Derivative oxazolidinone, methods for their preparation, containing the pharmaceutical composition, its preparation

 

(57) Abstract:

Describes the new derivative oxazolidinone formula (I), where R1denotes lidinopril, R3denotes H, A, C1- C10-alkanoyl, C1- C8-alkoxycarbonyl, benzoyl, Naftoli, C1- C6-alkylsulfonyl, benzylmethyl or unsubstituted or monosubstituted C1- C6the alkyl phenylsulfonyl, R3denotes hydrogen or C1- C6-alkyl, And denotes alkyl with 1 to 16 C-atoms, and their physiologically acceptable salts. The compounds have inhibitory effects on the binding of fibrinogen to the corresponding receptor and can be used for the treatment of thrombosis, osteoporosis, cancer, arteriosclerosis and osteolytic diseases. Also describes the methods for their preparation, containing pharmaceutical composition and method of reception. 5 S. and 2 C.p. f-crystals, 1 PL.

The invention concerns new derivatives of oxazolidinone formula I

< / BR>
where R1denotes lidinopril,

R2denotes H, A, C1-C10-alkanoyl, C1-C8-alkoxycarbonyl, benzoyl, Naftoli, C1-C6-alkylsulfonyl, benzylmethyl or not the and C1-C6-alkyl,

A denotes alkyl with 1-16 C atoms,

and their physiologically acceptable salts.

Similar compounds are known from application EP-A1-0381033.

The present invention is to provide new compounds with valuable properties, especially those that can be used to produce medicines.

This problem was solved with the invention. It was found that the compounds of formula I and their solvate and salt with good endurance have valuable pharmacological properties. First of all, they act as integrin inhibitors, while they, in particular, inhibit the interaction of receptors3or 5-integrin with a ligand. The particular effect of the compounds detected in the case of integrins and av3, av5, aIIb3. This activity can be, for example, is proved by the method described by J. W. Smith et al. Biol. Chem. 2265, 12267-12271 (1990). In particular, they inhibit the binding of fibrinogen, fibronectin and factor a background of Villebranda fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa), as well as linking them and other adhesive proteins such as vitronectin, collagen and the effect on the interaction type cell-cell and cell-matrix. They, in particular, prevents the formation of blood clots blood platelets and can therefore be used for the treatment of thrombosis, apoplexy, cardiac infarction, angina pectoris, osteolytic diseases, in particular osteoporosis, antiangiogenesis and restenosis after angioplasty, ischemia, inflammation, arteriosclerosis and acute renal failure. Further, the compounds have an effective impact on cancer cells by inhibiting the formation of metastases. Thus, they can also be used as anti-cancer tool.

There are indications that the cancer cells through the microthrombi fall in the blood vessels and thus protect themselves from detection cells immunosystem. Microclots also contribute to the binding of cancer cells to vessel walls. Since the formation of microthrombi is in close relationship with fibrinogen attachment to fibrinogenom receptor (glycoprotein IIb/iiia inhibitors), inhibitors fibrinogen links are also inhibitors of metastasis.

Compounds suitable as antimicrobial active substances, which can prevent the development of infections, such as, for example, are caused by bacteria, fungus or yeast. These substances can be adminimage effects on the body, with the use of substances alien to the body, such as, for example, biomaterials, implants, catheters or cardiac pacemakers. They act as antiseptics. Antimicrobial activity of compounds may be, for example, is proved by the method of P. Valentin - Weigand et al., which is described in Infection and Immunity, 2851-2855 (1988).

Other properties of the compounds can be determined according to the method described in patent specification EP-A1-0462960. Braking fibrinous connection with fibrinogen receptor can be proved by the method specified in the description of the invention EP-A1-0381033. The action of suppressing platelet aggregation can be determined in the laboratory by the method of born (Nature 4832, 927-929, 1962).

Further subject of the invention is a method for obtaining compounds of the indicated formula I and its salts, characterized in that

a) compound of the formula I is liberated from one of its functional derivatives by treatment solvolysis or hydrogenolysis means, or that

b) the compound of formula II

< / BR>
where Z denotes Cl, Br, I, OH or a reactive esterified OH-group, and

R1has the above value,

enter into the reaction of interaction with soedinyabschy from OH on the type of salt, or that

(C) a compound of formula IV

< / BR>
where R1, R2and R3have the above values,

enter in response interaction with a reactive derivative of carbonic acid, or that

(g) compound of formula V

< / BR>
where R2and R3have the specified values,

enter into interaction with the compound of the formula VI

< / BR>
where B is the specified value, and

Y means or

where m and n have the specified values, and

X' is Cl, Br, I or another easily nucleophile displaced off a whole group,

(d) to obtain guanidinonaltrindole the compounds of formula I (R1= phenyl residue, once substituted by a group H2N-C(=NH-CH2-) amine compound corresponding to the formula I, which contains, however, instead of a balance of R1aminomethylphenol group, process amidenus means, or that

(e) one residue R3turn in the remainder R3by saponification of ester of the formula I, or a carboxylic acid of the formula I, is subjected to esterification, or that

(W) residue (remainder) R1and/or R2turn in the remainder (other remains) R1and/or R2and/or

(C) connection forms bladud, at least one chiral center and can therefore act in several enantiomeric forms. All of these forms (for example, form D and L) and their mixtures (for example, form DL) included in formula I.

Above and below the remains or, respectively, the parameters A, B, D, X, Y, Z, R1-R3, Ac, Ar, k, m, and n have the meanings indicated in formula I-VI, unless expressly specified otherwise. If the molecule has several equally marked groups, they can independently from each other to adopt different definitions.

In the above formulas, the group A is 1-6, preferably 1, 2, 3 or 4 atoms C. In particular, A means is preferably 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.

R1is preferably phenyl residue substituted at the 4th position, but also in the 2nd or 3rd position, particularly preferably 2-, 3 - or (especially) 4-aminomethylphenol, 2-, 3 - or (especially) 4-AMINOPHENYL, 2-, 3 - or 4-houdiniserver, and in all cases, the primary amino group may also have aminosidine group. Then R1is idinnam, 1-amidino-4-piperidinylmethyl, 4-piperazinylmethyl, 4-piperazinylmethyl, 4-piperidinylmethyl, 1-amidino-4-piperazinylmethyl or 1-amidino-4-piperazinylmethyl balance.

R2represents preferably hydrogen, methyl, ethyl, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl or n-butylsulfonyl, toluensulfonyl or aminosidine group, if available.

R3is preferably hydrogen, stands or ethyl.

Ar is preferably unsubstituted phenyl or 4-were, Ac means preferably alkanoyl with 1-6 C atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or caproyl, then benzoyl, toluyl, 1 - or 2-naphtol or phenylacetyl.

The parameters k and m means preferably 0 or 1. The parameter n is preferably 2 or 3.

Among the compounds of formula I, preferred are those in which at least one of these residues, one of these groups and/or one of the specified parameters is one of these preferred values. Some groups preferred compounds are those of formulas Ia - If, which correspond to the formula I, where, however,

in Ia R1OSN 1 means aminomethylphenol and

R3means hydrogen or methyl;

in Iك R1means lidinopril and

R3means hydrogen or methyl;

in Ia R1means piperidinomethyl and piperidolate and

R2means hydrogen or-A-SO2;

S R1mean 1-amidinopropane and

R2means hydrogen or A-SO2-;

If R1means piperidinoethyl or piperazinediones and

R2means hydrogen or A-SO2-;

Z R1mean 1-amidinopropane or 1-amidinopropane and

R2means hydrogen or A-SO2.

The compounds of formula I, as well as source materials for their production usually get by known methods described in the literature (for example, in Houben - 1 Wey, Methods of organic chemistry, publishing house Georg - Thieme, Stuttgart; further description of the invention - EP-A1-0381033, EP-A1-0462960), namely under the reaction conditions which are known and suitable for the above reactions of metabolism. You can also use themselves known variants that are more not mentioned.

The initial substance can be obtained, if desired, in situ so that then they should not be separate from the reaction mixture, and can be obtained by highlighting them from their functional derivatives by solvolysis, in particular hydrolysis or hydrogenolysis.

The preferred initial agents for the solvolysis or hydrogenolysis are those substances which usually correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxy-group, the preferred way such that instead of the H atom associated with the N atom, are aminosidine group, such that instead of the group HN are the group R'-N, where R' means aminosidine group, and/or such that instead of the H atom of the hydroxy-group are hydroxyamino group, such which correspond to the formula I, but instead of the group-COOH are a group-COOR", where R" means gidrozaschitnym group.

In the molecule of the original substance may also be present several identical or different protected amino and/or hydroxyl groups. If the existing protective groups differ from each other, they can in many cases be selectively chipped off.

The expression "aminosidine group" is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which it is typical for such groups are, in particular, unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl, (DNP)), arelaxation (for example, benzoyloxymethyl (BOM) or kalkilya (for example, 4-nitrobenzyl, triphenylmethyl) group. As aminosidine groups are removed after carrying out the desired reaction (or sequence of reactions), their type and size in General are not critical: are preferred, however, such groups with 1-20, in particular 1-8 atoms C. the Expression "acyl group" is to be considered in connection with the present method in its broadest sense. It includes acyl groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such atilovykh groups are alkanoyl, such as acetyl, propionyl, butyryl; arkanoid, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoic, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.-butoxycarbonyl (BOC), 2-iodoxybenzoic; Uralelectromed, such as gasoline which the group is BOC, DNP and BOM, then CBZ, benzyl and acetyl.

The expression "hidroxizina group" is generally known and relates to groups which are suitable for the protection of the hydroxy-group from chemical reactions but which can be easily removed after the desired chemical reaction took place on location in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group, hereinafter also referred to as alkyl groups. The nature and size hydroxyamine groups are not critical, because after the desired chemical reaction or sequence of reactions they are again subject to removal; preferred are groups with 1-20, in particular 1-10 atoms C. Examples hydroxyamine groups are, in addition, tert.-butyl, benzyl, p-nitrobenzyl, R-toluensulfonyl and acetyl, with special preference is given to benzyl and acetyl.

Used as starting substances, the functional derivatives of compounds of formula I can be obtained in the usual manner, as described in the above references and applications for the grant of a patent, for example, by exchange reaction of compounds corresponding to formulas II and III, pripojenie compounds of the formula I from their functional derivatives are able to accomplish depending on the use of protective groups, for example using strong acids, expediently using triperoxonane acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, with strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids such as benzene or p-toluensulfonate acid. Perhaps the presence of an additional inert solvent, but it is not always required.

As the inert solvent usable preferably organic, for example carboxylic acids, such as acetic acid, in a simple ether like tetrahydrofuran or dioxane, amides, such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, sulfoxidov, such as dimethyl sulfoxide (DMSO), also referred to as alcohols, such as methanol, ethanol, or isopropanol, and also water. Next you can apply a mixture of the above 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. The reaction temperatures for the cleavage are Celje is the interval between 15 and 30oC (room temperature).

The BOC group can be chipped off, for example, preferably using triperoxonane acid in dichloromethane or using approximately 3 to 5N. HCl in dioxane at 15-60oC, the FMOC group using an approximately 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-60oC. Removal of the DNP group can be performed, for example, also by means of approximately 3-10% solution of 2-mercaptoethanol in DMF/water at 15-30oC.

Protective groups (for example, BOM, CBZ or benzyl), which can be removed hydrogenations may be, for example, removed by treatment with hydrogen in the presence of a catalyst (e.g. catalyst noble metal, such as palladium, expediently on a medium such as coal). As the solvent usable in this above-mentioned solvents, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is carried out usually at temperatures between approximately 0 and 100oC and a pressure of between about 1 and 200 bar, preferably, when 20-30oC and 1-10 bar. Hydrogenolysis of the CBZ group is able to enjoy, for example, on 5-10% Pd-C in methanol at 20-30oC. of formula II with a phenol derivative of the formula III. Use suitable way known methods of obtaining ethers.

Volatile group Z means the preferred way Cl, Br, I, C1-C6-alkylsulfonate, such as methane - or econsultancy or C6-C10-arylsulfonate as benzene, p-toluene - or 1 - or 2-naphthalenesulfonate.

The preferred reaction proceeds in the presence of an additional base, such as hydroxide or carbonate of alkali or alkaline earth metal, such as sodium hydroxide, potassium or calcium, sodium carbonate, potassium or calcium, in an inert solvent, for example in a halogenated hydrocarbon, such as dichloromethane, in a simple ether, such as THF or dioxane, in amide, such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures between approximately -10 and 200oC, the preferred manner between 0 and 120oC. If volatile group E is different from I, it is recommended that the addition of iodide such as potassium iodide.

Educt of the formula II are generally new. They can be obtained, for example, through reaction of substituted aniline of the formula R1-NH2with the compound of the formula R5CH2-CHR6-CH1-NH-CH2-CHR8-CH2OH (where R8means OH), through reaction with a derivative of carbonic acid, such as diethylmalonate with 3 R1-5-hydroxymethyl-2-oxazolidinones and, if necessary, by turning hydroxymethylene group CH2Z, for example, using SOCl2, SOBr2, methanesulfonamido or n-toluensulfonate. The compounds of formula III are generally known or can be obtained by analogy with known compounds from the appropriate phenol or derivatives of phenol.

The compounds of formula I can be further obtained by reaction of compounds of formula IV (or its reactive derivative) with a reactive derivative of carbonic acid.

As a derivative of carbonic acid are suitable, in particular, diallylmalonate, such as diethylmalonate, also referred to as alkilany ether of Harborview acid, such as ethylchloride. The preferred way derivative of acetic acid, which is expediently used in an excessive amount, also serves as a solvent or suspension agent. But it can be also one of these solvents, if he's in this reaction share tert.-butyl potassium. The work is the preferred way, at reaction temperatures between 0 and 150oC, the preferred way between 70 and 120oC.

Educt of the formula IV are generally new. They can, for example, be obtained by functionalliteracy the above-mentioned compounds of the formula R1-NH-CH2-CH(OH)-CH2OH in the compounds of formula R1-NH-CH2-CH(OH)-CH2-Z and reaction with compounds of formula III.

To obtain the compounds of formula I, where R1means guariniello group, you can handle the appropriate aminoaniline connection amidenus means. As amidaniel means the preferred 1-amidino-3,5-dimethylpyrazole, which, in particular, is used in the form of its nitrate. Work in an expedient manner with the addition of a base, such as triethylamine or ethyl-Diisopropylamine in an inert solvent or mixture of solvents, for example water/dioxane at temperatures between 0 and 120oC, preferably between 60 and 120oC.

Then there is the possibility in connection formulas I to turn one residue R3in the remainder R3by saponification of ester of the formula I, or by esterification CT>3= H), the excess amount of the alcohol of formula R3-OH (R3= A or benzyl), expediently in the presence of a strong acid, such as hydrochloric acid or sulfuric acid, at temperatures between 0 and 100 preferred manner between 20 and 50oC.

Conversely, an ester of formula I (R3= A or benzyl) can be transformed into the corresponding acid of the formula (R3= H), it is advisable with the help of solvolysis or hydrogenolysis in accordance with one of the above methods, for example, using NaOH or KOH in a mixture of water and dioxane at temperatures between 0 and 40oC, preferably between 10 and 30oC.

In addition, there is the possibility of transforming one residue1and/or R2in the remainder R1and/or R2.

In particular, can be primary or secondary amino group to alkilirovanii, allievate, amidinopropane or to provide temporary aminosidine groups or alkyl - or arylsulfonate or, conversely, to release them by removing these groups.

To obtain amidine formula I (R1= lidinopril) can be attached to the nitrile of formula I (R1= tianfei) ammonia. Accession shall be effected in the process of several stages, by PTV, for example, CH3I, translated into the corresponding complex S-alkyl-imitation, which, on its part reacts with NH3with the formation of amidine, method b) nitrile with alcohol, for example ethanol, in the presence of HCl in the corresponding complex aminoether, which is treated with ammonia, and the way in) by the entry of the nitrile in the exchange reaction with bis-(trimethylsilyl)-nidality and subsequent hydrolysis of the product.

Similarly, you can obtain the corresponding N-hydroxy-amidine formula I (R1= phenyl, substituted HO-NH-C(=NH)) from NITRILES, if you work according to method a) or b), but instead of ammonia to the use of hydroxylamine. Further, these products can be obtained derivatives in the recovery process them, for example, using hydrogen gas.

The base of formula I with acids can be translated into the corresponding acid additive salt. For this interaction are used, in particular, acids, which form physiologically acceptable salts. So, can be used inorganic acids, for example sulfuric acid, nitric acid, halogenation acid, such as, chlorodane acid or bromatologia acid, phosphoric is factual, alicyclic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, triperoxonane acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumana acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, methane - or econsultancy acid, ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluensulfonate acid, naphthalene mono - and desulfonema acid, louisanna acid. Salts with physiologically impervious acids. For example, picrate, can be used for isolation and/or purification of the compounds of formula I.

Free base of formula I can be free, if you wish, of their salts after treatment by strong bases such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium.

You can also convert the carboxylic acids of formula I (R3= H) by exchange reaction with the corresponding bases in their metal salts and which are chiral centers and therefore exist in racemic or in optically active form. Resulting racemates using well-known techniques can be separated mechanically or chemically to the enantiomers. The preferred manner from racemic mixtures by exchange reaction with optically active separating means are formed diastereomers. As the separating means are suitable, for example, optically active acids, such as D-form and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active compareallvalues acid, such as sulforaphane acid. It is preferable for the separation of enantiomers using a column filled with optically active separation means (for example, dinitrobenzoyl-phenyl-glycine) as a solvent (in chromatography) is suitable, for example, a mixture of hexane/isopropanol/acetonitrile, for example, in a volume ratio 82:15:3.

Of course there is the possibility of obtaining optically active compounds of the formula I according to the above methods, when using the original substance (for example, such substances of the formula (II), which are already optically active.

The new compounds of formula I and the e, at least one substance carrier or auxiliary substance and, if desired, together with one or more other active substances, translate into an appropriate dosage form. The resulting preparations can be used as a drug in medicine and veterinary medicine. In the case of substances-media we are talking about organic and inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation, and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glyceryltrinitrate and other glycerides of fatty acids, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc, cellulose. For oral administration are, in particular, tablets, coated tablets, capsules, syrups, juices or drops; interest are tablets having a lacquer coating, and capsules with shells, with resistance against the influence of gastric juice. For rectal use suppositories, for parenteral solutions, the preferred way oily or aqueous process is taken sprays, which contain the active compound either dissolved or in suspension in the mixture of the working gas. When this expedient way to apply the active ingredient in micronized form, and may be added one or more additional physiologically acceptable solvents, for example ethanol. Inhalation solutions can be prepared using conventional inhalers. The new compounds can also liofilizirovanny, and the resulting lyophilisate can be used, for example, to get injectables. These compositions can be sterilized and/or may contain auxiliary substances such as preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants and/or aromatic substances. If desired, they may contain one or more additional active substances, for example one vitamin or several vitamins.

Compounds according to the invention are, as a rule, by analogy with other known, commercially available as a pharmaceutical, in particular, by analogy with the compounds described in EP-A-459256, the preferred way as Debka is the preferred way about 0.1 and 20 mg/kg, in particular, 1 and 10 mg/kg of body weight. Special dose for each particular patient depends, however, on various factors, for example, the activity of the used compound, the age, body weight, General health, sex, time and route of administration, rate of excretion, from a combination of medication and severity corresponding disease undergoing therapy. It is preferable to oral administration.

Above and below the temperature is displayed in degrees Celsius. In the examples below, the expression "cooking in the usual way means: if necessary, water is added, depending on the Constitution of the final product set pH value between 2 and 8, are filtered through the ion exchange column, the organic phase is dried over sodium sulfate, evaporated, if necessary lyophilizer and purified using chromatography on silica gel and/or crystallization. In the following examples, the expression "4-piperidinoethyl" always means "2-(4-piperidyl)-ethyl", the expression "4-piperidinol" always "3-(4-piperidyl)-propyl" and the expression "4-piperidinoethyl" always "4-(4-piperidyl)-butyl". Similarly, the expression "4-piperazinylmethyl" always means "2-(4-p is 4-(4-piperazinil)-butyl". Included also provided with a protective group derived, for example BOC-protected connection.

Example 1

To a solution of 1.9 g of methyl ester of 2-N-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid (A) (derived from tyrosine by esterification with methanol and the introduction of a protective group BOC) in 20 ml of dimethylformamide (DMF) was added 1 equivalent of NaH and stirred for 30 min at room temperature. After that, add 1.8 g of 3-p-N-BOC-amidino-phenyl-5-methane-sulfonyloxy-methyl-oxazolidin-2-it (obtained by the reaction of p-aminobenzonitrile with 2,3-epoxypropan-1-I with the formation of p-(N-2,3-dihydroxypropyl-amino)-benzonitrile, exchange reactions with diethylmalonate in the presence of tert.-butylacetate with the formation of 3-p-tianfeng-5-hydroxymethyl-oxazolidin-2-it, exchange reactions with H2S, methyliodide and ammonium acetate to obtain amidine, by introducing a protective group BOC in amidin and subsequent esterification with methanesulfonanilide dissolved in 10 ml of DMF, and again stirred for 15 min at room temperature. After removal of the solvent and the implementation of "cooking in the usual way" has obtained 3-n-BOC-amidino-phenyl-5-[p-2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy] -metiloksi is sulfonyloxy-methyl-oxazolidin-2-it

3-(4-N-BOC-piperidyl)-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinoethyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinoethyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-idine-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2 - N-BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-isopropyl-4-piperidyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(1-isopropyl-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-methyl-4-piperidinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methanesulfonyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperazinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperazinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl - 2-N-BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperazinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl - 2-N-BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 2

A solution of 0.9 g of 3-p-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy] -methyl-oxazolidin-2-she obtained in example 1 by using the exchange reaction of methyl ester of 2-N-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid 3-p-cyan-phenyl-5-methansulfonate-methyl-oxazolidin-2-one] in 40 ml of 10%aqueous methanolic solution of NH3, hydronauts 0.6 g of Raney Nickel at room temperature and a pressure of 1 bar until the uptake of H2. After filtration and evaporation receive using "cooking in the usual way", 3-p-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amine is ronil-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it

3-m-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-m-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it

3-m-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyloxazolidine-2-he;

3-p-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it

3-p-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyloxazolidine-2-he;

3-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it

3-o-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it

3-o-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it.

Example 3

Analogously to example 1, from methyl ester of 2-N-butylsulfonyl-amino-3-(4-hydroxy-phenyl)-propanoic acid ("B") [derived from tyrosine by the esterification of methanol and using exchange reactions with butylsulfonyl] , using the exchange reaction Mino-piperidine with 2; 3-epoxypropan-1-I with the formation of 1-N-BOC-amidino-4-(N-2,3 - dihydroxy-propyl-amino)-piperidine, interaction with diethylmalonate in the presence of tert.-butylacetate with the formation of 3-(1-N-BOC-amidino-4-piperidyl)-5-hydroxymethyl-oxazolidin-2-it and subsequent etherification with methanesulfonamido] obtain 3-(1-BOC-amidino-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

In a similar manner by reaction of exchange "B" is received:

using 3-(4-N-BOC-piperidyl)-5-methanesulfonylaminoethyl - oxazolidin-2-it

3-(4-N-BOC-piperidyl)-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperidinyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl - oxazolidin-2-it

3-(4-N-BOC-piperidinoethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-ethyl-4-piperidyl)-5-methansulfonate-methyl - oxazolidin-2-it

3-(1-ethyl-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperidinyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-isopropyl-4-piperidyl)-5-methanamine)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-methyl-4-piperidinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(4-N-BOC-piperazinylmethyl)-5-methansulfonate - methyl-oxazolidin-2-it

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperazinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

using 3-(1-N-BOC-amidino-4-piperazinylmethyl)-5 - methansulfonate-methyl-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl - 2-N-butylsulfonyl-amino-ethyl) - Rev.-oxazolidin-2-it

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl - 2-N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

Example 4

1.2 g of 3-p-Amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyloxazolidine-2-[obtained in accordance with example 1] suspendered in 60 ml of methanol, mixed with 4 ml of 2 N NaOH solution and stirred for 4 h at room temperature. After removal of solvent the residue absorb water, the pH value is set to 3 by addition of dilute HCl and filtered through an acidic ion exchanger. The filtrate is dried over MSO4. After removal of the solvent and after lyophilization get 3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Similarly using the saponification products of example 1 are as

3-(4-N-BOC-piperidyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidine-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-isopropyl-4-piperidyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 5

0.6 g of 3-p-N-BOC-and the leader 4] suspendered in 40 ml of 2N HCl solution on the basis of dioxane and mixed for three hours at room temperature. After removal of the solvent and cook in the usual way" has obtained 3-p-amidino-phenyl-5-[p-(2-carboxy-2 - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it, dihydrochloride, so pl. 165oC (decomp.).

Similarly, after removal of the protective group BOC product obtained from example 4.

3-(4-piperidyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidyl)-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy] -methyl-oxazolidin--he the dihydrochloride;

3-(1-isopropyl-4-piperidyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, dihydrochloride.

Example 6

0.6 g of 3-p-N-BOC-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-[obtained in accordance with example 1] are suspended in 40 ml of 2N HCl solution on the basis of dioxane and stirred for three hours at room temperature. After removal of the solvent and cooking obychnoi, so pl. 132-133oC.

Similarly, after removal of the protective group BOC products obtained from example 1

3-(4-piperidyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)-phenoxy]- methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-of the-2-it, the dihydrochloride;

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, dihydrochloride;

3-(4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, dihydrochloride;

3-(1-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it, dihydrochloride.

Example 7

Analogously to example 4, from 3-(1-N-BOC-amidino-4-piperidyl)- 5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-[obtained in accordance with example 3], saponification receive 3-(1-N-BOC-amidino-4-piperidyl)-5-[p-(2-carboxy-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Similarly obtained by saponification
3-(4-N-BOC-piperidyl)-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperidinyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperidinoethyl)-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperidinoethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-ethyl-4-piperidyl)-5-[p-(2-methoxycarbonyl-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-ethyl-4-piperidyl)-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinylmethyl)-edelmetall)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperidinyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-isopropyl-4-piperidyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-isopropyl-4-piperidyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-methyl-4-piperidinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylphenyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(4-N-BOC-piperazinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-methoxycarbonyl-2 - N-butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it:

3-(1-N-BOC-amidino-4-piperazinylmethyl)-5-[p-(2-carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 8

To a solution of 0.6 g of 3-p-amido NaOH solution and stirred for 24 h at room temperature. After removal of the solvent and freeze-drying receive Na-salt of 3-p-amidino-phenyl-5-[n-(carboxy-2-N-BOC - amino-ethyl)-phenoxy] -methyl-oxazolidin-2-it, so pl. 120-121oC.

Similarly get:

sodium salt of 3-p-aminomethyl-phenyl-5-[n-(carboxy-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

sodium salt of 3-p-amidino-phenyl-5-[n-(carboxy-2-N - butylsulfonyl-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

sodium salt of 3-p-aminomethyl-phenyl-5-[n-(carboxy-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 9

A solution of 0.2 g of 1-amidino-3,5-dimethylpyrazol-nitrate in 17 ml of dioxane and 5 ml of water is mixed with 0.17 ml of ethyldiethanolamine and stirred for 15 minutes. After that add 0.4 g of 3-p-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it, the mixture is boiled for 30 h, evaporated, and "preparation of lead in the usual way". Get 3-p-guadiamar-phenyl-5-[p-(2-methoxy-carbonyl-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it.

Similarly get:

3-m-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-guadiamar-phenyl-5-[p-(2-methoxybutyrophenone-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-guadiamar-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-guadiamar-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it;

3-o-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl)-phenoxy]-methyl-oxazolidin-2-it,

3-o-guadiamar-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-o-aminomethyl-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-o-guadiamar-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC aminoethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 10

In a solution of 1.2 g of 3-p-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy] -methyl-oxazolidin-2-[obtained according to example 1 by reaction of exchange methyl ester 2-N-butylsulfonyl-amino-3-(4-hydroxy-phenyl)-propanoic acid 3-p-cyan-phenyl-5-methansulfonate-methyl-oxazolidin-2-he] in 50 ml of pyridine and 7 ml of triethylamine at -10oC injected gas H2S before saturation. Then mix the Le of this refresher stirring for 6 h, filtered, the precipitate washed with 5 ml of acetone to dissolve it in 30 ml of methanol, added 4.6 g of ammonium acetate and stirred at room temperature for 24 hours. After cooking in the usual way" get amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-oxazolidin-2-it, so pl. 162-163oC.

Similarly get:

3-m-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-p-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it,

3-p-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-he;

3-p-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-m-cyan-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

oC.

Similarly receive by means of saponification:

3-m-aminomethyl-phenyl-5-[p-(2-methylcarbamoyl-2-N - butylsulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-amidino-phenyl-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-p-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-amidino-phenyl-5-[p-(2-carboxy-2-N-p-toluensulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-m-amidino-phenyl-5-[p-(2-methoxycarbonyl-2-N-p - toluensulfonyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-m-amidino-phenyl-5-[p-(2-carboxy-2-N-p-toluensulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 12.

of 1.37 g of 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - methoxycarbonyl-2-N-ethyl-amino-ethyl)-phenoxy] -methyl-oxazolidin-2-[obtained according to example 1 by reaction of exchange methyl ester 2-N-ethyl-amino-3-(4-hydroxy-phenyl)-propanoic acid 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-methane - sulfanilyl-oxazolidin-2-he], of the races who live in a vacuum. The resulting product is treated with 20 ml of ethyl ether acetic acid by heating, and after cooling, the product is sucked off. Get 3-p-lidinopril-5-[p-(2-methoxycarbonyl - 2-N-ethyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Similarly reductive splitting of the group - 5-oxo-1,2,4-oxadiazoline get:

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - methoxycarbonyl-2-N-isopropyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-lidinopril-5-[p-(2-methoxycarbonyl-2-N-isopropyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it;

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - methoxycarbonyl-2-N-acetyl-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-lidinopril-5-[p-(2-methoxycarbonyl-2-N-acetyl-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it;

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - methoxycarbonyl-2-N-propionyl aminoethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-lidinopril-5-[p-(2-methoxycarbonyl-2-N-propionyl aminoethyl)-phenoxy]-methyl-oxazolidin-2-it;

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - methoxycarbonyl-2-N-BOC-amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it,

3-p-lidinopril-5-[p-(2-methoxycarbonyl-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it;
3-p-lidinopril-5-[p-(2-methoxycarbonyl-2-N-tert.-butyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it.

Example 13

Analogously to example 4 by saponification of the corresponding esters from example 12 given the following carboxylic acids:

3-p-lidinopril-5-[p-(2-carboxy-2-N-ethyl-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-it;

3-p-lidinopril-5-[p-(2-carboxy-2-N-isopropyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-p-lidinopril-5-[p-(2-carboxy-2-N-acetyl-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-he;

3-p-lidinopril-5-[p-(2-carboxy-2-N-propionyl aminoethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-p-lidinopril-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-he;

3-p-lidinopril-5-[p-(2-carboxy-2-N-tert. -butyl-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it.

Example 14

Analogously to example 4 by saponification of the corresponding esters from example 9 given the following carboxylic acids:

3-p-guadiamar-phenyl-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-m-guadiamar-phenyl-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he;

3-m-guadiamar-phenyl-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxgen-2-he;

3-o-guadiamar-phenyl-5-[p-(2-carboxy-2-N-butylsulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-he;

3-o-guadiamar-phenyl-5-[p-(2-carboxy-2-N-BOC-amino-ethyl)- phenoxy] -methyl-oxazolidin-2-it.

Example 15

Analogously to example 5 by removal of the protective group BOC, on the basis of the product of example 14, receive the following connections:

3-p-guadiamar-phenyl-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-he;

3-m-guadiamar-phenyl-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-he;

3-o-guadiamar-phenyl-5-[p-(2-carboxy-2-amino-ethyl)-phenoxy] - methyl-oxazolidin-2-it.

Example 16

0.5 g of 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-amino-ethyl)phenoxy]-methyl-oxazolidin-2-it [produced by exchange reaction of benzyl ester 2-N-BOC-amino-3-(4-hydroxy-phenyl)-propanoic acid, which is produced from tyrosine by introducing protective groups are BOC and esterification with benzyl alcohol, 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-methane-sulfanilyl - oxazolidin-2-one with 3-p-(5-oxo-1,2,4-oxadiazol-3-yl)- phenyl-5-[p-(2-benzyloxycarbonyl-2-N-BOC-amino-ethyl)-phenoxy]- methyloxazolidine-2-it and post-processing triperoxonane acid] R is nom cooling. After 1 h the reaction solution was washed with diluted hydrochloric acid (2 times) and water, and the organic phase is evaporated after drying over magnesium sulfate. The product was then purified by crystallization from ethyl acetate/petroleum ether and by chromatography on silica gel (toluene/acetone 4:1). Get 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)- phenyl-5-[p-(2-benzyloxy-carbonyl-2-N-propylsulfonyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-he; FAB-MS: m/e 635 (M+H+).

By analogy by the exchange reaction of 3-p-(5-oxo-1,2,4-oxadiazolyl - 3-yl)-phenyl-5-[p-(2-benzyloxycarbonyl-2-amino-ethyl)-phenoxy] -methyl - oxazolidin-2-he receive

using chloride econsultancy

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-ethylsulfonyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using toluenesulfonic acid chloride

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-toluensulfonyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride benzisothiazole

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-benzylmethyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride hexanesulfonate

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5 - [is pentanesulfonate

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-intercultural-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride hexadecanesulfonate

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-hexadecanesulfonyl-amino-ethyl)-phenoxy]- methyl-oxazolidin-2-he;

using butane chloride acid

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-butanoyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using the chloride pentanol acid

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-pentanoyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride hexanoic acid

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-hexanoyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride of benzoic acid

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-benzoyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride 1-naphthalene acid

3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxycarbonyl-2-N-(1-naphtol-amino)-ethyl)-phenoxy]-methyl - oxazolidin-2-he;

using chloride 2-naphthalene acid

Example 17

For cleavage of the benzyl ether and oxadiazoline ring of 0.4 g of 3-p-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl-5-[p-(2 - benzyloxy-carbonyl-2-N-propylsulfonyl-amino-ethyl)-phenoxy]-methyl - oxazolidin-2-dissolve it in 10 ml of dichloromethane and after adding 1 ml of acetic acid, 0.5 ml of water and 5 ml of methanol and 0.1 g of palladium/activated carbon (10%) is treated at room temperature with hydrogen. After 30 min, the catalyst was filtered, the reaction solution concentrate and get 3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-propylsulfonyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, flash point 200oWith (melting).

Similarly, using a hydrogenation product of example 16 get:

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-ethylsulfonyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 212oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-toluensulfonyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 205oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-benzylmethyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it, so pl. 211oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-hexylsilane - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it, so pl. 198oC (decomp.);C (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-hexadecanesulfonyl - amino-ethyl)-phenoxy]-methyl-oxazolidin-2-it, so pl. 220oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-butanoyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 190oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-pentanoyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 195oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-hexanoyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 188oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-benzoyl-amino-ethyl)- phenoxy]-methyl-oxazolidin-2-it, so pl. 204oC (decomp.);

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-(1-naphtol-amino)-ethyl)- phenoxy] -methyl-oxazolidin-2-he;

3-p-amidino-phenyl-5-[p-(2-carboxy-2-N-(2-naphtol-amino)-ethyl)- phenoxy] -methyl-oxazolidin-2-it, so pl. 226oC (decomp.).

The examples below relate to pharmaceutical drugs:

Example And Vials for injection

In a solution of 100 g of the active substance of the formula I and 5 g of dinitrogenase in 3 l of double-distilled water with 2 N. hydrochloric acid set a pH of 6.5, the solution is filtered under sterile conditions, poured into injection vials, lyophilized in sterile oslava. As the active substance used, the compound of formula I with a melting point of 120-121oC by example 8.

Example B: Suppositories

Melt a mixture of 20 g of biologically active substances of the formula (I) and 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and cooled. Each suppository contains 20 mg of biologically active substances, active substances used compound of formula I with a melting point of 162-163oC by example 10.

Example: Solution

Prepare a solution of 1 g of biologically active substances of the formula (I), 9,38 g NaH2PO42H2O, 28,48 g NAHPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH to 6.8, made up to a total volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops. As the active substance used, the compound of formula I with a melting point 236-237oC by example 11.

Example D: Ointment

Mix 500 mg of biologically active substances of the formula (I) with 99.5 g of vaseline under aseptic conditions, as the active substances used, the compound of formula I with a decomposition temperature of 212oC by example 17.

of starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablets such that each tablet contains 10 mg of biologically active substances, active substances used compound of formula I with a decomposition temperature of 211oC by example 17.

Example E: Bean

Analogously to example D is pressed tablets, which are then applied a coating of sucrose, potato starch, talc, tragant and dye, as the active substances used, the compound of formula I with a decomposition temperature of 215oC by example 17.

Example G: Capsules

2 kg of biologically active substances of the formula (I) in the usual way bring into hard gelatin capsules so that each capsule contains 20 mg of biologically active substances, active substances used compound of formula I with a decomposition temperature of 215oC by example 17.

Example C: Ampoules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is sterile filtered, filled them ampoules, lyophilizer in sterile sterile conditions and closed. Each ampoule contains 10 mg of biologically active substances, active substances used this data:

Determined the inhibitory activity of the compounds of General formula I:

< / BR>
< / BR>
Inhibition of binding of fibrinogen to GPIIb/IIIa (= aIIb III; GP = glycoprotein) was determined according to the method described by Smith and al. in J. Biol. Chem. 265, 12267-12271 (1990) and Smith and al. in J. Biol. Chem. 263, 18726-18731 (1988).

Inhibition of binding of alpha-v-beta-integrin was determined by the method described by Smith and al. in J. Biol. Chem. 265, 12267-12271 (1990).

The obtained data are given in the table.

From the table it is seen that the proposed according to the invention the compounds of formula I are antagonists of adhesion receptors, they inhibit the binding of fibrinogen with fibrinogenesis receptor GPIIb/IIIa, and thus platelet aggregation. Compounds prevent the formation of blood clots and can be used as a drug for the treatment of blood clots and tumors.

1. Derivative oxazolidinone formula I

< / BR>
where R1denotes lidinopril;

R2denotes H, A, C1- C10-alkanoyl, C1- C8-alkoxycarbonyl, benzoyl, Naftoli, C1- C6-alkylsulfonyl, benzylmethyl or unsubstituted or monosubstituted C1- C6the alkyl phenylsulfonyl;

R

2. Derivative oxazolidinone formula I on p. 1, representing: a) 3-p-amidino-phenyl-5-[p-(2-amino-2-carboxy-ethyl)phenoxy-methyl] -oxazolidin-2-it, b) 3-p-amidino-phenyl-5-[p-(2-amino-2-methoxycarbonylethyl)phenoxy-methyl] -oxazolidin-2-he) 3-p-amidino-phenyl-5-[p-(2-N-butylsulfonyl-amino-2-carboxyethyl)phenoxy-methyl] -oxazolidin-2-he, d) 3-p-amidino-phenyl-5-[p-(2-N-p-toluensulfonyl-amino-2-carboxy-ethyl)phenoxy-methyl] -oxazolidin-2-he, e) 3-p-amidino-phenyl-5-[p-(2-N-butylsulfonyl-amino-2-methoxycarbonyl-ethyl)phenoxy-methyl] -oxazolidin-2-it, as well as their physiologically acceptable salts.

3. The method of obtaining compounds of formula I on p. 1, characterized in that the compound of formula I is recovered from its functional derivative, containing the corresponding protected amino and/or hydroxy-group, by treatment with a strong acid, possibly in the presence of an inert solvent, or hydrogenations and the compound obtained is transferred, if necessary, into one of its salts by treatment with acid or base.

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

< / BR>
where R1has the meaning specified in paragraph 1;

Z - reactive Aten;

R2and R3are specified in paragraph 1 values

and the connection formula I is transferred into one of its salts by treatment with acid or base.

5. Derivative oxazolidinone formula I under item 1 as receptor antagonists of adhesion.

6. A method of obtaining a pharmaceutical composition having antagonistic activity against adhesion receptors consists in the fact that the compound of formula I under item 1 and/or one of its physiologically acceptable salts together in a solid, liquid or semi-liquid carrier or auxiliary substance is transferred to suitable for the reception of the form.

7. Pharmaceutical composition having antagonistic activity against receptors adhesion, characterized in that the active substance it contains an effective amount of at least one compound of formula I under item 1 and/or one of its physiologically acceptable salts.

Priority signs:

02.11.94 - all signs, except for R2-benzylmethyl;

16.03.95 - all signs, where R2-benzylmethyl.

 

Same patents:

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts

The invention relates to new derivatives of benzylpiperidine formula I, where R1denotes H or Hal, R2is unsubstituted or substituted Gal in the aromatic ring of the benzyl group in the 2 -, 3-or 4-position piperidino ring, provided that R2doesn't mean 4-benzyl when X represents-CO-, Y -, and Z represent CH2and R1- N; R3denotes H or A , X IS-CO-, Y is --CH2-, -NH - or-O-, Z is-CH2- or connection, And - alkyl WITH1-6In - OH, H+, HE, Hal Is F, Cl, Br or I, and their salts

The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them

The invention relates to new substituted heterocyclic compounds, process for the preparation of these compounds and pharmaceutical compositions containing them as active substances

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof

The invention relates to new derivatives of guanidine and their pharmaceutically acceptable salts, used as medicines
Up!