UA54367C2 - Oxasolyldinone derivatives, methods for their production, pharmaceutical composition and method for its preparation - Google Patents

Abstract

The novel derivatives of the oxasolyldinone of the formula (I) wherein R1 represents amidinophenyl, R3 represents Н, А, С1-С10-alkanoyl, С1-С8-alkoxycarbonyl, benzoyl, naphtoyl, С1-С6-alkylsulfonyl, benzylsulfonyl, or non-substituted or monosubstituted by С1-С6-alkyl phenyl-sulfonyl, R3 represents hydrogen or С1-С6-alkyl, А represents С1-С6-alkyl or pharmaceutically acceptable salts thereof. The substances inhibit fibrinogen binding with appropriate receptor and may be used for the treatment of thrombosis, osteoporosis, cancer, arteriosclerosis, and osteolytic diseases. The methods for their production, the pharmaceutical composition and method for its preparation are also described.

Description

Description of the invention

The invention concerns new derivatives of oxazolidinone formulas! I sho 4 - Ku Te o gde

What does TV mean? Kun (sv)yu she I -zh(/le) ; or 2-5

In H, A, Ac, A-5O»-, Ag-505- or amino-protecting group, if it is present,

AZN,A, cycloalkyl with 3-7 atoms of C, Ag or Ag-(CH"); -, A alkyl with 1-46 C atoms,

In NA or NoM-C(-MN)-,

Mon-CH»o-, NaM-C(-MH)- or No-M-C(-MH)-MH-CH 5, with primary amino groups! may also have amino-protecting groups,

Ac alkanoyl with 1-10 C atoms or aroyl with 7-11 C atoms, Ag unsubstituted or mono and/or disubstituted)

A, SI, Vg, I, CA, OH, MO», CM, IN», MNA or MA» phenyl or benzyl, 1, 2, 3 or 4, p2, Zyl4, and M zo K 1, 2, Z or 4, as well as their physiologically tolerable salts.

Similar lime compounds from the description of the invention - ER-AI-0 381 033.

The basis of the invention is the task of finding new compounds with valuable properties, in particular, those that can be used for the production of medicinal products.

This problem was solved with the help of the invention. It was found that the compounds of formula I, as well as their -

Зз5 sick! and salts with good tolerance have valuable pharmacological properties. First of all, they act as an integrin inhibitor, while they, in particular, inhibit the interaction of receptors

Vz - or De - integrin with ligands. The special effectiveness of the connection is found in the case of integrins and оуВ3, о//В5, «41603. This activity can be, for example, proven by the method described by M. Ztiy "ei a. Vioi Spent 2205, 12267-12271. In particular, they inhibit the binding of fibrinogens, fibronectin, and von Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein Pb/LPa), as well as the binding of them and other adhesive proteins, such as vitronectin, collagen, and laminin, to the corresponding receptors on surfaces of different types of cells. Thus, these compounds affect "cell-cell and cell-matrix" interactions. They, in particular, prevent the formation of blood platelet thrombi and therefore can be used for the treatment of blood clots, apoplexy, heart attack, angina! in particular, osteoporosis, anti-angiogenesis and restenosis after 1 angioplasty, ischemia, inflammation, arteriosclerosis and acute renal failure. Further, the compounds have an effective effect on cancer cells, resulting in the formation of metastases. Thus, they can also be used as an anti-cancer agent 9) There are indications that cancer cells get into blood vessels through microthrombi and, thus, protect themselves from detection by cells of the immune system. Microthrombi also contribute to binding

Cancer cells to the vessel walls. Since the formation of microthrombi is related to fibrinogen binding to the fibrinogen receptor (glycoprotein Pr/yi a), inhibitors of fibrinogen binding are also considered inhibitors of metastases.

Connections of adventure! also as antimicrobial active substances, which can prevent the development of infections such as, for example, viral infections! bacteria, fungus or yeast. These substances can be given, therefore, in a preferable way, as accompanying antimicrobial active i) substances, if effects on the body are undertaken, in which substances foreign to the body are used, such as, for example, biomaterials, an implant), a catheter or a stimulator! hearts They act as antiseptic agents. The antimicrobial activity of the compounds can be striking, for example, because it was proven by the method of R. Maiepiip - U/eidapa eyi a! which is described in Ipgesiops apa Ittipku, 2851-2855 (1988).

Other properties of compounds can be determined by the method described in the description of the invention

EP-AI-O 462 960. Inhibition of fibrin binding to the fibrinogenic receptor can be demonstrated by the method specified in the description of the invention EP-AI-O 381 033. The effect of suppressing platelet aggregation can be determined in laboratory conditions by the method of Born (Mayuge 4832, 927 -929, 1962). 65 Further, the subject of the invention is a method of obtaining compounds of the specified formulas! And, as well as ego salts, distinguished by the fact that a) the combination of formulas! And freed from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or that b) combination of formula II

Her name / M i

В Я о where 7 means SI, Vg, I, OH or a reactive esterified OH group, and

ВЕ" has the specified higher value, is introduced into the interaction reaction with the compound of the formulas! HER, (1) uh 5

X Hunya with nipples where

B2 and EZ have the indicated values, and

X means ОН or a residue formed from ОН according to the type of salt, or что с (c) compound of formulas IM (8)

What about me? 7 in'-mn-CH,-CH(OH)CH.-O soov" in (Se) where

В", 22 and ВЗ have a higher meaning, they are introduced into the reaction of interaction with a reactive carbonic acid derivative, or что "(g) the compound of the formula! M

IC c)

IN

- what do you think?

WE

N that mountain "o - s z" where to V? and З have the indicated meanings, are introduced into the interaction with the combination of formulas! MI /- (M) t v-K their KK / (95) where b 50 V has the specified value" and

І ІІ x ! "M U means -HO - (СНо)" - X or M -(085), -X, where the type has the already indicated meanings, and 22 X! mean SI, Vg, and the second easily nucleophilically displaceable leaving group,

HF) (e) to obtain a guanidinomethyl compound of the formulas and (B / - a phenyl residue, singly substituted by the group НоМ-С(-МН)-МН-СН»0-) an amine compound corresponding to the formula I!, which, however, contains instead of the rest of KE! the aminomethylphenyl group is treated with an amidinizing agent, or 60 Kk - Kk (e) one K" residue is converted into the other K" residue by the omylation of a complex sulfur of the formula I, or the carboxylic acid of the formulas I is subjected to esterification, or (g) the residue (residues) IN! and/or B? turn into a second remainder (second remainders) B! and/or B2, and/or that (from) the compound of formula I is converted into one of its salts by treatment with an acid or a base. b Compounds of formula I have at least one chiral center and can, therefore, appear in several znantiometric forms. All these forms (for example, the forms О and И) and their mixtures (for example, the form!

ОЙ ) inclusions in formula I.

Higher and lower residues or, respectively, parameters A, B, 0, X, M, 27-83, Ac, Ag, K, etc., have the meanings specified in the formulas I - MI, unless something else is clearly indicated. If there are several identically designated groups in the molecule, they can be assigned different definitions independently of each other.

In the above-mentioned formulas, group A has 1-6, preferably 1, 2, 3 or 4 C atoms. In particular, A preferably means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, dalele, also pentyl, 1-, 2- and 3-methydbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-methylpropyl, hexyl, 1-, 2-, 3- or 4-methyl-pentyl.

IN! is, preferably, a phenyl residue substituted in the 4th position, but also in the 2nd or in the G position, in particular, preferably 2-, 3- or (in particular) 4-aminomethylphenyl, 2-, 3- or ( in particular) 4-amidophenyl, 2-, 3- or 4-guadinomethylphenyl, and in all cases primary amino groups! may also have an amino-protecting group. Next, B! is also, preferably, 4-piperidyl, 4-piperidylmethyl, 4-piperidyl, 1-amidino-4-piperidyl, 1-amidino-4-piperidylmethyl, 4-piperazinyl, 4-piperazinylpropyl, 4-piperazinylbutyl, 1-amidino- 4-piperazinyl or 1-amidino-4-piperazinylpropyl residue.

IN? preferably represent hydrogen, methyl, zyl, methylsulfonyl, zylsulfonyl, n-propylsulfonyl or n-butylsulfonyl, toluenesulfonyl or an amino protecting group, if present.

R is preferably hydrogen, methyl or ethyl.

Ar is preferably unsubstituted phenyl or 4-methylphenyl, Ac means preferably alkanoyl with 1-6 C atoms, such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or caproyl, further, benzoyl, toluyl, 1- or 2 -naphthoyl or phenyl acetyl.

Parameter K and t mean, preferably 0 or 1. Parameter n - zto, preferably 2 or 3. s 29 Average of combined formulas! | those in which at least one of the specified residues, one of the specified groups and/or one of their specified parameters has one of the specified preferred values are considered to be preferred. Some groups of preferred compounds are those of the formula Ta - Ii, which correspond to the formula I, where, however, va B! means amidinophenyl; - at 16 V! means amidinophenyl and (Ce)

B2 means hydrogen; so in IV and B' means aminomethylphenyl and

VZ means hydrogen or methyl; With in g In! means amidinophenyl and Io)

VZ means hydrogen or methyl; in Eid B! means piperidylmethyl and piperidylethyl and 2 means hydrogen or -A-505-; " 20 Ie V! means 1-amidinopiperidylmethyl and sh-v c 2 means hydrogen or A-505-; and Eat In! means piperazinostil or piperazinopropyl and "B2 means hydrogen or A-505-;

From V! means 1-amidinopiperazinosyl or 1-amidinopiperazinopropyl and

IN? means hydrogen or A-50". o Combinations of formulas! 1, as well as the starting substances for their production are obtained casually according to their known methods, which are described in the literature (for example, in Notsrep - MUeu 1, Method of organic chemistry, publishing house SbSeogd - Tpiete, Stuttgart further, description of the invention - ЕР-АИ-О0 381 033, ЕР-АИ-О 462 960), and namely, in the conditions of the reaction, which are interesting and exciting! for the named exchange reactions. At the same time, it would also be possible to use a variant known by itself, which is not mentioned in more detail here.

The starting substances can be obtained, if desired, separately, so that they do not need to be isolated from the reaction "M" mixture, but can be introduced immediately into the exchange reaction with the formation of compounds of formula I.

Compounds of formula I can be obtained by isolating them from their functional derivatives by solvolysis, in particular, hydrolysis or hydrogenolysis.

Preferable starting materials for solvolysis or hydrogenolysis, respectively, are recognized

F! such substances which generally correspond to formula I, but instead of one or more free amino- and/or hydroxy groups contain the corresponding protection of amino- and/or hydroxy groups, preferably in the form of those which, instead of the H atom connected to the M atom, carry an amino-protecting group , in particular, those that carry a K-M group instead of the NM group, where K' means an amino-protecting group, and/or those that carry a hydroxy-protecting group instead of the H atom of the hydroxy group, for example, those that correspond to the formula !, but instead of the group - COOH carries the group -SOOK", where K" means a hydroxy-protecting group.

In the molecule of the starting substance, several - the same or different - protective amino and/or hydroxy groups may also be present. If the existing protective groups differ from each other, then they can in many cases selectively split off.

The belief "amino protective group" is common knowledge and refers to groups that for protection! (blocking) amino groups! from chemical ones transformed, but which; in addition, they can be easily removed after the desired chemical reaction has taken place in the second place of the molecule. Typical for such groups are, in particular, unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl, (OMR)), aralkyloxymethyl (for example, benzoyloxymethyl (BOM)) or aralkyl (for example, 4-nitro-benzyl, triphenylmethyl ) groups. Since amino-protecting groups are removed after the desired reaction (or series of reactions), their type and size, in general, are not considered critical: we recognize, however, such groups! with 1-20, in particular, 1-8 C atoms. The expression "acyl group" should be taken in connection with the present method in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkyloxycarbonyl, aryloxycarbonyl and, above all, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl, butyryl; aralkanoyl, such as -phenyl acetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as phenoxyacetyl; Alkoxycarbonyl, such as methoxycarbonyl, z-toxiccarbonyl, 2,2,2-trihexoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoxycarbonyl; aralkyloxycarbonyl, such as -benzyloxycarbonyl (sva, 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (EMOS). Preferred protective groups are BOS, OMR and VOM, hereinafter SVI, benzyl and acetyl.

The term "hydroxyprotective group" is also well-known and refers to groups that are useful for protection! hydroxy group! from chemical ones, but which can be easily removed after the desired chemical reaction has taken place in the second place of the molecules. Typical for such groups are the names of more unsubstituted or substituted aryl, aralkyl, or acyl groups, as well as alkyl groups. The nature and size of hydroxy-protecting groups are not considered critical, since after completion of the desired chemical reaction or sequence of reactions, they are again subject to removal; groups with 1-20, in particular, with 1-10 C atoms are preferred. Examples of i9) hydroxy-protecting groups include, in addition, tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, and acetyl, with particular preference given to benzyl and acetyl.

The functional derivatives of the compounds of formulas 1 used as starting materials can be obtained by ordinary methods, as described in the above-mentioned reference books and patent applications, for example, by exchange reactions of compounds corresponding to formulas I! and I, and, however, at least one of these compounds contains a protective group instead of an H. co atom

The release of compounds of the formulas and their functional derivatives can be carried out - depending on the protective group used - for example, with the help of strong alkalis, expediently with the help of trifluoroacetic acid or perchloric acid, but also with the help of other strong inorganic acids, such as hydrochloric acid or sulfuric acid, with the help of strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but it is not always required.

Suitable inert solvents are preferably organic, for example, carboxylic acids, such as acetic acid, solvents such as tetrahydrofuran or dioxane, amides), such as dimethylformamide (OME), halogenated hydrocarbons, such as dichloromethane, sulfoxides , takie kak - i"? dimethylsulphoxide (OM50O), dalehe, also alcohol, takie kak methanol, ztanol, or isopropanol, as well as water.

Further, mixtures of the above-mentioned solvents can be used. Trifluoroacetic acid is preferably used in excess without adding a second solvent, perchloric acid - in form 1 of a mixture of acetic acid and 7090 perchloric acid in a ratio of 9:11. Reaction temperatures! for splitting lie, expediently, in the interval between approximately 0 and approximately 50"C. e They work preferably in the interval between 15 and 30"C (room temperature). o The BOC group can be split off, for example, preferably with the help of trifluoroacetic acid! in dichloromethane or with the help of approximately 3-5 N HCl in dioxane at 15-60 "C, the EMOS group - with the help of an approximately 5-2096 solution of dimethylamine, distylamine or piperidine in OME at 15-60. "I Cleavage of the OMR group is possible to produce, for example, also with the help of an approximately 3-1096 solution of 2-mercaptostanol in OME/water at 15-3070.

Protecting groups (e.g. PTO, SV or benzyl) that can be removed hydrogenolytically can be, for example, removed by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, expediently on a support such as charcoal). Suitable solvents for this purpose are solvents, in particular, for example, alcohol, such as methanol or ethanol, or amides such as OME. Hydrogenolysis is usually carried out at temperatures between approximately 0 and 1007C and pressure between approximately 1 and 200 bar, preferably at 20-307C and 1-10 bar. Hydrogenolysis of the SV group can be carried out well, for example, at 5-1095-nom Ra-C in methanol at 20-3076.

Combinations of formulas! can be obtained, preferably, also with the help of reactions of compounds of formulas II with derivatives of phenol of formulas! PP. At the same time, they use the expedient image, known methods of obtaining simple zfirov. 65 Volatile group 7 preferably means C1, B2, I, b4-Ce-alkylsulfonyloxy, such as methane- or ethanesulfonyloxy or C-Cio-arylsulfonyloxy, such as benzene-, p-toluene- or 1- or

2-Naphthalenesulfonyloxy.

The reaction proceeds preferably in the presence of an additional base, for example, hydroxide or carbonate of an alkali or alkaline earth metal, such as sodium, potassium or calcium hydroxide, sodium, potassium or calcium carbonate, in an inert solvent, for example, in a halogenated hydrocarbon, such as - dichloromethane, in a simple ether such as TME or dioxane, in an amide such as -OME or dimethylacetamide, in a nitrile such as acetonitrile, at temperatures between approximately -10 and 200, preferably between 0 and 1207"C. If the volatile group E differs from 1, then the addition of an iodide, such as potassium iodide, is recommended. 70 The starting substances of the formulas II are recognized, as a rule, new. They can be obtained, for example, by the reaction of a substituted aniline of the formulas B! MH" with the compound formulas KeSnN» - snavb- Сsn»on (where 227, VFON or 2 and KZ together mean also 0) with the formation of a combination of the formulas! ВК! - МН - СНо - сНеЕЗ - СНООН (where KZ means OH), with the help of rea reactions with the production of carbonic acids, such as - distylcarbonate with the preparation of 3-K1-5-hydroxymethyl-2-oxazolidinones and, if necessary, with the help of 792 Conversion of the hydroxymethyl group to the CH 57 group, for example, with the help of 50ОСИ», 5ОВГг» methanesulfonyl chloride or p-toluenesulfonyl chloride. Compounds of formula III are, as a rule, known or can be obtained by analogy with known compounds from suitable phenolic derivatives or from phenol.

Combinations of formulas And they can also be obtained by means of the reaction of the combination of formulas! IM (or a reactive derivative) with a reactive carbonic acid derivative.

As derivatives of carbonic acid, in particular, dialkylcarbonate, such as distylcarbonate, and also alkyl chloroformic acid, such as zylchlorformate.

Preferably, a derivative of acetic acid!, which, expediently, is used in excess, will also be added as a solvent or suspending agent. But CM 29 can be present as well as one of the specified solvents, if it is inert in this exchange reaction. Further, it is recommended to add a base, in particular, an alkali metal alcoholate, such as potassium tert-butylate.

The work is preferably carried out at reaction temperatures between 0 and 150C, preferably between 70 and 12020.

The original substance of the formulas! IMs are recognized, as a rule, as new. They can, for example, be obtained by functionalizing the names of several connected formulas! В - МН - СНео - СН(ОН) - СННОН of compounds (Te) of formulas КВ! - MH - CH" -CH(OH) - CH" - 7 and reactions with compounds of the formulas! II. co

To obtain the compound formula where K / denotes a guadinophenyl group, it is possible to treat the corresponding aminophenyl compound with an amidinizing agent. 1-ami-dino-3,5-dimethylpyrazolyl is preferred as an amidinizing agent, which, in particular, is used in the form of its nitrate. They work, expediently, with the addition of a base such as tristilamine or; zyl-diisopropylamine in an inert solvent or solvent mixture, for example, water/dioxane at temperatures between 0 and 120°C, preferably between 60 and 12076.

Further, there is an opportunity to combine the formulas and turn one residue of KZ into the other residue of KU, "by combining a complex set of formulas!" Or with the help of esterification of carboxylic acid! formulas! In order to carry out esterification, it is possible to treat the acid of the formulas I (B 3-H) with an excess amount of the alcohol of the formula! E2-OH (2EZ-A or benzyl), expediently, in the presence of a strong acid, such as hydrochloric acid or sulfuric acid, at temperatures between 0 and 100, preferably between 20 and 5070.

Conversely, the complex ether of the formulas I (BZ - A or benzyl) can be turned into the corresponding acid of the formulas (BZ-H), expediently, with the help of solvolysis or hydrogenolysis in accordance with one of the above-mentioned methods, for example, with the help of MaOH or KOH in a mixture of hydrogen and dioxane at temperatures between 0 and 40°C, preferably between 10 and 3070.

In addition, there is a possibility of conversion of one residue B! and/or B2 in the second remainder of B! and/or V.

Mother In particular, primary or secondary amino groups are possible! alkylate, acylate, amidinate or

Gee! 20 are provided with temporary amino protecting groups or alkyl or arylsulfonyl groups or, conversely, . free them by removing those groups. c To obtain amidine of formulas I (B 7 - amidinophenyl) it is possible to add ammonia to the nitrile of formulas I (7 - cyanophenyl). The addition is carried out in the course of several steps, by the conversion of a nitrile with the help of HoC into a thisamide, which, with the help of an alkylating agent, for example, CH3, is converted into the corresponding complex 5-alkyl-imidothiosphyre,

HF) reacts with МН3з with the formation of amidine, method b) of a nitrile with the help of an alcohol, for example, ethanol, in 7 the presence of NCI into the corresponding imidospheric complex, which is subjected to ammonia treatment, and method c) by entering a nitrile into an exchange reaction with bis-(trimethylsilyl) )-amidolithium and exploratory hydrolysis of the product.

In a similar way, it is possible to obtain the corresponding M-hydroxy-amide formulas! (B! - phenyl, substituted HO-MH-C(-MH)) from nitriles, if you work according to method a) or b), but use hydroxylamine instead of ammonia. Further, derivatives can be obtained from these products, in the process of their reduction, for example, with the help of gaseous hydrogen. be The basis of formulas | with the help of acid can be converted into the corresponding acid-additive salt. From that interaction, acids are used, in particular, which form physiologically acceptable salts. So, inorganic acids can be used, for example, sulfuric acid, nitric acid, hydrohalic acid, such as hydrochloric acid or hydrobromic acid, phosphoric acid, such as orthophosphoric acid, sulfamic acid, and organic acids, in particular, aliphatic, alicyclic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic, or sulfuric acids, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, distyloxic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid , tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, /0 nicotinic acid, methane- or ztansulfonic acid, ztandasulfonic acid, 2-hydroxyztansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disu lphonic acid, lauryl sulfuric acid. Salts with physiologically impermeable acids. For example, picrat!, can be used to dilute and/or purify compounds of formulas! AND.

Free basis of the formula! can be freed, if desired, from their salts after treatment with strong bases, such as sodium or potassium hydroxide, sodium or potassium carbonate.

It is also possible to convert carboxylic acids of the formula | (B - NN) by exchange reactions with the corresponding bases in their metal or ammonium salts, for example, sodium, potassium or calcium salts.

Compounds of formula I contain one or more chiral centers and can therefore be present in a racemic or optically active form. Receipt of racemat! with the use of known methods, they can be separated mechanically or chemically into znantiometry. Preferably, diastereomers are formed from a racemic mixture by means of an exchange reaction with an optically active separating agent.

As a separating agent suitable, for example, optically active acids, such as - OO -form and Y. -form!i tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid

Acid, lactic acid or various optically active camphor-sulfonic acids, such as p-sulfocampharic acid. It is also preferable to separate znantiomers using a column filled with an optically active separating agent (for example, dinitrobenzoyl-phenyl-glycine); as a solvent (in chromatography), for example, a mixture of hexane/isopropanol/acetonitrile is suitable, for example, in a volume ratio of 82:15:3. what-

Naturally, it is possible to obtain optically active compounds of the formulas! according to the methods described above, when starting substances are used (for example, such substances of the formula! I), which are already optically active. co

The new compounds of formulas I and their physiologically acceptable salts can be used for the preparation of pharmaceutical preparations if they are combined with at least one carrier substance or

With an auxiliary substance and, if desired, together with one or more other active substances, transfer to the appropriate dosage form. Obtaining in this way the drug! can be used as a medicine in medicine and veterinary medicine. In the case of carrier substances, these are organic and inorganic substances that are suitable for enteral (for example, oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation, and 70 do not react with new compounds, for example, water, plant oils, benzyl alcohol, polyethylene glycol, glycerin triacetate and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc, cellulose. For oral use, in particular, tablets, dragees, capsules, syrups, juices or drops are used; tablets with a varnish coating and capsules with shells that are resistant to gastric juice are of interest. Suppositories are used for rectal use, and suppositories are used for parenteral administration administration of a solution, preferably an oily or aqueous solution, then a suspension, emulsion or implant. t For administration in the form of a spray on the day of inhalation, sprays can be used that contain the active substance (4) either in dissolved form or in the form of a suspension in mixture of working gas. In this case, the active substance is used in a micronized form, and one or more may be added

F additional physiologically acceptable solvents, for example, ztanol. Inhalation solution "| can be prepared with the help of ordinary inhalers. New compounds can also be lyophilized, and the obtained lyophilized! can be used, for example, to obtain injection drugs.

Indication of the composition can be sterilized! and/or may contain excipients such as

Preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing osmotic pressure, buffer substances, dyes and/or aromatic substances. If desired, they can contain i) also one or several additional active substances, for example, one -vitamin or several co-vitamins.

The compounds according to the invention are taken, as a rule, by analogy with other limes available on sale, pharmaceutical means, in particular, by analogy with the compounds described in EP-A-459 256, preferably in the form of dosages of approximately 5 mg and g, in particular, 50 and 50 Ω per dosage unit. The daily dosage is, preferably, approximately 0.1 and 20mg/kg, in particular, 1 and 1Omg/kg of body weight. The special dose for each specific patient depends, however, on various factors, for example, on the activity of the used special 65 compound, on age, body weight, general state of health, gender, on the time and method of administration, on the speed of elimination, on combinations of drugs and the severity of the corresponding disease that is being treated. Oral administration is preferred.

Higher and lower temperatures are indicated in degrees Celsius. In the examples below, the expression "preparation in the usual way" means: If necessary, add water, depending on

The pH of the final product is set between 2 and 8, the ion exchange column is filtered, the organic phase is dried over sodium sulfate, evaporated, if necessary, lyophilized and purified by chromatography on silica gel and/or by crystallization. In the following examples, the expression "4-piperidylyl" always means "2-(4-piperidyl)-ethyl", the expression "A-piperidylpropyl" always /"3-(4-piperidyl)-propyl" and the expression //"4-piperidylbutyl" " always 70 "4--4-piperidyl)-butyl". Similarly, the expression "d4-piperazinyl-xtyl" always means "2-(4-piperazinyl)-xtyl", the expression "4-piperazinylpropyl" means "3-(4-piperazinyl)-propyl" and the expression "d-piperazinylbutyl" - "4-(4-piperazinyl)-butyl". It also includes the provision of protective groups, for example, VOC-protective compounds.

Example 1

To a solution of 1.9 g of methyl sulfur, 2-M-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid! ("A") (obtained from tyrosine by esterification with methanol and the introduction of a BOC protecting group) add 1 equivalent of Mann to 20 ml of dimethylformamide (OME) and stir for 30 minutes at room temperature. After that, add 1.8 g of 3-p-M-BoC-amidino-phenyl-5-methane-sulfonyloxy-methyl-oxazolidin-2-one (obtained as a result of the reaction of p-aminobenzonitrile with 2,3-zpoxypropan-1-ol with the formation of p-(M-2,3-dihydroxypropyl-amino)-benzonitrile, reaction and exchange with distyl carbonate in the presence of tert.-butyl potassium with the formation of 3-p-dianphenyl-5-hydroxymethyl-oxazolidin-2-one, exchange reactions with

NH3, methyl iodide and ammonium acetate to obtain amidine, by introducing the protective group of BOC into amidine and subsequent esterification with the help of methanesulfonyl chloride) dissolved in 10 ml of OME, and the mixture is again stirred for 15 minutes at room temperature. After removing the solvent and carrying out the "preparation by the general method", 3-p-BOC-amidino-phenyl-5-|p)-(2-methoxy-sicarbonyl-2-M-BOC-amino-xyl)-phenoxy| -methyloxazolidin-2-one.

Anadogino by means of the exchange reaction "A" is obtained with the help of 3-(4-ChM-BOOS-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one M zo 3-(4-M-BOOS-piperidyl) -5- ( n -(-2-methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one ise) 3-(4-Ch4-BOC-piperidylmethyl)-5-| -2-11-BOC-amino-zyl)-phenoxy|-methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one « 3-(4-ChM-BOC-piperidylyl)-5-(n -(2-methoxycarbonyl-2- M-BOC-amino-zyl)-phenoxy)| yu -methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-M-BOC-piperidylpropyl)-5-(p-(2-methoxycarbonyl-2-M -BOC-aminonzyl)-phenoxy -methyl-oxazolidin-2-one; " with the help of 3-(4-M-BOC-piperidylbutyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one with 3-(4-M -BOC-piperidylbutyl)-5-(n -(2-methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy)-methyl-oxazolidin-2-one; ;" with the help of 3-(1-Ch4-BOC-amidino -4-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperidyl)-5-(p-(2-methoxycarbonyl-2-M-BOC) -aminoethyl) -phenoxy) "Methyl-oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazodidin-2-one 3-(1- M-BOC-amidino-4-piperidylmethyl)-5-(p (2-methoxycarbonyl-2-M-BOC-aminostil)-phenoxy o -methyl-oxazolidin-2-one; 2) with the help of 3-(1-I -BOC-amidino-4- piperidylyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-I- BOC-amidino-4- piperidylyl)-5- (n -(2-methoxy-carbonyl-2 -I-BOC-aminoacetyl)-phenoxy

Me. -methyl-oxazolidin-2-one; "M with the help of 3-(1-I-BOC-amidino-4-piperidylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperidylpropyl)-5-( n -(2-Methoxycarbonyl-2-II-BOC-amino-zyl)-phenoxy -methyl-oxazolidin-2-one; with the help of 3-(1-M-BOoC-amidino-4-piperidylbutyl)-5-methanesulfonyloxy- methyl-oxazolidin-2-one 3-1-M- BOC-amidino-4-piperidylbutyl)-5-(p - (2-methoxycarbonyl-2-M-BOC-amino-zyl)-phenoxy (F, -methyl- oxazolidin-2-one using 3-(1-isopropyl-4-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-isopropyl-4-piperidyl)-56- (n -( 2-Methoxycarbonyl-2-M-BOC-aminoethyl)-phenoxy bo7Methyl-oxazolidin-2-one; with the help of 3-(1-isopropyl-4-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 33- (I-isopropyl-4-piperidylmethyl)-56- (n -(2-methoxycarbonyl-2-M-BOC-aminostil)-phenoxy)-methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC -piperazinylethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 65 3-(4-M-BOC-piperazinylethyl)-5-(Ip-(2-methoxycarbonyl-2-M-BOC-aminoethyl)-phenoxy -methyl-oxazolidin-2-one;

with the help of 3-(4-M-BOC-piperazinylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-M-BOC-piperazinylpropyl)-5-(p-(2-methoxycarbonyl-2-H -BOC-aminoethyl)-phenoxy|)-methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperazinylbutyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-M-BOC-piperazinylbutyl)-5-I(Ip-(2-methoxycarbonyl-2- M-BOC-aminoacetyl)-phenoxy)-methyl-oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperazinylethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperazinyl)-5-|(n -(2-methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy 7/0 "methyl-oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperazinylpropyl)-5-methanesulfonyloxy- methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperazinylpropyl) | -5-(n. /-(2-methoxycarbonyl-2-M-BOC-aminoacetyl) / -phenoxy)-methyl -oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperazinylbutyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperazinylbutyl) ) -5- (n o -(2-methoxycarbonyl-2-M-BOoC-amino-zyl)-phenoxy -methyl-oxazolidin-2-one;

Example 2

A solution of 3-p-cyano-phenyl-5-(p-(2-methoxycarbonyl-2-M-BOC-aminosyl)-phenoxy-methyl-oxazolidin-2-one obtained according to example 1 with the help of methyl sulfur exchange reactions 2- 1-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid with 3-p-cyano-phenyl-5-methanesulfonyloxy-methyl-oxazolidin-2-one in 400 ml of a 1096% MNH solution in methanol are hydrogenated at 0 , bg of Raney nickel at room temperature and pressurized to | bar until the end of absorption

But. After filtration and evaporation, 3-p-aminomethyl-phenyl-5-P-(2-methoxy-carbonyl-2-M-BOC-aminosyl)-phenoxy)| -methyl-oxazolidin-2-one. high school

By analogy, we get; from 3-m-cyano-phenyl-5-|n -(2-methoxycarbonyl-2-M-BOC-aminosyl)-phenoxy)| -methyl-oxazolidin-2-one and) 3-m-aminomethyl-phenyl-5-(p -(-2-methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy)| -methyloxazolidin-2-one; from 3-m-cyano-phenyl-5- (p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy)-methyl-oxazolidin-2-one iso 3-m-aminomethyl-phenyl-5 -(n-(2-methoxycarbonyl-2-N-butylsulfonyl-aminostil)-phenoxy|-methyloxazolidin-2-one; so from 3-P -cyano-phenyl-5-|(n -(2-methoxycarbonyl-2 -M-butylsulfonyl-aminoethyl)-phenoxy-methyl-oxazolidin-2-one 3-P-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|

35 "M-methyloxazolidin-2-one; from 3-o-cyano-phenyl-5-|

3-o-aminomethyl-phenyl-5-5-[n-(2-methoxycarbonyl-2-N-butylsulfonyl-aminoacetyl)-phenoxy)-methyloxazolidin-2-one; « from 3-o-dian-phenyl-5-|(n -2-methoxycarbonyl-2-M-BOC-aminostil)-phenoxy)-methyl-oxazolidin-2-one from c 3-o-aminomethyl-phenyl- 5- Ir-(2-methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy)-methyloxazolidin-2-one.

Example C;" Analogously to example 1, starting from the methyl ester of 2-T-butylsulfonyl-amino-3-(4-hydroxy-phenyl)-propanoic acid! ("B") obtained by tyrosine

Esterification with methanol and with the help of exchange reactions with butylsulfonyl chloride|, with the help of exchange reactions with 3-(1-M-BOC-amidino-4-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one | obtained by the reaction 1-H -BOC-amidino-4-amino-pyreridine with 2,3-zpoxypropan-1-ol with the formation of pI-IM-BOC-amidino-4-(M-2,3-dihydroxy-propyl-amino)-piperidine, interaction with distylcarbonate in 2) the presence of tert-butyl takalium with the formation of 3-(I-"M-Boc-amidino-4-piperidyl) in 7-hydroxy-methyl-oxazolidin-2-one and subsequent esterification with methanesulfonyl chloride) is obtained

Me, 3-(1-M-BOC-amidino-4-piperidyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl).--phenoxy

I -methyl-oxazolidin-2-one.

In a similar way, by means of the exchange reaction "B", the following is obtained: with the help of 3-(4-M-BOC-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-ChM-BOC-piperidyl)-5 (n -(2-Methoxycarbonyl-2-N-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one;

F) with the help of 3-(4-M-BOC-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one and 3-(4-Ch4-BOOC-piperidylmethyl)-5-|n -(2-methoxycarbonyl- 2-M-butylsulfonyl-aminostil)-phenoxy-methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-4-M-BOC-piperidylyl)-5- |n /-(2-methoiccarbonyl-2- M-butylsulfonyl-aminostil)-phenoxy)-methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-M-BOC-piperidylpropyl)-5-|(n. --2-methoxycarbonyl-2 -M-butylsulfonyl-aminoacetyl)-phenoloxy b5 7 Methyl-oxazolidin-2-one; with the help of 3-(4-M-BOC-piperidylbutyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one

3-(4-M-BOC-piperidylbutyl)-5- (n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy -methyl-oxazolidin-2-one; with the help of 3-(1-zthyl- 4-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-ethyl-4-piperidyl)-5-(n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy-methyl -oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperidylmethyl) )-5-|(n-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy -methyl-oxazolidin-2-one; 70 with the help of 3-(1-M-BOC-amidino-4-piperidyl) -5-methanesulfonyloxy-methyl-oxazolidan-2-one 3-(1-M-BOC-amidino-4-piperidylostyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminostyl)-phenoxy -methyl -oxazolidin-2-one; with the help of -(1-M4-BOC-amidino -4-piperidylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 1--M-BOC-amidino -4-piperidylpropyl) (( K(-5-|(n--2-Methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy)|-methyl-oxazolidin-2-one; with the help of 3-(1-M-BOOS-amidine o-4-piperidylbutyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-M-BOC-amidino-4-piperidylbutyl)-5-|p. -(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one; with the help of 3-(1-isopropyl-4-piperidyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-isopropyl-4-piperidyl)-5- (n -(2-methoxycarbonyl-2-M -butylsulfonyl-aminoethyl)-phenoxy-methyl-oxazolidin-2-one; with the help of 3-(1-methyl-4-piperidylmethyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-methyl-4- piperidylmethyl) -5-(n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy -methyl-xazolidin-2-one; with the help of 3-(4-M-BOC-piperazinyl-ethyl)-5-methanesulfo -cyloxy-methyl-oxazolidin-2-one 3-(4-ChM-BOoC-piperazinyl) -5-(n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminostil)-phenoxy| i) -methyl-oxazolidin- 2-one; with the help of 3-(4-M-BOC-piperazinylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(4-M-BOC-piperazinylpropyl)-5-(p-(2 -methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl). it is) 3-(4-M-BOC-piperazinylbutyl)-5-|n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminoethyl)-phe noxyyl se -methyl-oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperazinyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one « 3-(1-M-BOC-amidino-4-piperazinyl)-5- (by -(2-methoxycarboxyl-2-M-butylsulfonyl-aminoacetyl) and -phenoxy)| -methyl-oxazolidin-2-one; with the help of 3-(1-M-BOC-amidino-4-piperazinylpropyl)-5-methanesulfonyloxy-methyl-oxazolidin-2-one 3-(1-Y-BOC-amidano-4-piperazinylpropyl)-5-(n- (2-Methoxycarbonyl-2-M-butylsulfonyl-amino-zyl)-phenoxy|-methyl-oxazolidin-2-one; " with the help of 3-(1-M-BOC-amidino-4-piperazinylbutyl)-5-methanesulfonyl- methyl-oxazolidin-2-one with 3-1-M-BOC-amidino-4-piperazinylbutyl)-5-(n-2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin- 2-on; ;" Example 4 1.27. 3-P -Amidano-phenyl-5-|(n. -(-2-methoxycarbonyl-2-M-BOC-amino-ztyl)-phenoxy)| -methyloxazolidin-2-one obtained according to example 1) is suspended in bOml of methanol, mixed with 4 ml of a 2 M Naon solution and stirred for 4 hours at room temperature. After removing the solvent, the precipitate is absorbed with water, the pH value is set equal to C by adding diluted HCl and filtered through a more acidic ion exchanger. The filtrate is dried over M5O). After removal of the solvent and after 2) additional lyophilization, 3-p-amidino-phenyl-5-(p-(2-carboxy-2-M-BOC-amino-xyl)5o7phenoxy)-methyl-oxazolidin-2-one is obtained.

Me. In a similar way, with the help of the omylation of the products from example 1, "M 3-(4-M-BOC-piperidyl)-5- (p -(2-carboxy-2-M-BOC-amino-zyl)-phenoxy)-methyl- oxazolidin-2-one; 3-(4-M-BOC-piperidylmethyl)-5-|n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; 3- (4-M-BOC-piperidylostyl)-5-|(n -(2-carboxy-2-M-BOC--aminostil)-phenoxy)|-methyl-oxazolidin-2-one; BOC-piperidylpropyl)-5-(n-2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)-methyl-oxazolidin-2-one; 3-(4-M-BOC-piperidylbutyl)-5-| (n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)|-methyl-oxazolidin-2-one;

F) 3-(1-M-BOC-amidino-4-piperidyl)-5-(n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one; ka 3-(1-M-BOC-amidino-4-piperidylmethyl)-56- (p-(2-carboxy-2-M-BOC-aminostil)-phenoxy -methyl-oxazolidin-2-one; in 3-( 1-M-BOC-amidino-4-piperidylstil)-5-(p-(2-carboxy-2-M-BOC-aminostil)-phenoxyl)-methyl-oxazolidin-2-one; 3-(1-M -BOC-amidino-4-piperidylpropyl) -56- (n -(2-carboxy-2-M-BOC-aminostil) -phenoxy) -methyl-oxazolidin-2-one; 3-1-M-BOC-amidino- 4-piperidylbutyl) -56- (n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy b5 7 Methyl-oxazolidin-2-one; 3-(I-isopropyl-4-piperidyl)-5- ( n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)|-methyl-oxazolidin-2-one;

3-(1-methyl-4-piperidylmethyl)-5- (n -(2-carboxy-2-M-BOC-aminostil)-phenoxy| -methyl-oxazolidin-2-one; 3-(4-M-BOC -piperazinylotyl) -5-(n -2-carboxy-2-M-BOC-aminosyl)-phenoxy 3 -methyl-oxazolidang-one; 3-(4-M-BOC-piperazinylpropyl) -5-|(n - -2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one; 3-(4-M-BOC-piperazinylbutyl)-5-(n -(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one; 3-(1-M-BOC-amidino-4-piperazinyl)-5-(p-(2-carboxy-2-M-BOC-aminostil)-phenoxy-methyl-oxazolidin-2-one; 3-1-M -BOC-amidino-4-piperazinylpropyl)-5-|(n -(2-carboxy-2-M-BOC-aminostil)-phenoxy -methyl-oxazolidin-2-one; 70 3-(I1-M-BOC- amidino-4-piperazinylbutyl)-5-|(n -(2-carboxy-2-M-BOC-aminostil)-phenoxy -methyl-oxazolidin-2-one.

Example 5 0, bg 3-p. -M-BOC-amidino-phenyl-5-(n. -(2-carboxy-2-M-BOC-aminosyl)-phenoxy| -methyl-oxazolidin-2-one (obtained in accordance with example 4) are suspended in 40 ml 2H solution of NCI based on dioxane and /5 are mixed for three hours at room temperature. After removing the solvent and carrying out "preparation by the usual method", 3-p-amidino-phenyl-5- (p -(2-carboxy-2-aminostil )-phenoxy)-methyl-oxazolidin-2-one, dihydrochloride, etc. 165" (exp.).

In a similar way, after removal of the protective group BCC, the products from example 4 are obtained. -(4-piperidylmethyl)-5- (n -(2-carboxy-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperidyl)-5- (n -(2 -carboxy-2-aminoethyl)-phenoxy)|-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperidylprolyl)-5- (p -(2-carboxy-2-aminoacetyl)-phenoxy|-methyl- oxazolidin-2-one, dihydrochloride; 3-4-piperidylbutyl)-5-(p-2-carboxy-2-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(I-amidino- 4-piperidyl)-56- (n -(2-carboxy-2-aminosyl)-phenoxy)-methyl-oxazolidin-2-one; ch dihydrochloride; 3-(1-amidino-4-piperidylmethyl)-5-|n -(2-carboxy-2-aminoacetyl)-phenoxy)|-methyl-oxazolidin-2-one, i) dihydrochloride; 3-(1-amidino-4-piperidyl)-5-|(p-(2-carboxy-2-aminosyl)-phenoxy)| -methyl-oxazolidin-2-one, dihydrochloride; iso 3-(I-amidino-4-piperidylpropyl)-5-(Ip -(2-carboxy-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; ix, 3-(I- amidino-4-pyridylbutyl)-5- |n -(2-carboxy-2-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one, c dihydrochloride; 3-(1-isopropyl-4-piperidyl)-56- (n -(2-carboxy-2-aminosyl)-phenoxy| -methyl-oxazolidin-2-one, « 5 dihydrochloride; 3-(1-methyl-4-piperidylmethyl)-5- (n -(2-carboxy -2-aminostil)-phenoxy)-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperazinylstil)-5-(p -(2-carboxy-2-aminostil)-phenoxy) | -methyl-oxazolidin- 2-one, dihydrochloride; 3-(4-piperazinylpropyl)-5-(p -(2-carboxy-2-aminosyl)-phenoxy| -methyl-oxazolidin-2-one, dihydrochloride; « 3-(4-piperazinylbutyl) -5-|(n-(2-carboxy-2-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; with c 3-(I-amidino-4-piperazinyl)-5-|(n- (2-carboxy-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; )-phenoxy|-methyl-oxazolidin-2-one , dihydrochloride; 3-(1-amidino-4-piperazinylbutyl)-5-(n/-(2-carboxy-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, c dihydrochloride.

Example 6 t-O,bg 2) 3-p-m-BOoOS-amidino-phenyl-5-(p-(2-methoxy-carbonyl-2-M-BOC-aminoacetyl)-phenoxy|-methyl-oxazolidine-2 - she 5r (obtained in accordance with example 1) | suspended in 40 ml of a 2M solution of NSI based on dioxane and

Me. stir for three hours at room temperature. "M After removal of the solvent and carrying out "preparation by the usual method", 3-p-amidino-phenyl-5-|N-methoxycarbonyl-2-aminosyl).-phenoxy)|-methyl-oxazolidan-2-one, dihydrochloride, i.e. sq. 132-133". 5B In a similar way, after removing the BOC protective group, the product obtained from example 1 is 3-(4-piperidyl)-5-|(p-(2-nontoxiccarbonyl-2-aminoacetyl)-phenoxy)| -methyl-oxazolidin-2-one, dihydrochloride;

F) 3-(4-piperidylmethyl)-5-(p-(2-methoxycarbonyl-2-amino-zyl)-phenoxy|-methyl-oxazolidin-2-one, ka dihydrochloride; 3-(4-piperidyl)-5 -(p-(2-methoxycarbonyl-2-amino-ztyl)-phenoxy|-methyl-oxazolidin-2-one, bo Ddihydrochloride; 3-(4-pyridylpropyl)-5-|(p-(2-methoxycarbonyl-2 -aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperidylbutyl)-5-(p-(2-methoxycarbonyl-2-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one , dihydrochloride; 65 3-(1-amidino-4-piperidyl)-5-(p-(2-methoxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride;

3-(1-amidino-4-piperidylmethyl)-5-|p-(2-methoxycarbonyl-2-aminoacetyl)-phenoxy| -methyl-oxazolidin-2-one, dihydrochloride; 3-(1-amidino-4-piperidyl)-5-|(p-(2-methoxycarbonyl-2-aminosyl)-phenoxy)| -methyl-oxazolidin-2-one, dihydrochloride; 3-(I-amidino-4-piperidylpropyl)-5-(n. -(2-methoxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(I-amidino-4- piperidylbutyl) -5-|(n -(2-methoxycarbonyl-2-aminoacetyl)-phenoxy)|-methyl-oxazolidin-2-one, dihydrochloride; 70 3-(I-isopropyl-4-piperidyl)-5- (n -(2-methoxycarbonyl-2-aminoethyl)-phenoxy|-methyl-oxazolidan-2-one, dihydrochloride; 3-(1-methyl-4-piperidylmethyl)-5- (n -(2-methoxycarbonyl-2- aminostil)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperazinylstil)-56- (n -(2-methoxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, 7/5 dihydrochloride; 3-(4-piperazinylpropyl)-5-|(n - (2-methoxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(4-piperazinylbutyl)- 5-|n -(-2-methoxycarbonyl-2-aminosyl)-phenoxy 3-methyl-oxazolidin-2-one, dihydrochloride; 3-(1-amidino-4-piperazinylsyl)-5-(n. -(2- methoxycarbonyl-2-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, dihydrochloride; 3-(1-amidino-4-piperazinylpropyl)-5-(p-(2-methoxycarbonyl-2-am inosyl)-phenoxy|)-methyl-oxazolidin-2-one, dihydrochloride; 3-(1-amidino-4-piperazinylbutyl)-5-(p-(2-methoxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, sc dihydrochloride.

Example 7 i)

Similarly to example 4, starting from 3-(1-M-BOC-amidino-4-piperidyl)-5-(p-(2-methoxy-carbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidine -2-one |I(obtained in accordance with example III, by methylation, Kk. zo 3-1-H-VOoC-amidino-4-piperidyl)-5|p-(2-carboxy-2-M-butylsulfonyl-aminostil )-phenoxy -methyl-oxazolidin-2-one. ix,

3-(4-M-BOC-piperidyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one is obtained in a similar way with the help of omylation: - 3-(4-M-BOC-piperidyl-5-|(n -(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy)|-methyl-oxazolidin-2-one, and 3-(4-M -BOC-piperidylmethyl)-5-|(n -(2-methoxycarbonyl-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one; 3-(4-M-BOC-piperidylmethyl)-5 -|(n-(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one; « 3-(4-M-BOC-piperidyllotyl)-5-|(n-( 2-Methoxycarbonyl-2-M-butylsulfonyl-aminoethyl)-phenoxy|-methyl-oxaz z olidin-2-one: 3-(4-M-BOC-piperidyl)-5-|(p-(2-carboxy- 2-M-butylsulfonyl-aminostil)-phenoxy;"-methyl-oxazolidin-2-one; 3-(4-M-BOC-piperidylpropyl)-5-(n-2-methoxycarbonyl-2-M-butylsulfonyl-aminostil )-phenoxy)-methyl- OoXazolidin-2-one: c 3-(4-M-BOC-piperidylpropyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl- oxazolidin-2-one; and 3-(4-M-BOC-piperidylbutyl)-5-(n-( 2-Methoxycarbonyl-2-M-butylsulfonyl-aminoethyl)-phenoxy|-methyl-oo oxazolidin-2-one: 3-(4-M-BOC-piperidylbutyl)-5-(p. -(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy |-methyl-

Me. oxazolidin-2-one; "M 3-(1-zyl-4-piperidyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one: 3-(1-zyl -4-piperidyl)-5-(n/-(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one; 3-(1-M-BOC-amidino-4- piperidylmethyl)-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy (F,-methyl-oxazolidin-2-one: ka 3-I1-M-BOC-amidino-4-piperidylmethyl )-5-(n-(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy)|-methyl-oxazolidin-2-one: in 3-(1-M-BOC-amidino-4-piperidylsyl)- 5-(n-(2-methoxy-sicarbonyl-2-N-butylsulfonyl-aminostil)-phenoxy-methyl-oxazolidin-2-one: 3-(1-Ch4-BoC-amidino-4-piperidylstil)-5-| (n -(2-carboxy-2-II-butylsulfonyl-aminoacetyl)-phenoxy)-methyl-oxazolidan-2-one; 3-1-M-BOC-amylino-4-piperidylpropyl)-5-(n-(2 -methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|) b5 methyl -oxazolidin-2-one: 3-1-M-BOC-amylino-4-piperidylpropyl)-5-(p-(2-carboxy-2 -N-butylsulfonyl-aminoacetyl)-phenoxy|-methyl

-oxazolidin-2-one; 3-1-M-BOC-amidano-4-piperidylbutyl)-5-(p-(2-methoxycarbonyl-2-II-butylsulfonyl-aminoacetyl)-phenoxy -methyl-oxazolidin-2-one: 3-(I1-M -BOC-amidino-4-piperidylbutyl)-5-|n-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; 3-(1-isopropyl-4-piperidyl )-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidan-2-one: 3-(1-isopropyl-4-piperidyl)-5-(p-( 2-carboxy-2-M-butylsulfonyl-aminoethyl)-phenoxy|-methyl-7/0 oxazolidan-2-one; 3-(1-methyl-4-piperidylmethyl)-5-|(p-(2-methoiccarbonyl- 2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidan-2-one; 3-(1-methyl-4-piperidylmethyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl) -phenoxy |-methyl-oxazolidan-2-one; 3-(4-M-BOC-piperazinyl-oyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminosyl)-phenoxy)|-methyl-oxazolidan -2-one: 3-(4-M-BOC-piperazinylotyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidan-2-one; 3-( 4-M-BOC-piperazinylpropyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl -aminoacetyl)-phenoxy)| -methyl oxazolidan-2-one: 3-(4-M-BOC-piperazinylpropyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy)| -methyl-oxazolidan-2-one; 3-(4-M-BOC-piperazinylbutyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy)| -methyl-oxazolidan-2-one: c 3-(4-M-BOC-piperazinylbutyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy)-methyl-oxazolidan-2- he i) 3-(1-M-BOC-amidino-4-piperazinyl)-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminostyl)-phenoxy -methyl-oxazolidan-2-one: 3- (-M-BOC-amidino-4-piperazinyl)-5-|(p-(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-o M zo xazolidan-2-one; 3-1 -M-BOC-amidino-4-piperazinylpropyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminosyl)-phenoxy)si|-methyl-oxazolidan-2-one: c 3-1- M-BOC-amidino-4-piperazinylpropyl)-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidan-2-one; - 3-(1-M- BOC-amidino-4-piperazinylbutyl)-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy i -methyl-oxazolidan-2-one: 3-(11-M-BOC-amidino- 4-piperazinylbutyl)-5-(p-(2-carboxy-2-N-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidan-2-one.

Example 8 "

To a solution of Obgooshlt-u with 3-p-amidino-phenyl-(2-methoxycarbonyl-2-M-BOC-amino-zyl)-phenoxy|-methyl-oxazolidin-2-one in 20 ml. TNE add 20 ml of 2095 MasoN solution and stir for 24 hours at room temperature. ;" After removal of the solvent and freeze-drying, the M-salt of 3-p-amidino-phenyl-5-(p-(carboxy-2-M-BOC-aminosyl)-phenoxy|-methyl-oxazolidin-2-one is obtained, m.p. 120-12126.

The sodium salt is obtained in a similar way

3-p-aminomethyl-phenyl-5-(p-(carboxy-2-M-BOC-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one, o sodium salt 2) 3-p-amidino-phenyl-5 -|(p-(carboxy-2-M-butylsulfonylamino-zyl)-phenoxy|-methyl-oxazolidin-2-one, sodium salt

Me, 3-p-aminomethyl-phenyl-5-(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one. "M Example 9

A solution of 0.2 g of 1-amidino-3,5-dimethylpyrazole nitrate in 1 ml of dioxane and ml of water is mixed with 0.7 ml of tyldiisopropylamine and stirred for 2 minutes. After that, add 0.4 g of 3-pdaminomethyl-phenyl-5-p-(-2-methoxy-carbonyl-2-M-BOC-aminosyl)-phenoxy p-methyl-oxazolidin-2-one, boil the mixture in for 30 hours, evaporate, and "preparation is carried out in the usual way." They receive 3 p

Ф) -Guadano-methyl-phenyl-5-(p-(2-methoxy-carbonyl-2-M-BOC-aminostil)-phenoxy|-methyl-oxazolidin-2-one. In a similar way: from 3-M -aminomethyl-phenyl-5-(p-(2-methoxycarbonyl-2-M-BOC-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, in 3-m-guadinomethyl-phenyl-5-|(p- (2-Methoxycarbonyl-2-M-BOC-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one;

3-m-aminomethyl-phenyl-5-(p-(2-methoxycarbonyl-2-M-butylsulfonylamino-ethyl)-phenoxy|-methyl-oxazolidin-2-one,

3-m-guadinomethyl-phenyl-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-oxazole 65 idin-2-one; from 3- p

-aminomethyl-phenyl-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-o, p-guadonomethyl-phenyl-5-|(p-(2 -methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one, from 3-o-aminomethyl-phenyl-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl) -phenoxy|-methyl-oxazolidin-2-one, 70 3-o-guadinomethyl-phenyl-5-|(p-(2-2-methoxycarbonyl-2-M-butylsulfonylamino-zyl)-phenoxy|-methyl-oxazo lidin -2-one, from 3-o-aminomethyl-phenyl-5-(p-(2-methoxycarbonyl-2-M-BOC-aminostil)-phenoxy|-methyl-oxazolidin-2-one,

3-o-guadinomethyl-phenyl-5-|(p-(2-methoxycarbonyl-2-M-BOC-aminosyl)-phenoxy|-methyl-oxazolidin-2-one,

Example 10 in a solution of 1.2 g of 3-p-cyano-phenyl-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one,

(obtained in accordance with example 1 by the exchange reaction of methyl sulfur with 2-M-butylsulfonyl-amino-3-(4-hydroxy-phenyl)-propanoic acid

3-p-cyano-phenyl-5-methanesulfonyloxy-methyl-oxazolidan-2-one | in 5HOml of pyridine and 7ml of trisethylamine at -10"7 2o, inject NO3 gas until saturation. After that, stir for 14 hours at room temperature, evaporate, dissolve the precipitate in 50ml of acetone and mix with 00ml of methyliodate. After that, stir again for 2 hours, filtered, the precipitate is washed with bml of acetone, dissolved in 30ml of methanol, 4.bg of ammonium acetate is added and stirred at room temperature for 24 hours.

After "preparation by the usual method" the compound amidino-phenyl-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy-oxazolidin-2-one, etc. 162-163 is obtained.

In a similar way: from 3-m-cyano-phenyl-5-(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminosyl)-phenoxy|- methyl-oxazolidin-2-one, iso 3-m- amidino-phenyl-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy|- methyl-oxazolidin-2-one, ix, from 3-p-cyano-phenyl-5-(p -(2-methoxycarbonyl-2-M-(BOC-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, c

3-p-amidino-phenyl-5-|(p-(2-methoxycarbonyl-2-M-(BOC-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, from 3-p-cyano-phenyl-5 -(p-(2-methoxycarbonyl-2-M-p-olpoolsulfonyl-aminostil) «-phenoxy|-methyl-oxazolidin-2-one,

3-p-amidino-phenyl-5-|p-(2-methoxycarbonyl-2-M-p-toluenesulfonyl-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one, from

3-m-cyano-phenyl-5-(p-(2-methoxycarbonyl-2-M-p-toluenesulfonylamino-ethyl)-phenoxy|-methyl-oxazolidin-2-one, « iz t s 3-m-amidino- phenyl-5-|(p-(2-methoxycarbonyl-2-M-p-toluenesulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one.;» Example 11

Similarly to example 4, based on

3-p-amidino-phenyl-5-|(p-(2-methoxycarbonyl-2-M-butylsulfonyl-2-M-aminostil)-phenoxy|-methyl-oxazolidin-c 2-one I (obtained in accordance with the example 191, by omMileniya receive

3-p-amidino-phenyl-5-|(p-(2-carboxy-2-M-butylsulfonyl-amino-zyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. t- 236-237 ". oo It is obtained in a similar way with the help of omyelination: iz

Me, 3-M-aminomethyl-phenyl-5-(p-(2-methylcarbonyl-2-M-butylsulfonyl-aminoacetyl)-phenoxy |-methyl-oxazolidcn-2-

And it, 3-M -amidino-phenyl-5-(p-(2-carboxy-2-M-butylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one; from 3-M -amidino-phenyl- 5-(p-(2-methoxycarbonyl-2-M-p-toluenesulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one a,

F) 3-M-amidino-phenyl-5-|(p-(2-carboxy-2-M-p-toluenesulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one; ka from 3-M-amidino -phenyl-5-(p-(2-methoxycarbonyl-2-M-p-toluenesulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one bo 8. 3-M -amidino-phenyl-5-|(p -(2-carboxy-2-M-p-toluenesulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one;

Example 12 1.37 g

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-methoxycarbonyl-2-M-zyl-amino-acetyl)-phenoxy|-methyl-oxase 65 olidin-2-one obtained in accordance with example 1 by means of exchange reactions of methyl sulfur with 2-M-methyl-amino-3-(4-hydroxy-phenyl)-propanoic acid

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-methane-sulfonylmethyl-oxazolidin-2-one, dissolved in 5 Oml of methanol and hydrogenated on Raney nickel. After that, the reaction mixture is filtered, and the filtrate is evaporated in a vacuum. The resulting product is treated with 20 ml of acetic acid. when heated, and after cooling, the product is sucked off. 3-p-amidinophenyl-5-|(p-(2-methoxycarbonyl-2-M-ethyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one is obtained.

Similarly, by reductive cleavage of the 5-oxo-1,2,4-oxadiazoline group: from 3-p -(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-(p-(2 -methoxycarbonyl-2-M-isopropyl-amino-zyl)-phenoxy|-methyl-oc 70 sazolidin-2-one, 3-p -amidinophenyl-5-|(p-(2-methoxycarbonyl-2-M-isopropyl- aminostil)-phenoxy|-methyl-oxazolidin-2-one, iz

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-methoxycarbonyl-2-M-acetyl-aminoacetyl)-phenoxy|-methyl-ox azolidin-2-one, 3-p -amidinophenyl-5-|(p-(2-methoxycarbonyl-2-M-acetyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one, from 3-p -(5 -oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-(p-(2-methoxycarbonyl-2-M-propionyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, 3 -p -amidinophenyl-5-|(p-(2-methoxycarbonyl-2-M-propionyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one,

Zp -(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-(p-(2-methoxycarbonyl-2-M-BOC-aminoethyl)-phenoxy|-methyl-oxazolidine-2 -one, from 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|p-(2-methoxycarbonyl-2-M-tert.-butyl-aminoacetyl)- phenoxy|-methyl sc ob p-oxazolidin-2-one, 3-p -amidinophenyl-5-|(p-(2-methoxycarbonyl-2-M-tert.-butyl-aminoacetyl)-phenoxy|-methyl-oxazolidin- 2-she. i)

Example 13

Analogously to example 4, the following carboxylic acids are obtained by the methylation of the corresponding complex esters from example 12: -2-one; 3-p -amidinophenyl-5-(p-(2-carbosi-2-M-isopropyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one; ise) 3-p -amidinophenyl-5 -(p-(2-carboxy-2-M-acetyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; c 3-p -amidinophenyl-5-(p-(2-carboxy-2-M- propionyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one; 3-p-amidinophenyl-5-|(p-(2-carboxy-2-M-aminostil)-phenoxy|-methyl-oxazolidin-2-one ; "3-p-amidinophenyl-5-(p-(2-carboxy-2-M-tert.-butyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one.

Example 14

Analogous to example 4, the following carboxylic acids are obtained by acidification of the corresponding complex esters from example 9:

3-p-Guadinomethyl-phenyl-5-|(p-(2-carboxy-2-M-BOC-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one;

3-m-guadinomethyl-phenyl-5-|(p-(2-carboxy-2-M-BOC-aminostil)-phenoxy|-methyl-oxazolidin-2-one; with 3-m-guadinomethyl-phenyl-5 -|(p-(2-carboxy-2-M-butylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-o n; ; » 3-p-guadinomethyl-phenyl-5-|(p-(2- carboxy-2-M-butylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; 3-o-guadinomethyl-phenyl-5-|(p-(2-carboxy-2-M-butylsulfonyl-aminoacetyl) -phenoxy|-methyl-oxazolidin-2-o c n; 3-o-guadinomethyl-phenyl-5-|(p-(2-carboxy-2-M-BOC-aminostil)-phenoxy|-methyl-oxazolidin-2 Example 15 2) Similar to example 5, by removing the protective group of BOS, based on the products of example 14, the following compounds are obtained:

Me, 3-p-guadinomethyl-phenyl-5-|(p-(2-carboxy-2-aminosyl)-phenoxy|-methyl-oxazolidin-2-one; "M 3-m-guadinomethyl-phenyl-5-| (p-(2-carboxy-2-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; 3-o-guadinomethyl-phenyl-5-|(p-(2-carboxy-2-aminoacetyl)-phenoxy| -methyl-oxazolidin-2-one.

Example 16

0.5g of 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-(p-(2-benzyloxycarbonyl-2-aminosyl)-phenoxy|-methyl-oxazolidine (F , -2-one (Obtained by the exchange reaction of the benzylic ester of 2-M-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid, which is obtained from tyrosine by introducing a protective group and esterification with benzyl alcohol , with 3-n-(5-xo-1,2,4-oxadiazolin-3-yl)-phenyl-5-methane-sulfonylmethyl-oxazolidin-2-one with

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-BOC-amino-ztyl)-phenoxy|-methyl -oxazolidan-2-one and subsequent treatment with trifluoroacetic acid are dissolved in 100 ml of dichloromethane and introduced into an exchange reaction with 1 equivalent of propanesulfonic acid chloride under ice cooling. After 1 hour, the reaction solution is washed with diluted hydrochloric acid (2 times) and water, and the organic phase b5 is evaporated after drying over magnesium sulfate. The product is purified by crystallization from ethyl acetate/petroleum ether and by chromatography on silica gel (toluene/acetone 4:1).

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxy-carbonyl-2-M-propylsulfonyl-aminoacetyl)-phenoxy|-methyl -oxazolidin-2-one; EAV-M: p/e 635 (MAN k).

By analogy, by the exchange reaction

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-amino-zyl)-phenoxy|-methyl-oxazolidine- 2-one is obtained with the help of 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-zylsulfonyl-amino) chloride -zyl)-phenoxy|-methyl-oxazolidin-2-one; 70 with the help of toluenesulfonic acid chloride 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p -(2-benzyloxycarbonyl-2-M-toluenesulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; with the help of benzylsulfonic acid chloride 3-p-(5-oxo-1,2,4-oxadiazolin-3- yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-benzylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one; with the help of hexanesulfonic acid chloride! 3-p-(5-oxo -1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-hexylsulfonyl-aminoethyl)-phenoxy|-methyl-oxazolidin-2-one; with pentanesulfonic acid chloride 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-pentylsulfonyl-aminoacetyl)-phenoxy|- methyl-oxazolidin-2-one; p with the help of hexadecane sulfonic acid chloride

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-hexadecanylsulfonyl-aminosyl)-phenoxy|-methyl- oxazolidin-2-one; trituration with butanoic acid chloride

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-butanoyl-aminoacetyl)-phenoxy |- i) methyl -oxazolidin-2-one; with the help of pentanoic acid chloride!

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-pentanoyl-aminoacetyl)-phenoxy|) M zo " methyl-oxazolidin-2-one; with the help of hexanoic acid chloride ix, 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl- 2-M-hexanoyl-aminosyl)-phenoxy |- with methyl-oxazolidin-2-one; with the help of benzoic acid chloride

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-benzoyl-aminosyl)-phenoxy|-methyl -oxazolidin-2-one, with the help of I-naphthalic acid chloride

3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|(p-(2-benzyloxycarbonyl-2-M-(1-naphthoyl-amino)-ztyl)- phenoxy i|-methyl-oxazolidin-2-one; " with the help of 2-naphthalic acid chloride in 3-p-(5-oxo-1,2,4-oxadiazolin-3-yl)-phenyl-5-|( p-(2-benzyloxycarbonyl-2-M-(2-naphthoyl-amino)-zyl)-phenoxy i|-methyl-oxazolidin-2-one.;" Example 17

For splitting the benzyl ether and the oxadiazoline ring o, 4 g of 3-p -(5-xo-1,2,4-oxadiazolin-3-yl)-phenyl-5-(p-(2-benzyloxy-carbonyl-2-M- propylsulfonyl-aminosyl)-phenoxy c|-methyl-oxazolidin-2-one is dissolved in 10 ml of dichloromethane and after adding ml of acetic acid, 0.5 ml of water and bml of methanol, as well as 0.1 g of palladium/activated carbon (1095) is treated at room temperature After 30 minutes, the catalyst is filtered, the reaction solution is concentrated and oo is obtained

3-p-amidino-phenyl-5-|(p-(2-carboxy-2-M-propylsulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one,

Me, flash point 200" (melting).

And in a similar way, with the help of hydrogenation of the products from example 16, the following is obtained: 3-p-amidino-phenyl-5-| , m.p. 2127 (dissolved); 3-p -amidino-phenyl-5-(p-(2-carboxy-2-M-toluenesulfonyl-aminoacetyl)-phenoxy|-methyl-oxazolidin-2-one, t .pl. 2057 (div.);

Ф) 3-p-amidino-phenyl-5-(p-(2-carboxy-2-M-benzylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, ca. pl. 2117 (exp.) ; 3-p -amidino-phenyl-5-|(p-(2-carboxy-2-M-heglylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one, b/t.pl. 1987 (div. ); 3-p -amidino-phenyl-5-(p-(2-carboxy-2-M-pentylsulfonyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 2157 (dec.);

3-p -amidino-phenyl-5-|(p-(2-carboxy-2-M-hexadecanylsulfonyl-aminostil)-phenoxy|-methyl-oxazolidin-2-one, b Tl. 220" (exp.); 3 -p -amidino-phenyl-5-(p-(2-carboxy-2-M-butanoyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 1907

(div.); 3-p -amidino-phenyl-5-(p-(2-carboxy-2-M-pentanoyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 1957 (exp.); 3- p -amidino-phenyl-5-|(p-(2-carboxy-2-M-hexanoyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 1887 (exp.); 3-p .-amidino-phenyl-5-(p-(2-carboxy-2-M-benzoyl-aminosyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 204" (exp.); 3-p -amidino-phenyl-5-(p-(2-carboxy-2-M-(1-naphthoyl-amino)-zyl)-phenoxy|-methyl-oxazolidin-2-one; 70 C-p. -amidino-phenyl -5-(p-(2-carboxy-2-M-(2-naphthoyl-amino)-zyl)-phenoxy|-methyl-oxazolidin-2-one, m.p. 2267 (dec.).

The following examples relate to pharmaceutical preparations:

Example A

Bubbles for injections

In a solution of 100 g of the active substance of formula 1 and 5 g of disodium hydrogen phosphate in 3 ml of twice distilled water with 2 N hydrochloric acid! the pH value is set to 6.5, the solution is filtered under sterile conditions, poured into injection vials, lyophilized under sterile conditions, and sterilely sealed. Each injection blister contains 5 mg of active substance.

Example B

Suppository

A mixture of 20 g of the active substance of the formulas! Melt 1 teaspoon of 100g of soy lecithin and 1400g of cocoa butter, pour into molds and leave to cool. Each suppository contains 20 mg of active substance.

Example B

A solution of

A solution is prepared from 1 g of the active substance of the formulas! 1, 9,3 g of ManNoRoO,:2NhoO, 28,48g of MagHRO.12H2oO, and 0.1 benzalkonium chloride in 940 ml twice! distilled driver. The pH value is set to 6.8, i) the solution is brought up to 1 liter, sterilized by irradiation. The solution can be used in the form of eye drops.

Example G cha

Ointment

Mix 500 mg of the active substance of the formula! 1c 99.5g of petroleum jelly in antiseptic conditions. at

Example D so

Tablets

A mixture of 1 kg of the active substance of the formula 1.4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.0 kg of magnesium stearate is compressed in a general way, so that each tablet contains 1 mg of the active substance.

Example U

Dragee

Similarly to example E, tablets are pressed, which are then covered in the usual way with a coating made of sucrose, potato starch, talc tragacanth and dye. 8 s Example Z and Capsule! "» 2 kg of the active substance of the formulas! 1 capsule is filled in the usual way! from solid gelatin, so that each capsule contains 20 mg of the active substance.

Example With sl Ampoule!

A solution of 1 kg of the active substance of formula 17 in a bottle of two! Distilled water is filtered in a flask under sterile conditions, poured into an ampoule, lyophilized and sealed under sterile conditions. Each ampoule d) contains 10 mg of active substance. b 50 -h

Claims (7)

The formula of the invention 1. Derivative of oxazolidinone of the formula I and its m te mn ime) vA-k o; because m SOOVZ 6) where is 65 V! means amidinophenyl, 22 means H, A, cC.i-Sir-alkanoyl, C.i.-Ci-alkoxycarbonyl, benzoyl, naphthoyl, Ci-Ci-alkylsulfonyl, benzylsulfonyl or monosubstituted C1-C8-alkyl phenylsulfonyl, BZ means hydrogen or C.--C-alkyl, A means alkyl with 1-16 C-atoms, as well as their physiologically acceptable salts. 2. Oxazolidinone derivative of formula I according to claim 1, characterized by the following: (a) 3-p-amidino-phenyl-5-(p-(2-amino-2-carboxy-ztyl)-phenoxy-methyl oxazolidin-2-one, (c) 3-p-amidino-phenyl-5-|(p-(2-amino-2-methoxycarbonylacetyl)-phenoxy-methyl|-oxazolidin-2-one, (c) 3-p -amidino-phenyl-5-(p-(2-M-butylsulfonyl-amino-2-carboxy-ztyl)-phenoxy-methyl|-oxazolidin-2-one, 70 (a) 3-p-amidino-phenyl-5 -|p-(2-M-p-toluenesulfonyl-amino-2-carboxy-ztyl)-phenoxy-methyl|-oxazolidin-2-one; (e) 3-p-amidino-phenyl-5-|(p- (2-M-butylsulfonyl-amino-2-methoxycarbonyl-zyl)-phenoxy-methyl|-oxazolidin-2-one, as well as their physiologically acceptable salts. 3. The method of obtaining compounds of formulas | according to point 11, distinguished by the fact that the combination of formulas | A functional derivative containing the corresponding protection of amino and/or hydroxy groups is isolated from it by treatment with a strong acid, possibly in the presence of an inert solvent, or hydrogenolytically and the resulting compound is converted, if necessary, into one of its salts by treatment with an acid or a base. 4. The method of obtaining compounds of formulas I! according to clause 17, distinguished by the fact that the combination of formulas! III III s t-8VOT 7 o В-х8 o) va c zo o Ge; where со В" has the meaning specified in point 1, 7 - the reactive esterified group OH, M is introduced into the interaction with the compound of the formula Ю Хх и | .-А-МНЕ? salt, B?, and BZ have the meanings indicated in claim 1, and it is possible to combine the formulas and convert into one of its salts by treatment with an acid or a base. with 5. Production of oxazolidinone formulas I according to claim 1, characterized by the fact that they are used as 5p adhesion receptor antagonists. (2) 6. The method of obtaining a pharmaceutical composition possessing antagonistic activity in relation to adhesion receptors, distinguished by the fact that the combination of formulas! | according to point 1 and/or one of its physiologically acceptable salts together with at least a solid, liquid or semi-liquid carrier or auxiliary substance are converted into a form suitable for reception. 7. A pharmaceutical composition possessing antagonistic activity in relation to adhesion receptors, distinguished by the fact that as an active substance it contains an effective amount, (F. at least one combination of formulas! | according to item 1 and/or one of its physiologically acceptable g salts. in the Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M Z , 15.03.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5