Oxazolidinone, and their salts, a method of production thereof, pharmaceutical preparation and method thereof


(57) Abstract:

The invention relates to new derivatives of oxazolidinones General formula (I) are given in the description, as well as their salts. The method of obtaining compounds of General formula (I) is that the compounds of formula (I), where R1is phenyl, substituted CN-group is converted into the compounds of formula (I), where R1is phenyl, substituted amedieval group, Y has the values specified in paragraph 1. Pharmaceutical drug, possess inhibitory activity of the binding of fibrinogen containing the compounds of formula (I) and a pharmaceutically acceptable carrier, and a method thereof. These compounds can be used for the treatment of thromboses, myocardial miokarda, inflammations, tumors. 4 C. and 1 C.p. f-crystals, 1 table.

The invention relates to new compounds of the formula I

< / BR>
where Y denotes unsubstituted or substituted R2piperidino-, 1-oxa-8-azaspiro[4,5]Decan-8-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group of OH, NH2, carbonyl group,

R1is phenyl, substituted by CN, H2N-CH2-, (A2)N-CH2-, H2N-C(=NH)-, H2N-C(= NH)-NH-,

R2- CmH2m-COOR3and>COOR3,

A is alkyl with 1-6 C-atoms,

m = 0, 1, or 2,

n = 1 or 2

p = 1 or 2

and also their salts.

Analogs of these compounds are known from EP-A1-0381033.

Object of the invention is to find new compounds with valuable properties, especially those which can be used to get drugs.

This problem is solved proposed new compounds of the formula I. the compounds of formula I and their solvate and salt with good compatibility possess valuable pharmacological properties. In particular, they inhibit the binding of fibrinogen, fibronectin and factor Willebrands fibrinogen the receptor thrombocyto /glycoprotein IIb/IIIa/ as well as linking the same and other adhesive proteins such as vitronectin, collagen and Lamin, with the corresponding receptors on the surface of different cell types. Connection is affected, thus, the interaction of cell-cell and cell-matrix. They prevent mainly the formation of blood platelets and can therefore be used for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis.

Compounds affect cell tumors, while they keep obrazovaniya can act as antimicrobial biologically active substances, preventing infections caused by, for example, bacteria, fungi or yeast. Substances can be used, therefore, preferably as co-microbial biocatalysts in cases when there are interventions in the body and apply foreign materials, such as, for example, biomaterials, implants, catheters or pacemakers. They act as antiseptics.

Connection properties can be confirmed by the methods described in EP-A1-0462960. The containment relation of fibrinogen with fibrinogen receptor can be confirmed on the basis of the method described in EP-A1-0381033. A deterrent effect in the formation of platelets can be proved in the laboratory according to the method of born /Nature 4832, 927 - 929, 1962/.

The subject invention is also a method for obtaining compounds of the indicated formula I and its salts, namely, that

the compound of the formula I

< / BR>
where R1is phenyl, substituted CN-group and

Y means unsubstituted or substituted by a group R2piperidino, 1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group of OH, NH2, a carbonyl group, and RIl, substituted amedieval group and Y have the above values, and if necessary, an acid of the formula I in which Y may be unsubstituted or substituted by a group R2piperidino;

1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group of OH, NH2, a carbonyl group, and

R2means CmH2mCOOR3or O-CpH2pCOOR3;

where R3= H

n = 1 or 2

p = 1 or 2

m = 0, 1, or 2,

handle base and get a salt of formula I, where R1and Y have the above values.

In the above formula group A 1-6 is preferably 1, 2, 3 or 4 C-atoms. In particular, A means predominantly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, hereinafter also referred to as pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl,

Y is preferably 2-(R3OCC)-piperidine, 3-(R3OCC)-piperidino, 4-(R3OCC)-piperidine, 2-(R3OCC-CH2-)-piperidino, 3-(R3OCC-CH2-)-piperidino,

4-(R3OCC-CH2-)-piperidino, 4-(R3OCC-CH2CH2-)-piperidino, 4-Gerona-4-(R3OCC-CH2)-piperidino, 3-oxo-4-(R3OCC-CH2-)-piperidino, 2-(R3OCC-CH2-O-)-piperidino, 3-(R3OCC-CH2-O-)-piperidino, 4-(R3OCC-CH2-O-)-piperidino, 1-oxa-2-oxo-8-azaspiro[4,5] -decane-8-yl, 4-(R3OCC-CH2-)-piperazine derivatives, 4-(R3OCC-CH2CH2-)-piperazine derivatives, 2-(R3OCC)-piperazine derivatives, 3-(R3OCC)-piperazine derivatives, 4-benzyl-3-(R3OCC)-piperazine derivatives,

preferably as A methyl or ethyl,

R1is predominantly substituted in the 4 position, and also in the 2 - or 3-position of the phenyl residue, as indicated, in particular, preferably 2-, 3 - or /features/ 4-tianfeng, 2-3 - or /features/ 4-aminomethylphenol, 2-, 3 - or /features/ 4 - dimethylaminophenyl, 2-, 3 - or /features/ 4-lidinopril, 2-, 3 - or 4-guanidinium, 2-, 3 - or 4-guanidiniocarbonyl, 2-, 3 - or /features/ 4-hydroxynicotinic,

R2is preferably COOR3, -CH2COOR3or-O-CH2COOR3,

R3is preferably H, methyl, ethyl, tertiary butyl or benzyl,

R4is preferably H, methyl, ethyl, benzyl or CH2COOR3.

The parameter m is preferably 0 or 1.

The parameter n is preferably 1.

The parameter p is site the data residuals, groups and/or options is one of these preferred values. Some preferred group of compounds are those compounds of formula Ib-Id, which correspond to the formula I, where

in Ib R1means tianfei,

in Ic R1means aminomethylphenol,

in Id R1means lidinopril.

Further preferred are the compounds of formula Ie, and Ibe, Ice and Ide, corresponding to the formulae I, Ib, Ic and Id, where more

Y represents a 2-R2-piperidino, 3-R2-piperidino, 4-R2-piperidino, 4-R2-piperazine derivatives or 3-R2-4-R4-piperazine derivatives,



Selected smaller group of compounds are compounds of formula If and Ig. They correspond to the formula I,

Y represents 2-, 3 - or 4-(R3OOC)-piperidino, 4-(R3OOC-CH2-)-piperidino, 3 - or 4-(R3OOC-CH2-O-)-piperidino, 4-(R3OOC-CH2)-piperazine derivatives or 3-(R3OOC-)-4-R4-piperazine derivatives,

R1means 4-tianfeng, aminomethylphenol, 4-lidinopril or 4-guanidiniocarbonyl,

R3means H, C1-C4-alkyl or benzyl and

R4means H or benzyl, panel, 4-aminomethylphenol or 4-lidinopril and

R3means H, C1-C4-alkyl or benzyl.

The compounds of formula I, as well as source materials for their education receive by known methods, as described in the literature (for example, in such sources as Houben Wegl, Methods der Organishen Chemie, Georg-Thieme-Verlag, also in EP-A1-0381033, EP-A1-0462960/, namely in terms of known and suitable for the above exchange reaction. You can use variations, known by themselves.

The initial substance can be formed at will, they are not isolated from the reaction mixture, and immediately used for further compounds of formula I.

The compounds of formula I can be obtained from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the process of the solvolysis or hydrogenolysis are those which correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain appropriate protective amine and/or gidrookisyei group, preferably such that instead of H-atom with a N-atom, contain aminosidine group, in particular, the e, which, instead of the H-atom of actigraphy contain a hydroxy protective group, for example those which correspond to formula I, but instead of the group-COOH contain a group-COOR", where R" means oxidising group.

In the original substance may contain several identical or different protective amine and/or exigrep. If the existing protective groups differ from each other, they can be selectively separated.

The expression "aminosidine group" is well known and refers to groups who are able to defend /block/ amino group from chemical reactions of metabolism, which, however, can easily be removed after carrying out the desired chemical reactions in the presence of the molecule in different location. Such typical groups are, in particular, unsubstituted or substituted acyl, aryl - /for example, 2,4-dinitrophenyl (DNP)/, Alcoceber- /for example, benzoyloxymethyl (BOM) and/ or Uralkaliy /for example, benzyl, 4-nitrobenzyl, triphenylmethyl/. As aminosidine group in the reaction are removed, their type and size in General are not critical; will be preferred, however, are those which have 1 to 20, especially 1 to 8 C-atoms. The expression "acyl group" in connection with the proposed method it is necessary to understand in Shiro or heterocyclic carboxylic acids or sulphonic acids, and, in particular, alkoxycarbonyl, aryloxyalkyl - and, above all, alcoxycarbenium. Examples of such acyl groups is alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tertiary butoxycarbonyl /BOC/ 2-iodoxybenzoic; Uralelectromed as benzyloxycarbonyl /CBZ/, 4-methoxybenzenesulfonyl, 9-fluorenylmethoxycarbonyl /FMOC/. Preferred aminosidine groups are BOC, DNP and BOM, in addition CBZ, benzyl and acetyl.

The expression "oxycodine group" is also generally known and relates to groups able to protect oxygraph from chemical reactions of metabolism, which, however, can be easily removed after carrying out the desired chemical reactions in the presence of the molecule in different location. Typical groups are the abovementioned unsubstituted and substituted aryl, aralkyl or accelgroup, in addition also altergroup. The nature and dimensions oxidising groups are not critical, since they are removed again after the desired chemical reaction; preferred ablauts is benzyl, p-nitrobenzoyl, p-toluensulfonyl and acetyl, and especially preferred are benzyl and acetyl.

Used as source materials for the functional derivatives of compounds of formula I can be obtained by conventional methods described in these sources and patent applications, for example using the exchange reaction of decomposition of the compounds, and, however, at least one of these compounds contains a protective group instead of the H atom.

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

As inert solvents are suitable mainly organic solvents, for example carboxylic acids, as acetic acid, ethers, nab, which measures dichloromethane, solitarii, such as dimethylsulphoxide /DMSO/, in addition, also alcohols, such as methyl, ethyl, isopropyl, and water. In addition, it is worth mentioning mixtures of the aforementioned solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. Reaction temperatures for the cleavage are expediently between 0 and 50oC, preferably the reaction is carried out at room temperature /15 - 30o/.

BOC group can be chipped off, for example, preferably 40% triperoxonane acid in dichloromethane or with 3 to 5 n HCl in dioxane at 15 - 60o, FMOC - group - 5 - 20% solution of dimethylamine, diethylamine or piperidine in DMF at 15 - 50o. The removal of DNP group can, for example, with 3 to 10% solution of 2-mercaptoethanol in DMF/water at 15 - 30o.

Protective groups such as BOM, CBZ or benzyl/ removed hydrogenolysis way, can be chipped off, for example, when processing with hydrogen in the presence of a catalyst (for example, catalysis using noble metals such as palladium, expediently on a substrate of a catalyst, such as coal/. who or amides, for example DMF. The hydrogenolysis is carried out usually at temperatures from 0 to 100oC and a pressure of from 1 to 200 bar, preferably at 20 to 30o1 - 10 bar. Hydrogenolysis of CBZ - group is good at, for example, when 5 to 10% Pd-C in the stands at 20 - 30o.

The group of volatile substances E consists mainly of Cl, Br, I, C1-C6-alkylsulfonate, for example methane - or econsultancy, or C6-C10-arylsulfonate, for example benzene-, p-toluene - or 1 - or 2-naphthalenesulfonate.

The reaction takes place preferably in the presence of an additional base, such as hydroxide of alkali or alkaline earth metal carbonate as caustic soda, caustic potash, calcium hydroxide, sodium carbonate, potassium, calcium in an inert solvent such as halogenated hydrocarbon, such as dichloromethane, or an ether, as TF or dioxane, or amide, such as DMF or dimethylacetamide, a nitrile, for example acetonitrile, at a temperature of from 10 to 200opreferably 0 to 120o. If the group of volatile substances E is different from I, it is recommended that the addition of iodide such as potassium iodide.

The initial substance, usually new. They can be obtained, for example, using the reaction is SUB> means E, R6XR7, R7- protective group, R5and R6together - O/ to obtain the compounds of formula R1-NH-CH2-CHR8-CH2OH /where R8means XR7or OH/, if necessary, removal of the protective group R7to obtain compounds of the formula R1-NH-CH2-CH(XH)-CH2OH, reaction with a derivative of carbonic acid, as diethylcarbamyl to obtain 3-R1-5-hydroxymethyl-2-oxazolidinone and turning hydroxymethylene group CH2E, for example with SOCl2, SOBr2methanesulfonate or p-toluenesulfonyl chloride.

The compounds of formula I can be obtained, in addition, by using the reaction of compounds /able to respond derivative of/ with a reactive derivative of carbonic acid.

As a derivative of carbonic acid is particularly suitable diallylmalonate, such as diethylmalonate, in addition, also difficult alkilany ether of Harborview acid, such as salt or ester of Harborview acid. A derivative of carbonic acid, which is suitable used in excess, is preferable as a solvent or suspending agent. Can be one of these solvents, the village is as alkali metal, for example tertiary butyl potassium. The reaction temperature from 0 to 150o, preferably 70 to 120o.

The initial substance, usually new. They can be obtained by functionalization of the above-mentioned compounds of the formula R1-NH-CH2-CH(XH)-CH2OH to obtain the formula R1-NH-CH2-CH(XH)-CH2-E.

To obtain the compounds of formula I, where R1means guanidinopentanoic group, the corresponding compound of AMINOPHENYL you can handle amidenus means, such as a preference for 1-amino-3,5-dimethylpyrazol, which is used mainly in the form of nitrate. Reaction occurs when adding a base, such as triethylamine or ethyldiethanolamine in an inert solvent or combination of solvents, for example water/dioxane at temperatures of 0 - 120o, preferably 60 to 120o. Then you can transform the compound of formula I, one or both of the residues R1and/or Y in other /no residue/Ki R1and/or y

In particular, it is possible to restore a cyano group aminomethyl or turn into a group of amidine or hydroquinidine, group carboxyla to atrificial, ether group split, the benzyl group to remove the Hydra is gruppe group aminomethyl possible using catalytic hydrogenation, for example, Raney Nickel, at a temperature of 0 - 100opreferably 10oand 30oand a pressure of 1 to 200 bar, preferably at normal pressure, in an inert solvent, for example in a lower alcohol as methyl or ethyl, expediently in the presence of ammonia. If the temperature of, for example, 20oand a pressure of 1 bar, the original material is retained existing group of benzylamine or N-benzyl. They are necessary and can split the hydrogenolysis using a catalyst of a noble metal, preferably Pd-coal, which can be added to a solution of the acid, for example acetic acid, and water.

To obtain amidine formula I /R1= lidinopril/ can to the nitrile of formula (I /R1= tianfei/ attach ammonia. The joining is preferably in several stages,

and/ nitrile with H2's turn in thioamide, who with the help of alkylating substances, such as CH3I transferred to the corresponding S-alkalinization, which, on its part reacts with NH3to obtain amidine,

b/ nitrile with alcohol, for example ethanol, in the presence of HCl is transformed into the corresponding imidoyl and treated with ammonia, or

c/ nitrile reacts exchange is arranged corresponding N-hydroxy-amidine formula I /R1= HO-NH-C(NH)-substituted phenyl/ from NITRILES, if followed by a/ or b/, but with hydroxylamine instead of ammonia. For the esterification can handle the acid of formula (I /R3=H/. Excessive alcohol of formula R3-OH(R3= A or benzyl), expediently in the presence of a strong acid, for example hydrochloric or sulfuric acid, at temperatures from 0 to 100o, preferably 20 - 50o.

On the contrary, an ester of formula I (R3= A or benzyl), which turn the corresponding acid of formula I (R3= H) can be obtained by solvolysis, according to one of the above-mentioned methods, for example with NaOH or KOH in water-dioxane at a temperature 0 - 40o, preferably 10 - 30o.

The basis of the formula I can translate using acid to the corresponding salt. Preferably physiologically acceptable. So, can be used inorganic acids, for example sulfuric acid, nitric acid, halogenation acid, for example hydrochloric or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic acid series, alicyclic, analiticheskie, aromaticity, for example formic acid, acetic acid, triperoxonane, propionic, trimethyllysine, diethyloxalate, malonic, succinic, Emelyanova, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinoyl, methansulfonate or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p toluensulfonate, naphthalene-mono - and disulfonate, louisanna acid. Physiologically acceptable salt, such as salt of picric acid, used for isolating and/or purifying compounds of formula I.

Free base of formula I can be released, upon request, from their salts by treatment of a strong base, such as caustic soda or caustic potash, sodium carbonate or potassium carbonate.

It is also possible by sharing with the appropriate base to turn carboxylic acid of the formula I /R3= H/ metal salt or ammonium salts, for example salts of sodium, potassium, calcium.

The compounds of formula I contain one or more chiral centers and therefore exist in racemic or optical form. Resulting racemates can be split by known methods of mechanical or himitangi material form geometric isomers of the compounds of the ethylene series. As the separation of the material used, for example, optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond, malic, lactic acid or the various optically active camphor sulphonic acids, for example, camphorsulfonate. It is also the enantiomeric separation using a column filled with optically active separation material /for example, dinitrobenzonitrile/; the solvent is suitable, for example, hexane/isopropanol/acetonitrile, for example, in a volume ratio 82:15:3.

Of course possible to obtain optically active compounds of formula I above ways, using source materials which are already optically active.

The new compounds of formula I and their physiological salt can be used to get drugs when they are together at least one carrier or auxiliary substance and, if necessary, together with one or more active substance/s is applied in a suitable dose. Thus obtained materials can be used as drugs in medicine and veterinary medicine. The quality of the measures, oral or rectal/ or parenteral use or for use in the form of an inhaler, and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycol, glycerol triacetate and other glycerides of the fatty acid series, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc, cellulose. For oral administration is used, mainly, tablets, pills, capsules, syrups, juices or drops; interest special tablets and capsules with a coating or membrane, which are not destroyed by gastric juice. For rectal use candles for parenteral use - solutions, mainly oil or water, furthermore suspensions, emulsions or implants.

For use as inhalers can be used aerosols containing gaseous mixture of biologically active substances, either in solution or in suspension. The biologically active substance is used it is helpful in microscopic form, and can be added to one or more secure in the physiological ratio of solvents, for example in order to Lisovets, for example, to obtain drugs for injection. These prepared materials can be sterilized and/or contain auxiliary substances such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and/or aromatic substances. They can, if necessary, also contain one or more other biologically active substances, for example one or more vitamins.

The stated substances are produced, generally, by analogy with other known and commercially available drugs, in particular as described in EP-P-459256 compounds, preferably in doses from 5 mg to 1 g, generally from 50 to 500 mg per unit dosage. The daily dose is preferably from 0.1 to 20 mg/kg, generally from 1 to 10 mg/kg of body weight. The specific dose for each particular patient depends on various factors, such as the effectiveness of special connections, age, body weight, General health, sex, diet, dates of issue, period of validity, the combination of medicinal substances and the severity of this disease. Oral administration is the most preferred which means: "Add, if necessary, water can be installed in accordance with the structure of the final product pH between 2 and 8, extracted with ethyl acetate or dichloromethane, separated, the organic phase is dried using sodium sulfate, evaporated and purified by chromatography on silica gel and/or crystallization. FAB = (M+ + 1)-peak in the mass spectrum is obtained by a method of rapid bombardment of atoms /"Fast Atom Bombardment"/.

Example 1. Dissolve 1 g of 1-tertiary butoxycarbonyl-4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-2-ethyl ether carboxylic acid obtained by the interaction of 3-(4-tianfeng)-5 - methyl bromide-2-oxazolidinone and 1-tertiary butoxycarbonyl-piperazine-2-ethyl ether carboxylic acid by the method described in example 3/ in 12 ml of dichloromethane and 12 ml triperoxonane acid, leave it for 1 hour at a temperature of 20oC and evaporated. Get 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-3-ethyl ether carboxylic acid, FAB 359.

In a similar manner from 1-tertiary butoxycarbonyl-4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-2-carboxylic acid or a complex ester of benzyl alcohol is prepared 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-3-carboxylic gnometerminal)- 2-oxo-5-oxazolidinyl)-piperidine-4-tert-complex butyl ether exucuse acid can be obtained from 3-(4-benzyloxycarbonylamino)-5-chloromethyl-2-oxazolidinone and piperidine-4-tert-complex butyl ether exucuse acid according to the method, described in example 3/ in a mixture of 38 ml of methanol, 6 ml of water and 6 ml of acetic acid, is subjected to hydrogenolysis with 0.6 g of 5% Pd-charcoal at a temperature of 20oand a pressure of 1 bar until the uptake of H2. Filtered, the filtrate is evaporated and get 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperidine-4-critic. an ester exucuse acid, so PP 95-96o, FAB 420.

Example 3. A mixture of 2,96 g of 3-(4-tianfeng)-5-methanesulfonylaminoethyl-2-oxazolidinone (I. PP 162-163o; which is obtained by interaction of 4-aminobenzonitrile with 2,3-epoxypropanol to obtain 4-(2,3-dihydroxypropane)-benzonitrile/oily/, followed by its interaction with diethylmalonate/ K-critic.-the butyl at a temperature of 110owith 3-(4-tianfeng)-5-hydroxymethyl-2-oxazolidinone /so pl. 130 - 131o/ and the formation of ester with methanesulfonamido) 1,69 g piperidine-4-clonetrooper ether carboxylic acid, 70 ml of acetonitrile, 1,38 potash and of 1.65 g of potassium iodide boil for 25 hours. The usual method receive 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-4 - complex ethyl ether carboxylic acid /"IA"/, FAB 358.

Similarly receive with benzyl ether Pieper the OIC acid, so pl. 96o, FAB 420;

from tert-butyl ether piperidine-4-carboxylic acid;

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidin-ylmethyl)-piperidine-4-carboxylic acid;

with ethyl ether piperidine-3-carboxylic acid;

ethyl ester of 1-(3-(4-sulfinyl)- 2-oxo-5-oxazolidinyl)-piperidine-3-carboxylic acid;

with benzyl ether piperidine-3-carboxylic acid;

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- piperidine-3-carboxylic acid, FAB 420;

from tert-butyl ether piperidine-3-carboxylic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-3-carboxylic acid:

with ethyl ester, piperidine-2-carboxylic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- piperidine-2-carboxylic acid;

with benzyl ether piperidine-2-carboxylic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-2-carboxylic acid;

FAB 420;

from tert-butyl ether piperidine-2-carboxylic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-2-carboxylic acid;

with ethyl ether pyrrolidin-2-carboxylic acid:

the first broadcast pyrrolidin-2-carboxylic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-pyrrolidin-2-carboxylic acid;

from tert-butyl ether pyrrolidin-2-carboxylic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-pyrrolidin-2-carboxylic acid;

with ethyl ether piperidine-4-acetic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-4-acetic acid;

with benzyl ether piperidine-4-acetic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-4-acetic acid;

from tert-butyl ether piperidine-4-acetic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)piperidine-4-acetic acid;

with ethyl ether piperidine-4-exucuse acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl) piperidine-4-exucuse acid;

with benzyl ether piperidine-4-exucuse acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- piperidine-4-exucuse acid;

from tert-butyl ether piperidine-4-exucuse acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5 - oxazolidinyl)-piperidine-4-exucuse acid, so is l)-2-oxo-5-oxazolidinyl)- piperidine-3-exucuse acid,

with benzyl ether piperidine-3-exucuse acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-3-exucuse acid;

from tert-butyl ether piperidine-3-exucuse acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-3-exucuse acid;

with ethyl ether piperazine-2-acetic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-4-acetic acid;

with benzyl ether piperazine-1-acetic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-4-acetic acid;

from tert-butyl ether piperazine-1-acetic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-4-acetic acid;

with ethyl ether, azetidin-3-exucuse acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- azetidin-3-exucuse acid;

with benzyl ether of azetidin-3-exucuse acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- azetidin-4-exucuse acid:

from tert-butyl ether, azetidin-3-exucuse acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo - acid;

ethyl ester of 1-benzyl-4-(3-(4-tianfeng)-2-oxo-5 - oxazolidinyl)-piperazine-2-carboxylic acid;

with benzyl ester 1-benzylpiperazine-2-carboxylic acid:

benzyl ether of 1-benzyl-4-(3-(4-tianfeng)-2-oxo-5 - oxazolidinyl)-piperazine-2-carboxylic acid;

from tert-butyl ether 1/benzylpiperazine-2-carboxylic acid:

tert-butyl ester 1-benzyl-4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperazine-2-carboxylic acid.

Similarly obtained from 3-(4-tianfeng)-5S-methanesulfonylaminoethyl-2-oxazolidinone /so pl. 141-142o; []2D0+ 75,3o/c = 3.9 mg/ml in methanol/; by reacting 4-aminobenzonitrile with 2R-2,3-epoxypropanol to obtain 4-(2S,3-dihydroxypropyl)-benzonitrile, interaction with diethylmalonate /K-tert-bootrom with 3-(4-tianfeng)-5S-hydroxymethyl-2-oxazolidinone and receipt of ester with methanesulfonamido) with benzyl ether piperidine-4-carboxylic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5S - oxazolidinyl)-piperidine-4-carboxylic acid,

so pl. 87-88o, []2D0-43,0o/c = 9,8 mg/ml in methanol/.

Similarly receive

with tipepidine-4-carboxylic acid;

with tert.butyl ether piperidine-4-carboxylic acid:

tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5S - oxazolidinyl)-piperidine-4-carboxylic acid.

Similarly from 3-(4-tianfeng)-5R-methanesulfonylaminoethyl - 2-oxazolidinone (can be obtained from the 2S-2,3-epoxypropanol using 4-(2R, 3-dihydroxypropyl)-benzonitrile and 3-(4-tianfeng)-5R-hydroxymethyl-2-oxazolidinone)) receive the ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)- piperidine-4-carboxylic acid, as well as the corresponding ester and the corresponding tertiary complex butyl ether.

Example 4. Analogously to example 3 from 3-(4-dimethylaminomethylphenol)-5 - methyl bromide-2-oxazolidinone /can be obtained by reacting 4-dimethylaminomethylene with 2,3-epoxypropanol with 3-(4-dimethylaminomethylene)-1,2-propane diol, followed by interaction with diethylmalonate /K-tert-butyl to obtain 3-(4-dimethylaminomethylphenol)-5-hydroxymethyl-2 - oxazolidinone and interaction with SOBr2/ tert-butyl ether piperidine-4-carboxylic acid get tert-butyl ester 1-(3-(4-dimethylaminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-4-carboxylic acid, FAB 432.

o. Evaporated, processed as usual and get "IA", FAB 358.

Example 6. Dissolve 201 mg 1-amidino-3,5-dimethylpyrazol-nitrate in 17 ml of dioxane and 5 ml of water, mixed with 0.17 ml of ethyldiethanolamine and stirred for 16 minutes Then add 375 mg of tert.butyl ester 1-(3-(4-AMINOPHENYL)-2-oxo-5 - oxazolidinyl)-piperidine-4-carboxylic acid (obtained by interaction of 4-amino-acetanilide with 2,3-epoxypropanol to obtain 4-(2,3-dihydroxypropane)-acetanilide, followed by reaction with diethylmalonate to obtain 3-(4-acetamidophenyl)-5 - hydroxymethyl-2-oxazolidinone, becoming methanesulfonate and interaction with tert-butyl ether piperidine-4-carboxylic acid), the mixture is heated for 45 hours, evaporated, processed as usual and receive tert-butyl ester 1-(3-(4-guanidine)-2-oxo-5-oxazolidinyl)-piperidine - 4-carboxylic acid.

Similarly, from tert-butyl ester 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperidine-4 - carboxylic acid with 1-amidino-3,5-dimethylbenzonitrile receive tert-butyl ester 1-(3-(4-guanido the I g "IA" in 40 ml of 10% methanolic solution of NH3solution hydronaut 0.6 g of Raney Nickel at 20oand a pressure of 1 bar until the uptake of H2. After filtration and evaporation receive the ethyl ester of 1-(3-(4-aminomethylphenol)-2-oxo-5 - oxazolidinyl)-piperidine-4-carboxylic acid, FAB 362.

Similarly obtained by hydrogenation of the corresponding NITRILES of the following 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperidine: 4-tert-butyl ether carboxylic acid, 3-ethyl ester of carboxylic acid, 3-tert-butyl ether carboxylic acid, 2-ethyl ether carboxylic acid, 2-tert-butyl ether carboxylic acid, 4-ethyl ester acetic acid, 4-tert-butyl ester acetic acid, 4-ethyl ester exucuse acid, 4-tert-butyl ether exucuse acid, so pl. 95-96o, FAB 420, 3-ethyl ester exucuse acid, 3-tert-butyl ether exucuse acid;

the following 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-pyrrolidine: 2-ethyl ether carboxylic acid, 2-tert-butyl ether carboxylic acid;

the following 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperazines: 4-ethyl ester acetic acid, 4-tert-butyl ester of acetic acid;

the following 1-(3-(4-aminomethylbenzoic acid;

the following 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- 4-benzylpiperazine: 3-ethyl ester of carboxylic acid, 3-tert-butyl ether carboxylic acid;

the following 1-(3-(4-aminomethylphenol)-2-oxo-5S - oxazolidinyl)-piperidine: 4-ethyl ester of carboxylic acid, 4-tert-butyl ether carboxylic acid;

the following 1-(3-(4-aminomethylphenol)-2-oxo-5R-oxazolidinyl)-piperidine: 4-ethyl ester of carboxylic acid, 4-tert-butyl ether carboxylic acids.

Example 8. In a solution of 3.57 g "IA", 50 ml of pyridine and 6.6 ml of triethylamine at -10oenter H2S /45 min/. Then stirred for 14 hours at a temperature of 20o, evaporate, dissolve the residue in 50 ml of acetone and add 9 ml of methyl iodide. After 6 hours stirring at 20ofiltered off, breaking the residue in a small amount of acetone, dissolved in 30 ml of methanol, added 4.6 g of ammonium acetate and stirred for 30 hours at a temperature of 20o. The obtained ethyl ester 1-(3-(4-AMINOPHENYL)-2 - oxo-5-oxazolidinyl)-piperidine-4-carboxylic acid is filtered off and use the share silica gel chromatographic method /dichloromethane/ methanol/acetic acid 70:30:2/; so pl. 200o/decomp who yl)-2-oxo-5-oxazolidinyl)- piperidine: 4-benzyl ether carboxylic acid, so pl. 204o/decomposition/; FAB 437; dihydrochloride, so pl. 182o, 4-tert-butyl ether carboxylic acid, 3-ethyl ester of carboxylic acid, 3-benzyl ether carboxylic acid, acetate, FAB 437, 3-tert-butyl ether carboxylic acid, 2-ethyl ether carboxylic acid, 2-benzyl ether carboxylic acid, FAB 437, 2-tert-butyl ether carboxylic acid, 4-ethyl ester acetic acid 4-benzyl ester of acetic acid, acetate, so pl. 206o, 4-tert-butyl ester acetic acid, 4-ethyl ester exucuse acid 4-benzyl ester exucuse acid, 4-tert-butyl ether exucuse acid, so pl. 187o/decomposition/, FAB 433, 3-ethyl ester exucuse acid, 3-benzyl ether exucuse acid, 3-tert-butyl ether exucuse acid; 1-(3-(4-AMINOPHENYL)-2-oxo-5 - oxazolidinyl)pyrrolidine: 2-ethyl ether carboxylic acid, 2-benzyl ether carboxylic acid, 2-tert-butyl ether carboxylic acid; 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperazines: 4-ethyl ester acetic acid 4-benzyl ester acetic acid, FAB 452, 4-tert-butyl ester of acetic acid; 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl) -azetidine: 3-etilovyy; the following 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)- 4-benzylpiperazine: 3-ethyl ester of carboxylic acid, 3-benzyl ether carboxylic acid, 3-tert-butyl ether carboxylic acid; 1-(3-(4-amidinophenoxy)-2-oxo-5S-oxazolidinyl) -piperidine:

4-ethyl ester of carboxylic acid, 4-benzyl ether carboxylic acid, 4-tert-butyl ether carboxylic acid; 1-(3-(4-amidinophenoxy)-2-oxo-5R-oxazolidinyl)- piperidine: 4-ethyl ester of carboxylic acid, 4-benzyl ether carboxylic acid, 4-tert-bouteloua ether carboxylic acids.

Example 9. Analogously to example 8, but with an equivalent number of hydroxylammonium, instead of ammonium acetate is obtained from "IA" ethyl ester 1-(3-(4-hydroxylaminopurine)-2-oxo-5-oxazolidinyl)- piperidine-4-carboxylic acid.

Example 10. Dissolve 1 g of tert-butyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-4-carboxylic acid in 12 ml of dichloromethane, add 12 ml triperoxonane acid, leave it for 5 min, evaporated, processed as usual and get 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinyl)-piperidine-4-carboxylic acid, FAB 330.

In a similar manner from the corresponding is - 3-carboxylic acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)piperidine-2-carboxylic acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-pyrrolidin - 2-carboxylic acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-4-acetic acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)piperidine-4 - oxucusu acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine - 3-oxucusu acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine - 4-acetic acid;

1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-azetidin-3-oxucusu acid;

1-benzyl-4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- piperazine-2-carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-4-carboxylic acid, so pl. 190o/decomposition/; FAB 334;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-3-carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-2-carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- pyrrolidin-2-carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-4-acetic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperidine-4-Oxi is acetic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- piperazine-4-acetic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)- azetidin-3-oxucusu acid;

1-benzyl-4-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperazine-2-carboxylic acid;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-4-carboxylic acid, so pl. 265o/decomposition/; FAB 347; dihydrochloride, so pl. 142o;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)- piperidine-3-carboxylic acid;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-2-carboxylic acid, so pl. 198o, FAB 347;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-pyrrolidin-carboxylic acid;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-4-acetic acid, so pl. 256o;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-4-oxucusu acid, oil, FAB 377;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-3-oxucusu acid, so pl. 167 -168o;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperazine-4-acetic acid, FAB 362;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-azetidin-3-oxucusu acid;

1-benzyl-4-(3-(4-amidinophenoxy)-2-oxo-piperidin-4-carboxylic acid;

1-(3-(4-guanidiniocarbonyl)-2-oxo-5-oxazolidinyl)- piperidine-4-carboxylic acid, FAB 376;

1-(3-(4-tianfeng)-2-oxo-5S-oxazolidinyl)-piperidine 4-carboxylic acid;

1-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)-piperidine-4 - carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5S-oxazolidinyl)- piperidine-4-carboxylic acid;

1-(3-(4-aminomethylphenol)-2-oxo-5R-oxazolidinyl)- piperidine-4-carboxylic acid;

1-(3-(4-amidinopropane)-2-oxo-5S-oxazolidinyl)- piperidine-4-carboxylic acid;

1-(3-(4-amidinopropane)-2-oxo-5R-oxazolidinyl)- piperidine-4-carboxylic acid;

1-(3-(4-dimethylaminomethylphenol)-2-oxo-5-oxazolidinyl)-piperidine-4-carboxylic acid.

Example 11. Dissolve 1 g of benzyl ester 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-piperidine-4 - carboxylic acid in 100 ml of methanol and 17 ml of acetic acid and 17 ml of water, the solution hydronaut 0.7 g of 5% Pd-charcoal at a temperature of 20oand a pressure of 1 bar to stop the absorption of H2. Filtered, evaporated, triturated with diethyl ether complex and get 1-(3-(4-amidinophenoxy)-2-oxo - 5-oxazolidinyl)-piperidine-4-carboxylic acid, so pl. 265o; FAB 347; dihydrochloride, so plasma originaltitel)-piperazine-2-carboxylic acid /"IB"; or "IB" benzyl ether/ get 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperazine-3-carboxylic acid.

The same substance can be obtained in a similar way by hydrogenation of 1-benzyl-4-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperazine-2-carboxylic acid or its benzyl ether/.

Similarly obtained from the ethyl ester IB or tert-butyl methyl ether IB ester 1-(3-4-aminomethylphenol)-2-oxo-5-oxazolidinyl)-piperazine-3-carboxylic acid or tert-butyl ester 1-(3-(4-aminomethylphenol)-2-oxo-5-oxazolidinyl)piperazine-3-carboxylic acid.

Example 13. Analogously to example 3 from 3-(4-tianfeng)-5-methanesulfonyl-oxymethyl-2-oxazolidinone get:

with benzyl ether piperidine-3-acetic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-piperidine-3-acetic acid, FAB 434;

with methyl ether 3-(1-piperazinil)-propionic acid:

methyl ester 3-(4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-1-piperazinil)-propionic acid, FAB 373;

with the ethyl ester of 3-(1-piperazinil)-propionic acid:

ethyl ester 3-(4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-1-piperazinil)-propionic acid the 5-oxazolidinyl)-3-oxopiperidin-4-acetic acid, FAB 387;

with the ethyl ester of 3-(2-oxo-1-piperazinil)-propionic acid:

ethyl ester 3-(4-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-2-oxo-1-piperazinil)-propionic acid, FAB 401;

with the ethyl ester of 4-hydroxy-piperidine-4-carboxylic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- 4-hydroxy-piperidine-4-carboxylic acid, FAB 374;

with the ethyl ester of 4-hydroxy-piperidine-4-acetic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-4-hydroxypiperidine-4-acetic acid, FAB 388;

1-oxa-8-azaspiro[4,5]decane-2-on(=the lactone 3-(4-hydroxy - 4-piperidinyl)-propionic acid):

8-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-1-oxa-8-azaspiro[4,5] decane-2-on, FAB 356.

Similarly from 3-(4-tianfeng)-5R or 5S-methanesulfonylaminoethyl-2-oxazolidinone get:

with benzyl ether piperidine-4-carboxylic acid:

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)-piperidine-4-carboxylic acid;

benzyl ester 1-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)- piperidine-4-carboxylic acid;

with ethyl ether piperazine-4-acetic acid:

ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)- piperazine-4-yoty, FAB 373;

with benzyl ether 3-(1-piperazinil)-propionic acid:

benzyl ether 3-(4-(3-(4-tianfeng)-2-oxo-5R-oxazolidinyl)-1-piperazinil)-pribinova acid, so pl. 90o;

benzyl ether 3-(4-(3-(4-tianfeng)-2-oxo-5S-oxazolidinyl)-1-piperazinil)-propionic acid, so pl. 90o.

Example 14. Analogously to example 8 from the corresponding NITRILES (see example 13/ get:

benzyl ester 1-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-piperidine-3-acetic acid, diacetate, so pl. 287 - 288o;

ethyl ester 3-(4-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-1-piperazinil)-propionic acid, so pl. 206o;

ethyl ester of 1-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-3-oxo-piperazine-4-acetic acid, so pl. 224o;

ethyl ester 3-(4-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-2-oxo-1-piperazinil)-propionic acid, FAB 418;

ethyl ester of 1-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-4-hydroxypiperidine-4-carboxylic acid;

ethyl ester of 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)- 4-hydroxypiperidine-4-acetic acid, acetate, so pl. 108o;

8-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-1-oxa-8-azaspiro- [4,5]decane-2on, FA is at, so pl. 225o[]2D0+40,5o/C = 1, methanol/;

benzyl ester 1-(3-(4-amidinophenoxy)-2-oxo-5S-oxazolidinyl)-piperidine-4-carboxylic acid, acetate, so pl. 225o[]2D0-41o/C = 1, methanol/;

ethyl ester of 1-(3-(4-amidinophenoxy)-2-oxo-5R-oxazolidinyl)-piperazine-4-acetic acid, FAB 390;

ethyl ester of 1-(3-(4-amidinophenoxy)-2-oxo-5S-oxazolidinyl)- piperazine-4-acetic acid, FAB 390.

Example 15

Analogously to example 9 from the corresponding NITRILES receive the ethyl ester of 1-(3-(4-hydroxynicotinic)-2-oxo-5-oxazolidinyl)- 4-hydroxy-piperidine-4-acetic acid, acetate, so pl. 178 - 180o;

methyl ester 3-(4-(3-(4-hydroxynicotinic)-2-oxo-5 - oxazolidinyl)-1-piperazinil) propionic acid, so pl. 202o;

benzyl ether 3-(4-(3-(4-hydroxynicotinic)-2-oxo-5R - oxazolidinyl)-1-piperazinyl)-propionic acid, so pl. 159o;

benzyl ether 3-(4-(3-(4-hydroxynicotinic)-2-oxo-5S - oxazolidinyl)-1-piperazinil)-propionic acid, so pl. 159o.

Example 16

A mixture of 1 g of ethyl ester 3-(4-(3-(4-amidinophenoxy)-2-oxo-5 - oxazolidinyl)-1-piperazinil)-propionic acid, 0.2 g of NaOH, the th receive processing 3-(4-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-1 - piperazinil-propionic acid, so pl. 269o.

Similar way by saponification of the corresponding esters receive:

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-3-oxo - piperazine-4-acetic acid, monohydrate, so pl. 261o;

3-(4-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-2-oxo - 1-piperazinil)-propionic acid, FAB 390;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4 - hydroxy-piperidine-4-carboxylic acid;

1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4-hydroxy - piperidine-4-acetic acid, so pl. 230o;

1-(3-(4-amidinophenoxy)-2-oxo-5R-oxazolidinyl)- piperazine-4-acetic acid, acetate, FAB 362; []2D0-28,0o/c = 1, DMSO 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)- piperazine-4-acetic acid, acetate, FAB 362; []2D0+24,0o/C = 1, DMSO/.

Example 17

and/ Dissolve 1 g of ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-4-methanesulfonate-piperidine-4-acetic acid is obtained from 4-hydroxy-compounds /see example 13/ and methanesulfonamide/pyridine/ a 2% solution of NH3in 10 ml of a mixture of /1:1/ ethanol and THF and leave for 2 hours at a temperature of 20o. Evaporated, processed as usual and get the ethyl ester of 1-(3-(4-colocat ethyl ester 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4-amino-piperidine-4-acetic acid, FAB 404;

in/ Analogously to example 16 using saponification get 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4-amino-piperidine-4 - acetic acid, FAB 376.

Example 18

and/ Analogously to example 17A/ of the ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)-4-methanesulfonate - piperidine-4-carboxylic acid is obtained from 4-hydroxy-compounds /see example 13/ methanesulfonamido/pyridine/ and NH3get the ethyl ester of 1-(3-(4-tianfeng)-2-oxo-5-oxazolidinyl)- 4-amino-piperidine-4-carboxylic acid, FAB 373;

b) Analogously to example 8 to obtain ethyl ester 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4-amino-piperidine-4 - carboxylic acid, FAB 390;

in/ Analogously to example 16 by saponification get 1-(3-(4-amidinophenoxy)-2-oxo-5-oxazolidinyl)-4-amino-piperidine-4-carboxylic acid, FAB 362.

Example 19

A solution of 1 g of benzyl ester 3-(4-(3-(4-hydroxynicotinic)- 2-oxo-5R or 5S-oxazolidinyl)-1-piperazinil)- propionic acid (see example 15/ 30 ml acetic acid with addition of 1 mm acetic anhydride hydronaut 0.2 g of 10% Pd-C at 20oand a pressure of 1 bar until the uptake of the calculated amount of hydrogen, filtered, processed as usual and get:

3-(4-(3-(´┐Żagenie/; []2D0+9o/c = 0.5 DMSO/


3-(4-(3-(4-amidinophenoxy)-2-oxo-5S-oxazolidinyl)-1 - piperazinil)-propionic acid, acetate, so pl. 200-220o/decomposition/; []2D0- 8o/C = 0,5, DMSO/.

The following examples relate to pharmaceutical methods of preparation:

Example A. Tablets

Of a mixture of 1 kg of biologically active substances of the formula I, 4 kg of lactose, 1.2 kg of corn starch, 200 g of talc and 100 g of magnesium stearate are made in the usual way tablets, with each tablet contains 100 mg of biologically active substances.

Example B. Bean

Analogously to example A prepare tablets, which are then in the normal way are coated with sucrose, corn starch, talc, tragant and dye.

Example C. Capsules

500 g of biologically active substances of the formula I put in the usual way in capsules of hard gelatin, and each capsule contains 500 mg of biologically active substances.

Example D. Ampoules

To a solution of 100 g of biologically active substances of formula 1 and 4 l of double-distilled water using 2 hydrochloric acid to establish a pH of 6.5, sterile filtered and filled capsules. the cally active substances.

Example E. Candle

A mixture of 50 g of biologically active substances melt with 10 g of soya lecithin and 140 g of cocoa butter, poured into moulds and cooled. Each candle contains 250 mg of biologically active substances.

Pharmacological report tests

By analogy with the method of Smith et al., J. Biol. Chem. 265, 12267-71 (1990) for some of the presented compounds of the formula I were determined value IC50(concentration in mcmash/liter; 50% inhibition of binding of fibrinogen on a stand-alone fibrinogen the receptor GPIIbllla; GP=Glycoprotein) (see table).

Similar results were obtained when testing other representatives of the compounds of General formula I.

1. Oxazolidinone General formula I

< / BR>
where Y is unsubstituted or substituted R2piperidino, 1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group HE, NH2, carbonyl group;

R1is phenyl, substituted JV, N2N-CH2(A)2N-CH2N2N-C(=NH), N2N-C(=NH)NH;

R2- CmH2mR3or O-CpH2PR3; where R3- N, or benzyl;

R4- N, A, CnH2nR is.

2. Connection on p. 1, which is 1-[3(4-amidinophenoxy)-2-oxo-5-oxazolidinyl]-piperidine-4-carboxylic acid.

3. The method of producing oxazolidinones General formula (I) under item 1 or its salts, characterized in that the compound of the formula I

< / BR>
where R1is phenyl, substituted JV group;

Y is unsubstituted or substituted by a group R2piperidino, 1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group HE, NH2, a carbonyl group, and R2or R4are specified in paragraph 1 values, is converted into a compound of formula (I), where R1is phenyl, substituted amedieval group and Y has the abovementioned meaning, and, if necessary, the compound of formula I in which Y may be unsubstituted or substituted by a group R2piperidino, 1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group HE, NH2, a carbonyl group, and R2- CmH2mR3or O-CpH2PR3where R3= N, n = 1 or 2, p = 1 or 2, m = 0, 1, or 2,

handle base and get a salt of formula I, where R1the eat, the compound of General formula I or its physiologically acceptable salt is mixed with one solid, liquid or semi-liquid carrier and transferred into a suitable dosage form.

5. Pharmaceutical drug, possess inhibitory activity of the binding of fibrinogen, comprising the active ingredient and pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound of General formula I on p. 1 or its physiologically acceptable salt in an amount of from 5 mg to 1 g

Priority points and features:

01.05.93 on PP.1 to 5, where Y is not substituted R2piperidino, 4-R4-pieperazinove the rest;

22.02.94 on PP. 1, 2, 3, 4, 5, where Y is replaced by R2piperidino, 1-oxa-8-azaspiro[4,5] -decane-yl or 4-R4-pieperazinove residue, each of which may optionally be substituted by a group HE, NH2or carbonyl group.


Same patents:

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts

The invention relates to new biologically active compound from the series of heterocyclic compound of the formula I, showing the property activator germination of wheat seeds

The invention relates to new heterocyclic compounds having therapeutic activity, to processes for their preparation and intermediate compounds used for their production, to pharmaceutical preparations containing these compounds and to the use of these compounds in medicine

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes

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 organic chemistry and can find application in biochemistry and medicine