Derivative oxazolidinone, the method of production thereof, pharmaceutical composition and method of reception


(57) Abstract:

Derivative oxazolidinone formula (I), where R1denotes unsubstituted or once substituted with CN, H2N-CH2-, H2N-C(=NH) -, or H2N-C(= NH)-NH-CH2phenyl residue; X is O; B represents a group of formula (II), where a denotes alkyl with 1 to 6 C-atoms, R2denotes H or A; R3represents H or (CH2)n-COOR2; E denotes CH; m represents 1; n represents 0 or 1, the compounds possess valuable properties and can find application in medicine as, for example, antineoplastic agents for the treatment of thrombosis, inflammation. A method of obtaining compounds of General formula (I) and their salts, where the compound of formula (III), where R1above, and Z Is Cl, Br, J, OH or a reactive esterified ester to the OH-group is subjected to interaction with the compound of the formula (IV) Y - B, where B above; Y is OH, SH, NH2, NAH or produced from OH or SH saltlike residue, or a compound of the formula (V) R1-NH-CH2-CH(OH)-CH2-X-B, where R1, B and X above. The method of obtaining pharmaceutical compositions possessing overwhelming linking of fibrin with fibrinogen receptor and ovocny form a solid, liquid or semi-liquid carrier. 4 S. and 2 C.p. f-crystals, 1 PL.

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The invention relates to a derivative of oxazolidinone formula (I).

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where R1denotes unsubstituted or once substituted with CN; H2N-CH2-; A2N-CH2-; H2N-C(=NH)-; H2N-C(=NH)-NH)-; H2N-C(=NH)-CH2- , HO-NH-C(= NH)- or HO-NH-C(=NH)- phenyl residue;

X denotes O, S, SO, SO2, -NH or-NA-;

B means:

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A denotes alkyl with 1 to 6 C-atoms;

R2denotes H, A, Li, Na, K, NH4or benzyl;

R3represents H or (CH2)n-COOR2;

E each represents, independently of each other CH or N;

Q represents O, S or NH;

"m" denotes 1, 2 or 3; and

"n" represents 0, 1, 2 or 3;

and their physiologically acceptable salts.

Similar compounds are known from European patent EP-Al - 0381033.

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

This problem is solved by the invention. It was found that the compounds of formula (I), and their solvate and salt with good compatible is ponectin and von Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIB/IIIA), as well as linking them and other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. The connection thus affect the interaction between cell-cell and cell-matrix. In particular, they prevent the formation trombotsitnoy of blood clots and can therefore be used for the treatment of thrombosis, apoplexy, heart attack, inflammation, arteriosclerosis. Further, the compounds have an impact on tumor cells because they inhibit metastasis. Thus they can also be used as antitumor agents.

Properties of compounds can be detected by the methods described in European patent EP-Al-0462960. Inhibition of binding of fibrin with fibrinogen receptor can be proved by the method described in the European patent EP-Al-0 381033. The vast platelet aggregation effect can be detected in vitro by the method of born (Nature, 4832, 927-929, 1962).

The subject invention further is a method for obtaining compounds of the indicated formula (I) and its salts, characterized in that the compound of formula (II):

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where R1has specified in paragraph I of the claims value;

Z is the activity with the compound of the formula (III):

Y - B (III),

where B has the above value, and

Y represents OH, SH, NH2, NAH or produced from OH or SH saltlike the rest,

or the compound of formula (IV):


where R1, B and X have the above values,

or one of its reactive derivatives enter into interaction with a reactive derivative of carbonic acid;

or to get guanidino-the compounds of formula (I) (R1= once replaced with H2-N-C(= NH)-NH-phenyl residue) aminosilicone corresponding to the formula (I), which, however, instead of a balance of R1contains AMINOPHENYL group, is treated with amidaniel tools;

or the compound of formula (I) release from one of its functional derivatives by treatment with solvolysis or gerogerigegege tools;

and/or the compound of formula (I) one or both of the remainder R1and/or B to turn into another (other) residue (remainder) R1and/or B and/or the compound of formula (I) by treatment with acid or base is translated into one of its salts.

The compounds of formula (I) contain at least one chiral center and therefore can n) included in formula (I).

Above and below the remains of, respectively, the parameters B, X, R1- R3, A, E, Q, Y, Z, "m" and "n" are indicated in the formulas (I), (II) or (III) values, unless nothing else.

In the above formulas A group contains 1 to 6, preferably 1, 2, 3 or 4 C-atoms. In particular, A preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert.-butyl, hereinafter also 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

X preferably represents O, however, also S, NH or NA, for example N-CH3or SO and SO2.

R1means are preferably substituted in position 4, but also the position 2 or 3, as described above, the phenyl residue, particularly preferably 2-, 3 - or especially 4-lidinopril, 2-, 3 - or 4-aminomethylphenol, 2-, 3 - or 4-guanidiniocarbonyl, 2-, 3 - or 4-tianfeng or, however, 2-, 3 - or 4-N-alkylaminocarbonyl, and in these cases, the alkyl is preferably methyl or ethyl.

"B" denotes a preferably one - or twofold substituted phenyl or pyrrolyl or, however, once substituted thienyl, also referred to as pyridinyl, furanyl or pyrimidinyl, in sesamee 2-, 3 - or 4-carboxymethyl-, 2-, 3 - or 4-methoxy-carbonyl - or etoxycarbonyl-phenyl, hereinafter, also preferably 2-carboxymethyl-Tien-4-yl, 2-carboxyethylpyrrole-4-yl, 3-carboxyethylpyrrole-4-yl, 2,5-dicarboxyethyl - or 2,3-dicarboximide-4-yl, 2-carboxymethyl-3-carboxy - or 2-carboxymethyl-5-carboxy-pyrrol-4-yl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-dicarboxyethyl, and preferably a complex of methyl or ethyl esters of the above preferred residues or produced from them the remains of Li-, Na-, K -, or ammonium salt.

R2represents preferably hydrogen, or A Na, while R3particularly preferably denotes H or carboxymethyl. E preferably represents CH, and Q preferably represents sulphur or NH.

The parameters "m" and "n" preferably denote I, then also 2 or 3. The variable "n", moreover, can also represent zero.

Of the compounds of formula (I) are preferred those in which the minimum one of these residues, groups, and/or parameters is one of these preferred values. Some groups preferred compounds are those of formulas (Ia) - (Ij), which correspond to the formula (I), where, however:

in Ia: X is oxygen and R1represents 2-, 3 - or 4-amidino-phenyl;

in Id: X denotes NH or R1represents 2-, 3 - or 4-amidino-phenyl;

Ie: X is sulfur and R1represents 2-, 3 - or 4-amidino-phenyl;

If X denotes oxygen and "B" denotes 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dicarboxyethyl;

in Ig: X denotes oxygen and "B" denotes 2-carboxymethyl-or 3-carboxymethyl-Tien-4-yl or pyrrol-4-yl;

in Ih: X denotes oxygen and "B" denotes a 2,3 - or 2,5-dicarboxyethyl - or 2-carboxymethyl-3-carboxy-, 2-carboxymethyl-5-carboxy-pyrrol-4-yl;

in Ii: X is oxygen;

B represents 2-, 3 - or 4-carboxyphenyl; and

R1represents 2-, 3 - or 4-lidinopril;

Ij: X denotes oxygen;

"B" denotes 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dicarboxyethyl; and

R1represents 2-, 3 - or 4-lidinopril.

Hereinafter, the preferred compounds, which themselves correspond to the formulas (Ia)-(Ij), however, where the carboxyl group residue "B" replaced methoxycarbonyl or ethoxycarbonyl group.

The compounds of formula (I) and also the source materials for their production however get itself known in ways that are described in the literature (for example, reference is 60), namely, when the reaction conditions which are known and suitable for the specified interactions. You can use itself known here more not mentioned options.

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

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

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

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

The expression "protection for the amino group" is well known and relates to groups which are suitable for protecting (blocking) an amino group from chemical interactions, which, however, can be easily removed once was desirable chemical reaction elsewhere in the molecule. Typical of such groups are especially unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl (DNP)), arelaxation (for example, benzoyloxymethyl/BOM/) or kalkilya group (for example, benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective group after the desired reaction (or sequence of reactions) are removed, they were kind and size, however, is not critical, however, preferred group with 1-20, in particular 1-8 C-atoms. The expression "acyl group" in connection with the present method should be understood in its broadest sense. It covers produced from aliphatic, alifaticheskih, aromatic or geterotsiklicheskikh and primarily alcoxycarbenium group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluoyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.-butoxycarbonyl (BOC), 2-iodoxybenzoic; Uralelectromed as benzyloxycarbonyl (CBZ), 4-methoxybenzeneboronic, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protective for amino groups are BOC, DNP and BOM, then, CBZ, benzyl and acetyl.

The expression "protection for the hydroxyl group, the group is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical interactions, which, however, can be readily separated after was desirable chemical reaction elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group, further, also alkyl groups. The nature and magnitude of the protective (hydroxyl groups) groups is not critical, as they again hatshepsuts after the desired chemical reaction or sequence of reactions; the preferred gruppioni, p-nitrobenzoyl, p-toluensulfonyl and acetyl and benzyl and acetyl is particularly preferred.

Used as starting substances, the functional derivatives of compounds of formula (I) can be obtained by conventional means, which are described, for example, in the above mentioned works and patent applications, for example, by reacting compounds which correspond to formula (II) and (III), whereby, however, at least one of these compounds contains a protective group instead of the H atom.

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

As the inert solvent is preferably suitable organic, for example carboxylic acids, as UK is by hydrocarbons, as dichloromethane; hereinafter, also alcohols as methanol, ethanol or isopropanol, and also water. Next, apply a mixture of the above solvents. Triperoxonane acid is preferably used in excess without the addition of another solvent; perchloric acid in a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperature suitable are O-about 50oC; preferably operate at 15-30oC (room temperature).

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

Hydrogenations removable protective group (for example, BOM, CBZ or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, expediently on the media, feces or ethanol, or amides as DMF. Hydrogenolysis, as a rule, is carried out at a temperature of about 0-100oC and pressures of about 1-200 bar, preferably at 20-30oC and 1-10 bar. Hydrogenolysis of CBZ - group, for example, flows well when using 5-10% palladium-on-coal in methanol at 20-30oC.

The compounds of formula (I) can be obtained preferably by the interaction of oxazolidinone formula (II) with the compound of the formula (III). When this expedient is used by itself, the known methods of esterification to ethers or N-alkylation of amines.

Remove the group Z in formula (II) preferably denotes Cl, Br, I, C1-C6-alkylsulfonates, such as methane - or econsultancy, or C6-C10-arylsulfonate as benzene-, p-toluene - or 1 - or 2-naphthalenesulfonate.

The reaction is carried out preferably in the presence of an additional base, such as hydroxide of alkali or alkaline earth metal as the hydroxide of sodium, potassium or calcium, potassium carbonate or calcium, in an inert solvent, for example, in a halogenated hydrocarbon like dichloromethane; simple ether as THF or dioxane; amide as DMF or dimetilan C. In case if the deleted group Z is different from iodine, it is recommended that the addition of iodide as the potassium iodide.

Educt of the formula (II), as a rule, are new. They can be obtained, for example, by reacting a substituted aniline of the formula R1-NH2where R1has a specified value, with the compound of the formula R5CH2-CHR6-CH2OH (where R5=Z, R6=OR7where R7denotes a protective group, and R5and R6together also denote oxygen) to produce the compounds of formula R1-NH-CH2-CHR8-CH2OH (where R8= OR7or OH), if necessary, removal of the protective group R7to obtain compounds of the formula R1-NH-CH2-CH/OH/CH2OH, interaction with a derivative of carbonic acid, as diethylcarbamyl, with 3 R1-5-hydroxymethyl-2-oxazolidinones and turning hydroxymethylene group in CH2Z - group, for example, using SOCl2THAT SOB2, methanesulfonamido or p-toluensulfonate. The compounds of formula V-B (III), generally known or are obtained by analogy with known compounds.

The compounds of formula (I), below, can be obtained by reacting connected the s.

As a derivative of carbonic acid in particular suitable diallylmalonate as diethylcarbamyl further complicated alkalemia esters of Harborview acid, as ethylchloride. Preferably use a derivative of carbonic acid, which is suitable used in excess as a solvent, respectively suspending agent. However, there might also be one of these solvents, if it is inert in this interaction. Further, it is recommended to add the base, in particular, the alcoholate of alkali metal tert.-butyl potassium. Suitable work when the reaction temperature 0-150oC, preferably 70-120oC.

Educt of the formula (IV), as a rule, are new. Get them, for example, by functionalization of the above compounds of formula R1-NH-CH2-CH/OH/CH2OH obtaining compounds of formula R1-NH-CH2-CH/OH/CH2-Z and administration in cooperation with the compounds of formula B-V (III).

To obtain the compounds of formula (I), where R1means guanidinopentanoic group corresponding aminoaniline connection can handle amidenus means. As amidine nitrate. It is advisable to work with the addition of a base as triethylamine or ethyldiethanolamine, in an inert solvent or mixture of solvents, such as water, dioxin, at temperatures 0-120oC, preferably 60 to 120oC.

Further, in the compound of formula (I) one or both of the remainder R1and/or "B" can be transformed into another (other) residue (remainder) R1or/and "B".

In particular, you can ceanography to restore to aminomethyl groups or to turn in amidinopropane, you can atrificial to esters of carboxylic groups, to cleave ester groups, hydrogenations to remove benzyl groups, translate aminomethyl group in guanidinoacetate group.

The restoration of the cyano groups in the aminomethyl group should be better carried out by catalytic hydrogenation, e.g. in the presence of Raney Nickel at temperatures of 0-100oC, preferably at 10-30oC, and pressures at 1-200 bar, preferably at normal pressure, in an inert solvent, for example, in the lower alkanol as methanol or ethanol, expediently in the presence of ammonia. If you are, for example, approximately at 20oC and a pressure of 1 bar, the original product ski, it is advisable to use a catalyst based on a noble metal, preferably palladium-on-charcoal, and the solution is to add an acid like acetic acid, and water.

To obtain amidine formula (I) (R1= lidinopril) to the nitrile of the formula (I) (R1= tianfei) to attach the ammonia. Accession preferably carry out multistage fact that in itself known (a) a nitrile using H2's turn in tioned that using alkylating agents, such CH3I, translated into the corresponding complex S-alkyl-imitation, which, for its part, enter into interaction with NH3getting amidine; b) the nitrile with an alcohol, for example ethanol, in the presence of HCl is transformed into the corresponding complex amidoethyl and it is treated with ammonia, or nitrile enter into interaction with bis-trimethylsilyl)/-amidon lithium and the product is then hydrolized.

Similarly, the corresponding N-hydroxy-amidine formula (I) (R1= substituted with HO-NH=C/=NH/phenyl) obtained from NITRILES, when working according to a) or b), however, with hydroxylamine instead of ammonia.

For the esterification to complex ester acid forms is the presence of a strong acid, as hydrochloric acid or sulfuric acid, at temperatures of 0-100oC, preferably at 20 to 50oC.

On the contrary, an ester of formula (I) (R2=A or benzyl) can be transformed into the corresponding acid of formula (I) (R2=H), it is by solvolysis according to one of the above methods, for example, using NaOH or KOH in a mixture of dioxane with water at temperatures of 0-40oC, preferably at 10-30oC.

The basis of the formula (I) with acids can be converted to the corresponding salt accession acid. For this transformation is used, in particular, acids, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, such as sulfuric acid, nitric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid; sulfamic acid; further, organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic, acetic, triperoxonane, propionic, pavlikova, diethyloxalate, malonic, succinic, polinikotinata acid; methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene mono - and di-sulfonic acids, louisanna acid. Salts with physiologically acceptable acids, such as the picrate, can be used for identifying and/or purifying compounds of formula (I).

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

You can also carboxylic acids of the formula (I) (R2=H) by reacting with the appropriate reason to turn in their metal salts or ammonium, for example, their sodium, potassium or calcium salt.

The compounds of formula (I) contain one or more chiral centers and therefore may exist in racemic or optically active form. Resulting racemates can be mechanically or chemically, according itself known methods to separate the enantiomers. Preferably the racemic mixture by introducing into interaction with optically-active dividing means to receive the diastereomers. As separating agent suitable for the slots, almond acid, malic acid, lactic acid or the various optically active camphorsulfonic as camphorsulfonate.

Preferably the separation of enantiomers using filled optically active separating means (for example, dinitrobenzoyl-phenyl-glycine) column; eluting suitable means, for example, a mixture of hexane with isopropanol and acetonitrile.

Naturally, it is also possible to obtain optically active compounds of formula (I) according to the above methods because they use the original substance (for example, those of formula (II)), which are already optically active.

The new compounds of formula (I) and their physiologically acceptable salts can be used to prepare pharmaceutical preparations because of their together with at least one carrier or auxiliary substance and, if desired, together with one or more other biologically active substances brought to a suitable dosage forms. Thus, the obtained composition can be used as a drug in medicine or veterinary medicine. As carriers to apply an organic or inorganic substances which th is RME inhalation spray and do not react with the new compounds, for example, as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates as lactose or starch, magnesium stearate, talc, cellulose. For oral administration are, in particular, tablets, coated tablets, capsules, syrups, juices or drops, are of special interest lacquered tablets and capsules resistant to gastric juice coatings, respectively shells of the capsules. For rectal use candles; for parenteral administration are solutions, preferably oily or aqueous solutions; further, suspensions, emulsions or implants.

For use as an inhalation spray, you can use sprays that contain biologically active compound either dissolved or suspended in a mixture of working gases. Expediently used in this biologically active substance in micronized form, and can be added one or more additional physiologically acceptable solvents, for example ethanol. Solutions for inhalation can be entered using a conventional inhalers. The new compounds can also be liofilizirovanny and obtained is sterilized and/or may contain auxiliary substances, as preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants and/or fragrances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

Proposed according to the invention substances normally administered analogously to other known, commercially available pharmaceutical preparations, in particular however, similar to the one described in European patent A-459256 compounds, preferably in doses from about 5 mg to 1 g, in particular 50-500 mg per dosing unit. The daily dose is preferably about 0.1-20 mg/kg, in particular 1-10 mg/kg body weight. Special dose for each particular patient, however, depends on various factors, for example, the effectiveness of used special compound, the age, body weight, General health, sex, cost, time of administration and route of administration, rate of excretion, combination of drugs and the severity of the respective disease, which has implications for therapy. Preferably oral administration.

Kabalat, if necessary, the water, depending on the structure of the target product set pH = 2-8, extracted with ethyl acetate or dichloromethane, separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or crystallization.

Example 1.

To a solution of 1.7 g of p-methoxycarbonylmethyl-phenolate sodium (obtained by converting the p-hydroxybenzylated to the corresponding carboxylic acid esterification with methanol to n-methoxycarbonylmethyl-phenol and subsequent transformation into a phenolate) in 20 ml of dimethylformamide (DMF) was added 1 equivalent of NaH and stirred for 30 minutes at room temperature. Then add 3.0 g of 3-tianfeng-5-methansulfonate-methyl-oxazolidin-2-it (A) (obtained by reacting p-aminobenzonitrile with 2,3-epoxypropan-1-I to obtain p-/N-2,3-dihydroxypropyl/-benzonitrile, interaction with diethylmalonate in the presence of tert.-the butyl potassium with 3-p-tianfeng-5-hydroxymethyl-oxazolidin-2-it and subsequent esterification to complex ester with methanesulfonanilide), dissolved in 10 ml of DMF, and again stirred for 15 minutes at room temperature. After removal of the RA is H. So pl. = 114-115oC.

Similarly, by reacting an "A"

with on-methoxycarbonylmethyl-phenolate sodium get 3-p-cyan-phenyl-5-/about-methoxycarbonyl-methyl-phenoxymethyl/- oxazolidin-2-it. M++1=366;

with m-methoxycarbonylmethyl-phenolate sodium get 3-p-cyan-phenyl-5-/m-methoxycarbonyl-methyl-phenoxymethyl/- oxazolidin-2-it. So pl. = 129-130oC,

from 2,4-bis-/methoxycarbonylmethyl/-phenolate sodium get 3-p-cyan-phenyl-5-[2,4-bis-/methoxycarbonyl-methyl/-phenoxymethyl]- oxazolidin-2-he;

with 2,5-bis-/methoxycarbonylmethyl/-phenolate sodium get 3-p-cyan-phenyl-5-[2,5-bis-/methoxycarbonyl-methyl/-phenoxymethyl]- oxazolidin-2-he;

with 2,6-bis-/methoxycarbonylmethyl/-phenolate sodium get 3-p-cyan-phenyl-5-[2,6-bis-/methoxycarbonyl-methyl/-phenoxymethyl]- oxazolidin-2-he;

with 3,4-bis-[ethoxycarbonylmethyl]-phenolate sodium get 3-p-cyan-phenyl-5-[3,4-bis-/methoxycarbonyl-methyl/-phenoxymethyl]- oxazolidin-2-he;

with 3,5-bis-/methoxycarbonylmethyl/-phenolate sodium get 3-p-cyan-phenyl-5-[3,5-bis-/methoxycarbonylmethyl/-phenoxymethyl]- oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-4-hydroxy-thiophene get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-Tien-4-yl - oxy-the Il-5-/3-methoxycarbonyl-methyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-3-hydroxy-thiophene get 3-p-cyan-phenyl-5-/2-methoxycarbonylmethyl-Tien-3-yl - oxymethyl/-oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-4-hydroxy-pyrrole get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

with a sodium salt of 3-methoxycarbonylmethyl-4-hydroxy-pyrrole get 3-p-cyan-phenyl-5-/3-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-3-carboxy-4-hydroxy-pyrrole get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-3-carboxy-pyrrol-4-yl-hydroxy-methyl/-oxazolidin-2-he;

sodium salt of 2-carboxy-3-hydroxy-5-methoxycarbonylmethyl-pyrrol get 3-p-cyan-phenyl-5-/2-carboxy-5-methoxycarbonylmethyl-pyrrol-3-yl - hydroxy-methyl/-oxazolidin-2-it.

Example 2.

A solution of 0.9 g of 3-p-tianfeng-5-/p-methoxycarbonyl-methyl - phenoxymethyl/-oxazolidin-2-it (so pl. = 114-115oC) in 40 ml of 10% methanolic solution of NH3hydronaut in the presence of 0.6 g of Raney Nickel at room temperature and a pressure of 1 bar until the cessation of hydrogen absorption. After filtration and evaporation produced by normal processing of 3-p-aminomethy is the formation of the corresponding NITRILES get:

3-p-aminomethyl-phenyl-5-/about-methoxycarbonyl-methyl-phenoxy-methyl/- oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/m-methoxycarbonyl-methyl-phenoxymethyl/- oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,4-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,5-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,6-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,4-bis-/methoxycarbonyl-methyl/- phenoxy-methyl] -oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,5-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-he ;







3-p-aminomethyl-phenyl-5-/2-carbox the o-methyl phenyl-5-/p-methoxycarbonyl-methyl-phenoxymethyl/-oxazolidin-2-it was dissolved in 20 ml of dichloromethane, add 12 ml triperoxonane acid and stirred for 20 minutes at room temperature. After evaporation and normal processing gain 3-p-aminomethyl-phenyl-5-/n-carboxymethyl-phenoxymethyl/-oxazolidin-2-it.

Similarly, by saponification of the corresponding esters have the following carboxylic acids:




3-p-cyan-phenyl-5-[2,4-bis/carboxy-methyl/-phenoxy-methyl] - oxazolidin-2-he;

3-p-cyan-phenyl-5-[2,5-bis-/carboxymethyl/-phenoxymethyl] -oxazolidin-2-he;

3-p-cyan-phenyl-5-[2,6-bis-/carboxymethyl/-phenoxymethyl] - oxazolidin-2-he;

3-p-cyan-phenyl-5-[3,4-bis-/carboxymethyl/-phenoxymethyl] -oxazolidin-2-he;

3-p-cyan-phenyl-5-[3,5-bis-/carboxymethyl/-phenoxymethyl] - oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-carboxymethyl-Tien-4-yl-oxymethyl/- oxazolidin-2-he;


3-p-cyan-phenyl-5-/2-carboxymethyl-Tien-3-yl-oxymethyl/- oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-carboxymethyl-pyrrol-4-yl-oximate the phenyl-5-/2-carboxymethyl-3-carboxy-pyrrol-4-yl - hydroxy-methyl/-oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-carboxy-5-carboxy-methyl-pyrrol-3-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/n-carboxy-methyl-phenoxymethyl/- oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-carboxymethyl-phenoxymethyl/- oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/m-carboxymethyl-phenoxymethyl/- oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,4-bis-/carboxy-methyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-[5-/2,5-bis-/carboxymethyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,6-bis-/carboxymethyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,4-bis-/carboxymethyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,5-bis-/carboxymethyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-carboxymethyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/3-carboxy-methyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-carboxymethyl-Tien-3-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-carboxymethyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/3-carboxy-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-carboxymethyl-3-carboxy-pyrrol - 4-yl-oxygen-2-it.

Example 4.

To a solution of 0.6 g of 3-p-aminomethyl-phenyl-5-/n-carboxy - methyl-phenoxymethyl/-oxazolidin-2-it in 20 ml of THF are added 20 ml of 20% NaOH solution and stirred for 24 hours at room temperature. Get the sodium salt of 3-p-aminomethyl-phenyl-5- /n-carboxy-methyl-phenoxymethyl-/-oxazolidin-2-it. So pl. 286 and 287oC.

Example 5.

A solution of 0.2 g of 1-amido-3,5-limitierte-nitrate in 17 ml of dioxin and 5 ml of water is mixed with 0.17 ml of ethyldiethanolamine and stirred for 15 minutes. Then add 0.4 g of 3-p-aminomethyl-phenyl-5-/p-methoxycarbonyl-methyl-phenoxymethyl/ -oxazolidin-2-it, the mixture is boiled for 30 hours, evaporated and treated as usual. Get 3-p-guanidinate-phenyl-5-/p-methoxycarbonyl-methyl-phenoxymethyl/- oxazolidin-2-it.

In a similar way:

3-p-aminomethyl-phenyl-5-/about-methoxycarbonyl-methyl - phenoxymethyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/about-methoxycarbonyl-methyl-phenoxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/m-methoxycarbonyl-methyl-phenoxymethyl/ -oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/m - methoxycarbonyl-methyl-phenoxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,4-bis-/methoxycarbonyl-methyl/- Fel]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,5-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-get hold 3-p-guanidinate-phenyl-5- [2,5-bis-/methoxycarbonyl-methyl/-phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[2,6-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-get hold 3-p-guanidinate-phenyl-5- [2,6-bis-/methoxycarbonyl-methyl/-phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,4-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-3-one obtained 3-p-guanidinate-phenyl-5- [3,4-bis-/methoxycarbonyl-methyl/-phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-[3,5-bis-/methoxycarbonylmethyl/- phenoxy-methyl] -oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-[3,5-bis-/methoxycarbonyl-methyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-methoxycarbonyl-methyl-Tien-4 - yl-hydroxy-methyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/2-methoxycarbonyl-methyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/3-methoxycarbonyl-methyl-Tien-4 - yl-oxymethyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/3-methoxycarbonyl-methyl-Tien-4-yl-oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-methoxycarbonyl-methyl-Tien-3 - yl-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl-oxymethyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/3-methoxycarbonyl-methyl-pyrrol-4 - yl-hydroxy-methyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/3-methoxycarbonylmethyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-methoxycarbonyl-methyl-3-carboxy - pyrrol-4-yl-oxymethyl/-oxazolidin-2-get hold 3-p-guanidinate-phenyl-5-/2-methoxycarbonyl-methyl-3 - carboxyphenyl-4-yl-hydroxy-methyl/-oxazolidin-2-he;

3-p-aminomethyl-phenyl-5-/2-carboxy-5-methoxycarbonyl-methyl - pyrrol-3-yl-oxymethyl/-oxazolidin-2-get hold 3-p-guanidino-methyl-phenyl-5-/2-carboxy-5-methoxycarbonylmethyl-pyrrol-3-yl-hydroxy-methyl/-oxazolidin-2-he;

Example 6.

In a solution of 1.2 g of 3-p-tianfeng-5-/p-methoxycarbonyl-methyl-phenoxymethyl/ -oxazolidin-2-it (obtained according to example 1) in 50 ml of pyridine and 7 ml of triethylamine at -10oC miss gaseous H2S. Then stirred for 14 hours at room temperature, evaporated, the residue is dissolved in 50 ml of acetone and mixed with 9 ml under the conditions. Once again paramashiva is added 4.6 g of ammonium acetate and stirred for 24 hours at room temperature. After the usual processing gain 3-p-amidino-phenyl-5-/p-methoxycarbonyl-methyl-phenoxymethyl/- oxazolidin-2-he (polyhydride). So pl. = 151 - 152oC.

In a similar way:

3-p-cyan-phenyl-5-/about-methoxycarbonyl-methyl-phenoxy-methyl/ -oxazolidin-2-get it 3-p-amidino-phenyl-5-/about-methoxycarbonyl - methyl-phenoxymethyl/-oxazolidin-2-it/)hydroiodide/ M++I = 384;

3-p-cyan-phenyl-5-/m-methoxycarbonyl-methyl-phenoxy-methyl/ -oxazolidin-2-get it 3-p-amidino-phenyl-5-/m-methoxycarbonyl-methyl-phenoxy-methyl/-oxazolidin-2-he/hydroiodide/ M++I = 384;

3-p-cyan-phenyl-5-[2,4-bis-/methoxycarbonyl-methyl/-phenoxymethyl] -oxazolidin-2-get it 3-p-amidino-phenyl-5-[2,4-bis-/methoxycarbonyl-methyl/-phenoxymethyl]- oxazolidin-2-he;

3-p-cyan-phenyl-5-[2,5-bis-/methoxycarbonyl-methyl/phenoxymethyl] -oxazolidin-2-get it 3-p-amidino-phenyl-5-[2,5-bis-/methoxycarbonyl-methyl/-phenoxymethyl] -oxazolidin-2-it;

3-p-cyan-phenyl-5-[2,6-bis-/methoxycarbonyl-methyl/- phenoxymethyl]-oxazolidin-2-get it 3-p-amidino-phenyl-5- [2,6-bis-/methoxycarbonyl-methyl/-phenoxymethyl]-oxazolidin-2-he;

3-p-cyan-phenyl-5-[3,4-bis-/methoxycarbonyl-methyl/- phenoxymethyl] -oxazolidin-2-get it 3-p-amidino-FeNi is Il-methyl/-phenoxymethyl] /oxazolidin-2-get it 3-p-amidino-phenyl-5-[3,5-bis-/methoxycarbonyl-methyl/-phenoxymethyl] -2-he;

3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-Tien-4-yl - oxymethyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5- /2-methoxycarbonyl-methyl-Tien-4-yl-hydroxy-methyl/-oxazolidin-2-he;

3-p-cyan-phenyl-5-/3-methoxycarbonyl-methyl-Tien-4-yl-hydroxy-methyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5- /3-methoxycarbonyl-methyl-Tien-4-yl-oxymethyl/oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-Tien-3-yl-hydroxy-methyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5-/2 - methoxycarbonyl-methyl-Tien-3-yl-oxymethyl/-oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5-/2 - methoxycarbonyl-methyl-pyrrol-4-yl-oxymethyl/-oxazolidin-2-he;

3-p-cyan-phenyl-5-/3-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5-/3-methoxycarbonyl-methyl-pyrrol-4-yl-oxymethyl/ -oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-3-carboxy - pyrrol-4-yl-hydroxy-methyl/-oxazolidin-2-get it 3-p-amidino-phenyl-5-/2-methoxycarbonyl-methyl-3-carboxy-pyrrol-4-yl-hydroxy-methyl/ oxazolidin-2-he;

3-p-cyan-phenyl-5-/2-carboxy-5-methoxycarbonyl-methyl-pyrrol-3-yl-oxymethyl/-oxazolidin-2-get it 3-p-amidino-2">

Analogously to example 3, by saponification of the corresponding esters from example 6 given the following carboxylic acids:

3-p-amidino-phenyl-5-/n-carboxymethyl-phenoxymethyl/-oxazolidin-2-it. So pl. = 281oC.

3-p-amidino-phenyl-5-/o-carboxy-methyl-phenoxy-methyl/- oxazolidin-2-it. So pl. = 274oC;

3-p-amidino-phenyl-5-/m-carboxy-methyl-phenoxy-methyl/-oxazolidin-2-he/hydrochloride/. So pl. = 271oC

3-p-amidino-phenyl-5-[2,4-bis-/carboxy-methyl/-phenoxy-methyl] -oxazolidin-2-he;

3-p-amidino-phenyl-5-[2,5-bis-/carboxy-methyl/-phenoxy-methyl] -oxazolidin-2-he;

3-p-amidino-phenyl-5-[2,6-bis-/carboxy-methyl/-phenoxymethyl] -oxazolidin-2-he;

3-p-amidino-phenyl-5-[3,4-bis-/carboxymethyl/-phenoxymethyl] -oxazolidin-2-he;

3-p-amidino-phenyl-5-[3,5-bis-/carboxymethyl/-phenoxymethyl] - oxazolidin-2-he;

3-p-amidino-phenyl-5-/2-carboxymethyl-Tien-4-yl-oxymethyl/ -oxazolidin-2-he;

3-p-amidino-phenyl-5-/3-carboxy-methyl-Tien-4-yl-methyl/- oxazolidin-2-he;

3-p-amidino-phenyl-5-/2-carboxy-methyl-Tien-3-yl-oxymethyl/- oxazolidin-2-he;

3-p-amidino-phenyl-5-/2-carboxy-methyl-pyrrol-4-yl-oxymethyl/ -oxazolidin-2-he;

3-p-amidino-phenyl-5-/3-carboxy-methyl-pyrrol-4-yl-oxymethyl/ -oxazolidin-2-he;

Example 8.

Analogously to example 3, by saponification of the corresponding esters from example 5 given the following carboxylic acids:

3-p-guanidinate-phenyl-5-/n-carboxy-methyl-phenoxy-methyl/- oxazolidin-2-it. So pl. > 300oC;

3-p-guanidino-phenyl-5-carboxymethyl-phenoxymethyl/ -oxazolidin-2-he;

3-p-guanidinate-phenyl-5-/m-carboxymethyl-phenoxymethyl/- oxazolidin-2-he;

3-p-guanidino-methyl-phenyl-5-[2,4-bis-/carboxymethyl/- phenoxymethyl]-oxazolidin-2-he;

3-p-guanidinate-phenyl-5-[2,5-bis-/carboxymethyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-guanidinate-phenyl-5-[2,6-bis-/carboxy-methyl/- phenoxymethyl]-2-he;

3-p-guanidinate-phenyl-5-[3,4-bis-/carboxymethyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-guanidinate-phenyl-5-[3,5-bis-/carboxymethyl/- phenoxymethyl] -oxazolidin-2-he;

3-p-guanidinate-phenyl-5-/2-carboxymethyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-guanidinate-phenyl-5-/3-carboxymethyl-Tien-4-yl - oxymethyl/-oxazolidin;

3-p-guanidinate-phenyl-5-/2-carboxymethyl-thiophene-3-yl - oxymethyl/-oxazolidin-2-;

3-p-hypnodomme-phenyl-5-/2-carboxymethyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

3-p-guanidinate-phenyl-5-/3-carboxylat the l-oximeter/-oxazolidin-2-he;

3-p-guanidinate-phenyl-5-/2-carboxy-5-carboxy-methyl - pyrrol-3-yl-oxymethyl/-oxazolidin-2-it.

Example 9.

Analogously to example 1, from p-methoxycarbonylmethyl-thiophenolate sodium (obtained by converting the p-mercapto-benzylcyanide to the corresponding carboxylic acid esterification to complex ester with methanol to obtain n-methoxycarbonylmethyl-thiophenol and subsequent transformation into thiophenolate), by entering into interaction with 3-p-tianfeng-5 - methane-sulfonyloxy-methyl-oxazolidin-2-one ("A") (obtained according to example 1), get 3-p-tianfeng-5-/p-methoxycarbonylmethyl - phenylthio-methyl/-oxazolidin-2-it.

Similarly, by reacting "A":

with on-methoxycarbonylmethyl-thiophenolate sodium get 3-p-cyan-phenyl-5-/about-methoxycarbonyl-methyl-phenylthio-methyl/-oxazolidin-2-he;

with m-methoxycarbonylmethyl-thiophenolate sodium get 3-p-cyan-phenyl-5-/m-methoxycarbonyl-methyl-phenylthio-methyl/-oxazolidin-he;

from 2,4-bis-/methoxycarbonylmethyl/-thiophenolate sodium get 3-p-cyan-phenyl-5-[2,4-bis-/methoxycarbonylmethyl/-phenylthiomethyl]- oxazolidin-2-he;

with 2,5-bis-/methoxycarbonylmethyl/-thiophenolate sodium get 3-p-cyan-phenyl-5-[2,5-beatrie get 3-p-cyan-phenyl-5-[2,6-bis-/methoxycarbonylmethyl/-phenylthiomethyl]- oxazolidin-2-he;

with 3,4-bis-/methoxycarbonylmethyl/-thiophenolate sodium get 3-p-cyan-phenyl-5-[3,4-bis-/methoxycarbonylmethyl/-phenylthiomethyl]- oxazolidin-2-he;

with 3,5-bis-/methoxycarbonylmethyl/-thiophenolate sodium get 3-p-cyan-phenyl-5-[3,5-bis-/methoxycarbonyl/-methyl/-phenylthiomethyl/- oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-4-hydroxythiophene get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-Tien-4-yl - oxymethyl/-oxazolidin-2-he;

with a sodium salt of 3-methoxycarbonylmethyl-4-hydroxy-thiophene get 3-p-cyan-phenyl-5-/3-methoxycarbonylmethyl-Tien-4-yl-oxymethyl/- oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-3-hydroxy-thiophene get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-Tien-3-yl - oxymethyl/-oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-4-hydroxy-pyrrole get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

with a sodium salt of 3-methoxycarbonylmethyl-4-hydroxy-pyrrole get 3-p-cyan-phenyl-5-/3-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;

sodium salt of 2-methoxycarbonylmethyl-3-carboxy-4 - hydroxy-pyrrole get 3-p-cyan-phenyl-5-/2-methoxycarbonyl-methyl-3-carboxy-pyrrol-4-yl - ACS is 3-p-cyan-phenyl-5-/2-carboxy-5-methoxycarbonyl-methyl-pyrrol-3-yl - oxymethyl/-oxazolidin-2-it.

Example 10.

Analogously to example 6, on the basis of the nitrile from example 9 are given the following derivative lidinopril-oxazolidin-2-it:




3-p-lidinopril-5-[2,4-bis-/methoxycarbonylmethyl/-phenylthiomethyl/- oxazolidin-2-he;

3-p-lidinopril-5-[2,5-bis-/methoxycarbonylmethyl/-phenylthiomethyl] - oxazolidin-2-he;

3-p-lidinopril-5-[2,6-bis-/methoxycarbonylmethyl/-phenylthio - methyl]-oxazolidin-2-he;

3-p-lidinopril-5-[3,4-bis/-methoxycarbonyl-methyl/- phenylthiomethyl]-oxazolidin-2-he;

3-p-lidinopril-5-[3,5-bis-/methoxycarbonylmethyl/-phenylthiomethyl] - oxazolidin-2-he;

3-p-lidinopril-5-/2-methoxycarbonyl-methyl-Tien-4-yl-hydroxy - methyl/-oxazolidin-2-he;

3-p-lidinopril-5-/3-methoxycarbonyl-methyl-Tien-4-yl - hydroxy-methyl/-oxazolidin-2-he;

3-p-lidinopril-5-/2-methoxycarbonyl-methyl-Tien-3-yl - oxymethyl/-oxazolidin-2-he;

3-p-lidinopril-5-/2-methoxycarbonyl-methyl-pyrrol-4-yl - oxymethyl/-oxazolidin-2-he;


3-p-lidinopril-5-/2-carboxy-5-methoxycarbonyl - methyl-pyrrol-3-yl-oxymethyl/-oxazolidin-2-it.

Example 11.

Analogously to example 3, by saponification of the corresponding esters from example 10 given the following carboxylic acids:



3-p-lidinopril-5-/m-carboxy-methyl-phenylthio-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-[2,4-bis-/carboxymethyl/-phenylthio-methyl]- oxazolidin-2-he;

3-p-lidinopril-5-[2,5-bis-/carboxymethyl/-phenylthio-methyl] - oxalide-2-he;

3-p-lidinopril-5-[2,6-bis-/carboxymethyl/-phenylthio-methyl]- oxazolidin-2-he;

3-p-lidinopril-5-[3,4-bis-/carboxymethyl/-phenylthio/-methyl] - oxazolidin-2-he;

3-p-lidinopril-5-[3,5-bis-/carboxymethyl/-phenylthio-methyl]- oxazolidin-2-he;

3-p-lidinopril-5-/2-carboxy-methyl-thiophene-4-yl-oxymethyl/- oxazolidin-2-he;

3-p-AMINOPHENYL-5-/3-carboxy-methyl-thiophene-4-yl-oxymethyl/- oxazolidin-2-he;

3-p-lidinopril-5-/2-carboxymethyl-thiophene-3-yl-oxymethyl/- oxazolidin-2-he;

3-p-lidinopril-5-/2-carboxy-methyl-pyrrol-4-yl-oxymethyl/- oxazolidin-2-he;

3-p-amidino the-mud-oximeter/- oxazolidin-2-he;

3-p-lidinopril-5-/2-carboxy-5-carboxy-methyl-pyrrol-3-yl - oxymethyl/-oxazolidin-2-it.

Example 12.

Analogously to example 1, from p-methoxycarbonyl-methyl-aniline (obtained by converting the p-amino-benzylcyanide in p-amino-phenylacetic acid and esterification to complex ester using methanol) by entering into interaction with 3-p-tianfeng - 5-methansulfonate-methyl-oxazolidin-2-one ("A") (obtained according to example 1), receive 3-p-tianfeng-5-/p-methoxycarbonylmethylene-methyl/-oxazolidin-2-it.

Similarly, by reacting "AND":

with on-methoxycarbonylmethyl-aniline get 3-p-tianfeng-5- /about-methoxycarbonyl-methyl-phenylamino-methyl/-oxazolidin-2-he;

with m-methoxycarbonylmethyl-aniline get 3-p-tianfeng-5- /m-methoxycarbonyl-methyl-phenylamino-methyl/-oxazolidin-2-he;

from 2,4-bis-/methoxycarbonylmethyl/-aniline get 3-p - tianfeng-5-/2,4-bis-/methoxycarbonylmethyl/-phenyliminomethyl]- oxazolidin-2-he;

with 2,5-bis-/methoxycarbonylmethyl/-aniline get 3-p-tianfeng-5-[2,5-bis/-methoxycarbonylmethyl/-phenyliminomethyl]- oxazolidin-2-he;

with 3,4-bis-/methoxycarbonylmethyl/-aniline get 3-p-tianfeng-5-[3,4-bis-/methoxycarbonyl is triglow of example 9, get the following derivative lidinopril-oxazolidin-2-it:

3-p-lidinopril-5-/p-methoxycarbonyl-methyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-/5-/about-methoxycarbonyl-methyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-/m-methoxycarbonyl-methyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-[2,4-bis-/methoxycarbonyl-methyl/- phenyliminomethyl]-oxazolidin-2-he;

3-p-lidinopril-5-[2,5-bis/methoxycarbonyl-methyl/- phenyliminomethyl]-oxazolidin-2-he;

3-p-lidinopril-5-[3,4-bis-/methoxycarbonylmethyl/- phenyliminomethyl]-oxazolidin-2-he;

Example 14.

Analogously to example 3, by saponification of the corresponding esters from example 13 given the following carboxylic acids:

3-p-lidinopril-5-/n-carboxymethyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-/o-carboxy-methyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-/m-carboxy-methyl-phenylamino-methyl/- oxazolidin-2-he;

3-p-lidinopril-5-[2,4-bis-/carboxymethyl/-phenylamino-methyl]- oxazolidin-2-he;

3-p-lidinopril-5-[2,5-bis-/carboxymethyl/-phenylamino-methyl]- oxazolidin-2-he;

3-p-lidinopril-5-[3,4-bis-/carboxymethyl/-phenylamino-methyl]- oxazolidin-2 is oluce by converting the p-N-methyl-aminopenicillanic in p-methylaminophenol acid and esterification to complex ester using methanol) by reacting with 3-p-tianfeng-5-methanesulfonylaminoethyl-oxazolidin - 2-one ("A") (obtained according to example 1), get 3-p-tianfeng-5-/p-methoxycarbonylmethyl-phenyl-N-methylamino-methyl - oxazolidin-2-it.

Example 16.

Analogously to example 6, on the basis of the nitrile from example 15, to obtain 3-p-lidinopril-5-/p-methoxycarbonyl-methyl-phenyl-N-methyl-amino-methyl/- oxazolidin-2-it.

Example 17.

Analogously to example 3, by saponification of ester from example 16 to obtain 3-p-lidinopril-5-/n-carboxymethyl-phenyl-N - methylaminomethyl/-oxazolidin-2-it.

The following examples relate to pharmaceutical compositions:

Example: Glass vials of medicine for injection

A solution of 100 g of biologically active substances of the formula (I) and 5 g of dinitrigenoxide in 3 l of double-distilled water using a 2H. hydrochloric acid set pH = 6.5, the solution is sterile filtered, poured into glass vials, lyophilizers and sterile closed. Each glass bottle of medicine for injection contains 5 mg of biologically active substances.

Example B: Candles

Melt a mixture of 20 mg of biologically active substances of the formula (I) with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically act is rmula (I), 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

Mix 500 mg of biologically active substances of the formula (I) with 99.5 g of vaseline under aseptic conditions.

Example D: Tablets

A mixture of 1 kg of biologically active substances of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablets such that each tablet contains 10 mg of biologically active substances.

Example E: Bean

Analogously to example D is pressed tablets, which are then the usual way is covered with a shell of sucrose, potato starch, talc, tragant and dye.

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.

Example C: Ampoules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is poured into imputing substances.

Derivatives oxazolidone General formula

< / BR>
given in the table.

These results were obtained on the claimed compounds represented as an adhesion receptor antagonists. They inhibit fibrinogen linking fibrinogenic receptor GPIIb/IIIa and prevent aggregation trombocitnim plates. These results clearly demonstrate the activity of the compounds according to the invention, concerning, in particular, the treatment of thrombosis and opukholeobrazovanie.

1. Derivative oxazolidinone formula (I):

< / BR>
where R1denotes unsubstituted or once substituted with CN, H2N-CH2-, H2N-C(=NH)-, or H2N-C(=NH)-NH-CH2is phenyl residue;

X denotes O;

In stands

< / BR>
R2denotes H or A;

And denotes alkyl with 1 to 6 C-atoms;

R3represents H or (CH2)n-COOR2;

E denotes CH;

m denotes 1;

n denotes 0 or 1,

and their physiologically acceptable salts.

2. Derivative oxazolidinone formula I, including:

(a) 3-p-Amidino-phenyl-5-(n-carboxymethyl-phenoxymethyl)-oxazolidin-2-it,

(b) 3-p-amidino-phenyl-5-(p-carboxylatomethyl-phenoxy the DIN-2-it,

(g) 3-p-guanidinate-phenyl-5-(n-carboxymethyl-phenoxy-methyl)-oxazolidin-2-it.

3. The enantiomeric compound of formula (I) under item 1 or one of its salts.

4. The method of obtaining derivatives oxazolidinone formula I under item 1, and their salts, characterized in that the compound of formula (II)

< / BR>
where R1has specified in paragraph 1 of the claims value;

Z denotes C1, Br, I, OH or a reactive esterified ester to HE group

enter into interaction with the compound of the formula (III): Y (III), where a has the above meaning and Y represents OH, SH, NH2, NAH or produced from OH or SH saltlike the rest,

or the compound of formula (IV)

R1-NH-CH2-CH(OH)-CH2-X-B, (IV)

where R1, B and X have the above values,

or one of its reactive derivatives enter into interaction with a reactive derivative of carbonic acid; or a compound of formula (I) release from one of its functional derivatives by treatment with solvolysis or hydrogenolysis funds; and/or the compound of formula (I) one or both of the remainder R1and/or convert to another(other) residue(remainder) R1and/or In 5. The method of obtaining pharmaceutical compositions possessing overwhelming linking of fibrin with fibrinogen receptor and platelet aggregation activity, characterized in that the compound of formula (I) under item 1 and/or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary substance is brought to a suitable dosage forms.

6. Pharmaceutical composition having an overwhelming linking of fibrin with fibrinogen receptor and platelet aggregation activity-based active agents and conventional additives, characterized in that it contains as active substance at least one compound of formula (I) and/or one of its physiologically acceptable salt in an effective amount.


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< / BR>
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