Triazolopyrimidine derivatives and pharmaceutical composition

 

(57) Abstract:

Triazolopyrimidine derivatives of General formula I given in the description, where one of R1and R2- C1-6-alkyl, the radical -(CH2)pOR, where p is 1-6, R - C1-6-alkyl, hydrogen or benzyl and the other is: hydrogen, halogen, C1-6-alkyl, N3OR4, SR4, NR5-R6or NH(CH2)n- NR5R6where R4- hydrogen or -(CH2)m, OR, where m is 1-4, R1- C1-6-alkyl; R5and R6- same or different and mean hydrogen, C1-6-alkyl, or together with the nitrogen form morpholino, pyrrolidino and piperidino; n is 1-4; X and Y are different and mean: N and group-C-R7where R7- H, C1-6-alkyl, the radical (CH2)n'OH, where n is 0-4, the radical SR', where R' is as defined above, or NR5R6where R5and R6- same or different and mean hydrogen or C1-6-alkyl; R3- aminocarbonylmethyl, carboxyphenyl or a radical of the formula

< / BR>
where Z Is N or CH; Z' Is S or O; R5is hydrogen or, when Z' Is O, halogen, which has antagonistic properties towards angiotensin II receptor and antiproliferative properties that enable their use in pharmaceutical compositions is iswalnum General formula (I), below, and their tautomeric forms, as well as, where appropriate, to their adducts, in particular pharmaceutically acceptable adducts.

The proposed compounds possess very valuable pharmacological profile actions, because they are characterized by antagonistic properties towards angiotensin II receptor and antiproliferative properties. Thus, they are particularly indicated for the treatment and prevention of cardiovascular diseases, in particular hypertension, for the treatment of heart failure and for the treatment and prevention of diseases of the arterial wall, particularly atherosclerosis.

In addition, the invention relates to a method for producing the said products and to their use in therapy.

Such triazolopyrimidine derivatives and their tautomeric forms meet the General formula (I)

< / BR>
where one of the radicals R1and R2denotes a lower alkyl radical containing from 1 to 6 carbon atoms; or a radical of the formula - (CH2)pOR, where p is an integer from 1 to 6, and R is a lower alkyl radical containing from 1 to 6 carbon atoms, or benzyl radical; or an alcohol residue of the formula - (CH2)pOH, where value is the higher alkyl radical, containing from 1 to 6 carbon atoms, or a radical selected from a class which includes radicals of N3OR4, SR4, NR5R6and NH(CH2)n- NR5R6where R4denotes a hydrogen atom, a lower alkyl radical containing from 1 to 6 carbon atoms or cycloalkenyl radical C3- C7a radical of the formula (CH2)m- COOR1where m is an integer from 1 to 4 and the symbol R' means a hydrogen atom or a lower alkyl radical containing from 1 to 6 carbon atoms, or a radical of the formula (CH2)m- O - R', where the meaning of the symbols m and R' are defined above; each of the symbols R5and R6that can be both identical and different, marked a hydrogen atom; or a lower alkyl radical containing from 1 to 6 carbon atoms or cycloalkenyl radical C3- C7or together with the nitrogen atom to which they relate, the radicals R5and R6form a heterocycle selected from the class of the research, pyrrolidine and piperidine, and n is an integer from 1 to 4; each of the symbols X and Y, which are different, in one case, the indicated nitrogen atom, and in another case - the group C - R7where the symbol R7indicated hydrogen atom; neither shall adical formula (CH2)n'OH, where n' is an integer from 0 to 4; radical SR', where the symbol R' is defined above; or a radical of the formula NR5R6where each of the symbols R5and R6that can be both identical and different, marked a hydrogen atom, a lower alkyl radical containing from 1 to 6 carbon atoms, or cycloalkenyl radical C3- C7; and the symbol R3marked a radical of the formula

< / BR>
where

Z is CH or N, or Z' is sulfur atom or oxygen;

R11is hydrogen atom or halogen atom; and

R12- tetrazolyl radical, CH, COOH or CONH.

The above derivatives should also be seen in their tautomeric form.

In the case when R2- azide group, in accordance with the equation, which is well known from the literature (see temple & Montgomery, J. Org. Chem. 30, 826, 1965), such compounds can be considered tricyclic tetrazolo(1,5-C)-1,2,4 - triazolo(1,5-a)pyrimidine form.

The above derivatives may take the form of adducts, in particular pharmaceutically acceptable acid adducts.

Preferred derivatives of the present invention must meet the General formula (I) above, where od is either a radical of the General formula (CH2)pOR, where p is an integer from 1 to 6, and R is a lower alkyl radical containing from 1 to 6 carbon atoms, or benzyl radical; or an alcohol residue of the formula - (CH2)pOH, where the symbol p is defined above; and the other of the symbols R1and R2indicated hydrogen atom; halogen atom; a lower alkyl radical containing from 1 to 6 carbon atoms; or a radical selected from a class which includes radicals of N3OR4, SR4, NR5R6and NH(CH2)n- NR5R6where R4denotes a hydrogen atom; or a radical of the formula - (CH2)m- O - R', where m is an integer from 1 to 4, and R' is a lower alkyl radical containing from 1 to 6 carbon atoms; each of the symbols R5and R6that can be both identical and different, marked a hydrogen atom; or a lower alkyl radical containing from 1 to 6 carbon atoms; or together with the nitrogen atom to which they relate, the radicals R5and R6form a heterocycle selected from the research, pyrrolidine and piperidine; and n is an integer from 1 to 4; each of the symbols X and Y, which are different, in one case, the indicated nitrogen atom, and in another case, a group of the formula C - R7/SUB>)n'OH, where n' is an integer from 0 to 4; radical SR', where the symbol R' is defined above; or a radical of the formula NR5R6where each of the symbols R5and R6that can be both identical and different, marked a hydrogen atom or a lower alkyl radical containing from 1 to 6 carbon atoms; and the symbol R3marked one of the following radicals

< / BR>
< / BR>
In the text of the description and the claims, the term "lower alkyl radical" should be understood as meaning linear or branched carbon chain containing from 1 to 6 carbon atoms. Examples of the lower alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentalogy, isopentylamine, hexyl or isohexyl radicals.

The term "cycloalkenyl radical C3-C7" should be understood as meaning a saturated cyclic hydrocarbon radical, preferably cyclopropyl, cyclobutyl, tsiklogeksilnogo or cycloheptyl radical.

The term "halogen atom" should be understood as denoting a chlorine atom, bromine, iodine or fluorine.

In one embodiment, R1-n-through gruelly group.

In one embodiment, R2-hydroxyl group.

In another embodiment, R2-n-through the group.

In another embodiment, R2-N-diethylaminopropyl.

In one embodiment, R2-2-(1H-tetrazol-5-yl)phenyl group.

In one embodiment, X is a nitrogen atom.

In one embodiment, Y is a CH group.

In another embodiment, the Y-group C-CH3.

In yet another embodiment, the Y-group C-NH2.

Particularly preferred compounds of the present invention are selected from the products of the formulae given in scheme 1.

In General, the method of obtaining compounds of formula (I) includes the steps:

a) obtaining compounds of formula (alpha)

,

where the symbols X, Y, and R3defined above; and each of the symbols A and B in one case indicated a hydroxyl group or a lower alkyl group containing from 1 to 6 carbon atoms, and in another case, a lower alkyl group containing from 1 to 6 carbon atoms, or a radical of the formula - (CH2)p-OR, where p is an integer from 1 to 6, and R is a lower alkyl radical containing from 1 to 6 carbon atoms, or a benzyl radical, by condensing 3-amino-1,2,4-triazole of the formula (II).


is a lower alkyl radical containing from 1 to 6 carbon atoms, or a residue of a simple ester of formula -(CH2)p-OR, where p is an integer from 1 to 6, and R is a lower alkyl radical containing from 1 to 6 carbon atoms, or a benzyl radical, R8is a lower alkyl radical containing from 1 to 6 carbon atoms, preferably methyl or ethyl, and the values of R3defined above, in an aprotic solvent, in particular in dichloro - or trichlorobenzene, in an acid solvent, in particular in acetic acid or alcohol in the presence of the corresponding sodium alcoholate or potassium or pyridine or 2-methyl-5-ethylpyridine in the presence or without the 4-dimethylaminopyridine, at a temperature of from 50 to 200oC;

b) lock, if it is positive, the group, which includes the radical R3in accordance with the method, which is in itself known;

(C) heating the derivative thus obtained from the derivative of formula (beta), when this last is keeeper, in an appropriate reagent, in particular in POCl3with the conversion of the hydroxyl group denoted by symbols A and B, chlorine atom;

d) heat that chlorinated derivative in presutti refrigerator in alcohol or in an autoclave at a temperature of 100oC in the presence of or without a base, such as sodium carbonate, to obtain a derivative of formula (alpha), where the symbols A and B are identical to the values of the symbols, respectively, R1and R2;

e) remove, if it's acceptable protective group for the group, which includes the radical R3;

e1) conversion of this group in the acid residue, for example, by hydrolysis in the case when such a group is a nitrile;

e2) conversion of this group in tetrazolyl group, for example, in the case when the group is a nitrile, the reaction with trialkylaluminium with heating in toluene or xylene, followed by treatment with gaseous hydrochloric acid in tetrahydrofuran; or

e3) conversion of this group in the amide group, for example, in the case when the group is a nitrile, the reaction with sulfuric acid or by reaction with hydrogen peroxide, or by reaction with polyphosphoric acid; and

f) conversion, if it is acceptable, derived in the adduct, preferably in a pharmaceutically acceptable adduct.

In accordance with the present invention allows for the synthesis of compounds of formula (I) in accordance with the below/BR> is a lower alkyl radical containing from 1 to 6 carbon atoms, or a residue of a simple ester of formula -(CH2)p-OR, where p is an integer from 1 to 6, and R is a lower alkyl radical containing from 1 to 6 carbon atoms, or a benzyl radical, and R8is a lower alkyl radical containing from 1 to 6 carbon atoms, or a lower O-alkyl group containing from 1 to 6 carbon atoms, preferably methyl or ethyl, can be used methods, which are in themselves known, in particular, by the reaction of Clausena or according to the method using acid Melodrama, and these methods can easily be found in the following literature references:

HAUSER, C. R.; Swamer F. W.; Adams, J. T.: Org. Reaction, vo1, Vi, 1954, 59 - 196.

Henne, A. L.; Tedder, J. M.; J. Chem. Soc., 1953, 3628,

Breslon D. S.; Baumgarten, E.; Hauser, C. R.; J. Am. Chem. Soc., 1944, 66, 1286,

Oikawa Y.; Sugano, K.; Yonemitsu O.; J. Org. Chem., 1978, 43 (10), 2087 - 88.

Wierenga W.; H. I. Skulnick, J. org. Chem., 1979, 44, 310,

Houghton R.; D. Lapham; Synthesis, 1982, 6, 451 - 2,

Bram G.; Vilkas M.; Bull. Soc. Chim. France, 1964 (5), 945 - 51,

Balyarina M. V.; Zhdanovich E. S.; Preobrazhenskii N. A.; Tr. Vses. Nauchn. Issled. Vitamin. Inst., 1961, 7, 8 - 16,

Renard M.; Maquinay A.; Bull Soc. Chim. Belg., 1946, 55, 98 - 105,

Bruce F. W.; Coower H. W.; J. Am. Chem. Soc., 1944, 66, 2092 - 94 and

Eby C. J. and Hauser, C. R.; J. Am. Chem. Soc., 1957, 79, 723 - 5.

The compounds of formula (V)

< / BR>
can be first, as sodium carbonate or potassium, in acetone, sodium alcoholate or potassium in alcohol or sodium hydride, or lithium, in solvents such as tetrahydrofuran, dioxane or dimethylformamide, for example, at a temperature of from 50 to 100oC, or in the presence of one equivalent of chloride or lithium bromide and two equivalents of diisopropylethylamine in tetrahydrofuran at the boiling under reflux in accordance with the following literature reference: Sung-Eun Yoo; Kyu Yang Yi; Bull. Korean Chem. Soc., 1989, 10 (1), 112.

These compounds of the formula (V) can also be obtained by condensation of an aldehyde of formula (VI)

< / BR>
with compounds of the formula (III) with subsequent hydrogenation in the presence of a catalyst, in particular Raney Nickel, palladium on coal or platinum oxide, in an environment of solvent, in particular ethanol or tetrahydrofuran, under an elevated pressure or normal pressure, if it could be done in the present reagents.

In a more General methods of preparing compounds of the formula (V) can be found in the following literature references:

Durgeshwari P.; Chaudhury N. D.; J. Ind. Chem. Soc., 1962, 39, 735 - 6,

Heinz P.; Kreglewski, A.; J. Prakt. Chem., 1963, 21 (3 - 49)b 186 - 197,

Zaugg, H. E. ; Dunnigan D. A.; Michaels, R. J.; Swett L. R.; J. Org. Chem., 1961, 26, 644 - 51,

Kagan, H. B.; Neig Y. Suen; Bull. Soc. Chio-Manas, M.; Chem. Lett., 1981, 2, 173 - 6,

Ioffe t.; Popov E. M.; Vatsuro K. V.; Tulikova E. K.; Kabachnik, M. I.; Tetrahedron, 1962, 18, 923 - 940 and

Shepherd T. M.; Chem. Ind. (London), 1970, 17, 567.

In the formula (IV) W is a halide atom, preferably chlorine or bromine.

In the same formula V may denote a group

< / BR>
where

R9is lower alkyl or benzyl radical, and in this case the compounds of formula (IV) is obtained by reaction of the magnesium-containing compound n-bromthymol with the compound of the formula

< / BR>
obtaining the compounds of formula

< / BR>
which is then hydrolized, receiving the connection formulas

< / BR>
Meyers A. I.: Mihelich, E. D.; J. Am. Chem. Soc., 1975, 97, 7383.

Next, the resulting acid etherification alcohol of formula R9OH, where values of R9defined above.

Then these derivatives bromilow or glorious, for example, N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as chetyrehhloristy carbon, dibromobutan or dichloroethane, obtaining the compounds of formula (IV), in which V is a group of the formula

< / BR>
Symbol V can be denoted by a group of the formula

< / BR>
moreover, in this case, the connection formula

< / BR>
received on the above, is subjected to conversion in the primary amide native ammonia solution, and then this amide is subjected to conversion to the nitrile by reaction with phosphorus oxychloride in dimethylformamide or with chloride tiomila. Similarly connected formulas

< / BR>
received on the above, can be subjected to conversion directly in carbonitrile derived by processing in pyridine in the presence of POCl3. The obtained nitrile derivative of formula

< / BR>
then subjected to bromirovanii or chlorination in the same conditions as described above for compound ether, resulting in the receive connection of the formula (IV), in which V is a group of the formula

< / BR>
Symbol V can be denoted by a group of the formula

< / BR>
moreover, in this case, the corresponding compounds of formula (IV) are synthesized as follows.

The magnesium compound of the formula

< / BR>
obtained from a conventional Grignard reaction, is subjected to conversion in EAF derivative by reaction with zinc chloride. This zinc-containing derivative condensed with 2-chloronicotinamide in the presence of the product formula [NiP (phenyl)3]2Cl2in the result, get the derived formulas

< / BR>
This compound is treated with tribromide boron in chloroform, gives compounds of formuta group of the formula

< / BR>
where the symbol R9defined above, and in this case, the corresponding compounds of formula (IV) can be obtained from the nitrile obtained in the above-mentioned formula

< / BR>
conventional hydrolysis of the nitrile group, followed by esterification of the resulting acid or a direct conversion of the nitrile group in the ester group by methods which are known to any person skilled in the technical field, and then spend processing tribromide boron in chloroform, obtaining the compounds of formula (IV) in which W is a bromine atom, and V is a group of the formula

< / BR>
Symbol V can be denoted by group

< / BR>
moreover, in this case, the corresponding compounds of formula (IV) are synthesized as follows.

The connection formulas

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is obtained using 4-chloro-4'-methylbutyrate formula

< / BR>
the receipt of which is illustrated in the description of the Belgian patent 577977, published may 15, 1959, summary CA: 54, 4629, by treatment with phosphorus oxychloride and dimethylformamide under conditions that are described in the following literature reference: Volodina M. A.; Tenent'ev A. P.; Kudryashova V. A.; Kabochina L. N.; Khim. Getetosik1. Soedim. 1967, 5 - 8.

Next, this compound is treated with sodium sulfide in Ratisbonne formula

< / BR>
which is then subjected to the conversion in two stages in nitrile derived by dehydration of the oxime obtained using aldehyde and hydroxylamine. This dehydration can be performed, for example, with acetic anhydride, receiving a nitrile compound of the formula

< / BR>
which can then be flavored by treatment with bromine in carbon tetrachloride to obtain the compounds of formula

< / BR>
Further, this connection can be gloriavale or bronirovat palodiruyut agent, in particular N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dichloromethane, resulting in a gain of compounds of formula (IV), in which the symbol V is denoted by a group of the formula

< / BR>
Symbol V can be denoted by a group of the formula

< / BR>
where the symbol R9defined above, and in this case, the corresponding compounds of formula (IV) can be obtained from the nitrile obtained in the above-mentioned formula

< / BR>
by conventional hydrolysis of the nitrile group, followed by esterification of the resulting acid or by direct conversion of the nitrile group in the ester group by methods which are known to any of specialised or N-bromosuccinimide, for example, carbon tetrachloride or dichloromethane, resulting in a gain of compounds of formula (IV), in which the symbol W is denoted by a bromine atom or a chlorine atom, and the symbol V is denoted by a group of the formula

< / BR>
Symbol V can be denoted by a group of the formula

< / BR>
where the symbol R9defined above, and in this case, the corresponding compounds of formula (IV) can be obtained by the reaction of diazotized derivative n-toluidine 3-Voronovo acid, resulting in a gain of compounds of formula

< / BR>
according to the method described in the following literature reference: A. Jurasek et al., Collect. Chem. Commun., 1989, 54, 215.

After that, the connection etherification according to conventional methods known to anyone skilled in the art, resulting in a gain of compounds of formula

< / BR>
where the symbol R9defined above, and after this it is derived bromilow or glorious reaction with N-bromosuccinimide or N-chlorosuccinimide, for example, carbon tetrachloride or 1,2-dichloroethane, resulting in a gain derivative (IV) in which W is bromine atom or chlorine atom, and V is a group of the formula

< / BR>
Symbol V can be marked group f is t conversion to the acid chloride of the acid by reaction with chloride tiomila, and then in the amide by reaction with ammonia. The obtained amide is subjected to conversion to the nitrile by reaction with phosphorus oxychloride in dimethylformamide to obtain compounds of the formula

< / BR>
Next is derived bromilow or glorious reaction with N-bromosuccinimide or N-chlorosuccinimide, such as carbon tetrachloride or 1,2-dichloroethane, resulting in a gain of compounds of formula (IV) in which W is bromine atom or chlorine atom, and V is a group of the formula

< / BR>
In the formula (V) values of the symbols R'1and R8defined above and the symbol V are as defined for formula (IV).

However, the compounds of formula (V) in which V is a group of the formula

< / BR>
react with one equivalent of sodium azide in a solvent, in particular in dimethylformamide, in the presence of ammonium salts, in particular ammonium chloride, or by heating in toluene or xylene with trialkylaluminium, resulting in the formation of compounds of formula (V) in which V is a group of the formula

< / BR>
In the formula (VI) value of the symbol V is identical to the one defined for formula (IV), but this method of condensation is only used in the case where the radical V includes a group that is not subjected II)

< / BR>
where the symbol R7defined above (these products are technically available or can be obtained by the methods described in the following literature references:

Huffmann and Schaefer, J. of Chem., 963, 28, p. 1812 - 1816 and p. 1816 - 1821,

Allen et al. , J. of Org. Chem., 1959, 24, p. 793 - 796, and Orgnanic Synthesis Collective volume 3, p. 95),

with compounds of the formula (V) where the values of the symbols and R8defined above and the symbol V denotes one of the groups of the formulae given in scheme 2.

where the symbol R9defined above, to obtain compounds of formula (VIIa) or (VIIb):

< / BR>
and their tautomeric forms, where the symbols X, Y, and V are defined above and the symbol R10marked hydroxyl group, when the compounds of formula (V) is a beta - ketoesters, and lower alkyl radical containing from 1 to 6 carbon atoms, when these same compounds of formula (V) is a beta-diketones, by condensation in an aprotic solvent, in particular in the dichloro - and trichlorobenzene, in an acid solvent, in particular in acetic acid, in alcohol in the presence of the corresponding sodium alcoholate or potassium, in pyridine or 2-methyl-5-ethylpyridine in the presence or without the 4-dimethylaminopyridine when temperatures the reaction temperature should not exceed 140oC to avoid decomposition of tetrazole.

Reaction aminotriazole or similar heteroaromatic amines with beta-ketoamine and beta-diketonate derivatives are well described in the literature, and the resulting shaped products identify, depending on the process conditions. As examples of the research are presented in the following publications:

J. A. van Allan et al., J. Org. Chem., p. 779 to p. 801 (1959).

L. A. Williams. J. Chem. Soc. p. 1829 (1960) and

L. A. Williams, J. Chem. Soc. p. 3046 (1961).

Thus, the compounds of formulas VIIa and VIIb must be identified for separate processing.

However, the applicant found that 2-methyl-5-ethylpyridine in the presence or without the 4-dimethylaminopyridine is the preferred solvent for orientation reaction almost exclusively in the direction of formation of derivatives of formula (VIIb); indeed, the use of such a solvent allows to reach a temperature of 170 - 180oC and pH, which are necessary for the orientation.

If derivatives of the formulas (VIIa) and (VIIb) in which R10- hydroxyl group is treated with this reagent, as pentasulfide phosphorus or reagent Lawesson, the floor is, for example, if derivatives of the formulas (VIIa) and (VIIb) in which the symbol R10marked hydroxyl group, heated in POCl3formed derivative of formula (VIIa) and (VIIb)

< / BR>
in which the symbols R'1X, Y, and V defined above.

Hydrogenation of derivatives of formula (VIIIa) and (VIIIb) in the presence of such a catalyst as palladium on charcoal, you can replace the chlorine atom hydrogen atom, and derivatives of the formula (IX)

< / BR>
where the symbols R1, R2X, Y, and V defined above, obtained by heating derivatives of formula (VIIIa) and (VIIIb) in the presence of nucleophilic compounds containing a nitrogen atom, oxygen or sulfur, by boiling under reflux in ethanol in the presence of, or without such a base as sodium carbonate, or in an autoclave at a temperature of 100oC.

Derivatives of the formulas (VIIa) and (VIIb) in which R'1group (CH2)pO-benzyl, where the symbol p is defined above, can be hydrogensulfate in the presence of palladium on coal in acetic acid to obtain compounds of the formulas (VIIa) and (VIIb) in which the symbol indicated an alcohol group.

These triazolopyrimidine formulas (VIIa) and (VIIb) can be also obtained by the reaction of derivatives of formula (X)

< / BR>

Depending on the process conditions, in particular temperature and pH of the reaction medium, receive 1,2,4-triazolo(4,3-a)pyrimidine derivative or 1,2,4-triazolo(1,5-a)pyrimidine products of their rearrangement.

The compounds of formula (X) can be obtained in accordance with one of the known methods for the synthesis of 2-hydrazinopyridazine (see "The Pyrimidines; The Chemistry of Heterocyclic Compounds"; D. J. Brown, publisher of "Willy entertains", 1970), in particular by substitution derivatives of the formula (XI)

< / BR>
where the symbols R1, R2and V defined above, using, for example, hydrazine hydrate is added.

The compounds of formula (XI) is obtained by condensation of S-methylthymidine, for example, derivatives of the formula (V), or according to one of the methods of synthesis of 2-dimethylpyrimidinol which are known from Libya ester group COOR9you can hydrolyze in acidic or basic environment or hydrogensulfate in the case when R9- benzyl, obtaining compounds of formula (I) in which the radical R9includes acid residue.

It is possible to conduct the reaction of compounds of formula (IX) in which the radical V includes a nitrile group, with one equivalent of sodium azide in a solvent such as dimethylformamide, in the presence of ammonium salt such as ammonium chloride, or by heating in toluene or xylene with azide triamcinolone, for example, azide trimacinolone or anti -, with subsequent acid treatment, for example, gaseous hydrochloric acid in tetrahydrofuran, resulting in a gain of compounds of General formula (I) in which the radical R9includes tetrazol-5-silt group.

It is possible to carry out the conversion of the same compounds in which the radical V includes a nitrile group, by reaction with sulfuric acid, by reaction with hydrogen peroxide or by reaction with polyphosphoric acid derivatives of General formula (I) in which the radical R9includes amide group.

You can also perform the conversion of derivatives, in which the radical V includes NIT is that the radical R9includes acid residue.

You can get adducts of some compounds of formula (I), in particular pharmaceutically acceptable adducts. Thus, in particular, when the molecules of the compounds of formula (I) include acid or tetrazole group, in this respect, mention can be made of salts of sodium, potassium, calcium, amine, in particular dicyclohexylamine or amino acids, for example lysine. In the same case when they contain amino groups, in this respect, mention can be made of salts of mineral or organic acids, in particular hydrochloride, methosulphate, acetate, maleate, succinate, fumarate, sulfates, lactates and citrates.

New connections in accordance with the present invention are characterized by remarkable pharmacological properties as antagonists of angiotensin II receptors and antiproliferative and can be used in therapy for the treatment and prevention of cardiovascular diseases, in particular for the treatment of hypertension, heart failure, and diseases of the arterial wall, particularly atherosclerosis.

Thus, the scope of this invention covers pharmaceutical compositions which comprise as active the unity of formula (I), defined above, and, if appropriate, one of its pharmaceutically acceptable adducts.

Such compounds can enter the body buccal, rectal, parenteral, transdermal or ocular route.

These compositions can be solid or liquid and can be prepared in the form of pharmaceutical preparative forms that are commonly used in human medicine, such as a simple tablet and tablet coating, gelatin capsules, granules, suppositories, injectable preparations, transdermal systems and eye lotions. They are prepared by conventional methods. In these compositions the active basis, consisting of a pharmaceutically effective amount of at least one of the compounds of formula (I) as defined above, or one of its pharmaceutically acceptable adducts, can be combined with bases for the preparation of drugs usually used in these pharmaceutical compositions, in particular, such as talc, Arabic gum, lactose, starch, magnesium stearate, polyvidone, derivatives of cellulose, cocoa butter, semisynthetic glycerides, aqueous and non-aqueous vehicles, fats of animal and vegetable origin, polymers, preservatives, perfumes and flavorings, and dyes.

The scope of the present invention is also covered by pharmaceutical composition with antagonistic activity against reception of angiotensin II and/or antiproliferative action, which enables a particularly successful treatment or prevention of cardiovascular diseases, in particular hypertension, heart failure, and diseases of the arterial wall, in particular, atherosclerosis, and this composition includes a pharmaceutically effective amount of at least one of the compounds of formula (I) above, or one of its pharmaceutically acceptable adducts, which can be entered into pharmaceutically acceptable basis for the preparation of medicines, carrier or filler.

The dosage will vary primarily depending on ways of introduction into the organism, the disease that must be treated, and subjected to treatment of the patient.

For example, for adult patients with an average weight of from 60 to 70 kg it can vary from 1 to 400 mg activitiesthese substances, administered orally in the form of one or more daily doses, I doses.

The present invention also covers a method of preparing a pharmaceutical composition, in the exercise of which is provided by the introduction of pharmaceutically acceptable basis for the preparation of medicines, carrier or filler pharmaceutically effective amount of at least one of the compounds of formula (I) as defined above, or one of its pharmaceutically acceptable adducts. Such pharmaceutical composition can be prepared in the form of gelatin capsules or tablets, each of which comprises from 1 to 400 mg activitiesthese substances, or drugs for injection, each of which comprises from 0.01 to 50 mg activitiesthese substances.

Moreover, the present invention covers a method of therapeutic treatment of mammals, in the exercise of which is provided by the introduction into the body of such a mammal a therapeutically effective amount of at least one of the compounds of formula (I) defined above, or one of its pharmaceutically acceptable adducts.

When therapeutic treatment of animals daily dose, which can be used is usually in the range from 1 to 100 mg/kg

The other characteristic is that examples of the preparation, which in any case are not limited to its scope, because they are shown for illustrative purposes.

Example 1. Ethyl-3-oxohexanoate

Formula (III): -n-propyl, R8-O-ethyl.

176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (acid Melodrama) is dissolved in 550 ml of dichloromethane and 188 ml of pyridine, the mixture is cooled to a temperature of 5oC in a water bath with ice and drops it added 133 ml of butyl chloride. After completion of this addition the mixture is stirred for 3 h at room temperature. The solution is washed with diluted hydrochloric acid, dried over magnesium sulfate and evaporated in vacuum to obtain butter-like product. This butter-like product is dissolved in 700 ml of ethanol and the mixture refluxed for 6 hours, the Ethanol is evaporated in vacuo and the resulting residue is distilled to obtain 145,4 ethyl-3-oxohexanoate in the form of a butter-like product.

Boiling point (under the residual pressure of 20 mm RT.article): 98 - 100oC.

The compound of example 2 was obtained according to the procedure of example 1.

Example 2. Ethyl-3-oxidated.

Formula (III): -n-butyl, R8-O-ethyl.

Boiling point (under the residual is (III): -CH2-O-CH2-phenyl, R8-O-ethyl.

80 g of 60% sodium hydride (NaH) separate portions add 800 ml of anhydrous tetrahydrofuran. This medium is cooled to a temperature of 10oC and maintain this temperature. Then added dropwise to 500 ml of benzyl alcohol. Then add a solution of 65.8 g ethyl-4-chloroacetoacetate in 200 ml of benzyl alcohol. The mixture is stirred at room temperature for 20 hours Cautious addition of 120 ml of acetic acid neutralize her, continuing to cool in a bath with ice. Then the whole mass is poured onto a mixture of ice water and subjected to extraction processing sulphuric ether. The organic phase is washed with sodium bicarbonate solution and dried over magnesium sulfate, followed by concentration, resulting in a gain orange butter-like product. This product is purified by two successive distillations, receiving yellow butter-like product.

Boiling point (under a residual pressure of 0.05 mm RT.article): 126 - 132oC.

Example 4. 4'-methyl bromide-2-cyanobiphenyl.

Formula (IV): W - bromo,

< / BR>
a) Obtaining 2-cyano-4'-methylbiphenyl

563,8 g (4'-methylbiphenyl-2-yl)carboxylic acid, obtained in accordance with the process is the mixture refluxed for 2 hours Chloride thionyl concentrated in vacuo and the residue poured in 28% solution of hydroxide ammonium, pre-cooled in a water bath with ice. This mixture is stirred for 30 min and the resulting crystals filtered off, washed with water and then ethyl ether and dried to obtain 554,8 g (4'-methylbiphenyl-2-yl)carboxamide in the form of crystals with a melting point 128-132oC. These crystals are dissolved in 1300 ml of chloride tiomila and the mixture is refluxed for 3 h, and then concentrated in vacuo, getting orange butter-like product. The latter is dissolved in 2 l of chloroform and washed with water, and then the organic phase is dried and concentrated to obtain 509,8 g butter-like product, which crystallized from pentane, getting 467,3 g 2-cyano-4'-methylbiphenyl.

Melting point: 46 - 48oC.

b) 4'-methyl bromide-2-cyanobiphenyl.

467,3 g 2-cyano-4'-methylbiphenyl obtained in the above, is dissolved in 4.7 l of 1,2-dichloroethane in the presence of 467,3 g of N-bromosuccinimide and 9.3 g of benzoyl peroxide. The mixture is carefully heated to ensure a good control of the exothermic effect. Further, it is refluxed in the content of inorganic fillers phase concentrate, getting cream-colored crystals.

As a result of recrystallization from isopropanol receive 451 g of white crystals of 4'-methyl bromide-2-cyanobiphenyl.

Melting point: 128oC.

Example 5. Ethyl-2-[(2'-cyanobiphenyl-4-)-methyl]-3-oxohexanoate.

Formula (V): R'1-n-propyl, R8-O-ethyl,

< / BR>
23 g of ethyl-3-oxohexanoate, obtained as described in example 1, is dissolved in 120 ml of tetrahydrofuran. Add to 30.3 g of 4'-methyl bromide-2-cyanobiphenyl obtained in the foregoing example 4, and 4.7 g of lithium chloride and the mixture is stirred at room temperature. Then dropwise enter 39 ml diisopropylethylamine that causes a slight exothermic effect. Next, the mixture is stirred for 3 h at room temperature, then boiled for 10 hours under reflux. Vacuum evaporate the solvent and the residue is dissolved in water, and then subjected to extraction treatment with chloroform. The organic phase is decanted, followed by washing with diluted hydrochloric acid, dried over magnesium sulfate and evaporated in vacuum, obtaining 38 g orange butter-like product.

Purification by chromatographic treatment of violence examples 6 through 10 receive according to the procedure of example 5 using the corresponding complex of beta-keeeper.

Example 6. Ethyl-2-[(2'-cyanobiphenyl-4-yl)-methyl]-3-oxogedunin.

Formula (V): -n-butyl, R8-O-ethyl,

< / BR>
Butter-like product, which is used as such in the next stage.

Example 7. Ethyl-2-[(2'-cyanobiphenyl-4-yl)-methyl]-3-oxobutanoate.

Formula (V): R'1is methyl, R8-O-ethyl,

< / BR>
Yellow butter-like product, purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform with 5% diethyl ether).

Example 8. Ethyl-2-[(2'-cyanobiphenyl-4-yl)-methyl]-3-oxopentanoate.

Formula (V): - ethyl, R8-O-ethyl,

< / BR>
Butter-like product, purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform with 5% diethyl ether).

Example 9. Ethyl-2-[(2'-cyanobiphenyl-4-yl)-methyl] -4-methoxy-3-oxobutanoate.

Formula (V): - methoxymethyl, R8-O-ethyl,

< / BR>
Yellow butter-like product, purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform with 5% diethyl ether).

Example 10. Ethyl-4-benzyloxy-2-[(2'-cyanobiphenyl-4-yl)-methyl]-3-oxobutanoate.

Formula (V): -CH2-O-CH2-phenyl, R8-O-ethyl,

< / BR>
Butter-like product, cleaned the Xan with 20% ethyl acetate).

Example 11. Ethyl-2-[4-(3-cyano-2-pyridyl)-benzyl[-3-oxohexanoate.

Formula (V): -CH2CH2CH3, R8-O-ethyl,

< / BR>
a) Obtaining 4-bromobenzylamine ether.

A solution of sodium methylate obtained from 11,8 g of sodium and 350 ml of methanol dropwise introduced into the suspension of 117.7 g of 4-bromobenzylamine in 350 ml of methanol. This mixture is stirred for 2 h at room temperature and left to stand overnight. The methanol is evaporated, the residue is dissolved in diethyl ether and the organic phase is washed with water, and then dried and concentrated, obtaining yellow butter-like product, which is purified by distillation to produce in the form of colorless liquid 102 g bromobenzylcyanide ether.

Boiling point under a residual pressure of 17 mm RT. Art.: 112 - 114oC.

b) Synthesis of 3-cyano-2-(4-methoxymethyl)pyridine.

2 g of 4-bromobenzylamine ether obtained in the above, added to a suspension of 18 g of magnesium in 50 ml of anhydrous THF. The formation of magnesium compounds trigger a few crystals of iodine and, if necessary, by heating in a bath of warm water. The solution level of 121.8 g of 4-bromobenzylamine ester in 200 ml of anhydrous THF is injected dropwise so that the overpressure of nitrogen injected 800 ml of solution zinc chloride in diethyl ether. The resulting white precipitate is formed. The reaction components can be performed during 1 h 30 min at room temperature. Add 800 mg of the catalyst of the reaction of a combination of bis-(triphenylphosphine)-Nickel(II)chloride, [NiP(phenyl)3]2Cl2and then enter solution 76.9 g of 2-chloronicotinoyl in 300 ml of THF. The mixture is stirred over night at room temperature and concentrated in vacuo. Next, the concentrate is dissolved in a mixture of 1 l of dichloromethane with 1 l of water 1 l of disodium salt of ethylenediaminetetraacetic acid. The emulsion is filtered by the material of Celite 545. The organic phase is decanted, washed with water, dried and concentrated, obtaining 133,6 g orange butter-like product, which is purified by two sequential chromatographic treatments (eluent: a mixture of 95% chloroform with 5% diethyl ether). Thus, in the form of orange butter-like product highlight is 69.4 g of 3-cyano-2-(4-methoxymethyl)pyridine, which crystallizes.

Melting point: 74oC.

c) Obtaining 3-cyano-2-(4-bromomethylphenyl)pyridine.

Formula (IV): W - bromo.

< / BR>
to 69.4 g of 3-cyano-2-(4-methoxymethyl)pyridine obtained in the preceding stage, are dissolved in 700 ml of chloroform, stabilisierung revisal 5oC, enter solution 66 ml tribromide boron in 200 ml of chloroform, stabilized amilina. The mixture is left for 1 h 30 min in an ice bath. After that, her first hydrolyzing the ice, and then water. After filtration of the suspension is dissolved in a mixture of water and chloroform. Then hold the decantation and the combined organic phases, dried and then concentrated, receiving 78.2 g painted in cream color crystals 3-cyano-2-(4-bromomethylphenyl)pyridine.

Melting point: 118oC.

d) Obtaining ethyl-2-[4-(3-cyano-2-pyridyl)benzyl]- 3-oxohexanoate.

Formula (V): -CH2-CH2-CH3, R8-O-ethyl,

< / BR>
In accordance with the procedure of example 5, the target derivative is obtained in the form of orange butter-like product, which is used as such in the next stage.

Example 12. Ethyl-2-[4-(3-cyano-2-thienyl)-benzyl]-3 - oxohexanoate.

Formula (V): -CH2-CH2-CH3, R8-O-ethyl,

< / BR>
a) Obtaining 4-chloro-1-(4-were)butanone.

A mixture of 560 ml of 4-chlorobutyronitrile with 550 ml of toluene are added dropwise to the suspension 740 g trichloride aluminum in 2 l of dichloromethane, and the temperature maintained within the range from 10 to 15oC. Reacts the practical phase is separated, and the aqueous phase is subjected to extraction treatment with dichloromethane. The combined organic phases are washed with water and then dried and concentrated in vacuo to obtain 994,5 g of 4-chloro-1-(4-were)butanone in the form of a butter-like product, which is used in the next stage without additional purification.

b) Obtaining 3-chloro-2-(2-chloroethyl)-3-(4-were)-prop - 2-EN-1-Ala.

390 ml POC13dropwise at a temperature of from 7 to 12oC enter into solution AZN 352.5 g of 4-chloro-1-(4-were)butanone obtained in the foregoing example 12 (a), 450 ml of DMF. The temperature was raised gradually: in the first case, up to 50oC for 2 h, and then up to 75oC for 45 minutes the Mixture was poured into ice three times and subjected to extraction processing diethyl ether, then the combined organic phases are washed with water and dried, followed by evaporation, resulting in the form of a butter-like product get 387,8 g of 3-chloro-2-(2-chloroethyl)-3-(4-were)prop - 2-EN-1-al, which is used as such at a later stage.

c) Obtaining 4,5-dihydro-3-formyl-2-(4-were)-thiophene.

A mixture of 200 g of 3-chloro-2-(2-chloroethyl)-3-(4-were)- prop-2-EN-1-al obtained in the experiment of example 12b), with 2.2 l of THF, 276,5 g is t in vacuum and the concentrate is dissolved in water, then three times subjected to extraction processing diethyl ether. The combined organic phases are washed with water, dried and concentrated, obtaining 170,3 g butter-like product, which crystallizes.

Melting point: below the 50oC.

d). Obtaining 4,5-dihydro-3-formyl-2-(4-were)-thiophenoxide.

132,1 g hydroxylaminopurine individual added in several portions in a solution 323,5 g of the aldehyde obtained as described in example 12 (c), in 800 ml of ethanol. Then added dropwise a solution of sodium carbonate prepared from 100,5 g of carbonate and 700 ml of water. The mixture was kept at a temperature of 40oC for 5 min, after which the reaction is left to proceed at room temperature for 1 h the Mixture is cooled to a temperature of 15oC and the solid material is filtered and washed with water and then with a mixture of 50% isopropyl ester with 50% petroleum ether, getting 252 g of the oxime. In the extraction processing of the filtrate with dichloromethane get the 2nd portion of the 99 g total number of target oxime.

e). Obtain 3-cyano-4,5-dihydro-2-(4-were)thiophene.

The solution 171,8 g of the oxime obtained by described in example 12 (d), in 680 ml of acetic acid and distilled, getting 115,3 g nitrile derivative.

Boiling point under a residual pressure of 0.05 mm RT.article: 140 - 150oC.

f). Obtain 3-cyano-2-(4-were)thiophene.

62 ml of bromine dropwise introduced into the solution, preheated to a temperature of 50oC, 1191,3 g of the nitrile obtained as described in example 12 (e), 1.85 l of carbon tetrachloride. The whole mass is refluxed until the termination of allocation of HBR. Carbon tetrachloride is evaporated and the residue is distilled, getting 115,3 g 3-cyano-2-(4-were)thiophene.

Boiling point under a residual pressure of 0.05 - 0.1 mm RT.article: 130 - 150oC.

g) 2-(4-bromomethylphenyl)-3-cyanothiophene.

Formula (IV): W - bromo,

< / BR>
of 182.2 g of compound obtained in the foregoing example 12 (f), bromilow as described in example 4, receiving 133,7 g of 2-(4-bromomethylphenyl)-3-cyanothiophene.

Melting point: 80 - 84oC.

b) Ethyl-2-[4-(3-cyano-1-thienyl)-benzyl]-3-oxohexanoate.

Formula (V): -CH2-CH2-CH3, R8- O-ethyl,

< / BR>
A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene obtained in the above with 40 g of ethyl-3-okage is ipatt under reflux for 15 hours Next, the mixture was concentrated in vacuo, add a dilute solution of hydrochloric acid and subjected to extraction treatment with ethyl acetate. The combined organic phases are washed with water, dried and evaporated, receiving in the form of a butter-like product of 62.4 g of ethyl-2-[4-(3-cyano-2-thienyl)-benzyl] -3-oxohexanoate, which is used without further purification.

Example 13. Ethyl-2-[4-(3-cyano-2-furyl)benzyl]-3-oxohexanoate.

Formula (V): -CH2-CH2-CH3, R8- O-ethyl,

< / BR>
a). Obtaining 2-( 4-were)-3 - furan acid.

to 70.7 g of p-toluidine, cooled in a water bath with ice, treated with 205 ml of 36% hydrochloric acid. The mixture is then stirred at a temperature of 55 - 60oC for 30 min followed by re-cooling to a temperature of 0oC. Next, the mixture is injected a solution of 45 g of sodium nitrite in 220 ml of water. The mixture is stirred for 1 h at 0oC. This cold solution is injected into cooled to a temperature of -5oC mixture of 49.3 g of 3-furan acid with 220 ml of acetone, and 23.4 g of the dichloride of copper and 6.3 g of water. The whole mass is stirred at a temperature of 0oC for 2 h and then at room temperature for 48 hours Then it is subjected to a double extraction processing is the which when treated with water gives crystals. These crystals are filtered and washed with 50 ml of a mixture of 50% methanol with water, getting a 13.4 g of 2-(4-were)-3-furan acid.

Melting point: 166oC.

b) Obtaining 2-(4-were)-furan-3-carboxamide.

20 ml of thionyl chloride are added to a solution of 13.4 g of furan acid obtained in the above, in 70 ml of toluene. This mixture is refluxed for 3 h and then distilled off the excess chloride tiomila and toluene, getting a butter-like product in which at a temperature of 5oC carry out the reaction with a solution of 100 ml of 1,2-dimethoxyethane saturated with ammonia. The precipitation is filtered and washed with water and then with isopropyl alcohol to obtain 7 g of white crystals of amide.

Melting point: 174oC.

c) Obtaining 3-cyano-2-(4-were)furan.

A mixture of 12.2 g of the amide obtained in the above, and 65 ml of thionyl chloride is refluxed for 3 h and concentrated in vacuo. Received butter-like product is dissolved in chloroform and then add the mixture of water with ice. After decanting, the aqueous phase is subjected to extraction treatments is STCA chromatographic processing on silica gel (eluent: toluene) to give 7.5 g butter-like product, which crystallizes.

Melting point: 66oC.

d) 2-(4-bromomethylphenyl)-3-cianfuran.

Formula (IV): W - bromo,

< / BR>
7.5 g of the compound obtained in the foregoing example 13 (c), bromilow as described in example 4, after receiving chromatographic purification treatment on silica gel (eluent: a mixture of 50% pentane with 50% toluene) of 4.6 g of 5-bromo-3-cyano-2-(4-were)-furan (melting point: 88oC), 2.2 g of 5-bromo-3-cyano-2-(4-bromomethylphenyl)-furan (melting point: 114oC) and 2 g of 2-(4-bromomethylphenyl)-3-cianfuran.

Melting point: 108oC.

Conduct additional reaction of the synthesized 5-bromo-3-cyano-2-(4-were)-furan in accordance with the foregoing example 4, resulting in a gain of 5-bromo-2-(4-bromomethylphenyl)-4-cyanobutane, which is a compound of example 13 (d) of bis.

e) Ethyl-2-[4-(3-cyano-2-furyl)benzyl]-3-oxohexanoate.

Formula (V): -CH2-CH2-CH3, R8- O-ethyl,

< / BR>
Derived 2-(4-bromomethylphenyl)-3-cianfuran treated as described in example 5, receiving ethyl-2-[4-(3-cyano-2-furyl)benzyl] -3-oxohexanoate in the form of a butter-like product is ω-2-(4-bromomethylphenyl)- 3-cianfuran of example 13d) bis processed in accordance with the foregoing example 5, receiving in the form of a butter-like product ethyl-2-[4-(5-bromo-3-cyano-2-furyl)benzyl] oxohexanoate, which is a product of the experiment of example 13 bis.

Example 14. 3-[(2'-cyanobiphenyl-4-yl)-methyl]-2,4-dioxetane.

Formula (V): - methyl, R8is methyl,

< / BR>
32,8 g of 2,4-dioxopentanoate, 69 g of 4'-methyl bromide-2-cyanobiphenyl obtained in the foregoing example 4, 88 ml of Diisopropylamine and 10.6 g of anhydrous lithium chloride in 300 ml of tetrahydrofuran is refluxed for 27 hours the Mixture is cooled and the precipitate filtered off. The organic phase is concentrated to dryness, obtaining and 88.5 g of crystals. They are dissolved in isopropanol and the mixture is filtered, allocating to 38.8 g of unreacted 4'-methyl bromide-2-cyanobiphenyl. The concentrated mother liquor gives 26,5 g butter-like product, after purification on silica gel (eluent: chloroform) gives in addition of 5.3 g of 4'-methyl bromide-2-cyanobiphenyl and 12.2 g of the target 3-[(2'-cyanobiphenyl-4-yl)methyl] -2,4-dioxopentanoate in the form of yellow butter-like product.

Example 15. 5-[(2'-cyanobiphenyl-4-yl)-methyl]-4,6-dioxanone.

Formula (V): -CH2-CH2-CH3, R8-CH2-CH2-CH3< / BR>
< / BR>
15.6 g of 4,6-dioxanonane, poluchennogo the 9f), dissolved in 160 ml of anhydrous DMF. In the form of portions add 4 g of 60% sodium hydride. After attenuation of the exothermic effect of the mixture is cooled to room temperature and added dropwise into it, introduce a solution of 27.2 g of 4'-methyl bromide-2-cyanobiphenyl obtained in the foregoing example 4, in 90 ml of DMF. The mixture is stirred for 30 min at room temperature and then for 2 h and maintained at a temperature of 60oC. It was concentrated in vacuo and the concentrate was dissolved in a mixture of water with dichloromethane and acidified with diluted hydrochloric acid. After decanting, the aqueous phase is subjected to a double extraction processing dichloromethane. The organic phase is washed with water, dried and then concentrated to obtain 36,3 g butter-like product, which is purified by two sequential chromatographic treatments (eluent: chloroform and then a mixture of 90% cyclohexane with 10% ethyl acetate) to give a solid product, which according to the NMR spectrum, is the enol tautomerism with a melting point 105oC, and butter-like product that matches diketonato tautomeric form.

Example 16. - 2,4-dioxo-3-[(2'-(1H-tetrazol-5-yl)-diphenyl-4-yl) methyl] pentane.

The mixture is cooled and concentrated to obtain a viscous butter-like product, which, after chromatographic processing on silica gel (eluent: a mixture of 90% chloroform, 10% methanol) to give 9.3 g of crystals.

As a result of additional processing acetonitrile obtain 6.2 g of analytically pure 2,4 dioxo-3-[(2'-(IH-tetrazol-5-yl)-diphenyl - 4-yl)methyl] pentane.

The empirical formula of the compound: C19H18N4O2.

Melting point: 166oC.

Example 17. Ethyl-2-([2'-(1H-tetrazol-5-yl)diphenyl-4-yl] methyl)-3 - oxohexanoate.

Formula (V): - H-propyl, R8- O-ethyl,

< / BR>
A mixture of 69.9 g of ethyl-2-[(2'-cyanobiphenyl-4-yl)-methyl]- 3-oxohexanoate obtained in accordance with the foregoing example 5, with 700 ml of anhydrous toluene and 47,5 g azide trimacinolone obtained from sodium azide and chloride trimethylamine, refluxed for 24 hours Add an additional 47,5 g azide trimacinolone and boiling under reflux is avatarname chromatographic treatments (eluent: a mixture of 90% chloroform and 10% methanol, and then a mixture of 95% chloroform and 5% methanol), resulting in a gain of 58 g orange butter-like product, which crystallizes.

Melting point: 65oC.

Example 18 (method A). 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-5 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIa): - n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
1.7 g of 3-amino-1,2,4-triazole, 7 g of beta-keeeper obtained in the foregoing example 5, and 30 ml of acetic acid is refluxed for 6 hours Acetic acid is evaporated. Received butter-like product was then purified by chromatographic processing on silica gel (eluent: a mixture of 90% chloroform, 10% methanol) to give 5.2 g of the original beta keeeper and 1.2 g of 6-[(2'- cyanobiphenyl-4-yl)-methyl]-7-hydroxy-5-propyl-1,2,4-triazolo-(1,5-a) pyrimidine.

Melting point: 200 - 205oC.

1H-NMR spectrum (200 MHz: DMCO-d6):to 2.65 (t, 2H, propyl CH2), and 8.2 (c. 1H, H2).

UV spectrogram (10 μg/ml, methanol): lambdaa= 209,1 nm, lambdab= 257,7 nm, lambdac= 286,8 nm.

Example 19 (method B). 6-[(2'-cyanobiphenyl-4-yl)-methyl]-5-hydroxy-7 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): - n-prop example 5 1.7 g of 3-amino-1,2,4-triazole and 70 ml of 1,2,4-trichlorobenzene is refluxed for 7 hours the Mixture is then concentrated in vacuo. After chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol) obtained a thick butter-like product highlight 0.8 g of isomer obtained in the experiment of example 18 (melting point: 200oC), and 2.2 g of 6-[(2'-cyanobiphenyl-4-yl)-5-hydroxy-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Melting point: 212oC.

1H-NMR spectrogram (DMCO-d6): 2,98 (t, 2H, propyl CH2), 8,1 (C., 1H, H2).

UV spectrogram (10 μg/ml, methanol): lambdaa= 207,5 nm, lambdab= 258,2 nm.

Example 20 (method C). 6-[(2'-cyanobiphenyl-4-yl)-5-hydroxy-7 - propyl-1,2,4-triazolo(4,3-a)pyrimidine.

Formula (VIIa): R'1- n-propyl, X is CH, Y is a nitrogen atom, a hydroxyl,

< / BR>
a) 5-[(2'-cyanobiphenyl-4-yl)methyl]-4-hydroxy-6-propyl-2 - mercaptopyrimidine.

11 g of thiourea with a spatula and add a solution of sodium methylate prepared from 4.6 g of sodium and 150 ml of methanol. Then the solution is added dropwise to 34.9 g of beta-keeeper obtained according to the above example 5, dissolved in 50 ml of methanol. The mixture is left to stadtrat dissolved in 500 ml of water, followed by acidification with concentrated hydrochloric acid to pH 1. Resinous precipitate is isolated and dissolved in methanol, receiving 17.3 g of white crystals 5[(2'-cyanobiphenyl-4-yl)methyl]-4-hydroxy-6-propyl-2-mercaptopyrimidine.

Melting point: 196oC.

b) 5-[(2'-cyanobiphenyl-4-yl)-methyl]-4-hydroxy-2-methylmercapto-6 - propylpyrimidine.

Formula (XI): R1-n-propyl, R2- OH,

< / BR>
17.3 g of the compound obtained in the above, is administered in individual portions in a mixture of 340 ml of methanol and 2.9 g of potassium hydroxide. After formation of a transparent solution is cooled and then added dropwise 3.4 ml under the conditions. This mixture is left at room temperature for reaction for 2 hours the Precipitate is filtered off with obtaining and 17.2 g of 5-[(2'-cyanobiphenyl-4-yl)-methyl]-4-hydroxy-2-methylmercapto-6-propyl - pyrimidine.

Melting point: 220oC.

c) 5-[(2'-cyanobiphenyl-4-yl)methyl-2-hydrazino-4-hydroxy-6 - propylpyrimidine.

Formula (X): R1-n-propyl, R2is hydroxyl,

< / BR>
12.4 g of 5-[(2'-cyanobiphenyl-4-yl)-methyl]-4-hydroxy-2-methylmercapto-6 - propylpyrimidine obtained in the above, dissolved in 370 ml of 2-methoxyethanol. Enter 33 ml of hydrazine hydrate is added and the mixture is then refluxed for 3 hours It koncentrerat and washed with diethyl ether and isopropyl ether to obtain 9,9 g of 5-[(2'-cyanobiphenyl-4 - yl)methyl]-2-hydrazino-4-hydroxy-6-propylpyrimidine.

Melting point: 191oC.

d) 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-7-propyl-1,2,4 - triazolo(4,3-a)pyrimidine.

Formula (VIIa): - n-propyl, X is CH, Y is a nitrogen atom, R10is hydroxyl,

< / BR>
10 g of 5-[(2'-cyanobiphenyl-4-yl)methyl]-2-hydrazino-4-hydroxy-6 - propylpyrimidine obtained in the above, is introduced into 100 ml of formic acid. The mixture is refluxed for 4 hours Its concentrated under reduced pressure and the resulting thick butter-like product is placed in water and grind to crystallization. This compound is purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol). The result of 8.3 g of 6-[(2'-cyanobiphenyl-4-yl)-methyl]-5-hydroxy-7-propyl-1,2,4 - triazole(4,3-a)pyrimidine.

Melting point: 217oC.

1H-NMR spectrogram (DMCO-d6): of 2.6 (t, 2H, propyl CH2), 9 (C., 1H, H3).

UV spectrogram (10 μg/ml, methanol): lambdaa= 210,2 nm, lambdab= 257,5 nm, lambdac= 303,4 nm.

Example 21. 6-[(2'-cyanobiphenyl-4-yl)-methyl]-7-hydroxy-5-propyl - 1,2,4-triazolo(4,3-a)pyrimidine.

Formula (VIIb): -n-propyl, X is CH, Y is a nitrogen atom, R10is hydroxyl,

< / BR>
In accordance with procedural-1,2,4-triazolo(4,3-a)pyrimidine.

Melting point: 204 - 206oC.

1H-NMR spectrogram (DMCO-d6): or 2.9 (t, 2H, propyl CH2), 9 (C., 1H, H3).

UV spectrogram (10 μg/ml, methanol): lambdaa= of 211.5 nm, lambdab= 260 nm.

The compound of examples 20 and 21 can also be obtained by reaction of the compound of example 20 (c) with triethylorthoformate boiling under reflux for 5 hours In this case the proportion of the compound of example 21 is determined to be somewhat more substantial.

Example 22 (method D). 6-[(2'-cyanobiphenyl-4-yl)methyl]-7 - hydroxy-5-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIa): -n-propyl, X is a nitrogen atom, Y is CH, R10- hydroxyl.

< / BR>
500 mg 6-[(2'-cyanobiphenyl-4-yl)-methyl]-5-hydroxy-7-propyl-1,2,4 - triazolo(4,3-a)pyrimidine, obtained by the described in example 20 d), kept in a metal bath at a temperature of 225oC for 2 h 30 min Then leave it to cool and then transferred to methanol, after which the ethyl acetate, receiving 300 mg painted in cream color crystals, identical to the crystals of the compound of example 18.

Example 23 (method E). 6-[(2'-cyanobiphenyl-4-yl)-methyl]-5 - hydroxy-7-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): -n is rimidine heated to a temperature of 175oC. dropwise it introduced 100 g of beta-keeeper obtained in the foregoing example 5, dissolved in 100 ml of 5-ethyl-2 - methylpyridine. The reaction mixture was kept for reaction for 6 hours at a temperature of 175oC. In vacuum distilled arylmethylidene and the residue was transferred to a mixture of water and chloroform. After decanting, the aqueous phase is subjected to extraction treatment with chloroform. The combined organic phases are washed with diluted hydrochloric acid and then water, dried and concentrated to obtain butter-like product, which when crushed crystallized in methanol. As a result of recrystallization from n-butanol gain of 35.2 g painted in cream color crystals of 6-[(2'- cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Melting point: 210oC.

In the treatment of uterine solutions chromatographic processing on silica gel to get the second portion of 6.9 g of target compound together with a 13.9 g of compound 6-[(2'-cyanobiphenyl-4 - yl)methyl]-7-oxo-5-propyl-1,2,4-triazolo(1,5-a)pyrimidine) obtained in above in example 18.

Melting point: 196oC.

The addition of 10.5 g of 4-dimethylene/P> Example 24. Hemihydrate-6-[(2'-cyanobiphenyl-4-yl)-methyl]-7-hydroxy-2-methyl-5-propyl - 1,2,4-triazolo(1,5-a)pyrimidinethione.

Formula (VIIa): -n-propyl, X is a nitrogen atom, Y is C-CH3, R10is hydroxyl,

< / BR>
A suspension of 10 g of compound of example 20) in 100 ml of phenylacetate refluxed for 4 hours Its concentrated under reduced pressure. The concentrate is dissolved in water and subjected to extraconal treatment with chloroform, after which the extract is dried and evaporated to obtain 9.8 g of white crystals, melting at 205oC. These crystals are dissolved in 50 ml of acetonitrile and 40 ml of 10% hydrochloric acid solution in diethyl ether, obtaining 7.5 g of 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-2-methyl-5-propyl-1,2,4-triazolo(1,5-a) pyrimidinethione.

The empirical formula of the compound:

C23H21N5OHCl(1/2)H2O

Melting point: 190oC.

1H-NMR spectrogram (DMCO-d6); to 2.65 (t, 2H, propyl CH2).

UV spectrum (methanol): lambdaand=213,7 nm, lambdab=257,7 nm, lambdawith= 285 nm.

Example 25. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-propyl-3-mercapto-1,2,4-triazolo (4,3-a)pyrimidine.

Formula (VIIa): -n is inane, received set forth in example 20) in 300 ml of butanol. This mixture is refluxed for 2 hours Add an additional 5,3 ml gray-carbon and boiling is then continued for 5 hours the Mixture was concentrated in vacuo. The concentrate is dissolved in water three times and subjected to extraction treatment with chloroform. The solvent is evaporated to obtain 10.8 g of amorphous crystals, which are purified by chromatographic on silica gel (eluent: a mixture of 90% chloroform, 10% methanol).

The first connection in the amount of 1.9 g is isolated and identified as 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-hydroxy-5-propyl-3-mercapto-1,2,4 - triazole(4,3-a)pyrimidine. He is a product of the experiment of example 25 bis.

Melting point: 240oC.

1H-NMR spectrogram (DMCO-d6): 3,5 (t, 2H, propyl CH2).

A second connection in the amount of 1 g is a target product, namely 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-7-propyl-3-mercapto - 1,2,4-triazolo(4,3-a)pyrimidine.

Melting point: 180oC.

1H-NMR spectrogram (DMCO-d6): 2,5 (m, propyl CH2+ DMCO - d6).

The third product in the amount of 6.2 g is C-7-propyl-1,2,4 - triazolo(4,3-a)pyrimidine.

Formula (VIIa): -n-propyl, X is C-OH, Y is a nitrogen atom, R10is hydroxyl,

< / BR>
4.6 g of carbonyldiimidazole added to a mixture of 10 g of the compound obtained by the described in example 20), with 500 ml of THF, heated to a temperature of 50oC. the Whole mass is refluxed for 7 h and concentrated in vacuo. The concentrate is dissolved in water three times and subjected to extraction treatment with chloroform. Evaporation of solvent gives 12.4 g of amorphous crystals, which are purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

The first connection in the amount of 3.1 g isolated and identified as 6-[(2'-cyanobiphenyl-4-yl)-methyl] -3,7-deoxy-5-propyl-1,2,4-triazolo(4,3-a) pyrimidine. He is a product of the experiment of example 26 bis.

Melting point: 228oC.

1H-NMR spectrogram (DMCO-d6): 3 (t, 2H, propyl CH2).

A second connection in the amount of 3.8 g represents the target product, namely 6-[(2'-cyanobiphenyl-4-yl)-methyl] -3,5-deoxy-7-propyl-1,2,4-triazolo(4,3-a) pyrimidine.

Melting point: 210oC.

1H-NMR spectrogram (DMCO-d6): 2,4 (t, 2H, propyl CH2).

Example 27. 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-2-methyl-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is C-CH3, R10is hydroxyl,

< / BR>
Conduct crystallization from methanol. Royal solutions cleanse chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Melting point: 218-220oC.

A second connection is isolated and identified as 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-hydroxy-2-methyl-5-propyl-1,2,4-triazolo (1,5-a)pyrimidine. He is a product of the experiment of example 27 bis.

Formula (VIIa): -n-propyl, X is a nitrogen atom, Y is C-CH3, R10is hydroxyl,

< / BR>
Melting point: 204 - 206oC.

Example 28. 6-[(2'-cyanobiphenyl-4-yl)methyl] -2-ethyl-5-hydroxy-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is C-CH2-CH3, R10is hydroxyl,

< / BR>
Conduct crystallization from methanol. Royal solutions cleanse chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Formula (VIIa): -n-propyl, X is a nitrogen atom, Y is a group C-CH2-CH3, R10is hydroxyl,

< / BR>
Melting point 186oC.

Example 29. 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-n-butyl-5-hydroxy-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
The compound is purified by recrystallization from n-butanol.

Melting point: 210oC.

Example 30. 2-amino-6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is C-NH2, R10is hydroxyl,

< / BR>
Conduct crystallization from a mixture of methanol and chloroform.

Purification of mother solutions chromatographic processing on silica gel(eluent: a mixture of 90% chloroform, 10% methanol).

Melting point: 260oC.

A second connection is isolated and identified as 2-amino-6-[(2'-cyanobiphenyl-4-yl)methyl] -7-hydroxy-5-propyl-1,2,4 - triazolo(1,5-a)pyrimidine. It is a product of the experiment of example 30 bis.

Formula (VIIa): - n-propyl, X is a nitrogen atom, Y is C-NH2, R10is hydroxyl,

< / BR>
Temperatuare(1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is C-SCH, R10is hydroxyl,

< / BR>
The chromatographic purification treatment on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Crystallization from isopropylacetate.

Melting point: 182oC.

Example 32. 6-[4-(3-cyano-2-thienyl)benzyl]-5-hydroxy-7-propyl-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Crystallization from a mixture of chloroform and water. Purification by recrystallization from 2-methoxyethanol.

Melting point: 246oC.

Example 33. 6-[4-(3-cyano-2-pyridyl)benzyl]-5-hydroxy-7-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Crystallization from methanol. Royal solutions cleanse chromatographic processing on silica gel (eluent: a mixture of 97.5% dichloromethane with 2.5% methanol). The whole mass purified by recrystallization from methanol.

Melting point: 212oC.

Example 34. 6-[4-(3-cyano-2-thienyl)benzyl] -5-hydroxy-2-methyl-7 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is C-CH, R10is hydroxyl,

< / BR>
Crystallize the effect: 277oC.

Example 35. 6-[4-(3-cyano-2-furyl)benzyl] -5-hydroxy-7-propyl-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (VIIb): -n-propyl, X is a nitrogen atom, Y is CH3, R10is hydroxyl,

< / BR>
Melting point: 256oC.

Example 36. 7-butyl-6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-2-methyl-1,2,4-triazolo (1,5-a)pyrimidine.

Formula (VIIb): -n-butyl, X is a nitrogen atom, Y is C-CH3, R10is hydroxyl,

< / BR>
Connection purified by recrystallization from n-butanol.

Melting point: 230oC.

Example 37. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-2-oxymethyl - 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): -N-propyl, X is a nitrogen atom, Y is C-CH2OH, R10is hydroxyl,

< / BR>
Purified chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Melting point: 214oC.

Example 38. 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydroxy-7-methoxymethyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): - -CH2-OCH3X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Clean chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol)

Melting point: 188oC.

The second soedin. He is a product of the experiment of example 38 bis.

Formula (VIIa): -CH2-OCH3X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Melting point: 240oC.

Example 39. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-methyl - 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIb): - CH3X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
This product was then purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol) and crystallized from methanol.

Melting point: 212oC.

A second connection is isolated and identified as 6-[(2'-cyanobiphenyl-4-yl)-methyl] -7-hydroxy-5-methyl-1,2,4-triazolo (1,5-a)pyrimidine. He is a product of the experiment of example 39 bis.

Formula (VIIa): - methyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Melting point: 252oC.

Example 40. 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-ethyl-5-hydroxy-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (VIIb): - ethyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Allocate chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol) and purified by recrystallization from n-butanol.

The temperature of the PLA is XI-1,2,4-triazolo(1,5-a)pyrimidine. He is a product of the experiment of example 40 bis.

Formula (VIIa): - group-CH2-CH3X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Melting point: 234oC.

Example 41. 6-[(2'-cyanobiphenyl-4-yl)methyl]-2-N,N-diethylamino-5-hydroxy-7-propyl-1,2,4-triazolo-(1,5-a)pyrimidine.

Formula (VIIb): - n-propyl, X is a nitrogen atom, R10is hydroxyl,

< / BR>
This product is crystallized from methanol.

Melting point: 220oC.

A second connection emit after chromatographic treatment of uterine solutions on silica gel (eluent: a mixture of 80% chloroform with 20% of Isopropylamine) in the form of amorphous crystals. Its identified as 6-[(2'-cyanobiphenyl-4-yl)methyl]-2-N,N-diethylamino-7-oxo-5-propyl-1,2,4 - triazolo(1,5-a)pyrimidine. It is a compound of example 41 bis.

The formula (VIIa): -n-propyl, X is a nitrogen atom , R10is hydroxyl,

< / BR>
Example 42. 6-[2'-cyanobiphenyl-4-yl)methyl] -5,7-dipropyl-1,2,4-triazolo(1,5-a)pyrimidine

Formula (VIIa): -n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
The product was then purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

The melting temperature of 16 is.

Formula (VIIb): -group-CH2-O-CH3is phenyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Purify by recrystallization from butanol, followed by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Melting point: 218oC.

A second connection is isolated and identified as 5-benzoyloxymethyl-6-[(2'-cyanobiphenyl-4-yl)methyl] -7-hydroxy-1,2,4-triazolo (1,5-a)pyrimidine. He is a product of the experiment of example 43 bis.

Formula (VIIa): -group-CH2-O-CH2is phenyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Melting point: 260oC.

Example 44. 5-chloro-6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIIb): -n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
of 25.9 g of the compound obtained according to the described above in example 19 or 23, the individual portions added to 260 ml of POCl3. The mixture is refluxed for 4 hours It was concentrated in vacuo, the concentrate was dissolved in 200 ml of chloroform, stabilized amilina, and then add the mixture of water with ice. After decanting, the aqueous phase is subjected to extraction treatment with chloroform, and the organic product. This product crystallized from isopropylacetate, resulting in a gain of 21 g of 5-chloro-6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4 - triazolo-(1,5-pyrimidine).

Melting point: 138oC.

Using the product obtained in the experiment of example 18, to obtain a derivative of example 45.

Example 45 7-chloro-6-[(2'-cyanobiphenyl-4-yl)methyl] -5-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (VIIIa): -n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
Melting point: 132oC.

Example 46. 6-[(2'-canadianr-4-yl)methyl]-7-mercapto-5-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Formula (IX): -SH, R2-n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
A mixture of 5 g of chlorinated compounds, obtained by the described in example 45, 2 g of thiourea and 150 ml of ethanol is refluxed for 7 h and concentrated in vacuo. The obtained yellow solid material was dissolved in 60 ml of 0.5 n sodium hydroxide solution. A small amount of insoluble material is filtered off. The filtrate is acidified with acetic acid. Precipitated precipitated yellow product is filtered and purified by chromatographic processing on silica gel (eluent: a mixture of 90% chloroform, 10% methanol) to give 3,deposits: 200 - 205oC.

Example 47. 6-[(2'-cyanobiphenyl-4-yl)methyl)-5-mercapto-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (IX): -n-propyl, R2Is SH, X is a nitrogen atom, Y is CH,

< / BR>
A mixture of 11.1 g of the product obtained in the experiment of example 19 or example 23, with 350 ml of toluene and 13.4 g of reagent Lawesson refluxed for 2 hours Obtained yellow solid material is filtered off. The chromatographic purification treatment on silica gel (eluent: a mixture of 90% dichloromethane with 10% acetone) to give 10 g of 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-mercapto-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Melting point: 226oC.

Example 48. 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-propyl-1,2,4-triazolo-(1,5-a)pyrimidine.

Formula (IX): -n-propyl, R2hydrogen atom, X is a nitrogen atom, Y is CH,

< / BR>
A solution of 5.4 g of the compound obtained in the experiment of example 44, 110 ml of 2-methoxyethanol containing 1.2 g of anhydrous sodium acetate, hydrogenized under atmospheric pressure and at room temperature in the presence of 1.4 g of 5% palladium on coal. Through the system nitrogen purge. The catalyst is filtered off and washed with hot 2-methoxyethanol. Filter and concentrate the obtained crystals resturuant: a mixture of 90% dichloromethane with 10% acetone) to give 2.5 g of white crystals of 6-[(2'-cyanobiphenyl-4-yl)methyl-7-propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Melting point: 180oC.

Example 49. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-methoxy-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (IX): -n-propyl, R2-OCH3X is a nitrogen atom, Y is CH,

< / BR>
A solution of sodium methylate prepared from 0.8 g of sodium and 25 ml of methanol, add in a solution of 11.6 g of compound of example 44 in 120 ml of 1,2-dimethoxyethane. The mixture is stirred at room temperature for 3 hours, the Insoluble material is filtered and the filtrate concentrated. The obtained crystals are transferred into water, filtered and washed first with water and then with isopropyl alcohol and diethyl ether, receiving 9.5 g 6[(2'-cyanobiphenyl-4-yl)methyl]-5-metoxi-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Melting point: 166oC.

Example 50. These-{6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine-5-yl}-mercaptoacetate.

Formula (IX): -n-propyl, R2-group-S-CH2-COO-CH2-CH3X is a nitrogen atom, Y is CH,

< / BR>
0.6 g of 60% sodium hydride in individual portions added to a solution of 1.8 g of ethylmercaptan in 50 ml of toluene. The mixture was kept at a temperature of 40oC for 1/2 h and then cooled to room temperature. Then enter rest is arranged at room temperature for 3 h, then at a temperature of 50oC for 4 h To complete the reaction add a second equivalent of sodium salt of ethylmercaptan obtained by the foregoing. After hydrolysis and decanting, the organic phase is washed with water, and then diluted solution of acetic acid, dried and concentrated. Received butter-like product was then purified by chromatographic processing on silica gel (eluent: a mixture of 90% dichloromethane with 10% acetone), resulting in a gain of 5.4 g of ethyl-{6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4 - triazolo(1,5-a)pyrimidine-5-yl}mercaptoacetate.

Melting point: 76oC.

The compound of example 51 receive in accordance with the procedure of example 50, but using 2-methoxyethanol instead of ethylmercaptan.

Example 51. { 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-propyl-1,2,4 - triazolo(1,5-a)pyrimidine-5-yl}-2-methoxyethylamine ether.

Formula (IX): -n-propyl, R2band-O-CH2-CH2-OCH3X is a nitrogen atom, Y is CH,

< / BR>
The product is crystallized from isopropyl ether.

Melting point: 102oC.

Example 52. 5-amino-6-[(2'-cyanobiphenyl-4-yl)methyl] -7-propyl - 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): -n-PR is ment of example 44, with 200 ml of 1,2-dimethoxyethane, saturated with ammonia, are loaded into the autoclave. Its contents are maintained at a temperature of 125oC for 24 h and transferred to a mixture of chloroform and water. After decanting, the aqueous phase is subjected to extraction treatment. The combined organic phases, dried and concentrated to obtain 8.1 g of 5-amino-6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Melting point: 206oC.

Example 53. 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-N, N-diethylamino-5 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): -n-propyl, R1- N(CH2-CH3)2X is a nitrogen atom, Y is CH.

< / BR>
A mixture of 5 g of the chlorinated derivative of example 45 with 100 ml of ethanol, 16 ml of diethylamine and 1.5 g of sodium carbonate is refluxed for 4 hours Then concentrated in vacuo and the resulting thick butter-like product is transferred into the water. Three times conduct extraction processing dichloride, the extracts dried and concentrated. The compound obtained purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol), receiving in the form of orange butter-like product 5 g of 6-[(2'-cyanobiphenyl-4-yl)-methyl] -7-N, N-diethyl-the Ana in examples 44 and 45, with the corresponding amines according to one of the two methods described in examples 52 and 53 receive the following compounds of examples 54 through 58.

Example 54. 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-N, N-diethylamino-7 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, R2group N(CH2-CH3)2X is a nitrogen atom, Y is CH,

< / BR>
The product is crystallized from hot isopropyl ether.

Melting point: 133oC.

Example 55. 6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-5- (pyrrolidin-1-yl)-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
The product is crystallized from hot isopropyl ether.

Melting point: 166oC.

Example 56. 6-[(2'-cyanobiphenyl-4-yl)methyl] -7-propyl-5-(morpholine - 4-ylethylamine)-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, X is a nitrogen atom,

< / BR>
Butter-like product was then purified by chromatographic processing on silica gel (eluent: a mixture of 95% chloroform and 5% methanol).

Example 57. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-(piperidine-1-yl)-7 - propyl-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
The connection is example 58. 6-[(2'-cyanobiphenyl-4-yl)methyl] -5-hydrazino-7-propyl - 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, R2group NH-NH2X is a nitrogen atom, Y is CH,

< / BR>
The product is crystallized from diethyl ether.

Melting point: 161oC.

Example 59. 5-azido-6-[(2'-cyanobiphenyl-4-yl)methyl] -7-propyl - 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (IX): - n-propyl, R2- a group of N3X is a nitrogen atom, Y is CH,

< / BR>
10.3 g of the compound obtained according outlined in example 58, mixed with 2.3 ml of concentrated hydrochloric acid and 300 ml of acetic acid. Add a solution of 1.9 g of sodium nitrite in 20 ml of water. The mixture is left overnight at room temperature. Add water and the mixture is decanted and subjected to extraction treatment with ethyl acetate. The combined organic phases are washed with water, dried and evaporated. Purification by two successive chromatographic treatments (eluent: a mixture of 95% dichloromethane and 5% methanol and 90% dichloromethane to 10% methanol) gives 4.3 g of 5-azido-6-[(2'-cyanobiphenyl-4-yl)methyl]-7-propyl-1,2,4-triazolo (1,5-a)pyrimidine.

Melting point: 134oC.

The same connection can be considered as tricyclic derivative, which is m., 30, 826, 1965).

Example 60. 3-amino-5-oximeter-1,2,4-triazole.

Formula (II): R7group - CH2OH

A mixture of 136 g of aminoguanidine with 80 g of glycolic acid step is heated to a temperature of 120oC. At this temperature the reaction continued for 5 hours the Mixture was transferred to 100 ml of ethanol and the solid material is filtered, receiving of 45.7 g of 3-amino-5-oximeter-1,2,4-triazole.

Melting point: 192 - 194oC.

Example 61. 3-amino-5-N-diethylamino-1,2,4-triazole

Formula (II):

10.3 ml diethylamine added to a solution of 16.1 g of diethyl-N-cyanodithioiminocarbonate in 160 ml of acetonitrile. The mixture is stirred for 1 h at room temperature and then refluxed until the termination of allocation of methylmercaptan. The solution is cooled in an ice bath and injected into 5 ml of hydrazine hydrate is added. The mixture is refluxed for 4 hours After removal of the solvent the product was transferred to acetonitrile, getting a 8.9 g of white crystals of 3-amino-5-N,N-diethylamino-1,2,4-triazole.

Melting point: 134oC.

Example 62. 7-hydroxy-5-propyl-6-{[2'-(1H-tetrazol-5-yl)-diphenyl-4-yl]methyl} -1,2,4 - triazole(1,5-a)pyrimidine

Formula (I): R1- hydroxyl, and 70 ml of 1,2,4-trichlorobenzene is maintained at a temperature of 120oC for 7 o'clock Rolled residue purified by chromatographic processing on silica gel (eluent: a mixture of 80% dichloromethane to 20% methanol). The compound obtained is dissolved in 1 N. solution of sodium hydroxide, insoluble material is filtered off and the clear solution is acidified by passing through it bubbles sulfur dioxide, receiving 2.4 g of white crystals of 7-hydroxy-5-propyl-6{[2'-(1H-tetrazol-5-yl)-diphenyl-4-yl]methyl}-1,2,4-triazolo (1,5-a)pyrimidine.

The empirical formula of the compound: C22H20N6O0,5H2O.

Melting point: 260 - 265oC (decomposition).

1P-NMR spectrogram (DMCO-d6): of 2.6 (t, 2H, propyl CH2), and 8.2 (C., 1H, H2).

UV spectrum (methanol): lambdaand= 210 nm, lambdab= 250 nm.

Example 63. 5-hydroxy-7-propyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl} -1,2,4-triazolo (1,5-a)pyrimidine

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
A mixture of 25 g of the compound obtained in the above example 19 or 23, with 750 ml of xylene and of 34.5 g of azide trimacinolone refluxed for 50 hours Obtained white precipitate is filtered off. It melts at a temperature of 290oC RA is islote, getting a General solution which is then concentrated in vacuo. This concentrate is transferred into the water and grind it. The resulting resinous mass is crystallized from acetonitrile. Recrystallization from isopropanol gives 15.2 g of the target is derived.

Melting point: 242oC.

Uterine fluid is concentrated, the concentrate is alkalinized by addition of 1N. solution of potassium hydroxide and subjected to extraction treatment with chloroform, followed by neutralization with acetic acid. The precipitation is twice recrystallized from isopropanol, receiving 4.5 g of the second portion of the compound 5-hydroxy-7-propyl-6-{[2'-(1H-tetrazol-5-yl)-diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

The empirical formula of the compound: C22H20N8O.

Melting point: 242 - 244oC.

1H-NMR spectrogram (DMCO-d6): only 2.91 (t, 2H, propyl CH2), 8,11 (C., 1H, H2).

In accordance with a certain procedure, which is described in examples 62 and 63, received the following compounds of examples 64 to 95.

Example 64. 7-hydroxy-2-methyl-5-propyl-6-{[2'-(1H-tetrazol-5-yl)-diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidinylsulfanyl

Formula (I): R1- Ki23H22N8O0,5H2SO4.

Melting point: 236 - 238oC.

1H-NMR spectrogram (DMCO-d6): of 2.6 (t, 2H, propyl CH2).

UV spectrum (methanol): lambdaa= 212,1 nm, lambdab= 250 nm.

Example 65. 5-hydroxy-7-propyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl} -1,2,4-triazolo (4,3-a)pyrimidine.

Formula (I): R1is hydroxyl, R2- n-propyl, X is CH, Y is a nitrogen atom,

< / BR>
The empirical formula of the compound: C22H20N8O.

Melting point: 251oC.

1H-NMR spectrogram (DMCO-d6): to 2.55 (t, 2H, propyl CH2), 9 (C., 1H, H3).

Example 66. 5-propyl-7-mercapto-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl] methyl}-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (I): R1- group SH, R2- n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C22H20N8S.

Melting point: 288oC.

1H-NMR spectrogram (DMCO-d6): at 2.59 (t, 2H, n-propyl CH2), or 8.6 (C. , 1H, H2).

Example 67. 5,7-dimethyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl}-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (I): R1is methyl,62 using 2,4-dioxo-3-{ [2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl}pentane, obtained during the experiment of example 16.

The empirical formula of the compound: C21H18N8< / BR>
Melting point: 264oC.

1H-NMR spectrogram (DMCO-d6): 2,48 (C., 3H, CH3), 2,81 (C., 3H, CH3), 8,56 (C., 1H, H2).

Example 68. 2-ethyl-7-hydroxy-5-propyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl] methyl}-1,2,4 - triazolo(1,5-a)pyridine.

Formula (I): R1is hydroxyl, R2- n-propyl, X is a nitrogen atom, Y is a group C-CH1-CH3,

< / BR>
The empirical formula of the compound: C24H24O.

Melting point: 246oC.

1H-NMR spectrogram (DMCO-d6): to 2.57 (m, 2H, propyl CH2+ DMCO-d6).

Example 69. 7-N, N-dimethylamino-5-propyl-6-{ [2'-(1H-tetrazol - 5-yl)diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1group N(CH2-CH3)2, R2-n-propyl, X is a nitrogen atom, Y is CH.

< / BR>
The empirical formula of the compound: C25H29N5.

Melting point: 192oC.

1H-NMR spectrogram (DMCO-d6): to 2.65 (t, 2H, n-propyl CH2), 8,5 (C. , 1H, H2).

Example 70. 5-azido-7-propyl-6{[2'-(1H-tetrazol-5-yl)defini - SUNY atom, Y is CH,

< / BR>
The empirical formula of the compound: C22H19N11,

Melting point: 212 - 213oC.

1H-NMR spectrogram (DMCO-d6): 3,17 (t, 2H, n-propyl CH2), 4,06 (S. , 2H, benzyl CH2), azido/tetrazolate balance - about 10%), 4,47 (S. , 2H, benzyl CH2), 8,56 (C., 1H, H2), azido/tetrazolate balance - about 10%), and 8.7 (C., 1H, H2).

Example 71. 3,5-dioxy-5-propyl-6-{ [2'(1H-tetrazol-5-yl) diphenyl-4-yl] methyl}-1,2,4-triazolo(4,3-a)pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a group of SON, Y is a nitrogen atom,

< / BR>
The empirical formula of the compound: C22H20N8O2.

Melting point: 252oC.

1H-NMR spectrogram (DMCO-d6): 2,93 (that is, n-propyl CH2), and 3.7 (SD, 2H, benzyl CH2).

Example 72. 5-hydroxy-2-methyl-7-propyl-6{-[2'-(1H-tetrazol-5-yl) diphenyl-4-yl]methyl}-1,2,4-triazolo(4,3-a)pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is a group C-CH3.

< / BR>
The empirical formula of the compound:C23H22N8O.

Melting point: 286oC.

1H-NMR spectrum of the-5-hydroxy-7-propyl-6-{-2'-(1H-tetrazol-5-yl) diphenyl-4-yl]methyl}-1,2,4-triazolo(4,3-a)pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is a group C - CH2CH3.

< / BR>
The empirical formula of the compound: C24H24N8O.

Melting point: 260oC.

1H-NMR spectrogram (DMCO-d6): of 2.86 (t, 2H, n-propyl CH2), 3,85 (S., 2H, benzyl CH2).

Example 74. 7-butyl-5-hydroxy-6-{ [1H-tetrazol-5-yl)diphenyl-4-yl] methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-butyl, R2is hydroxyl, X is a nitrogen atom, Y is a group CH,

< / BR>
The empirical formula of the compound: C23H22N8O.

Melting point: 255oC.

1H-NMR spectrogram (DMCO-d6): of 2.92 (t, 2H, n-propyl CH2), 3,86 (S., 2H, benzyl CH2), 8,11 (C., 1H, H2).

Example 75. 2-amino-5-hydroxy-7-propyl-6-{-[2'-(1H-tetrazol-5-yl) diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)-pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is a group CNH2,

< / BR>
The empirical formula of the compound: C22H21N9O.

Melting point: 282oC.

1H-NMR spectrogram (DMCO-d6): was 2.76 (t, 2H, n-propyl CH2), and 3.8 (SD , 2H, Benz is Iesolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2group N(CH2-CH3)2X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C26H29N9.

Melting point: 140oC, and then 205oC.

1H-NMR (DMCO-d6): only 2.91 (t, 2H, n-propyl CH2), 4,07 (S., 2H, benzyl CH2), 8,32 (C., 1H, H2).

Example 77. 5-amino-7-propyl-6-{-[2'-(1H-tetrazol-5-yl)diphenyl - 4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2- amino group, X is a nitrogen atom, Y is CH.

< / BR>
The empirical formula of the compound: C22H21N9.

Melting point: 276oC.

1H-NMR spectrogram (DMCO-d6): 2,98 (t, 2H, n-propyl CH2), a 4.03 (SD, 2H, benzyl CH2), 8,1 (C., 1H, H2).

Example 78. 5-hydroxy-2-mercaptomethyl-7-propyl-6-{ [2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1-n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is C-SCH3,

< / BR>
The empirical formula of the compound: C23H22N8OS

Melting point: 260oC.

1H-NMR spectrogram (DMCO-d6): 2,85 (t, 2H, n-propyl CH2), 3,84 the lo(1,5-a)pyrimidine.

Formula (I): R1-n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C20H18N8OS.

Melting point: 275oC.

1H-NMR spectrogram (DMCO-d6): 2,95 (t, 2H, n-propyl CH2), 3,91 (S., 2H, benzyl CH2), 8,12 (C., 1H, H2).

Example 80. 5-hydroxy-7-propyl-6-{4-[3-(1H-tetrazol-5-yl)-2-pyridyl]benzyl} -1,2,4 - triazolo(1,5-a)-pyrimidine

Formula (I): R1-n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C21H19N9O

Melting point: 244oC.

1H-NMR spectrogram (DMCO-d6): only 2.91 (t, 2H, n-propyl CH2), 3,89 (S., 2H, benzyl CH2), 8,11 (C., 1H, H2with pyridine H4).

Example 81. 5-hydroxy-2-methyl-7-propyl-6-{4-[3-(1H-tetrazol-5-yl) -2-thienyl] benzyl}-1,2,4-triazolo-(1,5-a)pyrimidine.

Formula (I): R1-n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is a group C-CH3,

< / BR>
The empirical formula of the compound: C21H20N8OS.

Melting point: 287oC.

1H-NMR spectrogram (DMCO-d6): or 2.9 (t, 2H, n-propyl CH2), 3,89 (S. , 2H, benzyl CH2).

Formula (I): R1-n-butyl, R2is hydroxyl, X is a nitrogen atom, Y is a group C-CH3,

< / BR>
The empirical formula of the compound: C24H24N8O.

Melting point: 275oC.

1H-NMR spectrogram (DMCO-d6): 2,87 (t, 2H, n-butyl CH2), 3,84 (S. , 2H, benzyl CH2).

Example 83. 5-hydroxy-2-oxymethyl-7-propyl-6-{[2'-(1H-tetrazol-5-yl) diphenyl-4-yl]methyl}-1,2,4-tritolo(1,5-a)pyrimidine.

Formula (I): R1-n-propyl. R2is hydroxyl, X is a nitrogen atom, Y is a group C-CH2OH,

< / BR>
The empirical formula of the compound: C23H22N8O2.

Melting point: 274oC.

1H-NMR spectrogram (DMCO-d6): is 2.88 (t, 2H, n-propyl CH2), 3,86 (S., 2H, benzyl CH2).

Example 84. 5-mercapto-7-propyl-6-{[2'-(1H-tetrazol-5-yl(diphenyl-4-yl] methyl}- 1,2,4-triazolo(1,5-a)-pyrimidine.

Formula (I): R1-n-propyl, R2-SH group, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C22H20N8S.

Melting point: 278oC.

1H-NMR spectrogram (DMCO-d6): 2,87 (t, 2H, n-propyl CH2), 3,37 (S., 2H, benzyl CH2), 8,29 (C., 1H, H2).

Formula (I): R1group-CH2-O-CH3, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C21H18N8O2.

Melting point: 264oC.

1H-NMR spectrogram (DMCO-d6): 3,91 (t, 2H, benzyl CH2), 4,79 (S., 2H, O-CH2), 8,12 (C., 1H, H2).

Example 86. 7-propyl-5-(pyrrolidin-1-yl)-6-{ [2'-(1H-tetrazol-5-yl)diphenyl-4-yl] methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1-n-propyl, R2group of the formula

X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C26H27N9.

Melting point: 280oC.

1H-NMR spectrogram (DMCO-d6): to 2.94 (t, 2H, propyl CH2), 4,22 (S., 2H, benzyl CH2) 8,18 (c. 1H, H2).

Example 87. 5-hydroxy-7-methyl-6-{[2'-(1H-tetrazol-5-yl) diphenyl-4-yl]- methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1is methyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C20H16N8O.

Melting point: 248oC.

1H-NMR spectrogram (DMCO-d6): 2,56 (C., 3H, CH3), 3,86 (S., 2H, benzyl CH2), 8,11 (C., 1H, CH2

Formula (I): R1group-CH2-CH3, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C21H18N8O.

Melting point: 245oC.

1H-NMR spectrogram (DMCO-d6): 2,94 (K., 2H, ethyl CH2), a 3.87 (SD, 2H, benzyl CH2), 8,12 (C., 1H, CH2).

Example 89. 2-N, N-dimethylamino-5-hydroxy-6-{ [2'-(1H-tetrazol-5-yl) diphenyl-4-yl]-methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is C-N(CH2-CH3)2,

< / BR>
The empirical formula of the compound: C26H29N9O.

Melting point: 207oC.

1H-NMR spectrogram (DMCO-d6): and 2.79 (t, 2H, n-propyl CH2), 3,80 (S., 2H, benzyl CH2).

Example 90. 5-(morpholine-4-ylethylamine)-7-propyl-6- {[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2group of the formula

< / BR>
X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C28H32N10O.

Melting point: 236oC.

1H-NMR spectrogram (DMCO-d6): to 2.99 (t, 2H, n-propylene-5-yl)diphenyl-4-yl]- methyl} -1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2-n-propyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C25H26N8.

Melting point: 226oC.

1H-NMR spectrogram (DMCO-d6): of 2.66 (t, 2H, n-propyl CH2) and 3.15 (t, 2H, n-propyl CH2), 4,14 (S., 2H, benzyl CH2).

Example 92. 7-propyl-6-{ [2'-(1H-tetrazol-5-yl)diphenyl-4-yl] - methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2hydrogen atom, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C22H20N8.

Melting point: 238oC.

1H-NMR spectrogram (DMCO-d6): and 3.16 (t, 2H, n-propyl CH2), 4,21 (S., 2H, benzyl CH2), 8,65 (S., 1H), 8,82 (S., 1H).

Example 93. 7-benzoyloxymethyl-5-hydroxy-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]methyl}- 1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1group CH2-O-CH2-phenyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C27H22N8O2.

Melting point: 270 - 5oC (decomposition).

1H-NMR spectrogram (DMCO-d6): 3,86 (S., 2H, benzyl is-7-propyl-6-{ [2'- (1H-tetrazol-5-yl)diphenyl-4-yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2a group of the formula , X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C27H29N9.

Melting point: 266oC.

1H-NMR spectrogram (DMCO-d6): is 2.88 (t, 2H, n-propyl CH2), 4.09 to (S., 2H, benzyl CH2), 8,35 (C., 1H, H2).

Example 95. { 7-propyl-6-[(2'-(1H-tetrazol-5-yl)diphenyl-4 - yl]methyl}-1,2,4-triazolo(1,5-a)pyrimidine-5-yl}-2-methoxyethylamine simple ether.

Formula (I): R1- n-propyl, R2group O-CH2-CH2-O-CH3X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C25H26N8O2.

Melting point: 224oC.

1H-NMR spectrogram (DMCO-d6): 3,14 (t, 2H, n-propyl CH2), of 4.04 (SD, 2H, benzyl CH2), to 8.41 (C., 1H, H2).

Example 96. 5-chloro-7-propyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl - 4-yl]methyl} -1,2,4-triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2- chlorine atom, X is a nitrogen atom, Y is CH,

< / BR>
Obtained by the diazotization product of the experiment of example 77 and processing diazonium chloride salt of monovalent copper in accordance with the classical reaction Sandmeier.

1- n-propyl, R2is hydroxyl, X is CH, Y is a nitrogen atom,

< / BR>
2 g of compound of example 20 (d) in 200 ml of 1 n sodium hydroxide solution is refluxed for 4 hours Then the mixture was concentrated in vacuo and the concentrate is acidified by the addition of 200 ml of 1N. hydrochloric acid solution. The obtained crystals are purified by recrystallization from 2-methoxyethanol to obtain 1.6 g of 6-[(2'-aminocarbonylmethyl-4-yl)methyl]-5-hydroxy-7-propyl-1,2,4-triazolo(4,3-a) pyrimidine.

The empirical formula of the compound: C22H21N5O2< / BR>
Melting point: 258oC.

1H-NMR spectrogram (DMCO-d6): 2,61 (t, 2H, n-propyl CH2), 3,9 (S. , 2H, benzyl CH2), 9 (C., 1H, H3).

Example 98. 6-[(2'-carboxyphenyl-4-yl)methyl]-5-hydroxy-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
A mixture of 9.4 g of the product obtained in the experiment of example 97, 200 ml of ethylene glycol and 20 ml of concentrated sodium hydroxide is refluxed for 10 hours, the ethylene Glycol is distilled off, add 200 ml of water and the mixture is acidified by adding hydrochloric acid. The obtained crystals cleanse the Asolo(1,5-a) pyrimidine.

The empirical formula of the compound: C22H20N4O3.

Melting point: 265oC.

1H-NMR spectrogram (DMCO-d6): 2,96 (t, 2H, n-propyl CH2), 3,92 (S., 2H, benzyl CH2), 8,12 (C., 1H, H2).

The compound of example 99 was obtained in accordance with the procedure set forth in example 23.

Example 99. 6-[4-(5-bromo-3-cyano-2-furyl)benzyl]-5-hydroxy-7-propyl-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (VIIb): - n-propyl, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
Melting point: 262oC.

Example 100. 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-oximeter-1,2,4-triazolo(1,5-a) pyrimidine.

Formula (VIIb): - group, CH2-OH, X is a nitrogen atom, Y is CH, R10is hydroxyl,

< / BR>
A solution of 9 g of the compounds obtained in the course of the experiment of example 43, 360 ml of acetic acid restores catalytic hydrogenation in the presence of 1.8 g of 5% palladium on coal. The reaction is carried out under atmospheric pressure and at a temperature of 50oC. the Catalyst is filtered off on the material of Celite 545 and washed with acetic acid and the filtrate is concentrated and then purified by chromatographic processing on silica gel (eluent: Sesil-1,2,4-triazolo(1,5-a) pyrimidine.

Melting point: 262oC.

The same connection can also be obtained by conducting the reaction with tribromide boron in chloroform.

In accordance with the procedure outlined in example 63, received the following derivatives of examples 101 and 102.

Example 101 5-hydroxy-7-oxymethyl-6-{[2'-(1H-tetrazol-5-yl)diphenyl-4-yl]-methyl}-1,2,-4 - triazole(1,5-a)pyrimidine.

Formula (I): R1group CH2- OH, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C20H15N5O2.

Melting point: over 360oC (decomposition).

1H-NMR spectrogram (DMCO-d6): 3,93 (S., 2H, benzyl CH2), 4,82 (S., 2H, CH2-O), 8,06 (C., 1H, H2).

Example 102. 6-{4-[5-bromo-3-(1H-tetrazol-5-yl)-2-furyl]benzyl}-5-hydroxy-7-propyl-1,2,4 - triazolo(1,5-a)pyrimidine.

Formula (I): R1- n-propyl, R2is hydroxyl, X is a nitrogen atom, Y is CH,

< / BR>
The empirical formula of the compound: C20H17BrN8O2.

Melting point: over 360oC.

1H-NMR spectrogram (DMCO-d6): of 2.93 (t, 2H, n-propyl CH2), 3,92 (S., 2H, benzyl CH2), 6,9 (C., 1H, furan proton), 8,03 (C., 1HLASS="ptx2">

The First Principle. The affinity of the products of the experiments described examples of angiotensin II receptor evaluated using the technique of offset is specifically linked radioligand to the receptors of angiotensin II adrenal glands of rats.

II Procedure. An aliquot of the homogenate of rat adrenal incubated in the presence taken only drug concentrations [125I]-SIAII (Sar1, Tyr4, Ile8- angiotensin II), which is an antagonist of angiotensin II receptors, and taken in two concentrations (10-5M, 10-7M) competitive agents in denie 60 min at a temperature of 25oC.

This reaction is completed by addition of a buffer followed by rapid filtration through filters of glass. Nonspecific relationship determined in the presence of angiotensin II.

III Expression results. To test the concentration of the obtained results expressed in percentage displacement of specifically bound radioligand to the angiotensin II receptor in the adrenal gland.

IV Results (see tab. 1).

B - measurement of the inhibition of the rapid proliferation of cells induced by growth factors (example: growth factor derived from platelets, or Htilominlo growth factors (for example, RFPT), estimate measurements introduction3H-tipitina in the smooth muscle cells of the aorta (CGMW).

II Procedure. KGVM cultivated at a temperature of 37oC in 5% carbon dioxide until pogliani and then placed for 24 h in a calm state in a poor serum environment. In the future, they are subjected to pre-treatment for 1 h experienced by the molecules (10-4), after this stimulated for 22 h growth factor (example: RFPT). In the last 4 hours to enter3H-thymidine. All these stages is carried out at a temperature of 37oC in the presence of 5% carbon dioxide.

This reaction complete suction of the reaction medium, the separation of cells and the subsequent filtering of the lysed cells through the filters of glass.

III Expression results. The results are expressed as percentage inhibition of promoting3H-thymidine by the action of the growth factor.

IV Results (see tab. 2).

Toxicology. The products of the experiment, the above examples are characterized by excellent tolerance to them patients by oral administration in the body.

the 50% lethal dose of these products for rats in quantities which have a good affinity to the receptors of angiotensin II. In this respect they can be used with success in cases of various pathological disorders involving angiotensin II, in particular in the treatment of hypertension and heart failure, in dosage from 1 to 400 mg oral introduction into the body and from 0.01 to 50 mg with internal injection in the form of one or more daily doses. Moreover, some of the compounds also possess antiproliferative action and in this respect they are potentially useful in the treatment of such proliferative diseases such as atherosclerosis.

Typical pharmaceutical compositions containing the compound according to the invention.

(A) Dry gelatin capsules containing a dose of 20 mg of active beginning.

Ingredients mg: -7-butyl--5-hydroxy-6-[(2'-(1-H-tetrazol-5) biphenyl-4)methyl] -1,2,4-triazolo[1,5-a]pyrimidine, 20; ministereth 10; lactose 170, gelatin capsule of size N 1.

(B) Tablets containing a dose of 20 mg of active beginning.

Ingredients mg: -7-butyl-5-hydroxy-6-[(2'-(1-H-tetrazol-5)biphenyl-4)methyl] - 1,2,4-triazolo[1,5-a]pyrimidine, 20; microcrystalline cellulose 430; covered gelatinous starch 47,5; ministart 2,5.

(C) Preparations for injection, sod the 4-triazolo[1,5-a]pyrimidine 5; Inositol 100; benzyl alcohol 20.

(G) Candle containing a dose of 50 mg of active beginning.

Ingredients mg: -7-butyl-5-hydroxy-6-[(2'-(1-H-tetrazol-5)biphenyl-4)methyl]- 1,2,4-triazolo[1,5-a]pyrimidine 50; wax for candles AML 1950.

(D) Ophthalmic solutions containing 1 mg/ml of the active beginning.

Ingredients mg/ml: -7-butyl-5-hydroxy-6-[(2'-(1-H-tetrazol-5) biphenyl-4)methyl] -1,2,4-triazolo[1,5-a] pyrimidine 1; the dibasic nutrifaster 10,4; odnoosnovny nutrifaster 2,4; hydroxypropylmethylcellulose 5; distilled water: sufficient quantity for" 1 ml, soda 1H: "sufficient for a pH of 7.4.

Pharmaceutical compositions containing other compounds according to the invention.

(A) Dry gelatin capsules containing a dose of 20 mg of active principle.

Ingredients mg-5-hydroxy-7-propyl-6-[(2'-(1-H-tetrazol-5) biphenyl-4)methyl] -1,2,4-triazolo[1,5-a]pyrimidine 20; ministart 10; lactose 170; gelatin capsules of size N 1.

(B) other dry gelatin capsules containing a dose of 50 mg of active principle, mg-2-amino-5-hydroxy-7-propyl-6-[(2'-(1-H-tetrazol-5)biphenyl-4) methyl] -1,2,4-triazolo[1,5-a] pyrimidine 50; ministart 10; lactose 140, gelatin capsules size # 1.

1- C6-alkyl or a radical of General formula -(CH)2)pOR, where p is an integer from 1 to 6, and R is the lowest C1- C6-alkyl, or benzyl radical, or an alcoholic residue of the formula - (CH)2)pOH, where p is the specified values, and the other of R1and R2hydrogen atom, halogen atom, lower C1- C6-alkyl, or a radical selected from the group comprising the radicals N3OR4, SR4, NR5R6and NH(CH2)n-NR5R6where R4hydrogen atom, or a radical of the formula (CH2)m-O-R', where m is an integer from 1 to 4, and R' is the lowest C1- C6-alkyl, each of R5and R6which may be identical or different, a hydrogen atom, or a lower C1- C6-alkyl, or together with the nitrogen atom to which they relate, R5and R6form a heterocycle selected from the research, pyrrolidine and piperidine, and n is an integer from 1 to 4;

each of X and Y, which are different, in one case, a nitrogen atom, and in another case, a group of the formula C - R7where R7hydrogen atom, a lower C1- C6-alkyl, the radical (CH2)n'OH, where n' is an integer from 0 to 4, the radical SR', where R' has the above meanings, or radicum, hydrogen atom or a lower C1- C6-alkyl;

R3- one of the following radicals:

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and their tautomeric forms and additive salts, in particular pharmaceutically acceptable additive salt.

2. Derived under item 1, where R1- n through n-bucilina group or N-diethylaminopropyl.

3. Derived under item 1 or 2, where R2is hydroxyl, n-sawn group or N-diethylaminopropyl.

4. Derivative according to any one of paragraphs. 1 to 3, where R3-2-(IH-tetrazol-5-yl)-phenyl group.

5. Derivative according to any one of paragraphs.1 - 4, where X is the nitrogen atom.

6. Derivative according to any one of paragraphs.1 to 5, where Y is a group-CH, -C-CH3or-C-NH2.

7. Derived under item 1 or 2, where the lowest C1- C6-alkyl, R2- hydroxyl group, R3-2-(IH-tetrazol-5-yl)-phenyl group, X is a nitrogen atom, and Y is a group-CH or-C-CH3.

8. Derived under item 1 or 2, representing 5-hydroxy-7-propyl-6-{ [(2-(IH-tetrazol-5-yl)-diphenyl-4-yl] -methyl-1,2,4-triazolo-(1,5-a)pyrimidine of the formula

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9. Derived under item 1 or 2, selected from derivatives of the formula

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10. The pharmaceutical composition exhibiting antagonistic in Rel is ffektivnoe amount of at least one of the compounds of formula I, which is defined according to any one of paragraphs.1 to 9, or one of its pharmaceutically acceptable salt additive in conjunction with a carrier or excipient.

11. The pharmaceutical composition according to p. 10, exhibiting antiproliferative activity containing a pharmaceutically effective amount of at least one of the compounds of formula I, as defined according to any one of paragraphs. 1 to 9, or one of its pharmaceutically acceptable salt additive in combination with a pharmaceutically acceptable carrier or excipient.

Priority signs and items:

24.02.92 in: p. 1 of the claims except for other values of R1and R2the lowest C1- C6-alkyl, the radical and PP.2 to 9;

30.04.92 when: the other of R1and R2lower C1- C6-alkyl.

 

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