Derivative oxazolidin-2-it, the method of production thereof and pharmaceutical composition based on them


(57) Abstract:

Describes the new derivative oxazolidin-2-it formula I

< / BR>
where X denotes OH,

Y denotes

< / BR>

< / BR>
R1indicates or

R2and R3each, independently of one another, denotes H, a or benzyl; And denotes alkyl with 1-6 C-atoms; D represents 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, wherein, if necessary, free amino - or amidinopropane can be protected partially or fully protective for AMINOPHENYL groups, as well as their enantiomers, diastereoisomers and their physiologically acceptable salts, and the way they are received. These compounds possess antagonistic activity against receptor adhesion and are used to obtain pharmaceutical compositions, with this effect. 3 S. and 2 C.p. f-crystals, 1 table.

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

< / BR>
where X is O,

Y denotes or

< / BR>
R1indicates or

R2and R3each, independently of one another, denotes H, a or said;", 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, diastereoisomers and their physiologically acceptable salts.

The objective of the present invention are new compounds with valuable properties, suitable for the production of medicines.

The problem is solved proposed according to the invention compounds. It is shown that the compounds of formula (I), and their solvate and salt along with good compatibility possess valuable pharmacological properties. In particular, they inhibit the binding of fibrinogen, fibronectin and factor of Villebranda with fibrinogenesis receptor of blood platelets (glycoprotein IIB/IIIA), and binding of the same 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 occurrence of trombotsitnoy clots and CPE is over and acute renal failure. Further, the compounds have an impact on tumor cells because they suppress their metastezirovanii. Thus, they can also be used as anticancer agents.

There is evidence that tumor cells due to microthrombi fall in the blood vessels and thus protected from recognition by cells of the immune system. Similarly, microthrombi act as a support for the binding of tumor cells to blood vessel walls. Since the formation of microthrombi associated with the binding of fibrinogen with fibrinogenesis receptor (glycoprotein IIB/IIIA), inhibitors of the binding of fibrinogen are also considered as inhibitors of metastasis.

Connections to the same suitable as antimicrobial bioactive substances that may prevent infections that are caused by bacteria, fungi or yeast. Substances therefore it is possible to introduce preferably as a concomitant antimicrobial biologically active substances when carried out interventions in the organisms which use foreign substances, as, for example, biomaterials, implants, kateri or electrostimulation of the heart. They act as an the igand and others, described in Infection and Immunity, 2851-2855 (1988).

Other properties of the compounds can be detected according to the methods described in EP A1-0462960. Inhibition of binding of fibrinogen with fibrinogenesis receptor is determined according to the method known from EP A1-0381033. The vast platelet aggregation action can be identified in vitro by the method of born (Nature, 4832, 927-929, 1962).

The subject of the invention is also a method of obtaining compounds of formula (I) and their salts, which consists in the fact that the compound of formula (II):


where R1and X have the above meanings, and

Z denotes Cl, Br, I, OH or a reactive, esterified ester to OH-group, enter into interaction with the compound of the formula (III):

H - Y (III),

where Y has the above meaning, and, if necessary, by treatment with acid or base is translated into one of its salts.

The compounds of formula (I) have at least one chiral center and may be in several enantiomeric forms. These forms, for example D - and L-forms and their mixtures, for example DL-form also corresponds to the formula (I).

These residues X, Y, Z, A, and R1- R3and r have the above in the case of formulas (I) - (III) values, Ruga, these groups can take different values.

Group A contains 1 to 6, preferably 1, 2, 3 or 4 C-atoms. Most preferably denotes A methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3 - or 4-methyl-pentyl.

R1preferably means

2-, 3 - or 4-amidino-phenyl; 4-(aminohydrocinnamic)-phenyl; 2-, 3 - or 4-aminomethylphenol; 2-, 3 - or 4-guanidiniocarbonyl or 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl.

R2and R3each, independently of one another, preferably denote hydrogen, methyl, ethyl or benzyl.

D preferably represents amidinopropane or aminomethyl. r preferably denotes 1, 2 or 3.

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

Ia: X is oxygen and R1denotes 4-lidinopril;

Ib: X is oxygen and R1denotes 4-lidinopril or 4-aminomethylphenol.

Preferred derivatives oxazolidin-2-she is of the formula (I) are:

a) 3-(4-amidinophenoxy)-5-(4-etoxycarbonyl-4-etoxycarbonyl-methyl-piperidinomethyl)-oxazolidin-2-it,

b) 3-(4-amidinophenoxy)-5-[4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl] -oxazolidin-2-it,

C) 3-(4-aminomethylphenol)-5-[4-(1,2-dibenzalacetone-ethyl) -piperidinomethyl]-oxazolidin-2-it,

g) 3-(4-aminomethylphenol)-5-[4-(1,2-dicarboxy-ethyl)-piperidinomethyl]-oxazolidin-2-it,

d) 3-(4-amidinophenoxy)-5-[4-(1,2-dicarboxy-ethyl)-piperidinomethyl]-oxazolidin-2-it,

e) 3-(4-guanidiniocarbonyl)-5-[4-(1,2-dicarboxy-ethyl)-piperidinomethyl] -oxazolidin-2-it, as well as their physiologically acceptable salts, in particular alkali metal salts.

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 in standard works, as Houben-Weil. Methods of organic chemistry, ed. Georg-Thieme, Stuttgart; further, European patent NN A 1-0381033, A 1-0462960), namely under reaction conditions which are known and suitable for the specified interactions. You can also use yourself on Sabena to obtain in situ, so that they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

In the molecule of the original substance can also contain two or more identical or different protected amino and/or hydroxyl groups. If the existing protective group different from each other, but in many cases they can be selectively split.

The expression "protection for the amino function group" is well known and relates to groups which are suitable for protecting (blocking) an amino group from chemical effects, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl (for example, 2,4-dinitrophenyl/DNF)), arelaxation (for example, benzoyloxymethyl (BPO) or kalkilya (for example, benzyl, 4-nitrobenzyl, triphenylmethyl) group. As for protective amino group functions after the desired reaction (or sequence of reactions) are removed, their family and the value however is not critical; however, a preferred group with 1-20, in particular 1-8 C-atoms. The expression "acyl group" in connection with this method you have animateduration carboxylic acids or sulfonic acids acyl group, in particular, alkoxycarbonyl, aryloxyalkyl and primarily alcoxycarbenium group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, isopropoxycarbonyl, tert.-butoxycarbonyl (SIDE), 2-iodoxybenzoic; Uralelectromed as benzyloxycarbonyl (CBZ), 4-methoxybenzeneboronic, 9-fluorenylmethoxycarbonyl (FMOC). Preferred protective for amino function groups are the SIDE DNF and BOM, then, CBZ, benzyl and acetyl.

The expression "hydroxyl protective for function group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical interactions, which, however, can be easily removed after elsewhere molecules was desired chemical reaction. Typical of such groups are the abovementioned unsubstituted or zameshannye aryl, kalkilya or acyl group, further, also alkyl groups. The nature and magnitude protective for hydroxyl group functionality is not critical, a t the s group with 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective for function groups are, inter alia, tert. -butyl, benzyl, p-nitrobenzoyl, p-toluensulfonyl and acetyl, and especially preferred benzyl and acetyl.

The compounds of formula (I) can be obtained by reacting the compounds of formula (II) with the amine of formula (III). It is reasonable to use itself known methods for N-alkylation.

Remove the group Z preferably denotes Cl, Br, J, (C1-C6)-alkylsulfonate group, such as methane - or econsultancy-group, or (C6-C10)-arylsulfonate as benzene-, p-toluene - or 1 - or 2-naphthalene-sulfonyloxy group.

The reaction is preferably carried out in the presence of an additional base, for example, hydroxide or carbonate of alkali or alkaline earth metal as the hydroxide of sodium, potassium or calcium; sodium carbonate, potassium or calcium; in an inert solvent, for example, in a halogenated hydrocarbon like dichloromethane; simple ether as THF or dioxane; amide as DMF or dimethylacetamide; nitrile as acetonitrile; at temperatures from about -10oC to 200oC, preferably at 0-120oC. If ODA formula (II) as a rule are new. They can be obtained, for example, by reacting substituted phenyl, piperidino or pieperazinove derivative of formula R1-NH2with the compound of the formula R5CH2-CHR6-CH2OH (where R5denotes Z; R6indicates XR7and R7denotes a protective group; R5and R6together also denote oxygen) to produce the compounds of formula R1-NH-CH2-CHR8-CH2OH (where R6indicates XR7or OH), if necessary by removal of the protective group R7to obtain compounds of the formula R1-NH-CH2-CH(XH)-CH2OH, reaction with a derivative of carbonic acid, as diethylcarbamyl, with 3 R1-5-hydroxymethyl-2-oxazolidinones and turning hydroxymethylene group in CH2Z-group, for example, using SOCl2, SOBr2, methanesulfonamido or p-toluensulfonate. The compounds of formula X-V (III) are generally known or are obtained by analogy with known compounds.

To obtain the compounds of formula (I), where R1denotes 1-amidinopropane or piperazinilnom group corresponding piperidine or pieperazinove connection can handle amidenus the tee, use in the form of its nitrate. It is advisable to work with the addition of a base as triethylamine or ethyldiethanolamine, in an inert solvent or mixture of solvents, such as water/dioxane, at temperatures 0-120oC, preferably at 60 to 120oC.

Further, in the compound of formula (I) one or both of the remainder R1and/or Y can be transformed into another residue (other residues)1and/or y

For example, 4-(5-oxo-1,2,4-oxadiazolyl-3-yl)-phenyl, or 4-(amino-hydroxylaminopurine) group by hydrogenation, for example using Raney Nickel, can be turned into a 4-amidinophenoxy group.

In particular, it is possible to atrificial to carboxyl ester group, cleave ester groups, hydrogenations to remove the benzyl group or treated with amino groups using amicininuaddy funds. Next, you can enter or to split the usual protective for amino or hydroxyl group functions.

For the esterification to complex ester of the acid of formula (I) (R3= H) can be treated with excess alcohol of formula R3-IT (R3= A or benzyl), expediently in the presence of a strong acid like hydrochloric acid or sulfuric acid, at tempera is ensil) can be transformed into the corresponding acid of formula (I) (R3= H), it is by solvolysis, according to one of the above methods, for example, using NaOH or KOH in a mixture of water with dioxane at temperatures 0-40oC, preferably 10-30oC.

The basis of the formula (I) with acids can be converted to the corresponding salt accession acid. For this transformation take into account, in particular, acids, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example 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 acid, acetic acid, triperoxonane acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbylpalmitate-econsultation, benzosulfimide, p-toluensulfonate, naphthalene-mono - or-disulfonate, louisanna acid. Salts with physiologically unacceptable acids, for example, picrate, can be used for isolation and/or purification of the compounds of formula (I).

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

You can also carboxylic acids of the formula (I) (R3= H) by entering into cooperation with the relevant reason to turn in their metal salts or ammonium, for example, salts of sodium, potassium or calcium.

The compounds of formula (I) contain one or more chiral centers and therefore may exist in racemic or in optically active form. Resulting racemates can be separated into the enantiomers mechanically or chemically itself known methods. Preferably the racemic mixture by introducing into its interaction with active optical dividing means to receive the diastereomers. As release agents are suitable, for example, optically active acids, such as D - or L-forms of tartaric acid, diacetylene pricheski active camphorsulfonic as camphorsulfacid. Preferably the separation of enantiomers using columns filled with optically active separation means (for example, as dinitrobenzoyl-phenyl-glycine) as an eluting suitable means, for example, a mixture of hexane with isopropanol and acetonitrile, for example, in a volume ratio 82:15:3.

Naturally, it is also possible to obtain optically active compounds of formula (I) above ways, 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 obtain pharmaceutical drugs, the fact that it, together with at least one carrier or auxiliary substance and, if desired, together with one or more other biologically active substances brought to a suitable dosage forms. The thus obtained composition can be used as drugs in medicine or veterinary medicine. As carriers take into account organic or inorganic substances which are suitable for intestinal (e.g., oral or rectal) or parenteral administration or for administration in formkey oil, 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, the shells of the capsules. For rectal use suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore, suspensions, emulsions or implants.

For use as inhalation pulverizing of drugs can be used pulverizate drugs that contain biologically active compound either dissolved or suspended in a mixture of working gases. It is expedient in this case, applying the biologically active agent in micronized form, and you can add one or more additional physiologically acceptable solvents such as ethanol. Solutions for inhalation can be entered using a conventional inhalers. The new compounds can also be liofilizirovanny and received lyophilize is designed 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 aromatic substances. 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 generally administered analogously to other known, commercially available as a pharmaceutical, in particular, however, similar to the one described in European patent A-459256 compounds, preferably in dosages of from about 5 mg to 1 g, in particular 50-500 mg, 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, on cost, time and route of administration, rate of excretion, combination of drugs and the severity of the respective disease, which has implications for therapy. Preferably oral administration. Above - and neukazovat, if necessary, water; depending on the structure of the target product establish a pH-value of 2-8; filtered through an ion exchanger is separated, extracted with ethyl acetate, the extract is dried over sodium sulfate, if necessary lyophilizer, evaporated and the residue purified by chromatography on silica gel and/or by crystallization.

Example 1

To a solution of 1.2 g of 4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidine ("A") in 20 ml DMF added 3.0 g of 3-/4-(5-oxo-1,2,4 - oxadiazolyl-3-yl)-phenyl/-5-methansulfonate-methyl-oxazolidin-2-it [produced by interaction of 4-(5-oxo-1,2,4 - oxadiazolyl-3-yl)-aniline with 2,3-epoxypropan-1-I to obtain N-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl) phenyl/-2,3-dihydroxypropane, interaction with diethylmalonate in the presence of tert.-the butyl potassium with 3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl)phenyl/-5-hydroxymethyl-oxazolidin-2-it and subsequent esterification to complex ester with methanesulfonanilide] , dissolved in 10 ml of DMF, and stirred for 60 minutes at room temperature. After removal of the solvent and the normal processing gain 3-/4-(5-oxo-1,3,4-oxadiazoline-3-yl)phenyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin--methyl-oxazolidin-2-one obtained 3-(1-methyl-4-piperidyl)-5-(4-etoxycarbonyl-4-etoxycarbonyl-methyl-piperidinomethyl)oxazolidin-2-he;

with 3-(1-N-BOC-amidino-4-piperidyl)-5-methanesulfonylaminoethyl-2-one obtained 3-(1-N-BOC-amidino-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)oxazolidin-2-he;

with 3-(1-benzyl-4-piperidyl)-5-methanesulfonylaminoethyl-2 - one obtained 3-(1-benzyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

with 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-benzyl-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-benzyl-4-piperidyl)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-N-BOC-amidino-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-N-BOC-amidino-4-piperidyl) ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

3-/3-(1-benzyl-4-piperidyl)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-benzyl-4-piperidyl)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)oxazolidin-2-he;


with 3-/4-(1-benzyl-4-piperidyl)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-benzyl-4-piperidyl)butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

with 3-/4-(1-N-BOC-amidino-4-piperidyl) butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-N-BOC-amidino-4-piperidyl) butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-benzyl-4-piperazinil)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-benzyl-4-piperazinil)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

3-/2-(1-N-BOC-amidino-4-piperazinil)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-N-BOC-amidino-4-piperazinil)-ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

3-/-(1-benzyl-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-benzyl-4-piperazinil)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

3-/3-(1-N-BOC-amidino-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-N-BOC-amidino-4-piperazinil) propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-PIP-2-one obtained 3-/4-(1-benzyl-4-piperazinil)butyl/-5- (4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

with 3-/4-(1-N-BOC-amidino-4-piperazinil)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-N-BOC-amidino-4-piperazinil)butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

with 3-(1-methyl-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-methyl-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl - piperidinomethyl) oxazolidin-2-he;

with 3- (1-isopropyl-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2 - one obtained 3-(1-isopropyl-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

with 3-(1-tert. -butyl-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-tert. -butyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

with 3-(1-ethyl-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-2-one obtained 3-(1-ethyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

3/2(1-isopropyl-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-isopropyl-4-piperidyl)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;


3-/3-(1-ethyl-4-piperazinil)propyl/-4-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-ethyl-4-piperazinil)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-he;

3-/3-(1-isopropyl-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-isopropyl-4-piperazinil)-propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-he;

with 3-/4-(1-propyl-4-piperazinil)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-propyl-4-piperazinil)butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl) oxazolidin-2-it.

Example 2

Analogously to example 1, by reacting 0.9 g of 1-(1,2 - dietoksikarbonil-ethyl)piperazine ("B") with one equivalent of 3-/4- (5-oxo-1,2,4-oxadiazolyl-3-yl)phenyl/-5-methanesulfonylaminoethyl-oxazolidin-2-[receive as described in example 1], after removal of the solvent and conventional treatment, receive 3-/4- (5-oxo-1,2,4-oxadiazolyl-3-yl)phenyl/-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl-oxazolidin-2-it.

Similarly, through the interaction of a "B"

with 3-(1-methyl-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-methyl-4-piperidyl)-5-/4-(1,2-dietoksikarbonil the one-2-one obtained 3-(1-N-BOC-amidino-4-piperidyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-(1-benzyl-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-benzyl-4-piperidinylmethyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-benzyl-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-benzyl-4-piperidyl)ethyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-N-BOC-amidino-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-N-BOC-amidino-4-piperidyl)-ethyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/3-(1-benzyl-4-piperidyl)propyl/-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-benzyl-4-piperidyl)propyl/-5-/4-(1,2- dietoksikarbonil-ethyl)piperidinomethyl/oxazolidin-2-he;

3-/3-(1-N-BOC-amidino-4-piperidyl)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-N-BOC-amidino-4-piperidyl)-propyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-/4-(1-benzyl-4-piperidyl)butyl/-5-methanesulfonylaminoethyl-oxazole;

with 3-/4-(1-N-BOC-amidino-4-piperidyl)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-N-BOC-amidino-4-piperidyl) butyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-benzyl-4-piperazinil)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-benzyl-4-piperazinil)-ethyl-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-N-BOC-amidino-4-piperazinil)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-N-BOC-amidino-4-piperazinil)ethyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/3-(1-benzyl-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-benzyl-4-piperazinil) propyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/3-(1-N-BOC-amidino-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-N-BOC-amidino-4-piperazinil)propyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-/4- (1-benzyl-piperazinil)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-benzyl-4-piperazinil)butyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-/4-(1-N-BOC-amidino-4-piperazinil)Boo is carbonyl-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-(1-methyl-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-methyl-4-piperidyl)-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/-oxazolidin-2-he;

with 3-(1-isopropyl-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-isopropyl-4-piperidyl)-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/-oxazolidin-2-he;

with 3-(1-tert. -butyl-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-tert.-butyl-4-piperidinylmethyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-(1-ethyl-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-ethyl-4-piperidinylmethyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-isopropyl-4-piperidyl)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-isopropyl-4-piperidyl)ethyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-methyl-4-piperazinil)ethyl/-5-methansulfonate-methyloxazolidine-2-one obtained 3-/2-(1-methyl-4-piperazinil)ethyl/-5-/4-(1,2-dietoksikarbonil - ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/3-(1-ethyl-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-2-one obtained 3-/3-(1-ethyl-4-piperazinil)propyl/-consultonline-oxazolidin-2-one obtained 3-/3-(1-isopropyl-4-piperazinil)-propyl/-5-/4- (1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he

with 3-/4-(1-propyl-4-piperazinil)butyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/4-(1-propyl-4-piperazinil) butyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-it.

Example 3

Analogously to example 1, on the basis of 1.6 g of 1-(1,2-dietoksikarbonil-ethyl) piperazine ("B") by entering into interaction with one equivalent of 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl/-5-methanesulfonylaminoethyl-oxazolidin-2-it [produced by interaction of 4-(5-methyl-1,2,4-oxadiazol-3-yl) aniline with 2,3-epoxypropan-1-I to obtain N-/4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl-2,3-dihydroxypropane, interaction with diethylmalonate in the presence of tert. -butyl potassium with 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl/-5-hydroxymethyl-oxazolidin-2-it and subsequent esterification to complex ester with methanesulfonanilide], after conventional treatment, receive 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl/-5-/4- (1,2-dibenzalacetone-ethyl)piperidinomethyl/oxazolidin-2-it. So pl. 119oC.

Example 4

1.3 g of 3-(4-Cyan-phenyl)-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/- oxazolidin-2-it [produced by interaction of 4-cyan-aniline with 2,3-epoxypropan-1-I to obtain N-/4-cyan-phenyl/-2,3-dihydroxy imethyl-oxazolidin-2-it, subsequent esterification to complex ester with methanesulfonanilide and interaction "In"] and 1.1 g hydroxylamine-hydrochloride in 125 ml ethanol in the presence of 2.24 g of sodium methylate is boiled for 2 hours. Then the reaction mixture was filtered and concentrated in vacuo. The residue is dissolved in water, the solution set pH 3 with 2 N. hydrochloric acid and the precipitated precipitate is sucked off. After recrystallization from a mixture of water with glacial acetic acid to obtain 3-/4-amino-(hydroxyamino)methyl-phenyl/5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-it, so pl. 186oC.

Example 5

Analogously to example 1, from 1-(1,2-dibenzalacetone-ethyl)-piperazine (C), by reacting it with 3-(4-N-SIDE-aminomethyl-phenyl)-5(R)-methanesulfonylaminoethyl-oxazolidin-2-one [obtained by interaction of 4-N-SIDE - aminomethyl-aniline with 2,3-epoxy-propane-1-I to obtain N-(4-N-SIDE-aminomethyl-phenyl)-2,3-dihydroxypropane, interaction with diethylmalonate in the presence of tert.-the butyl potassium with 3-(4-N-SIDE-aminomethyl-phenyl)-5-hydroxymethyl-oxazolidin-2-it and subsequent esterification to complex ester with methanesulfonanilide], after conventional treatment, receive 3-(4-N-BOC-s-way through the interaction of a "C"

with 3-(1-N-BOC-amidino-4-piperidyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-N-BOC-amidino-4-piperidyl)-5-/4-(1,2-dibenzalacetone-ethyl)piperidinomethyl/-oxazolidin-2-he;

with 3-(1-benzyl-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-benzyl-4-piperidinylmethyl)-5-/4-(1,2-dibenzalacetone-ethyl)-piperidinomethyl/-oxazolidin-2-he;

with 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-(1-N-BOC-amidino-4-piperidinylmethyl)-5-/4-(1,2-dibenzalacetone-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/2-(1-N-BOC-amidino-4-piperazinil)ethyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/2-(1-N-BOC-amidino-4-piperazinil) ethyl/-5-/4-(1,2-dibenzalacetone-ethyl)piperidinomethyl/-oxazolidin-2-he;

3-/3-(1-benzyl-4-piperazinil)propyl/-5-methanesulfonylaminoethyl-oxazolidin-2-one obtained 3-/3-(1-benzyl-4-piperazinil) propyl/-5-/4-(1,2-dibenzalacetone-ethyl)piperidinomethyl/-oxazolidin-2-it.

Example 6

0.9 g of 3-(1-N-BOC-amidino-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-[receive according to example 1] are suspended in 40 ml of 2 n HCl solution based dioxa and receive 3-(1-amidino-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-one-hydrochloride.

Similarly, after removal of the BOC-protective groups of the product of example 1 receive:





3-/2-(1-amidino-4-piperazinil) ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)oxazolidin-2-one-hydrochloride;

3-/3-(1-amidino-4-piperazinil)propyl/-5-(4-etoxycarbonyl-4 - ethoxycarbonylmethyl-piperidinomethyl)oxazolidin-2-one-hydrochloride;


Example 7

Analogously to example 6, on the basis of the compounds of example 2, by removal of the BOC-protective groups are given the following compounds in the form of their hydrochloride:

3-(1-amidino-4-piperidyl)-5-/4-(1,2-dietoksikarbonil-ethyl)Pipera Catholicon-2-he;

3-/2-(1-amidino-4-piperidyl)ethyl/-5-/4-(1,2-dietoksikarbonil-ethyl)-piperazine derivatives-methyl/oxazolidin-2-he;





3-/4-(1-amidino-4-piperazinil)butyl/-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/oxazolidin-2-it.

Analogously to example 6, on the basis of the compounds of example 5 by removal of the BOC-protective groups are given the following connections:

3-(4-aminomethyl-phenyl)-5 (R)-/4-(1,2-dibenzalacetone-ethyl)-piperidinomethyl/oxazolidin-2-he-trihydrochloride-hydrate, so pl. 187oC;




Example 8

1.1 g modestia 4-chloromethyl-aniline with 2,3-epoxypropan-1-I to obtain N-(4-chloromethyl-phenyl)-2,3-dihydroxypropane, interaction with diethylmalonate in the presence of tert. -butyl potassium with 3-(4-chloromethyl-phenyl)-5-hydroxymethylimidazole-2-it, subsequent esterification to complex ester with methanesulfonanilide and interaction with 1-(1,2-dibenzalacetone-ethyl) - piperazine] , dissolved in 30 ml DMF at room temperature is mixed with 0.9 g of freshly prepared guanidine dissolved in 10 ml of DMF, and stirred for 2 hours. After removal of the solvent and the normal processing gain 3- (4-guanidine-phenyl-5-(R)-/4-(1,2-dibenzalacetone-ethyl) piperidinomethyl/-oxazolidin-2-it.

Example 9

1.1 g of 3-(4-Aminomethyl-phenyl)-5-(R)-/4-(1,2-dibenzalacetone-ethyl)piperidinomethyl/-oxazolidin-2-[hydrochloride trihydrate, so pl. 187oC] dissolved in 30 ml of toluene and, at room temperature for one hour is treated with gaseous hydrogen (p = 1 ATM.) when the catalytic effects of 150 mg of Pd. - C (Pd content. = 1%). Then the reaction mixture is filtered and, after conventional treatment, receive 3-(4-aminomethylphenol)-5-(R)-/4-(1,2-dicarboxyethyl)piperidinomethyl/-oxazolidin-2-it is in the form of trihydrochloride-hydrate. So pl. 200oC.

Similarly, by removal of benzyl groups from 3-(4-g is dimethyl-phenyl)-5-(R)-/4-(1,2-dicarboxyethyl)piperidinomethyl/-oxazolidin-2-it. So pl. 262oC.

Example 10

1.3 g of 3-/4-(5-Oxo-1,2,4-oxadiazolyl-3-yl)phenyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-[receive according to example 1] is dissolved in 50 ml of methanol and hydronaut in the presence of Raney Nickel. Then the reaction mixture is filtered and the filtrate concentrated in vacuo. The resulting product is treated with 20 ml of ethyl acetate under heating and after cooling is sucked off. Get 3-(4-amidino-phenyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl - piperidinomethyl)oxazolidin-2-one-hydrochloride, T. pl. 123oC.

Example 11

Analogously to example 9, by reductive removal of 5 - oxo-1,2,4-oxadiazolyl group on the basis of 3-/4-(5-oxo-1,2,4-oxadiazolyl-3-yl) phenyl/-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/oxazolidin-2-it, after conventional treatment, receive 3-(4-amidinophenoxy)-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/-oxazolidin-2-he-acetate, so pl. 179oC.

Example 12

To a solution of 0.3 g of 3-(4-amidinophenoxy)-5-(4-etoxycarbonyl - 4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-it in 20 ml of THF are added 20 ml of 20% NaOH solution and stirred for 24 hours at room temperature. After removal of the solvent and suck the de sodium salt, so pl. > 330oC.

Similarly from 3-(4-amidinophenoxy)-5-/4-(1,2-dietoksikarbonil - ethyl)piperidinomethyl/-oxazolidin-2-get it 3-(4-amidinophenoxy)-5-/4-(1,2-dicarboxyethyl)piperidinomethyl/-oxazolidin-2-it is in the form of sodium salt, dihydrate, so pl. > 300oC.

Example 13

0.8 g of 3-(4-Amidinophenoxy)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-[receive according to example 9] are suspended in 60 ml of methanol, mixed with 10 ml of 2 n NaOH solution and stirred for 4 hours at room temperature. After removal of solvent the residue is treated with water, set the pH-value of 3, using supplements, diluted hydrochloric acid, the reaction mixture is filtered through an ion exchanger. After extraction with ethyl acetate, the filtrate is dried over magnesium sulfate. After removal of the solvent and subsequent freeze-drying receive 3-(4-amidinophenoxy)-5-(4-carboxybenzoyl-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-it.

Similarly, by saponification

3-(4-amidinophenoxy-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-he-acetate, so pl. 145oC;

3-(1-methyl-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazole-benzyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl - piperidinomethyl)-oxazolidin-2-get it 3-(1-benzyl-4-piperidinylmethyl)-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-benzyl-4-piperidyl)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/2-(1-benzyl-4-piperidyl)ethyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/3-(1-benzyl-4-piperidyl)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/3-(1-benzyl-4-piperidyl)propyl-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/4-(1-benzyl-4-piperidyl)butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it


3-/2-(1-benzyl-4-piperazinil)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/2-(1-benzyl-4-piperazinil)ethyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin - 2-he;

3-/3-(1-benzyl-4-piperazinil)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/3-(1-benzyl-4-piperazinil) propyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/4-(1-benzyl-4-piperazinil)butyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/4-(who uridyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl - piperidinomethyl)-oxazolidin-2-get it 3-(1-methyl-4-piperidyl)-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;< / BR>
3-(1-isopropyl-4-piperidyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-(1-isopropyl-4-piperidyl)-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-(1-tert. -butyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-(1-tert.-butyl-4-piperidinylmethyl)-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-(1-ethyl-4-piperidinylmethyl)-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl - piperidinomethyl)-oxazolidin-2-get it 3-(1-ethyl-4-piperidinylmethyl)-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-isopropyl-4-piperidyl)ethyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3-/2-(1-isopropyl-4-piperidyl)ethyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/2-(1-methyl-4-piperazinil)ethyl/-5-(4-etoxycarbonyl-4-etoxycarbonyl-piperidinomethyl)-oxazolidin-2-get it 3-/2-(1-methyl-4-piperazinil)ethyl/- 5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/3-(1-ethyl-4-piperazinil)propyl/-5-(4-etoxycarbonyl-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3- /3-(1-ethyl-4-piperazinil)propyl/-5-(4-carb is bonil-4-ethoxycarbonylmethyl-piperidinomethyl)-oxazolidin-2-get it 3- /3-(1-isopropyl-4-piperazinil)propyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-he;

3-/4-(1-propyl-4-piperazinil)butyl/-5-(4-etoxycarbonyl-4-etoxycarbonyl-piperidinomethyl)-oxazolidin-2-get it 3-/4-(1-propyl-4-piperazinil)butyl/-5-(4-carboxy-4-carboxymethyl-piperidinomethyl)-oxazolidin-2-it.

Example 14

Analogously to example 1, by reacting 1,3 g of 1-(1,2-dietoksikarbonil-ethyl)piperazine ("B") with one equivalent of 3-/4-(5-methyl-1,2,3-oxadiazolyl-3-yl)phenyl/-5-methanesulfonylaminoethyl-oxazolidin-2-it [produced by interaction of 4-cyan-aniline with 2,3-epoxy-propane-1-I to obtain N-/4-cyan-phenyl/-2,3-dihydroxypropane, interaction with diethylmalonate in the presence of tert.-the butyl potassium with 3-(4-cyan-phenyl)-5-hydroxymethyl-oxazolidin-2-it, translated by reaction of the nitrile with hydroxylamine and then with the acid chloride of acetic acid 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl/-5-hydroxymethyl-oxazolidin-2-he and subsequent esterification to complex ester with methanesulfonanilide], after removal of the solvent and the normal processing, get 3-/4-(5-methyl-1,2,4-oxadiazol-3-yl) phenyl/-5-/4-(1,2-dietoksikarbonil-ethyl)-piperidinomethyl/-oxazolidin-2-it, so pl. 126-127oC.

Similarly, through the interaction of a "B"

with 3-/4-(5-phenyl-1,2,4-oxadiazoline-ethoxycarbonyl-ethyl)piperidinomethyl/-oxazolidin-2-it.

Example 15

1.3 g of 3-/4-(5-phenyl-1,2,4-oxadiazoline-3-yl)phenyl/-5-/4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl/-oxazolidin-2-[receive according to example 14] is dissolved in 50 ml of methanol and hydronaut in the presence of Raney Nickel. Then the reaction mixture is filtered and the filtrate concentrated in vacuo. The resulting product is treated with 20 ml of ethyl acetate under heating and after cooling is sucked off and processed as usual. Get 3-/4- (N-benzoylamino)phenyl/-5-/4-(1,2-dietoksikarbonil-ethyl) piperidinomethyl/-oxazolidin-2-it, so pl. 136oC.

The following examples relate to pharmaceutical compositions:

Example a: 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 2 N. hydrochloric acid to establish a pH of 6.5, the solution is sterile filtered, filled them with glass bubbles for drugs for injection, lyophilizer in sterile sterile conditions and closed. Each glass bottle of medicine for injection contains 5 mg of biologically active substances.

Example B: Candles

Melt a mixture of 20 g of biologically active substances of the formula (Ergic 20 mg of biologically active substances.

Example B: a Solution of

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

Example D: Ointment

500 mg of biologically active substances of formula I are mixed 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, so that each tablet contains 10 mg of biologically active substances.

Example E: Bean

Analogously to example D is pressed tablets, then the usual way is applied a coating 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

Studied the inhibition of1)binding of fibrinogen receptor GPIIb/IIIa (= aIIb III; GP - glycoprotein) by the method described by J. W. Smith al., J. Biol. Chem. , 265, 12267-12271 (1990) and inhibition of2)aggregation of platelets induced by collagen according to the method described by Mueller, Circulation, 72, 1336-1345 (1985). The study was performed using compounds of the General formula. The obtained data are given in the table.

Data presented in table indicate inhibitory activity of the compounds according to the invention. The compounds of formula (I) inhibit the binding of fibrinogen receptor GPIIb/IIIa, and also prevent the aggregation of platelets, especially the aggregation of platelets induced by collagen in human blood, therefore proposed according to the invention compound suitable for the treatment of thrombosis and cancer.

1. PR will mean

R2and R3each, independently of one another, denotes H, a or benzyl;

And denotes alkyl with 1 to 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 AMINOPHENYL groups, as well as their enantiomers, diastereoisomers and their physiologically acceptable salts.

2. Derivative oxazolidin-2-it formula I on p. 1 representing:

a) 3-(4-amidinophenoxy)-5-(4-etoxycarbonyl-4-etoxycarbonyl-methyl-piperidinomethyl)-oxazolidin-2-it,

b) 3-(4-amidinophenoxy)-5-[4-(1,2-dietoksikarbonil-ethyl)piperidinomethyl] -oxazolidin-2-it,

C) 3-(4-aminomethylphenol)-5-[4-(1,2-dibenzalacetone-ethyl)piperidinomethyl]-oxazolidin-2-it,

g) 3-(4-aminomethylphenol)-5-[4-(1,2-dicarboxy-ethyl)-piperidinomethyl] -oxazolidin-2-it,

d) 3-(4-amidinophenoxy)-5-[4-(1,2-dicarboxy-ethyl)-piperidinomethyl]-oxazolidin-2-it,

e) 3-(4-guanidiniocarbonyl)-5-[4-(1.2-dicarboxy-ethyl)-piperidinomethyl] -oxazolidin-2-it,

and their physiologically acceptable clinical topics the compound of formula II

< / BR>
where R1and X are specified in paragraph 1 values;

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

enter into interaction with the compound of the formula III

H - Y,

where Y has the above meaning,

and, if necessary, by treatment with acid or base is translated into one of its salts.

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

5. Derivative oxazolidin-2-it formula I under item 1 as antagonist receptor adhesion.


Same patents:

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

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< / BR>
Preferably the invention relates to a specific polymorphic form, referred to hereinafter as the alpha form above hydrobromide salt

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