Derivatives oxazolidinecarboxylate acid, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Describes the new derivatives oxazolidinecarboxylate acid of the formula I, where R1- CN, CSNR6R7C(= NH)SA, C(=NH)R6R7CH2NR6R7C(=NH)NHOH, CH2NHCOPh-E, CH2NHCONHPh-E or D

; R2- OH, CH2Cl or E - CN, CSNH2, C(= NH)SA, C(=NH)NH2; X is OH, OA, AS, when Y is CH2or C= O; R3- (CH2)m-COOR5, m=1, 2; R4- (CH2)p-COOR5or (CH2)q-O-(CH2)r-COOR5; n= 3; p=0.1; q=0; r=1 or 2; RH - phenylene; AS - amino acid residue selected from the group consisting of Al, -Ala, Asp, Phe, Tight, Tight(OMe), N - phenethyl--Al; R5- H, A; R6and R7each is hydrogen; a - C1-6-alkyl, as well as their physiologically acceptable salts, enantiomers or diastereomers. The compounds inhibit the binding of fibrinogen with the corresponding receptor and can be used for the treatment of thrombosis, osteoporosis, neoplastic diseases, apoplexy, heart attack, inflammation, arteriosclerosis and osteolytic diseases. Describes the method of production thereof, pharmaceutical composition and method of reception. 3 S. and 2 C.p. f-crystals.

(I)

The invention relates to a derivative oxazolidinone is UP>, CSNR6R7C(=NH)SA, C(=NH)OA, C(= NH)SAr, C(= NH)NHOH, C(= NH)NR6R7CH2NR6R7CH2NHC(=NH)NR6R7, NHC(= NH)NR6R7CH2NHCO-alk-NR6R7CH2NHCO-Ph-E, CH2NHCO-Ph-CH2-NR6R7CH2NHCONH - Ph-E or D;

X denotes OH, OA, AS, AS-AS',

< / BR>
or

< / BR>
D stands

< / BR>
E represents-CN, -C(=NH)OA, -CSNH2, -C(=NH)SA or-C(NH)NH2;

Y denotes CH2, CHOR5or C=0;

R2denotes H, A, Ar, OH, OA, CF3, CCl3, NR6R7, -ALK-NR6R7, -ALK-(CH2Ar) NR6R7;

< / BR>
R3represents -(CH2)m-COOR5;

R4represents -(CH2)p-COOR5or -(CH2)q-O-(CH2)r-COOR5;

AS or AS' each, independently of one another, denote an amino acid residue selected from the group consisting of Ala, -Ala, Arg, Asn, Asp, Gln, Glu, Gly, Sr, Leu, Lys, Orn, Phe, Pro, Ser, Thr, Tyr, Tyr(OMe), Val, C-allyl-Gly, C-propargyl-Gly, N-benzyl-Gly, N-phenethyl-Gly, N - benzyl--Ala, N-methyl-Ala and N-phenethyl- -Ala, and free amino or carboxyl groups can also contain themselves known conventional protective group;

R5, R6and R7each, independently of one another, denote H or A
r denotes 1 or 2;

A denotes alkyl with 1-6 C-atoms;

-Ala - means alkylene with 1-6 C-atoms;

Ardenotes phenyl or benzene; and

Ph denotes a phenylene;

and their physiologically acceptable salts and/or solvate.

Connection with such activity are known from European patent EP-A1 - 0381033.

The basis of the invention is to obtain new compounds with valuable properties, especially those that can be applied to obtain drugs.

This problem is solved according to the invention. It was found that the compounds of formula (I), and their solvate and salt with good endurance have valuable pharmacological properties. In particular, they inhibit the binding of fibrinogen, fibronectin and von Willebrand factor with fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa), as well as linking them and other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. The compounds thus have an impact on the activity of exchange of cell-cell and cell-matrix. In particular, they prevent the appearance of blood clots and platelet counts and so they can * have an effect on the tumor cells, they inhibit metastasis. Thus, they can also be used as anticancer agents.

Further, the compound suitable for the prevention and treatment of osteolytic diseases, in particular osteoporosis and restenosis after angioplasty. Further, they possess antiangiogenic properties.

In addition, the compounds possess antimicrobial activity and can be used for treatments and interventions where necessary to prevent defeat germs.

Connection properties can be according to the methods described in the European patent EP-A1-0462960. Inhibition of binding of fibrinogen with fibrinogen receptor can be proved according to the method specified in European patent EP-A1-0381033. The vast platelet aggregation effect can be detected in vitro by the method of born (Nature, 4832, 927-929, 1962). Suppression of receptor interactions 3-integrin with suitable ligands can be identified by the method of J. W. Smith and others, J. Biol. Chem., 265, 12267-12271 (1990).

The subject invention are compounds of the indicated formula (I), their salts and solvate, as well as the method of obtaining these compounds, characterized in that

a) compound of formula (I) visualaid youseo means; or

b) the compound of formula (II):

< / BR>
where R1has a specified value and denotes Cl, Br, OH or a reactive, esterified ester to OH-group, respectively, it is easy nucleophile replaced the deleted group;

enter into interaction with the compound of the formula (III): H - X'(III), where X' denotes AS, AS-AS',

< / BR>
or

< / BR>
and Y, R3, R4and n have the above meanings; or

C) the remainder of X turns in the remainder of X that an ester of the formula (I) omelet, or atrificial to complex ester of carboxylic acid of the formula (I); or

g) the remainder R1turn in the remainder R1that

-NO2and/or CN group, catalytically hydronaut; or

- the nitro-group by reacting with ammonia is transformed into C(=NH)-NH2group; or

- nitrile group in turn thiocarbamoyl group; or

- thiocarbamoyl group is transferred to alkylsulfonates; or

- karbamoilnuyu group is transferred to alkylimidazole; or

- methylsulfinylpropyl transferred to amedieval group; or

- nitrile group by interacting with NH2OH turn in C(=NH)-NHOH group; or

-NH2group turn in goinig turn in alkanolammonium group, CH2NHC(= NH)NR6R7group, CH2HCO - Ph-C (=NH) NH2group

CH2NHCO-Ph-CH2NR6R7group or CH2NHCONH-Ph-E-group; or

-1,2,4-oxadiazolyl group, respectively, 1,2,4-oxadiazolines group in turn amedieval group;

d) or a compound of the formula (IV):

< / BR>
where R1and X have the above values, enter into interaction with a reactive derivative of carbonic acid; and/or

e) compound of formula (V):

< / BR>
enter into interaction with 2 equivalents of a reactive derivative of carbonic acid and then oxidized; or

g) the compound of formula (I) by treatment with acid or base is translated into one of its salts.

Above - and below-reducing amino acid residues indicate residues of the following amino acids:

Ala = alanine; -Ala= alanine; Arg = arginine; Asn = asparagine; Asp = aspartic acid; Asp(OBut)= -butyl ester of aspartic acid; Gln = glutamine; Glu = glutamic acid; Gly = glycine; Leu = leucine; Lys = lysine; Orn = ornithine; Phe = phenylalanine; Pro = Proline; Sar = sarcosine (N-methylglycine); Ser = serine; Thr = threonine; Tyr= tyrosine; Tyr(OMe)= 2-amino-3-p-methoxyphenyl-propionic acid; Val = valine.

Further, actionid; DMF = dimethylformamide; EDCl = N-ethyl - N'-(3-dimethylaminopropyl)-carbodiimide; Et = ethyl; Me = methyl; OMe = methyl ester; OET = complex ethyl ester; TPA = triperoxonane acid.

Above and below the remains of R1and X are specified in the formula (I) value. If the compound of formula (I) contains a chiral center, it may be in several enantiomeric forms. All of these forms and their mixtures, in particular racemates, are within the scope of the invention.

In above - and below formulas A group contains 1 to 6, preferably 1, 2, 3 or 4 C-atoms. In particular, A preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl; hereinafter, also pentyl, 1-, 2 - or 3-methylbutyl; 1,1-, 1,2 - or 2,2-dimethylpropyl; 1-ethylpropyl; hexyl; 1-, 2 - or 3-methylpentyl.

X preferably represents-OH, -OCH3, -O-CH2-CH3, 4-carboxypeptidase-, 4-carboxyethylpyrrole-, 4-carboxylcontaining, and the corresponding complex group alilovic esters of these balances; 4-alkoxycarbonylmethyl-, 4-carboxymethylamino-, 4-carboxyethylpyrrole or especially preferred amino acid or dipeptide residue that h is, particularly preferred residues: Ala, -Ala, Gly, AGD, and-Ala-Asp, Phe, N-fenetylline, N-phenethyl-alanine or Sar.

C-terminal amino acid residue also can be associated with a conventional protecting group. Especially taking into account the etherification to complex ether.

The group R1preferably means-NH2, -C(=NH)-NH2, -CH2-NH2, -CH2-NH-CO - ALK-NH2, -CH2-NH-CO-Ph-C(=NH)-NH2, -CH2-NH-CO-ALK-C(=NH)-NH2, -CH2-NH-CO-Ph-CH2-NH2, NO2or CN. Further, R1in addition, preferably represents-C(=NH)-S-A - CSHH2, -C(=NH)-NHOH or

The rest Ar denotes unsubstituted benzyl or phenyl.

The parameters m and n preferably denotes 1, further, however, preferably 2 or 3. The variable p is preferably denotes 0 or 1, while q and r is preferably equal to 1.

Of the compounds of formula (I) are preferred those in which at least one of these residues, groups, and/or parameters is one of these preferred values. Some groups preferred compounds are those of formula (1a) to (1f), which correspond to the formula (I), where, however,

in 1a; R1indicates the but, 4-carboxyethylpyrrole - or 4-carboxylcontaining;

in 1c; R1denotes C(=NH)NH2and X denotes-Ala, Asp, Tyr, Tyr(OMe), N-phenethyl--Ala or Phe, and the corresponding esterified to esters derived;

in 1d: R1denotes C(=NH)NH2and X is 4-alkoxycarbonylmethyl-, 4-alkoxycarbonylmethyl-, 4-alkoxycarbonylmethyl-, 4-alkoxycarbonylmethyl - or 4-alkoxycarbonylmethyl;

in 1e; R1denotes C(=NH)NH2and X is 4-carboxybenzene - or 4-carboxyethylpyrrole;

in 1f: R1denotes C(=NH)NHOH, and X denotes one of these in PP (1a) - (1e) residues.

Further, in the invention include those compounds which contain NH2group and the NH2the group, however, includes in itself known protective group.

The compounds of formula (I), as well as source materials for their production, however, get themselves known methods, which are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg - Thieme, Stuttgart; hereinafter, J. March, Adv. Org. Chem., 3rd ed. (1985), J. Wiley and Sons), namely under reaction conditions and which offer more not mentioned options.

The source of the substance, if desired, can also be obtained in situ by the fact that they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

The compounds of formula (I) can be obtained by the fact that their release from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis, respectively, hydrogenolysis are those which generally correspond to the formula (I), however, instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably such that instead of the H atom, which is connected with the N-atom, contain protective for AMINOPHENYL group, in particular such that instead of HN-groups contain R'-N-group, where R' denotes a protective for AMINOPHENYL group, and/or such which, instead of the H atom of the hydroxyl group containing protective for hydroxyl function group, for example, those that correspond to the formula (I), however, instead of the group-COOH contain a group-COOR", where R ' denotes a hydroxyl protective for the function group.

In the molecule of the original veshestvami existing protective groups differ from each other, in many cases they can be selectively split.

The expression "protective for AMINOPHENYL group" is well known and relates to groups which are suitable for protecting (blocking) an amino group from chemical interactions, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are especially unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl(DNP)), arelaxation (for example, benzyloxyaniline (BOM) or kalkilya group (for example, benzyl, 4-nitrobenzyl, triphenylmethyl). As protective for AMINOPHENYL groups are removed after the desired reaction (or sequence of reactions), they were kind and magnitude, however, is not critical; however, a preferred group with 1-20, in particular 1-8 C-atoms. The expression "acyl group" in connection with the present method should be understood in its broadest sense. It covers produced from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids acyl group, and in particular alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such R is insoil or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.-butoxycarbonyl (BOC), 2-iodoxybenzoic; Uralelectromed as benzyl oxycarbonyl (CBZ), 4-methoxybenzeneboronic, 9-fluoro-ylmethoxycarbonyl (FMOC). Preferred protective for AMINOPHENYL groups are BOC, DNP and BOM, then, CBZ, benzyl and acetyl.

The expression "hydroxyl protective for function group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical interactions, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group; hereinafter, also alkyl groups. The nature and magnitude protective for hydroxyl group functionality is not critical, since the flow of the desired chemical reaction or sequence of reactions they again removed; preferred group with 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective for function groups are, inter alia, tert.-butyl, benzyl, p-nitrie as starting substances, the functional derivatives of compounds of formula (I) can be obtained by conventional means, who, for example, described in the above reference publications and patent applications, for example, by reacting compounds which correspond to formula (II) and (III), whereby, however, at least one of these compounds instead of H-atom contains a protective group.

The release of the compounds of formula I from their functional derivatives is carried out - depending on the protective group, for example using strong acids, expediently using triperoxonane acid or perchloric acid, but also using other strong inorganic acids as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid, or sulfonic acids, as benzene - or p-toluensulfonate. The presence of an additional inert solvent may, however, not always necessary.

As the inert solvent is preferably suitable organic, for example carboxylic acids, as acetic acid; ethers, like tetrahydrofuran (THF) or dioxane; amides as dimethylformamide (DMF); halogenated hydrocarbons like dichloromethane; hereinafter, also alcohols as methanol, ethanol or isopropanol; and water. Next, take into Unibake another solvent; perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. The reaction temperature for the cleavage are expediently approximately 0 to 50oC; preferably operate at a temperature in the range of 15-30oC (room temperature).

BOC-group can be split, for example, preferably using 40% triperoxonane acid in dichloromethane or using approximately 3 to 5 N. HCl in dioxane at 15-60oC; FMOC group can be split, for example, preferably by approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-50oC. Removal of DNP-groups are, for example, also with about 2-10% aqueous solution of 2-mercaptoethanol in a mixture of DMF with water at 15-30oC.

Hydrogenations removable protective group (for example, BOM, CB or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, expediently on the media, as coal). As a suitable solvent in the above, in particular, for example, alcohols, like methanol or ethanol, or amides, as DMF. Hydrogenolysis, as a rule, carried out at the rate uppy well flows, for example, in the presence of 5-10% palladium-on-coal in methanol at 20-30oC.

Next, gidrodinamicheskoe the transformation of 1,2,4-oxadiazoline-5-on-3-ilen groups, respectively, 5-alkyl-1,2,4-oxadiazol-3-ilen group, amedieval group can be realized, for example, by catalytic hydrogenation.

The compounds of formula (I) is also preferably can be obtained by interaction of oxazolidinone formula (II) with the compound of the formula (III). When this use is reasonable in itself known methods of nucleophilic substitution and/or N-alkylation of amines, respectively, the reactions leading to the amides.

Remove the group L in formula (II) preferably denotes Cl, Br or OH, respectively, produced from them delete the group, as, for example, tripterocalyx, toluensulfonate or methysulfonylmethane.

The reaction is preferably carried out in the presence of an additional base, such as hydroxide of alkali or alkaline earth metal or carbonate of alkali or alkaline earth metal as the hydroxide of sodium, potassium or calcium, sodium carbonate, potassium or calcium, in an inert solvent, for example, in halogenerator the Le, as acetonitrile; at temperatures from about -10oC to 200oC, preferably at 0-120oC. the addition of iodide, such as potassium iodide, can favor the reaction.

Educt of the formula (II), generally known or can be obtained by analogy with known compounds. Obtaining them are described, for example, in the patent Germany 3723797 (European patent 300272). They can be obtained, for example, by reacting correspondingly substituted aniline with allyl-chloride, then the conversion of the double bonds diol, entering into interaction with a reactive derivative of carbonic acid such as phosgene. N, N-carbonyldiimidazole, complex alkilany ester of carbonic acid or diphosgene, the oxidation product 5-oxazolidinecarboxylate acid and, if necessary, further activation by derivatization of the acid group.

In the compound of formula (II) balance L can be transformed into another residue L, for example, the fact that the OH-group (Y=OH) enter into interaction with SOCl2, SOBr2, methanesulfonamido or p-toluensulfonate.

The compounds of formula (III), generally known and available in the market.

The interaction of oxazo is a proton or an aprotic polar inert solvent, at temperatures from 20oC to the boiling point of the solvent. The reaction times range from 10 minutes to 24 hours, preferably 2-10 hours.

As the solvent usable in particular alcohols as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, as etilenglikolevye or monotropy ether (methylglycol or ethylglycol), simple etilenglikolevye ether (diglyme); ketones, such as acetone or butanone; NITRILES like acetonitrile; nitro compounds, as nitromethane or nitrobenzene; esters like ethyl acetate or hexamethylene phosphoric acid, sulfoxidov as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons like dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons, as benzene, toluene or xylene. Further, suitable mixtures of these solvents with each other. Particularly suitable N-organic.

Derivatives with a free primary or secondary amino group, it is advisable injected into the interaction in a protected form. As protective groups take into account videocase the example you can atrificial to the ester (X = OA) of the free acid group (X = OH) or via a peptide bond to bind with the amino acid or dipeptide. In addition, it is also possible to convert, for example, acid amide.

Further, the compound of formula (I) can be obtained by the fact that the remainder R1in the compound of formula (I) is transformed into another residue R1.

Especially ceanography can be restored to the aminomethyl group or to turn in amidinopropane; benzyl groups can be removed hydrogenations; aminomethyl group can be converted to guanidinoacetate group or nitrile group can be converted to thiocarbamoyl group.

The restoration of the cyano groups to aminomethyl groups should be better carried out by catalytic hydrogenation, for example, Raney Nickel, at temperatures of 0-100oC; preferably 10-30oC and at a pressure of 1-200 bar, preferably at normal pressure, in an inert solvent, e.g. a lower alcohol, like methanol or ethanol, expediently in the presence of ammonia. If you are, for example, approximately at 20oC and a pressure of 1 bar, then save all the original material benzyl ester or N-bessilny is one metal, preferably palladium-on-charcoal, and can be added to a solution of the acid, as acetic acid, and water.

To obtain the compounds of formula (I), where R1means guanidinopentanoic group corresponding aminoaniline connection can handle amidenus means. As amidaniel means the preferred 1-amidino-3,5-dimethylpyrazole, which is used in particular in the form of its nitrate. It is advisable to work with the addition of a base as triethylamine or ethyldiethanolamine, in an inert solvent or solvent mixture, for example, water with dioxane, at temperatures 0-120oC, preferably 60 to 120oC.

To obtain amidine formula (I) to the nitrile of the formula (I) can be attached ammonia. Accession preferably carry out multi-stage, that is in itself known (a) a nitrile using H2's turn in tioned that using alkylating agents, such as CH3I, translated into the corresponding complex S-alkyl-imitation, which, for its part, enter into interaction with NH3getting amidine; b) the nitrile with an alcohol, for example ethanol, in the presence of HCl in turn corresponds with the house of lithium and the product is then hydrolized.

Similarly, the corresponding H-hydroxyamides formula (I) is obtained from NITRILES, when you work on PP. a) or b), however, instead of ammonia, using hydroxylamine.

Next, N-hydroxyamides by entering into interaction with the acid chlorides of aliphatic carboxylic acids can be converted to 1,2,4-oxadiazole, respectively, 1,2,4-oxadiazoline, and then by catalytic hydrogenation, e.g. in the presence of Raney Nickel, Pd/C or PtO2, preferably in methanol, dioxane, glacial acetic acid, a mixture of glacial acetic acid with acetic anhydride or DMF, to translate in amidine.

Further, the compound of formula (I) can be obtained by the fact that the compound of formula (IV) enter into interaction with a reactive derivative of carbonic acid. Reactive derivatives of carbonic acid may constitute, for example, above, and particularly preferred phosgene and diphosgene, and N,N - carbonyldiimidazole. As a derivative of carbonic acid, hereinafter, suitable especially diallylmalonate as diethylcarbamyl further complicated alkalemia esters of Harborview acid, as ethylchloride. Preferably a derivative of coal cilingiroglu agent. However, there might also be one of these solvents, if it is inert in this interaction. Further, it is recommended to add the base, especially alcoholate of alkali metal tert.-butyl potassium. Suitable work when the reaction temperature 0-150oC, preferably 70-120oC.

Educt of the formula (IV), as a rule, are new. Get them, for example, the fact that substituted on the aromatic ring of aniline enter into interaction with a-hydroxy-halogen-carboxylic acid.

In addition, the compound of formula (I) can be obtained by the fact that the diol of formula (V) enter into interaction with an excess of a reactive derivative of carbonic acid, namely preferably in the abovementioned conditions. While derivatives of carbonic acid are commercially available, the compounds of formula (V) can be obtained, for example, by interaction of allylchloride with p-aminobenzonitrile, conversion of double bonds in dihydroxypropyl and administration in cooperation with hydroxylamine.

The basis of the formula (I) with acids can be converted to the corresponding salt accession acid. For this interaction, in particular, apply acid that d is now acid; halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid; sulfamic acid; further, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, triperoxonane acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene-mono - and-disulfonate, louisanna acid.

Free base of formula (I), if desirable, can be free from their salts by treatment with strong bases like sodium hydroxide or potassium hydroxide, sodium carbonate or potassium.

You can also carboxylic acids of the formula (I) by entering into cooperation is Oli sodium, potassium or calcium.

The compounds of formula (I) may contain one or more chiral centers and therefore may be in racemic or optically active form. Resulting racemates can be split itself known methods, mechanically or chemically, to the enantiomers.

Preferably, from the racemic mixture by interaction with optically active separating agent formed diastereomers. As the separation agent is suitable, for example, optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphorsulfonic as camphorsulfonate.

Preferably the separation of enantiomers is carried out using filled optically active separating agent (such as dinitrobenzoyl-phenyl-glycine) column, as an eluting suitable means, for example, a mixture of hexane with isopropanol and acetonitrile.

Naturally, it is also possible to obtain optically active compounds of formula (I) according to the above methods, because they use the original substance (for example, those of formula (II), which should be used for the preparation of pharmaceutical preparations the fact that it, together with at least one carrier or auxiliary substance and, if desired, together with one or more other biologically active substances brought to a suitable dosage forms. The thus obtained composition can be used as a drug in medicine or veterinary medicine. As carriers to apply an organic or inorganic substances which are suitable for intestinal (e.g., oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates as lactose or starch, magnesium stearate, talc, cellulose. For oral administration in particular are tablets, coated tablets, capsules, syrups, juices or drops, are of special interest lacquered tablets and capsules resistant to gastric juice coatings, respectively, the shells of the capsules. For rectal use suppositories, for parenteral administration, solutions, preferably oily or aqueous rarional sprayers, which contain biologically active compound either dissolved or suspended in a mixture of working gases. It is advisable at this biologically active substance used in micronized form, and can be added one or more additional physiologically acceptable solvents, such as ethanol. Solutions for inhalation can be entered using a conventional inhalers. The new compounds can also be liofilizirovanny and received lyophilizate be used, for example, for the preparation of drugs for injection. These compositions can be sterilized and/or may contain auxiliary substances, such as preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants and/or fragrances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

Proposed according to the invention substances normally administered analogously to other known commercially available pharmaceutical preparations, in particular, however, similar to the one described in European patent EP-A-459256 SOEDINENIYa is about 0.1-20 mg/kg, in particular 1-10 mg/kg body weight. Special dose for each particular patient, however, depends on various factors, for example, the effectiveness of used special connections, age, body weight, General health, sex, cost, time and route of administration, rate of excretion, combination of drugs and the severity of the respective disease, which has implications for therapy. Preferably oral administration.

All above - and below the temperature specified in theoC. In the following examples, "conventional treatment" means add, if necessary, water; depending on the structure of the target product, set the pH-value at 2-8; extracted with ethyl acetate or dichloromethane; separated; the organic phase is dried over sodium sulfate; and evaporated and purified by chromatography on silica gel and/or by crystallization. If you specify the molecular weight, they represent common in mass spectrometry values "M" and the values of the FAB (fast atom bombardment), also known as "M + 1".

Example 1

To a solution of 3.6 g of dihydrate of sodium dihydrophosphate, 3,9 g metaperiodate sodium and 36 mg RuCl3in 23 ml of water with 2.3 ml diplomatickemu patent 300272), dissolved in 12 ml of acetonitrile. The reaction mixture was stirred at room temperature for 12 hours, filtered and processed as usual. After concentration to dryness in vacuo get 3-(4 - tianfeng)-2-oxo-5-oxazolidinecarboxylate acid. So pl.=204oC.

Example 2

27.9 g of 3-(4-Tianfeng)-2-oxo-5-oxazolidinecarboxylate acid (produced according to example 1) and 26.4 g of hydroxyammonium in a mixture of 750 ml of methanol and 30 ml of water in the presence of at 53.4 g of sodium carbonate is boiled for 5 hours. The formed precipitate is sucked off, washed with methanol and dried. Receive, after treatment with hydrochloric acid, the hydrochloride of 3-/4-(amino-(hydroxyimino)methyl)-phenyl/-2 - oxo-5-oxazolidinecarboxylate acid. So pl. 205-208oC.

Example 3

of 13.9 g of 3-/4-(Amino-(hydroxyimino)methyl)-phenyl/-2-oxo-5-oxazolidinecarboxylate acid (produced according to example 2) are dissolved in 210 ml of glacial acetic acid, add 11.3 g trichlormethane of ester Harborview acid and boiled for 3 hours. Then cooled to room temperature and processed as usual. Get 3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl/-2-oxo - 5-oxazolidinecarboxylate acid. So pl. 250-253oC.

Example opasno example 3), 2,77 g of tert. -butyl ether piperidine-4 - carboxylic acid, 2,02 g of 1-hydroxybenzotriazole and 2.86 g of N-(3 - dimethylaminopropyl)-N'-ethylcarbodiimide, in the form of hydrochloride in 20 ml of DMF added 3.03 g of N-methyl-research and stirred for 5 hours at room temperature. Then added dropwise, with vigorous stirring, 200 ml of water, the resulting crystalline precipitate was separated, treated it with 90 ml of dichloromethane and dried over

sodium sulfate. The solution was concentrated in vacuo, the resulting oil triturated with diethyl ether and receive tert.- butyl ether 1-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl/-2-oxo-5-oxazolidinecarboxylate}-piperidine-4-carboxylic acid. So pl. 171-175oC.

Similarly, by reacting 3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2 - oxo-5-oxazolidinecarboxylate acid tert.-butyl ether of 2-(piperidine-4-yl)-acetic acid tert get.-butyl ether 2-{ 1-/3-(4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl)-2 - oxo-5-oxazolidinecarboxylate/-piperidine-4-yl}-acetic acid;

with the ethyl ester of 2-(piperidine-4-yl)-acetic acid getting ethyl ester 2-{ 1-/3-(4-(5-oxo-1,2,4-oxadiazolyl - 3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/-piperidine-4-yl} -acetic acid; so th ether 2-{1-/3-(4-(5-oxo-1,2, 4-oxadiazoline-3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-yl-oxy}-acetic acid; so pl. 180-181oC;

with tert.-butyl ether of 2-(piperidine-3-yl-oxy)-acetic acid tert get. -butyl ether 2-{1-/3-(4-(5-oxo-1,2,4-oxadiazolyl-3 - yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/-piperidine-3-yl-oxy} -acetic acid, so pl. 92-95oC;

with tert.-butyl ether 2-(2-oxo-piperazine derivatives)- acetic acid tert get. -butyl ether 2-{4-/3-(4-(5- oxo-1,2,4-oxadiazolyl-3-yl)-phenyl)-2-oxo-5 - oxazolidinecarboxylate/-2-oxo-piperazine derivatives} -acetic acid; so pl. 155-157 C;

with tert. -butyl ester (2R)-2 - aminopropionic acid (H-Ala-OBut) receive tert.-butyl ether (2R)-2-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl/-2-oxo-5-oxazolidinecarboxylate-amino} -propionic acid, so pl. 105-107oC;

with methyl ether (2R)-2 - aminopropionic acid (H-Ala-OMe) get methyl ester (2R)- 2-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate}-propionic acid, so pl. 199-201oC;

with di-tert.-butyl ether (2R)-2-amino amber acid (H-Asp(OBut)-OBut) receive di-tert.-butyl ether (2R)-2-{ 3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate}-succinic acid, so pl. 175-176oC;<,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate}-propionic acid, so pl. 143 - 146oC;

with tert. methyl ether 3-aminopropionic acid (H-Ala-OMe) get methyl ester 3-(3-/4-(5-oxo - 1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate)-propionic acid, so pl. 230-232oC;

with tert. - butyl ester (2R)-2-amino-3-(4-hydroxyphenyl)-propionic acid (H-Tyr-OBut) receive tert.-butyl ether (2R)-2-(3- /4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate)-3-(4-hydroxyphenyl)-propionic acid;

with tert.-butyl ether (2R)-2-amino-3-(4-methoxyphenyl)-propionic acid (H-Tyr(OMe)-OBut) receive tert.- butyl ether (2R)-2-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl/-2-oxo-5-oxazolidinecarboxylate} -3-(4-methoxyphenyl)- propionic acid;

with tert. -butyl ether, 3-N-phenethyl-aminopropionic acid tert get. -butyl ether 3-{3-/4-(5-oxo-1,2,4 - oxadiazolyl-3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate-(N-phenethyl)-amino}-propionic acid;

with benzyl ether 2-piperazine derivatives, acetic acid getting benzyl ester 2-{ 1-/3(4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl)-2-oxo-5-oxazolidinecarboxylate/-piperazine-4-yl}-acetic acid, so pl. 165-170oC;

with benzyl ether 3-piperazine derivatives-propionic acid benzyl get aired 3-{ 1-/3-(4-(553oC.

Example 5

of 1.37 g of tert. -butyl ester 1-{ 3-/4(5-oxo-1,2,4-oxadiazolyl-3 - yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate} -piperidine-4-carboxylic acid are dissolved in 50 ml of methanol and hydronaut in the presence of Raney Nickel. Then the reaction mixture is filtered and the filtrate concentrated in vacuo. The resulting product by heating is treated with 20 ml of ethyl acetate and the product after cooling is sucked off. Receive tert.-butyl ester 1-{3-/4 - lidinopril/-2-oxo-5-oxazolidinecarboxylate}-piperidine-4-yl - carboxylic acid, so pl. 160oC.

Similarly, by reductive removal of 5-oxo-1,2,4-oxadiazolyl group, tert. -butyl ester 2- {1-/3-(4-(5-oxo-1,2,4-oxadiazolyl - 3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-yl} -acetic acid tert get.-butyl ether 2-{1-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-yl}-acetic acid; ethyl ester 2-{1-/3- (4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-yl} -acetic acid getting ethyl ester 2-{ 1-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-yl}-acetic acid, so pl.=210-211oC;

from tert. -butyl ester 2-{1-/3-(4-(5-oxo-1,2,4 - ox is lovy ether 2-{1-/3- (4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-yl-oxy}-acetic acid, so pl. 100oC;

from tert. -butyl ester 2-{1-/3-(4-(5-oxo-1,2, 4-oxadiazol-3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/- piperidine-3-yl-oxy} -acetic acid tert get. -butyl ether 2-{1-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- piperidine-3-yl-oxy} -acetic acid, so pl. = 139-144oC;

from tert.-butyl ether 2-{4-/3-(4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl)-2 - oxo-5-oxazolidinecarboxylate/-2-oxo-piperazine derivatives}-acetic acid tert get. -butyl ether 2-{4-/3-(4-amidinophenoxy)- 2-oxo-5-oxazolidinecarboxylate/-2-oxo-piperazine derivatives}-acetic acid, so pl. = 165-167oC;

from tert. -butyl ester (2R)-2-{3- /4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate-amino} -propionic acid tert get. -butyl ester (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate}- propionic acid, so pl. = 173-175oC;

from methyl ester (2R)-2-{3-/4-(5-oxo-1,2,4-oxadiazol - 3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate} -propionic acid get methyl ester (2R)-2-/3-(4-amidinophenoxy)-2 - oxo-5-oxazolidinecarboxylate/-propionic acid in the form of acetate, so pl. 190-192oC;

of di-tert.-butyl ether (2R)-2- /3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinyl is carbylamine/-succinic acid in the form of acetate, so pl. = 242oC-

from tert. -butyl ester 3-{3-/4-(5-oxo-1,2,4 - oxadiazolyl-3-yl)-phenyl] -2-oxo-5-oxazolidinecarboxylate} -propionic acid tert get. -butyl ester 3-{3-(4 - amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate}- propionic acid, so pl. = 164-167oC;

from methyl ester 3-{3-/4-(5-oxo-1,2,4-oxadiazol- -3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate} -propionic acid get methyl ether 3-/3-(4-amidinophenoxy) -2-oxo-5-oxazolidinecarboxylate-amino/-propionic acid in the form of acetate, so pl. = 207-209oC;

from tert. -butyl ester (2R)-2-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo - 5-oxazolidinecarboxylate-amino} -3-(4-hydroxyphenyl)-propionic acid tert get.-butyl ether (2R)-2-/3(4-amidinophenoxy)- 2-oxo-5-oxazolidinecarboxylate/-3-(4-hydroxyphenyl)- propionic acid;

from tert. -butyl ester (2R)-2-{3-/4-(5- oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate - amino]-3-(4-methoxyphenyl)-propionic acid tert get.-butyl ether (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-3-(4-methoxyphenyl)-propionic acid;

from tert. -butyl ester 3-{3-/4-(5-oxo-1,2,4-oxadiazolyl - 3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate-(N - fenati the - phenethyl)-amino/-propionic acid;

of the benzyl ester 2-{1-/3-(4-(5-oxo-1,2,4-oxadiazolyl - 3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/-piperazine-4-yl}- acetic acid getting benzyl ester 2-{1-/3- (4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-piperazine-4-yl}- acetic acid;

of the benzyl ester 3-{1-/3-[4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl] -2-oxo-5-oxazolidinecarboxylate}-piperazine-4-yl}-propionic acid benzyl get aired 3-{1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-piperazine-4-yl}-propionic acid.

Example 6

0,41 g of tert.-butyl ester 1-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-piperidine-4-yl-carboxylic acid in 40 ml of ethereal HCl solution is stirred for 2 hours at room temperature. The formed precipitate is sucked off and washed with 20 ml of ether. The product is then treated with 5 ml of acetonitrile for 10 minutes at 60oC, after cooling to room temperature is sucked off and washed with a small amount of acetonitrile. Get 1-/3(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate)-piperidine-4 - carboxylic acid hydrochloride. So pl. = 184oC (decomposition).

Similarly, by saponification of the corresponding esters, tert. -butyl lidinopril)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-yl} -acetic acid hydrochloride;

from tert. -butyl ester 2-{1-/3-(4-amidinophenoxy)-2- -oxo-5-oxazolidinecarboxylate/-piperidine-4-yl-oxy} -acetic acid get 2-{1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-yl-oxy} -acetic acid hydrochloride, T. pl. = 170-175oC (decomposition);

from tert.-butyl ether 2-{1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-3-yl-oxy}-acetic acid get 2-{1-/3(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-piperidine-3 - yloxy} -acetic acid hydrochloride, T. pl. = 127-129oC;

from tert. -butyl ester 2-{4-/3-(4-amidinophenoxy)-2 - oxo-5-oxazolidinecarboxylate/-2-oxo-piperazine derivatives} -acetic acid get 2-{4-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-2-oxo-piperazine derivatives} -acetic acid hydrochloride, T. pl. 63-70oC;

from tert. -butyl ester (2R)-2-/3-(4-amidinophenoxy)-2-oxo - 5-oxazolidinecarboxylate/-propionic acid get (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- propionic acid hydrochloride, T. pl. 190-194oC;

of di-tert.-butyl ether (2R)-2-/3-(4-amidinophenoxy)- 2-oxo-5-oxazolidinecarboxylate/-succinic acid get (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-disofenin)-2-oxo-5 - oxazolidinecarboxylate/-propionic acid is obtained 3-/3- (4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate-amino/-propionic acid hydrochloride, so pl. 243-244oC (decomposition);

from tert.-butyl ether (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-3-(4-hydroxyphenyl)-propionic acid get (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-3-(4-hydroxyphenyl)-propionic acid hydrochloride;

from tert. -butyl ester (2R)-2- /3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-3-(4 - methoxyphenyl)-propionic acid get (2R)-2-/3-(4- amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-3-(4 - methoxyphenyl)-propionic acid hydrochloride;

from tert. -butyl ester (2R)-2-/3-(4-amidinophenoxy)-2-oxo - 5-oxazolidinecarboxylate-(N-phenethyl)-amino/-propionic acid get (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate-(N-phenethyl)-amino/-propionic acid hydrochloride.

Example 7

1.0 g of Benzyl ester 2-{1-/3-(4-amidinophenoxy)-2 - oxo-5-oxazolidinecarboxylate/-piperazine-4-yl} -acetic acid in a mixture of 100 ml methanol and 50 ml of DMF catalytically hydronaut in the presence of palladium-on-coal until the cessation of hydrogen absorption. Then the reaction mixture is filtered and processed as usual. After trituration of the crude product with ether and drying receive 2-{ 1-/3-(4-amidine the>Similarly

of the benzyl ester 3-{1-/3-(4-amidinophenoxy)-2-oxo - 5-oxazolidinecarboxylate/-piperazine-4-yl} -propionic acid get 3-{1-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/- piperazine-4-yl}-propionic acid, so pl. 255 - 258oC (decomposition)

Example 8

Analogously to example 4, by reacting tert.-butyl ester of phenylalanine with 3-(4-tianfeng)-2-oxo-5-oxazolidin-carboxylic acid (produced according to example 1), receive tert.-butyl ether (2R)-2-/3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate/-3 - phenyl-propionic acid. So pl. 72oC.

Similarly, by reacting 3-(4-tianfeng) -2-oxo-5-oxazolidin-carboxylic acid

with benzyl ether piperidine-4-carboxylic acid get benzyl ester 1-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid, FAB (M + 1): 434;

with tert.-butyl ether of 2-(4-piperidinyloxy)-acetic acid tert get. -butyl ether 2-/1-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-4-piperidinyl-oxy/-acetic acid, so pl. 126-127oC.

Example 9

2.3 g of acid chloride of 3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate acid (so pl. 148-150oC; derived from acid pute-piperidinyloxy acid hydrochloride in 100 ml of dichloromethane in the presence of 5 ml of triethylamine at room temperature. After conventional treatment receive benzyl ester 2-{1-/3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate}- 4-piperazinil}-acetic acid. So pl. = 131-132oC.

Example 10

2.6 g of tert.-Butyl ether (2R)-2-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-3-phenylpropionic acid (produced according to example 8) dissolved in a mixture solvent consisting of 30 ml of pyridine and 5 ml of triethylamine, and stirred for 1.5 hours under ice cooling, and during this phase, continuously introducing gaseous hydrogen sulfide. Then the reaction mixture is stirred for further 24 hours at room temperature. After evaporation and normal processing of receive tert.-butyl ether (2R)-2-/3-(4- thiocarbamoyl-phenyl)-2-oxo-5-oxazolidinecarboxylate/-3 - phenyl-propionic acid. So pl. = 185-186oC.

Similarly

of the benzyl ester 1-/3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate/-piperidine-4-carboxylic acid get benzyl ester 1-/3-(4-thiocarbamoyl-phenyl)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid, so pl. = 167-169oC;

from tert. -butyl ester 2-{1-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-4-piperidinyloxy} -acetic acid tert get.-butyl ether 2-{ 1-/3-(4-dicarba delovogo ether 2-{1-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-4-piperazinil} -acetic acid getting benzyl ester 2-{1-/3-(4-thiocarbamoyl-phenyl)-2-oxo-5 - oxazolidinecarboxylate} -4-piperazinil/-acetic acid.

Example 11

0,92 g of tert. -Butyl ester (2R)-2-/3- (4-thiocarbamoyl-phenyl)-2-oxo-5-oxazolidinecarboxylate/-3 - phenylpropionic acid (produced according to example 10) was dissolved in 15 ml of acetone and mixed with 1.75 ml under the conditions. The solution is stirred for 2 hours at room temperature and processed as usual. Receive tert.-butyl ether (2R)-2-/3- (4-imino-(matalino)-were)-2-oxo-5-oxazolidinecarboxylate/- 3-phenylpropionic acid hydrochloride, T. pl. 140oC.

Similarly

of the benzyl ester 1-/3-(4-thiocarbamoyl-phenyl)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid get benzyl ester 1-/3-(4-imino-(matalino)-were)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid in the form of hydroiodide, so pl. 86-91oC;

from tert.-butyl ether 2-{1-/3-(4-thiocarbamoyl) -2 - oxo-5-oxazolidinecarboxylate/-4-piperidinyloxy} -acetic acid tert get.-butyl ether 2-{1-/3-(4-imino- (methylthio)-were/-2-oxo-5-oxazolidinecarboxylate/-4 - piperidinyloxy}-acetic acid, so pl. 157oC;

of the benzyl ester 2-{1-/3-(4-thiocarbamoyl-phenyl) -2-oxo-5-oxazolidinyl-carbonyl/-4-piperazinil} -acetic acid getting benzyl ester 2-{ 1-example 12

0.45 g of tert. -Butyl ester (2R)-2-/3-(4-imino-(methylthio) -were)-2-oxo-5-oxazolidinecarboxylate/ -3-phenylpropionic acid (produced according to example 11) are suspended in 5 ml of methanol, add to 0.47 g of ammonium acetate and stirred for 24 hours at room temperature. Then the reaction mixture is mixed with 10 ml of ether and separate the precipitate. After evaporation of the filtrate and normal processing and handling glacial acetic acid, receive tert.-butyl ether (2R)-2-/3-(4- amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-3-phenylpropionic acid in the form of acetate, so pl. 191-192oC.

Similarly

of the benzyl ester 1-/3-(4-imino-(methylthio)-were) -2-oxo-5-oxazolidinecarboxylate/-piperidine-4-carboxylic acid get benzyl ester 1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid in the form of acetate, so pl. 197-199oC;

from tert.-butyl ether 2-[1-/3-(4-imino-(methylthio)-were)- 2-oxo-5-oxazolidinecarboxylate/-4-piperidinyloxy} -acetic acid tert get. -butyl ether 2-{1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-4-piperidinyloxy}-acetic acid in the form of acetate, so pl. 127-125oC;

from benzyl e is t benzyl ester 2-{1- /3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-4 - piperazinil}-acetic acid in the form of acetate.

Example 13

0.25 g of tert-Butyl ester (2R)-2-/3-(4-amidinophenoxy)-2 - oxo-5-oxazolidinecarboxylate/-3-phenylpropionic acid (produced according to example 12) in 10 ml triperoxonane acid is stirred at room temperature until complete hydrolysis. Then the reaction mixture was concentrated and washed the residue repeatedly with toluene. After the treatment with ethyl acetate to obtain (2R)-2- /3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-3 - phenylpropionate acid in the form of triptoreline. FAB (M + 1): 397.

Similarly, by saponification of the corresponding esters from example 12 get:

triptorelin 1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid;

triptorelin 2-{ 1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-4-piperidinyloxy}-acetic acid;

triptorelin 2-{ 1-/3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinecarboxylate/-4-piperazinyl}-acetic acid.

Example 14

of 23.2 g of 3-(4-Cyan-phenyl)-2-oxo-5-oxazolidinecarboxylate acid (produced according to example 1) together with 33,0 g di-tert.-BUTYLCARBAMATE in 1000 ml of methanol and 110 ml of sodium hydroxide solution hydronaut in the presence of palladium-on-coal until the termination pokeronlineespanol)-2-oxo-5-oxazolidinecarboxylate acid. So pl. 166oC.

Example 15

Analogously to example 4, by reacting benzyl ester 3-(1-piperazinil)-propionic acid with 3-(4-tert. - butoxycarbonylmethylene)-2-oxo-5-oxazolidinecarboxylate acid get benzyl ester 3-{ 1-/3-(4-tert. -butoxy - carbonylmethyl)-2-oxo-5-oxazolidinecarboxylate/-4 - piperazinil}-propionic acid. So pl. 128-130oC.

Similarly, by introducing into the interaction of 3- (4-tert.-butoxycarbonylmethylene) -2-oxo-5-oxazolidinecarboxylate acid with benzyl ether piperidine-4-carboxylic acid get benzyl ester 1-/3-(4-tert. -butoxycarbonylmethylene) -2-oxo-5-oxazolidinecarboxylate/-piperidin-4-carboxylic acid;

with tert.-butyl ether of 2-(4-piperidinyloxy)-acetic acid tert get. -butyl ether 2-{1-/3-(4-tert.- butoxycarbonylmethylene)-2-oxo-5-oxazolidinecarboxylate/- 4-piperidinyloxy}-acetic acid, so pl. = 115 -119oC;

with benzyl ether of 2-(4-piperazinil)-acetic acid benzyl get aired 2-{ 1-/3-(4-tert.- butoxycarbonylmethylene)-2-oxo-5-oxazolidinecarboxylate/- 4-piperazinil}-acetic acid, so pl. 121oC;

with tert. -butyl ether 4-piperid originalnumber-4-piperidinecarboxylic acid, so pl. 63,6oC;

with tert. -butyl ester (2R)-2-amino-3-phenylpropionic acid tert get. -butyl ester (2R)-2-/3-(4- tert.-butoxycarbonylmethylene)-2-oxo-5 - oxazolidinecarboxylate/-3-phenylpropionic acid, so pl. 6.8-69oC.

Example 16

1.5 g of Benzyl ester 3-{1-/3-(4-tert.- butoxycarbonylmethylene)-2-oxo-5 - oxazolidinecarboxylate/-4-piperazinil} -propionic acid in 50 ml of DMF hydronaut in the presence of 5% palladium-on-charcoal grill. After the usual processing, the crude product is dissolved in a solvent mixture consisting of dichloromethane with methanol and glacial acetic acid (70:30:2), and chromatographic through silica gel. Receive, after trituration of the product with ether, 3-{ 1-/3-(4-tert. -butoxycarbonylmethylene)- 2-oxo-5-oxazolidinecarboxylate/-4-piperazinil}-propionic acid. So pl. 76-78oC.

Example 17

of 0.53 g of tert. -Butyl ester 2-{1-/3-(4-tert.- butoxycarbonylmethylene)-2-oxo-5-oxazolidinecarboxylate/-4 - piperidinyl-oxy} -acetic acid in 10 ml triperoxonane acid is stirred at room temperature. After normal processing of the crude product is triturated with ether and dried. Get 2-{1-/3-(4-aminomethylphenol)-2-oxo-5-oxazolidinedione is from tert. -butyl ester (2R)-2-/3-(4-tert.-butoxy - carbonylmethyl)-2-oxo-5-oxazolidinecarboxylate/-3 - phenylpropionic acid get (2R)-2-/3-(4-aminomethyl-phenyl) -2-oxo-5-oxazolidinecarboxylate/-3-phenylpropionate acid in the form of triptoreline, so pl. 178-185oC.

Example 18

0.5 g of tert.-Butyl ester 1-/3-(4-tert.- butoxycarbonylmethylene)-2-oxo-5-oxazolidinecarboxylate/- piperidine-4-carboxylic acid in 10 ml triperoxonane acid is stirred at room temperature. The solution was concentrated in vacuo. The crude product is then treated with ethereal solution of hydrogen chloride, sucked off and dried. Receive hydrochloride 1-/3-(4-aminomethylphenol)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid, so pl. 256-258oC (decomposition).

Example 19

0,43 N. Acetate 3-(1-/3-(4-tert.-butoxycarbonylmethylene)- 2-oxo-5-oxazolidinecarboxylate/-4-piperazinil/-propionic acid in 30 ml of ethereal HCl solution was stirred at room temperature. The formed precipitate is sucked off, washed with a small amount of ether and dried. Get dihydrochloride 3-{1-/3- (4-aminomethylphenol)-2-oxo-5-oxazolidinecarboxylate-4-piperazinil} -propionic acid. So pl. 184-185ooC.

Example 21

0.6 g of the Dihydrochloride benzyl ester 2-{1-/3-(4- -aminomethylphenol-2-oxo-5-oxazolidinecarboxylate/-4 - piperazinil}-acetic acid in a mixture of 30 ml of methanol, 5 ml water and 5 ml of glacial acetic acid hydronaut in the presence of palladium-on-charcoal grill. The reaction mixture is filtered and the filtrate concentrated in vacuo. After trituration of the crude product with ethyl-acetate receive dihydrochloride 2-{ 1-/3-(4-aminomethylphenol)- 2-oxo-5-oxazolidinecarboxylate/-4-piperazinil}-acetic acid; so pl. 91oC (decomposition).

Example 22

to 5.4 g of 3-(4-Aminomethylphenol)-2-oxo-5-oxazolidinecarboxylate acid are suspended in 70 ml of THF. Under stirring was added dropwise 35 ml of 1 n NaOH solution. After this was added dropwise a solution of 6.6 g of 4 - canbesold in 60 ml of THF. the pH value of the solution to support equal 9-10,5 due to additive 1 N. NaOH solution. After the interaction is acidified with 2 n HCl solution to pH 1. The solvent is removed, the residue is sucked off and washed the ptx2">

Similarly, by reacting 3-(4-aminomethylphenol)-2-oxo-5 - oxazolidinecarboxylate acid with p-chloro-carboalumination get 3-{ 4-/3-(4-tianfeng)- freedomites/-phenyl}-2-oxo-5-oxazolidinecarboxylate acid.

Example 23

Analogously to example 10, by reacting 3-/4-(4 - Lebensmittel)-phenyl/-2-oxo-5-oxazolidinyl-carboxylic acid with hydrogen sulfide receive 3-/4-(4-thiocarbamoylation)- phenyl/-2-oxo-5-oxazolidinecarboxylate acid. So pl. 105-110oC.

Similarly, by reacting 3-{4-/3-(4- -tianfeng)-freedomites/-phenyl} -2-oxo-5-oxazolidinecarboxylate acid with hydrogen sulfide receive 3-{ 4-/3-(4-thiocarbamoyl) -freedomites/-phenyl}-2-oxo-5-oxazolidinecarboxylate acid.

Example 24

Analogously to example 11, by reacting 3-/4-(4-thiocarbamoylation)-phenyl/-2-oxo-5-oxazolidinecarboxylate acid with methyliodide receive hydrochloride 3-/4-(4-imino-(methylthio)-methylbenzimidazolyl) -phenyl/-2-oxo-5-oxazolidinecarboxylate acid. So pl. = 209oC.

Similarly, by reacting 3-{4-/3-(4-thiocarbamoyl)-freedomites/-phenyl}-2-oxo - 5-oxazolidinecarboxylate acid with methyliodide recip is the notes.

Example 25

Analogously to example 12, by reacting 3- /4-(4-imino(methylthio)-methylbenzimidazolyl)-phenyl/-2-oxo-5 - oxazolidinecarboxylate acid with ammonium acetate receive acetate 3-/4-(4-amylinomimetic)-phenyl/-2-oxo-5 - oxazolidinecarboxylate acid, so pl. 294oC.

Similarly, by reacting benzyl ester 3- {3-/3-(4-imino-(methylthio)-were)-freedomites/-phenyl} -2-oxo-5-oxazolidinecarboxylate acid with ammonium acetate receive acetate 3-{4-/3-(4-amidinophenoxy)-freedomites/-phenyl}-2-oxo-5 - oxazolidinecarboxylate acid.

Example 26

Analogously to example 21, by cleavage of the ester benzyl group, based on benzyl ester 3-[4-(4 - amylinomimetic)-phenyl]-2-oxo-5-oxazolidinecarboxylate acid, receive 3-/4-(4-amylinomimetic)-phenyl/-2-oxo-5 - oxazolidinecarboxylate acid.

Similarly, by cleavage of the ester benzyl group, based on benzyl ester 3-{4-/3-(4-amidino-phenyl)- freedomites-/-phenyl} -2-oxo-5-oxazolidinecarboxylate acid, receive 3-{4-/3-(4-amidinophenoxy)-freedomites/-phenyl}-2-oxo - 5-oxazolidinyl-carboxylic acid.

Example 27

3,36 g 3-(4-tert. -Butoxycarbonylamino the ether and 30 ml of dioxane, which previously saturated with gaseous HCl, stirred for 1 hour at room temperature. Then the precipitate is sucked off and washed with ether. Get 3-(4-aminomethylphenol)-2-oxo-5 - oxazolidinecarboxylate acid. So pl. = 211-212oC.

Example 28

0,22 g of tert.-Butyl ether (2R)-2-/3-(4-tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-3-phenylpropionic acid (produced according to example 8) in 5 ml triperoxonane acid is stirred for 1 hour at room temperature. Then the solution was concentrated in vacuo and the residue triturated with ether. Get triptorelin (2R)- 2-/3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate/-3 - phenylpropionic acid.

Example 29

0.26 g of 3-/4-Amino-(hydroxyimino)-were/-2-oxo-5 - oxazolidinecarboxylate acid (produced according to example 2) in a mixture of 10 ml of glacial acetic acid and 10 ml of acetic anhydride is boiled for 2 hours. The reaction solution was concentrated in vacuo and the residue crystallized from ether. Get 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl/ -2-oxo-5-oxazolidinecarboxylate acid. So pl. = 215-218oC.

Example 30

1.06 g of 3-/4-Amino-(hydroxyimino)-were/-2-oxo-5 - oxazolidinecarboxylate acid (produced according to example will centerour in vacuum and the residue crystallized from ether. Get 3-/4-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate acid. So pl. 178-181oC.

Example 31

1,32 g 3-/4-Amino-(hydroxyimino)-were/-2-oxo-5 - oxazolidinecarboxylate acid (produced according to example 2) and 4.44 g of N-(chlorocarbonyl)- phthalimide in 20 ml of glacial acetic acid is boiled for 2 hours. The reaction solution is cooled to room temperature and the precipitate is sucked off, washed with ether and recrystallized from ethanol. Get 3-/4-(5-phthalimidomethyl-1,2,4 - oxadiazol-3-yl)-phenyl/-2-oxo-5-oxazolidinecarboxylate acid. So pl. 130 - 135oC.

Example 32

15 g of 3-/4-Amino-(hydroxyimino)-were)-2-oxo-5 - oxazolidinecarboxylate acid (produced according to example 2) in 370 ml of glacial acetic acid with the addition of 13 ml of acetic anhydride hydronaut in the presence of palladium-on-coal before the termination of the hydrogen absorption. Filtered from the catalyst and the filtrate discarded. Then the residue is treated with 100 ml of 1 n HCl and 200 ml of concentrated HCl solution and filtered. Hydrochloric acid, the filtrate was concentrated in vacuo and heat due to the crystalline residue is filtered off. After washing, a small amount of water and visus is 2">

Example 33

0.87 g of Benzyl ester 1-/3-(4-Tianfeng)-2-oxo-5 - oxazolidinecarboxylate/-piperidine-4-carboxylic acid (produced according to example 8), 0,43 g hydroxylaminopurine and 0,89 g of sodium carbonate in 12.5 ml of methanol with the addition of 0.5 ml of water is boiled for 3 hours. The reaction solution is then treated as usual. Get a mixture of benzyl ester 1-{3-/4-amino-(hydroxyimino)-were/-2-oxo-5 - oxazolidinecarboxylate} -piperidine-4-carboxylic acid; FAB (M + 1):467; and methyl ester 1-{3-/4-amino-(hydroxyimino)- were/-2-oxo-5-oxazolidinecarboxylate} -piperidine-4 - carboxylic acid; RAV (M + 1):391. The separation of the two substances is carried out using column chromatography (silica gel; dichloromethane/methanol = 93:7).

Example 34

1.12 g of Methyl ether 3-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl/-2-oxo-5-oxazolidinecarboxylate} -propionic acid (produced according to example 4) in 13.5 ml of water and 30 ml of methanol, with the addition of 1.35 g of potassium carbonate is stirred for 3 hours at room temperature. The reaction solution is then treated as usual. Get 3-{3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl/- 2-oxo-5-oxazolidinecarboxylate}- propionic acid. So pl. 221-223oC.

The following primucci

A solution of 100 g of biologically active substances of the formula (I) and 5 g of dinitrigenoxide in 3 l of bidistilled water using 2 N. hydrochloric acid to establish a pH of 6.5, the solution is sterile filtered, filled them with glass bubbles for drugs for injection, lyophilizer in sterile sterile conditions and closed. Each bottle of the drug for injection contains 5 mg of biologically active substances obtained in example 1.

Example B: Candles

Melt a mixture of 20 g of biologically active substances of the formula (I) with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically active substances obtained according to example 2.

Example: Solution

Prepare a solution of 1 g of biologically active substances of the formula (I), 9,38 g NaH2PO42H2O; 28,48 g Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH to 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops, as a biologically active substance of the formula (I) used the compound obtained according to example 3.

Example D: Ointment

500 mg Biological the active substances of the formula (I) used the connection, obtained according to example 3.

Example D: Tablets

A mixture of 1 kg of biologically active substances of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablets such that each tablet contains 10 mg of biologically active substances obtained in example 4 with a melting point 171-175oC.

Example E: Bean

Analogously to example D, pressed tablets, then the usual way is applied a coating of sucrose, potato starch, talc, tragant and dye. As biologically active substances of the formula (I) used the compound obtained in example 4 with a melting point 180-181oC.

Example G: Capsules

2 kg of Biologically active substances of the formula (I) in the usual way making capsules of hard gelatin, so that each capsule contains 20 mg of biologically active substances obtained according to example 5 with a melting point of 160oC.

Example 3: Ampoules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is sterile filtered, filled them ampoules, lyophilizer in sterile and sterile zakryvani 184oC.

1. Derivatives oxazolidinecarboxylate acid of the formula I

< / BR>
where R1- CN, CSNR6R7C(= NH)SA, C(=NH)R6R7CH2NR6R7C(=NH)NHOH, CH2NHCOPh-E, CH2NHCONHPh-E or D

< / BR>
R2- OH, CH2Cl or

E-CN, CSNH2C(=NH)SA, C(=NH)NH2;

X is OH, OA, AS, when Y is CH2or C = 0;

R3- (CH2)m- COOR5; m = 1, 2;

R4- (CH2)p- COOR5or (CH2)q- O -(CH2)r- COOR5;

n = 3;

p = 0,1;

q = 0;

r = 1 or 2;

Ph - phenylene;

AS - amino acid residue selected from the group consisting of Ala, -Ala, Asp, Phe, Tyr, Ter (OMe), N - phenethyl--Ala,

R5- H, A;

R6and R7each is hydrogen;

A - C1-C6-alkyl,

and their physiologically acceptable salts, enantiomers or diastereomers.

2. Derivatives oxazolidinecarboxylate acid on p. 1 representing:

(and) 2-/1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate)-piperidine-4-yl-oxy)-acetic acid;

(b) (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate-amino/-succinic acid;

() 3-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-propionic acid;

(d) tert.-butyl new ether (2R)-2-/3-(4-amidinophenoxy)-2-oxo-5-oxazolidinecarboxylate/-succinic acid;

(e) tert. -butyl ether 1-/3-(4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl)-2-oxo-5-oxazolidinyl/-piperidine-4-carboxylic acid;

(W) 3-/4-(amino(hydroxyimino)methyl)-phenyl/-2-oxo-5-oxazolidinecarboxylate acid;

(C) (2R)-2-/3-(4-tianfeng)-2-oxo-5-oxazolidinecarboxylate)-3-phenylpropionate acid;

(and) 3-/3-(4-(5-oxo-1,2,4-oxazolidin-3-yl)-phenyl)-2-oxo-5-oxazolidinecarboxylate/-propionic acid.

3. Derivatives oxazolidinecarboxylate acid of formula 1 to PP.1 and 2 with the activity of the receptor antagonists of adhesion.

4. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula II

< / BR>
where R1has a specified value;

L denotes Cl, esterified ester to IT-group, respectively easily nucleophile replaced the deleted group,

enter into interaction with the compound of the formula III

H - X;

X' denotes AS,

< / BR>
or

< / BR>
and Y, R3, R4and n have the specified values.

5. The pharmaceutical composition exhibiting the properties of a receptor antagonist adhesion, characterized in that it contains a compound of formula I under item 1 or one of its physiologically acceptable sole is

 

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