Derivatives pyridopyrimidines receiving them, pharmaceutical composition, method of treatment

 

(57) Abstract:

Describes the new derivatives pyridopyrimidines formula a in which Q represents -(CH2)m(m = 0, 1, 2), n = 1, 2, 3; R1is (1) hydrogen atom, (2) C1-6is an alkyl group which may be optionally substituted by one of the substituents selected from chinoline or indoline, (3) phenyl group, which optionally may be substituted by at least one C1-6-alkoxygroup, or (4) phenyl-C1-3is an alkyl group which may be optionally substituted by at least one Deputy, selected from C1-6-alkoxy and C1-6-alkylthio; R2is a hydrogen or C1-6is an alkyl group; R3is (1) phenyl or naftilos group, which optionally may be substituted by at least one Deputy, selected from C1-6-alkyl, C1-6-alkoxy, C1-6-alkylenedioxy, halogen atom, nitro, cyano, phenyl, C3-7-cycloalkyl, (2) pyridium, which optionally may be substituted C1-6-alkyl, (3) tanila, which optionally may be substituted C1-6-alkyl, (4) chinaillon, which optionally may be substituted by oxopropoxy or substituted C1-6-alkyl; R4is a group - R6in which R6represents (1) hydrogen atom, (2) C1-6is an alkyl group, optionally substituted by at least one Deputy from C3-7-cycloalkyl group, chinoline group, carboxyl group, cyano and phenyl groups; or (3) (C3-7-cycloalkyl; or the group-NR7R8in which R7and R8independently represent a hydrogen atom or a C1-6is an alkyl group; R5is (1) hydrogen atom, (2)1-6is an alkyl group or (3) a phenyl group which may be optionally substituted C1-6-alkylenedioxy, or its salt. Also described is a method of obtaining compounds of formula A, the pharmaceutical compositions based on compounds of the formula and a method antagonistic effects on endothelioma receptors in the treatment of renal failure, myocardial infarction, hypertension, cerebral infarction, chest angina, arteriosclerosis, Hepatology, pulmonary hypertension, asthma, organochiorine caused by surgery or organ transplantation. The new compounds of formula a and farbkomposition based on them can find a wide application in medicine. 4 C. and 16 h.p. f-e heterocyclic ring, which have excellent activity as a medicine, for example, antagonistic towards endothelina receptor activity, and are used as vasodilators and therapeutic compositions for the treatment of diseases, such as hypertension, acute renal failure, myocardial infarction, chest angina and cerebral angiospasm, and the method of obtaining these compounds.

Description of the prior art

It was hypothesized that the disease of adults, increased in the subsequent time, for example, cerebral infarction, chest angina, myocardial infarction and renal failure caused by ischemia, probably associated with endothelin. Endothelin is a peptide containing 21 amino acid secreted from endothelial cells, and endothelin-1, endothelin-2 and endothelin-3. Further, in this description, these endothelioma group United by the term "endothelin". It was reported that among in vivo or synthetic substances previously found, endothelin has the most powerful and long-lasting angioplasties action, Pressor activity and increased activity of cardiac muscle. It is believed that acts on the membrane of the smooth muscle of blood vessels, and so D. as endothelioma receptors known endothelin-A receptor and endothelin-B receptor (hereinafter called together "endotheliosis receptor").

Therefore, compounds showing affinity for endothelium receptor, as well as exhibiting antagonistic towards endothelina receptor activity, have preventive and therapeutic action against diseases caused by ischemia such as cerebral infarction, chest angina, myocardial infarction and renal failure, therefore, the development of such compounds is very promising.

As substances antagonistic towards endothelina receptor were obtained compounds of natural origin, as described in some studies, for example, Ishimaru et al. [JPA H4 (1992) - 134048], Fujimoto et al. [Federation of European Biochemical Societies Letters, 305 p. 41 (1992)]. Oh-hata et al. [JPA H3 (1991) - 047163], Miyata et al. [JPA H4 /1992/ - 046127] and Jano et al. [JPA H3 /1991// - 094692].

Further, the reports that were obtained peptide compounds were made by Henmi et al. [EP 457195-A2], Ishikawa et al. [EP 460679-A2 and EP 436189-A] Hashimoto et al. [JPA H3 /1992/ - 130299], Masaki et al. [JPA H3 /1992/ - 024099], G. Hamon et al. [EP 487410-A2], W. L. Cody et al. [J. Med. Chem. /1992/ 35, p. 3303] and Wakimasu et al. [Wo 9113089-A, EP 499266-A1].

However, when prinimayte and resistance to metabolism, synthetic antagonists endothelioma receptor, ones obtained by peptide synthesis of these compounds are very necessary. Under the circumstances, however, there are very few messages on ones synthetic antagonists endothelioma receptor, for example a recent report by K. Bali et al. [EP 510526-A1].

On the other hand, described H. R Haward et al. [WO 92/12979/ derivative 2,4/1H, 3H/-dioxobenzo[2,3-d] pyrimidine-3-acetic acid, which have a relatively similar structure as the compounds of the present invention. The substituents in these compounds, however, are clearly different from those of the present invention. Further, it was reported that the above-mentioned compounds used in therapy as inhibitors alsoreported to control some of the complications of chronic diabetes, but do not have the effect of antagonists endothelioma receptor.

The object of the present invention are new and useful compounds, each of which has a condensed heterocyclic ring, especially new compounds that can be used as synthetic ones antagonists endothelioma receptor, through which megalynaria, having antagonist properties endothelioma receptor, which is stable as a connection and has a prolonged pharmacological effect and metabolic stability.

A further object of the present invention is a method for obtaining compounds and composition antagonist endothelioma receptor.

The developers of the present invention conducted a thorough research on the above objectives, as a result it was found that these objectives can be achieved with new derivatives of pyridopyrimidines with antagonistic towards endothelina receptor activity, and thus, the present invention is generally based on the recognized fact.

The present invention relates to derivatives of pyrido-[2,3-d]pyrimidine of the formula A or their salts

< / BR>
where Q is -(CH2)m(m = 0, 1, 2), -O-, -S(O)p- (p = 0, 1, 2) or-NH-;

n = 0, 1, 2 3;

R1and R2independently are a hydrogen atom, optionally substituted C1-6-Akeley group optionally substituted aryl group or optionally substituted aranceles group;

R3is optionally substituted cyclic hydrocarbons the ode, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group or optionally substituted aranceles group, cyano, -COOR6(R6is a hydrogen atom, optionally substituted C1-6is an alkyl group, optionally substituted cyclic hydrocarbon group or optionally substituted aranceles group) or-CONR7R8(R7and R8independently are a hydrogen atom, optionally substituted C1-6is an alkyl group, optionally substituted cyclic hydrocarbon group or optionally substituted aranceles group);

R5is hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group, optionally substituted aranceles group, -X1R9(X1is-O-, -NR10- or-S-, R9and R10independently are a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group or optionally substituted aranceles group).

As particularly preferred examples of derivative pyridopyrimidines and their salts therefore invented the BR>R1is a hydrogen atom, a C1-6is an alkyl group or a C7-15-aranceles group, optionally substituted C1-6-alkoxygroup or C1-6-alkylthiophene;

R2is a hydrogen or C1-6is an alkyl group;

R3is C6-16-aryl group, optionally substituted with at least one group selected from the group comprising C1-6is an alkyl group, a C3-7-cycloalkyl group, C1-6-alkoxygroup, a halogen atom, a nitro-group, cyano and phenyl group, or a 5 to 13-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen and sulfur atom, optionally substituted with at least one group selected from the group comprising C1-6is an alkyl group. C1-6-alkoxygroup, oxoprop and the hydroxy-group;

R4is-COOR6(R6is a hydrogen atom, a C1-6is an alkyl group optionally substituted by carboxyl group or a 5 - to 10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom, C3-7-cycloalkyl group or a C6-15-aranceles group or a C6-14-aryl group;

R5is a hydrogen atom, a C1-6is an alkyl group or a C6-14-aryl group, optionally substituted C1-3-alkylenedioxy.

The present invention relates to a method of deriving pyrido[2,3-d]pyrimidine of the formula A or its salt, which consists in the fact that the compound of the formula I

< / BR>
in which n, R1and R2have the same values as above,

or its salt is subjected to reflux in a solvent together with a cyclic hydrocarbon or heterocyclic aldehyde of the formula R3Q-CHO (Q and R3have the same meanings as described above) and beta-ketefian, or together with the derived, obtained by dehydrating condensation of the specified aldehyde and keeeper, to obtain compounds of formula B

< / BR>
in which n, R1- R5have the same values as above,

or its salts.

Compound B or its salt is subjected to oxidation with an oxidizing agent to obtain compounds of formula A

< / BR>
in which n, Q, R1- R5have the same values as above,

or its salts.

Then for the case when R2is not atomo is where n, R1, R3- R5and Q have the same meanings as described above

or its salts.

Further, the present invention relates to a method of deriving pyrido[2,3-d] pyrimidine of the formula A or its salt, which consists in the fact that the compound of the formula I

< / BR>
in which n, R1and R2have the same values as above,

heat up together with 3,3-bioterriorism in dimethylformamide to obtain the compound of formula C.

< / BR>
in which n, R1, R2, R4and R5have the same values as above,

or its salts. Connection C or its salt is subjected to interaction with nucleophilic agent represented by the formula, R3QH (Q and R3have the same meanings as described above) to obtain the compounds of formula A

< / BR>
in which n, Q, R1- R5have the meanings specified above,

or its salts. Next, for the case when R2is not a hydrogen atom, a specified compound A or its salt can be hydrolyzed to obtain the compounds of formula Aa"

< / BR>
in which n, R1, R3, R4, R5and Q have the same meanings as described above

or its salts.

In addition, the present invention to the m the compound of formula II

< / BR>
in which R1has the same meaning indicated above,

or its salt is subjected to reflux in a solvent together with a derivative represented by the formula QR3CHCR4COR5(Q, R3, R4and R5have the same meanings as described above) obtained by dehydrates condensation cyclic hydrocarbon or heterocyclic aldehyde represented by the formula, R3Q-CHO (Q and R3have the same meanings as described above) and beta-keeeper with obtaining the compounds of formula B

< / BR>
in which Q, R1, R3- R5have the same values as above,

or its salts by oxidation of compounds B or its salt with an oxidizing agent to obtain compounds of formula D

< / BR>
in which Q, R1, R3- R5have the same values as above,

then subjecting the compound D or its salt reaction with halogenated alkylcarboxylic derivative of the formula X2(CH2)nCOOR2in which X2is a halogen atom, n and R2have the same values as described above, in a suitable solvent in the presence of a base to obtain the compounds of formula A and EBIT hydrolyzed to obtain the compounds of formula Aa or its salts.

In addition, the present invention relates to a method of deriving pyrido[2,3-d] pyrimidine of the General formula A or its salt, in which QR3is 2-(4-chinolone)-group, and R4- carboxyl group, which consists in heating the compounds of formula E or its salt

< / BR>
in which n, Q, R1, R2and R5have the same values as above,

under reflux with thionyl chloride to obtain the compounds of formula Ab

< / BR>
in which n, Q, R1, R2and R5have the same values as above,

or its salts.

Then for the case when R2is not a hydrogen atom, the specified connection Ab or its salt can be hydrolyzed to obtain the compounds of formula Ac or its salt

< / BR>
in which n, R1and R5have the values specified above.

In addition, the present invention relates to a method of deriving pyrido[2,3-d]pyrimidine of the General formula A or its salt which comprises the reaction of the compound or its salts;

< / BR>
in which n, Q, R2- R5have the meanings specified above,

halogenated alkyl, halogenated aryl or halogenated Uralkaliy of the what about the above, in a suitable solvent in the presence of a base to obtain the compounds of formula A and its salts. Then in the case when R2is not a hydrogen atom, a specified compound A or its salt can be hydrolyzed to obtain the compounds of formula Aa or its salts.

In addition, the present invention relates to a method of deriving pyrido[2,3-d]pyrimidine of the formula A or its salts, in which R4is-COOR6(R6is optionally substituted C1-6is an alkyl group, optionally substituted cyclic hydrocarbon group or optionally substituted aranceles group, which involves the reaction of the compounds of formula C or its salt:

< / BR>
in which n, Q, R1- R3and R5have the same values as above,

with halogenated alkyl, halogenated aryl or halogenated Uralkali compound represented by the formula, R6'X2in which X2is a halogen atom, R6'has the same meaning indicated above, in a suitable solvent in the presence of a base to obtain the compounds of formula A in which R4is - COOR6(R6has the same values as specified above) and e to be hydrolysed to obtain the compounds of formula Aa, in which R4is - COOR6(R6has the same values as specified above) or its salt.

In addition, the present invention relates to a method of deriving pyrido[2,3-d]pyrimidine of the General formula A, in which OR3is 2-(4-chinolone)group, R4is-COOR6or (-CONR7R8(R6, R7and R8have the same meanings as described above) or its salt which comprises the reaction of compounds of formula Ad, or salts thereof:

< / BR>
in which n, R2and R5have the same values as above,

with thionyl chloride in a suitable solvent, then the interaction with the halogenated alkyl, halogenated aryl or halogenated Uralkali compound of formula R1X2in which X2is a halogen atom, R1has the same meaning indicated above, in a suitable solvent in the presence of a base to obtain the compounds of formula H

< / BR>
in which n, R1, R2and R5have the same values as above,

or its salt, and then the interaction of the compound H or its salt with a nucleophilic reagent, which is able to introduce Deputy, presents-QR6or-NR7R83is 2-(4-chinolone)group, R4is - COOR6or-CONR7R8(R6, R7and R8have the same meanings as described above), and its salts.

Then for the case when R2is not a hydrogen atom, a specified compound A or its salt can be hydrolyzed to obtain the compounds of formula Ac where OR3is 2-(4-chinolone)group and R4is - COOR6or-CONR7R8(R6, R7and R8have the same meanings as described above) or its salt.

Also the present invention relates to antagonistic towards endothelina receptor agent containing as an effective component derived pyrido-[2,3-d] pyrimidine represented by the above formula A, or its pharmaceutically acceptable salt.

Further, the present invention relates to compositions specified antagonist to endothelina receptor as a therapeutic composition for the treatment of acute renal failure, myocardial infarction, hypertension, cerebral infarction, chest angina, arterial sclerosis, Hepatology, pulmonary hypertension, asthma, org the La treatment of acute renal failure and/or myocardial infarction.

The compound of the formula A according to this invention (hereinafter referred to as compound a) will be described below in detail.

In the formula A Q means - (CH2)m(m = 0 or 1, 2), -O-, -S(O)p(p = 0 or 1, 2) or-NH-, preferably Q is -(CH2)-, particularly preferably m = 0 or 1;

n = 0 or 1, 2, 3, preferably 1 or 2, particularly preferably 1.

In the formula A, R1and R2may be the same or different from each other and respectively represent a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group or optionally substituted aranceles group.

Examples of C1-6is an alkyl group include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, neopentyl group, tert-pentelow group, 1-ethylpropyl group, hexoloy group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group.

Among them, C1-4is an alkyl group, presents examples of methyl g is emer, are preferred. A methyl group is particularly preferred.

C1-6is an alkyl group can have 1 to 3 suitable substituents as an example, C3-7-cycloalkyl group, a 5-10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom, 5-to 10-membered non-aromatic heterocyclic group containing from 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfur atom, amino group, mono-(C1-6-alkyl)amino group, di(C1-6-alkyl)amino group, amidinopropane, C1-6-acylcarnitine group, C6-14-arylcarbamoyl group, C7-15-analceleberty group, C1-6-alkoxycarbonyl group, C6-14-aryloxyalkyl group, C7-15-aracelikarsaalyna group, carnemolla group, mono-(C1-6-alkylcarboxylic group, di(C1-6)alkylcarboxylic group, alfamarine group, mono-(C1-6)alkylsulfonyl group, di(C1-6)alkylsulfonyl group, carboxyl group, hydroxyl group, (C1-6)-CNS group, C2-6-alkenylacyl, C3-15-arancelaria, mercaptopropyl, C

According to the present invention, the aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, examples of C6-14-aryl group such as phenyl group, naftalina group, antenna group, phenanthroline group and acenaphthylene group, particularly preferred are a phenyl group, 1-naftalina group and 2-naftalina group.

The aryl group may have one or more, preferably from 1 to 3 suitable substituents as an example, C1-6is an alkyl group (e.g. methyl group, ethyl group and through the group), C2-6-Alchemilla group (for example, vinyl group, allyl group and 2-bucinellina group), C2-6-Alchemilla group (for example, propargyl group and 2-Butyrina group), cycloalkyl group (for example, C3-7-cycloalkyl group, such as cyclopropyl group, cyclobutyl group, cyclopentenone group and tsiklogeksilnogo group), C6-14-aryl group (e.g. phenyl group and naftalina group), an aromatic heterocyclic group (e.g., 5-9-membered aromaticity is and sulfur, as an example furilla group, thienyl group, a pyrrole group, thiazolidine group, imidazolidinyl group, Peregrina group, kinolinna group and chinaonline group), non-aromatic heterocyclic group (e.g., 5-9-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, as an example oxiranyl group, azetidinone group, acetanilide group, titanilla group, pyrrolidinyl group, tetrahydrofuryl group, milaninia group, piperideine group, tetrahydropyranyl group, Morganella group, thiomorpholine group and piperazinilnom group), kalkilya group (for example, C7-15-kalkilya group such as benzyl group, phenylethylene group, 1-naphthylmethyl, 1-naftalil), amino group, N-monosubstituted amino group (for example, C1-6-monoalkylamines, such as methylaminopropyl, atramentaria and Propylamine), N,N-substituted amino group (for example, N, N-disubstituted amino group, substituted C1-6is an alkyl group, as an example, dimethylaminopropan and diethylaminopropyl), actinograph, acyl group (for example, C1-8the I group; C6-14-arylcarbamoyl group, such as benzoline group; C7-15-analceleberty group, such as benzylcarbamoyl group, phenylethylenediamine group, C1-8-alkoxycarbonyl group, such as methoxycarbonyl group and ethoxycarbonyl group; C6-14-aryloxyalkyl group, such as vinyloxycarbonyl group, alpha nattermannallee group and C7-15-aracelikarsaalyna group, such as benzyloxycarbonyl group, 1-naphthalocyanine group), carnemolla group, N-monosubstituted carbonyl group (for example, C1-6-alkylcarboxylic group, such as methylcarbamoyl group, ethylcarbazole group and profilirovannaja group), N,N-disubstituted carnemolla group (for example, N,N-disubstituted carnemolla group, substituted C1-6-alkyl group, which is confirmed by the examples in dimethylcarbamoyl group and diethylcarbamoyl group), alfamarine group, N-monosubstituted Altamarena group (for example, N-alkylsulfonyl group having C1-6is an alkyl group as illustrated methylsulfonyl group, ethylsulfonyl group and propylsulfonyl group), N,N-disame the ing group, as an example dimethylsulphamoyl group and diethylcarbamoyl group), carboxyl group, hydroxyl group, C1-6-CNS group (e.g. methoxy group, ethoxypropan and propoxylate, C2-6-alkenylacyl (for example, vinyloxy and alliancegroup), cycloalkylation (for example, C3-7-cycloalkylation), such as cyclopropylamine and cycloamyloses), arancelaria (for example, C7-14-arancelaria such as benzyloxy, 1-naphthyloxy), alloctype (for example, C6-14-alloctype, such as fenoxaprop and naphthyloxy), mercaptopropyl, C1-6allylthiourea (for example, methylthiourea, ethylthiourea and PropertyGroup), kalkiliya (for example, C7-15-kalkiliya, such as menzilcioglu, 1-naphthylthiourea), aristocrata (for example, C6-14-aristocrata, such as phenylthiourea and naphthylthiourea), alphagraph, cyano, asiagraph, nitrogroup, nitrosurea, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom and iodine atom), C1-3-alkylenedioxy group (for example, methylendioxy, atlantoxerus) among others.

Mentioned kalkiliya aryl group is preferred the same as the above-mentioned aryl group, and as preferred alkyl groups implies C1-6is an alkyl group. Preferred kalkilya group includes C7-15-aracelio group, such as benzyl group, phenylethylene group, 3-phenylpropyl group, (1-naphthyl)methyl group and (2-naphthyl)methyl group, particularly preferred is phenyl-(C1-3) is an alkyl group such as benzyl group and penicilina group.

Aryl group aranceles group may have the same substituents, which may have the above-mentioned aryl group and the specified Deputy preferably is C1-6-alkoxygroup (for example, methoxy group, ethoxypropan or propoxylate), C1-6-alkylthiophene (for example, methylthiourea, ethylthiourea or PropertyGroup), particularly preferred substituents, which is C1-3-alkoxygroup, such as a methoxy group.

Preferred examples of R1include a hydrogen atom, a C1-6is an alkyl group (e.g. methyl group, ethyl group), C7-15-aracelio group, optionally substituted C1-6-alkoxygroup or C1-6-alkylthiophene (especially preferred is Oh or C1-6-alkylthiophene).

Preferred examples of R2include a hydrogen atom, a C1-6is an alkyl group (e.g. methyl group, ethyl group, through the group and the isopropyl group).

In the formula A, R3denotes optionally substituted cyclic hydrocarbon group or optionally substituted heterocyclic group, the cyclic hydrocarbon group represented in the examples of the aryl group or cycloalkyl group. Specified aryl group refers to the same aryl group as described in relation to R1and R2that may be, and aryl radicals, R1and R2one or more, preferably from 1 to 3 suitable substituents. As mentioned substituents listed are the same as described in relation to the aryl group of the radicals R1and R2. Especially preferred Deputy includes C1-6is an alkyl group, a C3-7-cycloalkyl group, C1-6-alkoxygroup, a cyano, a nitro-group, a halogen atom and phenyl group.

Examples specified cycloalkyl groups include C3-10-cycloalkyl group or a C3-10-bicycloalkyl group sing as a group, cycloheptyl group, cyclooctyl group, bicyclo/2,2,1/-heptylene group, bicyclo/2,2,2/octiles group, bicyclo/3,2,1/octiles group, bicyclo/3,2,1/nonalloy group, bicyclo/4,2,1/nonalloy group and bicyclo/4,3,1/decile group. A preferred example of the specified cycloalkyl group includes C4-7-cycloalkyl group (for example, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group). Specified cycloalkyl group may have 1 to 3 suitable substituents, such as C1-6-akilina group, C2-6-Alchemilla group, C2-6-Alchemilla group, carboxyl group, hydroxyl group, a nitro-group or halogen atom.

The examples mentioned heterocyclic groups include 5 to 13-membered aromatic heterocyclic group, an atom containing ring of 1 to 4 heteroatoms selected from O, S and N, or saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group).

Preferred examples of the specified heterocyclic group include aromatic monocyclic heterocyclic groups such as furilla group, thienyl group the group, imidazolidine group, pyrazolidine group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, furazolidine group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-thiazolidine group, 1,2,4-thiazolidine group, tetrataenia group, Peregrina group, pyridazinyl group, piramidalnaya group, piratininga group and trainline group; and an aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo/b/thienyl, indolyl, isoindolyl, 1H-indazole, benzoimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazolyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, hinely, quinoline-N-oxide-2-yl, quinoline-N-oxide-3-yl, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, polylina group, pteridinyl group, carbazolyl group, alpha carbonilla group, beta-carbonilla group, gamma-carbonilla group, accidenily group, phenoxypyridine group, Phenoxyethanol group, tintinnina group, phenanthridinone group, phenanthroline group, indolizinyl group, pyrrolo/1,2-b/pyridazinyl group, a pyrazolo/1,5-a/perederina the AOR/1,2-a/pyridazine group, imidazo/1,2-a/piramidalnaya group, 1,2,4-triazolo/4,3-a/peredelka group, and 1,2,4-triazolo/4,3-b/pyridazinyl group.

Especially preferred example is Peregrina group, kinolinna group, quinoline-N-oxide-2-yl, quinoline-N-oxide-3/Il, benzofuranyl group, benzo (b) thienyl group or thienyl group.

Preferred examples mentioned heterocyclic groups include oxiranyl group, azetidinol group, oxetanyl group, titanilla group, pyrrolidinyl group, tetrahydrofuranyl group, colaninno group, piperidino group, tetrahydropyranyloxy group, morpholinyl group, thiomorpholine group, and piperazinilnom group.

Also, the specified heterocyclic group may have one or more, preferably from 1 to 3 suitable substituents which are the same as described for the aryl group of the radicals R1and R2. Among others, preferred is a C1-6is an alkyl group.

Preferred examples of R3include C6-14-aryl group (e.g. phenyl group, naftalina group), optionally substituted by at least one Deputy, selected My halogen, the nitrogroup, cyano, and phenyl group; or a 5 to 13-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (for example, Peregrina group, kinolinna group, quinoline-N-oxide-2-yl, quinoline-N-oxide-3-yl group, benzofuranyl group, benzo (b) thienyl group, a thienyl group), optionally substituted by at least one Deputy, selected from the group consisting of C1-6is an alkyl group, a C1-6-alkoxygroup, oxoprop and hydroxyl group. Among others, phenyl group, naftalina group, Peregrina group, kinolinna group, thienyl group, quinoline-N-oxide-2-yl, quinoline-N-oxide-3-yl group, benzofuranyl group, methyl-benzo/b/thienyl group, and 4-chinaonline group (for example, 2-(4-chinaonline group) is particularly preferred as R3. 4-chinaonline group is chinaonline group, substituted oxopropoxy in the 4th position.

In the formula A, R4is a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group, optionally substituted aranceles group, cyano, -COOR6(R7R8(R7, R8independently represent hydrogen, optionally substituted C1-6is an alkyl group, optionally substituted cyclic hydrocarbon group or aracelio group).

The specified C1-6is an alkyl group, aryl group or kalkilya group have the same values that are referenced to R1and R2and the said cyclic hydrocarbon group has the same values that are specified for the same group in relation to the radical R3. These C1-6is an alkyl group, aryl group, kalkilya group and the cyclic hydrocarbon group may have, as in the case of the radicals R1, R2and R3one or more, preferably from 1 to 3 suitable substituents which are the same as described for R1, R2and R3.

Preferred examples of R4include-COOR6or-CONR7R8in which R6is preferably C1-6is an alkyl group, a C3-7-cycloalkyl group or a C7-15-aranceles group which may be optionally substituted by a hydrogen atom, a carboxyl group or a 5-10-membered heterocyclic group containing from 1 desteno, an atom of hydrogen, C1-6is an alkyl group or a C6-14-aryl group. Especially preferred example of R6is C1-6is an alkyl group, substituted pinolillo group.

Preferred examples - CONR7R8include karbamoilnuyu group or karbamoilnuyu group, substituted C1-6is an alkyl group.

In the formula A, R5denotes a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group, optionally substituted aracelio group, or-X1R9(X1means-O-, NR10- or-S-; R9and R10independently represent a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group or optionally substituted aracelio group). C1-6is an alkyl group, aryl group and kalkilya group in the radicals R5, R9and R10are the same as those groups specified in relation to the radicals R1and R2and the above aryl group and kalkilya group may have, as in the case for R1, R2and R3one or more, preferably from 1 to 3 suitable substituents. As e is CLASS="ptx2">

Preferred examples of R5include a hydrogen atom, optionally substituted C1-6is an alkyl group, an optionally substituted aryl group, particularly preferred are a hydrogen atom, a C1-6is an alkyl group (e.g. methyl group, ethyl group, through the group, isopropyl group, and isobutylene group), or C6-15-aryl group (e.g. phenyl group), optionally substituted C1-3-alkylenedioxy.

Preferred examples of the compound A according to this invention include the compound in which n = 1, 2, 3; R1is a hydrogen atom, a C1-6is an alkyl group or a C7-15-aranceles group, optionally substituted C1-6-alkoxygroup or C1-6-alkylthiophene; R2is a hydrogen or C1-6is an alkyl group; QR3is C6-14-aryl group, optionally substituted by at least one Deputy, selected from the group consisting of C1-6is an alkyl group, a C3-7-cycloalkyl group, C1-6-alkoxygroup, halogen atoms, the nitro-group, a cyano or phenyl group, or a 5 to 13-membered aromatic heterocyclic group containing from 1 to 4 etenim Deputy selected from the group consisting of C1-6is an alkyl group, a C1-6-alkoxygroup, oxoprop, and hydroxyl group; R4is-COOR6-1(R6-1is a hydrogen atom, a C1-6is an alkyl group optionally substituted by carboxyl group or a 5-10-membered heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom; C3-7-cycloalkyl group, or 6-15 aranceles group) or-CONR71R81(R71and R81- independently are a hydrogen atom, a C1-6is an alkyl group, or a C6-14-aryl group); R5is a hydrogen atom, a C1-6is an alkyl group or a C6-14-aryl group, optionally substituted C1-3-alkylenedioxy. Especially preferred example is, when 5 to 13-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, radical, R3selected from the group consisting of pyridyloxy group, pinolillo group, quinoline-N-oxide-2-yl, quinoline-N-oxide-3-yl group, benzofuranyl group, benzo (b) thienyl group and a thienyl group, and a 5-10 member of the sulfur atom, the radical R61is pinolillo group.

Typical examples of the preferred compounds of this invention include 2,4/1H, 3H/-dioxo-6-etoxycarbonyl-/-isopropyl-1-/2-methoxybenzyl/-5- /4-tolyl/pyrido/2,3-o/pyrimidine-3-acetic acid, 2,4/1H,3H/-dioxo-6-etoxycarbonyl-7-methyl-1-/2-methoxybenzyl/-5- /4-methoxyphenyl/pyrido/2,3-o/pyrimidine-3-acetic acid, ethyl/2,4/1H,3H/-dioxo-6-carboxy-7-isopropyl-1-/2-methoxybenzyl/-5- /2-/4-chinolone//pyrido/2,3-o/pyrimidine-3-acetate, 2,4/1H,3H/-dioxo-6-carboxy-7-isopropyl-1-/2-methoxybenzyl/-5- /2-/4-chinolone//pyrido/2,3-o/pyrimidine-3-acetic acid, 2,4/1H, 3H/-dioxo-6-carboxy-7-isopropyl-1-/2-methylthiomethyl/-5- /2-/4-chinolone//pyrido/2,3-o/pyrimidine-3-acetic acid and their salts.

As the salts of compound A according to the present invention add salt pharmaceutically acceptable acids are marked as especially preferred. As such salts are obtained using, for example, salts with inorganic acid (e.g. hydrochloric acid, phosphoric acid, Hydrobromic acid or sulfuric acid) or salts with an organic acid (e.g. acetic acid, formic acid, maleic acid, succinic acid, wines which I acid or benzolsulfonat acid). And for the case where the compound A of the present invention has an acidic group such as-COOH, the compound can form A salt with an inorganic base (e.g. alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium, or ammonia) or an organic base (for example, trialkylamine with C1-8is an alkyl group, such as triethylamine).

As salts of the starting compounds to obtain compound A according to the present invention using the salt obtained, for example, with an inorganic acid (e.g. hydrochloric acid, phosphoric acid, Hydrobromic acid or sulfuric acid) or salts with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, grape acid, citric acid, malonic acid, oxalic acid, benzoic acid, methanesulfonate acid or benzolsulfonat acid). And, for the case when the original compound has an acidic group such as-COOH, it can form a salt with an inorganic base (e.g. alkali metal or alkaline earth metal such as sodium, potassium, optimum group, such as triethylamine).

The compound A according to the present invention and salts thereof can be obtained by well-known specialists of ways, and, as typical, there are the following seven ways.

The method of obtaining 1

The derived state (i) represented by the formula, R1'NHCONH2(R1'means optionally substituted C1-6is an alkyl group, aryl group or aracelio group), which is synthesized on the basis of C1-6-alkylamine, arylamine or aralkylamines, heated in a suitable solvent, such as ethanol, in the presence of a derived tsianuksusnogo acid as a base, with 80-120oC for 2-240 h, preferably 24-100 hours, to obtain 1-/C1-6-alkyl/substituted, 1-aryl-substituted, or 1-aralkylamines derivative of 6-aminopyrimidine-2,4/1H,3H/Dion (ii).

This compound is mixed with halogenated derivatives of ether acetic acid or halogenated derivative ester of propionic acid in the presence of a base in a suitable solvent, such as dimethylacetamide or dimethylformamide, at 40-70oC usually within 4-96 hours, preferably 12-24 hours, to obtain the derived ester of 6-amino-2,4/1H,3H/or derived ester-6-amino-2,4/1H, 3H/dioxopyrimidine-3-propionic acid, represented by the formula /I'/.

Thus obtained derivative /I'/ in accordance with the synthetic method Ganch [A. Hautzseh, Ann. Chem. 215, 1/1882/] are heated with arilaldegidov and beta ketefian under reflux at 80-100oC, usually within 2-240 h, preferably 12-120 h, in a suitable solvent, such as ethyl alcohol, or previously subjected to the condensation reaction of Knoevenagel [T. Jamamori, J. Hiramatsu, K. Sakai and I. Adachi, Tetrahedron, 41, 913/1985/] obtaining digidratirovannogo condensed derived arylamidase and betakaroten, then digidratirovannogo condensed derived and derived /I/ heated under reflux at 100-130oC usually within 2-240 h, preferably 12-120 h, in a suitable solvent such as toluene with derivatization 5,8-dihydropyrido/2,3-o/pyrimidine-2,4-dione /B1/. Compound B1 is subjected to oxidation with a suitable oxidizing agent such as sodium nitrite in acetic acid to obtain compound A1 of the present invention. Further, if necessary, the connection A1 is subjected to appropriate conditions, for example, alkaline hydrolysis in a suitable solution, such as methanol, ethanol, tetr to be carried out by stirring the reaction mixture in the presence of a suitable basic catalyst (for example, sodium hydroxide, lithium hydroxide, potassium hydroxide or other), at room temperature or at elevated temperature (e.g., 40-100oC) usually within 2-48 hours, preferably within 2-24 hours

The reaction above described method of obtaining reduced in the following reaction scheme, in which each symbol has the same meaning indicated above.

The method of obtaining 1.

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The method of obtaining 2.

According to a similar method described by G. Tominaga et al. [Chim. Pharm. Bull. 32, 122 /1984/] derived ester-6-amino-2,4/1H,3H/-dioxopyrimidine-3-acetic acid /I/ heated 3,3-bioterriorism in dimethylformamide at 100-150oC usually within 1-12 hours, preferably 2-6 hours with derivatization pyrido/2,3-o/pyrimidine-2,4-dione /C1/. The nucleophilic reagent of the formula R3OH (R3and O have the meanings mentioned above) is subjected to interaction with the connection C1 with 40-100oC usually within 2-120 hours, preferably 2-24 hours, in a suitable solvent (e.g. methanol, ethanol, tetrahydrofuran, dioxane or dimethylformamide), with connection A1 of the present invention.

Then, if necessary, the connection A1 is subjected to under drofuran or dioxane to obtain compounds A2 of the present invention. The reaction of the alkaline hydrolysis can be carried out by stirring the reaction mixture in the presence of a suitable basic catalyst (for example, sodium hydroxide, lithium hydroxide, potassium hydroxide and other), at room temperature or at elevated temperature (e.g. 40-100oC) usually within 2-48 hours, preferably within 2-24 hours Above-mentioned reaction together shown in the following reaction scheme, in which R1is optionally substituted C1-6is an alkyl group, aryl group or aranceles group and each symbol has a value above /0029/.

The method of obtaining 2.

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The method of obtaining 3.

Derivative 1-(C1-6-alkyl)substituted, 1-aryl-substituted, or 1-aralkylamines 6-aminopyrimidine-2,4/1H,3H/Dion /ii/ in accordance with the previously mentioned synthetic method Ganch /A. Hautzseh, Ann. Chem. 215, 1 /1882// are heated with product dehydrates condensation derived aldehyde and beta-keeeping derived at 40-120oC usually for 0.5 to 4 hours, preferably 0.5 to 1 h, in a suitable solvent (for example, dimethylacetamide, dimethyl sulfoxide, dimethylformamide) to give the United aldehyde (for example, the quinoline-2-carboxaldehyde) beta-keto-ester derivative (for example, ethyl isobutyl acetate, 2-cyanoethyl the isobutyl acetate) under reflux in a suitable solvent (e.g. benzene, toluene) in the presence of a suitable catalyst (for example, pyrrolidin and acetic acid, piperidine acetic acid) at 100-120oC for usually 0.5-1 h

Connection D1 is subjected to oxidation with a suitable oxidizing agent such as sodium nitrite in acetic acid, in a suitable solvent, such as acetic acid, usually within a 0.25-24,0 hours, preferably 1-12 hours, to obtain the compound D2. Connection D2, thus obtained, is mixed with a halogenated derivative of the ester of acetic acid or halogenated derivative ester of propionic acid in the presence of a base (e.g. sodium hydride, potassium carbonate) in a suitable solvent (for example, dimethylacetamide, dimethylformamide) at room temperature or at elevated temperature, such as 40-120oC, for usually 0.5-12.0 hours, preferably 0.5 to 2.0 h, to obtain the compounds A1-derived ester of acetic acid on the 3rd position, or a complex ester of propionic acid, according to the present invention.

oC) usually within 2-12 hours

The reaction according to the above method of obtaining jointly shown forth in the following reaction scheme, in which each symbol has the same significance as indicated above.

The method of obtaining 3.

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The method of obtaining 4.

Here is an example of the replacement of the substituent in the compound according to the present invention.

5-/2-Chinolin/-6-cyanoethylidene derived E1 is subjected to stirring in a suitable solvent (e.g. methanol, ethanol, tetrahydrofuran or dioxane) in the presence of a suitable weak base (for example, an aqueous solution of sodium carbonate or sodium hydrogen carbonate) at room temperature or elevated temperature (e.g., 40-100oC): usually within 2-12 hours, preferably 0.5 to 2.0 h, obtaining 6-carbox the ID, carbon tetrachloride, 1,2-dichloroethane or toluene) and subjected to heating and reaction with excess thionyl chloride (for example, 10-fold from the equivalent) under reflux (for example, 41-120oC) during the 5-120mm min, preferably 5-60 minutes, the Reaction mixture was then concentrated to dryness to remove excess thionyl chloride. The residue is dissolved in a suitable solvent (e.g. acetonitrile, tetrahydrofuran, dioxane or dimethylacetamide). Adding a suitable weak base (for example, an aqueous solution of sodium carbonate or sodium bicarbonate) solution is subjected to stirring at room temperature, at elevated temperatures (e.g., 40-100oC) usually within 2-48 hours, preferably 2-24 hours, to obtain 4-chinaonline derived A3.

Then, if necessary, the compound A3 is subjected to alkaline hydrolysis in a suitable solvent, such as methanol, ethanol, tetrahydrofuran or dioxane to obtain compounds A4 of the present invention. The reaction of the alkaline hydrolysis can be carried out by stirring the reaction mixture in the presence of a suitable basic catalyst (for example, sodium hydroxide, lithium hydroxide, potassium hydroxide and other) at room campopiano way of getting together is shown in the following reaction scheme, in which R2'is optionally substituted C1-6is an alkyl group, aryl group or aranceles group, and each designation, except for R2has the same values as above.

The method of obtaining 4.

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The method of obtaining 5.

1-/2,4-Dimethoxybenzophenone/derived /F1/ is subjected to oxidation to obtain 1-gidroproizvodnam /F/. Oxidation is produced as follows.

Connection F1 is dissolved in a suitable solvent (e.g. aqueous solution of acetone or acetonitrile), to which is added a suitable oxidizing agent such as cerium ammonium nitrate /CAN/, and the mixture is stirred at room temperature or at elevated temperature (e.g., 40-60oC) generally for 0.5-2.0 hours, preferably 0.5 to 1.0 h, to obtain the compounds F.

Another way of oxidation involves the mixing of compounds in F1 triperoxonane acid /TFA/ 40-80oC usually within 1-12 hours, preferably 2-6 hours, to obtain compound F. Compound F, thus obtained, is subjected to the interaction when mixed with halogenated derivatives of lower alkyl (for example, methylidene) or halogenated Uralkaliy the walking solvent (for example, dimethylacetamide, dimethylformamide, acetone or tetrahydrofuran) in the presence of a suitable base (e.g. sodium hydride or potassium carbonate) usually for 0.5 to 4.0 hours, preferably 0.5 to 2.0 hours, with connection A.

Then, if necessary, the compound A is subjected to alkaline hydrolysis in a suitable solvent, such as methanol, ethanol, tetrahydrofuran or dioxane to obtain compounds Aa of the present invention. The reaction of the alkaline hydrolysis can be carried out by stirring the reaction mixture in the presence of a suitable basic catalyst (for example, sodium hydroxide, lithium hydroxide, potassium hydroxide and other) at room temperature or at elevated temperature (e.g. 40-100oC).

Reaction of the above-described method of obtaining jointly shown in the following reaction scheme, in which each symbol has the same meaning indicated above.

The method of obtaining 5.

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CAN: cerium (IV) ammonium nitrate

TFA: Triperoxonane acid

The method of obtaining 6.

Here is an example of a method of obtaining compound A of the present invention, in which the substituent in the 6-th position is - COOR61(Klionsky hydrocarbon group or optionally substituted aranceles group).

Compound A9, in which the substituent in the 6-th position is COOH, is subjected to mixing with a halogenated alkyl, halogenated cyclic hydrocarbon or halogenated Uralkali derivative (for example, ethylbromide, isobutyramide or benzylbromide) in a suitable solvent (for example, dimethylacetamide or dimethylformamide) in the presence of a suitable weak base (e.g. potassium carbonate, triethylamine or sodium bicarbonate) usually within 2-48 hours, preferably 2-24 hours, to obtain the compound A10 of the present invention, the substituent in the 6-th position which is-COOR61.

Then, if necessary, the A10 connection is subjected to alkaline hydrolysis in a suitable solvent, such as methanol, ethanol, tetrahydrofuran or dioxane, or acid hydrolysis in a suitable solvent, such as methylene chloride to obtain compounds A11 of the present invention.

The reaction of the alkaline hydrolysis can be carried out by stirring the reaction mixture in the presence of a suitable basic catalyst (e.g. sodium hydroxide, potassium hydroxide and other) at room temperature or at elevated temperature (e.g., 40-100oC is and stirring the reaction mixture with a catalytic amount or excess amount of a suitable acid, such as triperoxonane acid, at room temperature or at elevated temperature (e.g., 40-100oC) usually within 2 to 48 hours, preferably 2 to 24 hours

Reaction of the above-described method of obtaining jointly shown in the following reaction scheme, in which each symbol has the meaning specified above.

The method of obtaining 6.

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The way to obtain 7.

Here is an example of a method of obtaining compound A of the present invention, in which the substituent in the 5-th position is the 2-/4-chinaonline/group, and in the 6th position-COOR6or-CONR7R8(R6, R7and R8are independently a hydrogen atom, optionally substituted C1-6is an alkyl group, optionally substituted aranceles group).

Connection A12, Deputy which is in the 1st position is a hydrogen atom, is subjected to mixing with excess thionyl chloride (for example, preferably 5-20 5-10-fold relative to the equivalent) in a suitable solvent (for example methylene chloride or toluene) at room temperature (e.g., 40-60oC) generally for 0.5-2.0 hours, preferably 0.5-1.0 hours, the Reaction mixture was then conc filtrowa insoluble material (for example, filtering with sellita) (magnesium fluoride), the filtrate is concentrated to dryness, and, if necessary, washed with a suitable solvent (e.g. ethyl acetate) to obtain compound H1.

Connection H1, thus obtained, is dissolved in a suitable solvent (e.g. dimethylformamide, dimethylacetamide or acetonitrile) and then subjected to mixing with usually 1-3-, preferably 1-1,5-fold relative to the equivalent of a suitable halogenated alkyl derivative or halogenated alkyl derivative (for example, 2-methylthioethyl chloride or 2,3-dimethoxybenzyl chloride, etc.,) in the presence of usually 1-3-, preferably 1.5 to 2-fold compared to the equivalent of a suitable base (such as potassium bicarbonate, potassium carbonate or sodium hydride) at room temperature or at elevated temperature (e.g., typically 40-100oC, preferably 40-60oC) usually within 2-48 hours, preferably within 24-48 hours, to obtain the compound H2.

After clearing the appropriate method (for example, column chromatography on silica gel), if necessary, the connection of H2 dissolved in a suitable solvent (e.g. acetonitrile or dimethylformamide) and then p is a multidisciplinary reagent (for example, 2 n aqueous solution of potassium carbonate, aqueous ammonia or amine compounds) at room temperature or at elevated temperature (e.g., typically 40-120oC, preferably 40-80oC) usually within 1-6 hours, preferably 1-2 hours, to obtain the compound A13.

The reaction above described method of obtaining jointly shown in the following reaction scheme, in which R is-OR6or-NR7R8and every designation, with the exception of R, has the same values as specified above.

The way to obtain 7.

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In the above methods of obtaining 1 and 2 compound A, in which R1=H, can be obtained using the compound represented by R1"RH2(R1"denotes a protective group for ammonia) instead of starting compound R1'NH2(R1'has the same values as specified above), with the subsequent removal of the protective groups represented by R1"both during and after the reaction.

In the method of obtaining 3 compound a, in which R1= H, can be obtained using the compound (ii) with R1"(R1"denotes a protective group for ammonia) instead of R1'(R1'matter Okasan reaction.

Connection R1"NH2can be obtained, known in the art or equivalent means, or it may be commercially available.

For removal of the protective group can be applied, known in the art or analogous to, for example, using acid, base, oxidizing agent, reducing agent, ultraviolet irradiation, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium fluoride, palladium acetate, etc.

Starting compound C1-6-alkylamino, arylamino and aralkylamines can be obtained, known in the art or its equivalent.

The compound A obtained in this way, or its salt can be isolated and purified by usual method, for example, recrystallization, distillation or chromatography. When the connection has A receive so as a free compound, it can be converted into the corresponding salt is known to the specialist way or its analogue, and then the compound A obtained in the form of a salt may be converted into a free form or another salt known to the specialist method or its equivalent.

When a connection is adashim method for optical separation.

The compound A or its salt of the present invention have excellent antagonistic towards endothelina receptor activity, so it can be used as antagonist endothelioma receptor for warm-blooded animals (e.g. rat, mouse, Guinea pig, chicken, dog, cat, pig, bull, monkey, human and other).

Moreover, due to its excellent antagonistic activity against endothelium receptor compound a or its salt can be used as a prophylactic or therapeutic composition against cerebral infarction, chest angina, myocardial infarction and renal failure.

The compound A or its salt according to the present invention are safe and non-lethal.

At the same time, the compound A or its salt according to the present invention are used as antagonist endothelioma receptor or a prophylactic or therapeutic agent against acute renal failure, myocardial infarction, hypertension, cerebral infarction, chest angina, atherosclerosis, Hepatology, pulmonary hypertension, asthma, organochiorine connected oralno. Usually they are administered orally in the form of a solid preparation such as tablets, capsules, granules or powder, or nearline in the form of intravenous, subcutaneous or intramuscular injection, suppository or sublingual tablets. Dosage amount varies on the degree of symptoms, age of patients, sex, body weight, differences in susceptibility, time of drug administration, interval, drug quality, drug, types: types of effective components, among other things, and they do not specifically limited. Usually dosage for adult day ranges from about 0.1 to 500 mg, preferably from about 1 to 100 mg, more preferably from 5 to 50 mg, from 1 to 4 center of doses per day.

The connection according to the present invention can be prescribed orally or nearline in composition with pharmaceutically acceptable carriers, in the form of solid preparation, including tablets, capsules, granules and powder, or a liquid preparation such as syrup or injection.

The above-mentioned pharmaceutically acceptable carriers include conventional organic or inorganic carriers used in the manufacture of pharmaceutical preparations, namely nepomniatchi, isotonicity, buffer agents and local anesthetics for liquid preparations. If necessary, can also be used additives, such as protective additives, antioxidants, colorants, sweeteners or similar.

Preferred fillers are confirmed in the examples lactose, sucrose, D-mannitol, starch, crystalline cellulose and light anhydride salicylic acid.

Preferred lubricants in the examples shown stearate, calcium stearate, talc and colloidal silica.

The preferred binder is illustrated crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

The preferred leavening agents shown starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium Clairmarais and sodium carboximetilkrahmala.

Preferred solvents are shown by examples in distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.

Preferred solubilization shown in the examples of the polyethylene glycol, propylene glycol, D-mannitol,/P> Preferred examples suspendida agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzalconi chloride, benzarone and chloride and glycerol monostearate, hydrophilic polymers, such as polyvinyl and alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose and hydroxypropylcellulose.

Preferred isotonicity shown in the examples as sodium chloride, glycerin and D-mannitol.

Preferred buffering agents are illustrated buffer solutions such as phosphate, acetate, carbonate and citrate.

Preferred local anesthetics illustrated benzyl alcohol.

Preferred protective means shown para-hydroxybenzoic esters, chlorobutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid and sorbitol acid.

Preferred antioxidants shown in the examples of sulfur and ascorbic acid.

Adding suspendida mixture, a solubilizer, a stabilizing mixture, isotonicity, protective behold, subcutaneous and intramuscular injections. If necessary, these injections can be converted into liofilizada drugs.

The following examples are given for illustrative purpose but not for any restrictions.

Referential example 1.

Getting 2-methoxybenzylamine (chemical formula I)

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To aqueous solution (13 ml) containing 2-methoxybenzylamine /of 13.7 g, 0.1 mol/ added dropwise dilute sulfuric acid (prepared from ml to 2.8 ml of concentrated sulfuric acid and 6.7 ml of purified water) at room temperature. After completion of adding dropwise, to the reaction mixture at room temperature an aqueous solution (70 ml) containing sodium cyanate (of 7.65 g, 0.12 mol) over 15 minutes, the resulting suspension of the reaction mixture is heated at 80oC for one hour. The reaction mixture is cooled, the resulting crystalline precipitate is collected by filtration, followed by recrystallization from ethanol to obtain 17 g (yield 94%) as colorless prisms.

Referential example 2.

Obtain 6-amino-1-/2-methoxybenzyl/pyrimidine-2,4/1H,3H/Dion (chemical formula 2)

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The mixture obtained in reference example 1, compound (10.8 g, 60 mmol) atill in ethanol (100 ml) under reflux. The reaction mixture is cooled, then concentrated to dryness. To the concentrate is added a saturated aqueous solution of ammonium chloride /50 ml/. The mixture is stirred, then set pH 6 to 7 with 1 N. HCl. The precipitate is collected by filtration and recrystallized from a mixture of ethanol and methanol (1:1) in pale yellow prisms, so pl. 278-279oC. Values of elemental analysis are shown in table 1.

Reference example 3.

The method described in reference examples 1 and 2 is repeated, using different substituted amino compounds instead of 2-methoxybenzylamine. Compounds represented by chemical formula 3,

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thus obtained, together shown in table 2.

Reference example 4.

Getting ethyl/6-Mino-2,4/1H, 3H/-dioxo-1-/2-methoxybenzyl// pyrimidine-3-acetate (chemical formula 4)

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The mixture obtained in reference example 2, compound (6,65 g, 27 mmol) ethylbromoacetate (15.0 g, 90 mmol) and potassium carbonate (16.6 g, 120 mmol) is stirred in dimethylformamide (500 ml) for 72 h at 60oC. the Reaction mixture after cooling, concentrated to dryness, then add saturated aqueous solution of ammonium chloride (30 ml) and ethyl acetate (50 ml) then the mixture is stirred. On the practical layer, then dried. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 3.5 g (yield 39%) of yellow amorphous product.

The NMR spectrum of the thus obtained product to the following.

1H-NMR (200 MHz, CDCl3) ppm: of 1.27 (3H, t), 3,93 (3H, s), is 4.21 (2H, q), 4,70 (2H, s), 4,91 (1H, s), 5,12 (2H, s), 5,31 (2H, s), 6,91 - 7,00 (2H, t), 7,27 - 7,40 (1H, m), 7,50 - of 7.55 (1H, m).

Reference example 5.

Obtain ethyl[5,8-dihydro-2,4(1H, 3H)-dioxo-1-etoxycarbonyl - 7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido/2,3-d] pyrimidine] -3-acetate (chemical formula 5)

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The compound (0.5 g, 1.5 mmol) obtained in reference example 4, heated for 90 hours under reflux in ethanol (10 ml) together with n-tolualdehyde (0.54 g, 4.5 mmol) and ethyl-isobutyl acetate (0.71 g, 4.5 mmol). The reaction mixture is cooled, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 0.2 g (yield 23%) of yellow amorphous product. The NMR spectrum of the thus obtained product is as follows:1H-NMR (200 MHz, CDCl3ppm: to 0.80 (3H, d), of 1.06 (3H, d), 1,25 (3H, t), of 1.26 (3H, in), 2.25 (3H, s) to 3.58 (1H, m), of 3.96 (3H, s), of 4.12 (2H, q), 4,22 (2H, HF), to 4.62 (1H, d), 4.72 in (1H, d), 5,07 (loony example 5, I repeat, only using different aldehydes and ethyl isobutylacetate. Compounds represented by chemical formula 6,

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thus obtained, are summarized in table 3.

Reference example 7.

Getting 5,8-dihydro-2,4-(1H, 3H)-dioxo-6-etoxycarbonyl-7 - isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3 - acetic acid (chemical formula 7)

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The compound (0.2 g, 0.35 mmol) obtained in reference example 5 was dissolved in methanol (20 ml). To this solution was added 2 n aqueous sodium hydroxide solution (2 ml) and the mixture is stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, when establishing a pH in the range from 2 to 3 with 1 N. HCl, followed by extraction with ethyl acetate from the receipt of 0.13 g (yield 68%) of a yellow oily product.

Reference example 8.

Using connection as in reference example 6, repeat the method described in reference example 7. Compounds represented by chemical formula 8

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and thus obtained, are summarized in table 4.

Reference example 9.

Obtaining 2,4-(1H, 3H)-dioxo-(2-cyanoethoxy)-7 - isopropyl-1-(2-methoxybenzyl)-5-(2-hinai the least 2, stirred in dimethyl sulfoxide (23 ml) for 25 min at 125oC together with compound (6,1 g, 19 mmol) obtained dehydrates condensation of the quinoline-2-carboxaldehyde and 2-cyanoethyl isobutyrylacetate. The reaction mixture is cooled, then stir in ice water. The resulting brownish crystals are collected by filtration and dissolved in ethyl acetate. Washing the solution with water to obtain 4.3 g of a pale gray powder (yield 49%). The compound thus obtained (4.3 g, 7.8 mmol), dissolved in acetic acid (50 ml), to which is added sodium nitrite (5.9 g). The mixture is stirred for 15 min at room temperature. The reaction mixture is stirred into ice water, then subjected to extraction with ethyl acetate. The organic layer is dried and the solvent is then distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 4.1 g (yield 47%) of yellow amorphous product. Values of elemental analysis are shown in table 5.

The NMR spectrum and IR spectrum of the compound such as follows:

1H-NMR (200 MHz, CDCl3) ppm: 1.14 in (6H, d), 2,12 (2H, t) and 3.15 (1H, m) to 3.89 (3H, s), of 3.94 (2H, t), 5,61 (2H, s), 6,80 - of 6.96 (3H, m), 7,21 (1H, TD), 7,53 (1H, d), to 7.59 (1H, TD), 7,72 (1H, TD), 7,88 (1H, d), of 8.04 (1H, d), by 8.22 (1H, d), 8,77/P> Using other connections, repeat the method described in reference example 9. Compounds represented by chemical formula 10 obtained in this way are summarized in table 6.

Reference example 11.

Getting ethyl /2,4-(1H,3H)-dioxo-5-methylthio-6-etoxycarbonyl-7-isopropyl-1- (2-methoxybenzylthio/2,3-d/pyrimidine/-3-acetate (chemical formula 11.

< / BR>
To a methanol solution (5 ml) containing ethyl isobutyl acetate (0,48 g) added a methanol solution of sodium methoxide (28%, of 0.58 g) under cooling with ice. After stirring for 10 min under the same conditions to the solution is added dropwise carbon disulphide. After completion of adding dropwise added dimethylsulfate (0.75 ml) to the reaction mixture. The reaction mixture was stirred at room temperature for 15 minutes the Reaction mixture is mixed with water (30 ml), stirred for 5 min, then subjected to extraction with isopropyl ether to obtain a yellow oily product (0.40 g).

A mixture of this oily product, the compound obtained in reference example 4 (0.50 g, 1.5 mmol) and potassium carbonate (0.31 g) was stirred in dimethylformamide (10 ml) for 5 h at 150oC. the Reaction mixture is chilled after the 0 ml) and the mixture is then stirred. The aqueous layer was subjected to extraction with ethyl acetate (20 ml). The extract combined with the organic layer, which is then dried. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 0.06 g (yield 8%) of yellow amorphous product. The NMR spectrum and the mass spectrum of the thus obtained product of the following:

1H-NMR (200 MHz, CDCl3) / ppm: of 1.28 (3H, t), of 1.35 (6H, d), of 1.41 (3H, t), of 2.21 (3H, s), 3,86 (3H, s), 4,20 (2H, HF), and 4.40 (2H, q), 4,40 - 4,60 (1H, m), 4,84 (2H, s) 5,59 (2H, s), 6,7 - 7,0 (3H, m), 7,15 - of 7.3 (1H, m).

MS, m/z: 530 (MH).

Referential example 12.

Getting ethyl /1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6 - isopropylpyrimidine/4", 5"-: 6',5'/pyrido/3',4':4,3/pyrrole/1,2-a/ a quinoline/-3-acetate (chemical formula 12)

< / BR>
The compound (1.10 g, of 2.38 mmol) obtained in example 17 (compound 16) was dissolved in dichloromethane (100 ml). To the solution was added thionyl chloride (0,87 ml, 11,89 mmol) and the mixture stirred for 2 h at room temperature. To the reaction mixture are added 20 ml of toluene and then concentrated under reduced pressure. The residue is dissolved in dichloromethane, filtered, Selita. The filtrate is concentrated, and the thus obtained residue is washed with ethyl acetate to obtain 0,30 g the Mr-range, The IR spectrum and mass spectrum of the compound of the following:

1H-NMR (500 MHz, DMSO-d6) ppm: 1,32 - of 1.41 (9H, m), 4,28 (2H, HF), 4,37 (1H, m), 4,82 (2H, s), 7,47 (1H, t), 7,78 (1H, t), 8,30 (1H, d), 8,64 (1H, s), 8,78 (1H, s), 9,19 (1H, d).

IR (KBr): 1738, 1682, 1642, 1576, 1477, 1393 cm-1.

FAB-MS, m/x 461.1 (MH)+.

Reference example 13.

Obtain ethyl[1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6 - isopropyl-4-(2-methylthioethyl)pyrimido[4", 5": 6', 5'] pyrido[3', 4': 4,3]pyrrolo[1,2-a]quinoline]-3-acetate (chemical formula 13).

< / BR>
Dimethylformamide (5 ml) solution containing the compound (0.20 g, 0.43 mmol) obtained in reference example 12, 2-methylthioribose (0.74 g, 4.30 mmol) and potassium bicarbonate (0.07 g, 0.64 mmol) is stirred for 2 days at room temperature. To the reaction mixture is added saturated aqueous solution of ammonium chloride, the mixture is then subjected to separation by adding dichloromethane and saturated aqueous solution of sodium chloride. The organic layer is dried with MgSO4and then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain 0.21 g (yield 80%) of a yellow powdery product.

Values of elemental analysis are shown in table 8.

AMR (3H, t), to 2.57 (3H, s), 4,23 - 4,34 (3H, m), is 4.93 (2H, s), USD 5.76 (2H, s), 6,83 (1H, d), 7,03 (1H, t), 7,22 - to 7.35 (2H, m), 7,47 (1H, t), to 7.77 (1H, t), 8,32 (1H, d), 8,84 (1H, s), 9,18 (1H, s).

IR (KBr): 1725, 1680, 1640, 1578, 1475, cm-1.

FAB-MS m/z: 597,1 (MH+)

Reference example 14

Use of the compounds mentioned in reference example 12 is repeated, the method described in reference example 13. Compounds represented by chemical formula 14

< / BR>
thus obtained, are summarized in table 9.

Example 1.

Getting ethyl/2,4(1H, 3H)-dioxo-6-etoxycarbonyl-7-methyl-1- (2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido/2,3-d/pyrimidine/-3 - acetate (chemical formula 15)

< / BR>
Compound (2.1 g, 6.3 mmol) obtained in reference example 4 is heated over 130 hours under reflux in ethanol (40 ml) together with n-anisaldehyde (0,81 g, 60 mmol) and ethylacetoacetate (0,79 g, 6.1 mmol). The reaction mixture is cooled, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 2.6 g (yield 70%) of yellow amorphous product. Amorphous compound (2.3 g, 4.1 mmol) dissolved in acetic acid (50 ml), to which is added sodium nitrite (2.0 g). The mixture is stirred for one hour at room temperature is twice). The organic layer is dried and the solvent is then distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 1.8 g (yield 77%) of a yellow oily product. The NMR spectrum of this product is as follows:

1H-NMR (200 MHz, CDCl3) / ppm: to 0.97 (3H, t) to 1.22 (3H, t), of 2.51 (3H, s), of 3.84 (3H, s), 3,90 (3H, s), 3,98 (2H, q), is 4.15 (2H, q), 4,71 (2H, s), the 5.65 (2H, s), 6.75 in - to 7.61 (8H, m).

Example 2.

Using a suitable aldehyde instead of the p-anisaldehyde and ethyl isobutyrylacetate or ethyl acetoacetate, repeat the method described in example 1, to obtain the corresponding compounds of chemical formula 16

< / BR>
presented in table 10.

Example 3.

Obtain tert-butyl /2,4(1H,3H)-dioxo-6-(2-cyanoethoxy - carbonyl)-7-isopropyl-1-(2-methoxybenzyl)-5-(2-chinolin)pyrido/2,3 - d/pyrimidine/-3-acetate (chemical formula (17)

< / BR>
The compound (1.0 g, 1.9 mmol) obtained in reference example 9, stirred for 40 minutes at room temperature in dimethylformamide (5 ml) with tert-butyl bromoacetate (0,88 ml, 5.6 mmol) and potassium carbonate (0,76 g, 5.6 mmol). Set the pH of the reaction mixture from 1 to 2 with 1 N. HCl, then subjected to separation of the reaction mixture is handling this is OK purified column chromatography on silica gel to obtain 0.51 g (yield 41%) of yellow amorphous product. Values of elemental analysis of the compounds thus obtained are shown in table 11. The NMR spectrum and IR spectrum of the compound of the following:

1H-NMR (200 MHz, CDCl3) ppm: to 1.15 (6H, d), of 1.40 (9H, s), and 2.14 (2H, t) and 3.15 (1H, m), 3,90 (2H, s), of 3.94 (2H, t), 4,59 (2H, s) 5,69 (2H, s), 7,22 (1H, t), 7,54 (1H, d), 7,60 (1H, TD), 7,73 (1H, TD), 7,88 (1H, d), of 8.04 (1H, d), by 8.22 (1H, d).

IR (KB): 3452, 2976, 2938, 2364, 2258, 1742, 1721, 1678, 1603, 1574 cm-1.

Example 4.

Using the appropriate connection as the original product, repeat the method described in example 3, to obtain the compounds of chemical formula 18

< / BR>
which are summarized in table 12.

Example 5. Getting ethyl/2,4(1H,3H)-dioxo-6-/2-cyanoethoxy/-7-isopropyl-5- (2-chinolin/pyrido/2,3-d/pyrimidine-/3-acetate (chemical formula 19)

< / BR>
Compound (compound 10; 10.0 g, 15.0 mmol) obtained in example 4, dissolved in acetone-ether (1: 1 by volume 600 ml). To the solution was added cerium (IV) ammonium nitrate (24,7 g, 45,0 mmol) and the mixture stirred for 1 h at room temperature. The reaction mixture was concentrated to 1/2 volume and the residue is subjected to extraction with ethyl acetate.

The organic layer is dried over Na2SO4) and the solvent is distilled off under reduced pressure. The residue behaviour is by elemental analysis shown in table 13. The NMR spectrum and IR spectrum of the thus obtained compound is shown below.

1H-NMR (200 MHz, CDCl3) ppm: to 1.21 (3H, t), of 1.35 (6H, d), 2,17 (2H, t), of 3.25 (1H, m), of 3.97 (2H, t), is 4.15 (2H, q), br4.61 (2H, s), 7,53 (1H, d), to 7.61 (1H, t), 7,74 (1H, t), 7,89 (1H, d), with 8.05 (1H, d), 8,23 (1H, d), 8,56 (1H, s).

IR (KBr): 3424, 3264, 2976, 2362, 1734, 1680, 1620, 1578, 1504 cm-1.

Example 6. Getting ethyl /2,4(1H,3H)-loxo-6-(2-cyanoethoxy)-7-isopropyl-5-(2 - chinolin)pyrido/2,3-d/pyrimidine/-3-acetate (chemical formula 20)

< / BR>
A solution of the compound (compound 10; 9,1 g, 13.7 mmol) obtained in example 4, in triperoxonane acid (50 ml) is stirred for 4 h at 60oC. the Reaction mixture is concentrated by removing triperoxonane acid and the residue is subjected to separation in the ethyl acetate-aqueous solution of sodium chloride. The organic layer is dried (MgSO4) and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with getting 6,47 g (yield 92%) of a yellow powdery product.

Example 7.

Using the compound obtained in example 4 (compound No. 12), repeat the method described in example 5, to obtain the compounds of formula 21

< / BR>
Example 8. Getting ethyl /2,4(1H,3H)-dioxo-6-(2-cyanoethoxy (1.78 g, 3.5 mmol) obtained in example 5, methyl iodide (0,98 g, 6,9 mmol) and potassium carbonate (1.42 g, 10.4 mmol) dissolved in dimethylformamide (70 ml). To the solution was added 1 N. HCl and subjected to separation in ethyl acetate-water. The organic layer is dried over Na2SO4) and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 1.42 g (yield 78%) of yellow userimage product. The data of elemental analysis are shown in table 14. The NMR spectrum and IR spectrum of the thus obtained compound is shown below.

1H-NMR (200 Hz, CDCl3), pp: to 1.21 (3H, t) of 1.39 (6H, d), and 2.14 (1H, t), 3,30 (1H, m), 3,82 (3H, s), of 3.96 (2H, t), is 4.15 (2H, HF) and 4.65 (2H, s) to 7.50 (1H, d), to 7.59 (1H, t), 7,73 (1H, t), 7,88 (1H, d), 8,03 (1H, d), 8,21 (1H, d).

IR (KBr): 3452, 2974, 2364, 1742, 1719, 1673, 1620, 1601, 1574, 1506 cm-1.

Example 9.

Using appropriate connections as the original product, repeat the method described in example 8, to obtain the compound represented by chemical formula 23.

< / BR>
which has a different substituents in the 1st position. Compounds, thus obtained, are summarized in table 15.

Example 10. Obtaining 2,4(1H,3H)-dioxo-6-etoxycarbonyl-7-isopropyl-1-/2-methoxybenzyl/ -5-(Holocene in reference example 7, dissolved in acetic acid (20 ml). To the solution was added sodium nitrite (0.1 g) and the mixture is stirred for one hour at room temperature. The reaction mixture was poured into ice water and subjected to extraction with ethyl acetate (20 ml each time, three times). The organic layer is dried and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel. Thus obtained crude crystals are recrystallized from ethyl acetate-isopropyl ether (1:2) to give 0.06 g (yield 54%). yellow crystalline powder, so pl. 190-192oC (decomp. ). The data of elemental analysis are shown in table 16.

The NMR spectrum and IR spectrum of the thus obtained compound are as follows.

1H-NMR (200 MHz, CDCl3) / ppm: to 0.89 (3H, t), a 1.08 (6H, d), of 2.25 (3H, s), 2,9 - 3,1 (1H, m) to 3.41 (3H, s), 3,90 (2H, HF), to 4.41 (2H, s), of 5.53 (2H, s), and 6.6 to 7.2 (8H, m).

IR (KBr): 3456, 1717, 1671, 1562, 1518, 1495, 1466, 1386, 1371, 1305, 1247 cm-1.

Example 11.

Using the compounds presented in reference example 8, repeat the method described in example 10. The compounds thus obtained (chemical formula 25)

< / BR>
presented in table 17.

Example 12. Obtaining 2,4(1H,3H)-dioxo-6-atoxic is 26)

< / BR>
The connection (connection N 10; 1.5 g, 2.6 mmol) obtained in example 2 was dissolved in methanol (30 ml), to which add 2 N. aqueous sodium hydroxide solution (2.6 ml) and the mixture stirred for 20 h at room temperature. The reaction mixture was concentrated under reduced pressure, the pH of the concentrate set 2 - 3 using 1 N. HCl and subjected to extraction with ethyl acetate. The extract is purified by column chromatography on silica gel to obtain crude crystals, which are then subjected to recrystallization from isopropyl alcohol with getting to 0.63 g (yield 46%) of a yellow crystalline powder, so pl. 190-192oC. Elemental analysis of the product shown in the table. 18.

The NMR spectrum and IR spectrasuite the following:

1H-NMR (200 MHz, CDCl3) ppm: to 0.88 (3H, t), 2,39 (3H, s), with 3.79 (3H, s) to 3.89 (3H, s) to 3.92 (2H, HF), 4,18 (2H, s), vs. 5.47 (2H, s), 6,78 (1H, t), of 6.68 (1H, d), 6,91 (2H, d), 7,01 (1H, d), 7,06 (2H, d), 7,20 (1H, t).

IR (KBr): 3450, 1717, 1669, 1609, 1564, 1518, 1483, 1381, 1278, 1247 cm-1.

Example 13.

Using the connections shown in example 2 (except for the connection N 19), example 7 and example 9, repeat the method described in example 12. Thus obtained compound (chemical formula 27)

< / BR>
presented in table 19.


< / BR>
Compound (compound No. 5; 0.20 g, 0.31 mmol) obtained in example 4, dissolved in a mixture of methanol (1.0 ml) and 1,4-dioxane (2.0 ml) to which was added 1 N. aqueous solution of sodium hydroxide (0.63 ml, 1.3 mmol) and the mixture is stirred for 30 min at room temperature. Set the pH of the reaction mixture from 1 to 2 with 1 N. HCl, then share with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The residue is recrystallized from isopropyl ether to obtain 0.12 g (71% yield) of pale yellow crystalline powder, so pl. above 300oC. Elemental analysis of the product are shown in table 20.

AMC - IR spectrum of the compound of the following:

1H-NMR (200 MHz, DMSO-d6) ppm: of 1.05 (6H, d), 3,19 (1H, m), 3,90 (3H, s), 4,47 (2H, s), 6,83 (1H, t), 6,93 (1H, d), 7,05 (1H, d), from 7.24 (1H, DD), 7,52 (1H, d), the 7.65 (1H, DD), to 7.77 (1H, DD), to 7.93 (1H, d), 8,02 (1H, DD), 8,32 (1H, d), 12,97 (2H, W).

IR (KBr): 3430, 2980, 1715, 1671, 1576, 1493, 1464 cm-1.

Example 15.

Using the connections shown in example 4, repeat the method described in example 14. Thus obtained compound (chemical formula 29)

< / BR>
presented in table 21.

Example 16. Received the(chemical formula 30)

< / BR>
The compound (2.9 g, 4.3 mmol) obtained in example 3, dissolved in a mixture of methanol (130 ml) and water (17 ml), to which add 2 N. aqueous solution of potassium carbonate (8.6 ml, 8.6 mmol) and the mixture stirred for 1 h at room temperature. Set the pH of the reaction mixture from 2 to 3 with 1 N. HCl and subjected to the reaction mixture was separated by ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 2.3 g (yield 87%) of a yellow crystalline powder, so pl. above 300oC. Elemental analysis of the product are shown in table 22. The NMR spectrum and IR spectrum of the compound of the following:

1H-NMR (200 MHz, DMSO-d6), ppm: of 1.05 (6H, d), of 1.34 (9H, s), 3,19 (1H, m), 3,90 (3H, s), of 4.45 (2H, s) 5,54 (2H, s), 6,83 - 6,92 (2H, m), 7,06 (1H, d), from 7.24 (1H, TD), 7,53 (1H, d), the 7.65 (1H, m), to 7.77 (1H, m), 7,94 (1H, d), of 8.04 (1H, d), with 8.33 (1H, d).

IR (KBr): 3454, 2972, 2928, 2366, 1719, 1678, 1605, 1572, 1495 cm-1.

Example 17.

Using the compounds listed in example 4, and the other, repeat the method described in example 16.

The compounds thus obtained (chemical formula 31)

< / BR>
presented in the table is alanyl)]pyrido[2,3-d] pyrimidine]-3-acetate (chemical formula 32)

< / BR>
The compound (500 mg, 0.82 mmol) obtained in example 16, was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0,60 ml, 8.20 mmol) and the mixture is heated for 30 minutes under reflux. The reaction mixture is cooled and concentrated. The residue is dissolved in dimethylacetamide (40 ml) and stirred for 2 H. with an aqueous solution of potassium carbonate for 22 h at 90oC. After cooling, the reaction mixture is poured into ice water and set pH 1 to 2 using 1 N. HCl, then subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 180 mg (yield 37%) as pale-brown powder. Thus obtained powder is recrystallized from a mixed solvent of isopropanol and isopropyl ether to obtain 40 mg (yield 8%) of pale brown crystalline powder, so pl. more than 300oC. elemental analysis Data shown in table 24. The NMR spectrum and IR spectrum of the thus obtained compound are as follows.

1H-NMR (200 MHz, DMSO-d6) ppm: to 0.97 (3H, d), with 1.07 (3H, d), of 1.33 (9H, SS).

IR (KBr): 3452, 2974, 1717, 1673, 1638, 1601, 1570, 1510, 1473 cm-1.

Example 19. Using the connections shown in example 17, and the other, repeat the method described in example 18.

The compounds thus obtained (chemical formula 33)

< / BR>
presented in table 25.

Example 20. Obtaining 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl - 1-/2-methoxybenzyl/-5-[2-(4-chinolin)pyrido[2,3-d] pyrimidine] -3 - acetic acid (chemical formula 34)

< / BR>
The connection (connection # 2: to 0.19 g, 0.32 mmol) obtained in example 19 was dissolved in a mixture of methanol (2.0 ml) and tetrahydrofuran (2.0 ml) to which was added 1 N. aqueous sodium hydroxide solution (of 0.64 ml, 1.3 mmol) and the mixture stirred for 5 h at room temperature. Set the pH of the reaction mixture from 1 to 2 with 1 N. HCl, subjecting the reaction mixture to extraction with a mixed solvent of ethyl acetate and tetrahydrofuran.

The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The remainder perekristallizatsiya from a mixed solvent of methanol-isopropyl ether to obtain 0.08 g (yield 44%) of colorless crystalline powder, so pl. above 300H-NMR (200 MHz, DMSO-d6) ppm: a 1.01 (3H, d), of 1.13 (3H, d), 3,18 (1H, m), 3,90 (3H, s) 4,55 (2H, q), of 5.53 (2H, q), of 5.92 (1H, s), for 6.81 - 6,94 (2H, m),? 7.04 baby mortality (1H, d), from 7.24 (1H, t), 7,35 (1H, t), 7,47 (1H, d), the 7.65 (1H, t) to 8.12 (1H, d), 11,90 (1H, s), 13,01 (1H, user.C).

IR (KBr): 3444, 2974, 1719, 1676, 1574, 1493 cm-1.

Example 21. Using the connections shown in example 19, and the other, repeat the method described in example 20.

The compounds thus obtained (chemical formula 35)

< / BR>
presented in table 27.

Example 22. Obtain tert-butyl[2,4(1H,3H)-dioxy-6-etoxycarbonyl-7-isopropyl-1-/2 - methoxybenzyl/-5-[2-[4-chinolone)]pyrido[2,3-d]pyrimidine]-3 - acetate (chemical formula 36)

< / BR>
Compound (0.35 g, 0,56 mmol) obtained in example 18, mixed with ethyliodide (0.10 g, of 0.91 mmol) in dimethylformamide (5.0 ml) for 1 h at room temperature. Set the pH of the reaction mixture from 1 to 2 with 1 N. hydrochloric acid and then subjected to separation in ethyl acetate and water. The organic layer is dried, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain a pale brown amorphous product. Elemental analysis data of the compound thus obtained are shown in table 28.

IR (KBR): 3450, 2978, 2936, 1721, 1682, 1638, 1605, 1574, 1510, 1460 cm-1.

Example 23. Obtaining 2,4(1H,3H)-dioxo-6-etoxycarbonyl-7-isopropyl-1-/2-methoxybenzyl/- 5-[2-/4-chinolone/] pyrido[2,3-d] pyrimidine-3-acetic acid (chemical formula 37)

< / BR>
The compound (0.15 g, 0.23 mmol) obtained in example 22 was dissolved in dichloromethane and stirred with triperoxonane acid for 1 h at room temperature. The reaction mixture was distilled off under reduced pressure. The residue is recrystallized from a mixed solvent of isopropyl alcohol and isopropyl ether to obtain 0.12 g (yield 86%) of pale yellow crystalline powder, so pl. 214-216oC. Elemental analysis of the product are shown in table 29.

The NMR spectrum and IR spectrum of the compound are as follows.

1H-NMR (200 MHz, DMSO-d6) ppm: of 0.79 (3H, t) to 0.89 (3H, d), of 1.13 (3H, d), 3,10 (1H, m) to 3.89 (3H, s), of 4.00 (2H, t), 4,55 (2H, q), of 5.53 (2H, q), of 5.92 (1H, s), 6,79 - 6,92 (2H, m), 7,05 (1H, d), from 7.24 (1H, t), 7,37 (1H, t), 7,49 (1H, d), to 7.68 (1H, t), 8,13 (1H, d), 12,18 (1H, user).

IR (KBr): 3444, 2972, 2936, 1719, 1680, 1603, 1574, 1492, 1462 cm-1.

Example 24.

Using compounds in which the substituent in the 3-m polnye thus, presented in table 30.

Example 25. Obtain ethyl[2,4(1H,3H)-dioxo-6 - isobutoxide-7-isopropyl-1-/2-methoxybenzyl/-5- (2-chinolin)pyrido[2,3-d]pyrimidine]-3-acetate (chemical formula 39)

< / BR>
Compound (compound No. 1 (0.26 g, 0.44 mmol) obtained in example 17, was dissolved in dimethylformamide and stirred with isobutyramide (0,14 ml of 1.31 mmol) and potassium carbonate (0,19 g of 1.36 mmol) for 24 h at room temperature. Set the pH of the reaction mixture from 1 to 2 with HCl and subjected to separation in ethyl acetate and water. The organic layer is dried, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 0.21 g (yield 75%) of colorless amorphous product. Elemental analysis of the product are shown in table 31. The NMR spectrum and IR spectrum of the compound are as follows.

1H-NMR (200 MHz, CDCl3) ppm: 0,66 (6H, d), to 1.14 (6H, d), of 1.23 (3H, t), of 1.55 (1H, m), 3,14 (1H, m), 3,53 (2H, d), 3,91 (3H, s), 4,14 (2H, HF), and 4.68 (2H, s) 5,69 (2H, s), 6,36 - to 7.00 (3H, m), 7,21 (1H, TD), to 7.50 (1H, d), 7,56 (1H, t), 7,71 (1H, TD), 7,86 (1H, d), of 8.04 (1H, d), 8,19 (1H, d).

IR (KBr): 3456, 2976, 2968, 1721, 1678, 1574, 1495 cm-1.

Example 26.

Using the compounds obtained in examples 16 and 17, repeat the method described in example 4(1H, 3H)-dioxo-6-isobutoxide-7-isopropyl - 1-/2-methoxybenzyl/-5-(2-chinolin)pyrido[2,3-d] pyrimidine-3-acetic acid (chemical formula 41)

< / BR>
Connection (to 0.19 g, 0.30 mmol) obtained in example 25, dissolved in a mixture solvent of methanol (2.0 ml) and tetrahydrofuran (21,0 ml), to which add 2 N. aqueous sodium hydroxide solution (of 0.60 ml, 1.2 mmol) and the mixture stirred for 110 minutes at room temperature. The reaction mixture was adjusted to pH 1 to 2 using 1 N. HCl, then subjected to separation in ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixed solvent of isopropanol and hexane to obtain 0.11 g (yield 61%) of colorless crystalline powder, so square) 224-225oC. Elemental analysis of the product are shown in table 33. The NMR spectrum and IR spectrum of the compound of the following:

1H-NMR (200 MHz, DMSO-d6) ppm: 0,57 (6H, d), of 1.03 (6H, d), to 1.38 (1H, m), 3,10 (1H, m), 3,50 (2H, user), of 3.80 (3H, s), 4,50 (2H, s) 5,54 (2H, s), 6,83 (1H, t) 6,94 (1H, d), 7,06 (1H, d), from 7.24 (1H, t), 7,56 (1H, d), the 7.65 (1H, t), 7,78 (1H, t), of 7.90 (1H, d), 8,02 (1H, d), a 8.34 (1H, d).

IR (KBr): 3480, 2970, 1717, 1665, 1574, 1466 cm-1.

Example 28.

Spolszczenie thus compound (chemical formula 42)

< / BR>
presented in table 34.

Example 29. Obtaining 2,4(1H,3H)-dioxo-6-cyanoethoxy-7 - isopropyl-1-/2-methoxybenzyl-/5-(2-chinolin)pyrido/2,3-d/ pyrimidine-3-acetic acid (chemical formula 43)

< / BR>
Connection (0,30 g, 0.45 mmol) obtained in example 3 was dissolved in dichloromethane (3.0 ml) and stirred with triperoxonane acid (1 ml) for 4.5 h at room temperature. The reaction mixture was distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 0.31 g of pale yellow crystalline powder, crystals are recrystallized from a mixed solvent of ethyl acetate and hexane - obtain 0.21 g (yield 78%) of colorless crystalline powder, so pl. 115-116oC. Elemental analysis of the product are shown in table 35.

The NMR spectrum and IR spectrum of the compound of the following:

1H-NMR (200 MHz, DMSO-d6) / ppm: of 1.06 (6H, d), of 2.50 (2H, t), of 3.78 (2H, t), of 3.13 (1H, m), 3,91 (3H, s), 4,50 (2H, s), of 5.55 (2H, s), at 6.84 (1H, t), to 6.95 (1H, d), 7,05 (1H, d), 7,21 (1H, t), to 7.59 (1H, d), to 7.67 (1H, t), 7,79 (1H, t) of 7.97 (1H, d), of 8.04 (1H, d), 8,35 (1H, d).

IR (KBr): 3438, 2972, 2270, 1719, 1676, 1574, 1495, 1466 cm-1.

Example 30.

Using the compound obtained in example 4 (compound 1) and example 26 (compound N 10-12) presented in table 36.

Example 31. Obtain ethyl[2,4(1H,3H)-dioxo-6-carboxy-7 - isopropyl-1-/2-methylthiomethyl/-5-[2-(4-chinolone)] pyrido[2,3-d] - pyrimidine]-3-acetate (chemical formula 45)

< / BR>
A solution of acetonitrile (15 ml) containing the compound (150 mg, 0.25 mmol) obtained in reference example 13, 2 N. aqueous solution of potassium carbonate (1.25 ml, of 2.50 mmol) in water (1.5 ml), stirred for 30 min at 50oC. To the reaction mixture add 1 N. HCl (5 ml) and subjected to separation with ethyl acetate and saturated aqueous sodium chloride. The organic layer is dried over MoO4and then distilled under reduced pressure. The precipitate is recrystallized from isopropanol to obtain 85 mg (yield 54%) of colorless powdery product, so pl. 167-170oC. Elemental analysis of the product are shown in table 37. NMR spectrum, IR spectrum and mass spectrum of the compound of the following:

1H-NMR (500 MHz, DMSO-d6) ppm: of 1.03 (6H, d) and 1.15 (3H, t), at 2.59 (3H, s), 3,16 - 3,24 (1H, m), 4,11 (2H, d), 4,59 (1H, d), 4,69 (1H, d), of 5.53 (2H, s), of 6.29 (1H, s) 6,86 (1H, d), to 7.09 (1H, t), 7,29 (1H, t), 7,41 (1H, d), to 7.50 (1H, t), 7,63 (1H, d), 7,79 (1H, t), 8,21 (1H, d), 12,90 (1H, user.C).

IR (KBr): 3428, 1721, 1678, 1574, 1491, 1369 cm-1.

FAB-MS m/z: 615.1 (MH+).

Example 32.

Using the compound obtained in reference example 14, again with the Lena in table 38.

Example 33. Obtain tert-butyl[2,4(1H,3H)-dioxo-6-carbarnoyl - 7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-chinolone)] pyrido[2,3-d] pyrimidine/-3-acetate (chemical formula 47)

< / BR>
The compound (500 mg, 0.82 mmol) obtained in example 16, was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0,60 ml, 8.20 mmol) and the mixture is heated for 30 minutes under reflux. The reaction mixture is cooled and concentrated to dryness. The precipitate is suspended in a mixed solvent tetrahydrofuran (5 ml) and dimethylacetamide (20 ml) and then stirred with 25% aqueous ammonia (10 ml) for 15 min at room temperature. The reaction mixture was poured into ice water and set the pH of the reaction mixture from 1 to 2 with 1 N. HCl, then subjected to extraction with ethyl acetate (150 ml). The organic layer was washed with saturated aqueous sodium chloride and dried, then the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel to obtain 310 mg (yield 61%) of colorless powder. Thus obtained powder is recrystallized from a solvent mixture of isopropanol and isopropyl ether to obtain 170 mg (yield 33%) of colorless crystalline powder, so elbrusom connections the following:

1H-NMR (200 MHz, DMSO-d6) / ppm: a 1.01 (3H, d), of 1.13 (3H, d), of 1.37 (9H, s), 3,20 (1H, m), 3,90 (3H, s), a 4.53 (2H, s), of 5.53 (2H, s), the 6.06 (1H, s), 6,83 - 6,89 (2H, m), 7,06 (1H, d), 7.23 percent (1H, TD), 7,32 (1H, t), 7,44 (1H, d), 7,63 (1H, t), of 7.75 (1H, user), 7,95 (1H, user), 8,11 (1H, d), 11,82 (1H, user).

IR (KBr): 3428, 1721, 1678, 1638, 1605, 1572, 1512, 1475 cm-1.

Example 34.

Using the compound obtained in example 16, repeat the method described in example 33, but using 70% aqueous solution of ethylamine instead of 25% aqueous ammonia solution. The compound thus obtained (chemical formula 48)

< / BR>
presented in table 40.

Example 35. Obtain tert-butyl[2,4(1H,3H)-dioxo-6-carboxy-7 - isopropyl-1-(2-methoxybenzyl)-5-(quinoline-1-oxide-2-yl)- pyrido[2,3-d] pyrimidine-3-acetate (chemical formula 49)

< / BR>
The compound (300 mg, 0.49 mmol) obtained in example 16, was dissolved in dichloromethane (20 ml). To the solution was added m-chlorbenzoyl hydroperoxide (0.25 g) and the mixture stirred for 21 h at room temperature. To the reaction mixture is added isopropyl ether (80 ml) to give 200 mg (yield 65%) of colorless crystalline powder, so pl. 176-178oC. elemental analysis Data shown in table 41. The NMR spectrum and IR spectrum of the thus obtained compounds sledujushij), from 7.24 (1H, TD), the 7.43 (1H, d), 7,80 - of 7.97 (3H, m) to 8.12 (1H, d), 8,49 (1H, d).

IR (KBr): 3445, 2974, 2372, 1719, 1673, 1572, 1460 cm-1.

Example 36.

Using the compound obtained in example 17 (compound No. 13), repeat the method described in example 35. Thus obtained compound (chemical formula 50)

< / BR>
presented in table 42.

Example 37.

Preparation of tablets containing a compound of the present invention as an effective component (1).

Using compound 2 of example 19 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg avicel and 1 mg of magnesium stearate produce tablets in the usual way.

Example 38.

Preparation of tablets containing compound according to the invention as an effective component (2)

Using 100 mg of the compound from example 10 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 ml avicel and 1 mg of magnesium stearate are made pills accepted way.

Example 39.

Preparation of tablets containing a compound of the present invention as an effective component (3).

Using 1 the alcohol, 5 ml avicel and 1 mg of magnesium stearate, prepare tablets in the usual way.

Example 40.

Preparation of tablets containing a compound of the present invention as an effective component (4).

Using 100 mg of the compound of example 20 of the present invention, 165 mg of lactose, 25 corn starch, 4 mg of polyvinyl alcohol, 5 ml avicel and 1 mg of magnesium stearate, prepare tablets in the usual way.

Example 41.

Preparation of tablets containing a compound of the present invention as an effective component (5).

Using 100 mg of compound No. 9 obtained in example 21, 165 mg of lactose, 25 corn starch, 4 mg of polyvinyl alcohol, 5 ml avicel and 1 mg of magnesium stearate were prepared tablets accepted way.

Example 42.

Preparation of the injection containing the compound of the present invention as an effective component (1).

15 mg of 1 M aqueous sodium hydroxide solution dissolve 5 g of compound No. 2 obtained in example 19 of the present invention, the pH of the solution was adjusted to 7.6 with 0.1 M HCl to the solution add water for injection to achieve the full volume of 100 ml of This solution is subjected to sterile filtration,following lyophilization and receiving liofilizovannyh injection solutions in the form of 100 mg/bubbles.

Example 43.

Preparation of injection solution containing the compound of the present invention as an effective component (2).

15 mg of 1 M aqueous sodium hydroxide solution dissolve 5 g of compound of example 10 of the present invention. Set the pH to 7.6 with 0.1 M HCl, add water for injections with the establishment of the full volume of 100 ml of This solution is subjected to sterile filtration using to 0.22 micron membrane filter, distributing in sterile bubbles portions of 2 ml each, followed by lyophilization and receiving liofilizovannyh injection solutions in the form of 100 mg/bubbles.

Example 44.

Preparation of injection solution containing the compound of the present invention as an effective component (3).

15 mg of 1 M aqueous sodium hydroxide solution dissolve 5 g of compound of example 12 of the present invention. Set the pH to 7.6 with 0.1 M HCl, add water for injections with the establishment of the full volume of 100 ml of This solution is subjected to sterile filtration using to 0.22 micron membrane filter, distributing in sterile bubbles portions of 2 ml each, followed the 5.

Preparation of injection solution containing the compound of the present invention as an effective component (4).

In 15 ml of 1 M aqueous sodium hydroxide solution dissolve 5 g of compound of example 20 of the present invention. Set the pH to 6.7 with 1 M HCl, add water for injections with the establishment of the full volume of 100 ml of This solution is subjected to sterile filtration by 0.22 micron membrane filter, distributing in sterile bubbles portions of 2 ml each, followed by lyophilization and receiving liofilizovannyh injection solutions in the form of 100 ml/vial.

Example 46.

Preparation of the injection containing the compound of the present invention as an active ingredient (5).

In 15 ml of 1 M aqueous sodium hydroxide solution dissolve 5 g of compound No. 9 obtained in example 21. Bringing the pH to 7.6 with 0.1 to 1 M HCl, water is added to obtain a total volume injection 100 ml.

The solution is sterile-filtered using to 0.22 micron membrane filter, and complement them sterile vials of 2 ml, followed by lyophilization usual method to obtain liofilizovannyh injection solutions in the forms of the E.

Endothelin-A receptor were obtained by dilution fraction ventricular muscle membrane ventricle of the pig analytical buffer [200 mm Tris-HCl, 2 mm EGTA (ethylene glycol bis(2-aminoethanethiol)tetraoxane acid), 5 mm magnesium acetate, 0.1% of BSA (bovine serum albumin), 0,03% NaN3, 0.5 mm PMSF (phenylmethylsulfonyl), 20 g/ml leupeptin, 4 μg/ml E-64 (a product of the Institute of Peptides), 1 μg/ml of pepstatin (pH 7,2)] to obtain a solution of a membrane fraction of the ventricle of the pig 12 µg/ml).

Endotheliosis-B receptor was obtained by diluting the fractions of bovine cerebral membranes with the same analytical buffer to obtain a solution having a concentration of 180 μg/ml.

To 100 μl of each portion add 5 nm (125I) endothelin-1 (2 μl). Add there dimethylsulfoxide the sample solution (3 ml) and incubated at 25oC for 60 minutes

And to determine the maximum binding amount (C0) and non-specific binding amount (HCC) also are incubated samples, to which was added a solution of dimethyl sulfoxide (3 ml) or a solution of dimethyl sulfoxide (3 l) containing endothelin-1 (10-5M).

These samples complement 0.05% CHAPS (3-((3-harami the permanent filter CF/F (trade name: product Wattman Ltd (England)) and then also washed with buffer (1.5 ml).

The radioactivity of the filtrate was measured by gamma counter to determine the percentage of maximum binding (PMS) in accordance with the following calculation formula.

The concentration that causes PMS= 50% is specified as the value of the IC50. IC50the values of some compounds of the present invention synthesized in the above examples, shown in table 43.

PMS = ((C-HCC)/(C0-HCC)) 100

Pharmaceutical experiment 2.

Endotheliosis receptor - study.

Endothelioma (ET) receptors were prepared by dilution of the cell (Sf 9) membrane of the insect with a similar to human endothelin-A (ETA) receptors or human endothelin-B (ETVA) receptors, analytical buffer (20 mm Tris-HCl, 2 mm EGTA (ethylene glycol bis(2-aminoethanethiol)tetraoxane acid), 5 mm magnesium acetate, 0.1% of BSA (bovine serum albumin), 0,03% NaN3, 0.5 mm PMSF (phenylmethylsulfonyl), 20 μg/ml leupeptin, 4 μg/ml E-64 (a product of the Institute of Peptides), 1 μg/ml of pepstatin, (pH 7,2)), respectively at a concentration of 1.4 µg/ml in the first case, and 0.7 μg/ml in the subsequent case.

To 100 ml each portion add 5 nm (125I) endothelin-1 (2 μl). Add TA determine the maximum binding amount (C0) and non-specific binding amount (HCC), also incubated samples, to which was added a solution of dimethyl sulfoxide (3 ml) or a solution of dimethyl sulfoxide (3 ml) containing endothelin-1 (10-5M).

These samples complement 0.05% CHAPS (3-((3-haramidere)dimethylammonio)-1-propanesulfonate) analytical buffer (1.5 ml), subjected to filtration through a glass filter GF/F (trade name, product Wattman Ltd. (England)) and then washed with the same buffer (1.5 ml).

The radioactivity of the filtrate was measured by gamma counter to determine the percentage of maximum binding (PMS) according to the above formula. The concentration that causes PMS = 50% is taken as the value of the IC50. The value of the IC50some compounds of the present invention synthesized in the above examples, shown in table 44.

According to the results shown in tables 43 and 44, it is proved that the compound (A) or its salt of the present invention have excellent antagonistic towards endothelina receptor activity, as compared to endothelin-A receptor, and in relation to the endothelin-B receptor.

Compounds of the present invention have Anta is ticheskih and therapeutic agents in the treatment of acute renal failure, myocardial infarction, hypertension, atherosclerosis, Hepatology, pulmonary hypertension, asthma, organochiorine caused by surgery or transplantation of organs.

It is clear that various modifications can be applied in the acquisition and use of the new compounds according to the present invention without changing the nature of the invention as defined in the following claims.

1. Derived pyrido[1,3-d]pyrimidine of the formula A

< / BR>
in which Q represents - (CH2)m(m = 0, 1, 2);

n = 1, 2, 3;

R1is (1) hydrogen atom, (2) C1-6is an alkyl group which may be optionally substituted by one of the substituents selected from chinoline or indolyl, (3) phenyl group, which optionally may be substituted by at least one C1-6-alkoxygroup, or (4) phenyl-C1-3is an alkyl group which may be optionally substituted by at least one Deputy, selected from C1-6-alkoxy and C1-6-alkylthio;

R2is a hydrogen or C1-6is an alkyl group;

R3is (1)phenyl or naftilos group, which optionally may be substituted by at least one Deputy is ANO, phenyl, C3-7-cycloalkyl, (2) pyridium, which optionally may be substituted C1-6-alkyl, (3) tanila, which optionally may be substituted C1-6-alkyl, (4) chinaillon, which optionally may be substituted by oxopropoxy or a hydroxyl group; (5) chinyanja; (6) benzofuran or (7) benzothieno, which optionally may be substituted C1-6-alkyl;

R4is a group - COOR6in which R6represents (1) hydrogen atom, (2) C1-6is an alkyl group, optionally substituted by at least one Deputy from C3-7-cycloalkyl group, chinoline group, carboxyl group, cyano and phenyl groups, or (3) C3-7-cycloalkyl; or the group,- CONR7R8in which R7and R8independently represent a hydrogen atom or a C1-6is an alkyl group;

R5is (1) hydrogen atom, (2) C1-6is an alkyl group or (3) a phenyl group which may be optionally substituted C1-6-alkylenedioxy,

or its salt.

2. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, in which R6is C1-6is an alkyl group.

3. Derived pyrido[2,3 th least one Deputy, selected from the group consisting of C1-6-alkoxygroup or C1-6-allylthiourea.

4. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R2is a hydrogen atom.

5. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R3is pinolillo group, substituted oxopropoxy or a hydroxyl group, chinaonline or phenyl group, substituted C1-6-alkyl or C1-6-alkoxygroup.

6. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R3is 2-(4-chinaonline) group.

7. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R4is-COOR6where R6is a hydrogen or C1-6is an alkyl group.

8. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R5is C1-6is an alkyl group.

9. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, where R1is a benzyl group substituted with at least one C1-6-alkoxy - or alkylthiol, R2is a hydrogen atom, a QR3- chinaonline group, R4- carboxyl group, and R5- C1-6is an alkyl group.

10. The derivative of PI is 4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.

11. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, representing 2,4(1H, 3H)-dioxo-6-etoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d] pyrimidine-3-acetic acid or its salt.

12. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, which represents an ethyl[2,4(1H, 3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-chinolone)]-pyrido[2,3-d]pyrimidine]-3-acetate or its salt.

13. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, representing 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-chinolone)]-pyrido[2,3-d]pyrimidine-3-acetic acid or its salt.

14. Derived pyrido[2,3-d]pyrimidine or its salt under item 1, representing 2,4(1H, 3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthioethyl)-5-[2-(4-chinolone)] -pyrido[2,3-d] pyrimidine-3-acetic acid or its salt.

15. The method of deriving pyrido[2,3-d]pyrimidine or its salt under item 1, where QR3is 2-(4-chinaonline)group and R4is-COOR6or-CONR7R8where R6represents a hydrogen atom, a C1-6is an alkyl group, optionally substituted by at least one Deputy, selected from C3-7-cycloalkyl group, Hino is odorata or C1-6is an alkyl group, characterized in that the compound of the formula H

< / BR>
where n= 0, 1, 2, 3;

R1is (1) hydrogen atom, (2) C1-6is an alkyl group which may be optionally substituted by one of the substituents selected from chinoline or indolyl, (3) phenyl group, which optionally may be substituted by at least one C1-6-alkoxy group, or (4) phenyl-C1-3is an alkyl group which may be optionally substituted by at least one Deputy, selected from C1-6-alkoxy and C1-6-alkylthio;

R2is a hydrogen or C1-6is an alkyl group;

R5is (1) hydrogen atom, (2) C1-6is an alkyl group or (3) a phenyl group which may be optionally substituted C1-6-alkylenedioxy group

or its salt is subjected to reaction with a nucleophilic reagent selected from the group consisting of potassium carbonate, aqueous ammonia and amino compounds capable of interacting with the Deputy OR6or - NR7R8where the values of R6, R7and R8above.

16. The pharmaceutical composition active antagonist endothelioma receptor, compounds, selected from a derived pyrido[2,3-d]pyrimidine of the formula A under item 1, or its pharmaceutically acceptable salt.

17. The composition according to p. 16, characterized in that is used as a treatment for acute renal failure and/or myocardial infarction.

18. The composition according to p. 16, characterized in that is used as a treatment for hypertension, cerebral infarction, chest angina, atherosclerosis, Hepatology, pulmonary hypertension, asthma, organochiorine caused by surgery or transplantation of organs.

19. The way antagonistic effects on endothelioma receptors in the treatment of renal failure, myocardial infarction, hypertension, cerebral infarction, chest angina, arterial sclerosis, Hepatology, pulmonary hypertension, asthma, organochiorine associated with surgery or transplantation of organs, wherein the patient is administered an effective daily dose of 0.1 - 500.0 mg derived pyrido[2,3-d]pyrimidine of the formula A under item 1 or its pharmaceutically acceptable salts, or pharmaceutical compositions that contain the compound as an effective component.

20. Prosoloist endothelioma receptor.

Priorities for items:

29.12.92 on PP.1, 4, 10, 11, 16 and 17;

05.11.93 on PP.2, 3, 5 - 8, 9, 12, 13 and 18.

 

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< / BR>
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< / BR>
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SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

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wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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