylamine, N-cyclopentylamine-N,N-dimethylamine, N-methyl-1-piperidine, N-ethyl-1-piperidine, N-m is l-4-morpholine, N-methyl-4-thiomorpholine, N-benzyl-N,N-dimethylamine, N-allyl-1-piperidine, 4-hydroxy-N-methylpiperidine.

Examples of particularly preferred aryl groups contain:

4-isobutylphenyl, 4-cyclohexylmethanol, 4-(2-methyl)allylphenol, 3-phenoxyphenyl, 3-benzoylphenyl, 3-acetylphenyl, the individual (R)- and (S)-diastereoisomer and the mixture diastereoisomers (R,S) 3-C6H5-CH(OH)-phenyl, 3-CH3-CH(OH)-phenyl, 5-C6H5-CH(OH)-tanila, 4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl, 5-benzoylation-2-yl, 4-canolfannau, 3-nicotinoyl, 2-fluoro-4-phenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-acetoxyphenyl, 5-benzoyl-2-hydroxyphenyl, 4-cyclopentylphenol, 4-(2-oxocyclopent)phenyl, 4-(2-oxocyclohexyl)phenyl.

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

The preferred Allami formula (IIIc) are 2-(2,6-dichlorophenylamino)phenyl, 2-(2,6-dichlorophenylamino)-5-chlorophenyl, 2-(2,6-dichloro-3-methylphenylamine)phenyl, 2-(3-triptoreline)phenyl. Examples of substituted phenyl groups, R2contain phenyl groups, substituted with one to three halogen atoms, C1-C4-alkyl groups, methoxy, trifluoromethyl, nitro, cyano, halogenoalkane.

Especially preferred is sustained fashion the compounds according to the invention are:

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}trimethylammonium;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}trimethylammonium;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-N-ethyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-N-cyclohexylmethyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-cyclopentylmethyl)propionamido]propyl}trimethylammonium;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-N-isopropyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]butyl}trimethylammonium;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-1-methylpiperidine;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-1-methylpiperidine;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-4-methylmorpholine;

methanesulfonate (R)-{3-[2-(3-isopropylphenyl)propionamido]propyl}-4-methylthiophene;

bromide (R)-{2-[2-(4-isobutylphenyl)propionamido]ethyl}trimethylammonium;

p-toluensulfonate (R)-{2-[(4-isobutylphenyl)propionamido]-1,1-dimethyl}piperidine;

methanesulfonate (R),(S')-2-(4-isobutylphenyl)-N-[(1-carboxy-2"-N,N,N-ammonium)ethyl]propionamide;

iodide R(-)-2-[(4-isobutylphenyl)-N-(trimethylammonium)methylamide]propionamide;

methanesulfonate (R)-(3-{2-[2-(2,6-dichlorophenylamino)phenyl]propionamide}propyl)trimethylammonium;

iodide (2R),(4, S)-1-{4-is arbucci-4-[2-(4-isobutylphenyl)propionamido]butyl}-1-methylpiperidine;

iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(N-benzyl)-N,N-dimethylammonio;

iodide 2R-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4"-carboxamide)piperidine;

iodide (2R)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4-carbonyl)piperidine;

iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}of triethylamine;

bromide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-arylpiperazine;

iodide R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]propionamide;

iodide R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]propionamide.

Known methods of alkylation of the tertiary amine groups (reaction Menshutkin) is used to produce compounds of formula (I), the compounds of formula (IV), where Ar, R, R1, R2and X are as defined above, is subjected to reaction with compounds of formula R3Z, where R3defined above, and Z is the usual leaving group such as chloride, bromide, iodide, methanesulfonate, p-toluensulfonate or sulfate.

Alkylation reaction is usually carried out at room temperature using a proton or aprotic usually anhydrous solvents or mixtures thereof, optionally in the presence of strong dinucleophiles Foundation. Alternatively, some compounds of formula (I) can be received is s based on compounds of the formula (IV) by reacting with unsaturated substrates type of Michael, catalyzed by mineral acids such as HCl or HNO3.

Obtaining compounds of formula (IV) described in international patent application PCT/ER/01974. Some compounds of formula (IV) are new in relation to the specific compounds described in the patent application, and they are obtained by the methods described below in the section "Synthesis".

It is clear that the synthesis of compounds of formula (I)according to the amides of formula (IV), where the substituents R1and R2can independently represent-N, include in the process. If desirable, the primary and secondary amines can be subjected to interaction in terms of an exhaustive alkylation with compounds of formula R3Z, to obtain the compounds according to the invention of formula (I), where at least two residue is defined as R1, R2and R3are one and the same. The reaction is carried out under the same conditions described for the conversion of amides of the formula (IV) in the compounds of formula (I) according to the invention.

Alternatively, primary or secondary amides of the formula (IV) can be converted into compounds of formula (I) in two successive stages. In the first stage, mono - or dialkylamino the reaction is carried out at room temperature or by heating in the presence of one or two equivalents of alkylation agent R3Z depending on the extent to which Emesene the original amino group. The reaction is carried out in conventional proton or aprotic, preferably anhydrous solvents or their mixtures, optionally in the presence of strong dinucleophiles Foundation.

The compounds of formula (I) according to the invention is evaluated in vitro for their ability to inhibit chemotaxis of polymorphonuclear leukocytes (hereinafter referred to as PMN) and monocytes induced by fractions of complement Sa and C5a-desArg. For this purpose, to isolate PMN from heparinised human blood collected from healthy adult volunteers, remove mononuclear cells by sedimentation on dextran (according to the procedure disclosed W.J. Ming et al., J. Immunol., 138, 1469, 1987) and red blood cells by hypotonic solution. Cell viability calculated by excluding using Trypanosoma blue, while the ratio of circulating polymorphonuclear cells is determined on centrifugate cells after staining Diff Quick.

Recombinant fraction Sa and C5a-desArg (Sigma) of a person is used as stimulating agents in chemotactic experiments, obtaining almost identical results.

Liofilizovannye fraction Sa dissolved in a volume of balanced salt solution HBSS Hanks, containing 0.2% bovine serum albumin BSA, so that the original solution having a concentration of 10-5M, was razbavlen HBSS to a concentration of 10 -9M, for the analysis of chemotaxis.

In a chemotactic experiments, PMN incubated with the compounds according to the invention of formula (I) for 15 minutes at 37°C in an atmosphere containing 5% CO2.

Chemotactic activity So appreciate in circulating polymorphonuclear leukocytes (PMN), re-suspended in HBSS at a concentration of 1.5×106PMN in ml.

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

The compounds of formula (I) according to the invention is evaluated at concentrations ranging from 10-6up to 10-10M; for this purpose they are added at the same concentration as in the bottom of the pores, and at the top of the pores microcamera. Holes in the lower part contain the solution Sa or simple media, holes in the upper part contain the PMN suspension.

Inhibition Sa-induced chemotactic activity of individual compounds of the formula (I) according to the invention is assessed by incubation of microcamera for chemotaxis for 60 min at 37°C in an atmosphere containing 5% CO2.

The ability of the compounds of formula (I) according to the invention to inhibit CA-induced chemotaxis of human monocytes carried out according to the method opened Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989)Ingibirovanie Sa-induced chemotactic activity of individual compounds of the formula (I) according to the invention in relation to human monocytes appreciate at a concentration of between 10 -6and 10-10M by incubation of microcamera for chemotaxis for 120 min at 37°C in an atmosphere containing 5% CO2.

For example, the data of inhibition of PMN chemotaxis (C=10-6M) some examples of compounds according to the invention are presented in the following table:

CONNECTION% INHIBITION

(C=10-6M)
Iodide (R)-(3-{2-[2-(2,6-dichlorophenylamino)phenyl]propionamide}propyl)-trimethylammonium62±3
Iodide (R)(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}trimethylammonium53±6
Iodide (R)(-)-2-[(4'-isobutylphenyl)propionamido]-1,1-dimethylpiperidine18±9
Iodide (R)(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-methylpiperidine24±4
Methanesulfonate (R)(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-N-cyclohexylmethyl-N,N-dimethylammonio57±4
Iodide (R)(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(N-benzyl)-N,N-dimethylammonio22±4

The compounds of formula (I), an assessment which was performed ex vivo in whole blood according to the procedure disclosed Patrignani et al., in J. Pharmacol. .. Ther., 271, 1705, 1994, were found to be totally ineffective in quality and is of gibilaro enzymes cyclooxygenase (SOH).

In almost all cases, the compounds of formula (I) did not affect the production of PGE2induced in murine macrophages by stimulation with lipopolysaccharide (LPS, 1 μg/ml) at a concentration in the range from 10-5up to 10-7M. Inhibition of the production of PGE2that can be registered, is usually at the limit of statistical significance, and more often 15-20% below the base value.

Therefore, an additional object of this invention is the use of compounds according to the invention as medicaments.

In view of the experimental evidence discussed above, and the role performed by the complement cascade, namely its fractions So, in the processes that affect the activation and infiltration of neutrophils, the compounds according to the invention is particularly applicable in the treatment of diseases such as psoriasis (R.J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991), pemphigus 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 and idiopathic fibrosis (E.J. Miller, mentioned earlier, and P.C. Carry et al., J. Clin. Invest., 88, 1882, 1991), cystic fibrosis, chronic obstructive pulmonary disease, glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994), and in the prevention and treatment of lesions caused by ischemia and reperf the Zia.

The compounds of formula (IV) for use as medication are described in international patent application PCT/ER/01974. New amides of the formula (IV)described below in the section "Synthesis", have biological activity comparable to the activity of amides described in the referenced patent application, and can be used to treat the same disorders.

For this purpose the compounds of formula (I) according to the invention is usually prepared in the form of pharmaceutical compositions using conventional techniques and thinners, such as described in "Remington''s Pharmaceutical Sciences Handbook", MACK Publishing, new York, 18th ed., 1990.

Compounds according to the invention can be administered intravenously by injection, bolus, in the form of a dermatological preparations (creams, lotions, sprays and ointments), by inhalation, and oral in the form of capsules, tablets, syrup, compositions with controlled release and the like.

The average daily dose depends on various factors such as the severity of the disease state, age, sex and weight of the patient. The dose will vary, typically from 1 to 1500 mg of the compounds of formula (I) per day, which can be divided into several stages. Higher doses can be entered for long periods of time, due to the low toxicity of the compounds according to the invention.

The following examples and synthesis serve to explain the invention.

To easy the TBA superscripts (for example, R', S', S" and so on) show the absolute configuration present in the substituent R1in the compounds of formula (I) according to the invention. Abbreviations: THF: tetrahydrofuran, DMF: dimethylformamide, EtAc: ethyl acetate, HOBZ: hydroxybenzotriazole, DCC: dicyclohexylcarbodiimide.

Materials and methods

Amines used as reagents in the synthesis of compounds of formula (IV)are known products, usually commercially available, or they can be obtained according to the methods described in the literature.

Synthesis of 2-arylpropionic acids of the formula Φ-Ar3-C(CH3)H-CO2H and R-enantiomers disclosed in international patent application PCT/ER/01285.

Resolution of optical isomers is carried out by formation of salts with R(+)-N-methylbenzylamine according to the method described Akguen and others in Arzneim. Forsch., 46:9 891-894, 1996.

SYNTHESES

Getting omega-aminoalkylation R-2-arylpropionic acid

as intermediates

Obtaining compounds of formula (IV) are disclosed in international patent application PCT/ER/01974. Some compounds of formula (IV) are new and are described for the first time in this patent application.

Examples of obtaining new amides of the formula (IV) below.

SYNTHESIS of 1

R(-)-2-[(3-benzoyl)phenyl]-N-[3"-(N',N'-dimethylamino)propyl]propionamide

Hydroxybenzotriazole (0,604 g, 393 mmol) and N,N-dicyclohexylcarbodiimide (0,81 g, 3.93 mmol) are added to a solution of R(-)-Ketoprofen (1 g, 3.93 mmol) in anhydrous dichloromethane (25 ml). The mixture is stirred at room temperature for 30 min; the resulting suspension add N,N-dimethyl-1,3-propandiamine (0,49 ml, 3.93 mmol). The resulting suspension is stirred at room temperature overnight. Dicyclohexylamine (DCU) then filtered under vacuum and the filtrate evaporated under reduced pressure, the crude oily residue absorb acetonitrile (20 ml) and the mixture left overnight at T=4°C. After filtering off additional aliquots DCU the filtrate is again evaporated under reduced pressure and the residue purified by chromatography on silica gel (eluent CHCl3/CH3OH 8:2); R(-)-2-[(3'-benzoyl)phenyl]-N-[3"-(N',N'-dimethylamino)propyl]propionamide (0,997 g, to 2.94 mmol) obtained as a clear oil.

Yield 75%

[α]D= -20(c = 0,9; CH3OH)

1H-NMR (CDCl3) δ of 7.90-7,40 (m, 9H); to 7.25 (s, 1H, CONH); the 3.65 (m, 1H); to 3.36 (m, 2H); of 2.38 (m, 2H); of 2.20 (s, 6H); of 1.62 (m, 5H).

Similarly also receive the following connections:

R(-)-2-[(3'-benzoyl)phenyl]-N-(3"-N"-piperidinomethyl]propionamide

The output 80%

[α]D= -47,5(c = 0,3; CH3OH)

1H-NMR (CDCl3) δ a 7.85-7,42 (m, 9H + CONH); of 3.80 (m, 1H); 3,57 of 3.28 (m, 4H); to 2.85 (m, 2H); 2,10 (m, 2H); of 1.65 (m, 11H).

R(-)-2-[(4'-isobutyl)phenyl]-N-[3"-N'-(4",4"-piperidinyl)propyl]propionamide

[1 ]D= -19,5(c = 1; CH3OH)

1H-NMR (DMSO-d6) δ with 8.05 (t, 1H, J=6 Hz, CONH); to 7.25 (d, 2H, J=8 Hz); was 7.08 (d, 2H, J=8 Hz); 3,55 (m, 1H); 3.40 in (m, 2H); 3,35-of 3.25 (m, 6H); of 2.38 (d, 2H, J=7 Hz); is 2.05 (m, 4H); of 1.85 (m, 1H); 1,50 (m, 2H); 1,35 (d, 3H, J=7 Hz); of 0.87 (d, 6H, J=7 Hz).

R(-)-2-[(4'-isobutyl)phenyl]-N-[3"-N'-(4"-carboxamidotryptamine)propyl]propionamide

[α]D= -28,5(c = 1; CH3OH)

1H-NMR (DMSO-d6) δ to 8.45 (d, 2H, J=8 Hz, CONH2); 8,10 (t, 1H, J=6 Hz, CONH); to 7.35 (d, 2H, J=8 Hz); then 7.20 (d, 2H, J=8 Hz); the 3.65 (m, 1H); 3.42 points (m, 2H); 3,15-2,90 (m, 6H); 2,35 (d, 2H, J=7 Hz); of 2.15 (m, 1H); of 1.80 (m, 1H); of 1.55 (m, 6H); to 1.35 (d, 3H, J=7 Hz); of 0.85 (d, 6H, J=7 Hz).

R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N-dimethylaminomethylphenol]propionamide

[α]D= -35(c = 1; CH3OH)

1H-NMR (CDCl3): δ of 7.82 (DD, 1H, J1=8,4 Hz; J2=2 Hz); at 7.55 (d, 1H, J=2 Hz); 7,20 (m, 2H); 7,10 (m, 2H); 6,85 (d, 2H, J=8,4 Hz); 6,15 (USS, 1H, CONH); 3,70 (s, 2H); 3,50 (m, 1H); 3,20 (s, 6H); of 2.45 (d, 2H, J=7 Hz); of 1.88 (m, 1H); of 1.50 (d, 3H, J=7 Hz); of 0.85 (d, 6H, J=7 Hz).

EXAMPLES

QUATERNARY SALTS of OMEGA-AMINOALKYLATION

R-2-ARYLPROPIONIC ACIDS

Example 1

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-methylpiperidine

R(-)-2-[(4'-isobutyl)phenyl]-N-[3"-N'-(N'-methyl)piperidinomethyl]propionamide (0,095 g, 0,287 mmol) dissolved in anhydrous tetrahydrofuran (6 ml) under inert atmosphere. To the solution add methyliodide (0.1 ml, of 1.61 mmol), the solution was stirred at room temperature for 18 hours, until the original reagent Neuve is Sogno will be the next to discover. The solvent is then evaporated under reduced pressure, and the residue absorb simple isopropyl ether. A white precipitate is formed, which is stirred for 6 hours. The precipitate is filtered off and dried in vacuum at T=40°obtaining iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-methylpiperidine (0,114 g, 0.24 mmol) as a pale yellow waxy solid.

The output 84%

[α]D= -12(c = 0,7; CH3OH)

1H-NMR (DMSO-d6) δ with 8.05 (t, 1H, J=6 Hz, CONH); to 7.25 (d, 2H, J=8 Hz); was 7.08 (d, 2H, J=8 Hz); 3,55 (m, 1H); 3.25 to to 3.02 (m, 8H); 2,90 (s, 3H); of 2.38 (d, 2H, J=7 Hz); 1.85 to 1.55V (m, 7H); 1,50 (m, 2H); to 1.35 (d, 3H, J=7 Hz); to 0.88 (d, 6H, J=7 Hz).

The following connections receive, using the above method:

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}trimethylammonium

TPL 105-110°

[α]D= -17 (c = 1,0; CH3OH)

1H-NMR (CDCl3) δ 7,42 (d, 2H, J=8 Hz); then 7.20 (t, 1H, J=6 Hz, CONH); 7,07 (d, 2H, J=8 Hz); a 3.83 (m, 1H); of 3.77 (m, 2H); 3,55-3,20 (m, 2H); 3,18 (s, 9H); 2.40 a (d, 2H, J=7 Hz); is 2.05 (m, 2H); to 1.83 (m, 1H); 1,45 (d, 3H, J=7 Hz); 0,9 (d, 6H, J=7 Hz).

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]butyl}trimethylammonium

TPL 100-103°

[α]D= -25(c = 1,0; CH3OH)

1H-NMR (CDCl3) δ to 7.25 (d, 2H, J=8 Hz); to 7.09 (d, 2H, J=8 Hz); 6,18 (s, 1H, CONH); 3,61 (m, 1H); or 3.28 (m, 2H); of 3.12 (m, 2H); is 3.08 (s, 9H); 2,44 (d, 2H, J=7 Hz); is 1.81 (m, 1H); to 1.75 (m, 4H); 1.50 in (d, 3H, J=7 Hz); to 0.88 (d, 6H, J=7 Hz).

Iodide R(-)-2-[(4'-isobutylphenyl)propionamido-1,1-dimethylpiperidine

TPL 80-85°

[α]D= -7(c = 1,2; CH3OH)

1H-NMR (DMSO-d6) δ to $ 7.91 (d, 1H, J=7 Hz, CONH); 7,22 (d, 2H, J=8 Hz); was 7.08 (d, 2H, J=8 Hz); of 3.80 (m, 1H); of 3.53 (m, 1H); 3,35-3,30 (m, 4H); is 3.08 (s, 3H); 3,00 (s, 3H); 2.40 a (d, 2H, J=7 Hz); 1,95-of 1.65 (m, 5H); 1,3 (d, 3H, J=7 Hz); of 0.87 (d, 6H, J=7 Hz).

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-4-methylmorpholine

TPL 84-87°

[α]D= -17(c = 0.5; CH3OH)

1H-NMR (CDCl3) δ was 7.45 (d, 2H, J=8 Hz); 7,02 (m, 3H, CONH + 2Har.); of 4.25 (m, 2H); to 3.92 (m, 1H); 3,88 (m, 1H); of 3.80 (m, 1H); of 3.53 (m, 1H); to 3.35 (m, 2H); 3.15 in (m, 1H); 3,00 (s, 3H); 2,92-2,70 (m, 4H); 2.40 a (d, 2H, J=7 Hz); of 2.15 (m, 2H); of 1.88 (m, 1H); of 1.45 (d, 3H, J=7 Hz); to 0.92 (d, 6H, J=7 Hz).

Iodide R(-)-2-[(4'-isobutylphenyl)-N-(trimethylammonio)methylamide]propionamide

TPL 70-72°

[α]D= -18(c = 1,0; CH3OH)

1H-NMR (DMSO-d6) δ 7,22 (d, 2H, J=8 Hz); 7,11 (d, 2H, J=8 Hz); 6,25 (USS, 2H, CONH); 3,57 (m, 1H); 3,30 (m, 2H); 3,10 (s, 9H); of 2.45 (d, 2H, J=7 Hz); 2.40 a (m, 2H); of 1.88 (m, 1H); to 1.75 (m, 2H); of 1.52 (d, 3H, J=7 Hz); to 0.92 (d, 6H, J=7 Hz).

Iodide R(-)-{3-[2-(3'-benzoylphenyl)propionamido]propyl}trimethylammonium

TPL 62-65°

[α]D= -16,3(c = 1,0; CH3OH)

1H-NMR (DMSO-d6) δ to 8.20 (t, 1H, J=7 Hz, CONH); 7,81-7,47 (m, 9H); of 3.75 (m, 1H); 3.27 to 3,05 (m, 4H); 3,00 (s, 9H); of 1.85 (m, 2H); to 1.37 (d, 3H, J=7 Hz).

Iodide R(-)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-1-methylpiperidine

TPL 69-73°

[α]D= -10(c = 0,6; CH3OH)

1H-NMR (DMSO-d6) δ 8,18 (t, 1H, J=7 Hz, CONH); 7,80-7,47 (m, 9H); 3,70 (m, 1H);3,28 was 3.05 (m, 8H); 2,92 (s, 3H); 1,87-of 1.53 (m, 6H); to 1.42 (m, 2H); to 1.38 (d, 3H, J=7 Hz).

Iodide R(-)-{3-{2-[2-(2,6-dichlorophenylamino)phenyl]propionamide}propyl}trimethylammonium

[α]D= -15(c = 1,0; CH3OH)

1H-NMR (DMSO-d6) δ 8,48 (m, 1H, CONH); of 8.27 (s, 1H, NH); 7,52 (d, 2H, J=8 Hz); 7.18 in (q, 2H, J1=8 Hz, J2=16 Hz); 7,05 (t, 1H, J=7 Hz); to 6.88 (t, 1H, J=7 Hz); 6.30-in (d, 1H, J=8 Hz); of 3.75 (m, 1H); 3,30 (m, 11H); is 3.21 (m, 2H); of 1.88 (m, 2H); of 1.64 (d, 3H, J=7 Hz).

Iodide (2R),(4, S) 1-{4-carboxy-4-[2-(4-isobutylphenyl)propionamido]butyl}-1-methylpiperidine

[α]D= -9,5(c = 1,0; CH3OH)

1H-NMR (DMSO-d6) δ 8,66 (USS, 1H, CONH); 7,22 (d, 2H, J=8 Hz); 7.5 (d, 2H, J=8 Hz); 4,00 (m, 1H); of 3.80 (m, 1H); 2.95 and (m, 6H); 2,90 (s, 3H); of 2.45 (d, 2H, J=7 Hz); is 1.82 (m, 1H); 1.70 to to 1.33 (m, 10H); to 1.31 (d, 3H, J=7 Hz); to 0.89 (d, 6H, J=7 Hz).

Iodide (2R)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4-carbonyl)piperidine

[α]D= -39(c = 1; CH3OH)

1H-NMR (DMSO-d6) δ 8,15 (t, 1H, J=6 Hz, CONH); 7,28 (d, 2H, J=8 Hz); for 7.12 (d, 2H, J=8 Hz); of 3.80 (m, 1H); 3,70 (m, 2H); 3,35-of 3.25 (m, 6H); 3,18 (s, 3H); 2,35 (d, 2H, J=7 Hz); 2,12 (m, 4H); of 1.85 (m, 1H); 1,50 (m, 2H); to 1.37 (d, 3H, J=7 Hz); of 0.87 (d, 6H, J=7 Hz).

Iodide 2R-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4"-carboxyamide)piperidine

[α]D= -25(c = 1; CH3OH)

1H-NMR (DMSO-d6) δ a total of 8.74 (d, 2H, J=8 Hz, CONH2); 8,18 (t, 1H, J=6 Hz, CONH); 7,30 (d, 2H, J=8 Hz); 7,22 (d, 2H, J=8gts); of 3.75 (m, 1H); to 3.45 (m, 2H); at 3.35 (s, 3H); 3,20-3,00 (m, 6H); of 2.38 (d, 2H, J=7 Hz); of 2.15 (m, 1H); 1,90 (m, 1H); to 1.75 (m, 6H); to 1.35 (d, 3H, J=7 Hz); of 0.85 (d, 6H, J=7 Hz).

IO is the ID of the R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]propionamide

[α]D= -23(c = 1; CH3OH)

1H-NMR (DMSO-d6) δ 7,80 (DD, 1H, J1=8,4 Hz, J2=2 Hz); at 7.55 (d, 1H, J=2 Hz); from 7.24 (m, 2H); 7,10 (m, 2H); 7,00 (d, 2H, J=8,4 Hz); 6,20 (USS, 1H, CONH); 3,70 (s, 2H); 3,50 (m, 1H); 3,20 (s, 9H); of 2.45 (d, 2H, J=7 Hz); of 1.88 (m, 1H); of 1.50 (d, 3H, J=7 Hz); of 0.85 (d, 6H, J=7 Hz).

Example 2

The following connection receive according to the method described in example 1, but using as reagent ethyliodide:

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}of triethylamine

TPL 100-102°

[α]D= -19,5(c = 1,0; CH3OH)

1H-NMR (CDCl3) δ the 7.43 (d, 2H, J=8 Hz); 7,22 (t, 1H, J=6 Hz, CONH); 7,10 (d, 2H, J=8 Hz); a 3.83 (m, 1H); of 3.77 (m, 2H); 3,55-to 3.35 (m, 2H); 3.15 in (kV, 6H, J=7 Hz); 2.95 and (t, 9H, J=7 Hz); 2,42 (d, 2H, J=7 Hz); is 2.05 (m, 2H); of 1.85 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 0,9 (d, 6H, J=7 Hz).

Example 3

The following connection receive according to the method described in example 1, but using as the reagent bensulide:

Iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(N-benzyl)-N,N-dimethylammonio

TPL 97-100°

[α]D= -12(c = 1,0; CH3OH)

1H-NMR (CDCl3) δ 7,42 (d, 2H, J=8 Hz); 7,30-7,25 (m, 5H); then 7.20 (t, 1H, J=6 Hz, CONH); 7,07 (d, 2H, J=8 Hz); of 3.85 (m, 1H); and 3.72 (m, 2H); 3,68 (s, 2H); 3,55-of 3.32 (m, 2H); 3,20 (s, 6H); 2.40 a (d, 2H, J=7 Hz); was 2.05 (m, 2H); to 1.83 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 0,9 (d, 6H, J=7 Hz).

Example 4

The following connection receive according to the method described in example 1, but using as reagent Ziklag killticketresult:

Methanesulfonate R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-N-cyclohexylmethyl-N,N-dimethylammonio

[α]D= -23(c = 1,0; CH3OH)

1H-NMR (DMSO-d6) δ 7,44 (d, 2H, J=8 Hz); then 7.20 (t, 1H, J=6 Hz, CONH); was 7.08 (d, 2H, J=8 Hz); a 3.83 (m, 1H); of 3.77 (m, 2H); 3,55-3,20 (m, 4H); 3,18 (s, 6H); 3,00 (s, 3H); 2.40 a (d, 2H, J=7 Hz); is 2.05 (m, 2H); 1,83 (m, 1H); to 1.75 (m, 5H); to 1.48 (m, 1H); of 1.45 (d, 3H, J=7 Hz); 1,22 (m, 3H); of 0.95 (m, 2H); 0,9 (d, 6H, J=7 Hz).

Example 5

The following connection receive according to the method described in example 1, but using allylbromide instead of under the conditions:

Bromide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-arylpiperazine

[α]D= -14,5(c = 0.5; CH3OH)

1H-NMR (DMSO-d6) δ with 8.05 (t, 1H, J=6 Hz, CONH); to 7.25 (d, 2H, J=8 Hz); was 7.08 (d, 2H, J=8 Hz); 6,05 (m, 1H); to 5.35 (d, 1H, J=2 Hz); further 5.15 (d, 1H, J=2 Hz); of 3.80 (d, 2H, J=7 Hz); 3,55 (m, 1H); 3.25 to to 3.02 (m, 8H); of 2.38 (d, 2H, J=7 Hz); 1.85 to 1.55V (m, 7H); 1,50 (m, 2H); to 1.35 (d, 3H, J=7 Hz); to 0.88 (d, 6H, J=7 Hz).

Example 6

The following connection receive on the basis of hydrochloride iodide (4-AMINOPHENYL)trimethylammonium (commercial reagent):

iodide R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]propionamide

Hydroxybenzotriazole (0,62 g, 4,58 mmol) is added at T=0°to a solution of (R)(-)ibuprofen (1.01 g, 5 mmol) in DMF (4.5 ml). The solution is stirred at T=0°C for 30 min, then added to the mixture hydrochloride iodide (4-AMINOPHENYL)trimethylammonium (1,433 g, 4,56 mmol). Gradually small stands on the s added N,N-dicyclohexylcarbodiimide (1,02 g, of 4.95 mmol). After stirring at T=0°C for 2 h, the mixture is left to warm to room temperature, then stirred for 24 hours DCU) which is formed is filtered off and the DMF is distilled off under reduced pressure. The residue is dissolved in N2Oh and stirred in diisopropyl ether (30 ml) overnight at room temperature, the precipitate is filtered under vacuum and dried in an oven at T=40°C for 6 hours, getting a white solid (1,67 g, 3.58 mmol).

[α]D= -31(c = 1; CH3OH)

1H-NMR (DMSO-d6): δ a 7.85 (DD, 1H, J1=8,4 Hz, J2=2 Hz); a 7.62 (d, 1H, J=2 Hz); from 7.24 (m, 2H); 7,10 (m, 2H); 7,02 (d, 2H, J=8,4 Hz); 6,15 (USS, 1H, CONH); 3,50 (m, 1H); of 3.25 (s, 9H); of 2.45 (d, 2H, J=7 Hz); of 1.85 (m, 1H); of 1.52 (d, 3H, J=7 Hz); of 0.90 (d, 6H, J=7 Hz).

1. Compounds (R)-2-arylpropionate formula (I):

where Ar denotes aryl of formula (IIIb):

where Arbmeans phenyl, mono - or politeley groups: chlorine, fluorine, f denotes hydrogen, a linear or branched C1-C5alkyl residue, benzoyl, 2,6-dichlorophenylamino, 2,6-dichloro-3-methylphenylamine;

R is hydrogen, C1-C4-alkyl;

X means a linear or branched C1-C6-alkylene, optionally substituted by a group of CO2R4where R 4means hydrogen or linear or branched C1-C6is an alkyl group;

phenyl or a group of phenylmethylene formula

R1, R2and R3means independently linear or branched C1-C6-alkyl, C3-C7cycloalkyl,3-C6alkenyl, aryl, aryl-C1-C3-alkyl;

or R1and R2together with the N atom to which they are attached, form a nitrogen-containing 6-membered heterocyclic ring of formula (II) and R3independently has a value, as indicated above,

where Y represents a simple bond, a methylene group, oxygen atom or sulfur atom;

p means an integer 2;

Z-means pharmaceutically acceptable counterion of the Quaternary ammonium salts, provided that when Ar means biphenyl, R2and R3not mean ethyl.

2. Compounds according to claim 1, where Ar denotes aryl of formula (IIIb):

where Arbmeans phenyl, mono - or politeley groups: chlorine, fluorine, f denotes hydrogen, a linear or branched C1-C5the alkyl residue.

3. Compounds according to claim 2, where R is hydrogen;

X is the linear C1-C6-alkylen, predpochtite the flax, With 2-C4, optionally substituted C1group-CO2R4as defined above;

phenyl or a group of phenylmethylene formula

4. Compounds according to claim 3, where x is the linear C2-C4-alkylen.

5. Compounds according to claim 1, where the group NR1R2R3means the group of ammonium, triethylamine, N-methyl-N,N-diethylamine, N-methyl-N,N-Diisopropylamine, N-cyclohexylmethyl-N,N-dimethylamine, N-cyclopentylamine-N,N-dimethylamine, N-methyl-1-piperidine, N-ethyl-1-piperidine, N-methyl-4-morpholine, N-methyl-4-thiomorpholine, N-benzyl-N,N-dimethylamine, N-allyl-1-piperidine.

6. Compounds according to claim 2, where the group NR1R2R3means the group of ammonium, triethylamine, N-methyl-N,N-diethylamine, N-methyl-N,N-Diisopropylamine, N-cyclohexylmethyl-N,N-dimethylamine, N-cyclopentylamine-N,N-dimethylamine, N-methyl-1-piperidine, N-ethyl-1-piperidine, N-methyl-4-morpholine, N-methyl-4-thiomorpholine, N-benzyl-N,N-dimethylamine, N-allyl-1-piperidine.

7. Compounds according to any one of claims 1 to 6, where Z-means a halide selected from Cl-I-, Br-the sulfate anion, methanesulfonate or p-toluensulfonate.

8. Compounds according to any one of claims 1 to 6, where Ar is selected from values such as 4-isobutylphenyl, 3-benzoylphenyl.

9. Compounds according to claim 2, where Ar PR is dstanley the 2-(2,6-dichlorophenylamino)phenyl, 2-(2,6-dichlorophenylamino)-5-chlorophenyl, 2-(2,6-dichloro-3-methylphenylamine)phenyl.

10. Compounds according to claim 9, where Z-means a halide selected from Cl-I-, Br-the sulfate anion, methanesulfonate or p-toluensulfonate.

11. Compounds according to claim 1, selected from among the following:

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-trimethylammonium;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-trimethylammonium;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-N-ethyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-N-cyclohexylmethyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-cyclopentylmethyl)propionamido]propyl}-trimethylammonium;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-N-isopropyl-N,N-dimethylammonio;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]butyl}-trimethylammonium;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-1-methylpiperidine;

iodide (R)-{3-[2-(3-benzoylphenyl)propionamido]propyl}-1-methylpiperidine;

iodide (R)-{3-[2-(4-isobutylphenyl)propionamido]propyl}-4-methylmorpholine;

methanesulfonate (R)-{3-[2-(3-isopropylphenyl)propionamido]propyl}-4-methylthiophene;

bromide (R)-{2-[2-(4-isobutylphenyl)propionamido]ethyl}-trimethylammonium;

p-toluensulfonyl the (R)- {2-[(4-isobutylphenyl)propionamido]-1,1-dimethyl}piperidine;

methanesulfonate (R),(S')-2-(4-isobutylphenyl)-N-[(1-carboxy-2"-N,N,N-ammonium)ethyl]propionamide;

iodide R(-)-2-[(4-isobutylphenyl)-N-(trimethylammonium)methylamide]-propionamide;

methanesulfonate (R)-(3-{2-[2-(2,6-dichlorophenylamino)phenyl]propionamide}propyl)-trimethylammonium;

iodide (2R),(4, S)-1-{4-carboxy-4-[2-(4-isobutylphenyl)propionamido]butyl}-1-methylpiperidine;

iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(N-benzyl)-N,N-dimethylammonio;

iodide 2R-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4"-carboxamide)piperidine;

iodide (2R)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-(1"-methyl-4-carbonyl)piperidine;

iodide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-triethylamine;

bromide R(-)-{3-[2-(4'-isobutylphenyl)propionamido]propyl}-1-arylpiperazine;

iodide R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]-propionamide;

iodide R(-)-2-[(4'-isobutyl)phenyl]-N-[4"-N,N,N-trimethylaminoethyl]-propionamide.

12. Compounds according to any one of claims 1 to 6, 11 for use as drugs having inhibitory activity against the chemotaxis of polymorphonuclear leukocytes and monocytes induced by fractions of complement Sa.

13. Compounds according to any one of paragraphs. claims 1 to 6, 11 to use as inhibitor is the chemotaxis of neutrophils and monocytes, induced Sa.

14. The use of compounds according to any one of claims 1 to 6, 11 for the treatment of psoriasis, pemphigus and pemphigoid, rheumatoid arthritis, chronic inflammatory pathologies of the gut including ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary disease and glomerulonephritis.

15. The use of compounds according to any one of claims 1 to 6, 11 for the prevention and treatment of lesions caused by ischemia and reperfusion.

16. The pharmaceutical composition having inhibitory activity against the chemotaxis of polymorphonuclear leukocytes and monocytes induced by fractions of complement Sa containing compound according to claims 1-11 mixed with appropriate media.

17. The method of obtaining the compounds (R)-2-arylpropionate formula (I)

where Ar, X, R1, R2, R3have the meanings as defined in claim 1, including the interaction of amides of the formula (IV)

with compounds of formula R3Z, where Z means a conventional leaving group such as chloride, bromide, iodide, methanesulfonate, p-toluensulfonate, sulfate.



 

Same patents:

FIELD: chemistry of metalloorganic compounds, agriculture.

SUBSTANCE: invention describes derivatives of mepiquate borate of the general formula (I): wherein DMP means N,N-dimethylpiperidinium (mepiquate); M means metal cation acceptable for agriculture and chosen from a series comprising sodium, potassium, magnesium, calcium, zinc, manganese or copper, hydrogen atom or NH4+; O means oxygen atom; A means chelate of complex-forming fragment bound with one boron atom and representing (lower)-alkylglycols or sugars; n and m mean similar whole numbers in the range from 1 to 6; x means a whole or fraction number in the range from 0 to 10; y means a whole or fraction number in the range from 1 to 48; z means a whole or fraction number in the range from 0 to 48; v means a whole or fraction number in the range from 0 to 24, and w means a whole or fraction number in the range from 0 to 24. Also, invention describes methods for preparing compound of the formula (I) by interaction of N,N-dimethylpiperidinium hydroxide with boric acid and/or boron-containing oxides and optionally with metal hydroxides acceptable for agriculture indicated above or electrochemical method involving interaction of N,N-dimethylpiperidinium halide in the presence of water and boric acid and in the presence metal hydroxides acceptable for agriculture by bipolar electrodialysis. Invention describes electrochemical method for preparing N,N-dimethylpiperidinium hydroxide and a suspension concentrate possessing the plant growth-regulating effect prepared by mixing N,N-dimethylpiperidinium hydroxide, boron-containing compound chosen from boric acid and borate salt with a thickening agent and water, or by mixing compound of the formula (I) with Na2B8O13 x 4 H2O, a thickening agent and water. Prepared derivatives of mepiquate borate possess the improved indices of hygroscopicity and corrosion activity.

EFFECT: improved preparing methods, valuable properties of derivatives.

22 cl, 7 tbl, 16 ex

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

SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:

eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.

EFFECT: improved preparing method.

2 cl, 4 tbl, 4 ex

The invention relates to the field of organic chemistry and relates to new triiodide 1,2,3-substituted benzimidazole with antimicrobial and anti-tumor activity, which may find application in medicine, as well as methods for their preparation

The invention relates to the production technology of heterocyclic substances, in particular to the production technology, morpholine 3-methyl-1,2,4-triazolyl-5-thioacetate used in medicine and veterinary medicine

The invention relates to an improved method of obtaining a known regulator of growth - meekatharra, N,N-dimethylpiperidinium

The invention relates to medicine, specifically to medicines used in the treatment of ischemic heart disease, and arrhythmias complicating it

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

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:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

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

20 cl, 283 ex

The invention relates to a new group of individual chemical compounds - cyclic amino compounds represented by the following formula:

< / 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

The invention relates to new derivatives of biphenylamine formula (I)

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

or denotes the formula (II)

,

where X1oxygen,

or formula (III)

< / BR>
R1- cycloalkyl with 5-7 carbon atoms, Ar1, CR4R5AG2, (CH3)2R6, R2is hydrogen, alkyl, hydroxyl, halogen, O - alkyl, R3is hydrogen, alkyl, R4- alkyl, trifluoromethyl, CH2HE, R5is hydrogen, alkyl, trifluoromethyl, or R4and R5may together form alkylene, R6- CH2OH, CONR7R8CH2R7R8provided that R1means associated through alkylene unsubstituted phenyl residue, or their acid additive salts with pharmacologically acceptable acids

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B)

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 invention relates to a derivative butenova or propanolol acid having a phenyl or heterocyclic ring in the omega-position

FIELD: medicine, in particular gastroentherology.

SUBSTANCE: claimed method includes complex administration of thiamine bromide, cyancobalamine, tiotriazoline, legalone and pancreatine. 1.0 ml of 5 % Thiamine bromide solution and 0.05 % cyancobalamine solution are administered intramuscularly every other day for 1 month, wherein for the initial ten days 2.5 % tiotriazoline solution in dose of 2 ml two times per day also are administered intramuscularly, and for the next 20 days tiotriazoline in pelleted form is administered in dose of 100 u three times per day. Moreover for whole month legalone in dose of 2 pellet per day and pancreatine in dose of 0.25 mg per day also are administered. Method of present invention makes it possible to recover of patient ability to work for 6-12 months.

EFFECT: improved method for treatment of alcoholic liver diseases.

2 ex, 4 tbl

FIELD: pharmacy.

SUBSTANCE: invention relates to novel crystalline water-soluble salts of (2S,3S)-enantiomer of 2-[α-(2-ethoxyphenyl)benzyl]-morpholine that are its fumarate and succinate salts. Also, invention relates to a method for their preparing and their using in preparing pharmaceutical composition possessing property of selective inhibitor of reverse uptake of norepinephrine, and to a pharmaceutical composition comprising thereof.

EFFECT: improved and valuable properties of drug.

7 cl, 6 tbl, 5 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

Up!