Nitrogen-containing heterocyclic derivatives, pharmaceutical composition and method for the treatment or prevention of thrombotic diseases

 

(57) Abstract:

Describes nitrogen-containing heterocyclic derivatives of General formula I, where a, b and C independently represent CH2or C = O, X and Y are different from each other, and each represents CH or N; D is -(CH2)k- or -(CH2)m-CO-, where k is an integer of 1-4; and m is an integer of 0 to 3; E represents a group II or III, where n is an integer of 1-3; Z is-W-(CH2)p-R3where W represents-O - or a bond; p is an integer 1-4; R3represents hydrogen, lower alkyl; R1represents hydrogen or lower alkyl, substituted-2-oxadiazol-4-yl; R2represents a hydrogen atom, and their pharmaceutically acceptable salt and solvate having the ability to inhibit platelet aggregation. Describes the pharmaceutical composition on the basis of the above compounds and a method of treatment or prophylaxis of thrombotic diseases using compounds of formula I. 3 C. and 11 C.p. f-crystals.

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The present invention relates to nitrogen-containing heterocyclic derivative capable of inhibiting the aggregation of platelets, and to pharmaceutical coma, at least one of these derivatives.

Background of the invention

The number of cardiovascular diseases has increased due to change of diet and lengthening life expectancy. Almost fifty percent of these diseases can be caused by clots.

Platelets in plasma, mainly related to education in the body of blood clots. For the treatment and prevention of thrombotic diseases in clinical practice, used drugs that inhibit the platelet function or inhibit platelet aggregation, such as aspirin, which inhibits cyclooxygenase, and ticlopidine, which activates adenylyl cyclase.

In recent years intensively investigated glycoproteins on the platelet membrane. In the result, it was revealed that the receptor fibrinogen is a glycoprotein called GPIIb/IIIa. This led to the assumption that antagonists of GPIIb/IIIa can act as inhibitors of platelet aggregation with a new mechanism of action, which can be used effectively for the treatment and prevention of thrombotic diseases (Trends in Pharmaclogical Science 13, 413, 1992). Connection-antagonists GP11b/IIIa include monoclonal antibodies (Ann. New York Acad. spodnie of lidinopril (J. med. Chem., 35, 4393, 1992, Japanese patent laid publication N 264068/1992, 334351/1992, EP-483667, EP-502536, EP-525629, EP-29858, EP-537980, WO-9307867 and WO-9402472), derivatives of tyrosine (J. med. Chem., 35, 4640, 1992) and the derivatives of piperidine (EP-512831, EP-5403344 and EP-578535).

It is also desirable to create such a remedy, which would not have such side effects as hemorrhage, and would be very selective action as a therapeutic or preventive agent for combating thrombotic diseases.

The essence of the invention.

The authors of the present invention have found that some type of compounds is an antagonist of GPIIb/IIIa.

Thus, an object of the present invention are novel compounds inhibiting platelet aggregation.

Another object of the invention is a pharmaceutical composition containing a new connection with the above action.

The next object of the invention is a method of treatment or method of prevention of thrombotic diseases, which includes the introduction of a new connection with the specified activity.

Another object of the invention is the use of a new connection with the specified the ical disorders.

The compound of the present invention represented by formula (I):

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or its pharmaceutically acceptable salt or MES, where A, B and C independently represent CH2or C=O;

X and Y differ from each other and each represents CH or N;

D represents -(CH2)k- or -(CH2)m-CO (where k is an integer from 1 to 4 and m is an integer from 0 to 3)

E represents the following group (II) or (III):

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where n is an integer from 1 to 3, and Z represents-W-(CH2)p-COOR3(where W represents-O - or a bond, P is an integer from 1 to 4, and R3represents hydrogen, lower alkyl or ester fragment that can be removed under physiological conditions),

R1represents hydrogen or lower alkyl, in which at least one hydrogen atom may be substituted by hydroxyl, halogen, amino, lower alkylamino or imino, or lower alkyl substituted-2-oxadiazol-4-yl group,

R2represents hydrogen, lower alkyl, in which at least one hydrogen atom may be substituted by hydroxyl, halogen, amino, carboxyla, lower alkoxy, lower alkylamino or lower alkoxycarbonyl; phenyl, in which the hydroxy, lower alkylamino, lower alkoxycarbonyl or halo lower alkyl; or phenyl-lower alkyl in which at least one hydrogen atom of this phenyl group may be substituted by hydroxyl, halogen, amino, carboxyla, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or halogen-lower alkyl.

Detailed description of the invention

The compound of formula (I)

The term "lower alkyl" as a group or part of a group is meant here a branched or unbranched alkyl chain containing from 1 to 6, preferably from 1 to 4 carbon atoms. The term halogen atom means fluorine, chlorine, bromine or iodine. In addition, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms replaced by an atom or halogen atoms.

In the formula (I), A, B and C each represents CH2or C = O. In accordance with a preferred variant of the present invention, a compound in which A represents C = O, and the others represent CH2group, is preferred. In accordance with another alternative preferred is a compound in which two of A, B and C represent groups C = O, and the remaining alapochicola is the connection, in which X represents CH and Y represents n

In the formula (I), D represents -(CH2)k- (where k is an integer from 1 to 4, preferably 1 or 2), or -(CH2)m-CO- (where m is an integer from 0 to 3, preferably from 1 to 3, more preferably 1 or 2). D preferably represents -(CH2)m-CO-, and more preferably, -CH2-CO.

E represents the group (II) or (III). In group (II) or (III) n preferably is 1 or 2. That is, the number of substituents Z preferably is 1 or 2. The position of the substituent Z, preferably, is a para-position or meta-position relative to D.

In the group-W-(CH2)p-COOR3presented Z, W preferably represents-O-, p is preferably equal to 1 or 2, and R3preferably is a hydrogen or C1-4the alkyl (e.g. methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, or tert-butyl). Preferred examples of the ester residue represented by R3that can be removed under physiological conditions, includes pivaloyloxymethyl, 1-(cyclohexyloxycarbonyl)and ethyl (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

In the formula (I) R1

R2represents a hydrogen atom, a lower alkyl group, phenyl group or phenyl-lower alkyl group. At least one hydrogen atom in this lower alkyl group may be substituted. Preferred examples of such a substituent include a hydroxyl group, a halogen atom (preferably chlorine, bromine or fluorine), amino group, carboxyl group, lower alkoxygroup (preferably, methoxy, ethoxy, n-propoxy or isopropoxy), lower alkylamino (preferably methylamino, ethylamino, propylamino, dimethylamino or diethylamino), or lower alkoxycarbonyl group (preferably, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl). In addition, at least one hydrogen atom of the phenyl group may be substituted. Preferable examples of such a substituent include a hydroxyl group, an atom edocfile, methoxy, ethoxy, n-propoxy or isopropoxy), lower alkylamino (preferably methylamino, ethylamino, propylamino, diethylamino or dimethylamino), low alkoxycarbonyl group (preferably, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl or ISO-propoxycarbonyl), or halo-lower alkyl group (preferably trifluoromethyl or triptorelin). In addition, at least one hydrogen atom of the phenyl radical, the phenyl-lower alkyl group (preferably, benzyl, 2-phenylethyl, 3-phenylpropyl) may be substituted. Preferred examples of such a substituent include hydroxyl group, halogen atom (preferably chlorine, bromine or fluorine), amino group, carboxyl group, lower alkoxygroup (preferably, methoxy, ethoxy, n-propoxy or isopropoxy), lower alkylamino (preferably methylamino, ethylamino, propylamino, dimethylamino or diethylamino), or lower alkoxycarbonyl group (preferably, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl or ISO-propoxycarbonyl) or halo-lower alkyl group (preferably trifluoromethyl or triptorelin).

Preferred examples of the compounds represented BR> [[4-[[4-piperazine-4-yl)-piperidine-1-yl]acetyl]-o-phenylene]-dioxy]diuksusnoi acid,

4-[[4-piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]Phenoxyethanol acid,

diethyl[[4-[[4-piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl] -o-phenylene] dioxy]diacetate,

n-butyl-4-[[4-[piperidine-4-yl)-2,6-dioxopiperidin-1-yl]acetyl]-phenoxyacetate,

4-[[4-piperidine-4-yl)-2,6-dioxopiperidin-1-yl] acetyl] Phenoxyethanol acid,

n-butyl-4-[[4-(piperidine-4-yl)-3,3-dioxopiperidin-1-yl]acetyl]phenoxyacetate,

4-[[4-piperidine-4-yl)-2,3-dioxopiperazinyl-1-yl] acetyl] Phenoxyethanol acid,

n-butyl-4-[[4-(piperidine-4-yl)-2,5-dioxopiperazinyl-1-yl]acetyl]phenoxyacetate,

4-[[4-piperidine-4-yl)-2,5-dioxopiperazinyl-1-yl] acetyl] Phenoxyethanol acid,

n-butyl-4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]phenoxyacetate-dihydrochloride and

ethyl-4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]-phenoxyacetate.

The compound of the present invention can exist in salt form. Such salt includes pharmacologically acceptable non-toxic salt. Preferred examples of the salts include inorganic salts such as sodium salt, potassium salt, magnesium salt, calcium salt, salt accession acids, such as triptonic">

The compound of the present invention may be in the form of MES. MES, preferably, includes hydrate and ethanolate.

Obtaining the compounds represented by formula (I)

The compound of the present invention can be obtained in the following ways:

The following methods can be used protective group for amino groups, which are usually used in peptide synthesis. Preferred examples of the protective group include tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzenesulfonyl, 2,2,2-trichlorocyanuric, TRIFLUOROACETYL, allyloxycarbonyl, trityl. In addition, the following processes mono to apply a protective group for the carboxyl group, which is usually used in peptide synthesis. Preferred examples of the protective group include methyl, ethyl, tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl.

Method (A)

The compound represented by formula (I), where X is CH and Y is N, can be obtained in accordance with the stages presented in figure A.

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where R4is R1or a protected amino group,

R5represents a hydrogen atom or a protective or iodine), the lower alkylsulfonates (for example, methanesulfonate), tripterocalyx or arylsulfonate group (for example, p-toluensulfonate), and

A, B, C, R2, D, Z and n have the above values.

At stage (i), the compound of formula (IV) and the compound of formula (V) is subjected to reductive alkylation in an inert solvent (such as THF, dichloromethane, 1,2-dichloroethane, dioxane or DMF) to obtain the compounds of formula (VI). Therefore, reductive alkylation, you can use metal hydrides, such as laborgerate, laborgerate, borgerende, borhydride and triacetoxyborohydride. You can also use catalytic reduction catalyst such as palladium-on-charcoal, palladium black, palladium hydroxide, platinum oxide and Raney Nickel. The reaction can be conducted at temperatures from - 20oC to 100oC, preferably from 0 to 70oC for from 0.5 to 48 hours, preferably from 1 to 24 hours.

If R5in the compound of formula (VI) represents a protective group for the amino group, this protective group is removed in stage (ii).

At stage (iii), the compound of formula (I) is produced by the interaction Conn is olwal, xylene, 1,2-dichloroethane, DMF or dioxane), and, if necessary, removing the protective group. Examples of bases include sodium metal, sodium hydride, calcium hydride, lithium hydride, sodium amide, potassium carbonate, sodium hydroxide, potassium hydroxide, n-utility and sitedisability. If necessary, together with the reason it is possible to use a phase transfer catalyst (for example, tetraalkylammonium). The reaction can be conducted at a temperature of from -80oC to 150oC, preferably from -50oC to 120oC for from 0.5 to 72 hours, preferably from 0.5 to 36 hours.

The compound represented by formula (V) can be synthesized according to the method described in Bull. Chem. Soc. Jap., Vol. 46, p. 3612 (1973), and in EP 529858.

Method (B)

The compound represented by formula (I), where X is N and Y is CH, can be obtained in accordance with the stages presented in figure B.

Scheme IN

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where R4and R5have these values, and A, B, C, and R2also defined above. The interaction of the compounds of formula (IX) with the compound of the formula (X) at stage (i) can be carried out in the same conditions as in stage (i) of scheme A. in Addition, BR>
The compound represented by formula (I) where Z represents the group (III) can be obtained in accordance with the stages presented in figure C.

Scheme C

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where R6is R3or a protective group for carboxyl group, A, B, C, m, Z and n have the meanings specified for formula (I), and R4matter listed for diagrams A.

At stage (i) interaction of the compounds of formula (VII) or the compounds of formula (VII) with the compound of the formula (VIII) can be performed in the presence of a base in the same manner as the reaction of stage (iii) of scheme A.

If R6in the resulting compound of formula (XIV) represents a protective group for the carboxyl group, the protective group is removed in stage (ii).

At stage (iii), the compound of formula (XV) is subjected to interaction with the compound of the formula (XVI) in the presence of an agent activating the carboxylic acid to obtain the amide bond. The use of agents that activate the carboxylic acid include thionyl chloride, phosphorus oxychloride, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium and hexaphosphate.

Method (D)

The connection represented by formulait in accordance with the following stages of the schema D:

Scheme D

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where R4has the scheme A value.

At stage (i), the compound of formula (IV) and the compound of formula (XVII) is subjected to reductive alkylation in the presence of acid (or not) in an inert solvent (for example, THF, dichloromethane, 1,2-dichloroethane, dioxane or DMF) to obtain the compounds of formula (XVIII). In this way you can use the reagents reductive alkylation, which is used in stage (i) of scheme A. the Reaction can be conducted at temperatures from -20oC to 100oC, preferably from 0 to 70oC for from 0.5 to 48 hours, preferably from 1 to 24 hours.

At stage (ii), the compound of formula (I) are obtained in the interaction of the compounds of formula (XVIII) with the compound of the formula (VIII) in the presence of a base in an inert solvent (such as DMF, acetone, acetonitrile, dichloromethane, THF or dioxane), and, if necessary, remove the group. In this way you can also use the base that is used in stage (iii) of scheme A. the Reaction is conducted at temperatures from -78oC to 100oC, preferably from -30oC to 50oC for from 0.5 to 48 hours, preferably from 0.5 to 12 hours.

The connection represented by FD>/BR>The compound represented by formula (I), where X represents CH, Y represents N, A represents CH, and B and C each represent C=O, can be obtained in accordance with the following stages of schema E:

Scheme E

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where R7represents a protective group of amino group,

R8represents a hydrogen atom or a group of the lower alkyl (e.g. methyl, ethyl, n-propyl or n-butyl),

Hal represents a halogen atom (e.g. chlorine, bromine or iodine), and R4has the scheme A value.

At the stage of (i) the interaction of the compounds of formula (IV) with the compound of the formula (XIX) can be carried out in the same way as in stage (i) of scheme D

At stage (ii), the compound of formula (XX) is subjected to interaction with the compound of the formula (XXI) in the presence of a base (or not) in an inert solvent (e.g. dichloromethane, THF, dioxane or acetonitrile) to give the compounds of formula (XXII). Examples of bases that can be used in this reaction include pyridine, triethylamine, N-methylmorpholine and dimethylaminopyridine. The reaction can be at a temperature of from -50oC to 100oC, preferably from -20oC to 80oC during the period of time from 10 minutes to 24 hours, preferably the s amino group to obtain the compounds of formula (XXIII). The reaction can be conducted at temperatures from -20oC to 100oC, preferably from 0 to 80oC for 0.5 to 48 hours, preferably from 1 to 24 hours.

Then, the thus obtained compound of formula (XXIII) can be subjected to interaction with the compound of the formula (VIII) in the same way that you specified earlier stage (i) obtaining the compounds of formula (I).

The compound of formula (XIX) can be synthesized according to the method described in synthesis, p. 1032 (1984).

Method (F)

The compound represented by formula (I), where X represents CH, Y is N, A and B each represent C=O, and B is CH, can be obtained in accordance with the methods presented in the subsequent stages of the scheme F.

Scheme F

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where L represents a halogen atom (e.g. chlorine, bromine or iodine), lower alkylsulfonate (for example, methanesulfonate) or arylsulfonate (for example, p-toluensulfonate), and R7and R8have you specified for the schema E.

At the stage of (i) the interaction of the compounds of formula (IV) with the compound of the formula (XXIV) can be performed in the same way, and that way stage (i) of scheme D.

At stage (ii) compounds is nerton solvent (for example, DMF, dichloromethane, acetonitrile, THF or dioxane) to give the compounds of formula (XXVII). Examples of bases that can be used in this reaction include those that can be used in stage (iii) of scheme A. the Reaction can be conducted at temperatures from -20oC to 100oC, preferably from 0 to 80oC for from 0.5 to 48 hours, preferably from 1 to 24 hours.

The compound of formula (XXVII) may be subjected to interact in the same way as in stage (iii) of scheme E, to obtain the compounds of formula (XXVIII).

Thus obtained compound of formula (XXIII) may then interact with the compound of the formula (VIII) in the same way as in stage (iv) of scheme E to obtain the compounds of formula (I).

In each of these specialists should be clear that the sequence of synthesis can be chosen in such a way as to avoid adverse reactions with functional groups that do not pertain to the basic reactions, and that functional groups can be protected with appropriate protective groups, in order to eliminate such adverse reactions.

The use of compound/pharmaceutical composition

The connection is truly izaberete and fibrinogen. Thus, the connection of the present invention and its pharmacologically acceptable salt is effective in the treatment and prevention of thrombotic diseases caused by platelet aggregation, especially in therapy of brain, myocardial infarction, angina, or peripheral arterial occlusive disease.

The pharmaceutical composition containing the compound of the present invention or its pharmacologically acceptable salt as an active ingredient, can be administered to humans or animals in any way, for example, orally or parenterally, e.g. by intravenous injection, intramuscular injection, subcutaneous, rectal or through the skin.

Therefore, the pharmaceutical composition comprising the compound of the present invention are in the form of suitable dosage forms, depending on the method of application, and it can be particularly obtained in the form of drugs, which mainly include injections or drugs for oral administration such as capsules, tablets, granules, powders, pills, granules or tablets, preparations for rectal administration, oil suppositories or water suppositories.

Such drugs can prigerson, surface-active agent, lubricant, buffer, preservative, and agents that promote dissolution, antiseptics, perfumes, analgesics or stabilizers. The above are acceptable and non-toxic additives include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, magnesium stearate, methylcellulose, or their salts, gum Arabic, polyethylene glycol, syrup, vaseline, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite and sodium phosphate.

The compound of the present invention are presented in the pharmaceutical composition in a quantity which depends on the dosage forms, and is usually from about 1 to 70 wt.%, preferably, from about 5 to 50 wt.% the whole composition.

The dose is usually determined taking into account the application, age, sex and severity of the patient's condition. The usual dose is in the range of from about 0.1 to 1000 mg, preferably from 1 to 200 mg / day for adult patients in the treatment of thrombotic diseases. These doses can be entered at once or in several portions a day.

Further, the present invention is described in more detail with reference to examples, but these examples in no way limit the scope of usnei acid triptorelin

(a) a Mixture of 1-tert-butoxycarbonyl-4-oxopiperidine (2,985 g) and 2-oxopiperidine (1.5 g) is dissolved in 25 ml of methanol, and then add molecular sieves 3 angstroms (2.5 g) and 1 H. ethanol-hydrochloric acid (2.5 ml), then stirred for 45 minutes. 945 ml cyanoborohydride divided into three parts and successively added to the solution under ice cooling, and then stirred for 5 hours at room temperature. After the insoluble portion is removed by using sellaite, the obtained filtrate is concentrated. To the obtained residue, add a saturated solution of sodium bicarbonate, and extracted with ethyl acetate. An ethyl acetate layer was washed with saturated saline solution and then dried over magnesium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (300 g, eluent chloroform:methanol 30:1 to 10:1) to obtain 1,448 g 4/1-tert-butoxycarbonylamino-4-yl/-2-oxopiperidin.

1H NMR (CDCl3) : of 1.42 (2H, m) of 1.46 (9H, s), of 1.80 (2H, Shir), 2,46 (1H, TT, J = 3,6, 11.2 Hz), 2,7-2,8 (4H), of 3.27 (2H, s) to 3.35 (2H, TD, J = 3,0, 5,2 Hz), of 4.12 (2H, Shir.C) the 6.06 (1H, s).

E1M (m/Z: 283 (M+) (Mass spectrometry electron impact)

(b) a Mixture of sodium (35 mg) and toluene (10 ml) is heated to a temperature of 110 - 120 is e in (a), and the resulting solution was heated to boiling under reflux for 3 hours. After cooling to about 60oC add di-tert-butyl[(4-chloroacetyl-o-phenylene)dioxy]diacetate (1 g) and the solution heated to boiling under reflux for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate, washed with water, and then dried over magnesium sulfate. After evaporation of the solvent the residue is purified on a chromatographic column with silica gel (50 g, chloroform: methanol = 50:1) to give 116 mg of di-tert-butyl-[[4-[[4-(1-tert-butoxycarbonylamino - 4-yl)-2-oxopiperidin-1-yl] acetyl]-o-phenylene]dioxy]diacetate.

1H-NMR (CDCl3) : of 1.46 (9H, s) of 1.47 (9H, s) to 1.48 (9H, s), of 1.65 (2H, m), equal to 1.82 (2H, Shir.D.), 2,47 (1H, m) of 2.75 (2H, m), 2,84 (2H, m) to 3.36 (4H, m), 4,13 (2H, Shir. C), with 4.64 (2H, s), and 4.68 (2H, s), was 4.76 (2H, s), PC 6.82 (1H, d, J = 8,3 Hz), of 7.48 (1H, d, J = 1.9 Hz), 7,60 (1H, DD, J = 1,9, 8,3 Hz).

EIMS (m/Z): 661 (M+).

(c) Compound (115 mg), obtained earlier in (b), add to the mixture triperoxonane acid (1.5 ml) and anisole (0.1 ml), and the reaction is carried out at room temperature for 2 hours. Add 10 ml of diisopropyl ether under ice cooling, and the resulting precipitate is collected by filtration and then dried, resulting in a gain of 1, ,15 (2H, Shir.d), 2,78 (1H, Shir.t), 2,90 (2H, Shir.t), totaling 3.04 (2H, m), 3,39 - 3,51 (6H), with 4.64 (2H, s), and 4.68 (2H, s), equal to 4.97 (2H, s), 7,01 (1H, d, J = 8,4 Hz), 7,45 (1H, s) 7,743 (1H, d, J = 8,4 Hz).

SIMS (m/Z): 450 (M++1) (Mass spectrometry of secondary ions).

Example 2

Triptorelin[[1-[4-[piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl]piperidine-4-yl]-octoxynol acid

(a) Repeating the procedure of example 1 (b), except that di-tert-butyl-[[4-chloroacetyl-o-phenylene)dioxy] diacetate replace ethylbromoacetate to obtain [4-(1-tert-butoxycarbonylamino-4-yl)-2-oxopiperidin-1-yl]acetate.

1H-NMR (CDCl3) : of 1.28 (3H, t, J=7.2 Hz), of 1.40 (2H, m) of 1.46 (9H, s), of 1.80 (2H, Shir.d), of 2.45 (1H, m), is 2.74 (2H, Shir.t), 2,82 (2H, Shir.t), of 3.33 (2H, s), 3,39 (2H, t, J = 5.4 Hz), of 4.12 (2H, s), 4,20 (2H, square, J = 7,2 Hz).

EIMS (m/z): 369 (M+).

(b) Compound (360 mg) obtained in (a), dissolved in 5 ml of ethanol, and add 1 n sodium hydroxide solution (1.5 ml) and then stirred at room temperature for 3 hours. After the reaction solution is concentrated and water is added, and the pH of the solution set to 4.0 with 1 N. hydrochloric acid. Then the solution lyophilizer obtaining hydrochloride [4-(1-tert-butoxycarbonylamino-4-yl)-2-oxopiperidin-1-yl] acetic acid (349 mg). This product is C), a 2.12 (2H, Shir. d), 2,87 (2H, Shir.t), 3,42 (1H, Shir.t), 3,55 (2H, Shir.t) to 3.67 (2H, Shir.t) to 3.89 (2H, s), of 4.00 (2H, s), 4,18 - 4,27 (2H, Shir.C).

(c) Compound (151 mg), obtained earlier in (b), dissolved in 3 ml of methylene chloride and to the solution was added 1-hydroxybenzotriazole and benzotriazol-1-yloxytris(dimethylamino)phosphodiesterase (195 mg) and then stirred for 50 minutes. Then add tert-butyl-4-piperidineacetate (90 mg) in 2 ml of methylene chloride, and diisopropylethylamine (0,14 ml) and the solution stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, and then dried over magnesium sulfate. After the solvent is evaporated, the obtained residue is purified on a column of silica gel (30 g, chloroform:methanol=30:1) to give 170 mg of tert-butyl[[1-[4-[1-tert-butoxycarbonylamino-4-yl)-2 - oxopiperidin-1-yl]acetyl]piperidine-4-yl]oxoacetate.

1H NMR (CDCl3) : USD 1.43 (2H, m) of 1.46 (9H, s) to 1.48 (9H, s), 1.69 in (2H, m), 1.77 in-1,95 (4H, m) 2,44 (1H, m), is 2.74 (2H, Shir.t), 2,82 (2H, m), 3,23 is-3.45 (6H), 3,62-3,71 (2H, m), a-3.84 (1H, m), 3,98 (1H, d, J = 15.2 Hz), was 4.02 (1H, d, J = 15.2 Hz), 4,08 (1H, d, J = 15.7 Hz), of 4.12 (2H, Shir.C.), or 4.31 (1H, d, J = 15.7 Hz),

EIMS (m/Z): 538 (M+).

(d) the Compound obtained previously in (C), is treated in the same manner as in example 1 (C2,50 (2H, Shir. d), 3,11 - 3,24 (4H, m), and 3.31 (1H, m), 3,66 - a 3.87 (8H), of 4.00 (1H, m), 4,17 (2H, s), 4,28 (2H, s), to 4.46 (2H, s),

Example 3

Triptorelin [[4-[[4-(piperidine-4-yl)piperazine-1-yl]acetyl]-o-phenylene] dioxy]- luxusni acid

(a) According to the method of example 1(a), except using 1-tert-butoxycarbonyl-4-oxopiperidin and 1-benzylpiperazine, get 1-benzyl-4-/1-tert-butoxycarbonylamino-4-yl/piperazine.

1H NMR (CDCl3) : to 1.38 (2H, m) of 1.45 (9H, s), of 1.80 (2H, Shir.D.), of 2.35 (1H, m), 2.40 a - 2,75 (10H) to 3.50 (2H, s), of 4.12 (2H, Shir.C.), 7,30 (5H, m)

EIMS (m/Z): 359 (M+).

(b) Connection (2,75 g) obtained in (a), dissolved in 50 ml of methylene chloride, and added to the solution under ice cooling 1,91 g of sodium bicarbonate and 2,04 ml benzylchloride. The mixture is then stirred at room temperature and add benzylchloride in the amount of 0.8 ml after 4 hours and in the amount of 1.0 ml within 9 hours, and then continue to stir over night. The reaction solution was diluted with ethyl acetate, washed with water, and then dried over magnesium sulfate. After the solvent is evaporated, the residue is purified on a chromatographic column with silica gel (120 g, chloroform ---> chloroform: ethyl acetate = 1:4) to give 1-benzyloxycarbonyl-4-(1-tert-butoxycarbonylamino.t), 3,51 (4H, m), of 4.12 (2H, Shir.C) to 5.13 (2H, s), 7,37 (5H, m).

(c) Compound (1.0 g) obtained earlier in (b), dissolved in 5 ml of ethanol, and then to the solution was added 1 n solution of ethanol-hydrochloric acid (5 ml) and palladium black (50 mg). Catalytic reduction is carried out at atmospheric pressure for 3 hours. After removal of the spent catalyst by filtration, the obtained filtrate is concentrated. The resulting residue is dissolved in water and the pH of the solution was adjusted to 8 using ion-exchange resin Amberlite JR-45 (OH-). After removing the resin by filtration, the filtrate is concentrated. The resulting residue is purified by chromatographic column with silica gel (30 g, 1% Triethylenetetramine a mixture of chloroform:methanol = 20: 1 ---> 2% Triethylenetetramine a mixture of chloroform:methanol = 10:1) to obtain 277 mg of 4-/1-tert-butoxycarbonylamino-4-yl)piperazine.

1H NMR (CDCl3) : of 1.40 (2H, m) of 1.45 (9H, s) of 1.76 (2H, Shir.D.), the 2.46 (1H, m), 2,69 (2H, Shir.t), 2,82 (4H, m), 3,17 (4H, m), of 4.12 (2H, Shir.S.),

EIMS (m/Z): 269 (M+).

(d) Compound (135 g), obtained earlier in (c), dissolved in 2 ml DMF and the resulting solution was added 138 mg of potassium carbonate and 275 mg of di-tert-butyl-[[4-chloroacetyl-o-phenylene] dioxy]diacetate, and then stirred for 4 the e evaporation of the ethyl acetate the residue is purified on a chromatographic column with silica gel (chloroform:methanol = 40:1) to give 213 mg of di-tert-butyl-[[4-[[4-[1-tert-butoxycarbonylamino-4-yl]piperazine - 1-yl]acetyl]-o-phenylene]dioxy]diacetate.

1H NMR (CDCl3) : to 1.38 (2H, m) of 1.45 (9H, s) of 1.47 (9H, s) to 1.48 (9H, s), equal to 1.82 (2H, Shir. d), is 2.37 (1H, m), 2,55 was 2.76 (10H), 3,74 (2H, s), of 4.13 (2H, Shir. C), with 4.64 (2H, s), of 4.67 (2H, s), to 6.80 (1H, d, J = 8.5 Hz), 7,53 (1H, d, J= 8.1 Hz), to 7.64 (1H, DD, J = 1,8, 8.5 Hz),

EIMS (m/Z): 647 (M+).

(e) the Compound obtained previously in (d), is treated in the same way as in example 1 (c) obtaining specified in the connection header.

1H NMR (D2O) : 1,97 (2H, m), 2,46 (2H, Shir.d) and 3.15 (2H, Shir.t), 3,51 - 3,72 (9H), is 4.85 (2H, Shir.C) a 4.86 (2H, s), to 4.87 (2H, s), 4,91 (2H, s), 7,10 (1H, d, J = 8.6 Hz), 7,51 (1H, s), of 7.69 (1H, d, J = 8.6 Hz),

SIMS (m/Z): 435 (M++ 1).

Example 4

Diethyl-[[4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl]-o-phenylene] dioxy]diacetate

According to the method of example 1 (b) and (c), except that di-tert-butyl-[[4-chloroacetyl-o-phenylene] dioxy] diacetate substituted diethyl-[[4-chloroacetyl-o-phenylene)dioxy]diacetate, get specified header connection

1H NMR (D2O) : to 1.31 (3H, t, J = 7 Hz), 1,32 (3H, t, J = 7 Hz), from 2.00 (2H, m), 2,47 (2H, Shir.d) 3,18 (2H, Shir.t), 3,55 is 3.76 (7H, m), a 4.03 (2H, s) to 4.33 (4H, square, J = 7 Hz), 4,96 (2H, s), free 5.01 (2H, s), of 5.05 (2H, s), 7,14 (1H, d, J = 8 Hz), to 7.59 (1H, s), 7,79 (1H, d, J = 8 Hz),

SIMS (m/Z): 506 (M++ 1).

Example 5

4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl]venexiana acid

According to the method of example 1 (b) and (c), for phenoxyacetate, get listed at the beginning of the connection.

1H NMR (CD3OD) : 1,85 - of 1.95 (2H, m), 2,27 - of 2.30 (2H, m), 3,05 - 3,11 (2H, m), 3.15 and 3.21 - in (1H, m), 3,40 - of 3.42 (2H, m), of 2.51 - of 3.60 (4H, m), and 3.72 (2H, s), rate 4.79 (2H, s), is 4.93 (2H, s), 7,06 (2H, d, J = 8,9 Hz), 8,01 (2H, d, J = 8,9 Hz),

SIMS (m/Z): 376 (M++ 1).

Example 6

Triptorelin [[1-[4-(piperazine-4-yl] piperidine-1-yl]acetyl]piperidine-4-yl]exucuse acid

According to the method of example 2 (b) and (c), except that [4-[1-tert-butoxycarbonylamino-4-yl)-2-oxopiperidin-1-yl] acetic acid hydrochloride are substituted [4-[4-tert-butoxycarbonylmethyl-1-yl)piperidine-1-yl] acetic acid, receive specified in the title compound.

1H NMR (CD3OD) : 1,60 - of 1.73 (2H, m), 1,84 is 1.96 (3H, m), 2,10 - of 2.20 (2H, m), 2,68 - of 2.97 (4H, m), 3,05 - 3,30 (7H, m), 3,42 - of 3.48 (2H, m), 3,55 - 3,62 (2H, m), 3,67 of 3.75 (2H, m), 3,80 - are 3.90 (2H, m) to 4.16 (2H, s), 4,24 (2H, s).

SIMS (m/Z): 369 (M++ 1).

Example 7

The hydrochloride of n-butyl-4-[[4-(piperidine-4-yl)-2,6-dioxopiperidin-1-yl]acetyl]-phenoxyacetate

(a) a Mixture of 1-tert-butoxycarbonyl-4-oxopiperidine (9,06 g) and 2,6-dioxopiperidin (3,99 g) dissolved in 1,2-dichloroethane (170 ml) and the resulting solution was added 20 ml of acetic acid and make up 9.64 g triacetoxyborohydride sodium, and then stirred at room temperature for Anat sodium to neutralize the acetic acid. The reaction solution was poured into a separating funnel to separate the aqueous and organic layers. The aqueous layer was extracted with chloroform and then extracted organic layer combined with previously allocated organic layer. The combined organic layers washed with saturated saline and then dried over sodium sulfate. After evaporation of the solvent the residue is purified on a chromatographic column with silica gel (350 g, chloroform ---> chloroform: methanol = 60:1) to obtain crystals. Then to crystals add n-hexane, and the crystals are collected by filtration to obtain 6,46 g (62%) of 4-(1-tert-butoxycarbonylamino-4-yl)-2,6-dioxopiperidin.

1H NMR (CDCl3) : 1,35 - 1,52 (11H), or 1.77 (2H, Shir.d), 2,58 (1H, TT, J = 3,6, and 11.4 Hz), 2,73 (2H, Shir.t) of 3.46 (4H, s) to 4.15 (2H, Shir.C) 8,02 (1H, s).

EIMS (m/Z): 297 (M+).

(b) Compound (3.57 g), obtained earlier in (a), dissolved in 60 ml of dimethylformamide, and the resulting solution was added sodium hydride (60% oil suspension, 0,72 g), and then it is stirred for 10 minutes. To the reaction solution was added n-butyl-4-bromotetradecane (a 4.53 g) in 25 ml of dimethylformamide under ice cooling, and then stirred for 3 hours. To the reaction process is TAROM, and then dried over sodium sulfate. After the solvent is evaporated, the residue is purified on a chromatographic column with silica gel (250 g, hexane: ethyl acetate = 1:1) obtaining of 4.67 g (71%) of n-butyl-4-[[4-[1-tert-butoxy-carbonitriding-4-yl)-2,6-dioxopiperidin-1-yl] acetyl]phenoxyacetate.

1H NMR (CDCl3) : of 0.93 (3H, t, J = 7.4 Hz), 1.30 and 1,53 (13H), 1,56 is 1.70 (2H, m), 1,83 (H, Shir.d) of 2.64 (1H, TT, J = 3.3V, 11.3 Hz), 2,77 (2H, Shir.t), of 3.64 (4H, s) to 4.16 (2H, Shir.C), 4,22 (2H, t, J = 6,7 Hz), 4,70 (2H, s), 5,14 (2H, s), 6,97 (2H, d, J = 9.0 Hz), 7,95 (2H, d, J = 9.0 Hz),

EIMS (m/Z): 545 (M+).

(c) To the compound (4,67 g) obtained earlier in (b), add 7 ml of anisole and 20 ml triperoxonane acid and 10 ml of methylene chloride, and then stirred at room temperature for 1 hour. To the reaction solution was added water, and then neutralized with sodium bicarbonate. After evaporation of the solvent, to the residue water is added and extracted with ethyl acetate. The obtained extract is dried over sodium sulfate and the solvent is evaporated. The obtained residue is purified on a chromatographic column with silica gel (200 g, chloroform: methanol= 10:1 to 7:1) to give pale yellow crystals (4.15 g). These crystals are used in hydrolytic reactions following example 8. On the other hand, 1.02 minutes under ice cooling, thus equalising through a solution of gaseous hydrogen chloride. After stirring at room temperature for a further 1 hour the solvent is evaporated. To the obtained residue is added ether, the crystals are filtered, resulting in a gain 0,618 g (52%) specified in the connection header.

1H NMR (D2O) : from 0.76 to 0.85 (3H, m), 1,16 - of 1.29 (2H, m), 1,50 - of 1.62 (2H, m), 1,65 - to 1.79 (2H, m) of 2.16 (2H, Shir.d), 2,94 - 3,10 (3H), 3,52 (2H, Shir. d), 3,74 - a 3.87 (4H, m), 4,15 - 4.23 (2H, m), 4.80 to 4,89 (2H, m), 5,20 is 5.28 (2H, m), 6.90 to - to 7.09 (2H, m), 7,93 - 8,03 (2H, m).

EIMS (m/Z): 445 (M+).

Example 8

Hydrochloride 4-[[4-(piperidine-4-yl)-2,6-dioxopiperidin-1-yl]acetyl]phenoxyalkanoic acid

Pale yellow crystals (0.312 g) obtained in example 7 (c), while cooling with ice, add 7 ml of 5 N. hydrochloric acid and the resulting solution was stirred for 16 hours, warming to room temperature. After evaporation of the solvent, the obtained residue is purified using column high pressure (150 ml water and 5% aqueous acetone), and then lyophilizer obtaining 0,103 g (35%) specified in the connection header.

1H-NMR (D2O) : 2.57 m) - by 2.73 (2H, m), 2,10 (2H, Shir.d), 2,84 - 3,03 (3H), of 3.45 (2H, Shir.d), 3,74 (4H, s), 4,50 (2H, s), a total of 5.21 (2H, s), of 6.96 (2H, d, J = 8,8 Hz), 7,94 (2H, d, J = 8,8 Hz).

EIMS (m/Z): 389 (M
(a) According to the method of example 1(a) except that 2,6-dioxopiperidin replace hydrochloride N-benzyloxycarbonylamino gain of 14.7 g (87%) of N-benzyloxycarbonyl-N'-1-tert-butoxycarbonylamino-4-yl)Ethylenediamine.

1H-NMR (CDCl3) : 1,13 - of 1.27 (2H, m) of 1.45 (9H, s), is 1.81 (2H, Shir.d), 2,52 - 2,63 (1H, m) 2,44 (1H, m), is 2.74 (2H, Shir.t) 2,82 (2H, m), 2,70 - of 2.86 (4H, m), 3,22 of 3.28 (2H, m) 4,00 (2H, Shir.C.), at 5.10 (2H, s), 5,19 (1H, Shir.C.), 7,29 - 8,29 (5H, m).

EIMS (m/Z): 377 (M+).

(b) Compound (10.6 g), obtained earlier in (a), dissolved in 140 ml of methylene chloride and to the solution was added to 4.7 ml of triethylamine. Then add 3,1 ml of etylchlorhydrine under ice cooling, and then stirred for 30 minutes. To the reaction solution was added 140 ml of water under ice cooling and the reaction solution was poured into a separating funnel to separate the aqueous and organic layers. The aqueous layer was extracted with chloroform and extracted the organic layer is combined with the previously formed organic layer. The combined organic layers washed with water, saturated sodium bicarbonate solution and dried over sodium sulfate. After evaporation of the solvent the residue is purified on a chromatographic column with silica gel (300 g, hexane:etelaat is noslicinata.

1H-NMR (CDCl3) : of 1.36 (3H, t, J = 7.2 Hz), of 1.47 (9H), 1,69 of - 1.83 (4H, m), 2,55 - 2,82 (2H, m), 3,37 - 3,50 (5H), 4.09 to 4,30 (2H, m), 4,36 (2H, square, J = 7,2 Hz), 5,10 (2H, s), a total of 5.21 (1H, Shir.C) to 7.35 (5H, s).

FDMS (m/Z): 478 (M++1) (mass spectrometry with a field desorption).

(c) Connection (8,12 g) obtained earlier in (b), dissolved in 85 ml of ethanol and to the solution was added 270 mg of 10% palladium on charcoal, and then conduct catalytic reduction at atmospheric pressure for 4 hours. After the catalyst was removed by filtration, the solvent is evaporated, resulting in a gain 6,76 g of 4-(1-tert-butoxycarbonylamino-4-yl)-2,3-dioxopiperazinyl. This product is used in subsequent reactions without further purification.

1H-NMR (CD3OD) : of 1.46 (9H, s), 1.60 - to around 1.74 (4H, m), of 2.86 (2H, Shir.C), 3,41 - 3,47 (2H, m), 3,49 - 3,55 (2H, m), 4,20 (2H, Shir. d), 4,43 - a 4.53 (1H, m)

EIMS (m/Z): 297 (M+).

(d) According to the method of example 7 (b), except that 4-/1-tert-butoxycarbonylamino-4-yl/-2,6-dioxopiperidin replace the compound obtained previously in (c), receive 2,59 g n-butyl-4-[[4-[1-tert-butoxycarbonylamino-4-yl/-2,3-dioxopiperazinyl-1-yl]-acetyl]phenoxyacetate. (The product yield from the compound obtained previously in (b), 59%).

1H-NMR (CDCl3) : 0,93 (3), is 4.93 (2H, s), 6,97 (2H, d, J = 9.0 Hz), 7,94 (2H, d, J = 9.0 Hz),

The mass spectrum with a field desorption (m/Z): 545 (M+).

(e) the Compound obtained previously in (d), treated according to the method of example 1 (c) obtaining 0,298 g (52%) specified in the connection header.

1H-NMR (D2O) : of 0.82 (3H, t, J = 7,3 Hz), 1,25 (2H, m), 1,58 (2H, m), 1,97 - 2,07 (4H, m), 3,07 - 3,19 (2H, m), of 3.54 (2H, Shir.d) to 3.67 (4H, s), is 4.21 (2H, t, J = 6.5 Hz), 4,45 - of 4.54 (1H, m), a 4.86 (2H, s), 5,02 (2H, s), 7,05 (2H, d, J = 9,2 Hz), of 7.97 (2H, d, J = 9,2 Hz).

SIMS (m/Z): 446 (M++ 1).

Example 10

4-[[4-[piperidine-4-yl)-2,3-dioxopiperazinyl-1-yl] acetyl] venexiana acid, hydrochloride.

The compound obtained in example 9, is treated according to the method of example 8 to obtain 0,211 g (68%) specified in the connection header.

1H-NMR (CF3COOD) : 2,25 - of 2.34 (2H, m), 2,36 is 2.51 (2H, m), 3,40 - of 3.54 (2H, m), 3,81 - 4,01 (6H), to 4.87 (1H, Shir.t), equal to 4.97 (2H, s), 5,23 (2H, s), 7,17 (2H, d), J = 8,8 Hz), 7,38 (1H, Shir.C), 8,11 (2H, d, J = 8,8 Hz).

SIMS (m/Z): 390 (M++ 1). Mass spectrometry of secondary ions.

Example 11

n-Butyl-4-[[4-piperidine-4-yl)-2,5-dioxopiperazinyl-1-yl] acetyl] - phenoxyacetate-triptorelin

(a) According to the method of example 7 (a), except that 2,6-dioxopiperidin replace hydrochloride complex ether glycinate get 9,79 g (86%) of ethyl-(1-the Shire.d), 2,62 - a 2.71 (1H, m), 2,80 (2H, Shir.C) of 3.43 (2H, s), Android 4.04 (2H, Shir.d), 4,19 (2H, square, J = 7,2 Hz).

EIMS (m/Z): 286 (M+).

(b) Connection (9,38 g) obtained earlier in (a), dissolved in 100 ml of dimethylformamide and to the solution add benzotriazol-1-yloxytris-(dimethylamino)-phosphodiesterase (26,1 g) and N-methylmorpholin (7,6 ml) and then stirred at room temperature for 2 hours. To the reaction solution was added at room temperature N-benzyloxycarbonylglycine (6,86 g) in dimethylformamide (60 ml) and the resulting solution was continued to stir for 19 hours. Then to the reaction solution was added to 0.2 N. hydrochloric acid under ice cooling and the resulting reaction solution was poured into a separating funnel to separate the aqueous and organic layers. The aqueous layer was extracted with chloroform, and extracted the organic layer is combined with the previously obtained organic layer. The combined organic layers washed with water, saturated sodium bicarbonate solution and saturated saline, and then dried over sodium sulfate. After evaporation of the solvent the residue is added ethyl acetate and precipitated precipitated crystals are removed by filtration. The obtained filtrate is concentrated and the residue ochischeniya.html)-N-(1-tert-butoxycarbonylamino-4-yl) aminoacetate.

1H-NMR (CDCl3) : 1,24 - 1.55V (13H), 1,62 - of 1.81 (4H, m, 2,65 - 2,84 (2H, m,), 3,61 - 3,7, (4,57 - 4,67 ( 1H, 2xm), 3,86 - 4,00 (3H), 4,05 - 4,32 (5H), 5,12, 5,13 (2H, HC), 5,73, 5,80 (1H, Shir.C), 7,28 - 7,39 (5H, m).

SIMS (m/Z): 478 (M++ 1).

(c) the Compound obtained above (b), is treated according to the method of example 9 (c) and after recrystallization from ethyl acetate receive of 6.31 g (85%) of 4-(1-tert-butoxycarbonylamino-4-yl)-2,5-dioxopiperazinyl

1H-NMR (CDCl3) : 1,42 - 1,70 (13H), 2,80 (2H, Shir.t), 3,86 (2H, s) to 4.23 (2H, Shir.C), 4,58 (1H, TT, J = 4,4, and 11.8 Hz), 6,41 (1H, Shir.C).

EIMS (m/Z): 297 (M+).

(d) the Compound obtained previously in (c), is subjected to the interaction by the method of example 7 (b), and then to the reaction solution while cooling with ice, add 0.9 ml of acetic acid, then stirred for 15 minutes. Then to this add water while cooling with ice to terminate the reaction, and the reaction solution is extracted with ethyl acetate. The extract obtained was washed with water, saturated sodium bicarbonate solution and saturated saline, and then dried over sodium sulfate. After evaporation of the solvent the residue is purified on a chromatographic column with silica gel (150 g, chloroform: methanol = 100:1). Then to the resulting crystalline substance added ether and the one-4-yl)-2,5-dioxopiperazinyl-1-yl] acetyl]phenoxyacetate.

1H-NMR (CDCl3) : of 0.93 (3H, t, J = 7.4 Hz), of 1.36 (2H, m) of 1.47 (9H, s), 1,54 - 1,72 (6H), of 2.81 (2H, Shir.t), 3,98 (2H, s), 4,10 (2H, s), 4,16 is 4.35 (4H), 4,60 (1H, TT, J = 4,1, and 11.8 Hz), 4,70 (2H, s), rate 4.79 (2H, s), 6,97 (2H, d, J = to 7.93 (2H, d, J = 8.7 Hz).

IMS (m/Z): 545 (M+).

(e) To the compound (1,91 g) obtained earlier in (d), while cooling with ice, add 3.5 ml of anisole and 14 ml triperoxonane acid and stirring is continued for 1.5 hours. Then to the reaction mixture is added isopropyl ether under ice cooling. After decanting the solvent, add ether to induce crystallization. The resulting crystals are collected by filtration, washed with isopropyl ether and ether, and then dried to obtain 2,11 g (70%) specified in the connection header.

1H-NMR (CD3OD) : 0,93 (3H, t, J = 7.4 Hz), of 1.37 (2H, m), 1,60 was 1.69 (2H, m), 1,96 - of 2.16 (4H, m), 3,09 - 3,19 (2H, m), 3,52 (2H, Shir.d), 4.09 to (2H, s), of 4.12 (2H, s), is 4.21 (2H, t, J = 6.6 Hz), 4,50 (1H, TT, J = 3,9, 11.7 Hz), 4,84 (2H, s) to 4.92 (2H, s), 7,05 (2H, d, J = 9.0 Hz), 8,00 (2H, d, J = 9.0 Hz).

EIMS (m/Z): 445 (M+).

Example 12

Hydrochloride, 4-[[4-(piperidine-4-yl)-2,5-dioxopiperidin-1Z-yl] acetyl] phenoxyalkanoic acid.

The compound obtained in example 11, is treated according to the method of example 8, resulting in a gain 0,417 g (98%) specified in the connection header.<00 (2H, d, J = 8,8 Hz), to 7.93 (2H, d, J = 8,8 Hz).

SIMS (m/Z) : 390 (M++ 1).

Example 13

The dihydrochloride of n-butyl-4-[[4-/piperidine-4-yl/-2-oxopiperidin-1-yl] acetyl]phenoxyacetate

According to the method of example 4, except that use of n-butyl-(4-bromoacetyl)phenoxyacetate receive specified in the header of the connection.

1H-NMR (CD3OD) : 8,00 (2H, d, J = 9.0 Hz),? 7.04 baby mortality (2H, d, J = 9.0 Hz), to 4.87 (2H, s), 4,82 (2H, s), is 4.21 (2H, t), J = 6,7 Hz), 3,48 - of 3.42 (4H, m), 3,32 - 3,30 (2H, m), 3.04 from (2H, dt, J = 2.7 Hz, J = 2.3 Hz), with 2.93 (2H, t, J = 5,5 Hz), a 2.71 (1H, DDD, J = 3.5 Hz, J = 6,7 Hz, J = 13,8 Hz), 2,15 - 2,10 (2H, m), 1,83 - of 1.73 (2H, m), 1,67 - to 1.60 (2H, m) to 1.37 (2H, dt, J = 7,4 Hz, J = 14,9 Hz) of 0.93 (3H, t, J = 7,4 Hz).

Example 14

Ethyl-4-[[4-(-piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]phenoxyacetate

Repeating the method of example 4, except that the use of ethyl-/4-bromacetyl/phenoxyacetate, and the resulting gain is specified in the header connection.

1H-NMR (CD3OD) : of 1.28 (3H, t, J = 7.2 Hz), 1,80 - 1,90 (2H, m), 2,20 - of 2.27 (2H, m), 3,02 - 3,10 (3H, m), 3,20 is 3.23 (2H, m), 3,49 is 3.57 (4H, m), 3,61 (2H, Shir. C.), 4,25 (2H, square, J = 7,2 Hz), 4,82 (2H, s), 4,91 (2H, s),? 7.04 baby mortality (2H, d, J = 8,9 Hz), 8,00 (2H, d, J = 8,9 Hz).

SIMS (m/Z): 404 (M++ 1).

Example 15

Ethyl-4-[[4-[1-(5-methyl-2-oxadiazol-4-yl)methylpiperidin-4-yl] -2 - oxopiperidin-1-yl]acetyl]phenoxyacetate

1H-NMR (CDCl3) : of 1.30 (3H, t, J = 7.2 Hz), 1,57 - of 1.65 (2H, m), 1,83 is 1.86 (2H, m), 2,08 - of 2.15 (2H, m), 2,11 (3H, s), 2,28 - of 2.36 (1H, m), 2,83 - of 2.86 (2H, m), 2,92 - to 2.94 (2H, m), 3,32 (2H, s), 3,36 - to 3.38 (4H, m), 4,28 (2H, square, J = 7,2 Hz), 4,69 (2H, s), of 4.77 (2H, s), to 6.95 (2H, d, J = 8.6 Hz), 7,95 (2H, d, J = 8.6 Hz).

The mass spectrum with a field desorption (m/Z): 515 (M+).

Example 16

Triptorelin 3-[4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]phenyl]propionic acid

According to the method of example 1 (b) and (c), except that the use of diphenylmethyl-3-/4-chloroacetyl/phenylpropionate, get listed at the beginning of the connection.

1H-NMR (D2O) : 1,75 - to 1.83 (2H, m), 2,29 is 2.33 (2H, m), is 2.74 (2H, t, J = 7 Hz), 3,03 - 3,21 (7H, m)e text, see patterns of connections, obtained in the examples. The numbers of the compounds correspond to the numbers of the examples.

Pharmacological research

Inhibition of platelet aggregation

On PPP man (platelet rich plasma platelet-rich plasma) examine the effect of compounds of the present invention on the inhibition of platelet aggregation.

From Vienna healthy men syringe, which already has one solution volume of 3.8% sodium citrate, a sample is taken - nine volumes of blood. This blood sample will be centrifuged at 170 rpm at room temperature for 10 minutes. The obtained supernatant allocate as PRP. The remainder of the blood sample, which had taken PRP, centrifuged at 2700 rpm for 15 minutes. The supernatant is taken as depleted platelet plasma (PRP) (Platelet poor plasma-Tr).

The study of platelet aggregation is carried out with the help of aggregometry (PAM-8c) manufacturer MEBANICKS Co. Ltd). The investigated compound is dissolved in 50% DMSO saline solution, 50% methanol physiological solution or just in physiological solution. Connection and PRP pre-incubated for 2 minutes. As the inductor using ADP (CHRONO-PAR REAGENTS 384 ADP. CHRONO-LOG Corp.) in Uu platelet aggregation, expressed as the ratio of the inhibition of aggregation induced by ADP in the absence of the test compound as follows:

< / BR>
Table

N example - IR50(Ám)

1 - 0,055

2 - 0,08

3 - 0,15

4 - 0,56

5 - 0,032

6 - 2,3

7 - 0,24

8 - 0,019

9 - 1,2

10 - 0,47

11 - 1,1

12 - 1,2

13 - 0,049

14 - 0,25

15 - 0,3

16 - 0,427

1. Nitrogen-containing heterocyclic derivatives of General formula I

< / BR>
where a, b and C independently represent CH2or C=O;

X and Y are different from each other and each represents CH or N;

D represents -(CH2)m-CO-, where m is an integer of 0 to 3;

E represents a group II or III

< / BR>
< / BR>
where n represents an integer 1 to 3;

Z represents-W-(CH2)p-COOR3where W represents-O - or a bond, p is an integer 1 to 4; R3represents hydrogen or lower alkyl;

R1represents hydrogen or lower alkyl, substituted group of the lower alkyl - substituted-2-oxadiazol-4-Il,

R2represents a hydrogen atom,

and their pharmaceutically acceptable salt and solvate.

2. Connection on p. 1, where X represents CH and Y represents n

3. The connection is different is CH2.

4. Connection on p. 1, where Z represents-W-(CH2)p-COOR3where W represents-O-.

5. Connection on p. 1, selected from the group consisting of

[[4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl]-o-phenylene]dioxy] dioxyna acid,

[[4-[[4-(piperidine-4-yl)piperazine-1-yl] acetyl] -o-phenylene] dioxy]dioxyna acid,

4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]venexiana acid,

diethyl[[4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl] -o-phenylene] dioxy]diacetate,

n-butyl 4-[[4-(piperidine-4-yl)-2,6-dioxopiperidin-1-yl] acetyl] phenoxyacetate,

4-[[4-(piperidine-4-yl)-2,6-dioxopiperidin-1-yl] acetyl] venexiana acid,

n-butyl 4-[[4-(piperidine-4-yl)-2,3-dioxopiperazinyl-1-yl] acetyl] phenoxyacetate,

4-[[4-(piperidine-4-yl)-2,3-dioxopiperazinyl-1-yl] acetyl] venexiana acid,

n-butyl 4-[[4-(piperidine-4-yl)-2,5-dioxopiperazinyl-1-yl] acetyl] phenoxyacetate,

4-[[4-(piperidine-4-yl)-2,5-dioxopiperazinyl-1-yl] acetyl] venexiana acid,

n-butyl 4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl] acetyl]phenoxyacetate, dihydrochloride,

ethyl 4-[[4-(piperidine-4-yl)-2-oxopiperidin-1-yl]acetyl]phenoxyacetate.

6. The pharmaceutical composition of oplevani, containing an effective amount of the compounds under item 1 or its pharmacologically acceptable salt or MES, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to p. 6, used as an inhibitor of platelet aggregation.

8. The pharmaceutical composition according to p. 6, used for the treatment or prevention of thrombotic diseases.

9. The pharmaceutical composition according to p. 6 or 8, where the specified thrombotic disease is cerebral infarction, heart attack, angina, or peripheral arterial atresia.

10. The method of treatment or prophylaxis of thrombotic diseases, comprising the administration to a mammal an effective amount of the compounds under item 1.

11. The method according to p. 10, where the specified thrombotic disease is cerebral infarction, heart attack, angina, or peripheral arterial atresia.

12. Connection on p. 1 used in the preparation of an inhibitor of platelet aggregation.

13. Connection on p. 1 used in the preparation of pharmaceutical compositions for the treatment or prevention of thrombotic diseases.

14. Connection on p. 13, where the specified thrombotic diseases>/P>Priority signs:

15.07.94 - the compounds of formula I, where b and C are CH2E represents group II and III;

02.06.95 - the compounds of formula I, where b and C each represents CH2or and E represents a group II.

 

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< / BR>
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