SK99794A3 - Triazolopyrimidine derivatives as antiotensin ii receptor antagonists, method of their preparation, pharmaceutical agent and use - Google Patents

Abstract

The present invention relates to derivatives having the formula (I) and their tautomeric forms, as well as addition salts thereof and therapeutical utilization particularly for the treatment and prevention of cardiovascular diseases particularly for the treatment of hypertension, cardiac insufficiency, arterial wall diseases particularly atherosclerosis.

Description

TRIAZOLOPYRIMIDINE DERIVATIVES AS ANTAGONISTS OF ANGIOTENZINE RECEPTOR II, METHOD OF PREPARATION, PHARMACEUTICAL FORM AND USE

Technical field

The invention relates to novel triazolopyrimidine derivatives of the general formula (I) as defined below and their tautomeric forms and suitable addition salts, in particular pharmaceutically acceptable addition salts.

These compounds have a very valuable pharmacological profile as they exhibit angiotensin II receptor antagonistic properties and antiproliferative properties. Accordingly, the compounds are suitable for the treatment and prevention of cardiovascular diseases, and in particular for the treatment of hypertension, for the treatment of cardiac insufficiency, and for the treatment and prevention of arterial wall diseases, in particular atherosclerosis.

The present invention also relates to a process for the preparation of said compounds and their use as therapeutic agents.

SUMMARY OF THE INVENTION

The present invention relates to derivatives and their tautomeric forms, which triazolopyrimidine are characterized by the general formula I:

Y (I) wherein:

- one of the radicals R 4 and R ₂ :

a lower alkyl group having 1 to 6 carbon atoms, or

- an ether residue of the formula:

- (CH ₂ ) _p ° R in which p represents an integer from 1 to 6 and R represents a lower alkyl group having 1 to 6 carbon atoms or a benzyl group, and

- alcohol residue of the formula:

- (CH _{2) p} OH wherein p is as defined above and the

- the other of the radicals R @ 1 or R @ ₂ represents:

- a hydrogen atom,

- halogen atom,

a lower alkyl group having 1 to 6 carbon atoms, or

- a residue selected from the group consisting of n ₃ , OR ₄ , SR ₄ , NR ₅ R ₆ and NH (CH ₂ ) _n -NR ₅ R ₆ , in which:

R ₄ means:

- a hydrogen atom,

- a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms,

- the rest of the formula:

(CH ₂ ) _m -COOR ', wherein m is an integer from 1 to 4 and R' is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or

- the remainder of the formula < ^ch 2 V ⁰ - * '' in which R 'have the same meaning as above, ^r 5 and R g, which may be the same or different, represent:

a hydrogen atom, or

- a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, or

R ₅ and R _g together with the nitrogen to which they are attached, form a heterocyclic radical chosen from the group consisting of morpholino, pyrrolidino or piperidino, n is an integer from 1 to 4;

X and Y, which are different, represent:

- in one case a nitrogen atom and in the other a group:

CR _? wherein R ₇ means:

- a hydrogen atom

- a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms,

- the rest of the formula:

(CH ₂ ) _n 'OH wherein n' is an integer from 0 to 4, the remainder SR ', wherein R' has the same meaning as above, or

- radical NR ₅ R _6, wherein R and R, which may be the same or different, are H, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, and

R ₃ is a radical of the formula:

or

in which it means:

Z is CH or N and Z 'is sulfur or oxygen, ^R11 is hydrogen or halogen, and

R ₁₂ represents a tetrazole residue, CN, COOH or CONH ₂ .

It is also intended to include the above derivatives in their tautomeric forms.

Where R ₂ represents an azido group, the following compound may be considered to tricyklickejtetrazolo [l, 5-c] -l, 2,4-triazolo [l, 5-a] pyrimidine form, which results from the theory of equilibrium sufficiently known from the prior art literature (see Temple and Montgomery, J. Org. Chem., 30, 826 (1965)).

The above compounds of formula I may be in the form of their addition salts, in particular in the form of pharmaceutically acceptable addition salts.

In a preferred embodiment of the invention said compounds of formula I are compounds wherein:

- one of the radicals and R _2:

a lower alkyl group having 1 to 6 carbon atoms, and

- an ether group of the formula:

- (CH _{2) p} OR in which p is an integer from 1 to 6 and R is lower alkyl of 1 to 6 carbon atoms or benzyl, or

- an alcohol group of the formula:

- (CH _{2) p} OH wherein p is as defined above, and

- the second of R1 or R2 is:

- a hydrogen atom,

- halogen atom,

- a lower alkyl group having 1 to 6 carbon atoms, or a residue selected from the group consisting of N ₃ , OR ₄ , SR ₄ , NR ₅ R ₆ and NH (CH ₂ ) _n -NR ₅ R ₆ , in which:

R ₄ means:

a hydrogen atom, or

- a group of formulas:

- (CH ₂ ) "- OR · in which m is an integer from 1 to 4 and R 'represents a lower alkyl group having 1 to 6 carbon atoms, ^r 5 and R 8, which may be the same or different, represent:

a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or

R 8 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholine, pyrrolidine and piperidine, and n represents an integer from 1 to 4,

X and Y, which are different, mean:

in one case a nitrogen atom, and

- in the latter case, the group:

CR ₇ in which R ₇ represents:

- a hydrogen atom,

- a lower alkyl group having 1 to 6 carbon atoms,

- the rest of the formula:

(CH ₂ ) _n 'OH wherein n' is an integer from 0 to 4, the remainder SR · where R 'has the same meaning as above, or

- a radical NR ₅ R ₆ in which R ₅ and R ₆ which are the same or different represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and

R ₃ represents one of the following radicals:

In the description of the present invention and in the appended claims, the term lower alkyl refers to a linear or branched hydrocarbon chain containing 1 to 6 carbon atoms. The lower alkyl group may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl or isohexyl.

By C 3 -C 7 cycloalkyl is meant a saturated cyclic hydrocarbon radical, preferably a cyclopropyl group, a cyclobutyl group, a cyclohexyl group or a cycloheptyl group.

The term halogen as used herein refers to a chlorine, bromine, iodine or fluorine atom.

According to one variant of the compounds according to the invention, R is n-propyl.

In another embodiment, R _{x is} N-diethylamino.

In another embodiment, R is n-n-butyl.

In another variant of the compounds of the present invention, R _{2 is a} hydroxyl group.

In another embodiment, R _{2 is} n-propyl.

In another embodiment, R _{2 is an} N-diethylamino group.

In another variant of the compounds of the present invention, R _{3 is} 2- (1H-tetrazol-5-yl) phenyl.

by other variant compound by the invention is X atom nitrogen. by other variant compound by the invention is Y is CH. by other variant compound by the invention

R ₃ represents a 2- (1H-tetrazol-5-yl) phenyl group.

In another embodiment, Y is C-CH ₃ .

In another embodiment, Y is C-NHg.

According to the present invention, compounds of the following formulas C to H are obviously preferred:

(C)

(Η)

The process for the preparation of the compounds of the formula I according to the invention generally consists in carrying out the following steps:

(a) a compound of formula I-A is prepared:

(I-A) in which:

X, Y and R ₃ have the same meanings as above, and

A and B represent, according to one variant, a hydroxyl group or a lower alkyl group having 1 to 6 carbon atoms, and according to a second variant a lower alkyl group having up to 6 carbon atoms or an ether radical of the formula

- (CH ₂ ) _p -OR wherein p is an integer from 1 to 6 and R represents a lower alkyl group having 1 to 6 carbon atoms or a benzyl group by condensing 3-amino-1,2,4- triazole of formula II:

(II) in which R _{7 has the} same meaning as above, with a derivative of the general formula IB:

in which

R 1j represents a lower alkyl group having 1 to 6 carbon atoms or an ether radical of the formula:

- (CH _{2) p} OR in which p is an integer from 1 to 6 and R is lower alkyl of 1 to 6 carbon atoms or benzyl,

R ₈ represents a lower alkyl group having 1 to 6 carbon atoms or a lower O-alkyl group having 1 to 6 carbon atoms, preferably a methyl group or an ethyl group, and

R 8 has the same meaning as above, in an aprotic solvent such as dichlorobenzene or trichlorobenzene or in an acidic solvent such as acetic acid, or in another embodiment in an alcohol, in the presence of the corresponding sodium or potassium alcoholate, or according to another embodiment in pyridine or 2-methyl-5-ethylpyridine in the presence or absence

4-dimethylaminopyridine, and at a temperature ranging from 50 ° C to 200 ° C.

(b) introducing, if necessary, a R ₃ protecting group into this compound, using generally known methods; (c) heating the derivative thus obtained from a derivative of the general formula IB, if the compound is a ketoester, heated in a suitable reagent, such as POCl ₃ , to convert the hydroxyl group represented by A or B to a chlorine atom.

(d) the thus obtained chlorinated derivative is heated in the presence of a nucleophilic reagent containing nitrogen, oxygen or sulfur at reflux temperature in an alcohol or autoclave at 100 ° C in the presence or absence of a base such as sodium carbonate

Na ₂ CO ₃ to provide the compound of formula IA, in which A and B of the same meaning as R and R _2nd

(e) removing the protecting group attached to R ₃ , if necessary, (e ^) converting the group to an acid group, for example by hydrolysis when the group is a nitrile group, or (e ₂ ) converting the group to a tetrazole group. a group, for example when the group is a nitrile group, by reaction with a trialkyltin azide while heating in toluene or xylene, followed by treatment with gaseous hydrochloric acid in tetrahydrofuran, or (e ₃ ) converting the group to an amide group, e.g. where the group is a nitrile group, by reaction with sulfuric acid or by reaction with hydrogen peroxide, or, alternatively, by reaction with polyphosphoric acid, and (f) if necessary converting the derivative so obtained into an addition salt, preferably to a pharmaceutically acceptable addition salt.

According to the invention, compounds of formula I can be prepared in a synthetic manner according to the following reaction scheme.

Compound of formula III:

in which it means:

(III)

R '1 is a lower alkyl group having 1 to 6 carbon atoms or an ether moiety of the formula:

- (CH ₂ ) _p -or in which p represents an integer from 1 to 6 and R represents a lower alkyl group having 1 to 6 carbon atoms or a benzyl group,

R _g is a lower alkyl group having 1 to 6 carbon atoms or a lower O-alkyl group having 1 to 6 carbon atoms, preferably a methyl group or an ethyl group, are prepared by methods well known in the art, such as the Claisen reaction or a method using Meldrum acid, which methods can be found in the following references:

- Hauser C.R., Swamer F.W., Adams J.T., Org. Reaction, vol. VIII, 1954, 59-196,

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

- Breslow 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), 2087-2088.

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

- Houghton R., Lapham D., Synthesis, 1982, 6, 451-452,

- Br. G., Vilkas, M., Bull. Soc. Chim. France, 1964 (4),

945-951.

- Balyakina M. V., Zhdanovich E. S., Preobrazhenskii N. A., Tr. Vses. Nauch. Issled. Vítam in. Inst., 1961, 7, 8-16.

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

- Bruce F. ¥., Coover H. ¥., J. Am. Chem. Soc., 1944, 66,

2092-2094, and

Eby C.J. and Hauser C.R., J. Am. Chem. Soc., 1957, 79, 723-725.

Compounds of formula V:

(V) are obtained by benzylating a compound of formula III with a compound of formula IV:

(IV) in the presence of a base such as sodium carbonate or potassium carbonate in acetone, sodium alcoholate or potassium alcoholate in alcohol, or sodium hydride or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide, the reaction being is carried out at a temperature of, for example, from 50 ° C to 100 ° C, or, in another variant, in the presence of an equivalent portion of lithium chloride or lithium bromide and two equivalents of diisopropylethylamine in tetrahydrofuran at reflux. link:

- Sung-eun yoo, kyu yang yi, bull. Korean Chem. Soc., 1989, 10 (D, 112).

The compounds of formula (V) may also be prepared by condensation of an aldehyde of formula (VI):

CHO

(VI) with a compound of formula (III) followed by hydrogenation in the presence of a catalyst such as Raney nickel, palladium on charcoal or platinum oxide, in a solvent such as alcohol or tetrahydrofuran under pressure or at a pressure substituents allow.

normal pressure if that

The procedure for the preparation of compounds of general interest is described in the following publications:

of formula V is generally

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

- Heinz P., Kreglewski A. J., Prakt. Chem., 1963,21 (3-4,

186-197.

Zaugg H. E., Dunnigan D. A., Michaels R. J., Swett L. R., J. Org. Chem., 1961, 26, 644-651.

- Kagan H.B., Heng Suen Y., Bull. Soc. Chim. France, 1966, (6), 1819-1822.

- Rathke M. W., Deitch J., Tetrahedron Lett., 1971 (31),

2953-2956,

- Borries Kubel, Liebigs Ann. Chem., 1980, 1392-1401.

- Marguet J., Moreno-Manas M., Chem. Lett., 1981, 2, 173-176.

- 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 compound of formula (IV) above, W is halogen, preferably chlorine or bromine.

The substituent V may be a group of the formula:

wherein R _g is lower alkyl or benzyl, in which case compounds of formula IV are prepared by reacting a compound of magnesium and p-bromotoluene with a compound of formula X:

(X) to form a compound of formula XI:

(XI) which is then hydrolyzed to give a compound of formula (XII):

(ΧΠ)

Procedures for carrying out the above three steps are described in more detail in the following prior art publication:

Meyers A.I., Mihelich E. D., J. An. C hen. Soc., 1975, 97, 7383.

The acid thus obtained is then esterified with an alcohol of general formula

RgOH wherein R _g is as mentioned above.

These derivatives are then brominated or chlorinated using, for example, N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as carbon tetrachloride, dibromoethane or dichloroethane to give a compound of formula IV wherein V is represents a group:

The substituent V may also be a group of:

in which case the compound of formula XII is:

(XII), prepared as described above, is converted to the primary amide group by reacting the acid chloride obtained by reacting the compound with thionyl chloride or phosphorus oxychloride with an aqueous ammonia solution, the amide thus obtained is then converted to the nitrile compound by reaction with phosphorus oxychloride in dimethylformamide or thionyl chloride. In a similar manner, a compound of formula XI is possible:

(XI) obtained directly by the above process to be converted directly to a carbonitrile derivative by treatment in pyridine in the presence of POCl ₃ . The nitrile derivative of general formula XIII thus obtained:

(ΧΙΠ) can then be brominated or chlorinated under the same conditions as mentioned above for the above ester to give a compound of formula IV wherein V is:

The substituent V may also be a group of:

in which case the corresponding compound of formula (IV) is prepared by the following synthetic procedure.

The procedure is based on a magnesium (XIV) compound of formula XIV:

which can be prepared by conventional Grignard reaction, which compound is converted to a zinc derivative by reaction with zinc chloride. This zinc derivative is then condensed with 2-chloronicotinenitrile in the presence of [Ni (PG ₃ )] ₂ Cl ₂ to give a derivative of formula XV:

(XV)

From this compound, treatment with boron tribromide in chloroform affords a compound of formula IV wherein W is bromo and V is:

NC

The substituent V may also be a group of the formula:

wherein Rg has the same meaning as above, in which case a compound of formula IV is prepared from a nitrile compound of formula XV:

(XV) which has been prepared by the above process, by hydrolysis of a nitrile group by a conventional method followed by esterification of the acid thus obtained, or by direct conversion of a nitrile group to an ester group by conventional methods followed by bromide treatment boron in chloroform to give a compound of formula IV wherein W is bromo and V is:

NC, in which case the corresponding compound of formula IV is prepared by the following synthetic procedure.

First, a compound of formula XVI is prepared:

CH ₃

C - CH, - CH, - Cl

CHO (XVI) wherein the preparation of this compound is carried out from the starting 4-chloro-4'-methylbutyrophenone of formula XVII:

(XVII), the preparation of which is described in detail in Belgian patent no. No. 577,977 of May 15, 1959, CA: 54, 4629c, by treatment with phosphorus oxychloride and dimethylformamide under the conditions described in the following publication:

- Volodina M. A., Tenen ev A. P., Kudryashova V. A., Kaboshina

L. N. Khim. Geterosikl. Soedim, 1967, 5-8.

The compound is then treated with sodium sulfide in a solvent such as tetrahydrofuran at reflux temperature to give a derivative of formula XVIII:

OHC (XVIII), which is then converted by a two-step process to a nitrile derivative by dehydrating an oxime prepared from an aldehyde and hydroxylamine. This dehydration can be carried out, for example, with acetic anhydride to give a nitrile compound of formula XIX:

(XIX) which can then be aromatized by treatment with bromine in carbon tetrachloride to give compound X1X-a:

(XIXa)

The compound thus prepared may then be chlorinated or brominated with a halogenating agent such as N-chlorosuccinimide or N-bromosuccinimide in a solvent such as carbon tetrachloride or dibromoethane to give a compound of formula IV wherein V is:

NC

The substituent V may also be a group of:

wherein R _g has the same meaning as above, in which case the corresponding compound of formula (IV) may be prepared from the nitrile compound prepared by the above process of formula (XIx-a):

(XIXa) by conventional hydrolysis of a nitrile group followed by esterification of the acid thus obtained, or by direct conversion of the nitrile group to an ester group using methods known in the art, followed by chlorination or bromination of the ester with N-chlorosuccinimide or N-bromosuccinimide , carried out, for example, in carbon tetrachloride or dibromoethane, to produce a compound of formula IV wherein W is bromo or chloro and V is:

The substituent V may also be a group of:

wherein R _g has the same meaning as above, in which case the corresponding compound of formula IV can be prepared by reacting a diazotized p-toluidine derivative with pyroslizic acid to prepare a compound of formula XX:

(XX) following the method known and described in the literature, see:

- A. Jurasek et al., Collect. Czech. Chem. Commun. 1989, 54, 215.

This compound is then esterified by conventional methods known in the art to prepare a compound of formula XXI:

(XXI) wherein Rg is as defined above, wherein the derivative so obtained is then brominated or chlorinated by reaction with N-bromosuccinimide or N-chlorosuccinimide, for example in carbon tetrachloride or 1,2-dichloroethane, to prepare a derivative of the general formula of formula IV wherein W is bromo or chloro and V is:

The substituent V may also be a group of:

in which case the acid of formula XX:

(XX) prepared as described above, is converted to the acid chloride by reaction with thionyl chloride and then to the amide by reaction with ammonia. The amide thus obtained is then converted to a nitrile compound by treatment with phosphorus oxychloride in dimethylformamide to give (XXII) a compound of formula XXII:

This derivative can then be brominated or chlorinated by reaction with N-bromosuccinimide or N-chlorosuccinimide, for example in carbon tetrachloride, W is an atom of the group:

of bromine or or 1,2-dichloroethane, whereby a substituent of formula IV, a chlorine atom and a

V is

In the above structure, W are R ^ and R _g as defined above, and R W is as defined for a compound of formula IV.

However, compounds of formula V wherein V is:

NC

NC

NC

NC

can be reacted with one equivalent of sodium azide in a solvent such as dimethylformamide in the presence of an ammonium salt such as ammonium chloride or by heating in toluene or xylene together with a trialkyltin azide to prepare a compound of formula V wherein the substituent V represents groups:

In the compound of formula (VI), the substituent (V) has the same meaning as defined for formula (IV), but this condensation procedure can only be used where the substituent (V) provides a group unaffected by hydrogenation.

Thus, by reaction of a 3-amino-1,2,4-triazole of formula II:

(Π) in which R? has the above meaning (these products are commercially available or can be readily prepared by methods well known in the art, see:

Huffmann and Schaeffer, J. of Org. Chem., 1963, 28, p.

1812-1816 and p. 1816-1821,

- Alien et al., J. of Org. Chem., 1959, 24, p. 793-796 a

- Organic Synthesis Collective, Volume 3, p. 95) with a compound of formula V in which R 1 and R _{g have the} same meaning as above, and the substituent V is one of the following groups:

l |

RgOOC

NC

H

in which R _g has the same meaning as above, a compound of the general formulas III-a and / or III-b is prepared:

(Fairy)

(VIIIb) forms of these and V the same hydroxyl of formula V is, up to 6 atoms of formula V is compounds, meaning as a group in β-ketoester.

and the R ₁₀ when the compound and the lower alkyl group is that compound, wherein the reaction is, for example, a solvent in sodium alcohol or a tautomeric R '1, X, Y is generally carried out by condensation in an aprotic solvent such as dichlorobenzene or trichlorobenzene, or in an acid such as acetic acid, or else alcoholate or 2-methyl-5-ethylpyridine of 4-dimethylaminopyridine and at 50 ° C to 200 ° C.

as in the presence of potassium, in the presence or temperature of the corresponding or otherwise in pyridine in the absence of

In the case where the substituent V provides, the reaction temperature must not exceed the decomposition of the tetrazole.

a tetrazole group,

140 'C

Said reactions of aminotriazoles or similar heteroaromatic amines with β-ketoester and β-diketone derivatives are well known in the art and described in the literature, the form of these derivatives depending on the operating conditions used. The following references are examples:

J. A. Van Allan et al., J. Org. Chem. 779-801 (1959),

Williams, A. A., J. Chem. Soc., P. 1829 (1960);

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

compounds of formula III-a and VII-b will therefore identified different processing. by the invention was found that 2-methyl-5-ethylpyridine v presence or in absentia

4-dimethylaminopyridine is a suitable and preferred solvent for directing the reaction towards the formation of derivatives of formula III-b, wherein the desired temperature (i.e., 170-180 ° C) and the pH necessary to direct this reaction in that direction can be achieved using this solvent.

If derivatives of the formulas VIII-a and VIII-b, in which R 6 is a hydroxyl group, are treated with a suitable reagent such as P ₂ S ₅ ^and / ^or Lawesson's reagent, then derivatives of the formula VIII-a are obtained. a and VIII-b, wherein R ₁₀ represents a thiol group.

For example, if derivatives of formulas VIII-a and VIII-b, in which R ₁₀ represents a hydroxyl group, are heated in POCl ₃ in oxychloride, then derivatives of formulas VIII-a and VIII-b are prepared:

(VIIIa) (VIIIb) in which the substituents R _ha X, Y and W are as stated above.

Hydrogenation of a derivative of formula (II-a) and (II-b) in the presence of a catalyst such as palladium on carbon can replace the chlorine atom with a hydrogen atom, wherein the derivative of formula (IX):

(IX)

in which R p R ₂ , X, Y and V have the same meaning as above, is obtained by heating a derivative of the formula VIII-a or VIII-b in the presence of a nucleophilic group containing nitrogen, oxygen or sulfur, a reflux condenser in an alcohol in the presence or absence of a base such as sodium carbonate Na ₂ CO ₃ or in an autoclave at 100 ° C.

The derivatives of the general formulas VII-a and VII-b, in which R '^ represents a group:

(CH ₂ ) p -O-benzyl in which p has the same meaning as described above, can be hydrogenated in the presence of palladium on carbon in acetic acid to give compounds of the general formulas VII-a or VII-b, wherein R 'is an alcohol group.

The following triazolopyrimidine derivatives of formulas VIII-a and VII-b can also be obtained by reaction of a derivative of formula XXIII:

(XXIII) wherein R 1, R ₂ and V have the same meaning as above,

- with acids, with acid chlorides or with carboxylic acid esters,

- isocyanates or isothiocyanates,

- with orthoesters

carbonyldiimidazole, or

urea, potassium xanthate, carbon disulfide or an analogous reagent, heating in the absence of a solvent or in a solvent such as N-methylpyrrolidone or an alcohol such as ethanol or methoxyethanol in the presence or absence of a base such as for example triethylamine, pyridine or 2-methyl-5-ethylpyridine.

Depending on the operating conditions, especially the temperature and pH of the reaction, 1,2,4-triazolo [4,3-a] pyrimidine derivatives or 1,2,4-triazolo [1,5-a] pyrimidine products are obtained obtained by rearrangement of these compounds.

Compounds of formula (XXIII) may be obtained by any of the well known methods for the synthesis of 2-hydrazine pyrimidines (see The Pyrimidines; The Chemistry of Heterocyclic Compounds; DJ Brown; Wiley Interscience, 1970), in particular a method in which are substituted derivatives of formula XXIV:

(XXIV)

CH in which R _1, R ₂ and V have the same meanings as described above, for example with hydrosinhydrate.

Compounds of formula XXIV are obtained by condensation

S-methylthioureas with derivatives of the general formula V, for example by any of the methods used for the synthetic preparation of 2-thiomethylpyrimidines which are well known in the literature (see, for example, The Pyrimidines, supra).

Compounds of formula (IX) wherein the substituent

V contains an ester group COOR _g , it is possible to hydrolyze

I, the acid or basic medium, or may be hydrogenated, if R _g is benzyl to give a compound of formula I, wherein

R ₃ contains an acid group i

I I

A compound of formula IX wherein the substituent

V contains a nitrile group, may be reacted with one equivalent of sodium azide in a solvent such as dimethylformamide in the presence of an ammonium salt such as ammonium chloride, or heated in toluene or xylene with a trialkyl tin azide such as trimethyltin azide or tributyltin azide followed by treatment with an acid such as gaseous hydrochloric acid in tetrahydrofuran to give a compound of formula I wherein the substituent

R ₃ contains a tetrazol-5-yl group.

These same compounds in which the substituent V contains a nitrile group can be carried out by reaction with sulfuric acid or by reaction with hydrogen peroxide, or otherwise by reaction with polyphosphoric acid, to derivatives of the formula I in which the substituent R ₃ contains an amide group.

Derivatives in which the substituent V contains a nitrile group or an amide group can also be carried out by basic or acid hydrolysis to a derivative of the formula I in which R ₃ contains an acid group.

For some of the compounds of formula I, addition salts, especially pharmaceutically acceptable addition salts, may be prepared. In particular, when the compounds of formula I of the present invention contain an acid group or a tetrazole group, these include sodium salt, potassium salt, calcium salt, amine such as dicyclohexylamine, or an amino acid such as for example lysine. When these compounds contain an amine group, particular examples of such salts include salts with inorganic or organic acids such as the hydrochloride salt, methanesulfonate salt, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate.

The novel compounds of the present invention exhibit significant pharmacological activity, can be used as angiotensin II receptor antagonists and as antiproliferative agents, and can also be used as therapeutic agents for the treatment and prevention of cardiovascular diseases, particularly for the treatment of hypertension, cardiac insufficiency. and arterial wall diseases, in particular atherosclerosis.

Accordingly, the present invention also provides a pharmaceutical composition comprising, as an active ingredient, a medicament comprising a pharmaceutically effective amount of at least one compound of formula (I) as defined above, together with one of the pharmaceutically acceptable addition salts thereof, as appropriate. .

The pharmaceutical compositions of the present invention may be administered by buccal, rectal, parenteral or transdermal routes or administered to the eye.

The above compositions may be in solid or liquid form, and may be in the form of pharmaceutical compositions commonly used in human medicine, such as simple or coated tablets, gelatin capsules, granules, suppositories, injectables, transdermal systems and ophthalmic liquid. dosage forms. These compositions are prepared by conventional methods known and used in the art. The active ingredient, which is a pharmaceutically effective amount of at least one compound of formula I as defined above, or at least one pharmaceutically acceptable addition salt thereof, may be combined with excipients commonly used in the preparation of such pharmaceutical compositions, such as for example talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicle, fatty substances of animal or natural origin, glycols, various wetting agents, dispersing or emulsifying agents, silicone gels various polymers or copolymers, preservatives and coloring agents.

The present invention also relates to a pharmaceutical composition having angiotensin II receptor antagonist activity and / or antiproliferative activity, which means that the composition is apparently suitable for the treatment or prevention of cardiovascular diseases, particularly hypertension, cardiac insufficiency and arterial wall disease, in particular atherosclerosis, said composition comprising a pharmaceutically effective amount of at least one compound of formula I above, or one of the pharmaceutically acceptable salts thereof, which can be incorporated or combined with a pharmaceutically acceptable excipient, a vehicle or a carrier.

The dose employed may vary depending, in particular, on the route of administration, the disease being treated and the subject to which the dose is administered.

For example, in the case of an adult subject having an average weight in the range of 60 to 70 kilograms, the dosage may be in the range of 1 to 400 milligrams of the active ingredient administered orally in the form of one or more daily doses, or from 0.01 to 50 milligrams, administered parenterally in the form of one or more daily doses.

Within the scope of said pharmaceutical composition, at least a defined acceptable acceptable is incorporated

This pharmaceutical composition of the invention also includes a process comprising combining a pharmaceutically active compound of the formula or at least one or more of the above, a salt derived therefrom, with an excipient, a vehicle or a preparation in which

I, which has been both a pharmaceutical pharmaceutical and a carrier, can be formulated in a gelatin capsule or tablet containing 1 to 400 milligrams of active ingredient, or as an injectable preparation containing 0.01 to 50 milligrams of active ingredient.

The present invention also includes a method of therapeutic treatment of a mammal comprising administering to the mammal a therapeutically effective amount of at least one compound of formula I as defined above, or at least one pharmaceutically acceptable addition salt.

When these therapeutic agents are used in animals, the daily dose is usually in the range of 1 to 100 milligrams per kilogram.

DETAILED DESCRIPTION OF THE INVENTION

In the following examples, the novel compounds of the present invention will be described in more detail, the process for their preparation and use, including pharmacological tests demonstrating the effect of these compounds of the invention. These examples are illustrative only and are not intended to limit the scope of the present invention in any way, and the essential features and advantages of the present invention will be apparent from these examples.

Example 1

Preparation of 3-oxohexanoic acid ethyl ester

Compound of formula III:

R ₈ = n-propyl, R ₈ = O-ethyl.

176 grams of 2,2-dimethyl-4,6-dioxo-

1,3-dioxane (Meldrum acid) dissolved in 550 ml of dichloromethane and 188 ml of pyridine was then cooled to 5 DEG C. using an ice-water bath and 133 ml of butyryl chloride were added dropwise slowly. After the addition was complete, the reaction mixture was stirred for three hours at room temperature. The resulting solution was washed with dilute hydrochloric acid, then dried over magnesium sulfate and evaporated in vacuo to give the product as an oil. The oil was dissolved in 700 mL of ethanol and the reaction mixture was heated at reflux for six hours. The ethanol was evaporated in vacuo and the residue distilled to give 145.4 g of 3-oxohexanoic acid ethyl ester as an oil.

Boiling point (2.66 kPa): 98-100 C.

The compound of Example 2 below was prepared in the same manner as in Example 1.

Example 2

Preparation of 3-oxoheptane ethyl ester

Compound of formula III:

R 1 = n-butyl, R 8 = O-ethyl.

Boiling point (2.66 kPa): 115-120 ° C.

Example 3

Preparation of 4-Benzyloxy-3-oxobutanoic acid ethyl ester

Compound of Formula III: R8 = O-ethyl.

Sodium was added in portions of 60 grams of hydride

800 milliliters of anhydrous temperature was maintained. 500 ml of benzyl alcohol are then added dropwise.

the added solution containing 65.8 grams of 4-chloroacetate in the reaction mixture was then for 20 hours. Next to THF. The material was cooled to 10 ° C and ethyl benzyl alcohol was added. The reaction mixture was neutralized by slow addition (120 ml) with cooling while cooling. The whole was then poured onto and extracted with ether. The organic phase was sodium bicarbonate, dried over sulfate and concentrated to give an orange oil. The product was purified in two successive distillations to give a yellow oil.

65.8

The 200 ml stirred in the process was acetic acid in an ice bath. water / ice mixture washed with MgSO ₄ solution

Boiling point (at 50 psi): 126-132 ° C.

Example 4

4'-Bromomethyl-2-cyanobiphenyl

Compound of Formula IV:

W = Br

(a) Preparation of 2-cyano-4'-methylbiphenyl

563.8 grams of (4'-methylbiphenyl-2-yl) carboxylic acid, prepared according to the procedure of: Meyers A.I., Mihelich E.D., J. Am. Chem. Soc., 1975, 97 (25), 7383 added in small portions to 800 milliliters of thionyl chloride. The reaction mixture was refluxed for two hours. The thionyl chloride solution was concentrated under reduced pressure, and the obtained residue was poured into a 28% ammonium hydroxide solution, which was pre-cooled in a water-ice bath. The reaction mixture was stirred for 30 minutes, the crystals were filtered off, washed with water and then with ether, and dried to give 554.8 g of (4'-methylbiphenyl-2-yl) carboxamide as crystals with a melting point of 128-132 ° C. The crystals were placed in 1300 ml of thionyl chloride and the reaction mixture was refluxed for 3 hours and then concentrated in vacuo to give an orange oil. The product was taken up in two liters of chloroform and washed with water, and the organic phase was concentrated to prepare

509.8 grams of an oil which was crystallized from pentane. In this way the desired product was obtained, m.p. j. 2-cyano-4'-methylbiphenyl.

Yield: 467.3 g. Melting point: 46 - 48 ° C.

(b) A process for preparing 4'-bromomethyl-2-cyanobiphenyl

467.3 grams of 2-cyano-4'-methylbiphenyl prepared as described above were dissolved in 4.7 liters of 1,2-dichloroethane in the presence of

467.3 grams of N-bromosuccinimide and 9.3 grams of benzoyl peroxide. The reaction mixture was heated gently slowly so as to carefully control the exothermic reaction. The product was refluxed for 4 hours, cooled to 50 ° C and washed three times with hot water and dried, and the organic phase was concentrated to give cream-colored crystals.

The product was recrystallized from isopropanol to give 451 grams of white crystals of 4'-bromomethyl-2-cyanobiphenyl. ¹

Melting point: 128 ° C.

Example 5

Preparation of 2 - [(2'-cyanobiphenyl-4yl) methyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R'2 = n-propyl,

R ₈ = 0-ethyl.

23 grams of 3-oxohexanoic acid ethyl ester prepared as described in Example 1 was dissolved in 120 ml of tetrahydrofuran. To this solution was added 30.3 g of 4 ' -bromomethyl-2-cyanobiphenyl prepared as described in Example 4 and 4.7 g of lithium chloride, and the reaction mixture was stirred at room temperature. Next, 39 ml of diisopropylethylamine was added dropwise, causing a slight exothermic effect. The mixture was stirred for three hours at room temperature and then for ten hours at reflux. The solvents were removed by evaporation under vacuum and the residue was taken up in water and then extracted with chloroform. The organic phase was decanted and then washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated in vacuo to give 38 grams of an orange oil.

The product is purified by chromatography on silica gel (elution with CHC1 ₃ was used) to yield the desired ethyl 2 - [(2'-cyanobiphenyl-4-yl) methyl] -3-oxohexanoate.

The compounds of Examples 6-10 were obtained in the same manner as in Example 5 using the appropriate β-ketoester to prepare the compounds below.

Example 6

Preparation of 2 - [(2'-cyanobiphenyl-4yl) methyl] -3-oxoheptanoic acid ethyl ester

Compound of Formula V:

R 1 = n-butyl,

Rg = O-ethyl,

The oil prepared by this procedure was used as such to carry out the next step.

Example 7

Preparation of 2 - [(2'-cyanobiphenyl-4yl) methyl] -3-oxobutanoic acid ethyl ester

Compound of Formula V:

R? = methyl, Rg = O-ethyl.

The yellow oil prepared by this procedure was purified by silica gel chromatography (eluent: 95% chloroform / 5% ether).

Example 8

Preparation of 2 - [(2'-cyanobiphenyl-4-yl) methyl] -3-oxopentanoic acid ethyl ester

Compound of Formula V:

R ' _χ = ethyl,

R8 = O-ethyl.

CN

The oil prepared by this procedure was purified by silica gel chromatography (eluent: 95% chloroform / 5% ether).

Example 9

Preparation of 2 - [(2'-cyanobiphenyl-4yl) methyl] -4-methoxy-3-oxobutanoic acid ethyl ester

Compound of Formula V:

R'1 = methoxymethyl, _R8 = O-ethyl.

CN

The yellow oil prepared by this procedure was purified by silica gel chromatography (eluent: 95%).

In chloroform / 5% ether).

Example 10

Preparation of 2 - [(2'-Cyanobiphenyl-4-yl) methyl] -3-oxobutanoic acid ethyl ester

Compound of Formula V:

R8 = O-ethyl.

CN

The oil prepared by this procedure was purified by chromatography twice in succession (eluent: chloroform and then 80% cyclohexane / 20% ethyl acetate).

Example 11

Preparation of 2- [4- (3-cyano-2-pyridyl) benzyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R _x = CH ₂ CH ₂ CH _3, R = O-ethyl.

CN

V (a) Preparation of 4-bromobenzyl methyl ether

A solution containing sodium methylate prepared from 11.8 grams of sodium and 350 milliliters of methanol was added dropwise carefully to a suspension containing 117.7 grams of 4-bromobenzyl bromide in 350 milliliters of methanol. The reaction mixture was stirred for 2 hours at room temperature and allowed to stand overnight. The methanol was evaporated and the residue taken up in ether, the organic phase washed with water, dried and concentrated to give a yellow oil which was purified by distillation. The desired bromobenzyl methyl ether was prepared as a colorless liquid.

Yield: 102 g. Boiling point (at 20 psi): 112-114 ° C.

(b) Preparation of 3-cyano-2- (4-methoxymethylphenyl) pyridine

In this embodiment, 2 grams of 4-bromobenzyl methyl ether, i.e., the compounds prepared above, were added to a suspension containing 18 grams of magnesium in 50 milliliters of anhydrous THF. The formation of the magnesium compound was initiated by several crystals of iodine and, if necessary, by heating with a hot water bath. A solution containing 121.8 g of 4-bromobenzyl methyl ether in 200 ml of anhydrous THF was added dropwise in such a way that the temperature did not exceed 40 ° C. The components were then reacted for 1 hour at room temperature, after which 800 ml of a solution of zinc chloride in ether was added under a positive pressure of nitrogen gas. This gave a white precipitate. The reactants were then allowed to react for 1 hour 30 minutes at room temperature. 800 mg of bis (triphenylphosphine) nickel (II) chloride [NiPienylphenyl] -1H 2 O was added, and a solution containing 76.9 grams of 2-chloronicotinenitrile in 300 ml of THF was added. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The concentrate was then added to a mixture of one liter of dichloromethane, one liter of water and one liter of disodium EDTA. The resulting emulsion was filtered on Celite 545. The organic phase was decanted, washed with water, dried and concentrated to give

133.6 grams of orange oil. This product was then purified twice by sequential chromatography (eluent: 95% chloroform / 5% ether). 69.4 g of 3-cyano-2- (4-methoxymethylphenyl) pyridine was isolated as an orange oil which crystallized.

Melting point: 74 DEG C. (c) Preparation of 3-cyano-2- (4-bromomethylphenyl) pyridine

Compound of Formula IV:

According to this embodiment

3-cyano-2- (4-methoxymethylphenyl) pyridine, dissolved as above in 700 ml, stabilized with amylene. 69.4 g of the above-prepared chloroform were obtained and the solution was cooled to -10 ° C. To this was added a solution containing milliliters of boron tribromide BBr ₃ in 200 milliliters of chloroform, which had been stabilized with amylene, and was carefully added dropwise such that the temperature did not exceed 5 ° C. The resulting reaction mixture was then allowed to stand for one hour and 30 minutes in an ice bath. Hydrolysis was carried out and then water. The mixture was filtered and the suspension was taken up in a mixture of water and chloroform. After decanting, the organic phases were combined, dried and then concentrated to give 78.2 grams of cream-colored 3-cyano-2- (4-bromomethylphenyl) -pyridine crystals.

Melting point: 118 ° C.

(d) Preparation of 2- [4- (3-cyano-2-pyridyl) benzyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

^R 1 = ch ₂ -ch ₂ -ch ₃ ,

Rg = O-ethyl,

The preparation of this compound was carried out in the same manner as in Example 5, whereby the expected derivative was obtained as an orange oil, which was then used as it was for the next step.

Example 12

Preparation of 2- [4- (3-cyano-2-thienyl) benzyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R 1 = ch ₂ -ch ₂ -ch ₃ ,

Rg = O-ethyl,

S (a) Preparation of 4-chloro-1- (4-methylphenyl) butanone

A mixture of up to 560 milliliters of 4-chlorobutyryl chloride and 550 milliliters of toluene was added dropwise to a slurry containing 740 grams of AlCl ₃ aluminum chloride in 2 liters of dichloromethane, maintaining the temperature of the reaction mixture at 10-15 ° C. C. The reaction mixture was stirred for 30 minutes at room temperature and poured onto ice. After decanting, the organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, dried and concentrated in vacuo to give 994.5 g.

4-chloro-1- (4-methylphenyl) butanone as an oil, which was then used for the next step without further purification.

(b) Preparation of 3-chloro-2- (2-chloroethyl) -3- (4-methylphenyl) -2-propen-1-alu

390 ml of phosphorus oxychloride POCl _{3 was} added dropwise at a temperature ranging from 7 ° C to 12 ° C to a solution containing 352.5 grams of 4-chloro-1- (4-methylphenyl) butanone prepared in advance according to the procedure of Example 12 ( The temperature of this reaction mixture gradually increased, in the first case to 50 ° C over a period of 2 hours and then to 75 ° C over a period of 45 minutes, and the reaction mixture was poured over ice and extracted three times. ether, the combined organic phases are washed with water and then dried and evaporated to give the desired product.

3-Chloro-2- (2-chloroethyl) -3- (4-methylphenyl) -2-propen-1-al as an oil, which was used as such in the next step.

Yield: 387.8 grams.

(c) A process for the preparation of 4,5-dihydro-3-formyl-2- (4-methylphenyl) thiophene

A mixture containing 200 grams of 3-chloro-2- (2-chloroethyl) -3- (4-methylphenyl) -2-propen-1-alu prepared as described in Example 12 (b) was further 2.2 liters of THF, 276.5 grams of Na ₂ S. 9 H ₂ O and 373 milliliters of water are refluxed for 6 hours. The reaction mixture was concentrated under vacuum and the concentrate was taken up in water and extracted three times with ether. The combined organic phases were washed with water, dried and concentrated to give an oil which gradually crystallized.

Yield: 170.3 g. Melting point: below 50 ° C.

(d) Preparation of 4,5-dihydro-3-formyl-2- (4-methylphenyl) thiophenoxime

132.1 grams of hydroxylamine hydrochloride was added portionwise to a solution containing 323.5 grams of the aldehyde prepared by the procedure of Example 12 (c) in 800 milliliters of ethanol. Sodium carbonate solution prepared from 100.5 grams of sodium carbonate Na ₂ CO ₃ and 700 ml of water was added dropwise to the reaction mixture. The reaction mixture was heated at 40 ° C for 5 minutes, and the reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was cooled to 15 ° C and the solid was filtered and washed with water and then with 50% isopropyl ether / 50% petroleum ether to give 252 grams of the desired oxime. Extraction of the filtrate with dichloromethane gave a second crop of 99 g of the desired oxime.

(e) Preparation of 3-cyano-4,5-dihydro-2- (4-methylphenyl) thiophene

A solution containing 171.8 grams of oxime, prepared as described in Example 12 (d) in 680 milliliters of acetic anhydride, was heated at reflux for 3 hours. The reaction mixture was concentrated to remove excess anhydride and then distilled to give the desired nitrile derivative.

Yield: 115.3 g

Boiling point (below 6.65 Pa): 140-150 ’C.

(f) Preparation of 3-cyano-2- (4-methylphenyl) thiophene

To an 62 ml of bromine in place of dropwise to the solution which was preheated to 50 ° C, said solution containing 191.3 g of the nitrile compound obtained in Example 12 (e) in 1.85 L of carbon tetrachloride CC1 ₄ . The whole was then heated at reflux until the HBr release ceased. Second CC1 ₄ carbon tetrachloride was evaporated and the residue was distilled to give the desired 3-cyano-2- (4-methylphenyl) thiophene.

Yield: 115.3 grams Boiling point (below 6.65-13.3 Pa): 130-150 ° C.

(g) Preparation of 2- (4-bromomethylphenyl) -3-cyanothiophene

General formula IV:

W = Br,

CN

IN

182.2 g of the compound of Example 12 (f) were brominated in the same manner as in Example 4 to give the desired 2- (4-bromomethylphenyl) -3-cyanothiophene.

Yield: 133.7 g Melting point: 80-84 ° C.

(h) Procedure for preparing 2- [4- (3-cyano-2-thienyl) benzyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R ₁ = CH ₂ -CH ₂ -CH ₃ ,

_Rg = O-ethyl,

According to this embodiment, 2- (4-bromomethylphenyl) -3-cyanothiophene, as described above, was further a mixture of 50 grams which was prepared as grams of ethyl ester of the acid.

3-oxohexane prepared as described in Example 1,

300 ml of tetrahydrofuran THF, 62 ml of diisopropylethylamine and 15.6 g of lithium bromide were heated at reflux for 15 minutes. The reaction mixture was concentrated under vacuum, dilute hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried and evaporated to give the desired 2- [4- (3-cyano-2-thienyl) benzyl] -3-oxohexanoic acid ethyl ester as an oil. used for other purposes without purification.

Yield: 62.4 g.

Example 13

Preparation of 2- [4- (3-cyano-2-furyl) benzyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R 1 = ch ₂ -ch ₂ -ch ₃ ,

Rg = O-ethyl,

CN (a) Preparation of 2- (4-methylphenyl) -3-furanoic acid

70.7 grams of p-toluidine, which was cooled in an ice-water bath, were treated with 205 ml of a 36% hydrochloric acid solution. The reaction mixture was stirred at 55 to 60 ° C for 30 minutes and then cooled back to 0 ° C. A solution containing 45 grams of sodium nitrite NaNO ₂ in 220 ml of water was then added. The reaction mixture was stirred for 1 hour at 0 ° C. The cooled solution was then added to the mixture containing

49.3 g of 3-furan acid, 220 ml of acetone, 23.4 g of copper chloride CuCl ₂ and 6.3 g of water that was cooled to -5 ^{& C.} The whole is then stirred at 0 ° C for 2 hours, then stirred at room temperature for 48 hours. The reaction mixture was stirred for 48 hours. The reaction mixture was extracted twice with ether and the organic phase was decanted, dried and concentrated to give an oil which crystallized after treatment with water. The crystals were filtered off and washed with 50 ml of a 50% methanol / water mixture to give the desired 2- (4-methylphenyl) -3-furanoic acid.

Yield: 13.4 g.

(b) Process for preparing 2- (4-methylphenyl) furan-3-carboxamide

20 milliliters of SOCl _{2 was} added to a solution containing 13.4 grams of furanoic acid prepared as described above in 70 milliliters of toluene. The mixture was heated to reflux for 3 hours, and the excess of SOC1 ₂ and the toluene was then distilled off to give an oil, which was then reacted with a solution comprising 100 ml of 1,2-dimethoxyethane saturated with ammonia The reaction was carried out at 5 ° C. The precipitate obtained was filtered off and washed with water and then with isopropanol to give white crystals of the desired amine.

Yield: 7 grams Melting point: 174 ° C.

(c) Preparation of 3-cyano-2- (4-methylphenyl) furan

The mixture, containing 12.2 g of the amide prepared above and 65 ml of SOCl ₂ , was refluxed for 3 hours and then concentrated under vacuum. The oil was taken up in chloroform and water and ice were added. After decanting, the aqueous phase was extracted with chloroform and the organic phases were combined, dried and evaporated to give an oil product. The oil was purified by silica gel chromatography (eluent: toluene) to give the product as an oil, which was then clarified.

Yield: 7.5 g

Melting point: 66 ° C.

(d) Preparation of 2- (4-bromomethylphenyl) -3-cyanofuran

Compound of Formula IV:

W = Br

CN

7.5 g of the compound of Example 13 (c) was brominated in the same manner as in Example 4 to give a silica gel chromatography (50% pentane / 50% toluene). 6 g of 5-bromo-3-cyano-2- (4-methylphenyl) furan (m.p. 88 DEG C.), 2.2 g

5-bromo-3-cyano-2- (4-bromomethylphenyl) furan (melting point: 114 ° C) and 2 grams of 2- (4-bromomethylphenyl) -3-cyanofuran.

Melting point: 108 C. C.

The compound, i.e., 5-bromo-3-cyano-2- (4-methylphenyl) furan, was then subjected to a further bromination reaction in the same manner as in Example 4 to give 5-bromo-2- (4-bromomethylphenyl). 13-Cyanofuran, which was another product of Example 13 (d) bis.

(e) Preparation of 2- [4- (3-cyano-2-furyl) benzyl) -3-oxohexanoic acid ethyl ester

Compound of Formula V:

^R 1 = CH ₂ -CH ₂ -CH ₃ , R ₈ = O-ethyl,

The 2- (4-bromomethylphenyl) -3-cyanofuran derivative obtained above was treated in the same manner as in Example 5 to give 2- [4- (3-cyano-2-) ethyl ester. furyl) benzyl] -3-oxohexane as an oil, which was then used in this crude state as obtained for the next procedure.

In a similar manner, the derivative obtained in Example 13 (d) bis, i.e. 5-bromo-2- (4-bromomethyl-phenyl) -3-cyanofuran, was treated in the same manner as in Example 5 to give the ethyl ester

2- [4- (5-bromo-3-cyano-2-furyl) benzyl] -3-oxohexane as an oil, which was another derivative of Example 13 bis.

Example 14

3 - [(2'-Cyanobiphenyl-4-yl) methyl] -2,4-dioxopentane

Compound of Formula V:

R 1 = CH ₃ ,

A mixture of 32.8 grams of 2,4-dioxopentane, 68 grams of 4'-bromomethyl-2-cyanobiphenyl prepared as described in Example 4, 88 milliliters of diisopropylamine and 10.6 grams of anhydrous lithium chloride in 300 ml of tetrahydrofuran at reflux for 27 hours. The reaction mixture was cooled and the precipitate was filtered off. The organic phase was concentrated to dryness to give 88.5 g of crystals. This was taken up in isopropanol and the mixture was filtered again to separate 38.8 grams of unreacted 4 ' -bromomethyl-2-cyanobiphenyl. The mother liquors were concentrated to give 26.5 grams of an oil which was purified on silica gel (eluent: chloroform) to give an additional 5.3 grams of 4'-bromomethyl-2-cyanobiphenyl and 12.2 grams of the desired 3- [(2'-cyanobiphenyl-4-yl) methyl] -2,4-dioxopentane as a yellow oil.

Example 15

Preparation of 5 - [(2'-cyanobiphenyl-4-yl) methyl] -4,6-dioxononanu 1 ^{Λ R} 8 CH ₂ CH ₂ CH _3, CH ₂ CH ₂ CH _3,

CN

According to this

The 4.6-dioxononane, an embodiment, was initially dissolved in 160 ml of anhydrous dimethylformamide DMF, 15.6 g, which was prepared from methylpropyl ketone and ethyl butyrate in the presence of lithium amide (according to CA 42: 4129 f). 4 grams of 60% sodium hydride NaH was added portionwise. After the exothermic reaction ceased, the reaction mixture was cooled to room temperature and a solution containing 27.2 grams was added.

4´-Bromomethyl-2-cyanobiphenyl prepared according to the procedure of Example 4 in 90 ml of dimethylformamide DMF was added dropwise. The reaction mixture was stirred for 30 minutes at room temperature and then heated at 60 ° C for 2 hours. The mixture was concentrated under vacuum and the concentrate was taken up in water / dichloromethane and acidified with dilute hydrochloric acid. After decantation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water, dried and concentrated to give 36.3 g of an oil which was purified twice by chromatography (eluent: chloroform and then 90% cyclohexane / 10% ethyl acetate). to give a solid identified by NMR as an enol tautomer with a melting point of 105 ° C and an oil corresponding to the diketone tautomeric form.

Example 16

Preparation of 2,4-dioxo-3 - [(2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methyl] pentane

Compound of Formula V:

R 1 = CH ₃ , R 8 ⁼ CH 3,

IN

A mixture of 11.8 g of 3 - [(2'-cyanobiphenyl-4-yl) methyl] -2,4-dioxopentane, prepared as described in Example 14, 200 ml of xylene and 9.3 g of azide was added. trimethyltin, heated at reflux for 50 hours. After 24 hours, a second equivalent portion of trimethyltin azide was added.

The reaction mixture was cooled and concentrated to a viscous oil which was chromatographed on silica gel (eluent: 90% chloroform / 10% methanol) to give 9.3 g of crystals.

Further work-up of acetonitrile gave 6.2 g of analytically pure 2,4-dioxo-3 - [(2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) methyl] pentane.

Empirical formula: ^C 19 ^H 18 ^N 4 ° 2 Melting point: 166 ° C.

Example 17

Preparation of 2 - [(2 '- (1H-Tetrazol-5-yl) -biphenyl-4-yl) methyl] -3-oxohexanoic acid ethyl ester

Compound of Formula V:

R'i = n-propyl,

R ₈ = O-ethyl,

IN

A mixture containing 69.9 g of 2 - [(2'-cyanobiphenyl-4-yl) methyl] -3-oxohexanoic acid ethyl ester, prepared as described in Example 5, was further treated with 700 ml of anhydrous toluene and 47 ml. 5 grams of trimethyltin azide, prepared from sodium azide and trimethyltin chloride, was heated at reflux for 24 hours. An additional portion of trimethyltin azide (47.5 g) was added and the reaction mixture was heated at reflux for an additional 16 hours. The mixture was then concentrated to 50%. The orange solution was purified twice by flash chromatography (eluent: 90% chloroform / 10% methanol, then 95% chloroform / 5% methanol) to give the final product as an orange oil, which crystallized out .

Yield: 58 grams.

Melting point: 65 ° C.

Example 18 (Method A)

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-

5-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R? = n-propyl group,

X = nitrogen,

Y = CH R ₁₀ = OH,

NC

IN

A mixture of 1.7 grams of 3-amino-1,2,4-triazole, 7 grams of the β-ketoester prepared according to Example 5 and 30 milliliters of acetic acid was refluxed for 6 hours. hours. The acetic acid was evaporated. The oil thus obtained was purified by silica gel chromatography (eluent: 90% CHCl ₃ /10% MeOH) to give 5.2 g of the starting β-ketoester and 1.2 g.

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

Melting point: 200-205 ° C.

^X H NMR (200 MHz, _DMSO-d6):

2.65 (t, 2H, propyl _CH2), 8.2 (s, 1 H, ₂ H)

UV (10gg / ml, MeOH):

_a = 209.1 nm, b = 257.7 nm, _c = 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

Compound of Formula VIII-b:

R ₃ = n-propyl,

X = nitrogen,

Y = CH,

R ₁₀ = OH,

A mixture containing 7.1 grams of β-ketoester, prepared as described in Example 5,

1.7 g of 3-amino-1,2,4-triazole and 70 ml of 1,24-trichlorobenzene were heated at reflux for 7 hours. The reaction mixture was then concentrated under vacuum. This gave a thick oil which was chromatographed on silica gel (eluent: 95% CHCl ₃ /5%).

MeOH) to give 0.8 g of the isomer prepared according to the procedure of Example 18 (melting point: 200 ° C) and 2.2 g of 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-hydroxy -7-propyl-1,2,4-triazolo [1,5-a] pyrimidine.

Melting point: 212 ° C.

NMR (200 MHz, DMSO-d?): 2.98 (t, 2H, propyl _CH2);

8.1 (S, 1H, H ₂ ).

UV (10 µg / ml, MeOH): _a = 207.5 nm, _b = 258.2 nm.

Example 20 (Method C)

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

Compound of Formula III-a:

R ¹ ! = n-propyl, X = CH,

Y = nitrogen,

R ₁₀ = OH,

(a) Preparation of 5 - [(2 '-cyanobiphenyl-4-yl) methyl] -4-hydroxy-6-propyl-2-mercaptopyrimidine

11 grams of thiourea were added with a spatula to a sodium methylate solution prepared from 4.6 grams of sodium and 150 milliliters of methanol. 34.9 g of β-ketoester prepared as described in Example 5 and dissolved in 50 ml of methanol was added dropwise. The reaction mixture was allowed to stand overnight and then heated at reflux for 7 hours. The reaction mixture was concentrated under vacuum, the concentrate was taken up in 500 ml of water and acidified by the addition of concentrated hydrochloric acid to pH 1. The gummy precipitate was collected and taken up in methanol. The above procedure yielded 17.3 grams of white crystals of the desired 5 - [(2'-cyanobiphenyl-4-yl) methyl] 4-hydroxy-6-propyl-2-mercaptopyrimidine.

Melting point: 196 ° C.

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

Compound of Formula IX: = n-propyl,

R ₂ = OH,

17.3 g of the compound prepared above were introduced portionwise into a mixture containing 340 ml of methanol and 2.9 g of potassium hydroxide KOH. After a clear solution was formed, the mixture was cooled, and 3.4 ml of ICH ₃ was added dropwise.

The reaction mixture was allowed to react for 2 hours at room temperature.

The resulting precipitate was filtered to give 17.2 g of 5 - [(2'-cyanobiphenyl-4-yl) methyl] -4-hydroxy-2-methylmercapto-6-propylpyrimidine.

Melting point: 220 ° C.

(c) Preparation of 5 - [(2'-Cyanobiphenyl-4-yl) methyl] -2-hydrazine-4-hydroxy-6-propylpyrimidine

Compound of formula (X):

Rj = n-propyl,

R ₂ = OH,

IN

67 In this embodiment, 12.4 grams of 5 - [(2'-cyanobiphenyl-4-yl) methyl] -4-hydroxy-2-methylmercapto-6-propylpyrimidine prepared as described above were dissolved in 370 ml of 2-methoxyethanol. . To the reaction mixture was added 33 mL of hydrazine hydride, and the mixture was heated at reflux for 3 hours. The reaction mixture was concentrated under vacuum, the concentrate was taken up in acetonitrile and triturated. The resulting solid was filtered and washed with ether and isopropyl ether to give the desired 5 - [(2'-cyanobiphenyl-4-yl) methyl] -2-hydroxy-4-hydroxy-6-propylpyrimidine.

Yield: 9.9 g

Melting point: 191 C. C.

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

Compound of Formula III-a:

R’l = n-propyl group,

X = CH,

Y = nitrogen,

R ₁₀ = OH,

10 grams of 5 - [(2'-cyanobiphenyl-4-yl) methyl] -2-hydrazine-4-hydroxy-6-propylpyrimidine prepared as described above was placed in 100 ml of formic acid. The mixture was then heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure to give a thick oil, which was then taken up in water and triturated until the residue crystallized.

The compound was purified by chromatography on silica gel (eluent: 95% CHCl _3/5 / MeOH).

By the above procedure, the desired was prepared

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

Yield: 8.3 grams Melting point: 217 C. C.

^T H NMR _(DMSO-d6):

2.6 (t, 2H, propyl _CH2), 9 (s, 1 H, ₃ H)

UV (10 µg / ml, MeOH):

_a = 210.2 nm, 257.5 nm, a = _c = 303.4 nm.

Example 21

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-

5-propyl-1,2,4-triazolo [4,3-a] pyrimidine

Compound of Formula VIII-b:

R'j = n-propyl,

X = CH,

Y = nitrogen,

R &lt; ₁₀ &gt;

In the same manner as in Example 20, step (d), 1.1 grams of 6 - [(2'-cyanobiphenyl-4-yl) methyl] were also obtained in addition to the compound of this example. -7-hydroxy-5-propyl-1,2,4-triazolo [4,3-a] pyrimidine.

Melting point: 204 - 206 C.

¹ H NMR (DMSO-d 6):

2.9 (t, 2H, propyl _CH2), (s, 1 H, ₃ H).

UV (10 µg / ml, MeOH): _a = 211.5 nm, _b = 260 nm.

The above compounds of Examples 20 and 21 can also be prepared by reacting compound 20 (c) with triethyl orthoformate, refluxing for 5 hours. In this case, the proportion of the compound of Example 21 was found to be slightly higher.

Example 22 (Method D)

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-

5-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R = n-propyl,

X = nitrogen,

Y = CH, R ₁₀ = OH,

500 mg of 6 - [(2'-cyanobiphenyl-4-ylmethyl) -5-hydroxy-7-propyl-1,2,4-triazolo [4,3-a] pyrimidine, i.e., the compound prepared according to of Example 20 (d) heated in a metal bath at 225 ° C for 2 hours and 30 minutes, then allowed to cool, then taken up in methanol and further in isopropyl acetate to yield 300 mg of cream-colored crystals the product obtained was identical to the compound of the example

18th

Melting point: 200 ° C.

Example 23

Preparation of 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-hydroxy-

7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R '= n-propyl,

X = nitrogen,

Y = CH, R 10 = OH,

CN

IN

According to this embodiment, a mixture containing 24 grams of 3-amino-1,2,4-triazole and 200 grams of 5-ethyl-2-methylpyridine was heated to 175 ° C. 100 grams of the β-ketoester, prepared as described in Example 5, dissolved in 100 milliliters of 5-ethyl-2-methylpyridine, was added dropwise. The reaction was then allowed to proceed spontaneously for 6 hours at 175 ° C. Next, ethylmethylpyridine was distilled off under vacuum and the residue was taken up in a mixture of water and chloroform. After decantation, the aqueous phase was extracted with chloroform. The combined organic phases were washed with dilute hydrochloric acid solution and then with water, dried and concentrated to give an oil which crystallized upon trituration in methanol. Recrystallization from n-butanol gave cream colored crystals of the desired product, m.p. j. 6 - [(2 &apos; -cyanobiphenyl-4-yl) methyl] -5-hydroxy-7-propyl-1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 35.2 g.

Purification of the mother liquors by silica gel chromatography gave a second crop of 6.9 g of the title compound together with 13.9 g of the derivative, m.p. zn.

6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine, a product prepared according to the procedure of Example 18.

Melting point: 196 ° C.

The yield of this reaction can be improved by about 10% by addition

10.5 grams of 4-dimethylaminopyridine to the initial reaction mixture.

Example 24

Preparation of 6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-2-methyl-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine hydrochloride hemihydrate

Compound of Formula III-a:

R '= n-propyl,

X = nitrogen,

Y = C-CH _3,

R ₁₀ = OH,

CN

A suspension containing 10 grams of the compound of Example 20 (c) in 100 mL of phenylacetate was heated at reflux for 4 hours. The reaction mixture was then concentrated under reduced pressure. The concentrate was taken up in water and the mixture was extracted with chloroform, the extract was dried and evaporated to give 9.8 g of white crystals, mp 205 ° C. The crystals were added to a mixture of 50 ml of acetonitrile and 40 ml of a 10% solution of hydrochloric acid in ether to give the desired hydrochloride,

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

Yield: 7.5 g. Empirical formula: C 23 H 21 N 5 O. HCl. 1/2 H ₂ O. Melting point: 190 ^e C.

^X H NMR _(DMSO-d6):

2.65 (t, 2H, propyl _CH2);

UV (MeOH): _a = b ⁼ c ⁼ 213.7 nm, 257.7 nm, 285.0 nm. Example 25

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydroxy-

7-propyl-3-mercapto-1,2,4-triazolo [4,3-a] pyrimidine

Compound of Formula III-a:

R'1 = n-propyl,

X = C-SH

Y = nitrogen,

R ₁₀ = OH,

5.3 milliliters of carbon disulfide was added to a suspension containing 10 grams of the compound of Example 20 (c) in 300 milliliters of butanol. The reaction mixture was heated at reflux for 2 hours. An additional 5.3 ml of CS ₂ was then added and refluxing was continued for 5 hours. The reaction mixture was concentrated under vacuum. The concentrate was taken up in water and then extracted three times with chloroform. Then, the solvent was evaporated to give 10.8 g of amorphous crystals, which are then purified by chromatography on silica gel (eluent: 90% CHC1 ₃ / 1O% MeOH).

The first isolated and identified compound was 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propyl-3-mercapto-1,2,4-triazolo [4,3-a] pyrimidine, which was obtained in an amount of 1.9 g. This product is a compound of Example 25 bis.

Melting point: 240 ° C.

^X H NMR (DMSO-d):

3.5 (t, 2H, propyl _CH2).

The second isolated compound was the predicted product, i.e. 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-hydroxy-7-propyl-3-mercapto-1,2,4-triazolo [4,3-a] pyrimidine, which was obtained in an amount of 1 gram.

Melting point: 180 C.

¹ H NMR (DMSO-d 6):

2.5 (m, propyl _CH2 + DMSO-d?).

The third product isolated was the starting hydrazine compound 20 (c), which was obtained in an amount of 6.2 grams.

Example 26

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -3,5-dihydroxy-7-propyl-1,2,4-triazolo [4,3-a] pyrimidine

Compound of Formula III-a:

R'1 = n-propyl,

X = C-OH

Y = nitrogen,

Rjq = OH,

4.6 grams of carbonyldiimidazole was added to a mixture containing 10 grams of the compound of Example 20 (c) and 500 mL of THF, heated to 50 ° C. The whole was heated to reflux for 7 hours and then concentrated under vacuum. The concentrate was taken up in water and extracted three times with chloroform. Evaporation of the solvent gave 12.4 g of amorphous crystals which were purified by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH).

The first isolated and identified compound was 6 - [(2'-cyanobiphenyl-4-yl) methyl] -3,7-dihydroxy-5-propyl-1,2,4-triazolo [4,3-a] pyrimidine, which was obtained in an amount of 3.1 grams. This product is a compound of Example 26 bis.

Melting point: 228 DEG C. @ ¹ H NMR (DMSO-d6): _.delta .

(t, 2H, propyl _CH2).

The second isolated compound was the predicted product, i.e. 6 - [(2'-cyanobiphenyl-4-yl) methyl] -3,5-dihydroxy-7-propyl-1,2,4-triazolo [4,3-a] pyrimidine, which was obtained in an amount of 3.8 g.

Melting point: 210 C. C.

¹ H NMR (DMSO-d 6):

2.5 (t, 2H, propyl _CH2).

The following compounds obtained according to Examples 27 to 43 were prepared using one of the methods described in Examples 19 or 23 (Method B or Method E), and the appropriate aminotriazoles were reacted with the β-ketoesters prepared according to the Examples. 5 to

15th

Example 27

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

Compound of Formula VIII-b:

R'j = n-propyl,

X = nitrogen,

Y = C-CH _3,

R ₁₀ = OH,

CN

Crystallization of the product was performed from methanol. The mother liquors were purified by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH).

Melting point: 218-220 ° C.

The second isolated and identified compound was 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-2-methyl-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine. This compound was the product of Example 27 bis.

Compound of Formula III-a:

R'2 = n-propyl,

X = nitrogen,

Y = C-CH _3,

R ₁₀ = OH,

Mp .: 204-206 ° C.

Example 28

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

Compound of Formula VIII-b:

R'2 = n-propyl,

X = nitrogen,

Y = C-CH ₂ CH ₃

R ₁₀ = OH,

Crystallization of the product was performed from methanol. The mother liquors were purified by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH).

The second isolated and identified compound was 6 - [(2'-cyanobiphenyl-4-yl) methyl] -2-ethyl-7-hydroxy-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine. the product of Example 28 bis.

Compound of Formula III-a:

R'i = n-propyl,

X = nitrogen,

Y = C-CH ₂ CH ₃

R ₁₀ = OH,

NC

Melting point: 186 ° C.

Example 29

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-n-butyl-

5-hydroxy-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R'1 = n-butyl,

X = nitrogen,

Y = CH,

R ₁₀ = OH,

NC

The product was crystallized from n-butanol.

Melting point: 210 ^e C.

Example 30

Preparation of 2-amino-6 - [(2'-cyanobiphenyl-4-yl) methyl] -

5-hydroxy-7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R? = n-propyl group,

X = nitrogen,

Y = _C-NH2,

_Lo R = OH,

NC

Crystallization of the product was performed from a mixture of methanol and chloroform.

The mother liquors were purified by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH).

Melting point: 260 C.

The second isolated and identified compound was 2-amino-

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine. This compound was the product of Example 30 bis.

Compound of Formula III-a:

R ' ₃ = n-propyl,

X = nitrogen,

Y = _C-NH2,

R ₁₀ = OH,

Melting point: 325-330 ° C.

Example 31

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydroxy-2-methylthio-7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R'j = n-propyl,

X = nitrogen,

Y = SCH ₃ group

= OH group,

NC

Purification of the product was performed by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH).

Crystallization of the product was performed from isopropyl acetate.

Melting point: 182 C. C.

Example 32

Preparation of 6- [4- (3-cyano-2-thienyl) benzyl] -5-hydroxy81

7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R '= n-propyl,

X = nitrogen,

Y = CH,

_Lo R = OH,

NC

Crystallization of the product was performed from a mixture of chloroform and water. The product was purified by recrystallization from 2-methoxyethanol.

Melting point: 246 ° C.

Example 33

6- [4- (3-Cyano-2-pyridyl) benzyl] -5-hydroxy-

7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R'1 = n-propyl group,

X = nitrogen,

Y = CH,

R ₁₀ = OH .N.

NC

Crystallization of the product was performed from methanol. mother

The liquors were purified by chromatography on silica gel (eluent: 97.5% CH ₂ Cl ₂ / MeOH 2.5%). The whole was purified by recrystallization from methanol.

Melting point: 212 ° C.

Example 34

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

Compound of Formula VIII-b:

R'2 = n-propyl,

X = nitrogen,

Y = C-CH _3,

R ₁₀ = OH,

Crystallization of the product was performed from a mixture of water and chloroform. The product was purified by recrystallization from 2-methoxyethanol.

Melting point: 277 C. C.

Example 35

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

Compound of Formula VIII-b:

R ' _T = n-propyl,

X = nitrogen,

Y = CH,

R ₁₀ = OH,

Melting point: 256 ° C.

Example 36

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

Compound of Formula VIII-b:

R'2 = n-butyl,

X = nitrogen,

Y = C-CH _3,

R ₁₀ = OH,

The product was purified by recrystallization from n-butanol.

Melting point: 230 ° C.

Example 37

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydroxy-2-hydroxymethyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

= N-propyl, = N, = C-CH ₂ -OH, = OH,

Purification of the product was performed by chromatography on silica gel (eluent: 95% CHCl ₃ /5% MeOH).

Melting point: 214 ° C.

Example 38

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

Compound of Formula VIII-b:

R'j = -CH ₂ -OCH ₃ ,

X = nitrogen,

Y = CH,

R ₁₀ = OH,

Purification of the product was performed by chromatography on silica gel (eluent: 95% chloroform / 5% methanol).

Melting point: 188 ° C.

The second isolated and identified compound was 6 - [(2 ', cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-methoxymethyl-1,2,4-triazolo [1,5-a] pyrimidine. This compound was the product of Example 38 bis.

Compound of Formula III-a:

R ₁ = -CH ₂ -OCH ₃

X = nitrogen,

Y = CH,

R ₁₀ = OH,

NC

Melting point: 240 ’C.

Example 39

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydroxy-7-methyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R? = CH ₃ ,

X = nitrogen,

Y = CH,

_Rig = OH,

Purification of the product was carried out by chromatography on silica gel (eluent: 95% CHCl ₃ /5% MeOH) and crystallization from methanol.

Melting point: 212 ° C.

The second isolated and identified compound was

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-methyl-1,2,4-triazolo [1,5-a] pyrimidine. This compound was the product of Example 39 bis.

Compound of Formula III-a:

R'j = CH ₃ ,

X = nitrogen,

Y = CH,

R ₁₀ = OH,

Mp .: 252 ° C.

Example 40

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

Compound of Formula VIII-b:

R'j = ethyl,

X = nitrogen,

Y = CH,

Rjq = OH,

NC

The product was isolated by silica gel chromatography (eluent: 95% CHCl ₃ /5% MeOH) and purified by recrystallization from n-butanol.

Melting point: 224 ’C.

The second isolated and identified compound was

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-ethyl-7-hydroxy-1,2,4-triazolo [1,5-a] pyrimidine. This compound represented the product of Example 40 bis.

Compound of Formula III-a:

R ¹ ! = -CH ₂ -CH ₃

X = nitrogen,

Y = CH,

R ₁₀ = OH,

NC

Melting point: 234 C. C.

Example 41

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

Compound of formula III-b: R 'j = n-propyl,

X = nitrogen,

R10 = OH,

This product was crystallized from methanol.

Melting point: 220 ° C.

The second compound was isolated as amorphous crystals which were obtained after chromatographic treatment of the mother liquors on silica gel (eluent: 80% CHCl ₃ /20% isopropylamine). This compound was identified as 6 - [(2'-cyanobiphenyl-4-yl) methyl] -2-N, N-diethylamino-7-hydroxy-5-propyl 89,2,4-triazolo [1,5-a] pyrimidine . This compound was the product of Example 41bis.

Compound of Formula III-a: R ' = n-propyl group,

X = nitrogen,

R ₁₀ = OH,

Example 42

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5,7-dipropyl-

1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R'j = n-propyl,

X = nitrogen,

Y = CH,

R _lo = n-propyl,

IN

Purification of the product was performed by silica gel chromatography (eluent: 95% chloroform / 5% methanol).

Melting point: 160 ’C.

Example 43

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

Compound of Formula VIII-b:

X = nitrogen,

Y = CH,

R ₁₀ = OH,

The product was purified by recrystallization from butanol followed by purification by silica gel chromatography (eluent: 95% chloroform / 5% methanol).

Melting point: 218 C.

The second isolated and identified compound was

5-benzyloxymethyl-6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-l, 2,4-triazol [l, 5-a] pyrimidine. This compound was the product of Example 43bis.

Compound of Formula III-a: X = nitrogen,

Y = CH,

Rjq = OH,

Melting point: 260 C.

Example 44

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

Compound of Formula VIII-b:

R'1 = n-propyl,

X = nitrogen,

Y = CH,

IN

25.9 grams of the compound of Example 19 or 23 were added portionwise to 260 mL of POCl 2. The reaction mixture was heated to reflux for 4 hours. It was then concentrated under vacuum and the concentrate was added to 200 ml of chloroform, which had been stabilized with amylene, and a solution of water and ice was added. After decantation, the aqueous phase was extracted with chloroform and the organic phases were combined. After washing with water and drying, it was concentrated under vacuum to give a thick oil. The product was crystallized from isopropyl acetate to give 5-chloro-6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-propyl-1,2,4-triazole [1,2-a], m.p. 5-a] pyrimidine.

Yield: 21 grams.

Melting point: 138 ° C.

The derivative of Example 45 was prepared according to the procedure of Example 44 using the compounds of Example 18.

Example 45

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

Compound of Formula VIII-a:

R'2 = n-propyl,

X = nitrogen,

Y = CH

Melting point: 132 DEG C.

Example 46

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-mercapto-

5-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₂ = n-propyl,

X = nitrogen,

Y = CH, = SH

A mixture of 5 grams of the chlorinated compound obtained by the procedure of Example 45, 2 grams of thiourea and 150 ml of ethanol was heated at reflux for 7 hours, and the mixture was concentrated under vacuum. The resulting yellow solid was added to 60 mL of 0.5 N NaOH. A small portion of the undissolved material was filtered off. The filtrate was acidified with acetic acid. The resulting yellow precipitate was filtered and purified by silica gel chromatography (eluent: 90% chloroform / 10% methanol) to give the desired 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-mercapto-5- propyl-1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 3.4 grams.

Melting point: 200-205 ° C.

Example 47

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-mercapto-

7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

Rj = n-propyl,

X = nitrogen,

Y = CH,

R ₂ = SH

NC

A mixture of 11.1 grams of the derivative prepared according to Example 19 or 23, further 350 ml of toluene and 13.4 grams of Lawesson's reagent, was heated at reflux for 2 hours. The resulting yellow solid was filtered off. Purification of the product by silica gel chromatography (eluent: 90% CH ₂ Cl ₂ /10% acetone) afforded the desired 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-mercapto-7- propyl

1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 10 grams.

Melting point: 226 ° C.

Example 48

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-propyl-

1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R-L = n-propyl,

X = nitrogen,

Y = CH,

R _{2 is} hydrogen.

In this embodiment, a solution of 5.4 grams of the compound of Example 44 in 110 milliliters of 2-methoxyethanol containing 1.2 grams of anhydrous sodium acetate was hydrogenated at atmospheric pressure and at room temperature in the presence of 1.4 grams of 5% - palladium on activated carbon. The hydrogenation system used was purged with nitrogen. After hydrogenation, the catalyst was filtered off on Celite 545 and washed with hot 2-methoxyethanol. The filtrate was concentrated and the obtained crystals were added to ether to give 3.7 grams of crude product. This product was purified by silica gel chromatography (eluent: 90% dichloromethane / 10% acetone) to give the desired 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-propyl-1,2,4 -triazolo [1,5-a] pyrimidine in the form of white crystals.

Yield: 2.5 g.

Melting point: 180 ° C.

Example 49

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-methoxy-

7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R @ 1 = n-propyl,

X = nitrogen,

Y = CH,

R ₂ = OCH _third

A solution containing sodium methylate prepared from 0.8 g of sodium and 25 ml of methanol was added to a solution containing 11.6 g of the compound of Example 44 in 120 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for 3 hours. The resulting insoluble material was filtered off and the filtrate was concentrated. The crystals thus obtained were taken up in water, the mixture was filtered and the product was washed first with water and then with isopropyl alcohol and ether to obtain the desired 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-methoxy-7-propyl -l, 2,4-triazolo [1,5-a] pyrimidine.

Yield: 9.5 g.

Melting point: 166 ’C.

Example 50

[6 - [(2'-Cyanobiphenyl-4yl) methyl] -7-propyl-1,2,4-triazolo [1,5-a] pyrimidin-5-yl] mercaptoacetic acid ethyl ester

Compound of Formula IX:

R = n-propyl,

X = nitrogen,

Y = CH,

R ₂ = -S-CH ₂ -COOCH ₂ -CH ₃ .

IN

97 grams of 60% NaH was added portionwise to a solution containing 1.8 grams of mercaptoacetic acid ethyl ester in 50 ml of toluene. The reaction mixture was kept at 40 ° C for 1/2 hour and then cooled to room temperature. A solution containing 5 grams of the compound of Example 44 in 50 ml of anhydrous toluene was then added. The reaction was then allowed to proceed at room temperature for 3 hours and then at 50 ° C for 4 hours. To complete the reaction, a second equivalent portion of the sodium salt of mercaptoacetic acid ethyl ester, prepared as described above, was added. After hydrolysis and decantation, the organic phase was washed with water and then with dilute acetic acid solution, dried and concentrated. The oil was then purified by silica gel chromatography (eluent: 90% dichloromethane / 10% acetone) to give the desired [6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-propyl-1 ethyl ester. 2,4-triazolo [1,5-a] pyrimidin-5-yl] mercaptoacetic acid.

Yield: 5.4 g

Melting point: 76 ° C

The compound of Example 51 was prepared in the same manner as in Example 50, but using 2-methoxyethanol instead of mercaptoacetic acid ethyl ester.

Example 51

[6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-propyl-

1,2,4-triazolo [1,5-a] pyrimidin-5-yl] -2-methoxyethyl ether

Compound of Formula IX:

= n-propyl group,

X = nitrogen,

Y = CH,

R ₂ = -O-CH ₂ -CH ₂ -OCH ₃ .

The product obtained was crystallized from isopropyl ether.

102 °.

Example 52

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

Compound of Formula IX:

R @ 1 = n-propyl,

X = nitrogen,

Y = CH,

R ₂ = NH _second

A mixture of 10 grams of the derivative prepared according to Example 44 and 200 ml of an ammonia-saturated solution of 1,2-dimethoxyethane was placed in an autoclave. The mixture was heated to 125 ° C and held at this temperature for 24 hours before transferring the reaction mixture to chloroform / water. After decanting, the aqueous phase was extracted. The combined organic phases were dried and concentrated to give the desired product

5-amino-6 - [(2 &apos; -cyano-biphenyl-4-yl) methyl] -7-propyl-1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 8.1 grams.

Melting point: 206 ° C.

Example 53

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

Compound of Formula IX:

R ₂ = n-propyl,

X = nitrogen,

Y = CH.

CH, —CH, ^β = C — N

A mixture of 5 grams of the chlorinated derivative prepared according to Example 45, 100 ml of ethanol, 16 ml of diethylamine and 1.5 g of sodium carbonate was refluxed for 4 hours. The reaction mixture was concentrated under vacuum and the thick oil was then obtained

100 embedded in water. The mixture was extracted three times with dichloromethane and the combined extracts were dried over silica gel, eluting with 95% chloroform / 5% methanol to give the desired 6 - [(2'-cyanobiphenyl-4-). yl) methyl] -7-N, N-diethylamino-5-propyl-1,2,4-triazolo [1,5-a] pyrimidine as an orange oil.

Yield: 5 grams.

The compounds exemplified in Examples 54-58 were prepared by reacting one of the derivatives described in Examples 44 or 45 with the appropriate amines by one or two of the methods described in Examples 52 and 53.

Example 54

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

Compound of Formula IX:

R = n-propyl,

X = nitrogen,

Y = CH.

CH, CH ^_3/2-N C \

ch ₂ —CH ₃

NC

The product obtained was crystallized by isopropyl ether.

hot

101

M.p .: 133 ° C.

Example 55

Preparation of 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-propyl

5- (pyrrolidin-l-yl) -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

Rj = n-propyl,

X = nitrogen,

Y = CH.

NC

The product obtained was crystallized from hot isopropyl ether.

Melting point: 166 ’C.

Example 56

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -7-propyl-5- (morpholin-4-ylethylamino) -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R = n-propyl,

X = nitrogen,

Y = CH.

102

NC

The resulting oil was purified by silica gel chromatography (eluent: 95% chloroform / 5% methanol).

Example 57

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5- (piperidin-1-yl) -7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₂ = n-propyl,

X = nitrogen,

Y = CH.

NC

IN

103

The obtained compound was purified by recrystallization from 2-methoxyethanol.

Melting point: 266 ° C.

Example 58

6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydrazine-7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula IX:

R _x = n-propyl,

X = nitrogen,

Y = CH,

R ₂ = NH-NH _second

NC

The obtained compound was purified by crystallization from ether. Melting point: 161 C.

Example 59

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

Compound of Formula IX:

R 11 = n-propyl group,

X = nitrogen,

Y = CH, ^{R2 =} ^ 3 '

104

10.3 g of the compound prepared according to Example 58, 2.3 ml of concentrated hydrochloric acid and 300 ml of acetic acid were mixed. A solution containing 12.9 grams of sodium nitrite NaNO ₂ in 20 ml of water was added to the mixture. The reaction mixture was left overnight at room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried and evaporated. The product was then purified twice by chromatography (eluent: 95% dichloromethane / 5% methanol and 90% dichloromethane / 10% methanol) to give the desired 5-azido-6 - [(2'-cyanobiphenyl-4-yl). (methyl) -7-propyl-1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 4.3 grams. Melting point: 134 C.

The same compound can be considered a tricyclic derivative due to the known azide equilibrium at the 2-position of the nitrogen-containing rings (see Temple and Montgomery, J. Org. Chem., 30, 826 (1965)).

Example 60

Preparation of 3-amino-5-hydroxymethyl-1,2,4-triazole

Compound of Formula II:

105

R? = -CH ₂ OH.

According to this example, the mixture containing 136 grams of aminoguanidine bicarbonate and 80 grams of glycolic acid was gradually heated to 120 ° C. The reaction was then carried out at this temperature for 5 hours. The reaction mixture was added to 100 ml of ethanol and the solid was filtered to give the desired 3-amino-5-hydroxymethyl-

1,2,4-triazole.

Yield: 45.7 grams. Melting point: 192-194 ° C.

Example 61

Preparation of 3-amino-5-N, N-diethylamino-1,2,4-triazole

Compound of Formula II:

10.3 milliliters of diethylamine was added to a solution containing 16.1 grams of N -cyanodithioiminocarbonic acid dimethyl ester in 160 milliliters of acetonitrile. The reaction mixture was stirred for one hour at room temperature and then heated to reflux until no more methyl mercaptan was released. The reaction solution was cooled in an ice bath and 5 ml of hydrazine hydrate were added. The reaction mixture was refluxed for 4 hours. After distilling off the solvent, the product was added to acetonitrile to give the desired 3-amino-5-N, N-diethylamino-1,2,4-triazole as white solids.

106 crystals.

Yield: 8.9 grams.

Melting point: 134 ° C.

Example 62

7-Hydroxy-5-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R _T = OH,

R ₂ = n-propyl,

X = nitrogen,

Y = CH.

A mixture containing 7.8 grams of the β-ketoester prepared according to Example 17, 1.7 grams of 3-amino-1,2,4-triazole and 70 ml of 1,2,4-trichlorobenzene was heated at 120 ° C. for 7 hours. A precipitate was obtained, which was purified by silica gel chromatography (eluent: 80% CH ₂ Cl ₂ /20% methanol). The compound thus obtained was dissolved in 1 N NaOH, the insoluble matter was filtered off and the resulting clear solution was acidified by bubbling sulfur dioxide gas to give a white precipitate of the desired 7-hydroxy-5-propyl-6 - [(2'- (1H-Tetrazol-5-yl) biphenyl-4-ylmethyl] -1,2,4-triazolo [1,5-a] pyrimidine.

Yield: 2.4 g.

107

Empirical formula: C ₂₂ H ₂ qN ₈ O · ^{0/5 H} 2 ^0, Melting point: 260-265 ° C with decomposition.

^X H NMR (DMSO-d):

2.6 (t, 2H, _CH2 propy1).

8.2 (s, 1 H, ₂ H)

UV (MeOH): _X = 210 nm = 250 nm

Example 63

5-Hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = CH.

N,

A mixture of 25 grams of the compound of Example 19 or 23, 750 ml of xylene, and 34.5 grams of trimethyltin azide was heated to reflux for 50 hours. A white precipitate was obtained, which was filtered off. The melting point of this compound was 290 ° C with decomposition. This compound was then suspended in 500 mL of THF. Hydrochloric acid gas was bubbled through the solution for 30 minutes to give a solution which was then concentrated in vacuo.

108

The concentrate was transferred to water and then triturated. The gum was crystallized from acetonitrile. Recrystallization from isopropanol gave the expected derivative.

Yield: 15.2 g.

Melting point: 242 ° C.

The mother liquors were then concentrated, the concentrate was basified with 1 N potassium hydroxide solution and extracted with chloroform, followed by neutralization with acetic acid. The resulting precipitate was recrystallized twice from isopropanol to yield

4.5 grams of a second crop of the desired compound, i. 5-hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,2,4-triazolo [1,5-a] pyrimidine.

Empirical formula: ^c 22 ^H 20 ^N 9 ^O Melting point: 242-244 ° C.

¹ H NMR (DMSO-d 6):

2.91 (t, 2H, propyl _CH2);

8.11 (s, 1H, H ₂ ).

The compounds of Examples 64-95 were prepared by any of the methods described in Examples 62 and 63 above.

Example 64

Preparation of 7-hydroxy-2-methyl-5-propyl- hemisulphate

6 - [(2 '- (1H-Tetrazol-5-yl) biphenyl-4-yl) methyl) -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R ₃ = OH,

R ₂ = n-propyl,

X = nitrogen,

109

Y = C-CH-j.

R

Empirical formula: C ₂₃ H ₂₂ N ₈ O 0.5 H ₂ SO ₄ Melting point: 236-238 ° C.

¹ H NMR (DMSO-d 6):

2.6 (t, 2H, propyl _CH2);

UV (MeOH): _a = 212.1 nm, b = 250 nm.

Example 65

5-Hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [4,3-a] pyrimidine

Compound of Formula I:

R1 = OH,

R ₂ = n-propyl,

X = CH,

Y = nitrogen.

110

Empirical formula: ^c 22 ^H 20 ^N 8 ^O, Melting point: 251 ° C.

¹ H NMR (DMSO-d 6):

2.55 (t, 2H, propyl _CH2), 9 (s, 1 H, ₃ H).

Example 66

5-Propyl-7-mercapto-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R ₁ = SH,

R ₂ = n-propyl, X = N,

Y = CH.

Empirical formula: ^c 22 ^H 20 ^N 8 ^S *

Melting point: 288 ° C.

^{Χ Η} NMR (DMSO-d):

2.59 (t, 2H, n-propyl _CH2);

8.6 (s, 1H, H ₂ ).

Example 67

5,7-Dimethyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl)

-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

111

Compound of Formula I:

R = CH _3,

R ₂ = CH _3, X = N,

Y = CH.

This compound was obtained according to the procedure for EXAMPLE 62 using 2,4-dioxo-3 - [(2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl) -methyl] -pentane, prepared as described in Example 16.

Empirical formula: ^C 21 ^H 18 ^N 8 · Melting point: 264 ° C.

¹ H NMR (DMSO-d 6):

2.48 (s, 3H, CH _3),

2.81 (s, 3H, CH _3),

8.56 (s, 1H, H ₂ ).

Example 68

Preparation of 2-ethyl-7-hydroxy-5-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] ] pyrimidine

Compound of Formula I:

R @ 1 = OH;

R2 = n-propyl,

X = nitrogen,

Y = C-CH ₂ -CH _third

112

Empirical formula: ^C 24 ^H 24 ^N 8 ° ·

Melting point: 246 ° C.

NMR _(DMSO-d6):

2.57 (m, 2H, propyl _CH2 + DMSO-d?).

and

Example 69

7-N, N-Diethylamino-5-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] ] pyrimidine

Compound of Formula I:

_/ CH ₂ ~ ch ₃

R1 = \

CH ₃ - CH ₃

R ₂ = n-propyl, X = N,

Y = CH.

113 r ₃ =

Empirical formula: C ₂₅ H ₂ N ₅ .

Melting point: 192 C. C.

^X H NMR (DMSO-d):

2.65 (t, 2H, n-propyl _CH2);

8.5 (s, 1H, H ₂ ).

Example 70

5-Azido-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R = n-propyl, ^ 2 ⁼ ^ 3>

X = nitrogen,

Y = CH.

EF: C 22 ^H 19 ^N 11 · m.p. 212-213 ° C

- 114 ¹ H NMR (DMSO-d 6):

3.17 (t, 2H, n-propyl _CH2);

4.06 (s, 2 H, benzyl _CH2, azido / tetrazole equilibrium - 10%),

4.47 (s, 2 H, benzyl CH _2),

8.56 (s, 1H, _H2, azido / tetrazole equilibrium - 10%),

8.7 (s, 1H, H ₂ ).

Example 71

Preparation of 3,5-dihydroxy-5-propyl-6 - ((2 * - (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [4,3-a] pyrimidine

Compound of Formula I:

R @ 1 = n-propyl,

R ₂ = OH,

X = COH

Y = nitrogen.

Empirical formula: C ₂₂ H ₂₀ NgO ₂ . Mp .: 252 ° C.

¹ H NMR (DMSO-d 6):

2.93 (t, 2H, n-propyl _CH2);

3.7 (s, 2 H, benzyl _CH2).

115

Example 72

5-Hydroxy-2-methyl-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [4,3-a] ] pyrimidine

Compound of Formula I:

R2 = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = C-CH ₃ .

Empirical formula: C ₃ H ₂ 2NgO.

Melting point: 286 ° C.

¹ H NMR (DMSO-d ₆ ):

2.85 (t, 2H, n-propyl _CH2);

3.84 (s, 2 H, benzyl _CH2).

Example 73

Preparation of 2-ethyl-5-hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [4,3-a] ] pyrimidine

Compound of Formula I:

R2 = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = C-CH ₂ -CH _third

116

Empirical formula: ^C 24 ^H 24 ^N 8 ⁰ 'Melting point: 260 ° C.

¹ H NMR (DMSO-d 6):

2.86 (t, 2H, n-propyl _CH2);

3.85 (s, 2 H, benzyl _CH2).

Example 74

7-Butyl-5-hydroxy-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

A compound of formula I: R = n-butyl, R ₂ = OH,

X = nitrogen,

Y = CH.

Empirical formula: Ο ₂₃ Η ₂₂ ΝθΟ. Mp .: 255 ° C.

^{117; H} NMR (DMSO-d):

2.92 (t, 2H, n-propyl _CH2); 3.86 (WITH, 2H, benzyl CH ₂ ), 8.11 (with, 1H, h ₂ ).

Example 75

Preparation of 2-amino-5-hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5-a] pyrimidine

Compound of Formula I:

R 11 = n-propyl group,

R2 = OH,

X = nitrogen,

Y = C-NH ₂ .

Empirical formula: C ₂₂ H ₂₁ NgO. Melting point: 282 ° C.

¹ H NMR (DMSO-d 6): 2.76 (t, 2H, n-propyl CH ₂ ),

3.8 (s, 2 H, benzyl _CH2).

Example 76

5-N, N-Diethylamino-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] ] pyrimidine

118

Compound of Formula I:

R 1 = n-propyl, CH 2 -CH ₃

R ₂ - _{χ χ} CH ₃ - CH ₃

X = nitrogen,

Y = CH.

Empirical formula: ^C 26 ^H 29 ^N 9 *

Melting point: 140 ° C, then 205 ° C.

¹ H NMR (DMSO-d 6):?

2.91 (T, 2H, propyl ch ₂ ) 4.07 (with, 2H, benzyl ch ₂ ) 8.32 (WITH, 1H, h ₂ ).

Example 77

5-Amino-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R ₂ = -NH ₂

X = nitrogen,

Y = CH.

119

Empirical formula: C ₂ 2H 21 ^N 9 'Melting point: 276 ° C.

^X H NMR (DMSO-d):

2.98 (t, 2H, propyl _CH2), 4.03 (s, 2 H, benzyl _CH2), 8.1 (s, 1 H, ₂ H).

Example 78

5-Hydroxy-2-mercaptomethyl-7-propyl-6 - [(2 '(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5- a] pyrimidine

Compound of Formula I:

R ₃ = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = C-SCH _third

120

Empirical formula: C ₂₃ H ₂₂ N ₈ OS.

Melting point: 260 ’C.

^X H NMR (DMSO-d):

2.85 (t, 2H, n-propyl _CH2);

3.84 (s, 2 H, benzyl _CH2).

Example 79

5-Hydroxy-7-propyl-6- [4- [3- (1H-tetrazol-5-yl) -2-thienyl] benzyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = CH.

Empirical formula: ^C 20 ^H 18 ^N 8 ^OS · Melting point: 275 ° C.

^X H NMR (DMSO-d):

2.95 (t, 2H, n-propyl _CH2);

3.91 (s, 2 H, benzyl CH _2),

8.12 (s, 1H, H ₂ ).

121

Example 80

5-Hydroxy-7-propyl-6- [4- [3- (1H-tetrazol-5-yl) -2-pyridyl] benzyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R ₂ - OH,

X = nitrogen,

Y = CH.

Empirical formula: ^C 21 ^H 19 ^N 9 ^O, Melting point: 244 ° C.

^X H NMR (DMSO-d):

2.91 (t, 2H, n-propyl _CH2);

3.89 (s, 2 H, benzyl CH _2),

8.11 (s, 1H, H ₂ with pyridine H ₄ ).

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

Compound of Formula I:

R = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = C-CH ₃ .

122

Empirical formula: ^c 2i ^H 20 ^N 8 ^axis '

Melting point: 287 C. C.

¹ H NMR (DMSO-d 6):

2.9 (t, 2H, n-propyl _CH2);

3.89 (s, 2 H, benzyl _CH2).

Example 82

Preparation of 7-butyl-5-hydroxy-2-methyl-6- [2 '- (1H-tetrazole)

5-yl) biphenyl-4-yl) METHYL-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-butyl,

R ₂ = OH,

X = nitrogen,

Y = C-CH ₃ .

Empirical formula: c ₂₄ H ₂₄ N ₈ o. M.p .: 275 ° C.

123 ^{Χ Η} NMR (DMSO-d):

2.87 (t, 2H, n-butyl _CH2), 3.84 (s, 2 H, benzyl _CH2).

Example 83

5-Hydroxy-2-hydroxymethyl-7-propyl-6- [2 '(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] ] pyrimidine

Compound of Formula I:

Ry = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = C-CH ₂ OH.

Empirical formula: ^C 23 ^H 22 ^N 8 ° 2 · Melting point: 274 ° C

^X H NMR (DMSO-d):

2.88 (t, 2H, n-propyl _CH2);

3.86 (s, 2 H, benzyl _CH2).

Example 84

Preparation of 5-mercapto-7-propyl-6- [2 '- (1H-tetrazol-5-yl)]

124 biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R ₂ = SH,

X = nitrogen,

Y = CH.

Empirical formula: C ₂₂ H ₂₀ N ₈ S.

Melting point: 278 ° C.

^X H NMR _(DMSO-d6):

2.87 (t, 2H, n-propyl _CH2);

3.37 (s, 2 H, benzyl CH _2),

8.29 (s, 1H, H ₂ ).

Example 85

5-Hydroxy-7-methoxymethyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R 1 = -CH ₂ -O-CH ₃

R ₂ = OH,

X = nitrogen,

Y = CH.

125

Empirical formula: ^C 21 ^H 18 ^N 8 ° 2 · Melting point: 264 ° C.

NMR (DMSO-d6):

3.91 (T, 2H, benzyl CH ₂ ) 4.79 (with, 2H, o-ch ₂ ), 8.12 (with, H, h ₂ ).

Example 86

7-Propyl-5- (pyrrolidin-1-yl) -6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5- a] pyrimidine

Compound of Formula I:

R ₁ = n-propyl,

X = nitrogen,

Y = CH.

126

Empirical formula: C ₂ gH ₂₇ N _g . Melting point: 280 C.

¹ H NMR (DMSO-d 6):

2.94 (T, 2H, propyl ch ₂ ) 4.22 (with, 2H, benzyl ch ₂ ) 8.18 (with, 1H, h ₂ ).

Example 87

5-Hydroxy-7-methyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R ₂ = OH,

X = nitrogen,

Y = CH.

Empirical formula: ^c 20 ^H 16 ^N 8 ^O, Melting point: 248 ° C.

^{127; H} NMR _(DMSO-d6):

2.56 (s, 3H, CH

3.86 (s, 2H, benzylCH

8.11 (s, 1H, H)

Example 88

7-Ethyl-5-hydroxy-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R = -CH ₂ CH _3,

R ₂ = OH,

X = nitrogen,

Y = CH.

Empirical formula: C ₂ H ₁₈ N ₈ O. Melting point: 245 ° C.

^X H NMR (DMSO-d):

2.94 (q, 2H, _CH2 of ethyl);

3.87 (s, 2 H, benzyl CH _2),

8.12 (s, 1H, H ₂ ).

Example 89

Preparation of 2-N, N-diethylamino-5-hydroxy-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5-a]

128 pyrimidine

Compound of Formula I:

R2 = n-propyl,

R2 = OH,

X = nitrogen,

CHj — CH ₃ ^Y - \

CH ₃ - CH ₃

Empirical formula: € ₂₆ Η ₂₉ Ν ₉ Ο. Melting point: 207 C.

¹ H NMR (DMSO-d ₆ ):

2.79 (t, 2H, n-propyl _CH2);

3.80 (s, 2 H, benzyl _CH2).

Example 90

5- (Morpholin-4-ylethylamino-7-propyl-6- [2 '(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5- a] pyrimidine

Compound of Formula I:

R2 = n-propyl,

129

NH-

CH ₂ —CH ₂ —NO \ y

X = nitrogen,

Y = CH,

Empirical formula: ^c 28 ^H 32 ^N 10 ° 'Melting point: 236 ° C.

1 H NMR (DMSO-d ₆ ):

2.99 (t, 2H, n-propyl _CH2); 4.02 (with, 2H, benzyl CH ₂ ), 8.13 (with, 1H, h ₂ ).

Example 91

5,7-Dipropyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I: = n-propyl,

R ₂ = n-propyl, X = N,

Y = CH,

130

Empirical formula: ^c 25 ^h 26 ⁿ 8 · Melting point: 226 ° C.

¹ H NMR (DMSO-d 6):

2.66 (t, 3.15 (t, 2H, n-propyl _CH2) 2 H, n-propyl _CH2) 2 H, benzyl CH _2), 1 H, ₂ H). 4.14 8.26 (S, (s, Example 92

Preparation of 7-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R ₃ = n-propyl,

R2 = hydrogen,

X = nitrogen,

Y = CH.

Empirical formula: C ₂₂ H ₂₀ Ng Melting point: 238 C.

131 ¹ H NMR (DMSO-d 6):?

3.16 (t, 2H, n-propyl _CH2); 4.21 (s, 2 H, benzyl CH _2), 8.65 (s, 1 H), 8.82 (s, 1 H).

Example 93

7-Benzyloxymethyl-5-hydroxy-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R ₂ = OH, X = N,

Y = CH.

R ₃ =

Empirical formula: C27 ^H 22 ^N 8 ⁰ 2 ·

Melting point: 270-275 ° C (decomposed).

^{132; H} NMR _(DMSO-d6):

3.86 (WITH, 2H, benzyl CH ₂ ), 4.62 (with, 2H, o-ch ₂ ), 4.88 (with, 2H, o-ch ₂ ), 8.11 (WITH, 1H, h ₂ ).

Example 94

5- (piperidin-1-yl) -7-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1,5- a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

X = nitrogen,

Y = CH.

Empirical formula: C, H, Ng. Melting point: 266 DEG C.

^{Σ Η} NMR (DMSO-d):

2.88 (t, 2H, n-propyl _CH2);

133

4.09 (s, 2 H, benzyl CH _2),

8.35 (s, 1H, H ₂ ).

Example 95

Preparation of [7-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidin-5-yl Of 2-methoxyethyl ether

Compound of Formula I:

R _x = n-propyl,

R ₂ = -O-CH ₂ -CH ₂ -O-CH _3,

X = nitrogen,

Y = CH.

Empirical formula: ^C 25 ^H 26 ^N 8 ° 2 Melting point: 224 ° C.

¹ H NMR (DMSO-d 6):

3.14 (t, 2H, n-propyl _CH2) 4.04 (with, 2H, benzyl CH ₂ ), 8.41 (with, 1H, h ₂ ).

Example 96

5-Chloro-7-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

134

Rj = n-propyl,

R ₂ = chlorine,

X = nitrogen,

Y = CH.

This compound was obtained by diazotization of the derivative obtained according to the procedure of Example 77 and treatment of the diazonium salt with cuprous chloride following the classical Sandmeyer reaction.

Example 97

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

R = n-propyl,

R ₂ = OH,

X = CH,

Y = nitrogen.

The mixture was 2 grams of compound

135 prepared according to the procedure of Example 20 (d) in 200 ml 1

N sodium hydroxide solution was heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the concentrate was acidified with 200 mL of 1 N hydrochloric acid. The resulting crystals were purified by recrystallization from 2-methoxyethanol to give the desired product

6- [2 ' aminokarbonylbifenyl-4-yl) methyl] -5-hydroxy-7-propyl-l, 2,4-triazol [4,3-a] pyrimidine.

Yield: 1.6 g.

Empirical formula: C ₂₂ ^H ₂₁ ^N 5 ^O 2 · Melting point: 258 ° C.

¹ H NMR (DMSO-d 6):

2.61 (t, 2H, n-propyl _CH2);

3.9 (s, 2 H, benzyl CH _2), 9 (s, 1 H, ₃ H).

Example 98

6 - [(2'-Carboxybiphenyl-4-yl) methyl] -5-hydroxy-

7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R! = n-propyl group,

R ₂ = OH,

X = nitrogen,

Y = CH.

HOOC

136 A mixture of 9.4 grams of the product obtained in Example 97 above, 200 ml of ethylene glycol and 20 ml of concentrated NaOH was heated at reflux for 10 hours. The ethylene glycol was distilled off, 200 ml of water was added to the reaction mixture, and this mixture was then acidified with a hydrochloric acid solution. The crystals thus prepared were purified by recrystallization from 2-methoxyethanol to give the desired product

6 - [(2'-carboxy-biphenyl-4-yl) methyl] -5-hydroxy-7-propyl-l, 2,4-triazolo [1,5-a] pyrimidine.

Yield: 5.8 g.

Empirical formula: ^c 22 ^H 20 ^N 4 ° 3 · Melting point: 265 ° C.

^X H NMR _(DMSO-d6):

2.96 (t, 2H, n-propyl _CH2);

3.92 (s, 2 H, benzyl CH _2),

8.12 (s, 1H, H ₂ ).

Example 99 was prepared according to the same procedure as in Example 23.

Example 99

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

Compound of Formula I:

R'y = n-propyl,

X = nitrogen,

Y = CH and R ₀ = OH.

137

Melting point: 262 DEG C.

Example 100

Preparation of 6 - [(2'-cyanobiphenyl-4-yl) methyl] -5-hydroxy-7 hydroxymethyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R'j = CH ₂ OH,

X = nitrogen,

Y = CH,

R _lo = OH.

A solution of 9 grams of the compound of Example 43 in 360 ml of acetic acid was reduced by catalytic hydrogenation in the presence of 1.8 grams of 5% palladium on charcoal. The reaction was carried out at atmospheric pressure and at 50 ° C. The catalyst was then filtered off

138 on Celite 545 and washed with acetic acid, the filtrate was concentrated and then purified by silica gel chromatography (eluent: 95% chloroform / 5% methanol) to give 4.5 g of the starting material and 2.2 g of the desired 6- [(2'-cyanobiphenyl-4-yl) methyl] -5-hydroxy-7-hydroxymethyl-1,2,4-triazolo [1,5-a] pyrimidine.

Melting point: 262 C. C.

The same compound can also be obtained by reaction with boron tribromide BBr ₃ in chloroform.

The following derivatives of Examples 101 and 102 were prepared in the same manner as in Example 63.

Example 101

5-Hydroxy-7-hydroxymethyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

R = CH ₂ OH,

R ₂ = CH,

X = nitrogen,

Y = CH.

139

Empirical formula: ^C 20 ^H 15 ^N 5 ° 2 Melting point:> 360 ° C (dec.).

^X H NMR (DMSO-d):

3.93 (with, 2H, benzyl CH ₂ ) 4.82 (with, 2H, ch ₂ -o) 8.06 (WITH, 1H, Hj). Example 102

Preparation of 6- [4- [5-bromo-3- (1H-tetrazol-5-yl)]

2-furyl] benzyl] -5-hydroxy-7-propyl-1,2,4-triazolo [1,5-a] pyrimidine

Compound of Formula I:

Rj = n-propyl,

R2 = OH,

X = nitrogen,

Y = CH.

Empirical formula: ^c 20 ^H 17 ^BrN 8 ° 2 'Melting point:> 360 ° C.

¹ H NMR (DMSO-d 6):

2.93 (t, 2H, n-propyl _CH2), 3.92 (s, 2 H, benzyl CH _2),

6.9 (s, 1H, furan proton), 8.03 (s, 1 H, ₂ H).

140

Pharmacological tests

A. Experiments with adrenal angiotensin II receptors.

(I) Principle of the method

The affinity of the compounds of the above examples for angiotensin II receptors was evaluated using a method of replacing radiolabeled ligands specifically bound to the adrenal angiotensin II receptors in rats.

(II) Procedure

Aliquots of rat adrenal homogenate were incubated using one concentration of [ ¹²⁵ ] -SIAH (Sar ¹ , Tyr ¹ , Ile ⁸ -angiotensin II), an angiotensin II receptor antagonist, and two concentrations of competing agents (10 M, 10 M) after 60 minutes at 25 ° C.

The reaction was completed by addition of buffer followed by rapid filtration using glass filters. Non-specific binding was determined in the presence of angiotensin II.

(III) Evaluation of results

The results obtained were expressed at each of the concentrations tested as a percentage replacement of radiolabeled ligands specifically bound to the adrenal angiotensin receptors

II.

(IV) Results

The results obtained are shown in the following table.

141

The product according to % replacement labeled ligands 1 Example 1 E-5 M 1 E-7 m Example 62 65 52 Example 63 61 52 Example 65 63 47 Example 68 69 59 Example 69 69 19 Example 75 61 60 Example 76 63 28 Example 77 63 31 Example 79 58 26 Example 82 58 11

B. Measurement of inhibition of growth factor-induced cell proliferation (example: platelet-derived growth factor or PDGF) using aortic smooth muscle cells in rats (I) Principle of the method

The inhibition of growth factor-induced cell proliferation (example: PDGF) was evaluated by measuring the incorporation of ³ H-thymidine into rat aortic smooth muscle cells (VSMC).

(II) Procedure

VSMCs were cultured at 37 ° C in 5% CO ₂ until discontinuous, and then transferred to rest in serum-poor medium for 24 hours. They were then pretreated for one hour with test molecules (10 ^-4 M) and then stimulated with a growth factor at an interval of 22 hours (example: PDGF). ³ H-thymidine was incorporated over the last 4 hours. All these steps were performed at 37 ° C in 5% CO ₂ .

The reaction was terminated by aspiration of the reaction medium, separation

142 cells and then filtering the lysed cells through glass fiber filters.

(III) Evaluation of results

The results obtained were expressed as percent inhibition of stimulation of βH-thymidine incorporation relative to the growth factor effect.

(IV) Results obtained

The results obtained are shown in the following table.

Product according to Example % inhibiting PDGF induced @ 1 H-thymidine incorporation 1E-4M Example 69 100

Toxicological evaluation

All the products of the above examples showed excellent tolerance after oral administration.

In these tests, it was found that the 50% lethal dose of these compounds in rats was greater than 300 mg / kg.

Final evaluation

All compounds of the above examples showed good affinity for angiotensin II receptors. For this reason, these compounds can be advantageously used for the treatment of various pathologies in which angiotensin II is involved, in particular for the treatment of arterial hypertension and cardiac insufficiency, in doses ranging from 1 to 400 milligrams for oral administration and in the range of

143 from 0.01 to 50 milligrams in the case of intravenous administration, in the form of one or more dosage units per day. In addition, some of these compounds also have antiproliferative activity and are therefore of great importance in the treatment of proliferative diseases such as atherosclerosis.

Claims (13)

1. Triazolopyrimidine derivatives of formula I: (I) in which: - one of the radicals R @ 1 and R @ ₂ : - a lower alkyl group having 1 to 6 carbon atoms, - an ether residue of the formula: - (CH _{2) p} OR in which p is an integer from 1 to 6 and R is a lower alkyl group having 1 to 6 carbon atoms or benzyl, and - alcohol residue of the formula: - (CH _{2) p} OH wherein p is as defined above and the - the other of the radicals R @ 1 or R @ ₂ represents: 145 - a hydrogen atom, - halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or - a residue selected from the group consisting of N ₃ , OR ₄ , SR ₄ , NR g R g and NH (CH ₂ ) _n NR ₅ R g, in which: R ₄ means: - a hydrogen atom, - a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, - the rest of the formula: (CH ₂ ) _m -COOR ', wherein m is an integer from 1 to 4 and R' is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or - a radical of the formula ^ ^CH2 ^ m ^-O-R '' in which R 'have the same meaning as described above, R ₅ and R ₆ , which may be the same or different, represent: a hydrogen atom, or - a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, or R 11 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholine, pyrrolidine or piperidine, and n represents an integer from 1 to 4, X and Y, which are different, represent: - in one case a nitrogen atom and in the other a group: 146 cr ₇ in which R ·? means: - a hydrogen atom - a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, - the rest of the formula: <CH ₂ ) _n 'OH wherein n' is an integer from 0 to 4, the remainder SR ', where R' has the same meaning as above, or - a NRgRg residue in which Rg and Rg, which may be the same or different, represent a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, and R ₃ is a radical of the formula: in which it means: Z is CH or N and Z ' is sulfur or oxygen, R _{&lt; 1} &_gt; is hydrogen or halogen, and R ₁₂ represents a tetrazole residue, CN, COOH or conh ₂ . and tautomeric forms and addition salts thereof, especially pharmaceutically acceptable addition salts. Compounds of the formula I according to claim 1, in which: 147 - one of R ₃ and R _2: a lower alkyl group having 1 to 6 carbon atoms, and - an ether group of the formula: - (CH ₂ ) _p OR. r is an integer from 1 to 6 and R is a lower alkyl group having 1 to 6 carbon atoms or a benzyl group, or - an alcohol group of the formula: - <CH ₂ ) _p OH in which p has the same meaning as given above, and - the second of R ₃ or R ₂ means: - a hydrogen atom, - a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a residue selected from the group consisting of N ₃ , OR ₄ , SR ₄ , NR 4 R 8 and NH (CH ₂ ) _n -NR 8 R 8, in which: »R ₄ means: a hydrogen atom, or - a group of formulas: - (CH ₂ ) _m - ° -R 'wherein m is an integer from 1 to 4 and R' represents a lower alkyl group having 1 to 6 carbon atoms, R ₅ and R 8, which may be the same or different, represent: a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or 148 R ₅ and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholine, pyrrolidine and piperidine, and n is an integer from 1 to 4, X and Y, which are different, mean: in one case a nitrogen atom, and - in the latter case, the group: Cr ₇ wherein R ₇ represents: - a hydrogen atom, - a lower alkyl group having 1 to 6 carbon atoms, - the rest of the formula: (CH ₂ ) _n 'OH wherein n' is an integer from 0 to 4, a residue of SR ', where R' has the same meaning as above, or - a NRgRg residue in which Rg and Rg, which are the same or different, represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ₃ represents one of the following radicals: br 149 Derivatives according to claim 1 or 2, wherein they are n-propyl, n-butyl or N-diethylamino. Derivatives according to any one of claims 1 to 3, wherein R ₂ represents a hydroxyl group, an n-propyl group or an N-diethylamino group. Derivatives according to any one of claims 1 to 4, wherein R ₃ represents 2- (1H-tetrazol-5-yl) phenyl. Derivatives according to any one of claims 1 to 5, wherein X represents a nitrogen atom. Derivatives according to any one of claims 1 to 6, wherein Y represents CH, C-CH ₃ or C-NH ₂ . Derivatives according to any one of claims 1 or 2, wherein R 1 represents a lower alkyl group having 1 to 6 carbon atoms, R ₂ represents a hydroxyl group, R ₃ represents 2- (lH-tetrazol-5-yl) phenyl, X is N and Y is CH or C-CH _third A compound according to claim 1 or 2 which is 5-hydroxy-7-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole [1] 5-a] pyrimidine of formula C: OH 150 Derivatives according to claim 1 or 2, selected from the group consisting of derivatives of the following formulas D to H: OH (D) 151 G Process for the preparation of a compound of the formula I according to any one of claims 1 to 10, characterized in that it comprises the following steps: (a) a compound of formula I-A is prepared: (I-A) 152 in which: X, Y and R ₃ have the same meanings as above, and A and B represent, according to one variant, a hydroxyl group or a lower alkyl group having 1 to 6 carbon atoms, and according to a second variant a lower alkyl group having 1 to 6 carbon atoms or an ether radical of the formula - (CH ₂ ) _p -OR wherein p is an integer from 1 to 6 and R represents a lower alkyl group having 1 to 6 carbon atoms or a benzyl group, which process is carried out by condensation 3-Amino-1,2,4-triazole of formula II: (Π) in which has R _? same meaning as above, with derivative of general formula IB: (I-B) in which 153 R 1 represents a lower alkyl group having 1 to 6 carbon atoms or an ether radical of formula: - (CH _{2) p} OR in which p is an integer from 1 to 6 and R is lower alkyl of 1 to 6 carbon atoms or benzyl, R 8 represents a lower alkyl group having 1 to 6 carbon atoms or a lower O-alkyl group having 1 to 6 carbon atoms, preferably a methyl group or an ethyl group, and R ₃ has the same meaning as defined in claim 1 in an aprotic solvent such as dichlorobenzene or trichlorobenzene or in an acidic solvent such as acetic acid or another embodiment in an alcohol in the presence of the corresponding sodium or potassium alcoholate or another Embodiments in pyridine or 2-methyl-5-ethylpyridine in the presence or absence 4-dimethylaminopyridine, and at a temperature ranging from 50 ° C to 200 ° C. (b) introducing, if necessary, a R ₃ protecting group into this compound, using generally known methods; (c) heating the derivative thus obtained from a derivative of the general formula IB, if the compound is a ketoester, heated in a suitable reagent, such as POCl ₃ , to convert the hydroxyl group represented by A or B to a chlorine atom. (d) heating the chlorinated derivative so obtained in the presence of a nucleophilic reagent containing nitrogen, oxygen or sulfur at reflux in an alcohol 154 or in an autoclave at 100 ° C in the presence or absence of a base such as sodium carbonate Na ₂ CO ₃ to give a derivative of formula IA wherein A and B have the same meaning as and R ₂ . (e) if necessary, removing the protecting group is attached to R>, * (E _3), this group is converted to the acid group by hydrolysis in the case where this group is a nitrile, and (e ₂₎ converting this group to a tetrazole group, for example when the group is a nitrile group, by reaction with a trialkyltin azide while heating in toluene or xylene, followed by treatment with gaseous hydrochloric acid in tetrahydrofuran, or (e ₃ ) converting the group to an amide group, for example, when the group is a nitrile group, by reaction with sulfuric acid or by reaction with hydrogen peroxide, or, in another embodiment, by reaction with polyphosphoric acid, and * (f) if necessary, convert the derivative so obtained into? an addition salt, preferably a pharmaceutically acceptable addition salt. A pharmaceutical composition, in particular an antagonist of angiotensin II receptors, for the treatment or prevention of cardiovascular diseases, in particular hypertension, cardiac insufficiency and arterial wall diseases, comprising a pharmaceutically effective amount of at least one compound of the general formula I, as defined in any one of claims 1 to 10, or at least one pharmaceutically acceptable addition salt derived therefrom, which may or may not be incorporated or combined with a pharmaceutically acceptable excipient, 155 material or carrier. A pharmaceutical composition, in particular having an antiproliferative effect, by which it is possible to successfully treat or prevent diseases of the arterial wall, in particular atherosclerosis, comprising a pharmaceutically effective amount of at least one compound of formula I as defined in any one of claims 1 to 10 or at least one pharmaceutically acceptable addition salt derived from these compounds, which may or may not be incorporated or combined with a pharmaceutically acceptable vehicle, excipient or carrier material.