New derivatives of ndimethylacetamide, the method of production thereof, pharmaceutical composition and protease inhibitors based on them

 

(57) Abstract:

The invention relates to new compounds of the formula (I), where R0- phenyl, R1- phenyl, heteroaryl, lower alkyl which may be substituted or unsubstituted, R2substituted or unsubstituted phenyl, lower alkyl, R3is hydrogen, acyl group, sulfonylurea group, X and Y independently represent a nitrogen atom or a carbon atom, Z is methylene group. These compounds possess inhibitory activity against proteases type of disease and can be used as inhibitors of these enzymes, especially as inhibitors of chymase, and as the active ingredient in the pharmaceutical composition. Also the present invention relates to a new method of obtaining derivatives of ndimethylacetamide formula (I) by oxidation of compounds of formula (II) after removal of the protective groups specified connection, if it is present. 10 S. and 14 C.p. f-crystals, 17 PL.

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The technical field to which the invention relates

The invention relates to new derivatives of ndimethylacetamide, having substituted heterocyclic group, and the number of consecutive dicarbonyl structures, for example: compounds 1-pyrimidinediamine chymotrypsin, especially chymase inhibitors. These compounds may be used as a prophylactic or therapeutic agent against diseases whose development is considered usually involves protease type chymotrypsin. For example, it is believed that the protease-type chymotrypsin directly or indirectly involved in the development of diseases such as asthma, allergies, inflammation, rheumatism, hypertension, heart failure, myocardial infarction, cardiac hypertrophy, vascular damage, accompanied by angiogenesis and atheroma, nephritis and renal failure etc., the Present invention includes intermediate compounds that can be used for the synthesis of compounds of heterocyclic amides with serial number dicarbonyl structures, the method of obtaining compounds of heterocyclic amides and pharmaceutical composition containing such compounds heterocyclic amides as active ingredient, and a method of using such pharmaceutical composition.

Art

It is known that chymase refers to the protease-type chymotrypsin among serine proteases and is cytotoxic protein that accumulates in the secretory granules of mast cells (udaetsya in the conversion of angiotensin I to angiotensin II, involved in the regulation of blood pressure in vivo. In addition, it is also known that the chymase inhibitor inhibits the release of histamine from mastocytes (Arch. Biochem. Biophys. 1988. V. 38. P. 291) and the release of cytotoxic protein from eosinophils (Arch. Biochem. Biophys. 1994. V. 312. P. 67). Thus, at the present time it is known that chymase is involved not only in cytotoxicity, but also in the release of various mediators in vivo.

In addition, the effect of chymase may be different depending on the type of animal, and described particularly large differences in its action in humans in comparison with dogs and rodents (Proc. Natl. Acad. Sci. USA. 1987. V. 84. P. 364).

Currently, among the compounds inhibiting himizu only known inhibitor of chymotrypsin as a digestive enzyme, and it is unsatisfactory for inhibitory activity and selectivity of inhibition of other proteases, their own stability in vivo, toxicity, etc. and have not received use as a pharmaceutical composition. There is therefore a need in the chymase inhibitor having a high degree of safety and at low concentrations selectively inhibiting himizu.

The invention

In connection with these obstacles the stitching of the above problems, and as a result came to the present invention.

Specifically, the present invention relates to the following items (1) through (30):

(1) New derivatives of ndimethylacetamide represented by the following chemical formula, or their pharmacologically acceptable salts.

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where R0is a phenyl group, ring which may contain one or more groups of the substituents selected from group a defined below (group a; group a consists of halogen, a nitro-group, a hydroxyl group, a lower alkoxygroup, a lower alkyl group or halogen-substituted lower alkyl group).

R1(i) aryl, (ii) heteroaryl or (iii) C1-6 pramana, branched or cyclic alkyl group, which may independently contain one or more groups of the substituents defined in relation to the group; or R1can independently contain one or more groups of the substituents selected from the group containing ORa, COORa, CONRbRc, NRbRc, NRbCHO, NRbCORa, SO2ORa, SO2Ra, CONRbSO2Raand P(O)(ORa)2included in the above groups (i) to (iii) (in which the group Rato RcSUB> independently represent an aryl-(1-7C-alkyl, heteroaryl-(1-7C) alkyl, aryl and heteroaryl, among which the aryl or heteroaryl ring may contain one or more, generally from 1 to 3, groups of substituents, selected from those defined above, group A. Substituted lower alkyl contains from 1 to 3 atoms or groups selected from halogen, nitro or hydroxyl group as a substitute group; or R1can contain as a substitute groups of the above groups (i) to (iii) one or more cyclic groups G, defined below (the cyclic group G; a cyclic group G represents a heterocyclic group, a 5 - or 6-membered ring containing 1 to 3 atoms of oxygen or nitrogen, and may contain the group-Deputy);

R2represents a (1-8C) alkyl, aryl-(1-7C-alkyl, heteroaryl-(1-7C-alkyl and aryl; or R2to pose the above group b or (1-8C) alkyl containing group as a substitute of the group; or (1-8C) alkyl, defined above containing cyclic group G as a substitute group;

R3is hydrogen; or R3represents (i) D(CH2)0-3WITH, (ii) D or (iii) DSO2ECO is the quality sulfonyloxy group (where the group D represents hydrogen, 1-6C promoteyou, branched or cyclic alkyl group, aryl group, halogen-substituted lower alkyl, halogen-substituted lower alkoxygroup, amino group, lower alkoxyamino, halogen-substituted lower alkylamino, RbRcN, RbRcNO, RaO, Ra, RaOCO, RbRcNCO, RaSO2NRb, RaS defined above and the group G; and group E represents a divalent linking group containing from 1 to 6 carbon atoms); or R3group type urea represented by the group RbRcNCO; or R3- thiourea represented by RbRcNCS; or R3is an Ra;

X and Y independently represent a nitrogen atom or a carbon atom and may be substituted by groups representing groups from Rato Rc;

Z represents polymethene group in which the hydrogen atoms present in polymethene group may be independently substituted with Raand Rb.

(2) New derivatives of ndimethylacetamide, in accordance with the preceding paragraph. (1) or their pharmacologically acceptable salts, where R2in the formula (I) represents the following:

R2is (1-8C) alkyl, armhole (I) Y - the nitrogen atom, and X is a carbon atom, R2represents a group other than ORaor NRbRc), or (1-8C) alkyl containing group as a substitute of the group; or (1-8C) alkyl, defined above containing cyclic group G as a substitute group.

(3) New derivatives of ndimethylacetamide in accordance with the above paragraphs. (1) or (2) or their pharmacologically acceptable salts, where the cyclic group G is a group selected from the group comprising: pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinone, pyrazolone, pyridazine, piperazine-1-yl, which may optionally contain in the 4th position of the lower alkyl group or the group aryl-lower alkyl, pyrrolidin-1-yl, piperidine-1-yl, 4-morpholine-4-yl and pyrrol-1-yl.

(4) New derivatives of ndimethylacetamide, prior p. (1) or their pharmacologically acceptable salts, where each corresponding symbol in the formula (I) represents the following:

R0is a phenyl group, ring which may contain 1 to 5 groups of the substituents selected from the group consisting of halogen, hydroxyl group, lower alkoxygroup, lower alkyl groups and triptorelin group;

R1- phenyl, thienyl, furyl, IMO contain one or more groups of deputies, defined above for the group A; or1may contain one or more groups of the substituents selected from the group containing ORa, COORa, CONRbRc, NRbRc, NRbCHO, NRbCORa, SO2ORa, SO2Ra, CONRbSO2Raand P(O)(ORa)2included in the above-mentioned phenyl, thienyl, furyl, pyridyl, pyrrolyl or C1-6 promoteyou, branched or cyclic alkyl group (including a group from Rato Rcindependently are hydrogen or lower alkyl; or the group Rato Rcindependently represent an aryl-(1-7C-alkyl, heteroaryl-(1-7C) alkyl, aryl and heteroaryl, where the aryl or heteroaryl ring may contain one or more groups of the substituents selected from group a); or R1can contain as a substitute group of the above-mentioned phenyl, teinila, furil, pyridyl, pyrrolyl or C1-6 premiani, branched or cyclic alkyl groups of one or more cyclic groups G are selected from the group consisting of pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinone, pyrazolone, pyridazine, piperazine-1-yl, which may optionally contain in the 4th position of the lower ALK is

R2represents (1-4C)-alkyl, aryl-(1-3C) alkyl, heteroaryl-(1-3C) alkyl and aryl; or R2to pose the above group b or (1-3C) alkyl containing group as the group's Deputy; or (1-3C) alkyl, defined above containing cyclic group G as the group's Deputy.

R3represents hydrogen; or R3represents (i) D(CH2)0-3WITH, (ii) D or (iii) DSO2ECO as an acyl group; or R3represents the D(CH2)0-3SO2or DCOESO2as sulfonyloxy group; or R3- thiourea represented by RbRcNCS; or R3is an Rawhere D represents hydrogen, C1-6 promoteyou, branched or cyclic alkyl group, triptorelin group, 2,2,2-triptracker, amino group, methoxyamino, 2,2,2-triptoreline, RbRcN, RbRcNO, RaO, Ra, RaOCO, RbRcNCO,

RaSO2NRb, RaS defined above or a group G. the Group E represents a divalent benzene ring, 1,4-piperazine-di-yl, and promoteyou, branched or cyclic dohale and can be substituted by the groups which groups of Rato Rc; a

Z represents-CH2- where 2 of the hydrogen atom may be independently substituted with Raand Rb.

(5) New derivatives of ndimethylacetamide in accordance with the above paragraphs. from (1) to (4) or their pharmacologically acceptable salts, where the corresponding symbols in the formula (I) are the following:

R0is a phenyl group which may contain from 1 to 3 groups of substituents selected from halogen, hydroxyl group, lower alkoxygroup, lower alkyl groups and triptorelin group as a group in the ring;

R1is a phenyl group which may independently contain in the ring one or more of the above defined groups; or R1may contain one or more groups of the substituents selected from the group consisting of ORa, COORa, CONRbRc, NRbRc, NRbCHO, NRbCORa, SO2ORa, SO2Ra, CONRbSO2Raand P(O)(ORa)2; R2represents (1-4C)-alkyl, aryl-(1-3C) alkyl, heteroaryl-(1-3C) alkyl and aryl; or R2to pose the above group b or (1-3C) alkyl containing group as a group-Zam the feature group G is a cyclic group G, including pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, primidealhalbgrouppen, pereselenskomu, ericailcane, piperazine-1-yl, optionally containing in the 4th position of the lower alkyl group or an aryl-(1-7C)-alkyl group, pyrrolidin-1-yl, piperidine-1-yl, 4-morpholin-1-yl and pyrrol-1-yl.

R3represents hydrogen; or R3represents (i) D(CH2)0-3WITH, (ii) D or (iii) DSO2ECO as an acyl group; or D(CH2)0-3SO2and DSO2as sulfonyloxy group (where the group D represents hydrogen, alkyl group with a direct 1-6C chain, branched or cyclic, triptorelin group, 2,2,2-triptracker, 2,2,2-triptoreline, COORa, CONRbRc, NRbRc, defined above or group (G); or R3- thiourea represented by RbRcNCS; or E independently represents a divalent benzene ring, a divalent heteroaryl ring, 1,4-piperazine-di-yl, divalent tsiklogeksilnogo group and divalent 1,4-cyclohexadienyl group; or R3is an Ra.

X and Y independently represent a nitrogen atom or n is replaced by Raand Rb.

(6) New derivatives of ndimethylacetamide in accordance with the above paragraphs. from (1) to (5) or their pharmacologically acceptable salts, where the corresponding symbols in the formula (I) are the following:

R0- unsubstituted phenyl group or substituted phenyl group with 1 or 2 groups-substituents selected from halogen, lower alkyl, hydroxyl group, lower alkoxygroup and lower alloctype; R1- unsubstituted phenyl group, R2- unsubstituted phenyl group, unsubstituted (1-8C)-alkyl group or a substituted (1-8C) is an alkyl group containing a group-Deputy selected from carboxyl group, lower alloctype, phenyl group, pyrrolidin-1-yl, peredelnoj group, pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinamine, persianmirror, pyridazinones, or substituted lower alkyl piperazine-1-yl, or substituted lower alkyl piperazine-1-yl-carbonyl, and morpholino group, R3is hydrogen, lower acyl group, formyl, sulfamoyl, lower alkylsulfonyl, substituted aryl lower alkylsulfonyl, heteroarylboronic, trifloromethyl or tetrahydrofuroyl, X is unsubstituted whom accordance with the above paragraphs. from (1) to (6) or their pharmacologically acceptable salts, where the corresponding symbols in the formula (I) are the following:

R0- unsubstituted phenyl group, R1- unsubstituted phenyl group, R2- unsubstituted (1-8C)-alkyl group, or (1-8C) is an alkyl group containing a group-Deputy selected from pyrrolidin-1-yl, pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinamine, persianmirror, pyridazinones, substituted lower alkyl piperazine-1-yl or substituted lower alkyl piperazine-1-yl-carbonyl, X is unsubstituted carbon atom, Y is a nitrogen atom, and Z represents-CH2-.

(8) New derivatives of ndimethylacetamide in accordance with the above paragraphs. from (1) to (7) or their pharmacologically acceptable salts, where R3in the formula (I) represents a group selected from among hydrogen, lower alkylsulphonyl, lower alkoxycarbonyl, acyl, sulfonyl and sulfamoyl.

(9) New derivatives of ndimethylacetamide, in accordance with the Polynesians (1) or their pharmacologically acceptable salts, where the corresponding symbols in the formula (I) are the following:

R0- unsubstituted phenyl group or phenyl group,R3is hydrogen or lower alkoxycarbonyl, X is unsubstituted carbon atom, Y is a nitrogen atom, and Z represents-CH2-.

(10) New derivatives of ndimethylacetamide or their pharmacologically acceptable salts, where the following symbols in the formula (I) are the following:

R0- unsubstituted phenyl group, R1- unsubstituted phenyl group, R2- 3-(2-oxo-1,2-dihydropyridines-1-yl)propyl, R3group selected from among hydrogen, tert-butyloxycarbonyl, formyl, acetyl, lower alkylsulfonyl, substituted aryl lower alkylsulfonyl, heteroarylboronic, triftormetilfullerenov, lower alkylaminocarbonyl, substituted aryl lower alkylaminocarbonyl, replaced by heteroaryl lower alkylaminocarbonyl and heteroarylboronic, X is unsubstituted carbon atom, Y is a nitrogen atom, a Z represents-CH2-.

(11) New derivatives of ndimethylacetamide or their pharmacologically acceptable salts, where the following symbols in the formula (I) are the following:

R0- unsubstituted phenyl group, R1- unsubstituted phenyl group, R2- 3-(2-pyridyloxy)propyl, R3group selected from among hydrogen, tert-butyloxycarbonyl, triftormetilfullerenov, lower alkylaminocarbonyl, substituted aryl lower alkylaminocarbonyl, replaced by heteroaryl lower alkylaminocarbonyl and heteroarylboronic, X is unsubstituted carbon atom, Y is a nitrogen atom, and Z represents-CH2-.

(12) 2-(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-(3-forfinal)methyl} butylacetamide or its pharmacologically acceptable salt.

(13) 2-(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl} exilerated or its pharmacologically acceptable salt.

(14) 2-(5-Amino - or tert-butyloxycarbonyl - or acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-oxo-1,2-dihydropyridines-1-yl)}-exilerated or its pharmacologically acceptable salt.

(15) 2-(5-Amino - or tert-butyloxycarbonyl or benzylmethylamine or formylamino or benzylaminocarbonyl - or 4-pyridylmethylamine - or acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-6-(2-pyridyloxy)-1-phenylmethyl}exilerated or its pharmacologically acceptable salt.

(16) (A) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyri the oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-methoxycarbonyl-1-(3-fluoro-4-hydroxyphenyl)methyl-2-oxo} ethylacetamide, (C) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylcarbamoyl-1-phenylmethyl)ethylacetamide, (D) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-benzylcarbamoyl-2-oxo-1-phenylmethyl)ethylacetamide, (E) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylethanol-1-phenylmethyl)ethylacetamide, (F) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-methoxycarbonyl-1-(4-methoxyphenyl)methyl-2-oxo}ethylacetamide, (G) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylethanol-1-phenylmethyl)ethylacetamide, (N) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-methoxycarbonyl-1-(4-methoxyphenyl)methyl-2-oxo}ethylacetamide, or their pharmacologically acceptable salts.

(17) (A) 2-(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide, (B) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-6-phenyl-1-phenylmethyl)exilerated, (C) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-5-phenyl-1-phenylmethyl)ventilated, (D) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)heptylate, (E) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-3-phenyl-1-phenylmethyl)propylacetamide, (F) 2-(5-AMI is phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-fluoro-4-hydroxyphenyl)methyl} butylacetamide, (H) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-forfinal)methyl} butylacetamide, (I) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-chlorophenyl)methyl} butylacetamide, (J) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-were)methyl} butylacetamide, (K) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(4-forfinal)methyl} butylacetamide, (L) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(4-chlorophenyl)methyl} butylacetamide, (M) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-etoxycarbonyl-1-(3-forfinal)methyl} exilerated, (N) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 1-(3-forfinal)methyl-7-(4-methylpiperazin-1-yl)-2,3,7-trioxo} heptylate, (O) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl} exilerated, (R) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated, (Q) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated, (R) 2-(2-amino-3-oxo-5-phenyl-3,4-dihydropyridin-4-yl)-N-(2-methoxycarbonyl-2-oxo-1-phenylmethyl} ethylacetamide, (S) - 2-(6-amino-5-oxo-3-phenyl-4,5-dihydro - 1,2,4-triazine-4-yl)-N-(2-methoxycarbonyl-(2,3-dioxo-1-phenylmethyl)butylacetamide, (U) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)exilerated, (V) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)heptylate, (W) 2-{ 5-(3-tetrahydrofurfurylamine)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-(2,3-dioxo-6-phenyl-1-phenylmethyl)exilerated, (X) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(2-forfinal)methyl}butylacetamide, or their pharmacologically acceptable salts.

(18) new Salt derivative ndimethylacetamide according to the above p. (1), where the pharmacologically acceptable salt is selected among (A) salts of alkali metals, salts of alkaline-earth metals, aluminum salts, ammonium salts or salts derived from organic bases, forming a pharmaceutically acceptable cations, if the new derivatives ndimethylacetamide in the formula (I) are acid compounds, and (B) salts with the addition of the acid obtained with the use of acid forming pharmaceutically acceptable anions, if new derivatives of ndimethylacetamide in the formula (I) are the main compounds.

(19) a Pharmaceutical composition containing the new derived ndimethylacetamide in the above paragraphs. from (1) to (18) or its pharmacologically proizvodnje of ndimethylacetamide in the above paragraphs. from (1) to (19) or its pharmacologically acceptable salt as an active ingredient.

(21) a New inhibitor of chymase containing the new derived ndimethylacetamide in the above paragraphs. from (1) to (20) or its pharmacologically acceptable salt as an active ingredient.

(22) a New inhibitor of degranulation mastocytes or a new inhibitor of the release of mastocytoma of histamine, which includes a new derived ndimethylacetamide in the above paragraphs. from (1) to (18) or its pharmacologically acceptable salt as an active ingredient.

(23) a New inhibitor of activation of eosinophils or inhibitor release by eosinophils active oxygen, which includes a new derived ndimethylacetamide in the above paragraphs. from (1) to (18) or its pharmacologically acceptable salt as an active ingredient.

(24) the Way to obtain new derivatives ndimethylacetamide in the above paragraphs. from (1) to (18) or their pharmacologically acceptable salts, comprising the following steps (a) And (b):

(A) in the synthesis of new derivatives of ndimethylacetamide formulas (I) - phase oxidation of an alcohol of the formula (II)

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after removal of the protective for alcohol groups, if present, to turn it into a new proizvodstvennaya between the compound of formula (III) or a compound of the formula (IV), where R3'is hydrogen,

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where R3'in formulas (III) or (IV) has the same meaning as R3defined earlier in paragraph (1), and the compound of the formula (V)

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or a compound of the formula (VI)

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(In the above formulas, R0, R1, R2X, Y and Z have the same meaning as previously defined in paragraph (1).)

(25) Compounds of formula (II) in accordance with the foregoing p. (24) and their salts, where R0, R1, R2X, Y and Z are groups defined earlier in paragraph (1).

(26) Compounds of formula (III) in accordance with the foregoing p. (24) and their salts, where R0, R2and Z are the groups previously defined in paragraph (1), a R3'the group previously defined in paragraph (24).

(27) Compounds of the formula (IV) in accordance with the foregoing p. (24) and their salts, where R0, R2and Z are the groups previously defined in paragraph (1), a R3'the group previously defined in paragraph (24).

(28) the compounds of formula (V) in accordance with the foregoing p. (24) and their salts, where R1, R3X and Y are groups defined earlier in paragraph (1).

(29) the compounds of formula (VI) in accordance with the foregoing p. (24) and their salts, where R1and R3are the groups previously defined in paragraph (1).0, R2and Z are the groups defined in paragraph 1, a R3'means the same as the group R3defined in paragraph 1.

Preferred embodiments of the invention

The present invention relates to new derivatives of ndimethylacetamide, having substituted heterocyclic group, and the number of consecutive dicarbonyl structures, for example: compounds 1-pyrimidinediamine, connections 4-personrelated, connections 4-treasonrelated and so on, and protease inhibitors comprising these compounds or their salts (hereinafter referred to as "connection information") as an active ingredient, having inhibitory effect on the activation of leukocytes by mastocytoma, eosinophils, and so on, as well as inhibitory effect on the production of angiotensin II, and, for example, expected they can be a means for the prevention or treatment of diseases such as asthma, allergies, inflammation, rheumatism, hypertension, heart failure, myocardial infarction, cardiac hypertrophy, vascular damage, accompanied by angiogenesis and atheroma, nephritis and renal failure.

In this description uses the following definitions, unless given other definitions:

Groups the group, lower alkyl group substituted with halogen lower alkyl group.

Group b is a group selected from the group consisting of ORa, COORa, CONRbRc, NRbRc, NRbCHO, NRbCORaSC2ORa, SO2Ra, CONRbSO2Raand P(O)(ORa)2.

Groups from Rato Rcindependently represent a group selected from hydrogen, lower alkyl, aryl-(1-7C) alkyl, heteroaryl-(1-7C) alkyl, aryl and heteroaryl, which aryl or heteroaryl ring may contain one or more groups of substituents, selected from those defined above, group A.

A cyclic group G represents a heterocyclic group consisting of 5 - or 6-membered ring containing 1 to 3 atoms of oxygen or nitrogen, and may contain a group-Deputy.

Group D is hydrogen, 1-6C pramana, branched or cyclic alkyl group, halogen-substituted lower alkyl, such as trifluoromethyl, etc. , halogen-substituted lower alkoxygroup, such as 2,2,2-triftoratsetata and so on, the lowest alkoxyamino, such as methoxyamine etc. , halogen-substituted lower alkyl which RaOCO, RbRcNCO, RaSO2NRb, RaS defined above and the group G.

Group E represents a divalent sewn group containing from 1 to 6 carbon atoms and may contain 1 to 3 heteroatoms selected among oxygen, nitrogen and sulfur, for example divalent benzene nucleus, as phenylene, divalent heteroaryl nucleus, as heteroaryl, 1,4-piperazine-di-yl, and a divalent C1-6 pramana or branched aliphatic cross-linking group, as methylene dimetilan, trimethylene, 2-metallisation, or alicyclic linking group, as cyclohexene, 1,4-cyclohexadienyl etc.

Halogen means fluorine, chlorine, bromine and iodine.

The alkyl chain in the alkyl and alkoxygroup is premiani, branched or cyclic alkyl, the number of carbon atoms which is preferably from 1 to 20.

Lower alkyl or lower alkoxygroup are branched or pramocaine groups, each of which contains from 1 to 6 carbon atoms. Lowest alloctype is a group in which the number of carbon atoms in the alkyl chain attached to a carbonyl group is from 1 to about 6. Aryl represents substructure ring, moreover, at least one ring of these atoms connected in the ortho-position is the aromatic ring. Heteroaryl contains from 2 to 4 heteroatoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur, and is a monocyclic aromatic ring formed of 5 or 6 atoms forming a ring structure, or heterobicyclic ring formed approximately 8-10 atoms forming the ring structure and connected to the ring in ortho-position.

As for the carbon atom, asymmetrically substituted in the position of the chiral center indicated by "*" in the formula (I), the compound of formula (I) exists as a single optical isomer, or as a racemate. If the compound of formula (I) has one chiral element, compound of formula (I) exists as a single diastereoisomer or as a mixture of diastereoisomers. There is a possibility that you can select any of these compounds. The compounds of formula (I) in the present invention include compounds that form a number of individual diastereoisomer to a mixture of diastereoisomers and further the compounds of formula (I) include compounds forming a number from the individual enantiomers to a mixture of enantiomer is Le (I) may exist in the form of MES, in particular in the form of a hydrate. Accordingly, the MES of the compounds of formula (I) is included in the present invention.

The compound of formula (I) may specify, in addition to the above MES, multiple polymorphism, such as tautomer of MES, in addition to the above MES. Therefore, the present invention includes any compounds that have inhibitory action on the enzyme type chymotrypsin, regardless of what form of polymorphism they exist - in the form of a racemate, optical isomer or MES.

In the following paragraphs groups specifically illustrated, but they are shown taking into account ease of illustration and it does not mean that they are restrictive.

Preferred examples of the group And are fluorine, chlorine, bromine, nitro-group, hydroxyl, methyl, ethyl group and a methoxy group.

Examples Ra, Rband Rcare hydrogen and such low alkali as methyl, ethyl, propyl, butyl, isopropyl, and so on, such aryl-(1-7C)-alkili as benzyl, phenetyl, phenylpropyl and so on, such heteroaryl-(1-7C)-alkili as pyridylmethyl, pyridylethyl, pyridylmethyl, furylmethyl, purolater, fullprofile and so on , such arily">

Examples ORain group b or group D, and so on, are hydroxy, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, benzyloxy, pyridyloxy, phenoxy, pyridyloxy, pyrrolidinone and other groups.

Examples COORain group b or group D, and so on, are methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl, pyrimidinetrione, phenoxycarbonyl etc.

Examples CONRbRcin group b or group D, and so on, are dimethylaminoethyl, methylaminomethyl, diethylaminoethyl, dipropylthiocarbamate etc.

Examples NRbRcin group b or group D, and so on, are monomethylamine-, dimethylamino-, methylethylamine, diethylamine, dipropylamine etc.

Examples NRbCHO in group b and so on are group formylamino, formylmethionine etc. Examples NRbCORain group b, etc. are group methylcobalamine, ethylcarbodiimide, propylnitrosamine, methylcarbamoylmethyl etc. are Examples of SO2ORain group b, etc. are the group of sulfonic acids, etc. Examples of SO2Rain group b, etc. are methylsulphonyl, Atila who were radioactive, formamidinesulfinic, nitrobenzenesulfonyl, methoxybenzenesulfonyl, pyridylsulfonyl, pyridylmethylamine, trifloromethyl etc.

Examples CONRbSO2Rain group b, etc. are methylsulfonylmethane, vinylsulfonylacetamido, phenylmethanesulfonyl etc. Examples P(O)(Ra)2in group b, etc. are group diethylphosphino, diphenylphosphino, dibenzalacetone etc. Preferred examples of the group In the groups are: methoxy, ethoxy, propyloxy, isopropoxy, phenylmethoxy, penetrate, phenylpropoxy, pyridylmethylene, pyridinethione, pyridylmethylene, fullmetaljacket, filetrace, fullprofile, pyridylacetate, pyridylcarbinol.

Examples of the group G are 5-6-membered ring containing heteroaryl or heteroatom alicyclic group 5-6-membered ring, and preferred groups are 4-morpholine-4-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl, piperidine-1-yl and 2-oxo-1,2-dihydropyridines-1-yl, and 2-pyridyloxy.

Preferred examples of the group D are hydrogen, methyl, cyclohexyl, phenyl, pyridyl, trifluoromethyl, group, 2,2,2-cryptometrics, methoxyamino the sludge, propionyl, cyclopropanecarbonyl, valeryl, butisol, cyclopropanecarbonyl, pivaloyl, TRIFLUOROACETYL, phenylacetyl, 3-phenylpropionyl, pyridylcarbonyl, benzoyl, tetrahydro-2-furoyl, tetrahydro-3-furoyl, methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichlorocyanuric, allyloxycarbonyl, gidroksosoli etc.

Acyl group in D or DSO2ECO in R3includes 4-[1-(4-morpholine-1-yl)carbonyl] benzopyranyl, 4-[(1-pyrrolidin-1-yl)carbonyl] benzopyranyl, 4-[(1-piperidine-1-yl)carbonyl] benzopyranyl, vinylsulfonylacetamido etc.

D(CH2)0-3SO2in R3includes, for example, toluensulfonyl, benzazolyl, formamidinesulfinic, nitrobenzenesulfonyl, methoxybenzenesulfonyl, pyridylsulfonyl, pyridylmethylamine, methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, tert-butylsulfonyl, bansilalpet, trifloromethyl, pencilsharpener, aminosulfonyl, methylaminomethyl, ethylaminomethyl, propylaminosulfonyl, isopropylaminocarbonyl, butylaminoethyl, tert-butylimidazole is S="ptx2">

DSO2in R3includes benzylaminocarbonyl etc.

Thiourea represented in R3the group RbRcNCS includes methylenedioxybenzyl, ethylaminoethanol, propylaminosulfonyl, butylaminoethyl, isopropylaminocarbonyl, valariebertinelli, benzylaminocarbonyl etc.

A preferred example of R0is a phenyl group, ring which may contain from 1 to 4 groups substituents selected from halogen, nitro, hydroxyl group, lower alkoxygroup, lower alkyl groups, and triptorelin group as group A.

A preferred example of R1is phenyl, furyl, thienyl or pyridyl ring which may contain 1 or 2 groups-the Deputy, identified as group A.

Preferred examples of R2- (1-4C)-alkyl, aryl-(1-3C) alkyl and G (1-3C) alkyl, containing as group Deputy previously defined group G. More preferred examples are methyl, ethyl, propyl, butyl, isopropyl, benzyl, phenethyl, phenylpropyl, pyridylmethyl, pyridylethyl, pyridylmethyl, furylmethyl, purolater, fullprofile, pyridylacetate, pyridylacetic, pyridyloxy, or groups that MSIL or pyrimidinyl, such as piperazine-1-yl-(1-3C) alkyl, piperidine-1-yl-(1-3C) alkyl, 4-morpholine-4-yl-(1-3C) alkyl, 2-pyridyloxy-(1-3C) alkyl, pyrrolidin-1-yl-(1-3C) alkyl, 2-oxo-1,2-dihydropyridines-1-yl-(1-3C) alkyl, methoxycarbonyl-(0-3S)-alkyl, etoxycarbonyl-(0-3C) alkyl, propylenecarbonate-(0-3C) alkyl, butyloxycarbonyl-(0-3C) alkyl, benzyloxycarbonyl-(0-3S)-alkyl, tert-butoxycarbonyl-(0-3C) alkyl, vinyloxycarbonyl-(0-3C) alkyl, nitrophenylacetylene-(0-3C) alkyl and bromophenylacetate-(0-3C) alkyl. The most preferred examples are methyl, ethyl, propyl, butyl, phenylpropyl, 4-morpholine-4-yl-(1-3C) alkyl, 2-oxo-1,2-dihydropyridines-1-yl-(1-3C) alkyl, 2-pyridyloxy-(1-3C) alkyl, etoxycarbonyl-(0-3S)-alkyl and 4-methylpiperazin-1-yl-carbonyl-(1-3C) alkyl.

Preferred examples of R3are hydrogen, formyl, acetyl, propionyl, cyclopropanecarbonyl, valeryl, butyryl, cyclopropanecarbonyl, pivaloyl, TRIFLUOROACETYL, phenylacetyl, 3-phenylpropionyl, pyridylcarbonyl, benzoyl, tetrahydro-2-furoyl, tetrahydro-3-furoyl, methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichlorocyanuric, allyloxycarbonyl, hydroxycu the carbonyl] benzopyranyl, toluensulfonyl, benzazolyl, formamidinesulfinic, nitrobenzenesulfonyl, methoxybenzenesulfonyl, pyridylsulfonyl, pyridylmethylamine, methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, tert-butylsulfonyl, bansilalpet, trifloromethyl, pencilsharpener, aminosulfonyl, methylaminomethyl, ethylaminomethyl, propylaminosulfonyl, isopropylaminocarbonyl, butylaminoethyl, tert-butylaminoethyl, phenylenesulfonyl, benzylaminocarbonyl, pyridinemethanol, methylenedioxybenzyl, ethylaminoethanol, propylaminosulfonyl, butylaminoethyl, isopropylaminocarbonyl, valariebertinelli, benzylaminocarbonyl (where these groups can contain in the ring one or two halogen groups, or a methyl group, if these groups are phenyl or heteroaryl as part of the structure), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, phenethyl, thiazolyl, pyrimidinyl or 5-tetrazolyl (and if these groups include phenyl or heteroaryl as part of the structure, the ring may be one or two halogen groups, or a methyl group).

Element, preferred as X and Y is carbon or nitrogen.

Particularly preferred groups for (1-8C) Ramazanova and branched alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, heptyl and octyl. Particularly preferred groups for cyclic alkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Suitable groups as alkylene in aryl-(1-7C) alkyl and heteroaryl-(1-7C) alkyl are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and heptamethine. Particularly preferred aryl group is phenyl. The most suitable groups for heteroaryl are pyridyl, pyrimidinyl, furyl and thienyl. Preferred examples of aryl-(1-7C) alkyl - phenylmethyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, finalizable, vanillyl, phenylethenyl, phenylgesic and finalgather, and preferred examples of heteroaryl-(1-7C) alkyl are the same as in the case of phenyl groups, when heteroaryl are pyridyl, pyrimidinyl, furyl or thienyl.

Particularly suitable groups as the lower alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. Especially preferred groups as inferior alkoxygroup the R and bromine.

With regard to individual groups in the compound according to formula (I), R0, R2, R3X, Y and Z can be any group of the above, a R1is phenyl.

One of the special groups among the more well-defined compounds of formula (I) is a compound in which each symbol has the following meaning.

R0is a phenyl group, ring which may contain 1 to 3 groups of substituents selected among halogen, hydroxyl group, lower alkoxygroup, lower alkyl groups and triptorelin group as group A.

R1is a phenyl group, ring which may independently contain one or more of the above defined groups And the ring; or R1may contain one or more groups of the substituents selected from the group consisting of ORa, COORa, CONRbRc, NRbRc, NRbCHO, NRbCORa, SO2ORa, SO2Ra, CONRbSO2Raand P(O)(ORa)2.

R2represents pyridyloxy-(1-4C)-alkyl.

R3is hydrogen; or R3- acyl group in (i) D(CH2)0-3WITH, (ii) D or (iii) DSO2ECO, or sulfonylurea group D(CH2a, CONRbRc, NRbRc, defined above or a group G; or R3- thiourea represented by RbRcNCS; and E independently represents a phenyl, heteroaryl, 1,4-piperazine-di-yl, cyclohexyl, 1,4-Nikogosian); or R3is an Ra.

X and Y independently represent a nitrogen atom or unsubstituted carbon atom.

Z represents-CH2- where 2 of the hydrogen atom may be independently substituted with Raand Ra.

Special groups more precisely defined compounds of formula (I) R0represents a phenyl group (the phenyl group may independently contain 1 or 2 groups of the substituent in the form of Halogens, hydroxyl groups or methyl groups), R2is methyl, butyl, phenylpropyl, 4-morpholine-4-yl-propyl, 1-(etoxycarbonyl)propyl, 4-methylpiperazin-1-yl-propyl, 2-oxo-1,2-dihydropyridines-1-yl-propyl or 2-pyridylacetate, R3is hydrogen or formyl, X and Y are unsubstituted carbon or nitrogen, and Z is unsubstituted methylene group. More precisely, R0- phenyl, 3-forfinal, 4-forfinal, 3,4-differenl, 3,5-differenl or 3-ftory, and (a) if the compound of formula (I) represents, for example, an acid compound, its pharmaceutically acceptable salts are salts of alkali metals, salts of alkaline-earth metals, aluminium salts, ammonium salts or salts derived from organic bases, forming a pharmaceutically acceptable cations, such as lower alkylamines followed (from primary to tertiary), and so on; (C) if the compound of formula (I) represents the main connection, its pharmacologically acceptable salts are formed by adding an acid salt formed by the use of such acids, as hydrochloric acid, sulfuric acid, acid, phosphoric acid and so on, forming a pharmacologically acceptable anions.

The compound of formula (I) can be obtained by a method including known among the chemical methods, the step of deriving structurally similar heterocyclic compounds or peptide compounds. For example, the target compound of formula (I) is obtained by condensation between the compound of formula (V) or its derivative, activated at the carboxyl group, and a compound of formula (III), where R3'- hydrogen, to obtain the compounds of formula (II), with its subsequent acelerometro in scheme 1 (see at the end of the description).

The condensation between the compound of formula (V) or its derivative, activated at the carboxyl group, and a compound of formula (III), where R3'is hydrogen, can be carried out in an inert solvent, for example in such polar solvents as dimethylformamide, tetrahydrofuran or other solvent, or in a mixed solvent, a mixture of one of them with a polar solvent, for example, at a temperature of from about 0 to about 80oC, preferably at a temperature in the range of from about 0 to 40oWith, for about from 0.5 to 50 hours At a reaction molar ratio of the compounds of formula (V) or its derivative, activated at the carboxyl group, and the compounds of formula (III), where R3'- hydrogen, preferably selected such that the compound of formula (III) is used in an excessive amount, a little more theoretical values, however, the amount of the compounds of formula (III) can be arbitrarily changed in the interval from 0.5-fold to 5-fold excess per mole of the compounds of formula (V).

Especially when the connection is obtained, in which R3represents a group other than hydrogen, hydroxyl grupul group (Vos scheme 1) for the amino group is removed, for example, in a solution of Hcl/1,4-dioxane, to obtain the compound of formula (XVI), and then injected group protective group, R3in the usual way, depending on the type of group, to obtain the compound of formula (XVII). Removing protection from a hydroxyl group in the formula (XVIII) gives compound of formula (XVIII), followed by oxidation to obtain the target compound of formula (I). Rdin the formula (XV) can be any protecting group used to protect the hydroxyl group, and usually use acyl group and others cited in the definition of3. Preferably use a protective group that is not removed during subsequent removal of the protective group for amino group.

As it is obvious for specialists in this area, the raw materials can be synthesized by various routes of synthesis.

For example, for the compounds of formula (III) or its salts corresponding ketone derivative of oxazolidine subjected to the usual way of the reaction remove the protection of the amino group and the reaction disclosure ring of oxazolidine, whereby it is easy to obtain the compound of formula (III) or its salt. R3'in the formula (III), regardless of R3has the same meaning as R3and is predpochtitelno compound of formula (V) or formula (VI). Ketone derivative of the specified oxazolidine can be synthesized, as shown in the following steps from (1) to (4):

(1) In accordance with the method described by R. Nishizawa et al. (J. Med. Chem. V. 20, No. 4. R. 510-515), 3-amino-2-hydroxy-4-substituted or unsubstituted fenilalanina acid can be easily synthesized using amino acids as the starting material.

The amino acid used as starting material may be a commercial product, for example, substituted or unsubstituted phenylalanine, etc. If there is no commercial amino acids, conduct a normal reaction for the synthesis of amino acids, for example the reaction of condensation commercial acetamide ester of malonic acid with substituted benzylchloride, and then the ester is subjected to hydrolysis and subsequent decarboxylation reaction and remove the protection of the amino group, resulting in you can get the desired amino acid: for example, substituted phenylalanine containing group is a substituent in the aromatic ring.

(2) 3-Amino group of the obtained 3-amino-2-hydroxy-4-substituted or unsubstituted, phenylalkanoic acid protects such suitable protecting group as tert-butyloxycarbonyl group and so on, and then subjected to the t 3-N-protected amino-2-hydroxy-4-substituted or unsubstituted connection fenilalanina acid-N, O-dimethylhydroxylamine.

(3) the Obtained amide is treated in the usual way, for example, a catalytic amount of p-toluenesulfonic acid 2,2-dimethoxypropane, as a result can easily be obtained 3-N-protected-5-(N-methoxy-N-methyl)carbarnoyl-2,2-dimethyl-4-substituted or unsubstituted, fenilmetilketil.

(4) For professionals in this field it is obvious that the obtained amide known as activated amide. Therefore, it can easily be converted to a ketone derived by the following operations. Specifically, oxazolidin subjected to known reactions, for example the processing reagent Grignard corresponding to the group R2in an inert solvent in the atmosphere of argon, in accordance with the above-described method disclosed in Japanese laid out the application 143517/1996, where N,O-dimethylhydroxylamine substituted by a group R2and in this way can be synthesized ketone derivative of oxazolidine containing typed in his group, R2. The resulting ketone derivative of oxazolidine and its salts may be represented by the following chemical formula (XXV):

< / BR>
where R0, R2and Z - groups defined in paragraph 1 of the formula a R3'has the same meaning as oxazolidin, who was quoted in this detailed description, has the same meaning as in the formula (XXV).

Further, the intermediate compound of formula (V), i.e., pyrazin-3-one-4-acetic acid (in the formula (V) X is nitrogen, a Y - carbon), can be synthesized by the route shown in scheme 2 (see the end of the description), in accordance with one of the suitable synthetic routes. In this scheme, BOC - tert-butyloxycarbonyl group, a CBZ - benzyloxycarbonyl group.

The aldehyde of formula (VII) can be easily synthesized according to the method of synthesis described Rich D. H. et al. (J. Org. Chem. 1978. V. 43, N 18. R. 3624-3626). This aldehyde is treated with a suitable alcohol (in this case methanol) in the presence of acid catalyst, the result can be obtained compound of the formula (VIII). Benzyloxycarbonyloxy group in the formula (VIII) is subjected to hydrogenolysis in the usual way, resulting in the connection can be easily converted into the compound of the formula (IX). Amine of formula (IX) and monoether tert-butyloxycarbonyl acid is subjected to condensation in the usual way, the result can easily be obtained compound of formula (X).

The compound of formula (X) may be converted to the compound of formula (XI) by reaction of the circuit is Obedinenie formula (XI) is treated with a suitable base in the presence of such alkylating reagent, as allylbromide, which may be synthesized 4,5-di-substituted-3-pyrazine-2-carboxylate represented by formula (XII).

Protective for carboxyl group in the compound of formula (XII) hydrolyzing the usual way, with the result that the connection is easily converted to carboxylic acid. After that, carboxylic acid, purified or in some cases not clear, the connection is treated with diphenylphosphorylacetate and a suitable base, such as triethylamine, in an inert solvent, which may be obtained from the corresponding isocyanate. In a simple way, as it is obvious for specialists in this field, the reaction is carried out in the presence of, for example, butyl alcohol, the result of which can be easily synthesized from a compound of formula (XIII), where, for example, R3represents a tert-butyloxycarbonyl group.

Translation of the compounds of formula (XIII) to a compound of formula (V) may be carried out in 3 stages in the usual way, namely the translation of the compounds of formula (XIII) in the diol of formula (XIV) can be carried out by using catalytic amounts of osmium tetroxide in the presence of such soogilauaga agent, as the N-methylmorpholin-N-oxide. Then the connection FFL, the result can easily be obtained compound of the formula (V).

The intermediate compound of formula (V), i.e., the pyrimidine-6-one-1-acetic acid (in the formula (V), X is carbon, a Y - nitrogen), known on the basis of, for example, publications 286946/1993 in the list of disclosure of Japanese patents, and unknown compounds can also be obtained according to the method described in the literature, or by the method described above. The intermediate compound of formula (VI), the triazine-6-one-1-acetic acid, can be synthesized by the path shown in figure 3.

Nicolson formula (XIX) can be synthesized according to the method of synthesis described Metz H. J. and H. Neunhoeffer (Chem. Ber. 1982. V. 115. R. 2807-2818). This Nicolson can be converted into 3,4-di-substituted-5-triazine-6-carboxylate of formula (XX) by the introduction of it without isolation and purification in the reaction ring closure with diethylmalonate in the presence of a suitable base. The protective group for carboxyl in the formula (XX) hydrolyzing the usual way, so that this compound can be converted to 3,4-di-substituted-5-triazine-6-carboxylic acid of formula (XXI).

Carboxylic acid of formula (XXI) can be converted to a compound of formula (XXII) (R3- tert-butyloxycarbonyl is Kim as, for example, triethylamine, in the presence of tert-butyl alcohol. It is known that this transformation happens through isocyanate, therefore, experts in this field it is obvious that, if instead of tert-butyl alcohol use amine or a similar reagent, the connection can easily be turned into such a compound, where R3group type urea.

The conversion of compounds of formula (XXII) in the compound of formula (VI) can be performed in the same manner as the conversion of compounds of formula (XIII) to a compound of formula (V).

Stages and intermediate compounds for obtaining the compounds of formula (I) described above represent the other aspects of the present invention, which are disclosed in the following steps. Used here groups are groups defined above.

(A) the oxidation Reaction of the alcohol of formula (II) in the carbonyl group.

Oxidation of compounds of formula (II) can be made common method used for oxidation of the hydroxyl group to a carbonyl group, however, it is preferable to use a method that is less prone to adverse reactions. Usually this can be accomplished by oxidation in an inert solvent, predpochtitel the body, as methylene chloride, or in a mixed solvent mixture of these solvents, preferably in the presence of an excess of oxidizing agent at a temperature in the range -10oWith up to 100oC, preferably at a temperature in the range from 10oWith up to 50oWith or near this, more preferably at room temperature or near it. The preferred oxidizing agent includes an agent using an excess of dimethyl sulfoxide and water-soluble carbodiimide, and as a catalyst - trifenatate pyridinium; the agent using the 3 compounds: oxalicacid, dimethyl sulfoxide and tertiary amine; the agent using chlorochromate pyridinium in methylene chloride, etc.

If the amino group is unstable in the conditions of the oxidation reaction, it is preferable or necessary before oxidation to introduce the amino protective group, such as R3and remove the protective group after oxidation.

(B) Synthesis of compounds of formula (I) containing a free amino group.

From the corresponding compounds containing a conventional protective group for the amino group, this protective group can be removed using the traditional method. The traditional method of removing the protection includes natorial, as 1,4-dioxane; or unprotect heat treatment with simultaneous presence of p-toluenesulfonic acid in methanol. These reactions can be conducted at a temperature in the range -10oWith up to 100oC, preferably at a temperature in the range from 10oWith up to 50oWith or near this, more preferably at room temperature or close to it.

The following compounds can be obtained by condensation between the compound of formula (V) or its derivative, activated at the carboxyl group, and the compounds of formula (III), where R3'- hydrogen, but they can also be obtained in accordance with the following methods.

(C) Synthesis of the compounds of formula (I), where R3- acyl group.

Of the compounds of formula (V), where R3- tert-butoxycarbonyl group specified tert-butoxycarbonyl group is removed as follows: obtain the connection formula (I) containing a primary amino group, where R3is hydrogen, and the specified primary amino group acelerou to obtain the target compound. A simple method is to acylation using acid halide corresponding to the acyl group in an inert solvent, such as tetrahydrofur the acid and cross-linking reagent, such as cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its salt, etc.

(D) Synthesis of the compounds of formula (I), where R1or R2or R3contain COORa, CONRbRc.

The connection may also be obtained by acylation using the condensation reaction between a compound containing a group HORa, HNRbRcand a compound of formula (I) containing R1or R2the COOH group (or its activated derivative).

(E) Synthesis of the compounds of formula (I), where R3- sulfonylurea group.

The compound of formula (I) containing a free amino group, where R3is hydrogen, sulfonylureas sulphonylchloride in accordance with the target compound, which may be obtained from the target connection. In this case, the reaction can be conducted at room temperature or while cooling in an ice bath in the presence of a tertiary amine in such an inert solvent like tetrahydrofuran. If there is no commercial sulphonylchloride necessary sulphonylchloride can be synthesized by a known method.

(F) a common reaction to substitute aminoguanidinium formula (I), where R3is hydrogen, uralauluminium, triftormetilfullerenov, with the aim of synthesizing the compound of formula (I), where R3is an Rawith the exception of hydrogen.

(G) the cleavage Reaction of the corresponding alkyl-ether or acyloxy-ether compound of the formula (I), which aryl or heteroaryl group as group Deputy lowest alkoxygroup or as a group-Deputy lowest alloctype, with the aim of synthesizing the compound of formula (I) where at least one of the groups R1, R2and R3contains aryl or heteroaryl ring hydroxyl group as the group's Deputy.

A suitable method is the hydrolysis of alloctype under acidic or alkaline conditions, etc.

(H) Synthesis of compounds of formula (I), where R1or R2substituted by carboxyl, or R2- carboxyl group (Rain the group COORa- hydrogen).

The connection can be obtained by removal of the ester group of the corresponding ether compounds containing carboxyl group. This reaction involves the hydrolysis of such alkali as sodium hydroxide, hydrogenolysis in the case of the benzyl ether and the destruction of tert-butyl methyl ether at kislotnoNCS, a Rc- hydrogen.

The connection can be obtained in the usual way by acylation of aminogroup in the compound of formula (I) containing a free amino group, isocyanate or thioisocyanate, in accordance with a group of the formula RbNCO or RbNCS.

(J) Synthesis of compounds of formula (III), where R2- alkyl, arylalkyl or heteroaromatic.

The connection can be obtained by alkylation of compounds of formula (III) containing a carboxyl group, or activated derivative by reaction with alkyl reagent Grignard, arylalkyl reagent Grignard or heteroarylboronic reagent Grignard with the group related to R2.

(K) Standard synthesis of the compounds of formula (I) or (II).

The connection can be obtained in the usual way by condensation between the compound of formula (V) or (VI) (or its derivatives, activated

the COOH group in the structural formula) and the compound of the formula (IV) or (III), where R3- hydrogen.

(L) the Above paragraphs. (C), (D), (E), (F), (G), (H) and (I) are the reactions for producing compounds represented by formula (I), and in accordance with these reactions, can be obtained compound, before whom these intermediate compounds can likewise give the compounds of formula (I). There are cases when it is desirable to use a protective group in each of the above stages of the synthesis. This protective group can be removed at the stage when the synthesized final product or the target connection. For specialists in this area it is obvious that the set of steps leading to the source material and the final product in the present invention, may be modified by the selection of a suitable method of condensation and method of removal of the protective group.

Among the compounds of formula (I) obtained by the methods described above, the preferred compounds described above include compounds 72, 73, 74, 75, 76, 77, 78, 79, 80 and 82, etc. are Particularly preferable 79 and 82, etc.

Preferred examples of compounds of the formula (V) are the following:

2-tert-butyloxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyridin-4-ilocana acid (in the formula (V) X is nitrogen, Y is carbon, R3- tert-butyloxycarbonyl, R1- phenyl),

5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinylidene acid (in the formula (V) X is nitrogen, Y is carbon, R3- tert-butyloxycarbonyl, R1- phenyl), and

6-tert-butyloxycarbonyl-5-oxo-3-phenyl-4,5-dihydro-1,2,4-triethynylbenzene acid (heimerle preferred compounds of the formula (III) are the following:

(A) methyl-3-amino-2-hydroxy-4-(4-hydroxyphenyl)-butyrate,

(B) methyl-3-amino-2-hydroxy-4-(3-fluoro-4-hydroxyphenyl)-butyrate;

(C) 3-amino-2-hydroxy-4-phenyl-propanamide;

(D) 3-amino-2-hydroxy-4-phenyl-N-phenylmethyl-butylamide;

(E) 3-amino-2-hydroxy-4-phenyl-N-phenylethyl-butylamide;

(F) methyl-3-amino-2-hydroxy-4-(4-methoxyphenyl)-butyrate.

The following compounds are also listed as preferred:

(A) 2-amino-3-hydroxy-4-oxo-1-phenylpentane;

(B) 2-amino-1,7-diphenyl-3-hydroxy-4-oxalate;

(C) 2-amino-1,6-diphenyl-3-hydroxy-4-oxohexyl;

(D) 2-amino-3-hydroxy-4-oxo-1-phenyloctane;

(E) 2-amino-1,4-diphenyl-3-hydroxy-4-oxobutyl;

(F) 7-amino-3-hydroxy-5-oxo-8-phenyloctanoic acid;

(G) 2-amino-1-(3-fluoro-4-hydroxyphenyl)-3-hydroxy-4-oxopent;

(H) 2-amino-1 -(3-forfinal)-3-hydroxy-4-oxopent;

(I) 2-amino-1 -(3-chlorophenyl)-3-hydroxy-4-oxopent;

(J) 2-amino-3-hydroxy-1-(3-were)-4-oxopent;

(K) 2-amino-1-(4-forfinal)-3-hydroxy-4-oxopent;

(L) 2-amino-1 -(4-chlorophenyl)-3-hydroxy-4-oxopent;

(M) ethyl-2-amino-1 -(3-forfinal)-3-hydroxy-4-oxooctanoate;

(N) 2-amino-1-(3-forfinal)-3-hydroxy-4-accountan-(4-methylpiperazin)amide;

(O) 2-amino-3-hydroxide;

(Q) 2-amino-3-hydroxy-4-oxo-1-phenyl-7-(2-pyridyloxy)heptane;

(R) methyl-3-amino-2-hydroxy-4-phenylbutyrate.

If this compound is used as a chymase inhibitor, it is used by itself or mixed with fillers or carriers, and is administered orally or parenterally in the form of a pharmaceutical composition, such as injection, inhalant, pills, pellets, granules, powder, capsules, suppositories, instillation, stickers, ointments, sprays, etc. as fillers or carriers choose pharmaceutically acceptable additives, and the type and composition determine, on the basis of route of administration and route of administration. For example, in the case of injections, it is generally preferable chloride sodium or sugars such as glucose, mannitol, etc., In the case of oral preparations are preferred starch, lactose, crystalline cellulose, magnesium stearate, etc.

The content of this compound in the pharmaceutical composition varies depending on the drug, but it usually is in the range from 0.1 to 100 weight %, preferably from 1 to 98 weight %. For example, in the case of injection, the content of the active ingredient is in the range of usually from 0.1 to 30 weight %, preferably from 1 to 10 weight %., is renal, liquid, dry syrup etc., Capsules, tablets, granules and powders usually contain from 5 to 100 weight % of active ingredient, preferably from 25 to 98 weight %.

Although the dosage is determined depending on age, weight and symptoms of the patient, object, therapy and so on, usually, therapeutic dose is from 1 to 100 mg/kg/day for parenteral administration and from 5 to 500 mg/kg/day for oral administration.

For these compounds it is characteristic that they have low toxicity, and even progressive introduction of these compounds does not cause accumulation of toxic manifestations. For example, even in the case of the introduction of this compound to rats orally at a dose of 100 mg/kg twice a day for 3 weeks, it was not observed any symptoms of toxicity.

Further, the present invention describes non-limiting examples. Unless otherwise specified, the following methods were used.

(1) the Solution was concentrated under reduced pressure (5 to 20 mm RT. Art.) in a rotary evaporator in a water bath at a temperature of 50oWith or below.

(2) Performing chromatography on silica gel using a column BW-820 MN (Fuji Sitica); for preparative thin-layer rotini 20x20 cm) (Merck); the ratio of the volume of eluting solution and the developing solution is listed as volume/volume.

(3) the melting Point is specified without amendment, and (destr.) refers to the destruction of the substance, the melting point of which is specified, is a substance synthesized in examples method, and even if it was synthesized by the same method, the melting point may differ from the value given above, if the substance has a crystalline polymorphism.

(4) the Final product is characterized by a satisfactory range of nuclear magnetic resonance (NMR).

For NMR used the spectrometer Gemini-200 (200 MHz) firm Varian, chemical shifts are given in ppm relative to tetramethylsilane (TMS) as internal standard; for the form of rectified signals used standard abbreviations.

(5) Mass spectra were measured on a mass spectrometer VG Auto Spec (firm VG Co., Ltd.) method EI or FAB).

(6) Infrared (IR) absorption spectra were measured on NC spectrophotometer As-202 (Nippon Bunko) using standard polystyrene film.

(7) generally, for reaction monitoring was used TLC; the reaction times are given for illustration only, and outp is Yong necessarily correspond to the amount of the substance the synthesized optimal way; if it was necessary to obtain a significant amount of material, its synthesis was performed again until they received the desired quantity of substance.

Examples

Further, the present invention is described in detail with reference to examples, which, however, are not intended to limit the present invention. The table below shows data on the compounds of formula (I) (tables 1 through 5) and the compounds of the formula (II) (tables 6 through 10) synthesized in accordance with the following examples.

Ketone derivative [compound of formula (XXV)] oxazolidinone as intermediate compounds for the compounds of formula (III) used in the examples are shown in tables 11 and 12.

Example 1

Synthesis of hydrochloride of 2-(5-tert-butyloxycarbonyl-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide (compound N 37) and 2-(5-amino-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide (compound 38) was performed, as described below.

(1) (4S, 5R)-3-Tert-butyloxycarbonyl-2,2-dimethyl-5-(1-oxoethyl)-4-fenilmetilketil (intermediate compound 1).

(4S, 5R)-3-Tert-butyloxycarbonyl-5-(N-methoxy-N-methyl)to the Lyali dropwise at a temperature of -14oC for 10 minutes in an argon atmosphere a solution of methyl-magnesium bromide in tetrahydrofuran (0.9 M solution 4,84 ml, 4,36 mmol). After adding the reaction solution was stirred at room temperature for 2 h, was added a saturated aqueous solution of ammonium chloride and was extracted reaction solution with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (in the system hexane/ethyl acetate with a ratio of 8/1 to 7/1), the result has been specified in the title compound (1.29 g, yield 98%).

1H-NMR (CDCl3): 1,15-1,70 (15 NM, a complex spectrum), 2,00-of 2.20 (3H, broadened singlet), 2,70-3,30 (2H, m), 4,16 (1H, s), 4,13-to 4.14 (1H, m), 7,12-7,39 (5H, m) (note: m - multiplet, s - singlet).

The intermediate (intermediate compound) shown in table. 11 and 12 were synthesized in the same manner. The physical properties of the target compounds are the following:

Intermediate compound 2. Mass spectrometry (MS): m/z=P (Dl3): or 0.83 (3H, t, J=7.2 Hz), 1,11-of 1.33 (2H, m), 1,32-of 1.57 (2H, m), 1,10-1,60 (6N, m), 1,58 (N, s), 2,15-2,52 (2H, m), 2,70-3,11 (1H, m), up 3.22 (1H, dd, J=2,9 and 13.2 Hz), 4,15-to 4.28 (1H, m), 4,30-4,48 (1H, m), 7,14-7,39 (5H, m) (note: t - triplet, d - doublet, dd = double doublet).

The intermediate compound 5.1H-NMR (Dl3): 1,29-1,80 (15 NM, a complex spectrum), 2,74-3,03 (1H, m), 3,22-3,47 (1H, m), to 4.81 (1H, usher d, J=9.7 Hz), free 5.01 (1H, user. d, J=14,3 Hz), 7,15-7,89 (10H, complex spectrum).

The intermediate compound 6.1H-NMR (DCl3): of 1.23 (3H, t, J=7,1 Hz), 1.41 to 1,67 (15 NM, a complex spectrum), of 1.80 (2H, quintet, J=7,1 Hz), 2,24 (2H, t, J=7,1 Hz), 2,34-by 2.73 (2H, m), 2,75-of 3.12 (1H, m), 3,20 (1H, dd, J=3.3V, and 13.2 Hz), 4,10 (1H, quintet, J=7,1 Hz), 4,18 (1H, user. s), and 4.40 (1H, user. s), 7,16 and 7.36 (5H, m).

Intermediate compound 7. MS: m/z = 368 (M + 1).

Intermediate compound 8.1H-NMR (CDCl3): 1,12-1,66 (15 NM, a complex spectrum) by 2.13 (3H, s), 2,70-3,24 (2H, complex spectrum), 4,13 (1H, user. s), 4,30-a 4.53 (1H, m), 6.87 in-7,06 (3H, complex spectrum), 7,20-7,40 (1H, m).

Intermediate compound 9.1H-NMR (Dl3): 1,10-1,63 (15 N, complex spectrum), to 1.24 (3H, t, J=7,1 Hz) and 1.83 (2H, quintet, J=7,3 Hz), and 2.27 (2H, t, J=7,3 Hz), 2,35-of 3.25 (4H, complex spectrum), 4,10 (2H, q, J=7,1 Hz), 4,11-4,19 (1H, m), 4,27-4,55 (1H, m), 6,86-7,06 (3H, complex spectrum), 7,19-7,34 (1H, m) (note: the q - Quartet).

Intermediate compound 10.1H-NMR (Dl3): 1,10-1,70 (15 NM, the complex spectrum is (2H, complex spectrum), 4,10-to 4.23 (1H, m), 4,25-4,55 (1H, m), 6,86? 7.04 baby mortality (3H, complex spectrum), 7,20 and 7.36 (1H, m).

Intermediate compound 11.1H-NMR (Dl3): 1,45-1,58 (15 NM, a complex spectrum), 1,60-1,75 (2H, complex spectrum), to 2.18 (2H, user. t), 2,32 (6N, user. t, J=4,8 Hz), 3,14-to 3.35 (2H, complex spectrum) and 3.59 (4H, user. s), 4.26 deaths (1H, user. s), 4,42 (1H, user. s), 7,18-to 7.35 (5H, complex spectrum).

Intermediate compound 12. Described below.

The intermediate connection 13. Described below.

The intermediate connection 14.1H-NMR (CDCl3): 1,19-1,57 (15 NM, a complex spectrum), 2,11 (3H, user. s), 2,70-3,20 (2H, complex spectrum), 4,05-4,18 (1H, m), 4,30 ñ 4.50 (1H, m), 6,94-7,06 (2H, complex spectrum), to 7.09-7.29 trend (3H, complex spectrum).

Intermediate compound 15.1H-NMR (CDCl3): 1,18-1,59 (15 NM, a complex spectrum), 2,12 (3H, user. s), 2,70-is 3.21 (2H, complex spectrum), 4.09 to (1H, user. s), 4,30-a 4.53 (1H, m), 7,09-7,34 (4H, m).

The intermediate connection 16.1H-NMR (Dl3): 1,19-1,57 (15 NM, a complex spectrum), to 2.06 (3H, user. s), 2,32 (3H, s), 2,70-of 3.07 (1H, m), 3,18 (1H, dd, J= 3.0 and 13.1 Hz), 4,10-4,27 (1H, m), 4,32-of 4.54 (1H, m), 6,95-7,13 (3H, complex spectrum), 7,13-of 7.25 (1H, m).

Intermediate compound 17. MS: m/z = 369 (M + 1).

The intermediate connection 18.1H-NMR (Dl3): 1,53 (N, s) by 2.13 (3H, s), 2,85 (1H, user. s) 3,18 (1H, dd, J=3.2 and 13.3 Hz), 4.09 to to 4.17 (1H, m), 4,42 (1H, user. s), 7,21-7,33 (3H, complex is,3S)-(2-hydroxy-3-oxo-1-phenylmethyl)butylacetamide (connection 1).

(4S, 5R)-3-Tert-butyloxycarbonyl-2,2-dimethyl-5-(1-oxoethyl)-4-fenilmetilketil (1.29 g, a 3.87 mmol) was dissolved in a solution of 4 N. hydrochloric acid/1,4-dioxane (29 ml, 116 mmol), to this was added distilled water (2.9 ml) and the mixture was stirred at room temperature for 3 hours the Reaction solution was concentrated under reduced pressure, the obtained residue was added diethyl ether and collecting the precipitated solid (950 mg). It is solid without further purification were subjected to the condensation reaction.

Obtained in the reaction described above solid (950 mg) and 5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (1.42 g, 4.14 mmol) was dissolved in a mixed solvent mixture of dimethylformamide (5 ml) and tetrahydrofuran (5 ml), and then to the solution while cooling in an ice bath was added sequentially in the following order: 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1,03 g, 5,38 mmol), 1-hydroxybenzotriazole2O (825 mg, 5,38 mmol) and 4-methylmorpholine (0,70 ml, 6,37 mmol). The reaction solution was diluted with ethyl acetate and washed successively with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate, distilled in the underwater sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 60/1-30/1), eventually got mentioned in the title compound (1.39 g, yield 65%).

1H-NMR (Dl3): 1,53 (N, s) to 2.06 (3H, s), 2,56-of 2.81 (2H, s), 3,99 (1H, d, J= 4.4 Hz), 4,33 (1H, dd, J=2.5 and 4.4 Hz), and 4.40 (1H, d, J=15.2 Hz), to 4.52 (1H, d, J= 15.2 Hz), with 4.64-4,82 (1H, m), to 6.67 (1H, d, J=8,8 Hz), 7,05-EUR 7.57 (11N, complex spectrum), 8,73 (1H, s).

(3) 2-(5-Tert-butyloxycarbonyl-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide (compound 37).

2-(5-Tert-butyloxycarbonyl-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2-hydroxy-3-oxo-1-phenylmethyl)butylacetamide (904,6 mg of 1.74 mmol) was dissolved in dimethyl sulfoxide (6 ml) were added successively triptorelin pyridinium (is 171.3 mg, 890 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1,00 g, 5,23 mmol) in that order and stirred for 6 h and 20 min To the reaction solution was added ethyl acetate, then washed successively with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and filicales (chloroform/methanol = 60/1), the result has been specified in the title compound (720,4 mg, yield 80%).

1H-NMR (Dl3): 1,54 (N, s), of 2.33 (3H, s), 2,99 (1H, dd, J=8.0 and a 14.1 Hz), up 3.22 (1H, dd, J=5,6 and 14, 1 Hz), 4,48 (2H, s), 5,17-5,31 (1H, m), 6.48 in (1H, d, J=6.3 Hz), 6,99-7,63 (11N, complex spectrum), 8,71 (1H, s); MC: m/z = 519 (M + 1).

(4) 2-(5-Amino-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide hydrochloride (compound 38).

2-(5-Tert-butyloxycarbonyl-6-oxo-1,6-dihydro-2-phenyl-1-pyrimidinyl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide (623,4 mg, 1.2 mmol) was dissolved in a solution of 4 N. hydrochloric acid/1,4-dioxane (9 ml, and 36.2 mmol) and stirred at room temperature for 3 hours To the reaction solution was added diethyl ether and the resulting solid was collected by filtration, resulting in the received specified in the title compound (51.8% of mg, yield 9%). MC: m/z = 419 (M + 1).

Example 2

Synthesis of 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-2,3-dioxo-1-(3-fluoro-4-hydroxyphenylethyl)butylacetamide (compound 49) was carried out as follows.

(1) (2S, 3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-(3-fluoro-4-hydroxy)phenylalkanoic acid N,O-dimethylhydroxylamine.

(2S,3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-(-4-history added substance tetrafluoroborate acid-N-fluoro-3,5-dichloropyridine (commercial name Onoda Florinate FP-B700) (2,11 g, 8,31 mmol) and stirred at 50oC for 2 days in an atmosphere of argon. The reaction solution was allowed to cool to room temperature, diluted with methylene chloride and washed successively with 20% aqueous citric acid solution and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/10/1), eventually got mentioned in the title compound (686,8 mg, 30% yield).

1H-NMR (DCl3): 2,73 are 2.98 (2H, m) and 3.15 (2H, s), of 3.46 (3H, s), to 3.67 (1H, d, J=6.6 Hz), 4,19 (1H, d, J=5.5 Hz), or 4.31-4,47 (1H, m), equal to 4.97-5,12 (3H, complex spectrum), 6,77-7,21 (3H, m), 7,22-7,42 (5H, m); MS: m/z = 407 (M + 1).

(2) (2S, 3R)-3-Tert-buyacticinonline-2-hydroxy-4-(3-fluoro-4-hydroxy)phenylalkanoic acid N,O-dimethylhydroxylamine.

(2S, 3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-(3-fluoro-4-hydroxy)phenylalkanoic acid N, O-dimethylhydroxylamine (674,8 mg of 1.66 mmol) was dissolved in methanol (50 ml), the solution was added a solution of 4 N. hydrochloric acid/1,4-dioxane (0,42 ml) and palladium black (67 mg) and stirred overnight under nitrogen atmosphere. Pony the residue was dissolved in 1,4-dioxane (3.3 ml), then to the solution was added distilled water (1.6 ml), acid sodium carbonate (168 mg, 1,99 mmol) and di-tert-BUTYLCARBAMATE (435 mg, 1,99 mmol) and stirred at room temperature for 1 hour. Then the reaction solution was diluted with ethyl acetate and washed successively with a saturated aqueous solution of ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/10/1), eventually got mentioned in the title compound (557 mg, yield 90%).

1H-NMR (DCl3): 1,39 (N, s), 2,72-of 2.93 (2H, m), 3,17 (3H, s), of 3.46 (3H, s), 3,63 (1H, d, J=5,9 Hz), 4,14 (1H, d, J=5,1 Hz), 4,29-to 4.46 (1H, m), of 5.34 (1H, d, J=3,4 Hz), 6,74-7,19 (3H, m).

(3) (4R, 5S)-3-Tert-butyloxycarbonyl-5-(N-methoxy-N-methyl)-carbarnoyl-2,2-dimethyl-4-(3-fluoro-4-hydroxyphenylethyl)oxazolidin.

(2S, 3R)-3-Tert-butyloxycarbonyl-2-hydroxy-4-(3-fluoro-4-hydroxy)phenylalkanoic acid N, O-dimethylhydroxylamine (512,1 mg, 1.38 mmol) was dissolved in toluene (5,1 ml), to the solution was added 2,2-dimethoxypropane (1,69 ml of 13.8 mmol) and p-toluwalase with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1), the result has been specified in the title compound (346 mg, yield 61%).

1H-NMR (Dl3): 1,38-1,68 (15 NM, a complex spectrum), 2,55-2,87 (1H, m), 3,02-of 3.25 (4H, complex spectrum), 3,32-of 3.64 (3H, complex spectrum), of 4.54 (1H, user. d), with 4.64 (1H, user. s), lower than the 5.37 (1H, user. s), 6,83? 7.04 baby mortality (3H, m).

(4) (4R, 5S)-3-Tert-buyoxycodone-5-(1-oxoethyl)-2,2-dimethyl-4-(3-fluoro-4-hydroxyphenyl)methyloxazolidine (intermediate compound 7).

(4R, 5S)-3-Tert-butyloxycarbonyl-5-(N-methoxy-N-methyl)carbarnoyl-2,2-dimethyl-4-(3-fluoro-4-hydroxyphenyl)methyloxazolidine (424,4 mg of 1.03 mmol) was dissolved in tetrahydrofuran (10 ml) in an argon atmosphere and cooled to -30oC. To this solution was added dropwise methyl magnesium bromide (0.9 M solution in tetrahydrofuran, of 3.43 ml, to 3.09 mmol). Then gave the temperature to rise to room temperature and after 30 min the solution was diluted with ethyl acetate and saturated aqueous ammonium chloride. After the fragmentation of the organic layer was washed successively with saturated aqueous estazolam sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated in an evaporator under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1), the result has been specified in the title compound (354,3 mg, yield 94%). MS: m/z = 368 (M + 1).

(5) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1R, 2S)-2-hydroxy-1-(3-fluoro-4-hydroxyphenyl)methyl-3-oxo}butylacetamide (compound 19).

(4R, 5S)-3-Tert-butyloxycarbonyl-5-(1-oxoethyl)-2,2-dimethyl-4-(3-fluoro-4-hydroxyphenyl)methyloxazolidine (354,3 mg, 0.96 mmol) was dissolved in a mixture of 4 N. hydrochloric acid/1,4-dioxane (2.4 ml), to the solution was added distilled water (to 0.24 ml) and the mixture was stirred at room temperature for 30 minutes the Reaction solution was concentrated under reduced pressure, the obtained residue was added toluene and the mixture is again concentrated, haven't got white solid (256,9 mg). This substance was used in subsequent reactions without further purification.

White solid (256,9 mg) obtained in the previous reaction, and 5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (334,4 mg, 0.97 mmol) was dissolved in a mixed solution ethylcarbodiimide hydrochloride (243 mg, of 1.27 mmol), 1-hydroxybenzotriazole2O (194 mg, of 1.27 mmol) and 4-methylmorpholine (0.15 ml, 1.50 mmol) in that order, and the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and washed successively with 20% aqueous citric acid solution, saturated aqueous sodium bicarbonate, distilled water and saturated aqueous sodium chloride. After the organic layer was dried by adding anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated in an evaporator under reduced pressure. The obtained residue was purified preparative thin-layer chromatography on silica gel (hexane/utilitiesman/methanol = 10/10/1), eventually got mentioned in the title compound (112 mg, yield 21%).

1H-NMR (DCl3): 1,53 (N, m), of 2.20 (3H, s), of 2.86 (2H, d, J=7.8 Hz), 3,93 (1H, user. s) of 4.05 (1H, user. s), or 4.31 (1H, d, J=15,4 Hz) to 4.41 (1H, d, J= 15.2 Hz), 4,62 was 4.76 (1H, m), 6,45-7,00 (5H, complex spectrum), 7,38-7,50 (6N, complex spectrum), 8,68 (1H, user. s); MS: m/z = 555 (M + 1).

(6) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1R, 2S)-2-hydroxy-1-(4-atomic charges-3-forfinal)methyl-3-oxo} butylacetamide (compound 7).

2-(5-Tert-Butylochka acetamid (or 105.3 mg, 0,19 mmol) was dissolved in 2-propanol (1,26 ml), to the solution was added at 0oWith an aqueous solution of sodium hydroxide (7,6 mg/1.25 ml) and acetic anhydride (17,9 μl, 0,19 mmol). After stirring at 0oWith over 10 min to the solution was added acetic anhydride until a yellow discoloration of the reaction solution. This solution was diluted with ethyl acetate and washed successively saturated aqueous solution of sodium bicarbonate and sodium chloride. After drying the organic layer over anhydrous sodium sulfate was removed in the drying agent by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (methylene chloride/methanol = 20/1), eventually got mentioned in the title compound (98,4 mg, yield 87%).

1H-NMR (Dl3): 1,53 (N, m), of 2.20 (3H, s), of 2.33 (3H, s), 2,95 (2H, d, J= 8.0 Hz), 3,83 (1H, user. s) of 4.05 (1H, user. d), 4,32-of 4.57 (1H, m), with 4.64-rate 4.79 (1H, m), 6,24 (1H, d, J=9.5 Hz), 6,91-7,13 (3H, m), 7,29 (1H, s), 7,39-7,56 (5H, m), 8,23 (1H, s).

(7) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(4-atomic charges-3-forfinal)methyl} butylacetamide (compound 65).

Oxalicacid (35 ml) was added to methylene chloride (1.7 ml) at room temperature is Yes (0,057 ml) and methylene chloride (0.5 ml) and after 15 min to the resulting solution was added dropwise a solution of 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1R, 2S)-2-hydroxy-1-(4-atomic charges-3-forfinal)methyl-3-oxo}butylacetamide accounted for 98.9 mg, 0,17 mmol) in methylene chloride (1.7 ml). After the addition the mixture was stirred for 40 min and then added to it triethylamine (0,12 ml). The reaction solution was diluted with methylene chloride and washed successively with distilled water and saturated sodium chloride solution. After drying the organic layer over anhydrous sodium sulfate was removed in the drying agent by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 80/1), eventually got mentioned in the title compound (57,8 mg, yield 59%).

1H-NMR (Dl3): 1,53 (N, s), 2,32 (3H, s), of 2.34 (3H, s), 2,55-a 3.01 (1H, m), is 3.08-3,37 (1H, m), 4,12-4,48 (2H, complex spectrum), 4,70-5,12 (1H, m), 6,82-7,11 (3H, complex spectrum), 7.23 percent-7,58 (6N, complex spectrum), 8,72 (1H, user. s).

(8) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-fluoro-4-hydroxyphenyl)methyl} butylacetamide (compound 49).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(4-atomic charges-3-forfinal)methyl}butylacetamide (54 mg, 0,091 mmol) was dissolved in a mixture of methanol (1.3 ml) and water (the temperature. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, removing the drying agent by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (methylene chloride/methanol = 20/1), eventually got mentioned in the title compound (16.1 mg, yield 32%).

1H-NMR (DCl3): 1,53 (N, m), of 2.34 (3H, s), 2,87 (1H, dd, J=8,1, 14.4 Hz), 3,14 (1H, dd, J=5,2, 14.1 Hz), 4,48 (1H, s), 5,09 with 5.22 (1H, m), 6,23-to 6.88 (5H, complex spectrum), 7,21-7,56 (6N, complex spectrum), at 8.60-8,76 (1H, user. s); MS: m/z = 553 (M + 1).

Example 3.

Synthesis of 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-hydroxy-3-oxo-6-phenyl-1-phenylmethyl)exilerated (compound 39) was performed in the following way.

(1) (2R, 3S)-2-Amino-1,7-diphenyl-3-hydroxy-4-oxopent-p-toluensulfonate (g p-toluenesulfonic acid compounds of the formula (III), where R0= phenyl, R2= phenylpropyl, R3'= Rd= hydrogen, Z=methylene).

(4R, 5S)-3-Tert-butyloxycarbonyl-5-(1-oxo-3-phenyl)butyl-2,2-dimethyl-4-fenilmetilketil the mole), and the mixture was heated under reflux for 4 hours the Reaction solution was concentrated under reduced pressure and the obtained residue was added hexane (10 ml) and diethyl ether (10 ml). The precipitated solid was collected by filtration, and as a result received the above mentioned product (631,5 mg, 75% yield).

1H-NMR (DMSO-d6): 1,72 (2H, quintet, J=7,3 Hz) to 2.29 (3H, s), 2,59 (2H, overlapped with solvent peak), 2,83 of 2.92 (2H, complex spectrum), 3,50-3,70 (2H, overlapped with solvent peak), 3,85 (1H, user. d) 7,09-7,35 (M, complex spectrum), 7,51 (2H, J=8.1 Hz), 7,78-7,88 (2H, user. s).

(2) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-hydroxy-3-oxo-6-phenyl-1-phenylmethyl)exilerated (compound 2).

5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (447 mg, of 1.30 mmol) and (2R,3S)-2-amino-1,7-diphenyl-3-hydroxy-4-oxalate-p-toluensulfonate (651 mg, of 1.30 mmol) was dissolved in a solvent mixture of dimethylformamide (2 ml) and tetrahydrofuran (1 ml) and cooled to 0oC. To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (248 mg, of 1.30 mmol), 1-hydroxybenzotriazole2O (198 mg, of 1.30 mmol) and 4-methylmorpholine (0,14 ml of 1.30 mmol) in that order and sabablari with ethyl acetate and washed successively with 20% aqueous citric acid solution, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried by adding anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/utilitiesman/methanol = 30/10/1), eventually got mentioned in the title compound (439,7 mg, yield 54%).

1H-NMR (Dl3): 1,53 (N, s) to 1.86 (2H, complex spectrum), and 2.26 is 2.44 (1H, m), 2,50-by 2.73 (3H, complex spectrum), to 2.94 (2H, d, J=7.8 Hz), a-3.84 (1H, d, J= 3,7 Hz), 3,95 (1H, user. d), or 4.31 (1H, d, J=15.3 Hz), 4,49 (1H, d, J=15.3 Hz), and 4.68 (1H, user. dd), to 6.39 (1H, d, J=9,2), 7,06-7,47 (15 NM, the complex spectrum is overlapped with solvent peak), 8,73 (1H, user. s).

Example 4

Synthesis of hydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated (compound 73) was carried out as follows.

Hydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-oxo-1,2-dihydropyridines-1-yl)} exilerated (compound 73).

2-{(5-Tert-butyloxycarbonyl-2-phenyl-1,6-dihydro-6-oxo)pyrimidine-1-yl} -N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-star 4 N. hydrochloric acid/1,4-dioxane (2.3 ml) and the mixture was stirred at room temperature for 2 hours the Reaction solution was concentrated under reduced pressure, the obtained residue was added chloroform and collected by filtration of the precipitated solid. Finally received the mentioned product (167 mg, yield 93%).

1H-NMR (CD3OD): 1,95-of 2.21 (2H, complex spectrum), 2,53-2,96 (4H, complex spectrum), 3,98-4,70 (5H, complex spectrum), 6,87-8,09 (14N, complex spectrum); MS: m/z = 540 (M + 1).

Example 5

Synthesis of 2-{ 5-(3-tetrahydrofuranyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-{ 2,3-dioxo-6-phenyl-1-phenylmethyl} exilerated (compound 81) was carried out as follows.

(1) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{(1R,2S)-2-atomic charges-3-oxo-6-phenyl-1-phenylmethyl}exilerated (compound 34).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1R, 2S)-2-hydroxy-3-oxo-6-phenyl-1-phenylmethyl} exilerated (compound 2) (2.65 g, 4,34 mmol) was dissolved in pyridine (5.5 ml) was added thereto dropwise while cooling in an ice bath, acetic anhydride (0,82 ml, 8,68 mmol). After the addition the mixture was stirred at room temperature for 6 hours the Reaction solution razrabota sodium and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/ethyl acetate = 3/1 to 1/1), eventually got mentioned in the title compound (2.70 g, yield 95%).

1H-NMR (DCl3): 1,53 (N, s), 1,74-of 1.93 (2H, m), are 2.19 (3H, s), 2.26 and at 2.59 (4H, complex spectrum), of 2.81 (1H, dd, J=8,8, and 13.5 Hz), of 3.12 (1H, dd, J=6,45, and 13.5 Hz), to 4.38 (1H, d, J=15.3 Hz), 4,48 (1H, d, J=15.3 Hz), and 4.75 (1H, m), 4,91 (1H, d, J=2.0 Hz), 6,34 (1H, d, J=9,2 Hz), 7,09-7,35 (11N, overlapped with solvent peak), 7,35-7,45 (5H, complex spectrum), is 8.75 (1H, s).

(2) 2-{ 5-(3-Tetrahydrofuranyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl}-N-{(1R,2S)-2-atomic charges-3-oxo-6-phenyl-1-phenylmethyl}exilerated (compound 32).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1R, 2S)-2-atomic charges-3-oxo-6-phenyl-1-phenylmethyl} exilerated (2,69 g of 4.12 mmol) was dissolved in a mixture of 4 N. hydrochloric acid/1,4-dioxane (31 ml) and stirred at room temperature for 3 hours the Reaction solution was concentrated under reduced pressure, to the obtained residue was added hexane and collected by filtration of the resulting solid (2,39 g). This solid substances is l, 6.0 mmol) was dissolved in methylene chloride (9 ml) and to the solution was added dropwise thionyl chloride (to 4.38 ml, 60,0 mmol) at room temperature in argon atmosphere. After the addition the mixture was stirred for 3 h at room temperature, after which the reaction solution was concentrated under reduced pressure. To the obtained residue were added methylene chloride (10 ml), cooled in an ice bath, was added sequentially pre-obtained solid (2,39 g) and triethylamine (3.12 ml of 22.4 mmol) and was stirred over night at room temperature. The reaction solution was diluted with methylene chloride and washed successively with distilled water and 5% citric acid. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 30/1), eventually got mentioned in the title compound (2.15 g, yield 86%).

1H-NMR (CDCl3): 1,74-of 1.93 (2H, m), are 2.19 (3H, s, overlapped with 2H), 2,35-2,60 (4H, complex spectrum), 2,82 (2H, dd, J=9,2, to 13.6 Hz), 2,93-3,14 (2H, complex spectrum), 3,78-of 4.05 (4H, complex spectrum), to 4.46 (2H, s), 4,70-4,84 (1H, m), the 4.90 (1H, d, J=1.5 Hz), and 6.25 (1H, d, J=9,4 THE P> (3) 2-{ 5-(3-Tetrahydrofuranyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-{ (1R,23)-2-hydroxy-3-oxo-6-phenyl-1-phenylmethyl}exilerated (compound 33).

2-{5-(3-Tetrahydrofuranyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-{(1R,2S)-2-atomic charges-3-oxo-6-phenyl-1-phenylmethyl}exilerated (2.15 g, to 3.49 mmol) was dissolved in a mixed solvent: methanol (9 ml) and distilled water (1 ml) were added potassium carbonate (2,41 g, 17.5 mmol) and stirred 1 day at room temperature. The reaction solution was concentrated under reduced pressure, thereto was added ethyl acetate, then washed successively with distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 30/1), eventually got mentioned in the title compound (555,6 mg, yield 28%).

1H-NMR (Dl3): to 1.86 (2H, quintet, J=7.5 Hz), 2,24 (1H, m), 2,54 of 3.28 (7H, complex spectrum), 3,85 (2H, m), 3,99 (2H, d, J=6.6 Hz), of 4.45 (2H, s), and 5.30 (1H, q, J=6.6 Hz), 6,40 (1H, d, J=6.6 Hz), 6,95-was 7.08 (2H, complex spectrum), 7,08-7,34 (8H, complex spectrum), 7,46 (5H, s), 8,Il-1-phenylmethyl}exilerated (compound 81).

2-{5-(3-Tetrahydrofuranyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-{(1R,2S)-2-hydroxy-3-oxo-6-phenyl-1-phenylmethyl}exilerated obtained before this, were subjected to the same procedure as in example 1 (3), so named product was obtained by oxidation reaction of the alcohol corresponding to the formula (II).

1H-NMR (Dl3): 1,91 (1H, quintet, J=7.5 Hz), 2,24 (1H, m), 2,54 of 3.28 (7H, complex spectrum), 3,85 (2H, m), 3,99 (2H, d, J=6.6 Hz), of 4.45 (2H, s), and 5.30 (1H, q, J=6.6 Hz), 6,40 (1H, d, J=6.6 Hz), 6,95-was 7.08 (2H, complex spectrum), 7,08-7,34 (8H, complex spectrum), 7,46 (5H, s) to 8.12 (1H, s), the remaining 9.08 (1H, s).

Example 6

Synthesis of 2-tert-butyloxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyridin-4-luxusni acid as the compounds of formula (V) was carried out as follows.

(1) 1 Benzyloxycarbonylamino-2,2-dimethoxy-1-Penilaian.

N-Benzyloxycarbonylglycine (1,38 g, 5,12 mmol) was dissolved in methanol (2.6 ml), to the solution was added triethylorthoformate (1,12 ml, 10,24 mmol) and camphorsulfonic (59,5 mg, 0,256 mmol) and was stirred over night at room temperature. The reaction solution was concentrated under reduced pressure and purified the resulting residue column chromatography on aluminium oxide (50 g aluminum oxide, hexane/ethyl acetate = 2/1), the result is received , ), 5,07 (1H, d, J=1.1 Hz), of 5.53-5,74 (1H, m); MS: m/z = 316 (M + 1).

(2) 2,2-Dimethoxy-1-phenylethylamine hydrochloride.

1 Benzylcarbamoyl-2,2-dimethoxy-1-phenyl-ethane (1,21 g of 3.84 mmol) was dissolved in methanol (38,4 ml), thereto was added a mixture of 4 N. hydrochloric acid/1,4-dioxane (0,96 ml of 3.84 mmol) and palladium black (121 mg) and perform the hydrogenolysis over night at room temperature in a hydrogen atmosphere. After removal of palladium black by filtration, the filtrate was concentrated under reduced pressure and the obtained residue was added methylene chloride and diethyl ether. The precipitated solid was collected by filtration, and the result has been specified in the title substance (760,3 mg, yield 91%).

1H-NMR (CDCl3): of 3.25 (3H, s), 3,40 (3H, s), 4,17-4,34 (1H, m), 4,78 (1H, d, J=6.4 Hz), 7,27-EUR 7.57 (5H, m), 8,86 (2H, user. s).

(3) N-{ (N-Tert-butyloxycarbonyl-2-etoxycarbonyl)glycyl} -2,2-dimethoxy-1-phenylethylamine.

(N-Tert-butyloxycarbonyl-2-etoxycarbonyl)glycine (7,19 g of 29.1 mmol) and 2,2-dimethoxy-1-phenylethylamine hydrochloride (6,33 g of 29.1 mmol) was dissolved in a mixed solvent: dimethylformamide (72 ml) and tetrahydrofuran (72 ml), to this solution was added 1-hydroxybenzotriazole2O (5,11 g, 37.8 mmol), 1-(-dimethylaminopropyl)-3-Etiler is over night at room temperature. The reaction solution was diluted with ethyl acetate and washed successively with distilled water and saturated sodium chloride solution. After drying the organic layer over anhydrous sodium sulfate drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. To the obtained residue was added toluene, and then spent azeotropic distillation. The resulting residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1), the result has been specified in the title compound (10.6 g, yield 93%).

1H-NMR (Dl3): of 1.20 to 1.37 (3H, m), USD 1.43 to 1.48 (N, m), 3,34-3,43 (6N, m), 4,06 is 4.35 (2H, m), 4,43 (1H, d, J=3,4 Hz), 4,81-is 4.93 (1H, m), 5,03-5,14 (1H, m), 5,68-of 5.82 (1H, m), 7.24 to 7,38 (5H, complex spectrum); MS: m/z = 411 (M + 1).

(4) 2-Ethoxycarbonyl-3-hydroxy-5-vinylpyrazine.

N-{ (N-tert-butyloxycarbonyl-2-etoxycarbonyl)glycyl}-2,2-dimethoxy-1-phenylethylamine (10.6 g, of 25.7 mmol) was dissolved in triperoxonane acid (100 ml) and was stirred over night at room temperature. The residue obtained by concentrating the reaction solution under reduced pressure, was dissolved in acetonitrile (130 ml) and again stirred overnight at room temperature. The residue obtained policial (hexane/ethyl acetate/methanol = 10/10/1), the result has been specified in the title compound (1,93 g, yield 31%).

1H-NMR (Dl3): is 1.51 (3H, t, J=7,1 Hz), 4,58 (2H, q, J=7,1 Hz), of 7.48-7,58 (3H, m), 8,08-8,19 (2H, m), 8,78 (1H, s); MS: m/z = 245 (M + 1).

(5) 4-Allyl-2-etoxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyrazine.

2-Ethoxycarbonyl-3-hydroxy-5-vinylpyrazine (214,4 mg, 0.88 mmol) was dissolved in dimethylformamide (2.1 ml) to the solution while cooling in an ice bath was added sodium hydride (60% solution in oil, 42,1 g, 1.05 mmol) and was stirred for 30 minutes After adding allylbromide (0,11 ml of 1.32 mmol) and the mixture was stirred at room temperature for 1 hour and then at 80oC for 1 hour. The reaction solution was allowed to cool to room temperature, after which the reaction was stopped by adding distilled water, and the product was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1), the result has been specified in the title compound (24 mg, yield of 9.6%).

1H-NMR (Dl3): the 1.44 (3H, t, J=7,1 Hz), to 4.46 (2H, d, J=7,1 Hz), 4,49-4,56 (2H, m), 4,88-5,-5-phenyl-3,4-dihydropyrazine.

4-Allyl-2-ethoxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyrazine (1,09 g of 3.85 mmol) was dissolved in a mixed solvent consisting of methanol (25 ml) and tetrahydrofuran (10 ml), to this solution was added while cooling in ice 1 N. aqueous solution of sodium hydroxide (4,2 ml, 4.20 mmol) and the mixture was stirred at room temperature for 2 hours, the Reaction solution was neutralized with hydrochloric acid and concentrated under reduced pressure. Once added to the obtained residue distilled water, the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, resulting in a received 1,02 g solids. The obtained solid (1,02 g) was dissolved in tert-butyl alcohol (10,2 ml), 1,4-dioxane (2.6 ml) and triethylamine (1,11 ml), to the solution was added diphenylphosphoryl (0,86 ml, 3,98 mmol) at room temperature in an argon atmosphere and was stirred with heating at 90oC for 8 hours, the Reaction solution was allowed to cool to room temperature, and then thereto was added distilled water and product was extracted with ethyl acetate. The organic layer was dried n is igenom pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1), the result has been specified in the title compound (850 mg, yield 68% after 2 steps).

1H-NMR (CDl3): 1,54 (N, s), 4,45-to 4.52 (2H, m), a 4.83-equal to 4.97 (1H, m), 5,13 with 5.22 (1H, m), 5,67-5,88 (1H, m), 7,27 (1H, m), 7,30-of 7.55 (5H, complex spectrum), 8,32 (1H, s); MS: m/z = 328 (M + 1).

(7) 2-Tert-butyloxycarbonyl-3-oxo-5-phenyl-4-(2,3-dihydroxy)propyl-3,4-dihydropyrazine.

4-Allyl-2-tert-butyloxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyrazine (850 mg, 2,60 mmol) was dissolved in tetrahydrofuran (10.4 ml), to the solution was added 4-methylmorpholine-N-oxide (1,22 ml, 5,19 mmol) and 4% aqueous solution of osmium tetroxide (0,83 ml, 0.13 mmol) and the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and then washed sequentially with saturated aqueous sodium thiosulfate solution, distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 50/1), the result has been specified in m, overlaps with1N), 3,68-of 3.85 (1H, m), 4,06 (2H, d, J=6.2 Hz), 7,14 (1H, s), 7,29-7,53 (5H, complex spectrum), 8,29 (1H, s); MS: m/z = 362 (M + 1).

(8) 2-Tert-butyloxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyridin-4-ilocana acid.

2-Tert-butyloxycarbonyl-3-oxo-5-phenyl-4-(2,3-dihydroxy)propyl-3,4-dihydropyrazine (750 mg, a 2.01 mmol) was dissolved in tetrahydrofuran (10 ml), to the solution was added an aqueous solution of periodate sodium (solution 533 mg (2.49 mmol) of periodate sodium 6.7 ml of distilled water) and the mixture was stirred at room temperature for 4 h, the Tetrahydrofuran drove away under reduced pressure, then the reaction solution was diluted with ethyl acetate and then washed successively with distilled water and saturated sodium chloride solution. After that, the organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a colorless foam substances (710,7 mg).

The obtained compound (710 mg) was dissolved in tert-butanol (10,8 ml), then successively added 2-methyl-2-butane (1,01 ml, 9.50 mmol), an aqueous solution of disubstituted phosphate {solution 306,3 mg (2,16 mmol) of the disubstituted postia 6.8 ml of distilled water), and the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and then was extracted three times with saturated aqueous sodium bicarbonate solution. The aqueous layer was acidified anhydrous citric acid and was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the above compound (502,5 mg, yield 70% after two steps).

1H-NMR (Dl3): 1,53 (N, s), a 4.53 (2H, s), to 7.15 (1H, s), 7,30-rate of 7.54 (5H, complex spectrum), 8,14-to 8.34 (1H, m); MS: m/z = 346 (M + 1).

Examples 7 through 18

5-Tert-buyacticinonline-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid as the compound of the formula (V) and the compound of formula (III), where R3'- tert-butyloxycarbonyl, Z is methylene, a R0and R2- groups defined below, were subjected to condensation in the same manner as described in example 1 (1) and (2), have been synthesized compounds of formula (II), where R1- phenyl, R3- tert-butyloxycarbonyl, X is carbon, Y is nitrogen, Z is methylene, R0and R2- groups defined below.

The compounds of formula (III) are formed in react is soedinenii formula (II) are as follows.

Example 7: R0- phenyl, R2- butyl (compound 4):

1H-NMR (Dl3): of 0.85 (3H, t, J=7,1 Hz), 1,14-of 1.35 (2H, m), 1,42 is 1.58 (2H, m), 1,53 (N, s), 2,33 (1H, dt, J=7,4, to 17.4 Hz), 2,58 (1H, dt, J=7,4, to 17.4 Hz), 2,95 (2H, d, J=8.0 Hz), a 3.87 (1H, d, J=3.6 Hz), a 4.03 (1H, dd, J= 1,1, 3.5 Hz), or 4.31 (1H, d, J=15.3 Hz), 4,47 (1H, d, J=15.3 Hz), 4,70 (1H, ddt, J= 1,4, 8,1, 8,4 Hz), 6,40 (1H, d, J=9.5 Hz), 7,15-of 7.55 (1H, complex spectrum), 8,72 (1H, s).

Example 8: R0= R2= butyl (compound 5):

1H-NMR (DCl3): 1,53 (N, s), 2,98 (1H, dd, J=9,5, 13.1 Hz), is 3.08 (1H, dd, J=6,0, 13.1 Hz), 3,95 (1H, d, J=4,8 Hz), 4,32-4,89 (3H, complex spectrum), equal to 4.97 (1H, d, J=3,7 Hz), 6,36 (1H, d, J=9,2 Hz), 6,80-6,91 (1H, m), 7.03 is-7,13 (1H, m), 7,18-7,69 (14N, complex spectrum), 7,98-8,07 (1H, m), 8,65-8,77 (1H, m).

Example 9: R0= phenyl, R2= 3-ethoxycarbonylphenyl (compound 6):

1H-NMR (DCl3): to 1.21 (3H, t, J=7,1 Hz), 1,53 (N, s) to 1.87 (2H, quintet, J=7.0 Hz), 2,28 (1H, t, J=7,0 Hz) to 2.29 (1H, t, J=7.4 Hz), 2.40 a-2,49 (1H, t, J= 7.4 Hz), 2,67 was 2.76 (1H, t, J=7,1 Hz), 2,96 (2H, d, J=7.8 Hz), 3,70-4,20 (1H, user. s) of 4.04 (1H, user. s) 4,08 (2H, q, J=7,1 Hz), 4,34 (1H, d, J= 15.3 Hz), of 4.44 (1H, d, J=15.3 Hz), 4,60 was 4.76 (1H, m), 6.42 per (1H, d, J=9.4 Hz), 6.87 in-7,07 (3H, m), 7,19-7,33 (2H, m), 7,39-to 7.50 (5H, complex spectrum), 8,72 (1H, s).

Example 10: R0= 3-forfinal, R2= 3-ethoxycarbonylphenyl (compound 9):

1H-NMR (DCl3): to 1.21 (3H, t, J=7,1 Hz), 1,53 (N, s) to 1.87 (2H, quintet, J= 7,1 Hz), 2,28 (1H, t, J=7,0 Hz) to 2.29 (1H, t, J=7.4 Hz), 2.49 USD (1H, t, J= 7.4 FOR THE 60-4,76 (1H, m), 6.42 per (1H, d, J=9.4 Hz), 6.87 in-7,07 (3H, m), 7,19-7,33 (2H, m), 7,39-7,50 (2H, complex spectrum), 8,72 (1H, s); X (CVG): 3700-2800, 1720, 1677, 1512, 1492, 1370, 1252, 1221, 1154, 1087 cm-1.

Example 11: R0= phenyl, R2= 2-phenylethyl (compound 3):

MS: m/z = 548 (M + 1).

Example 12

Synthesis of 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-hydroxy-3-oxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl}exilerated (compound 12).

(1) (4R, 5S)-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-5-methoxycarbonyl-4-fenilmetilketil.

Methyl(2S, 3R)-3-tert-butyloxycarbonyl-2-hydroxy-4-phenylbutyrate (43 g, 0.14 mol) suspended in 2,2-dimethoxypropane (510 ml), to this was added p-toluensulfonate2O (2.6 g, 0.015 mol), the mixture is then warmed up in the atmosphere of argon, and the reaction solution gradually drove away. After 6 h, when the solution was completely removed, the heating was stopped and gave the contents to cool to room temperature. The residue was dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then received the second in the title compound (43 g, yield 88%).

1H-NMR (Dl3): 1,28-1,80 (15 NM, a complex spectrum), 2,72-is 3.08 (1H, m), 2,86 (1H, user. s) of 3.25 (2H, user. d, J=6.3 Hz), to 3.67 (3H, s), 4,37 (1H, d, J= 4.0 Hz), 4,50 (1H, user. d, J=13.5 Hz), 7,10-7,40 (5H, m).

(2) (4R, 5S)-3-(N-Tert-butyloxycarbonyl)-2,2-dimethyl-5-hydroxymethylimidazole.

(4R, 5S)-3-(N-Tert-butyloxycarbonyl)-2,2-dimethyl-5-methoxycarbonyl-4-fenilmetilketil (43 g, 0.12 mol) was dissolved in tetrahydrofuran (610 ml), to this was added under cooling in an ice bath, lithium-aluminum-hydride (7.0 g, 0.18 mol) and was stirred for 30 minutes, To this was added dropwise distilled water (10 ml), 3 N. aqueous solution of sodium hydroxide (10 ml) and distilled water (30 ml) in the sequence, then the precipitated solid was removed by filtration through celite and washed with melanoxylon. The organic layer was collected, washed with distilled water and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 4/1), eventually got mentioned in the title compound (35 g, yield 88%).

1H-NMR (DCl3): 1,21-1,73 (15 NM, SL is), 7,14 and 7.36 (5H, m).

(3) (4R, 5S)-3-(N-Tert-butyloxycarbonyl)-2,2-dimethyl-5-formyl-4-fenilmetilketil.

Methylene chloride (530 ml) and distilled water (53 ml) was added to a mixture of (4R,5S)-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-5-hydroxymethylcytosine (35 g, 0.11 mol), free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (185 mg, 0.01 mol), sodium bromide (12 g, 0.12 mol) and acidic sodium carbonate (26 g, 0.31 mol) forming a 2-phase system. After cooling the reaction system in ice to it was added dropwise with intensive stirring 0,62 M aqueous solution of hydrochloride sodium (200 ml, 0.12 mol). After this was stirred reaction solution for 10 min and then washed sequentially with 10% aqueous solution of acid potassium sulfate, with 0.6% aqueous solution of potassium iodide, then 10% aqueous sodium thiosulfate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 4/1), eventually got mentioned in the title compound (21 g, yield 62%).

1H-NMR (CDCl3): 1,10-1,80 (15 NM, a complex spectrum), 2,62-3,45, hydroxy-4-phenylmethoxy)-4-fenilmetilketil.

(4R, 5S)-3-(N-Tert-butyloxycarbonyl)-2,2-dimethyl-5-formyl-4-fenilmetilketil (19 g, 0.6 mol) was dissolved in tetrahydrofuran and cooled to -30oFrom then to this solution was added dropwise to 0.63 M 3-phenylethylenediamine-magnesium bromide in tetrahydrofuran (140 ml, 0.8 mol). After the addition has removed the cooling bath and stirred the mixture at room temperature for 2 hours thereafter, to the reaction solution was added an aqueous solution of ammonium chloride, and the solid precipitate was removed by filtration through celite. After adding to the filtrate ethyl acetate filtrate was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 4/1), eventually got mentioned in the title compound (28 g, yield 90%). This compound is a mixture of stereoisomers due to the different configuration of the hydroxyl group. Was defined spectrum of this mixture. Listed below are the signals 25 for the main isomer.

1H-NMR (CDCl3, main isomer): 0,97-1,80 (17H, complex spectrum), of 2.51 (1H, d, J=4,8 Hz), 2,60-of 3.00 (1H, user. s) and 3.15 (1H, dd, J=3,0, 13.1 Hz), 3,23-3,56 (Tret-butyldimethylsilyloxy-4-phenylmethoxy)-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil.

(4R, 5S)-3-(N-Tert-butyloxycarbonyl)-5-(1-hydroxy-4-phenylmethoxy)-4-fenilmetilketil (28 g, 0.06 mol) and imidazole (10 g, 0.15 mol) was dissolved in N, N-dimethylformamide (120 ml), to the solution was added while cooling in ice tert-butyldimethylsilyloxy (12 g, 0.08 mol), then the solution was stirred over night at room temperature. To the reaction solution was added diethyl ether, after which it was washed successively with distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 9/1), eventually got mentioned in the title compound (26 g, yield 72%). This compound is a mixture of stereoisomers due to the different configuration tert-butyldimethylsilyloxy. Was defined spectrum of this mixture. Listed below are the signals for the main isomer.

1H-NMR (Dl3, main isomer): 0,02 (6N, s) 0,77 (N, s), is 1.35 and 1.80 (M, complex spectrum), is 2.88 (1H, dd, J=9,4 and 12.8 Hz), totaling 3.04 (1H, dd, J=3,6 and 12.8 Hz), of 3.45 (1H, t, J=6.2 Hz), 3,63 is 3.76 (1H, m), 3,76-of 3.94 (1H, m), 4,11-4,22 (1H, m) to 4.52 (2H, s), 6,16-7,40 (10H, complex spectrum).

(6) (4R,5S)-5-(1-Tert->/P>(4R, 5S)-5-(1-Tert-butyldimethylsilyloxy-4-phenylmethoxy)-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (32 g, 0.54 mmol) was dissolved in methanol (270 ml), then to the solution was added palladium black (1.6 g) and the mixture was stirred at room temperature for 4 h in an atmosphere of hydrogen. Palladium black was removed by filtration, then the filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 14/1), eventually got mentioned in the title compound (26 g, yield 98%). This compound is a mixture of stereoisomers due to the different configuration tert-butyldimethylsilyloxy. Was defined spectrum of this mixture. Listed below are the signals for the main isomer.

1H-NMR (Dl3, main isomer): 0,02 (6N, s) 0,76 (N, s), 1,38-1,85 (N, complex spectrum), of 2.86 (1H, dd, J=9.3 and 12.9 Hz), totaling 3.04 (1H, dd, J=3,9 and 12.9 Hz), 3.25 to of 3.78 (3H, complex spectrum), 3,85-4,00 (1H, m), 4,08-is 4.21 (1H, m), 7,15-7,34 (5H, m).

(7) (4R, 5S)-5-{ 4-Bromo-1-(1-tert-butyldimethylsilyloxy)butyl} -3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil.

(4R, 5S)-5-(1-Tert-butyldimethylsilyloxy-4-hydroxybutyl-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-phenylmethyl is niphophila (14 g, 0,052 mol) and N-bromosuccinimide (9.3 g, 0,052 mol), the temperature was raised and the mixture was stirred at room temperature for 2 hours Solid precipitate was removed by filtration through celite, and the filtrate was washed successively with 5% aqueous sodium thiosulfate solution, 1 N. aqueous solution of sodium hydroxide and a saturated solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, the obtained residue was added hexane, and the precipitated solids were removed by filtration, and the filtrate was again concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 14/1), eventually got mentioned in the title compound (24 g, yield 82%). This compound is a mixture of stereoisomers due to the different configuration tert-butyldimethylsilyloxy. Was defined spectrum of this mixture. Listed below are the signals for the main isomer.

1H-NMR (Dl3, main isomer): 0,02 (6N, s) 0,76 (N, s), 1,40-2,00 (N, complex spectrum), 2,85 (1H, dd, J=9,1 and 13.0 Hz), 3,05 (1H, dd, J=3,9 and 13.0 Hz), to 3.38 (2H, m), of 3.78 (1H, user. D, J=8.5 Hz), 4,07-is 4.21 (1H, m), 7,11-7,41 (5H, m); MS: m/z = 556 (M + 1).

(8) (4R, 5S)-5-{1-Tert-butyldimethylsilyloxy">

Sodium hydride (0,72 g, 0.018 mol) is suspended in N,N-dimethylformamide (45 ml) and to this solution was added dropwise with cooling in ice, a solution of 2-hydroxypyridine (1.7 g, 0.018 mol) in N,N-dimethylformamide (15 ml). After that, the mixture was stirred at room temperature for 1 hour and the reaction system was again cooled in ice. To this solution was added dropwise a solution of (4R,5S)-5-{4-bromo-1-(1-tert-butyldimethylsilyloxy)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-perimeterisation (5 g, 9 mmol) in N,N-dimethylformamide (30 ml) and the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and washed sequentially with distilled water, 10% aqueous citric acid solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 7/1), eventually got mentioned in the title compound (3.7 g, yield 71%).

1H-NMR (CDCl3): 0,04 (6N, s) 0,71 (N, user. s), 1,34-1,89 (N, complex spectrum), 2,73 of 2.92 (1H, m), 3,01 (1H, dd, J=3,6 and 12.9 Hz), 3,55-of 3.97 (3H, complex spectrum), 4,01-4,16 (1H, m), 6,13 (1H, dt, J=1,3 and 6.7 Hz), 6,50-6 the e accompanying product was obtained (4R,5S)-5-{1-tert-butyldimethylsilyloxy-4-(2-pyridyloxy)butyl} -3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (1.3 g, yield 24%).

1H-NMR (DCl3): 0,00 (6N, s, overlapping with the peak of the internal standard), of 0.64 to 0.97 (N, m), 1,38-1,90 (N, complex spectrum), 2.77-to and 3.16 (2H, m), 3,66-4,34 (5H, complex spectrum), 6,70 (1H, d, J=8,4 Hz), 6,83 (1H, ddd, J= 1,9, a 5.1 and 8.4 Hz), 7,09-7,34 (5H, m), 7,54 (1H, ddd, J=0,9, of 7.0 and 8.4 Hz), 8,13 (1H, ddd, J=0,9, to 1.9 and 5.1 Hz).

(9) (4R, 5S)-5-{ 1-Oxo-4-(2-oxo-1,2-dihydropyridines-1-yl)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (intermediate compound 12).

(4R, 5S)-5-{ 1-Tert-butyldimethylsilyloxy-4-(2-oxo-1,2-dihydropyridines-1-yl)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (3.8 g, 6.6 mmol) was dissolved under cooling in ice in a 1.0 M solution of tetrabutylammonium in tetrahydrofuran (10 ml) and was stirred for 4 h the Reaction solution was diluted with ethyl acetate and washed sequentially with 10% aqueous citric acid solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain the crude product.

To methylene chloride (2.4 ml) was added in argon atmosphere oxalicacid (1.5 ml, 17 mmol) and cooled to -60oC. To this RC was stirred for 15 min and then thereto was added dropwise a solution of the above crude product in methylene chloride (20 ml). Then the mixture was stirred for 1 hour, the reaction temperature was raised to -40oWith and to the mixture was added triethylamine (9.5 ml, 68 mmol). The reaction solution was diluted with methylene chloride and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform/methanol = 30/1), the result has been specified in the title compound (2.6 g, yield 89%).

1H-NMR (Dl3): 1,17-1,65 (15 NM, a complex spectrum), with 1.92 (2H, dd, J=2,2 and 7.3 Hz), 2,25-a 2.71 (2H, m), 2,73-of 3.12 (1H, m), 3,21 (1H, dd, J=3.0 and 13.3 Hz), 3,85 (2H, dt, J=2,2 and 7.3 Hz), is 4.21 (1H, user. s), 4,30 ñ 4.50 (1H, m), 6,13 (1H, dt, J=1,3 and 6.7 Hz), of 6.52 (1H, d, J=9,2 Hz), 7,13 was 7.45 (7H, complex spectrum).

(10) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-hydroxy-3-oxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl}exilerated (compound 12).

(4R,5S)-5-{1-Oxo-4-(2-oxo-1,2-dihydropyridines-1-yl)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (2.6 g, 5.8 mmol) was dissolved in methanol (28 ml), to this solution was added p-toluensulfonate2Oh (2.4 g, 13 mmol), the mixture was warmed up to reflux for 1.5 hours the Reaction solution is of trihydrogen (8 ml), to the solution were added successively 5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (2.4 g, 7.0 mmol), 1-hydroxybenzotriazole2O (1.3 g, 8.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.3 mmol) and N-methylmorpholine (1.5 ml, 14 mmol), then the temperature was raised to room temperature and the mixture was stirred over night. The reaction solution was diluted with ethyl acetate and washed sequentially with distilled water, saturated aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was added diethyl ether to precipitate solids. Precipitated solids were collected by filtration and recrystallized from a solvent mixture of chloroform/methanol/diethyl ether, the result has been specified in the title compound (2.3 g, yield 56%).

1H-NMR (Dl3): 1,60 (N, s), 1,99 (2H, quintet, J=7.0 Hz), 2,43 (1H, dt, J=7,0 to 18.1 Hz), is 2.74 (1H, dt, J=7,0 and 18.1 Hz), 2,97 (1H, d, J=7.8 Hz), 3,88 (1H, q, J=7.0 Hz), a 4.03-4,18 (2H, complex spectrum), to 4.41 (2H, d, J=3.3 Hz), to 4.62 (1H, q, J=7.8 Hz), 6,16 (1H, dt, J=1,4 and 6.7 Hz), 6,45-is 6.54 (1H, m), 6,70 (1H hydropyridine-1-yl)-N-{ 2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 13).

(1) (4R, 5S)-5-{ 1-Oxo-4-(2-pyridyloxy)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (intermediate compound 13).

(4R, 5S)-5-{ 1-Tert-butyldimethylsilyloxy-4-(2-pyridyloxy)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (1.3 g, 2.2 mmol), obtained as a side product in example 12 (8), was dissolved in 1.0 M solution of tetrabutylammonium in tetrahydrofuran (6.3 ml, 6.3 mmol) while cooling in ice and was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and washed sequentially with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1 to 2/1) to give the crude product. To methylene chloride (10 ml) in an argon atmosphere was added oxalicacid (0,38 ml, 4.4 mmol) and cooled to -60oC. To this solution was added dropwise a mixture of dimethyl sulfoxide (of 0.62 ml, 8,7 mmol) and methylene chloride (0,62 ml). After that, the reaction solution was stirred for 15 minly for 15 min, the reaction temperature was raised to -40oWith and to the mixture was added triethylamine (9.5 ml, 68 mmol). The reaction solution was diluted with methylene chloride and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform/ethyl acetate = 1/1 to 1/1,5), the result has been specified in the title compound (874 mg, yield 88%).

1H-NMR (Dl3): 1,09-1,80 (15 NM, a complex spectrum), 1,88-of 2.09 (2H, m), 2,38-to 3.34 (4H, complex spectrum), 4,14-4,34 (3H, complex spectrum), 4,34-of 4.57 (1H, m), 6,53-6,72 (1H, m), 6,77-6,93 (1H, m), 7,11-7,38 (5H, m), 7,45 to 7.62 (1H, m), 8,04-8,16 (1H, m).

(2) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 13).

(4R, 5S)-5-{ 1-Oxo-4-(2-pyridyloxy)butyl} -3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-fenilmetilketil (867 mg, 1.9 mmol) was dissolved in methanol (9 ml), to this solution was added p-toluensulfonate2(762 mg, 4.2 mmol) and the mixture was heated under reflux for 1.5 hours, the Reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in a mixture of N,N-dimethyl-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (763 mg, 2.2 mmol), 1-hydroxybenzotriazole2O (402 mg, 2.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (503 mg, 2.6 mmol) and N-methylmorpholin (0,49 ml, 4.4 mmol), then the temperature was raised to room temperature and the mixture was stirred over night. The reaction solution was diluted with ethyl acetate and washed sequentially with distilled water, saturated aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform/methanol = 40/1 to 30/1). The solid is precipitated with addition of purified material diethyl ether and hexane. The solid precipitate was collected by filtration, and the result has been specified in the title compound (2.3 g, yield 56%).

1H-NMR (CDCl3): 1.52m (N, s), 1,91-of 2.16 (2H, m), of 2.54 (1H, dt, J=7,2 and 17.8 Hz), and 2.79 (1H, dt, J=7,2 and 17.8 Hz), 2,97 (2H, d, J=8.0 Hz), 3,90 (1H, d, J=3,4 Hz), 4.04 the-4,12 (1H, m), 4,13-4,37 (3H, complex spectrum) 4,48 (1H, d, J=15.3 Hz), 6,40 (1H, d, J=9.4 Hz), only 6.64 (1H, dt, J=0,9 and 8.4 Hz), PC 6.82 (1H, ddd, J= 0,9, of 5.1 and 7.1 Hz), 7,13-to 7.59 (M, complex spectrum), 8,07 (1H, ddd, J=0,9 and 2.2 and 5.1 Hz), 8,72 (1H, s).

(3) In this example was n the)-2,2-dimethyl-4-perimeterisation and p-toluenesulfonic acid in methanol formed 2 product. Therefore, after the heat treatment, the portion of the reaction solution in the usual way were subjected to tert-butyloxycarbonyl. In the result, it was determined that these 2 products are the following compounds:

(2S, 3R)-2-tert-butyloxycarbonyl-3-hydroxy-4-oxo-1-phenyl-7-(2-pyridyloxy)heptane

1H-NMR (CDCl3): 1,38 (N, s), 1,79-2,12 (2H, complex spectrum), 2,38-of 2.81 (4H, complex spectrum), 4,10 (1H, user. s), 4,18-4,39 (4H, complex spectrum), to 5.03 (1H, d, J=8,4 Hz), 6,69 (1H, dt, J=0,8 and 8.4 Hz), 6,85 (1H, m) 7,10-7,29 (5H, complex spectrum), at 7.55 (1H, ddd, J=2,1, to 7.2 and 8.4 Hz), 8,12 (1H,m);

(2S, 3S)-2-tert-butyloxycarbonyl-3-hydroxy-4-oxo-1-phenyl-7-(2-pyridyloxy)heptane

1H-NMR (CDCl3): 1,35 (N, s), 1,96-2,12 (2H, complex spectrum), 2,44-to 2.67 (1H, m), 2,73 are 2.98 (3H, complex spectrum), 3,83 (1H, user. d) a 4.03 (1H, user. s), 4,19-4,43 (3H, complex spectrum), was 4.76 (1H, d, J=9.9 Hz), of 6.65 (1H, user. d, J= 8,3 Hz), 6,83 (1H, m), 7.24 to 7,53 (5H, complex spectrum), 7,53 (1H, ddd, J=2,0, a 7.1 and 8.7 Hz), of 8.09 (1H, m).

Example 14: R0= 3-were, R2= methyl (compound 17);

1H-NMR (CDCl3): 1,53 (N, s), measuring 2.20 (3H, s), 2,32 (3H, s), of 2.92 (2H, d, J= 8.0 Hz), 3,82 (1H, d, J=3.5 Hz), of 4.05 (1H, dd, J=1.3 and 3.5 Hz), or 4.31 (1H, d, J= 15,4 Hz), 4,49 (1H, d, J=15,4 Hz), 4,65-to 4.81 (1H, m), of 6.29 (1H, d, J= 9.5 Hz), 7,01 for 7.12 (2H, complex spectrum), 7,16 (1H, d, J=7,3 Hz), 7,25-to 7.32 (1H, overlapped with solvent peak), was 7.36-7,50 (61H-NMR (CDCl3): 1,53 (N, s) by 2.13 (3H, s), to 2.57 (1H, dd, J=6,1 and 14.4 Hz), 2,71 (1H, dd, J=8.6 and 14.4 Hz), 4,13 (1H, d, J=4.5 Hz), or 4.31-4,37 (1H, m), 4,47 (2H, dd, J=2,3 and 15.3 Hz), 4.63 to-and 4.68 (1H, m), 6,79 (1H, d, J=8,8 Hz), 6,94-7,00 (1H, m), 7,12-7,50 (N, complex spectrum, overlapped with solvent peak), the 7.43 (1H, s).

Example 16: R0= 4-forfinal, R2= methyl (compound 15);

1H-NMR (CDCl3): 1,53 (N, s), are 2.19 (3H, s), with 2.93 (2H, d, J=8.0 Hz), 3,85 (1H, user. s), as 4.02 (1H, d, J=1.2 Hz), 4,33 (1H, d, J=15,4 Hz), 4,46 (1H, d, J= 15,4 Hz), 4,62-4,80 (1H, m), of 6.26 (1H, d, J=9.5 Hz), 6,93-7,06 (2H, m), 7,20-to 7.32 (5H, complex spectrum), 7,39-of 7.48 (5H, complex spectrum), 8,71 (1H, s); MC: m/z = 539 (M + 1).

Example 17: R0= 4-chlorophenyl, R2= methyl (compound 16);

1H-NMR (Dl3): 1.52m (N, s), are 2.19 (3H, s), with 2.93 (2H, d, J=7.8 Hz), a 3.87 (1H, user. s), as 4.02 (1H, d, J=15,4 Hz), 4,46 (1H, d, J=15,4 Hz), with 4.64-rate 4.79 (1H, m), of 6.29 (1H, d, J=9.4 Hz), 7,17-to 7.32 (5H, complex spectrum), 7,39-7,56 (5H, complex spectrum), 8,72 (1H, s); MS: m/z = 556 (M + 1).

Example 18: R0= 3-forfinal, R2= {4-(4-methylpiperazin-1-yl)-4-oxo} propyl (compound 10);

1H-NMR (Dl3): 1,53 (N, s), 1,81-of 1.97 (3H, complex spectrum), and 2.26-2,80 (11N, complex spectrum), 2,95 (2H, d, J=7,6 Hz) to 3.41 (2H, user. dd), of 3.57 (2H, user. dd), 4,08 (1H, user. d), 4,35 (1H, d, J=15,4 Hz), of 4.45 (1H, d, J= 15,4 Hz) and 4.65 (1H, m), 6,59 (1H, user. d), 6.87 in-7,51 (3H, complex spectrum), 8,72 (1H, s).

Example 19: R0= 2-forfinal, R2= METI is), 4,10-4,58 (3H, complex spectrum), 4,70-of 4.90 (1H, m), 6,47 (0.5 H, d, J=9.5 Hz), 6.75 in (0.5 N, d, J=7.9 Hz), 6,97-7,43 (N, complex spectrum).

Example 20: R0= 3-fluoro-4-hydroxyphenyl, R2= methyl (compound 19);

1H-NMR (Dl3): 1,53 (N, m), of 2.20 (3H, s), of 2.86 (2H, d, J=7.8 Hz), 3,93 (1H, user. s) of 4.05 (1H, user. s), or 4.31 (1H, d, J=15,4 Hz) to 4.41 (1H, d, J= 15.2 Hz), 4,62 was 4.76 (1H, m), 6,45-7,00 (5H, complex spectrum), 7,38-7,50 (6N, complex spectrum), 8,68 (1H, user. s); MS: m/z = 555 (M + 1).

Example 21: R0= phenyl, R2= methoxy group (compound 14);

2-Tert-butyloxycarbonyl-3-oxo-5-phenyl-3,4-dihydropyridin-4-ilocana acid as the compound of the formula (V) and the compound of formula (III), where R3'- amino group, Z is methylene, R0is a phenyl group, a R2- methoxy group, were subjected to condensation by the method described in example 1 - p. (1) and p. (2), were synthesized compounds of formula (II), where R1- phenyl, R3-tert-butyloxycarbonyl, X is nitrogen, Y is carbon, Z is methylene, and R0and R2- groups defined below. The compounds of formula (III) are formed in the reaction system from their respective oxazolidinone derivatives.

The physical properties of the target compounds of formula (II) as follows:

R0= phenyl, R2= methoxy group (compound 14);

, ,53-4,68 (1H, m), of 6.52 (1H, d, J=9,2 Hz), 7,13 (1H, s), 7,14-7,53 (11N, complex spectrum), 8,23 (1H, s); MS: m/z + 537(M + 1).

Examples 22 through 34

The same method as in example 1 (3), was used for an oxidation reaction of the alcohol of formula (II), to obtain the compounds of formula (I), where R1- phenyl, R3- tert-butyloxycarbonyl, X is carbon, Y is nitrogen, Z is methylene, and R0and R2group below. The physical properties of the compounds of formula (I) are as follows.

Example 22 (1): R0= phenyl, R2= 3-phenylpropyl (compound 39);

1H-NMR (Dl3): 1,53 (N, s), 1,83 is 2.00 (2H, m), 2,59-2,82 (4H, complex spectrum), 2,91-to 3.02 (1H, dd, J=7.8 and 14.1 Hz), 4,47 (2H, user. d), 5,22-5,33 (1H, m), 6,47 (1H, user. d, J=6.6 Hz), 7,00-7,50 (N, complex spectrum, overlapping with solvent peak), 8,72 (1H, s).

Example 22 (2): R0= phenyl, R2= 2-phenylethyl (compound 41);

1H-NMR (Dl3): 1,53 (N, s), 2,85-3,20 (4H, complex spectrum), 4,47 (2H, user. d) at 5.27 (1H, m), 6,47 (1H, user. d, J=6.2 Hz), 6,95-7,50 (N, complex spectrum), 8,72 (1H, s).

Example 23: R0= phenyl, R2= butyl (compound 43);

1H-NMR (Dl3): to 0.92 (3H, t, J=7,1 Hz), 1,22 was 1.43 (2H, m), 1,47-of 1.65 (2H, m), and 1.54 (N, s), 2,61-and 2.83 (2H, m), 2,99 (1H, dd, J=7,8 and 14.0 Hz), 3,21 (1H, dd, J=5.3 and 14.1 Hz), 4,48 (2H, d, J=1.3 Hz), to 5.21-of 5.34 (1H, m), of 6.50 (1H, d, J=6.5 Hz), 7,01-7,54 (11N, complex spectrum) 8,71 (1H, s(N, s), and 3.16 (1H, dd, J=5,1 and 14.2 Hz), 4,42 (2H, s), 5,13 (1H, ddd, J=5,1, of 6.4 and 8.7 Hz), 6,72 (1H, d, J=6.4 Hz), 7,00-7,70 (14N, complex spectrum), to 7.93-8,03 (2H, m), 8,67 (1H, s); MS: m/z = 581 (M + 1).

Example 25: R0= phenyl, R2= 3-carboxypropyl (compound 47);

1H-NMR (Dl3): 1,34 (1.5 N, s), 1,36 (1.5 N, s), for 1.49 (3H, s) and 1.51 (3H, s), 1,60-2,00 (2H, m), 2,24-3,24 (6N, complex spectrum), 4,10-the 4.29 (1H, m), of 4.38-and 4.68 (2H, complex spectrum), 6,80-7,56 (10H, complex spectrum), 8,43-8,63 (1H, m); MS: m/z = 589 (M - N).

Example 26: R0= 3-forfinal, R2= 3-ethoxycarbonylphenyl (compound 53);

1H-NMR (Dl3): a 1.25 (3H, t, J=7,1 Hz), and 1.54 (N, s), with 1.92 (2H, quintet, J= 7,1 Hz), was 2.34 (2H, t, J=7,1 Hz), of 2.81 (1H, t, J=7,1 Hz), 2,82 (1H, t, J= 7,3 Hz), of 2.97 (1H, dd, J=9.1 and of 14.0 Hz), up 3.22 (1H, dd, J=5.3 and 14.1 Hz), of 4.12 (2H, q, J=7.2 Hz), of 4.49 (2H, s), 5,16 is 5.28 (1H, m), 6,62 (1H, d, J=6.2 Hz), 6,78-of 6.99 (3H, m), 7,16-7,29 (2H, m), 7,43-to 7.50 (5H, m), 8,71 (1H, s); X (KBr): 3410, 2990, 1727, 1655, 1510, 1490, 1369, 1250, 1152 cm-1. MS: m/z = 581 (M + H - 56).

Example 27: 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl}exilerated (compound 72).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-hydroxy-3-oxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated (115 mg, 0.18 mmol) was dissolved in dimethyl sulfoxide (2 ml) in an argon atmosphere, to this RA is ing (17 mg, 0.1 mmol) and the mixture was stirred for 3.5 hours the Reaction solution was diluted with ethyl acetate and washed successively with distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (chloroform/methanol = 30/1), then was added to the residue purified hexane to precipitate solids. The solid precipitate was collected by filtration, and as a result received the above mentioned product (96 mg, yield 83%).

1H-NMR (Dl3): 1,60 (N, s), 1,99 (2H, quintet, J=7.0 Hz), 2,43 (1H, dt, J= 7,0 and 18.1 Hz), is 2.74 (1H, dt, J=7,0 and 18.1 Hz), 2,97 (1H, d, J=7.8 Hz), 3,88 (1H, q, J=7.0 Hz), a 4.03-4,18 (2H, complex spectrum), to 4.41 (2H, q, J= 3.3 Hz), to 4.62 (1H, q, J=7.8 Hz), 6,16 (1H, dt, J=1,4 and 6.7 Hz), 6,45-is 6.54 (1H, m), 6,70 (1H, d, J=9.5 Hz), 7,13-7,53 (N, complex spectrum), 8,68 (1H, s).

Example 28: 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-pyridyloxy)-1-phenylmethyl} exilerated (compound 74).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-hydroxy-3-oxo-1-phenylmethyl-(2-pyridyloxy)}exilerated (823 mg, 1.28 mmol) was dissolved in dimethyl sulfoxide (0,46 ml), to this is Shandong Jinlong (123,6 mg, 0.64 mmol) and the mixture was stirred for 1.5 hours the Reaction solution was diluted with ethyl acetate and washed successively with distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, the obtained residue was purified column chromatography on silica gel (chloroform/ethyl acetate = 2/1 to 1/1), and then to a purified residue was added diethyl ether to precipitate solids. The solid precipitate was collected by filtration, eventually got mentioned in the title compound (401 mg, yield 49%).

1H-NMR (Dl3): 1.52m (N, s) 2,07 (2H, quintet, J=6.5 Hz), 2,75 be 3.29 (4H, complex spectrum), 4,30 (2H, t, J=6.5 Hz), to 4.41-a 4.53 (2H, m), 5,22 is 5.38 (1H, m), 6,63 (1H, d, J=6.6 Hz), 6,69 (1H, dt, J=1,0 and 8.4 Hz), at 6.84 (1H, ddd, J= 1,0, the 5.1 and 7.1 Hz), 6,94-7,50 (11N, complex spectrum), at 7.55 (1H, ddd, J=2,0, a 7.1 and 8.4 Hz), 8,10 (1H, ddd, J=1,0, 2,0 and 5.1 Hz), 8,71 (1H, s); MS: m/z = 640 (M + 1).

Example 29: R0= 3-were, R2= methyl (compound 59);

1H-NMR (Dl3): 1,54 (N, s) to 2.29 (3H, s), of 2.33 (3H, s), to 2.94 (1H, dd, J= 8,1 and 14.0 Hz), and 3.16 (1H, dd, J=5.4 and of 14.0 Hz), of 4.49 (2H, s), a total of 5.21 (1H, ddd, J= 5,4, 6.1 and 8.1 Hz), 6.48 in (1H, d, J=6,1 Hz), 6,79-7,63 (10H, complex spectrum), 8,71 (1H, s).

Example 30: R0= 3-chlorophenyl, R2= methyl (compound 61);

1H-d, J=6.3 Hz), 6.89 in-7,05 (1H, m), 7,11 (1H, s), 7,15-7,24 (3H, m), 7.24 to to 7.59 (5H, m), 8,72 (1H, s).

Example 31: R0= 4-forfinal, R2= methyl (compound 55);

1H-NMR (Dl3): 1,54 (N, s), of 2.34 (3H, s), 2,96 (1H, dd, J=7.8 and 14.1 Hz), 3,13-3,37 (1H, m), 4,48 (2H, s), 5,15 at 5.27 (1H, m), 6,50 (1H, d, J=6.6 Hz), 6,83-7,58 (10H, complex spectrum), 8,72 (1H, user. s); MS: m/z = 536 (M + 1).

Example 32: R0= 4-chlorophenyl, R2= methyl (compound 57);

1H-NMR (Dl3): 1,54 (N, s), of 2.34 (3H, s), to 2.94 (1H, dd, J=7,9 and 14.1 Hz), 3,21 (1H, dd, J=5.3 and 14.1 Hz), 4,48 (2H, s), 5,13-a 5.25 (1H, m), 6,55 (1H, d, J= 6.6 Hz), 6,97-7,27 (5H, complex spectrum), 7,31-7,56 (5H, complex spectrum), 8,72 (1H, user. s); X (CVG): 3400, 1718, 1658, 1509, 1490, 1414, 1389, 1365, 1250, 1219, 1150, 1082 cm-1; MS: m/z = 554 (M + 1).

Example 33: R0= 3-forfinal, R2= {4-(4-methylpiperazin-1-yl)-4-oxo} propyl (compound 68).

1H-NMR (Dl3): 1,53 (N, s), 1.85 to 2.05 is (2H, complex spectrum), 2,27-2,50 (N, complex spectrum), 2,75-of 3.27 (4H, complex spectrum), 3,43-the 3.65 (4H, complex spectrum), 4,50 (2H, s), 5,10 (1H, m), 6,78-7,02 (4H, complex spectrum), 7,16-to 7.35 (2H, overlapping with solvent peak), 7,40-rate of 7.54 (5H, complex spectrum), to 8.70 (1H, s).

Example 34: R0= 2-forfinal, R2= methyl (compound 63).

1H-NMR (Dl3): 1,54 (N, s), of 2.38 (3H, s), 3,21 (2H, user, d) 4,50 (2H, s), 5,41 (1H, dd, J=5,8 and 7.0 Hz), 6,46 (1H, d, J=7,0 Hz), 6.90 to-7,27 (4H, complex specs for oxidation reaction of the alcohol of formula (II), to obtain the compound of formula (I) (compound 66), where R1- phenyl, R3- tert-butyloxycarbonyl, X is nitrogen, Y is carbon, Z is methylene, R0is a phenyl group, a R2- methoxy group.

1H-NMR (Dl3): 1,56 (N, s), of 2.51-to 3.33 (2H, m), 3,65-to 3.89 (3H, m), 4,21-5,50 (3H, complex spectrum), 6,36-6,60 (1H, m), 6,98-7,52 (11N, complex spectrum), 8,12-of 8.27 (1H, m); MS: m/z = 535(M + 1).

Examples 36 through 49

The same method as in example 1 (4) was applied to unprotect the compounds of formula (I), where R3- tert-butyloxycarbonyl group to obtain the corresponding hydrochloride compounds of formula (I), where R3is hydrogen, R3= phenyl, X is carbon, Y is nitrogen, Z is methylene, and R0and R2- groups defined below.

Example 36: R0= 3-fluoro-4-hydroxyphenyl, R2= methyl (compound 50);

1H-NMR (CD3OD): 2,23-2,39 (3H, m), 3,12-the 3.65 (2H, m), 4,48-5,12 (3H, complex spectrum), 6,68? 7.04 baby mortality (3H, m), 7,22-of 7.90 (6N, complex spectrum).

Example 37: R0= phenyl, R2= butyl (compound 44);

1H-NMR (Dl3): 0,86 (3H, t, J=6.9 Hz), 1,17 is 1.58 (4H, m), 2.40 a-2,78 (2H, m), 2,80-3,18 (2H, m), 4,30-4,80 (2H, m), 5,12-of 5.53 (1H, m), 6,84-7,82 (11N, complex spectrum); MS: m/z = 461 (M + 1).

Example 38: R0= R2= phenyl (compound 46);

1H-NMR (CDCl3): 3,16 (1st range), 7,94-with 8.05 (2H, m); MS: m/z = 481 (M + 1).

Example 39: R0= phenyl, R2= 3-phenylpropyl (compound 40);

MC: m/z = 560(M + 1).

Example 40: R0= phenyl, R2= 2-phenylethyl (compound 42);

MS: m/z = 546 (M + 1).

Example 41: R0= phenyl, R2= 3-carboxypropyl (compound 48);

1H-NMR (CD3D): 1,73-2,05 (11N, complex spectrum), 2,15-3,25 (6N, complex spectrum), 3.95 to 4,72 (3H, complex spectrum), 7,05-7,65 (11N, complex spectrum); MS: m/z = 491 (M + 1).

Example 42: R0= 3-forfinal, R2= 3-ethoxycarbonylphenyl (compound 54);

1H-NMR (DMSO-d6): of 1.17 (3H, t, J=7,1 Hz), 1,72 (2H, quintet, J=7.2 Hz), 2,31 (2H, t, J=7.4 Hz), 3,62-2,90 (3H, m), 3,10 (1H, dd, J=4,5 and 13.9 Hz), of 4.05 (2H, q, J=7,1 Hz), 4,36 (1H, d, J=16.5 Hz), 4,42 (1H, d, J=16.5 Hz), 4,82-is 4.93 (1H, m), 6,86-7,10 (3H, m), 7,21-the 7.65 (7H, m), 9,01 (1H, d, J=6.6 Hz); X (CVG): 37000-2400, 1683, 1646, 1540, 1373, 1250, 1180 cm-1; MS: m/z = 537 (M + 1).

Example 43: R0= phenyl, R2= 3-(2-pyridyloxy)propyl (compound 75);

1H-NMR (DMSO-d6): 1,94 (2H, quintet, J=6,7 Hz), 2,58-3,20 (4H, complex spectrum), 4,27 (2H, t, J=6,7 Hz), of 4.44 (1H, user. s) of 4.45 (1H, user. s), 4,88-free 5.01 (1H, m), 6,78-6,94 (1H, m), of 6.96-was 7.08 (1H, m), 7,08-7,70 (11N, complex spectrum), 7,70-7,86 (1H, m), 8,10-to 8.20 (1H, m), 8,90-9,05 (1H, m); MS: m/z = 540 (M + 1).

Example 44: R0= 3-were, R2= methyl (compound 60);

1H-NMR (DMSO), 4,73-4,94 (1H, m), 6,82-7,24 (4H, m), 7,25-to 7.68 (5H, m), to 8.94 (1H, d, J=6.2 Hz).

Example 45: R0= 3-chlorophenyl, R2= methyl (compound 62);

1H-NMR (DMSO-d6): 2,07-of 2.34 (3H, m), a 2.75 (1H, dd, J=9,3 and 14.0 Hz), to 3.09 (1H, dd, J=4,7 and 14.0 Hz), 3,80-and 5.30 (3H, complex spectrum, overlapping with solvent peak), of 6.96-7,80 (N, complex spectrum), 9,04 (1H, d, J=6.3 Hz).

Example 46: R0= 4-chlorophenyl, R2= methyl (compound 58);

1H-NMR (DMSO-d6): of 2.24 (3H, s), is 2.74 (1H, dd, J=9,2 and 13.9 Hz), of 3.07 (1H, dd, J= 4,7 and 13.9 Hz), and 4.40 (2H, s), 4,10-5,20 (4H, complex spectrum), 7,10-to 7.64 (10H, complex spectrum), 8,97 (1H, d, J=6.6 Hz); MS: m/z = 454 (M + 1).

Example 47: R0= 4-forfinal, R2= methyl (compound 56);

1H-NMR (DMSO-d6): of 2.23 (3H, s), is 2.74 (1H, dd, J=9.0 to 13.9 Hz), 3,06 (1H, dd, J= 4.9 and a 13.9 Hz), and 4.40 (2H, overlapping with solvent peak), 4,74-of 4.90 (1H, overlap with solvent peak), 6,88-7,66 (10H, complex spectrum), of 8.95 (1H, d, J=6.4 Hz); MS: m/z = 437 (M + 1).

Example 48: R0= 3-forfinal, R2= {4-(4-methylpiperazin-1-yl)-4-oxo} propyl (compound 69);

MS: m/z = 691 (M + 1).

Example 49: R0= 2-forfinal, R2= methyl (compound 64);

1H-NMR (Dl3): of 2.23 (3H, s), of 2.86 (1H, dd, J=8,2 and 13.8 Hz), 4,42 (2H, s), 4,88-of 4.95 (1H, m), 7,01-7,62 (N, complex spectrum), 8,96 (1H, d, J=6.5 Hz).

Example 50

The same method CA group, to obtain the corresponding hydrochloride of the compound (compound 67) of the formula (I), where R3is hydrogen, R1= phenyl, X is nitrogen, Y is carbon, Z is methylene, R0is a phenyl group, a R2- methoxy group.

1H-NMR (Dl3): 2,95 (1H, dd, J=8,2 and 14.1 Hz), and 3.16 (1H, dd, J=5,7 and 14.1 Hz), of 3.84 (3H, s), 4,43 (2H, s), 5,18 to 5.35 (1H, m), 6,47-6,60 (1H, m), 7,08-7,53 (11N, complex spectrum), 8,59 (1H, d, J=7,1 Hz), 9,17 (2H, user. s); MS: m/z = 435 (M + 1).

Example 51

Synthesis of hydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-forfinal)methyl} butylacetamide (compound 52) was performed in the following way.

(1) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{1-(3-forfinal)methyl-2-hydroxy-3-oxo}butylacetamide (compound 8).

3-Tert-butyloxycarbonyl-2,2-dimethyl-5-(1-oxoethyl)-4-(3-forfinal)methyloxazolidine (17,94 g of 51.1 mmol) was dissolved in ethanol (180 ml), to this solution was added p-toluene-sulfonylation2O (10.7 g, 56.2 mmol) and the mixture was warmed up to reflux for 2 h with stirring. The reaction solution was concentrated under reduced pressure and the resulting residue was dried with a vacuum pump (2 mm RT. Art.) if 50oWith the result obtained crude 2-amino-1-(3-forfinal)-3-geraniales purification in the subsequent reaction of the condensation.

Solid (21,5 g) obtained in the reaction described above, and 5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (1.42 g, 4.14 mmol) was dissolved in dimethylformamide (311 ml) and then cooled in ice was sequentially added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.7 g, to 66.4 mmol), 1-hydroxybenzotriazole2O (10.2 g, to 66.4 mmol) and 4-methylmorpholine (7,6 ml, to 66.4 mmol), the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and washed successively with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate, distilled water and saturated sodium chloride solution. After drying of the organic layer by adding anhydrous sodium sulfate drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/methanol = 80/20 to 65/35), eventually got mentioned in the title compound (18.7 g, yield 68%).

1H-NMR: 1,53 (N, s), of 2.21 (3H, s), 2,97 (2H, d, J=15,4 Hz), 4,48 (1H, d, J= 15,4 Hz), 4,67-4,82 (1H, m), 6.35mm (1H, d, J=9.4 Hz), 6,88-was 7.08 (3H, complex spectrum), 7,24-of 7.48 (7H, overlapping with solvent peak), cnoe compound 8), used above were obtained in the following way.

In accordance with the method described by R. Nishizawa et al. (J. Med. Chem. V. 20, N 4. R. 510-515), acetamide ester of malonic acid and 3-tormentilla are condensed, and then the ether of the reaction product is hydrolyzed, and then spent the decarboxylation and removing the protection of the amino group, and the resulting 3-forfinally used as the starting material, to obtain 3-amino-2-hydroxy-4-(3-forfinal)butyric acid, which is then defended it 3-amino group using tert-butyloxycarbonyl group and the conventional method were subjected to the condensation reaction with N,O-dimethylhydroxylamine, as a result, we get 3-tert-butyloxycarbonyl-2-hydroxy-4-(3-forfinal)butyric acid N,O-dimethylhydroxylamine.

The obtained amide was treated with a catalytic amount of p-toluenesulfonic acid 2,2-dimethoxypropane, resulting in easy to obtain 3-tert-butyloxycarbonyl-2,2-dimethyl-5-N-methoxy-N-methyl-4-(3-forfinal)oxazolidin.

Received oxazolidin were treated with reagent Grignard in an inert solvent in an argon atmosphere according to the method described in example 1 (1), it was possible to synthesize the desired connected is oxcarbazepine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-(3-forfinal)methyl}butylacetamide (compound 51).

Oxalicacid (of 5.06 ml, 58,0 mmol) was added to methylene chloride (566 ml) at room temperature under nitrogen atmosphere and cooled to -75oC. After adding this solution dropwise dimethyl sulfoxide (5,49 ml, 77.4 mmol) were added dropwise a solution of 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 1-(3-forfinal)methyl-2-hydroxy-3-oxo} butylacetamide (20,8 g of 38.7 mmol) in methylene chloride (900 ml). After 20 min to the reaction mixture was added dropwise a triethylamine (21,6 ml, 155 mmol), and gave the temperature of the reaction solution to rise to room. The reaction solution was washed sequentially with 10% aqueous citric acid solution and distilled water, then the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate is then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform/ethyl acetate = 20/1 to 9/1), eventually got mentioned in the title compound (24,0 g, yield 58%).

1H-NMR (Dl3): 1,54 (N, s), of 2.34 (3H, s), 2,96 (1H, dd, J=7.8 and 14.1 Hz) 3,13-3,37 (1H, m), 4,48 (2H, s), 5,15 at 5.27 (1H, m), 6,50 (1H, d, J=6.6 Hz), 6,83-7,555 (11N, complex spectrum), 8,67-8,77 (1H, m); MS: m/z = 537 (M + 1).

(3) SS="ptx2">

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 1-(3-forfinal)methyl-2,3-dioxo}butylacetamide (24,0 g of 44.7 mmol) was dissolved in a mixture of 4 N. hydrochloric acid/1,4-dioxane (9 ml, and 36.2 mmol) and stirred at room temperature for 1.5 hours the Reaction solution was concentrated under reduced pressure, the obtained residue was added diethyl ether and the solid precipitate was collected by filtration. The result has been specified in the title compound (21.1 g, yield 99%).

1H-NMR (DMSO-d6): of 2.24 (3H, s), 2,78 (1H, dd, J=9.1 and a 13.9 Hz), 3,11 (1H, dd, J=4,7 and 13.9 Hz), and 4.40 (2H, user. s), 4,79 to 4.92 (1H, m), 6,93-to 7.09 (3H, complex spectrum, overlapping with1N), 7,20-the 7.65 (7H, complex spectrum, overlapping with1N), 9,06 (1H, d, J=6.5 Hz); MS: m/z = 437 (M + 1).

Example 52

The synthesis of the dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-(4-(morpholine-4-yl)-1-phenylmethyl}exilerated (compound 71) was performed in the following way.

(1) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2R, 3S)-{ 2-hydroxy-3-oxo-6-(4-(morpholine-4-yl)-1-phenylmethyl} exilerated-triptorelin (compound 11).

(4S, 5R)-3-Tert-butyloxycarbonyl-2,2-dimethyl-5-{4-(4-(morpholine-4-yl)-1-oxobutyl}-4-fenilmetilketil (130,3 g, 270 MSMEs with stirring and warmed up for 6 h under reflux. The reaction solution was concentrated under reduced pressure and the obtained residue (2-amino-3-hydroxy-7-(4-(morpholine-4-yl)-4-oxo-1-phenylheptane-monohydrochloride-mono-p-toluensulfonate) was subjected without isolation and purification followed the condensation reaction.

As mentioned above, the remainder of the reaction and 5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinemethanol acid (60.1 g, 174 mmol) was dissolved in solvent mixture of dimethylformamide (145 ml) and tetrahydrofuran (290 ml), then successively added while cooling in ice 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (or 37.4 g, 191 mmol), 1-hydroxybenzotriazole2On (26,6 g, 174 mmol) and 4-methylmorpholine (19.1 ml, 174 mmol), then the mixture was stirred over night at room temperature. The reaction solution was diluted with ethyl acetate and washed successively with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate, distilled water and saturated sodium chloride solution. After drying of the organic layer by adding anhydrous sodium sulfate drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (1500 Madoc was collected by filtration, the result has been named product (72,7 g, yield 56%).

1H-NMR (Dl3): 1,53 (94, s), 1,60 to 1.76 (1H, m), 1.77 in-1,92 (14, m), 2,10-2,60 (8H, complex spectrum), 2,93-2,99 (2H, complex spectrum), 3,55 (4H, t, J= 4.6 Hz), 4,11 (1H, s), 4,33 (1H, d, J=15.3 Hz), 4,48 (1H, d, J=15.3 Hz), 4,63-of 4.77 (1H, m), 6,28 (1H, d, J=9.5 Hz), 7,22-7,34 (6N, complex spectrum), 7,35-7,49 (5H, complex spectrum), to 8.25 (1H, s).

(4S, 5R)-3-Tert-butyloxycarbonyl-2,2-dimethyl-5-{4-(4-(morpholine-4-yl)-1-oxobutyl} -4-fenilmetilketil (intermediate compound 11), used above, was obtained in the following way.

In accordance with the method described by R. Nishizawa et al. (J. Med. Chem. V. 20, N 4. R. 510-515), (2R,3S)-3-amino-2-hydroxy-4-phenylalanyl acid was obtained using as a starting material L-phenylalanine, defended the 3-amino group, tert-butyloxycarbonyl group and then subjected to the usual way the condensation reaction with N,O-dimethylhydroxylamine, as a result received the corresponding (2R,3S)-3-tert-butyloxycarbonyl-2-hydroxy-4-phenylalkanoic acid N,O-dimethylhydroxylamine.

The obtained amide was treated in the usual way, for example a catalytic amount of p-toluenesulfonic acid 2,2-dimethoxypropane, the result can easily be obtained from (4S,5R)-3-tert-butyloxycarbonyl-2,2-d is Grignard in inertia solvent in an argon atmosphere in accordance with the method, described in example 1 (1), the result can be synthesized with the desired compound (4S, 5R)-3-tert-butyloxycarbonyl-2,2-dimethyl-5-{ 4-(4-(morpholine-4-yl)-1-oxobutyl}-4-fenilmetilketil.

(2) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl} exilerated (compound 70).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2R,3S)-{2-hydroxy-3-oxo-6-(4-(morpholine-4-yl)-1-phenylmethyl}exiled-triptorelin (70,3 mg, 94,1 mmol) was dissolved in a mixture solvent of methylene chloride (470 ml) and dimethyl sulfoxide (33,4 ml), to this solution was added at room temperature triperoxonane acid (3.6 ml, and 47.0 mmol), pyridine (3.8 ml, and 47.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55,2 g, 282 mmol) in that order and the mixture was stirred for 50 minutes the Reaction solution was diluted with methylene chloride and then washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the solution was concentrated under reduced pressure, resulting in the received specified in the title compound.

This compound was subjected to the subsequent reacceleration-1-yl)-N-{2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl}exilerated (compound 71).

2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl}exilerated obtained in the previous experiment was dissolved in a mixed solvent of ethyl acetate (235 ml) and the mixture 4 N. hydrochloric acid/1,4 dioxane (235 ml) and was stirred over night at room temperature. The solid precipitate was removed from the reaction mixture by filtration, the result has been specified in the title compound (56,8 g, yield 99%).

R0= phenyl, R2= 3-(4-(morpholine-4-yl)propyl (compound 71); MS: m/z = 532 (M + 1).

The following describes the method of synthesis of compounds of formula (I) from compounds of formula (XIII), i.e. 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated synthetic route in scheme 1.

Example 53

The following describes the method of synthesis known intermediate connection:

dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 23).

(1) 2-(5-Tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pirlimycin-1-yl)-N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (1 g, 1.56 mmol) was dissolved in pyridine (1.6 ml), to this solution was added while cooling in ice acetic anhydride (0,176 ml of 1.87 mmol) and the mixture was stirred at 0oC for 30 min and at room temperature for 2 hours After adding saturated aqueous sodium bicarbonate solution, the reaction solution was extracted with ethyl acetate, then washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/10/1), was obtained as a white solid substance specified in the title compound (1.08 g, quantitative yield).

1H-NMR (Dl3): 1.52m (N, s), 1,92-of 2.08 (2H, m), are 2.19 (3H, s), 2,45-3,30 (4H, complex spectrum), are 4.24 (2H, t, J= 6.5 Hz), of 4.44 (2H, d, J=7,6 Hz), 4.72 in-4,89 (1H, m), equal to 4.97 (1H, d, J=2.2 Hz), 6,44 (1H, d, J=9.4 Hz), of 6.68 (1H, d, J= 8,3 Hz), PC 6.82 (1H, ddd, J=0,93, of 4.0 and 7.1 Hz), 7,11-to 7.35 (7H, complex spectrum), was 7.36-7,58 (5H, complex spectrum), 8,08 (1H, ddd, J=1,0, 1.8 and 4.0 Hz), 8,72 (1H, user. s), MS: m/z = 684 (M + 1), 1367 (2M + 1).

(2) the Dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyrimidin-1-yl)-N-{(1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (1.08 g, was 1.58 mmol) was dissolved in 2 ml of dioxane, and to this solution while cooling in ice, was added a mixture of 4 N. hydrochloric acid/1,4-dioxane (7.9 ml of 31.6 mmol), the mixture was stirred at 0oC for 30 min and at room temperature over night. The reaction solution was concentrated under reduced pressure, the result has been specified in the title compound as a white solid (1.08 g, quantitative yield).

1H-NMR (CD3D): 2,09-OF 2.23 (2H, m), of 2.20 (3H, s), 2,61-3,50 (4H, complex spectrum), 4,34-4,85 (5H, complex spectrum), 5,04 (1H, d), 7,15-7,31 (5H, complex spectrum), 7,43-to 7.67 (7H, complex spectrum), 7,69-7,79 (1H, m), 8,32 is 8.38 (1H, m), 8,46 (1H, ddd, J=1,7, 7.3 and 10 Hz). MS: m/z = 584 (M + 1).

Example 54

Synthesis of 2-(5-benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 77) was carried out as follows.

(1) 2-(5-Benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{(1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 24).

Known intermediate connection: the dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (760 mg, of 1.16 mmol) was dissolved in pyridi is at 0oC for 1 hour and at room temperature for 1 hour. After adding saturated aqueous sodium bicarbonate solution, the reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer, after drying over anhydrous sodium sulfate, concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/20/1), was obtained as a white solid substance specified in the title compound (590 mg, yield 69%).

1H-NMR (Dl3): 1,85-2,02 (2H, m) to 2.29 (3H, s), 2,42 is 2.75 (2H, m), 2,82-of 3.07 (2H, m), 4,07 (2H, d, J=4,1 Hz) to 4.16 (2H, t, J=6.3 Hz), 4.75 V to 4.92 (1H, m), 4,94 (1H, d, J=1.9 Hz), only 6.64 (1H, d, J=8,4 Hz), 6,72-6,86 (2H, complex spectrum), 7,02-7,62 (N, complex spectrum), 8,02-8,07 (1H, m), of 8.04 (1H, m), 8,15-8,35 (1H, m); MS: m/z = 738 (M + 1).

(2) 2-(5-Benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{(1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 25).

2-(5-Benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (590,4 mg, 0.8 mmol) was dissolved in methanol (3.2 ml) and after adding cooling in LDI temperature for 3 hours After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with ethyl acetate and washed the organic layer with a saturated solution of sodium chloride. The organic layer, after drying over anhydrous sodium sulfate, concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 5/5/1), eventually got mentioned in the title compound as a pale yellow solid (572 mg, quantitative yield).

1H-NMR (Dl3): 1,85-2,07 (2H, m), 2,50 (1H, dt, J=7,2 and 17.9 Hz), 2,78 (1H, dt, J= 7,1 and 17.9 Hz), 2,96-is 3.08 (2H, m), 3,90 (1H, d, J=4.6 Hz), 4.04 the-4,28 (5H, complex spectrum), to 4.38 (2H, s), 4,58-of 4.75 (1H, m), to 6.58 (1H, d, J= 9.5 Hz), 6,60 (1H, d, J=8,4 Hz), for 6.81 (1H, ddd, J=0,9, 5,0 and 7.1 Hz), 7,10-to 7.59 (M, complex spectrum), 7,82-of 8.00 (1H, user. s), of 8.09-8.17 and (1H, m), 8,18 (1H, s); MS: m/z = 696 (M + 1).

(3) 2-(5-Benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 77).

2-(5-Benzylmethylamine-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (571,9 mg, 0,822 mmol) was dissolved in methylene chloride (1 ml) and dimethyl sulfoxide (0,87 ml), after which the follower is(474 mg, 2,47 mmol) and the mixture was stirred at 0oC for 30 min and at room temperature for 2 hours Then added water, then the reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (methylene chloride/ethyl acetate = 1/1), the result has been specified in the title compound as a pale yellow solid (80 mg, yield 14%).

1H-NMR (Dl3): 1,92-of 2.09 (2H, m), 2,66-3,26 (4H, complex spectrum), 4,05 was 4.42 (6N, complex spectrum), and 5.30-of 5.45 (1H, m), 6,63 (1H, d, J=6.6 Hz), 6,77-of 6.90 (1H, m), of 6.96 (1H, d, J=7,0 Hz), 7,08-7,63 (N, complex spectrum), 8,01-8,13 (2H, complex spectrum), 8,18 (1H, s), MC: m/z = 694 (M + 1).

Example 55

2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 79) was synthesized by the following method.

(1) 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 28).

To acetic anhydride (0.25 ml, 2.6 mmol) was added while cooling in ice formic acid (0,12 ml, 3.2 mmol) and stirred at 60oSince t is inane - dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (656 mg, 1.0 mmol) in a mixed solvent mixture of tetrahydrofuran (2 ml) and triethylamine (to 0.29 ml, 2.1 mmol), the mixture was stirred for 1 hour, and during this time the temperature was increased to 0oC. the Reaction solution was concentrated as such under reduced pressure, and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/10/1), eventually got mentioned in the title compound as a white solid (570 mg, yield 93%).

1H-NMR (Dl3): 1,92-of 2.09 (2H, m) to 2.18 (3H, s), 2,49-a 2.71 (2H, m), 2,85 (14, dd, J= 8.8 and 13.5 Hz), of 3.00 (1H, dd, J=6.5 and 13.5 Hz), 4,15 is 4.36 (2H, m), 4,48 (2H, dd, J=8.4 and 15.3 Hz), 4,70-of 4.90 (1H, m), to 4.98 (1H, d, J=2.2 Hz), of 6.52 (1H, d, J=9,2 Hz), 6,69 (1H, dt, J=1,0 and 8.3 Hz), at 6.84 (1H, ddd, J=0,9, 5.1 and 7.2 Hz), 7,10-to 7.61 (11N, complex spectrum), 8,08 (1H, ddd, J=0.8 is a 2.0 and 5.1 Hz), with 8.33 (1H, s), 8,49 (1H, s), 9,11 (1H, s); MC: m/z = 612 (M + 1).

(2) 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 29).

2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (570,4 mg, 0,93 maidenii in ice and the mixture was stirred at 0oC for 30 min and at room temperature for 3 hours After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with ethyl acetate, and washed the organic layer with a saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure, the result has been specified in the title compound (379 mg, 71% yield).

1H-NMR (DCl3): 1,96-2,12 (2H, m), to 2.55 (1H, dt, J=7.1 and is 18.0 Hz), 2,77 (1H, dt, J=7,0 and 17.8 Hz), 2,97 (2H, d, J=7,0 and 17.8 Hz) to 3.92 (d, J=3,7 Hz) 4,05-of 4.12 (1H, m), 4,14-4,48 (4H, complex spectrum), with 4.64-4,82 (1H, m), 7,15-7,58 (11N, complex spectrum), 8,07 (1H, dd, J=1.8 and 5.2 Hz), of 8.27 (1H, s), 8,44 (1H, s), which is 9.09 (1H, s), m/z = 570 (M + 1).

(3) 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 79).

2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (374 mg, 0.66 mmol) was dissolved in methylene chloride (0.7 ml) and dimethylsulfoxide (0.7 ml), to this solution was added triptorelin pyridinium (64 mg, 0.33 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (378 mg, 1.97 mmol) and the mixture was stirred at room temperature in Teulada sodium. The organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (methylene chloride/ethyl acetate = 1/2), the result has been specified in the title compound (257 mg, yield 69%).

1H-NMR (Dl3): 2,00-of 2.16 (2H, m), was 2.76-to 3.09 (3H, complex spectrum), 3,23 (1H, dd, J=5.4 and 14.1 Hz), 4,32 (2H, t, J=6.4 Hz), 4,50 (2H, d, J=1.3 Hz), to 5.21-5,33 (1H, m), 6,50 (1H, d, J=6.6 Hz), 6,70 (1H, d, J=8,3 Hz), 6,85 (1H, ddd, J= 0,9, of 5.1 and 7.1 Hz), 7,00-7,11 (2H, m), 7,14-7,65 (N, complex spectrum), 8,10 (1H, ddd, J=0.7 and 2.0 and 5.0 Hz), 8,24 (1H, user. s), 9,10 (1H, s); MS: m/z = 568 (M + 1).

Example 56

2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 82) was synthesized as follows.

(1) 2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 35).

To a solution of dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (1.0 g, of 1.52 mmol) in tetrahydrofuran (3 ml) was added while cooling in ice 2,6-lutidine (of 0.62 ml, 5,32 mmol) and 1 M solution of benzylaminocarbonyl in tetrahydrofuran (of 1.52 ml, 1,52 m saturated aqueous sodium bicarbonate solution, the reaction solution was extracted with ethyl acetate and washed with saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure and the resulting residue was purified using eluent hexane/ethyl acetate = 1/1 to 0/1, eventually received 2-(5-benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (602 mg, yield 53%).

1H-NMR (Dl3): 1,91-2,02 (2H, m), is 2.05 (3H, s), 2,44-a 2.71 (2H, m), 2,75-3,03 (2H, m), 4,14-4,29 (44, complex spectrum), to 4.41 (2H, s), 4,71-4,88 (1H, m), equal to 4.97 (1H, d, J=2.1 Hz), of 5.50 (1H, t, J=5,9 Hz), 6,47 (1H, d, J=9.4 Hz), of 6.66 (1H, d, J= 8,4 Hz), 6,78-6,86 (1H, m), 7,08-7,62 (17H, complex spectrum), of 8.06 (1H, dd, J=1.5 and 5.1 Hz), 8,15 (1H, s); MS: m/z = 753 (M + 1).

(2) 2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{(1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 36).

2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (601 mg, 0.8 mmol) was dissolved in methanol (3.2 ml) to this solution cooled in ice was added an aqueous solution (1 ml), potassium carbonate (332 mg) and the mixture was stirred at 0oC for 1 h After adding a saturated aqueous solution of ammonium chloride, the reaction solution aktivne over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure, the result has been specified in the title compound (405 mg, 71% yield).

1H-NMR (DCl3): 1,84-2,02 (2H, m), 2,46 (1H, dt, J=7.2 and is 18.0 Hz), 2,78 (1H, dt, J=7,0 and 17.9 Hz), 2,95 (2H, d, J=3.0 Hz), was 4.02-4,18 (4H, m), 4,27 (2H, s), 4,34-4,43 (1H, br. s), 4,50-of 4.75 (1H, m), to 6.58 (1H, d, J=8,3 Hz), 6.73 x-6,87 (2H, complex spectrum), 7,12-7,54 (N, complex spectrum), 8,01 (1H, ddd, J=0.7 and 1.5 and 5.1 Hz), 8,16 (1H, s), MS: m/z = 711 (M + 1).

(3) 2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 82).

2-(5-Benzylaminocarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (405 mg, or 0.57 mmol) was dissolved in methylene chloride (0.6 ml) and dimethyl sulfoxide (0.6 ml), then added triptorelin pyridinium (55 mg, 0.29 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg, 1,71 mmol) and the mixture was stirred at room temperature for 1.5 hours After adding water, the reaction solution was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the obtained residue was purified column chromatography on silica gel (methylene chloride/ethyl acetate = 1/1), eventually got specified is of 14.0 Hz), 3,18 (1H, dd, J=5,6 and 14.1 Hz), 4,21-the 4.29 (4H, complex spectrum), to 4.46 (2H, s), 5,24-of 5.34 (1H, m), vs. 5.47 (1H, t, J=6,1 Hz), 6,64-6,72 (2H, complex spectrum), 6,83 (1H, ddd, J= 0,9, of 5.1 and 7.2), 7,02-to 7.09 (1H, m), 7,14-7,66 (N, complex spectrum), 8,06-8,11 (1H, m), 8,15 (1H, s); MS: m/z = 709 (M + 1).

Example 57

Synthesis of 2-{ 6-oxo-2-phenyl-5-(4-pyridylmethylene-carbylamine)-1,6-dihydropyrimidin-1-yl}-N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 78) was carried out as follows.

(1) 2-{ 6-Oxo-2-phenyl-5-(4-pyridylmethylene-carbylamine)-1,6-dihydropyrimidin-1-yl} -N-{ (1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 26).

To a solution of known intermediate - dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl} -N-{(1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (656,5 mg, 1.0 mmol) in methylene chloride (10 ml) was slowly added while cooling in ice, in an argon atmosphere a solution of triphosgene (445 mg, 1.5 mmol) in methylene chloride (1 ml), the mixture was stirred for 45 minutes Then to the mixture was added 4-pyridine-methanol (349 mg, 3.2 mmol) and the mixture was stirred at 0oC for 1 h and at room temperature over night. After adding saturated aqueous sodium bicarbonate solution, the reaction solution is one sodium sulfate the organic layer was concentrated under reduced pressure and purified the resulting residue column chromatography on silica gel (ethyl acetate/methanol = 20/1), in the end, received in the form of a white solid 2-{ 6-oxo-2-phenyl-5-(4-pyridylmethyl)oxycarbonyl-1,6-dihydropyrimidin-1-yl} -N-{ (1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (544 mg, yield 76%).

1H-NMR (Dl3): 1,92-2,10 (2H, m), are 2.19 (3H, s), 2,46-to 2.67 (2H, m), 2,84 (14, dd, J=8,5 and 13.7 Hz), 2,98 (1H, dd, J=6,6 and 13.6 Hz), 4,25 (2H, dt, J= 1.1 and 6.2 Hz), 4,47 (2H, d, J=3.3 Hz), 4,74-4,89 (1H, m), to 4.98 (1H, d, J=2.1 Hz), 5,23 (2H, s), 6.35mm (1H, d, J=9,2 Hz), 6,67 (14, d, J=8,4 Hz), PC 6.82 (1H, ddd, J= 0,9, to 5.2 and 7.1 Hz), 7,11-7,63 (13H, complex spectrum), 8,04-8,11 (1H, m), to 8.62 (1H, dd, J=1.6 and 4.5 Hz), 8,76 (1H, user. s); MS: m/z = 719 (M + 1).

(2) 2-{ 6-Oxo-2-phenyl-5-(4-pyridylmethylene-carbylamine)-1,6-dihydropyrimidin-1-yl} -N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 27).

This compound was synthesized in the same manner as in example 56 (2), using as starting material 2-{6-oxo-2-phenyl-5-(4-pyridylmethylamine)-1,6-dihydropyrimidin-1-yl} -N-{ (1S,2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated.

1H-NMR (DlC): 1,91-of 2.16 (2H, m), 2.40 a-only 2.91 (2H, m), 2,97 (2H, d, J=8.1 Hz), 3,88 (1H, d, J=3,7 Hz), a 4.03-4,11 (1H, user. s), 4,18-4,32 (2H, m), 4,33 (1H, d, J=15,5 Hz), 4,48 (1H, d, J=15.3 Hz), with 4.64-4,82 (1H, m), 5,23 (2H, s), 6,24 (1H, d, J=9.4 Hz), 6,62 (1H, d, J=8,3 Hz), 6,77-6,89 (14, m), 7,15-7,65 (14N, complex spectrum), of 8.06 (1H, dd,laminitis)-1,6-dihydropyrimidin-1-yl} -N-{2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (compound 78)

This compound was synthesized in the same manner as in example 56 (3), using as starting material 2-{6-oxo-2-phenyl-5-(4-pyridylmethylamine)-1,6-dihydropyrimidin-1-yl} -N-{ (1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated.

1H-NMR (DlC): 2,01-of 2.16 (2H, m), 2,74-to 3.09 (3H, complex spectrum), up 3.22 (1H, dd, J=5,5 and 14.0 Hz), or 4.31 (2H, t, J=6.2 Hz), 4,50 (2H, s), of 5.24 (2H, s), 5,26 is 5.38 (1H, m), 6,59 (1H, d, J=6.8 Hz), 6,64-6,74 (1H, m), at 6.84 (1H, ddd, J=0,9, 6.0 and 7.2 Hz), 7,00-7,69 (14 N, complex spectrum), 8,06-to 8.14 (1H, m), to 8.62 (1H, dd, J=1.6 and 4.5 Hz), the rate of 8.75 (1H, s); MS: m/z = 675 (M + H).

Example 58

Synthesis of 2-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 80) was carried out as follows.

(1) 2-(5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 30).

Known intermediate connection - the dihydrochloride of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated (of 0.62 g, 1.0 mmol) suspended in a mixture solvent of tetrahydrofuran (3 ml) and methylene chloride (2 ml), to this solution while cooling in ice was added to tritium the add acetylchloride (0,03 ml) and further stirring the mixture for 1 h the reaction solution was diluted with ethyl acetate and washed successively with distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and purified the resulting residue column chromatography on silica gel (hexane/ethyl acetate/methanol = 10/10/1), eventually got mentioned in the title compound (506 mg, yield 81%).

1H-NMR (Dl3): 1,93-2,10 (2H, m), are 2.19 (3H, s), of 2.21 (3H, s), 2,49-2,69 (2H, m), 2.77-to totaling 3.04 (2H, m), 4,24 (2H, t, J=6.3 Hz), to 4.46 (2H, d, J=4.5 Hz), 4,74-4,89 (1H, m), to 4.98 (1H, d, J=2.2 Hz), 6,34 (1H, d, J=9,2 Hz), of 6.68 (1H, d, J= 8,3 Hz), PC 6.82 (1H, ddd, J=1,0, a 5.1 and 6.0 Hz), 7,12-7,58 (11N, complex spectrum), 8,01 (1H, user. s), 8,05-8,10 (1H, m), which is 9.09 (1H, m); MS: m/z = 626(M + 1).

(2) 2-(5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)} exilerated (compound 31).

This compound was synthesized in the same manner as in example 56 (2), using as starting material 2-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated.

1H-NMR (Dl3): 1,96-to 2.13 (2H, m), of 2.21 (3H, s), 2,45-2,89 (2H, m), 2,98 (2H, d, J=8.1 Hz), with 3.89 (1H, d, J=3.8 Hz), 4.09 to (1H, d, J=3,4 Hz), 4,18-to 4.52 (4H, complex spectrum) and 4.65-4,80 (1H, m), 6,24 (1H, d, J=9.5 Hz), 6,63 (1H, d, J=8,3 Hz), 6,83 (1H, ddd, J=0,98, of 5.1 and 6.0 Hz), 7,06-7,60 (11N, complex spectrum), 8,01 (1H, user. s), 8,04-8,10 (1H, m), which is 9.09 (1H, s); MC (FAB)}exilerated (compound 80).

This compound was synthesized in the same manner as in example 54 (3), using as starting material 2-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S,2R)-2-hydroxy-3-oxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated.

1H-NMR (Dl3): 2,00-to 2.18 (2H, m), of 2.21 (3H, s), 2,75 of 3.28 (4H, complex spectrum), or 4.31 (2H, t, J=6.2 Hz), 4,50 (2H, s), 5,27 of 5.39 (1H, m), to 6.57 (1H, d, J=6.5 Hz), 6,69 (14, d, J=8,4 Hz), 6,85 (1H, ddd, J=0,93, of 4.0 and 7.1 Hz), 7,01-to 7.09 (2H, complex spectrum), 7,15-7,30 (3H, complex spectrum), 7,35-to 7.61 (6N, complex spectrum), 7,98 (1H, user. s), 8,10 (1H, ddd, J=0,77, of 2.0 and 6.0 Hz), the remaining 9.08 (1H, s); MS: m/z = 582 (M + 1).

Example 59

Synthesis of 2-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated (compound 76) was carried out as follows.

(1) 1-Allyl-5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin.

To a solution of 1-allyl-5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidine (2 g, 6,11 mmol) in methanol (12 ml) was added with cooling in ice, the mixture of 4 N. hydrochloric acid/dioxane (31 ml, 122,2 mmol) and stirred at 0oC for 30 min and at room temperature over night. The reaction solution was concentrated under reduced pressure, the result has been mentioned in the title, 3.5 Hz), 4,90-of 5.06 (1H, m), 5,18 at 5.27 (1H, m), 5,77-5,97 (1H, m), 7,68 (1H, s), EUR 7.57-7,82 (54, m).

(2) 5-Acetylamino-1-allyl-6-oxo-2-phenyl-1,6-dihydropyrimidin.

Hydrochloride of 1-allyl-5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine was dissolved in tetrahydrofuran (27 ml) and triethylamine (1,16 ml of 8.33 mmol) to this solution while cooling in ice was added acetylchloride (0,284 ml of 3.99 mmol) and the mixture was stirred at 0oC for 30 min and at room temperature for 2 hours After adding saturated aqueous sodium bicarbonate solution, the reaction solution was extracted with ethyl acetate and washed with saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/2), the result has been specified in the title compound (617 mg, yield 69%).

1H-NMR (Dl3): of 2.24 (3H, s), 4,59 (24, dt, J=1.6 and 5.2 Hz), 4,88-5,02 (1H, m), 5,18 at 5.27 (1H, m), 5,86 (1H, ddt, J=5,2, to 10.3 and 17.2 Hz), of 7.48 (5H, s), with 8.05 (1H, br, s), 9,07 (1H, s); MS: m/z = 539 (2M + N).

(3) 3-(5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-1,2-propandiol.

To a solution of 5-acetylamino-1-allyl-6-oxo-2-phenyl-1,6-dihydropyrimidine (888,6 mg, 3.3 mmol) in Tetra is troxide osmium (of 1.06 ml, 0,165 mmol) and the mixture was stirred at room temperature for 2 days. After adding a saturated aqueous solution of sodium thiosulfate reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. After drying over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (methylene chloride/methanol = 10/1), eventually got mentioned in the title compound as a white solid (1.06 g, quantitative yield).

1H-NMR (DCl3): of 2.25 (3H, s), 2,40-of 2.58 (1H, m), 3,29-3,63 (3H, complex spectrum), 3,78-of 3.95 (1H, m), 4,08-4.26 deaths (2H, m), 7,41-rate of 7.54 (5H, s), of 8.04 (1H, m), of 9.00 (1H, s); MS: m/z = 304 (M + 1).

(4) (5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetaldehyde.

To a solution of 3-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-1,2-propane diol (1.06 g, 3.50 mmol) in tetrahydrofuran (100 ml) was added water

solution (11.2 ml) periodate sodium (897 mg, 4,19 mmol) and the mixture was stirred over night at room temperature. The reaction solution was concentrated as such and after adding water thrice product was extracted with ethyl acetate and washed the feast upon the Wali under reduced pressure, the result has been specified in the title compound as a white solid (800 mg, yield 84%).

1H-NMR (Dl3): of 2.23 (3H, s), 4,80 (2H, s), 7,38-EUR 7.57 (5H, m), 7,95 (1H, user. s), 9,11 (1H, s), being 9.61 (1H, s); MS: m/z = 272 (M + 1).

(5) (5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid.

To a solution of (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetaldehyde (800 mg, 2,95 mmol) in 2-methyl-2-propanol (14,8 ml) was added 2-methyl-2-butene (1,38 ml, 12,98 mmol), an aqueous solution of 4.2 ml) one-deputizing phosphate natren2O (419 mg, 2,95 mmol) and aqueous solution (9.3 ml) of sodium chlorite (934 mg, 10,32 mmol), the mixture was stirred over night at room temperature. The reaction solution was washed with diethyl ether, and then the pH of the aqueous layer was brought citric acid to pH 4 and extracted 6 times with methylene chloride. The organic layer after drying over anhydrous sodium sulfate then concentrated under reduced pressure, the result of which was received in the form of a white solid of 5-acetylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinedione acid (537 mg, yield 63%).

1H-NMR (Dl3): of 2.23 (3H, s), 4,20-4,80 (1H, user. s), with 4.64 (2H, s), 7,45-of 7.55 (5H, user. s), 8,16 (1H, s), 9,11 (1H, s); MS: m/z = 288 (M + 1), 575 (2M + 1).

(6) Forces)-1-phenylmethyl}exilerated (compound 21) was carried out as follows.

(4R, 5S)-5-{ 1-Oxo-4-(2-oxo-1,2-dihydropyridines-1-yl)butyl}-3-(N-tert-butyloxycarbonyl)-2,2-dimethyl-4-phenyl-methyloxazolidine (intermediate 12) (684 mg, 1.5 mmol) was dissolved in methanol (7.5 ml), to this solution was added p-toluensulfonate2O (573 mg, 3.0 mmol) and the mixture was heated for 1.5 hours under reflux. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in a solvent mixture of N, N-dimethylformamide (7.5 ml) and tetrahydrofuran (7.5 ml) and then cooled in ice was sequentially added (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid (400 mg, 1.4 mmol), 1-hydroxybenzotriazole2O (245 mg, 1.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (347 mg, 1.8 mmol) and N-methylmorpholin ones (0.46 ml, 4.5 mmol), then the temperature was raised to room temperature and the mixture was stirred over night. The reaction solution was diluted with ethyl acetate and washed sequentially with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate, distilled water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, to the obtained residue, d is the substance was collected, the result has been specified in the title compound (536 mg, yield 66%).

1H-NMR (Dl3): 1,88-2,07 (24, m), 2,22 (3H, s), 2,46 (1H, dt, J=7,0 and 18.6 Hz), 2,77 (1H, dt, J=6,8 and 18.4 Hz), 2,98 (2H, d, J=7,7 Hz), 3,78-was 4.02 (2H, m), as 4.02-4,06 (1H, m), 4,17 (1H, d, J=4,8 Hz), to 4.46 (2H, s), 4,55-4,72 (1H, m), 6,16 (1H, dt, J=1,3 and 6.7 Hz), 6.48 in (1H, d, J=8.5 Hz), 6,56 (1H, d, J= 9,2 Hz), 7,16-7,55 (N, complex spectrum), 8,29 (1H, s), 9,06 (1H, s); MS: m/z = 584 (M + 1), 1167 (2M + 1).

(7) 2-(5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated (compound 76).

This compound was synthesized in the same manner as in example 56 (3), using as starting material 2-(5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ (1S, 2R)-2-atomic charges-3-oxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl} exilerated {in the formula (II): R0= phenyl, R1= phenyl, R2= (2-oxo-1,2-dihydropyridines-1-yl)propyl, R3= acetyl, X = carbon, Y is nitrogen, Z = methylene}.

1H-NMR (Dl3): 1,88-and 2.14 (2H, m), of 2.21 (3H, s), 2,60-only 2.91 (2H, m) of 3.00 (1H, dd, J=8,1 and 13.9 Hz), 3,21 (1H, dd, J=5,9 and 14.1 Hz), with 3.89 (2H, t, J= 7,1 Hz), 4,51 (2H, d, J=1.9 Hz), 5,02-of 5.15 (1H, m), 6,17 (1H, dt, J=1,3 and 6.6 Hz), 6,46 (14, d, J=8,9 Hz), 7,10-7,53 (N, complex spectrum), 7,83 (1H, d, J=6.6 Hz), 8,35 (1H, s), of 9.02 (1H, s); MS: m/z = 582 (M + 1).

Example 60

The following compounds C is the way, as in example 1 (3), was carried out for the reaction of oxidation of the corresponding alcohol of formula (II), to obtain the compounds of formula (I), where R1- phenyl, R3- tert-butyloxycarbonyl. X is carbon, Y is nitrogen, Z is methylene, R0and R2- the following groups. The physical properties of the compounds of formula (I) below.

(1): R0= phenyl, R2= benzylamine (compound M1);

1H-NMR (DMSO-d6): 1,48 (94, s), of 2.86 (1H, dd, J=8,5 and 13.9 Hz), 3,10 (1H, dd, J=4,1 and 13.9 Hz), 4,35 (1H, d, J=6.4 Hz), 4,47 (1H, d, J=3.3 Hz), 5,26 (1H, ddd, J=4,1, 6,9 and 8.5 Hz), 6,98-EUR 7.57 (15 NM, a complex spectrum), 8,02 (1H, s), 8,40 (1H, s), 8,67 (1H, d, J=6.9 Hz), 9.28 are (1H, t, J=6.4 Hz); MS: m/z = 610 (M + 1).

(2): R0= 4-methoxyphenyl, R2= methoxy group (compound M2);

1H-NMR (Dl3): 1,54 (N, s), to 3.02 (1H, dd, J=6,4 and 14.2 Hz), 3,20 (14, dd, J= 5,9 and 14.2 Hz in), 3.75 (3H, s), with 3.89 (3H, s), 4,50 (2H, d, J=2.2 Hz), 5,43 (14, dd, J=6,4 and 13.3 Hz), of 6.49 (1H, d, J=7,0 Hz), 6,77 (2H, d, J=8,8 Hz), 6,97 (2H, d, J=8,8 Hz), 7,27 (solvent peak, overlapping with 1H), 7,46 (5H, s), 8,72 (1H, s).

Example 61

The following compounds were synthesized in accordance with example 1 or the other examples above.

Specifically, the same method as in example 1 (4), was performed to remove the protection from compounds of formula (I), where3- tert-butyloxycarbonyl the 1
is phenyl, X is carbon, Y is nitrogen, Z is methylene, R0and R2- the following group.

(1) R0= phenyl, R2= benzylaminopurine (connection M3);

1H-NMR (CDCl3): 2,73-2,90 (1H, m), 3.04 from-and 3.16 (1H, m), 4,28-4,50 (4H, m), 5,20 to 5.35 (1H, m), 7,01-7,51 (N, complex spectrum), 8,61 (1H, d, J=7,0 Hz), 9.28 are (1H, t, J=6.3 Hz); MS: m/z = 510 (M + 1).

(2) R0= 4-methoxyphenyl, R2= methoxy group (connection M4);

1H-NMR (DMSO-d6): 2,77 (1H, dd, J=8,6 and 14.1 Hz), to 3.02 (1H, dd, J=5.4 and 14.1 Hz), of 3.57 (3H, s), 4,35-equal to 4.97 (peak of the solvent, overlaps with 3N), TO 6.80 (2H, d, J= 8.6 Hz), to 7.50 (2H, d, J=8.6 Hz), 7,34 to 7.62 (5H, complex spectrum that overlaps with 1H), 9,06 (1H, t, J=6.5 Hz).

Example 62. The example of the pharmaceutical composition (injection)

To 30 weight parts of the compound of the present invention and 18 weight parts of sodium chloride (100 parts by weight of glucose) add purified water to get all 2000 parts by weight of the solution, then filtered through a Millipore filter type GS for removal of bacteria; 2 g of the filtrate is transferred by pipette into the vial and sealed it to get an injection containing 30 mg of this compound.

Example 63. The example of the pharmaceutical composition (pill)

10 weight parts of the compound of the present invention, 30 parts by weight of potatoes the new parts of magnesium stearate are mixed in a mixer V-shaped and tabletirujut into tablets weighing 60 mg, to obtain tablets each containing 2 mg of this compound.

Further specifically describes the biological activity of these compounds with reference to test examples.

Example test 1

(1) Inhibitory activity against chymase.

It is known that chymase is present in the tissues of various animals, and methods of isolation and purification is described in Anal. Biochem. 1984. V. 137. R. 449 and FEBS Letters. 1993. V. 323. R. 119. In this invention the cleaning chymase was performed by the methods described in these works and was tested inhibitory activity of these compounds in relation to chymase, in relation to the activation of mastocytes and eosinophils, as well as their pharmacological effects on animals. The following describes specific methods.

(A) Obtaining chymase rats.

Crushed razor blades and scalpel 50 g languages rats, suspended in 0.1 M phosphate buffer (pH 8.0) and was destroyed in the homogenizer transmitter station for 5 min to obtain a solution of the crude enzyme chymase. This solution was centrifuged at 23500 g for 20 min and precipitation was used as the fraction of the enzyme chymase. The sediments were washed with double repetition of the above procedure, then suspender 100000 g for 45 min, to obtain the supernatant as a fraction of chymase. The supernatant was applied on the column with octyl-separate 4B (40100 mm), equilibrated previously with 0.1 M phosphate buffer (pH 8.0) containing 2 M sodium chloride and 5% ammonium sulfate, and protein was suirable linear concentration gradient of sodium chloride from 2 M to About M was Collected and concentrated active fraction splitting succinyl-leucyl-leucyl-poured-tyrosyl-methylcoumarine (hereinafter referred to as the synthetic substrate chymase, the product of the firm Peptide Kenkyusho), and this fraction was used as purified himizu rats in the subsequent activity measurements.

(B) Obtaining human chymase.

Finely crushed razor blades and scalpel 60 g of human tonsils, suspended in 0.1 M phosphate buffer (pH 8.0) and was destroyed in the homogenizer Potytron for 5 min to obtain a solution of the crude enzyme chymase. It was centrifuged at 22000 g for 30 min and precipitation was used as the fraction of the enzyme chymase. The sediments were washed with double repetition of the above procedure, and then suspended in 0.1 M phosphate buffer (pH 8.0) containing 2 M sodium chloride and 5% ammonium sulfate and centrifuged at 27000 g for 20 min ion-exchange membrane, then was applied on the column with G2000 SW-XL (6,h mm) and were suirable 0.1 M phosphate buffer (pH 8.0). Was collected and concentrated active fraction that cleave the synthetic substrate chymase, and this product was used as purified himizu person in the subsequent activity measurements.

(C) Obtaining chymase dogs.

Finely crushed razor blades and scalpel 60 g of a dog's heart, suspended in 0.1 M phosphate buffer (pH 8.0) and was destroyed in the homogenizer Potytron for 5 min to obtain a solution of the crude enzyme chymase. It was centrifuged at 22000 g for 15 min and precipitation was used as the fraction of the enzyme chymase. The sediments were washed with double repetition of the above procedure, and then suspended in 0.1 M phosphate buffer (pH 8.0) containing 2 M sodium chloride and 5% ammonium sulfate and centrifuged at 27000 g for 40 min to obtain the supernatant as a fraction of chymase. To remove macromolecular components and concentration fraction chymase was passed through the ultrafiltration membrane, and the concentrate was then applied on the column, Superdex 200 HR 10/30 (10300 mm) and were suirable 0.1 M phosphate buffer (pH 8.0). Was collected and concentrated active fraction, splitting SEH activity.

(D) Measurement of inhibitory activity against chymase.

(a) measured using a synthetic substrate.

Synthetic substrate chymase was used as a substrate for measurement of inhibitory activity against rat chymase, with the spectrophotometer measured the fluorescence generated after the reaction of aminoethylamino. Specifically, 200 μl of 0.15 M Tris-Hcl buffer (pH 8.0) containing 0.1 mm synthetic substrate chymase, is 0.0002 μl of solution chymase rats and 2 μl of the compounds according to this invention in a solution of dimethylsulfoxide was made in a measuring cell with a volume of 0.5 ml and incubated at 37oC for 15 minutes After completion of the reactions was immediately measured the amount of the formed aminoethylamino at a wavelength of excitation of 370 nm and the wavelength of detection of 460 nm to determine the activity of chymase, and expected concentration of 50% inhibition (IC50nm).

(b) Measurement using angiotensin I as a substrate.

Inhibitory activity against human chymase and chymase dogs was measured using as the substrate, in addition to the above synthetic substrate, angiotensin I (Peptide Kenkyus or dogs and 2 μl of the compounds according to this invention in a solution of dimethyl sulfoxide, made in a test tube with a volume of 1.5 ml and incubated at 37oC for 60 minutes After the end of the reaction the amount of the formed angiotensin II was immediately measured using high-performance liquid chromatography. to determine the activity of chymase, with the calculation of the concentration of 50% inhibition (IC50nm).

(E) Measurement of inhibitory activity against other proteases, chymase in addition.

Measured the inhibitory activity of the compounds of the present invention in relation to the human elastase, cathepsin G, human, human urokinase, human thrombin and factor XA person, using their respective synthetic substrates, in the same way as for chymase. All of the above protease represented commercial products company Boehringer Mannheim or were purified using a combination of known methods. Synthetic substrates consisted of substrates supplied by the firm Peptide Kenkyusho. In the table And the synthetic substrates for the respective proteases.

The test was performed several times. Himizu for each test were prepared as described above. Test compounds were compounds prepared in accordance with op who compared the chymase and other proteases the results are presented in tables 13 and 14.

As follows from tables 13 and 14, the compounds of the present invention at low concentrations inhibit himizu rats, himizu dogs and himizu person and, in addition, show selectivity between different proteases and hemati. Furthermore, chymase man and dog chymase inhibited in a similar manner at low concentrations of the compounds, if the measurements used and the angiotensin I, which is one of the substrates chymase in vivo. In addition, the connection 50, the connection 54, compound 72, compound 73, compound 74, 75 connection, the connection 77, the connection 78, the connection 79, the connection 80 and the connection 82 have a high inhibitory activity against human chymase, but do not have inhibitory activity against other proteases person, so it is expected that they can be therapeutic agents that do not have adverse effects on thrombosis, blood clotting, etc., In particular, the compounds listed in table 14, have particularly high inhibitory activity against chymase and therefore are considered as the most preferred compounds.

Sample test 2

Inhibitory effect on degranulyatsii sodium, 3.7 mm potassium chloride, 3.0 mm disubstituted phosphate sodium, 3.5mm one-deputizing sodium phosphate, 5.6 mm dextrose, pH 7.0) were injected with in the abdominal cavity of rats (line SD, male, age 8-10 weeks) were selected cells intraperitoneal cavity and centrifuged at 800 rpm for 5 min, and then was collected in the form of precipitation infiltration of cells of the peritoneum. Precipitated cells are then washed twice with buffer solution for mastocytes, again suspended at a certain beforehand density and used in target experiments.

(B) Inhibitory effect on degranulation of mastocytes (inhibitory effect on the release of histamine from mastocytes rats).

Mastocyte obtained by the method described above in (A), suspended at a density of 1105cells per ml in buffer solution for mastocytes and kept at 37oC. In a test tube 1.5 ml, pre-aged at 37oC, was added 2 μl of each inhibitor and 200 ál of cell suspension and incubated at 37oC for 10 min After the end of the incubation the contents of the tube were added 2 μl of the antibody anti-IgE (production company BETHYL Lab., Inc. ), and incubated for 15 min at 37oC. After the reaction reacciona the charging fluid was collected and stored. Histamine in the supernatant modified ortho-phthalaldehyde and its amount was measured using high performance liquid chromatography to determine the concentration of 50% inhibition (IC50microns). The results are shown in table 15.

Example test 3

Inhibitory activity against activation of eosinophils.

(A) Obtaining eosinophils.

Polymyxin B (production company Sigma) was administered intraperitoneally to a Guinea pig (line Hartley, male 6-week old) at a dose of 1 mg once a week for 6-8 weeks. After the last injection of polymyxin b in the peritoneal cavity of Guinea pigs were injected with 50 ml of PBS (phosphate buffered sodium chloride solution) and was extracted cells. The cells were centrifuged at 800 rpm for 5 min, collected by infiltration of cells of the peritoneum in the form of precipitation and suspended them in 1 ml of 40% picola (40% solution picola (production company Pharmacia) in a balanced salt solution Hanks) was layered on top of the step density gradient picola (from 40 to 90%). Centrifuged at 1500 rpm for 40 min and was selected fraction of eosinophils. This procedure is usually eosinophils with a purity of 99% or higher. Then the cells were twice washed anee certain density and used in the target experiment.

(B) Inhibitory effect on eosinophils (inhibitory effect on the release of active oxygen from the Guinea-pig eosinophils).

Eosinophils (purity 99% or higher) obtained by centrifuging the gradient picola described above in (A), suspended at a density of cells 4105cells per ml in buffer solution (0,136 M sodium chloride, 2.7 mm potassium chloride, 1.8 mm calcium chloride, 1.0 mm magnesium chloride, 11.9 mm sodium bicarbonate, 5.5 mm D-glucose, 5.0 mm HEPES, 0.36 mm one-deputizing sodium phosphate, pH 7,2). Each inhibitor (2 mm) and 180 μl of cell suspension was placed in a cell 96-cell tablet (white for measuring chemiluminescence) pre-aged at 37oS, and incubated at 37oC for 10 min After the end of the incubation were added to each well 20 μl of FOP (platelet activating factor) (510-6M) and 20 μl of a solution lyuminola and immediately was measured by the chemiluminescence (fluorimeter company Luminoscan Labosystem). Was measured by a chemiluminescence for 5 min to calculate the concentration of 50% inhibition (IC50microns). The results are presented in table 16.

As follows from tables 15 and 16, the compounds of the present invention, having inhibitory activestats simultaneous inhibition of mastocytes and eosinophils.

Examples of studies of the toxicity of the claimed compounds

Each of compounds 37, 54 and 79 were injected into mice intraperitoneally at a dose of 50 mg/kg / day for four consecutive days to study their respective toxicity. None of the investigated compounds did not cause any abnormal change in the overall data, neither in body weight of mice, and showed no toxicity.

Each of the connections 52 and 71 oral was administered to hamsters at a dose of 200 mg/kg / day for 23 consecutive days in order to determine whether they are appropriate toxicity, causing changes in body weight or not. Studies have shown that these compounds do not cause noticeable abnormal changes in body weight even on the 23rd day and, thus, can be considered high security compounds.

Although the cytotoxicity is not described in test Examples 2 and 3 of the present description (see S. 105-108), however, in accordance with the observations above the test cells revealed that all samples of the obtained compounds have no significant cytotoxicity.

Industrial applicability

As described above, the compounds of the present invention, the region is but also himizu person, no inhibition of other proteases. In addition, the compounds of the present invention inhibit the conversion of hemati of angiotensin I to angiotensin II and also exhibit an inhibitory effect on the activation of eosinophils, therefore, it is expected that they can be medicines for the treatment or prevention of diseases such as asthma, allergies, inflammation, rheumatism, hypertension, heart failure, myocardial infarction, cardiac hypertrophy, vascular damage, accompanied by angiogenesis and atheroma, nephritis and renal failure, etc. T

1. Derivatives ndimethylacetamide General formula (I) or their pharmacologically acceptable salts.

< / BR>
where R0is a phenyl group, ring which may contain one or more groups of the substituents selected from group a defined below (group a consists of halogen and a hydroxyl group);

R1represents phenyl, which may independently contain one or more groups of the substituents selected from: the group consisting of ORaand COORa(where Rarepresents hydrogen, lower alkyl, phenyl-(1-7C-alkyl, heteroaryl-(1-7C-alkyl, phenyl and heteroaryl, where the heteroaryl group is a 5 - or 6-membered ring, mA2represents a (1-8C) alkyl, phenyl-(1-7C) alkyl or phenyl; or R2to pose the above group B, or (1-8C) alkyl containing group as a substitute of the group; or (1-8C) alkyl containing cyclic group G as a substitute group (a cyclic group G represents a heterocyclic group consisting of 5 - or 6-membered rings containing 1 to 2 nitrogen atoms, or 1 nitrogen atom and 1 oxygen atom, and may contain as a substituent oxoprop or(1-7)-alkyl group);

R3is hydrogen; or R3represents: (i)D(CH2)0-3CO, (ii) D or (iii) DSO2ECO as an acyl group; or R3represents the D(CH2)0-3SO2as sulfonyloxy group (where the group D represents hydrogen, C1-6 promoteyou or branched alkyl group, phenyl, RbRcN, RaO or Rawhere the group Ra, Rband Rcindependently are the same as defined above, the group Ra; and E represents a divalent linking group containing from 1 to 6 carbon atoms);

X and Y independently represent a nitrogen atom or a carbon atom; and

Z represents a methylene is the fact that what R2is as follows: R2is(1-8C) alkyl, phenyl-(1-7C) alkyl or phenyl; or R2is defined above group (except when in the formula (I) Y is a nitrogen atom, and X is a carbon atom), or (1-8C) alkyl containing group as a substitute of the group; or (1-8C) alkyl, defined above containing cyclic group G as a substitute group.

3. Derivatives ndimethylacetamide or their pharmacologically acceptable salts under item 1 or 2, characterized in that a cyclic group G selected from the group consisting of pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinone, pyrazolone, pyridazine, piperazine-1-yl, optionally containing in the 4th position of the lower alkyl group, pyrrolidin-1-yl, piperidine-1-yl, 4-morpholine-4-yl and pyrrol-1-yl.

4. Derivatives ndimethylacetamide or their pharmacologically acceptable salts under item 1, characterized in that each corresponding symbol in the formula (I) represents the following: R0is a phenyl group, ring which may contain 1 to 5 groups of the substituents selected from the group consisting of halogen and a hydroxyl group; R2represents (1-4C)-alkyl, phenyl-(1-3C) alkyl or phenyl; or R2represents a specific higher the group the higher the cyclic group G as the group's Deputy; group E in R3represents a C1-6 promoteyou divalent aliphatic linking group.

5. Derivatives ndimethylacetamide or their pharmacologically acceptable salt according to any one of paragraphs.1-4, characterized in that each of the following symbol in the formula (I), respectively, is as follows: R0- unsubstituted phenyl group or substituted phenyl group with 1 or 2 groups-substituents selected from halogen and hydroxyl group; R1- unsubstituted phenyl group, R2- unsubstituted phenyl group, unsubstituted (1-4C)-alkyl group, or substituted (1-4C)-alkyl group containing a group-Deputy selected from carboxyl group, phenyl group, pyrrolidin-1-yl, pyridyl, pyridyloxy, 2-oxo-1,2-dihydropyridines-1-yl, pyrimidinamine, persianmirror, pyridazinones, or substituted (1-3C) alkyl piperazine-1-yl, or substituted (1-3C) alkyl piperazine-1-yl-carbonyl, and morpholinopropan; 3is hydrogen, lower acyl group, formyl, sulfamoyl, lower alkylsulfonyl, phenyl-(1-3C)-alkylsulfonyl, or tetrahydrofuryl, X is unsubstituted carbon atom, Y is a nitrogen atom, Z represents-CH2-.

6. Derivatives and represent a group selected from hydrogen, lower alkylsulphonyl, lower alkoxycarbonyl, lower acyl, sulfonyl and sulfamoyl.

7. Derivatives ndimethylacetamide or their pharmacologically acceptable salts under item 1, characterized in that each of the following symbol in the formula (I), respectively, is as follows: R0- unsubstituted phenyl group, R1- unsubstituted phenyl group, R2- (1-6C)-alkoxygroup, R3is hydrogen or (1-6C)-alkoxycarbonyl, X is unsubstituted carbon atom, Y is a nitrogen atom, Z represents-CH2-.

8. Derivatives ndimethylacetamide or their pharmacologically acceptable salt according to any one of paragraphs.1-4, characterized in that each of the following symbol in the formula (I), respectively, is as follows: R0- unsubstituted phenyl group, R1- unsubstituted phenyl group, R2- 3-(2-oxo-1,2-dihydropyridines-1-yl)propyl, R3group selected from hydrogen, tert-butyloxycarbonyl, formyl, acetyl, substituted phenyl lower alkylsulfonyl, substituted phenyl lower alkylaminocarbonyl, and replaced by heteroaryl lower alkylaminocarbonyl, X is unsubstituted carbon atom, Y is a nitrogen atom, Z represents-CH2-.

11. Derived ndimethylacetamide or its pharmacologically acceptable salt according to p. 1, where formula (I) represents 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl} exilerated.

12. Derived ndimethylacetamide or its pharmacologically acceptable salt according to p. 1, where formula (I) represents 2-(5-amino - or tert-butyloxycarbonyl - or acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-oxo-1,2-dihydropyridines-1-yl)}exilerated.

13. Derived ndimethylacetamide or pharmacologists is benzylmethylamine-, or formylamino or benzylaminocarbonyl-, or 4-pyridylmethylamine-or acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-pyridyloxy)-1-phenylmethyl} exilerated.

14. Derived ndimethylacetamide or its pharmacologically acceptable salt according to p. 1, where formula (I) represents 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2,3-dioxo-6-(2-pyridyloxy)-1-phenylethyl} exilerated.

15. Derivatives ndimethylacetamide, corresponding to the following formula:

(A) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{2-methoxycarbonyl-1-(4-hydroxyphenyl)methyl-2-oxo}ethylacetamide,

(B) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-methoxycarbonyl-1-(3-fluoro-4-hydroxyphenyl)methyl-2-oxo} ethylacetamide,

(C) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylcarbamoyl-1-phenylmethyl)ethylacetamide,

(D) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-benzylcarbamoyl-2-oxo-1-phenylmethyl)ethylacetamide,

(E) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylethanol-1-phenylmethyl)ethylacetamide,

(F) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-met the Il-1,6-dihydropyrimidin-1-yl)-N-(2-oxo-2-phenylethanol-1-phenylmethyl)ethylacetamide,

(H) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2-methoxycarbonyl-1-(4-methoxyphenyl)methyl-2-oxo}ethylacetamide,

or their pharmacologically acceptable salts.

16. Derivatives ndimethylacetamide, corresponding to the following formula:

(A) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide,

(B) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-6-phenyl-1-phenylmethyl)exilerated,

(C) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-5-phenyl-1 - phenylmethyl)ventilated,

(D) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)heptylate,

(E) 2-(5-amino-6-oxo-3-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-3-phenyl-1-phenylmethyl)propylacetamide,

(F) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(6-carboxyl-2,3-dioxo-1-phenylmethyl)exilerated,

(G) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-fluoro-4-hydroxyphenyl)methyl}butylacetamide,

(H) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3 - forfinal)methyl}butylacetamide,

(I) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(3-chlorophenyl)methyl}butylacetamide,

(J) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-enyl)methyl}butylacetamide,

(L) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-(4-chlorophenyl)methyl}butylacetamide,

(M) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6 - etoxycarbonyl-1-(3-forfinal)methyl}exilerated,

(N) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 1-(3-forfinal)methyl-7-(4-methylpiperazin-1-yl)-2,3,7-trioxo}heptylate,

(O) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(4-(morpholine-4-yl)-1-phenylmethyl}exilerated,

(R) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-6-(2-oxo-1,2-dihydropyridines-1-yl)-1-phenylmethyl}exilerated,

(Q) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-{ 2,3-dioxo-1-phenylmethyl-6-(2-pyridyloxy)}exilerated,

(R) 2-(2-amino-3-oxo-5-phenyl-3,4-dihydropyridin-4-yl)-N-(2-methoxycarbonyl-2-oxo-1-phenylmethyl)ethylacetamide,

(S) 2-(b-amino-4,5-dihydro-5-oxo-1,2,4-triazinyl)-N-(2-methoxycarbonyl-2-oxo-1-phenylmethyl)ethylacetamide,

(T) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)butylacetamide,

(U) 2-(5-tert-butyloxycarbonyl-b-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(2,3-dioxo-1-phenylmethyl)exilerated,

(V) 2-(5-tert-butyloxycarbonyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-(-yl}-N-(2,3-dioxo-6-phenyl-1-phenylmethyl)exilerated,

(X) 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-M-{ 2,3-dioxo-1-(2-forfinal)methyl}butylacetamide,

or their pharmacologically acceptable salts.

17. Salts derived ndimethylacetamide according to any one of paragraphs.1-16, characterized in that the pharmacologically acceptable salt is selected among (A) salts of alkali metals, salts of alkaline earth metals, aluminum salts, ammonium salts or salts derived from organic bases, forming a pharmaceutically acceptable cations, if the new derivatives ndimethylacetamide formula (I) are acid compounds, and (B) salts with the addition of the acid obtained with acids, forming a pharmaceutically acceptable anions, if new derivatives of ndimethylacetamide formula (I) are the main compounds.

18. The pharmaceutical composition having inhibitory activity against proteases containing the active ingredient, characterized in that as the active ingredient it contains a derived ndimethylacetamide or its pharmacologically acceptable salt according to any one of paragraphs.1-17.

19. The protease inhibitor containing as an active ingredient derived ndimethylacetamide or its pharmacologically acceptable salt according to any one of paragraphs. 1-17.

20. Ki acceptable salt according to any one of paragraphs. 1-17.

21. Inhibitor of degranulation mastocytes or inhibitor of the release of mastocytoma of histamine, which includes as an active ingredient derived ndimethylacetamide or its pharmacologically acceptable salt according to any one of paragraphs. 1-17.

22. Inhibitor of activation of eosinophils or inhibitor release by eosinophils active oxygen, comprising as an active ingredient derived ndimethylacetamide or its pharmacologically acceptable salt according to any one of paragraphs.1-17.

23. The method of obtaining derivatives of ndimethylacetamide or pharmalogical acceptable salts, characterized in that the specified method is a synthesis of new derivatives of ndimethylacetamide (I) or their pharmological acceptable salts according to any one of paragraphs.1-17 and includes the stage of the compounds of formula (II)

< / BR>
after removal of the protective group of the compounds, if present, to turn it into a new derived ndimethylacetamide formula (I),

where Rdis hydrogen or a protective group for hydroxyl group:

R0, R1, R2X, Y and Z have the same meaning as defined in paragraph 1.

24. The compounds of formula (II), as defined in paragraph 23, and their salts, wherein R0, R1, R

 

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