SK99894A3 - Pyrazolopyrimidine derivatives, 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

PYRAZOLOPYRIMIDINE DERIVATIVES, METHOD OF PREPARATION, PHARMACEUTICAL FORM AND USE

Technical field

The invention relates to novel pyrazolopyrimidine derivatives of the following general formula I 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, these compounds are useful in the treatment and prevention of cardiovascular diseases, and in particular in the treatment of hypertension, in the treatment of cardiac insufficiency and in the treatment and prevention of arterial wall diseases, in particular atherosclerosis.

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

SUMMARY OF THE INVENTION

The present invention provides pyrazolopyrimidine derivatives and tautomeric forms thereof, which are characterized by the general formula I:

(I) in which:

- one of R, and R _2:

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

- an ether residue of the formula:

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

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

- a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a radical selected from the group consisting of 0R _4, SR _4, NR ₅ R ₆ and NH (CH _{2) n} -NR ₅ R _6, wherein:

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 < ^c H ₂ > _n ^-O - ^R ', in which R' have the same meaning as 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 8 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 may be in the 2-position or 3-position of the pyrazolo [1,5-a] pyrimidine ring, representing:

- a hydrogen atom,

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

- a group selected from the group consisting of hydroxyl and COOR ', wherein R' has the same meaning as above, and

R ₃ is a radical of the formula:

in which it means:

Z is CH or N and the radical Z 'is sulfur or oxygen, R ₁₃ represents a hydrogen atom or a halogen atom, and

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

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

- one of R ^ and R _2:

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

- the second of the radicals or R ₂ is:

- a hydrogen atom,

- a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a radical selected from the group consisting of OH, NR ₅ R ₆ and NH (CH _{2) n} -NR ₅ R _6, wherein:

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

R ₅ and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group selected from morpholine and pyrrolidine, and n represents an integer from 2 to 4,

X may be in the 2-position or 3-position of the pyrazolo [1,5-a] pyrimidine ring, representing:

«. a hydrogen atom, or

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

R j represents one of the following radicals:

HOOC

It is also intended to include the above derivatives in their tautomeric forms within the scope of the present invention.

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 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.

In one embodiment, the compounds of the present invention are n-propyl.

In another embodiment, R 1 is a hydroxyl group.

In another embodiment, R 1 is morpholine-ethylamine.

In another embodiment, R 1 is an amino group.

In another embodiment, R 1 is diethylamino.

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

In another embodiment, R _{2 is a} hydroxyl group.

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

In another variant of the compounds of the present invention, X is hydrogen.

In another variation, the compound of the present invention is R ₃ 2- (1H-tetrazol-5-yl) phenyl.

Compounds of the following formulas (C) to (G) are obviously preferred according to the present invention:

(D)

ON-CH ₂ -CH _2>.

\ / NH N-N

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:

in which:

X and R ₃ are as stated 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, the process being carried out by condensation of the 3-aminopyrazole of formula II:

N ---- NH

(Π) in which X has the same meaning as above, with a derivative of the general formula I-B:

in which

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

- (ch ₂ ) _p -or wherein 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 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 another embodiment in an alcohol in the presence of the corresponding sodium or potassium alcoholate or 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 give a derivative of the general Formula IA in which A and B have the same meaning as R 1 and R ₂ .

(e) removing the protecting group attached to R ₃ , if necessary, (e ₃ ) 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 into an amide group, e.g. wherein 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:

(III) in which:

R '1 is a lower alkyl group containing an ether moiety of the formula:

up to 6 carbon atoms

- (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, are prepared by methods generally known in the art, such as a Claisen reaction or method using Meldrum acid, these methods can be found in the following references:

- Hauser C.R., Swamer F.W., Adam and 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,

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

945-951.

- Balyakina M. V., Zhdanovich E. S., Preobrazhenskii N. A., Tr.

Vses. Nauch. Issled. welcome in. Inst. , 1961, 7, 8-16 Renard M., Maquinay A., Bull. Soc. Chim. Belgium. , 1946, 55 98-105, Bruce F.,., Coover H. W., 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:

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 another variant, in the presence of an equivalent portion of lithium chloride or lithium bromide and two equivalents of diisopropylethylamine in tetrahydrofuran at reflux, according to the following literature. link:

- Sung-eun yoo, kyu yang yi, bull. Korean Chem. Soc., 1989, 10 (1), 112.

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

CHO

V (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 or under pressure normal pressure, if the nature of the substituents allows it.

The preparation of compounds of formula V is generally described in the following publications:

- 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.

- Marquet 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;

- 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 8 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:

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

(XII)

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. Am. Chem. Soc., 1975, 97, 7383.

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

R ₉ OH wherein R _g is as mentioned above.

These derivatives are then brominated or chlorinated, for example using N-bromosuccinimide, N-chlorosuccinimide or bromine, the reaction being carried out with carbon tetrachloride, the dibromoethane of the compound of formula V is:

in a solvent, such as, or dichloroethane, to form

IV wherein the substituent

The substituent V may also be a group of:

in which case the compound of formula XII is:

The HOOC (XII) prepared 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, and then converting the amide into a nitrile compound by reaction with phosphorus oxychloride in dimethylformamide or with thionyl chloride. In a similar manner, a compound of formula XI is possible:

(XI) converted directly to the carbonitrile derivative as described above by treatment in pyridine in the presence of phosphorus oxychloride POCl ₃ · The nitrile derivative XIII thus obtained:

(XIII) can then be brominated or chlorinated under the same conditions as described 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 compound of formula XIV:

(XIV), which can be prepared by a 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 the compound

Ni (PO ₃ ) Cl ₂ to give a derivative of the general 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:

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

wherein R _g is as defined above, in which case the compound of formula IV is prepared from the 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:

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.

First, a compound of formula XVI is prepared:

CH ₃

C — C — CH, —CH, —C1

I I

C1-C11 (XVI) wherein the preparation of this compound is carried out starting from

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., Tenenev 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:

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

(χιχ) which can then be aromatized by treatment with bromine in carbon tetrachloride to give compound XlX-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:

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 the 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 prepare a compound of formula IV wherein W is bromo or chloro and V is:

The substituent V may also be a group of:

wherein Rg has the same meaning as above, in which case the corresponding compound of formula IV can be prepared by reaction of 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 R _g has the same meaning as 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 formula IV wherein W is bromo or chloro and V is:

Substituent V may

also group:

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 a compound of formula XXII:

(XXII)

The derivative may then be brominated or chlorinated by reaction with N-bromosuccinimide or N-chlorosuccinimide, for example in carbon tetrachloride or 1,2-dichloroethane, to prepare a compound of formula IV wherein W is bromo or chloro and substituent V is a group:

In the above general formula (V), R and R _are as defined above, and the substituent (V) is as defined for the compound of formula (IV).

However, compounds of formula (V) wherein the substituent

V represents groups:

or

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 the 3-aminopyrazole of formula II:

N --- NH

in which X is as defined above (these products are commercially available or can be readily prepared by methods known in the art by reacting hydrazine hydrate with a ketoacetonitrile of the formula x-co-ch ₂ -cn wherein X is as defined as have been mentioned above, or by other methods known from the prior art, see for example: Comprehensive Heterocyclic Chemistry, Pergamon Press, call 5, pp. 280 and 281) with a compound of formula V in which R 1j and R _{g have the} same and V is the following groups:

'IN/

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)

(VHb) and the tautomeric forms of the compounds in which R 1, X and V have the same meaning as above and R ₁₀ represents a hydroxyl group when a compound of the formula

V is a β-ketoester and a lower alkyl group having 1 to 6 carbon atoms when the compound of the formula

V is β-diketone, which reaction is carried out by condensation in an aprotic solvent such as dichlorobenzene or trichlorobenzene or in an acidic solvent such as acetic acid or otherwise in an alcohol in the presence of the corresponding sodium or potassium alcoholate or otherwise in pyridine or 2-methyl-5-ethylpyridine in the presence or absence of 4-dimethylaminopyridine and at a temperature ranging from 50 ° C to 200 ° C.

In the case where the substituent V provides a tetrazole group, the reaction temperature must not exceed 140 ° C to avoid decomposition of the tetrazole.

Said reactions of aminopyrazoles 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. , p. 779-801 (1959),

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

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

Compounds identified of formula III-a and VII-b will therefore different processing. according to 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 (VII-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.

For example, if derivatives of formulas VIII-a and VII-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) wherein R ' ₃ , X and V have the same meanings as 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 6, R ₂ , X and V have the same meaning as above, is obtained by heating a derivative of the general formula (II-a) or (II-b) in the presence of a nucleophilic group containing nitrogen, oxygen or sulfur, at reflux 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.

Compounds of formula (IX) wherein the substituent

V contains an ester group COOR _g , can be hydrolyzed in acid or in a basic medium, or can be hydrogenated when R _g represents a benzyl group to give a compound of formula I wherein R ₃ contains an acid group.

A compound of formula IX wherein the substituent

V contains a nitrile group, 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 heated in toluene or xylene with a trialkyltin 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 R ₃ contains a tetrazol-5-yl group.

The 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) according to the invention contain an acid group or a tetrazole group, such salts 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 diseases of the arterial wall, especially 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, lace, injectables, transdermal systems and ophthalmic liquid drug formulations. 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 includes 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 dose may be in the range of 1 to 400 milligrams of active ingredient administered orally in the form of one or more daily doses or 0.01 to 50 milligrams, administered parenterally in the form of one or more daily doses.

The invention also encompasses a process comprising combining a pharmaceutically active compound of the formula or at least one of the compound with a vehicle or pharmaceutical composition possible or preparing in that an amount of one of the above, excipient-derived salts,

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

The present invention also provides a method for the 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'2 = n-propyl,

R8 = 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 that of Example 1.

Example 2

Preparation of 3-oxoheptanoic acid ethyl ester

Compound of formula III:

R'2 = n-butyl,

R8 = 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:

_Rg = O-ethyl.

CH, -O-CH.

80 grams of 60% sodium hydride was added portionwise to 800 milliliters of anhydrous tetrahydrofuran THF. The material was then cooled to 10 ° C, followed by ethyl benzyl alcohol ethyl ester. 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, which was then purified in two successive yellow oil forms.

and was maintained at this temperature. 500 ml of benzyl alcohol was added dropwise. a solution containing 4-chloroacetate was added in the reaction mixture for 20 hours. In the next

65.8 grams

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

Boiling point (at 6.65 kPa): 126-132 ° C.

Example 4

4'-Bromomethyl-2-cyanobiphenyl

Compound of Formula IV:

W = Br

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

One To 563.8 g ⁽¹ 4-methylbiphenyl-2-yl) carboxylic acid, prepared following the procedure of Meyers AI, ED Mihelich, 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 manner, the desired product, i.e. 2-cyano-4 ¹ 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.

This product was recrystallized from isopropanol to give 451 grams of white crystals.

4'-Bromomethyl-2-cyanobiphenyl.

Melting point: 128 C.

Example 5

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

Compound of Formula V:

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

23 grams of ethyl acid ester was used

3-oxohexane, prepared as in Example 1, dissolved in 120 mL of tetrahydrofuran. 30.3 g of 4'-bromomethyl-2-cyanobiphenyl prepared according to Example 4 and 4.7 g of lithium chloride were added to the obtained solution, and they were 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 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 following compounds.

Example 6

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

Compound of Formula V:

R? = n-butyl,

R ₈ = 0-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 1 = methyl, R 8 = 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-4yl) methyl] -3-oxopentanoic acid ethyl ester

Compound of Formula V:

R? = ethyl, Rg = O-ethyl.

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 2. 2. ~ methoxymethyl,

R8 = O-ethyl.

CN

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

Example 10

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

Compound of formula (V)

_Rq = O-ethyl

CH, -O-CH

CN

IN

The oil prepared by this procedure was purified twice by chromatography (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 ₁ = CH ₂ -CH ₂ -CH ₃ , R 8 = O-ethyl.

(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 25 mm Hg): 112-114 ° C.

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

According to this embodiment, there were 2 grams

Of 4-bromobenzyl methyl ether, i.e. the compound prepared as above, is 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. Next, 800 milligrams of bis (triphenylphosphine) nickel (II) chloride [NiP (phenyl) ₃ ] ₂ C1 ₂ addition catalyst was added, and a solution containing 76.9 grams was added

Of 2-chloronicotinenitrile in 300 ml of THF.

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 g of an orange oil. This product was then purified twice by sequential chromatography (eluent: 95% chloroform / 5% ether). 69.4 grams were isolated by the above procedure

3-cyano-2- (4-methoxymethylphenyl) pyridine as an orange oil which crystallized.

(c) Preparation of 3-cyano-2- (4-bromomethylphenyl) pyridine

Compound of Formula IV:

W = Br,

According to this embodiment was

69.4 grams

3-cyano-2- (4-methoxymethylphenyl) pyridine, prepared as described above, dissolved in 700 ml, stabilized with amylene. The thus obtained previous step, the chloroform solution, was then cooled to -10 ° C. To this was added a solution containing milliliters of BBr ₃ boron tribromide in 200 mL of amylene-stabilized chloroform, dropwise carefully, so that the temperature did not exceed 5 ° C. The reaction mixture was allowed to stand for a period of time. one hour and 30 minutes on 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 ,

R ₈ = 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,

(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. 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 grams of 4-chloro-1- (4-methylphenyl) butanone as an oil which was 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 beforehand according to the procedure of Example 12 (a), in 450 ml of DMF The temperature of the reaction mixture gradually increased, initially to 50 ° C over 2 hours and then to 75 ° C. The reaction mixture was poured onto ice and extracted three times with ether, the combined organic phases were washed with water, 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) below, 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 were 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 of 171.8 grams of oxime, prepared as described in Example 12 (d) in 680 ml 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 grams Boiling point (below 6.65 Pa): 140-150 ° C.

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

One To 62 ml of bromine in place of dropwise to the solution which was preheated to 50 ° C, the solution contained 191.3 g of the nitrile of the compound from example 12 (e) in 1.85 L of carbon tetrachloride CC1 ₄ . The whole was heated to 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

182.2 g of the compound of Example 12 (f) was 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 the 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,

According to this embodiment, 2- (4-bromomethylphenyl) -3-cyanothiophene, as described above, was followed by a mixture of 50 grams containing 50 grams of which was prepared grams of ethyl ester

3-oxohexane prepared as described in Example 1,

300 ml of tetrahydrofuran

THF, 62 mL of diisopropylethylamine and 15.6 grams 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,

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

70.7 g of p-toluidine, 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, 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 added to a mixture of 49.3 grams of 3-furanoic acid, 220 milliliters of acetone, 23.4 grams of CuCl _2, and 6.3 grams of water, which was cooled to -5 ° C. The whole was stirred at 0 ° C for 2 hours and 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 grams Melting point: 166 C. C.

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

20 ml of SOCl _{2 was} added to a solution of 13.4 g of furanoic acid prepared as described above in 70 ml 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 resulting precipitate 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 then crystallized.

Yield: 7.5 g

Melting point: 66 ° C.

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

Compound of Formula IV:

W

IN

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 another bromination reaction in the same manner as in Example 4 to give 5-bromo-2- (4-bromomethylphenyl). -3-cyanofuran, which was another product of Example 13 (d) bis.

(e) Procedure for the 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,

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-) ethyl ester. 2-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 according to the procedure of 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 2- [ethyl ester]. 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:

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 g 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

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

R'l-CH ₂ CH ₂ CH _3, R ₈ = CH ₂ CH ₂ CH _3,

According to this embodiment, it was initially 15.6 grams

4,6-dioxononane, prepared from methylpropyl ketone and ethyl butyrate in the presence of lithium amide (according to CA 42: 4129 f), dissolved in 160 ml of anhydrous dimethylformamide DMF. 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 of 4 ^1- bromomethyl-2-cyanobiphenyl prepared as described in Example 4 in 90 ml of DMF was added. the addition was carried out 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 prepare 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? = CH ₃ ,

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? = n-propyl, Rg = O-ethyl,

A mixture containing 69.9 grams of 2 - [(2'-cyanobiphenyl-4-yl) methyl] -3-oxohexanoic acid ethyl ester, prepared according to the procedure of Example 5, 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 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.

Example 18 (Method A)

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

5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R ' ⁼ n-propyl,

X = hydrogen,

R ₁₀ = OH,

NC

A mixture of 5 grams of 3-aminopyrazole, 20.6 grams of the β-ketoester obtained according to Example 5 and 90 milliliters of acetic acid was heated to reflux for 1 hour 30 minutes. The precipitate was collected by filtration and washed with ether and then ethanol to give the desired 6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazole [1,5-a]. ] pyrimidine.

Yield: 12.7 g

Melting point: 251 C. C.

¹ H NMR (DMSO-d 6):

2.65 (t, 2H, propyl _CH2);

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

6.1 (d, 1H, H ₃ );

7.85 (d, 1 H, ₂ H, J (H ₂ -H _3): 2 Hz)

Example 19 (Method B)

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

7-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula VIII-b:

R'j = n-propyl,

X = hydrogen, ^R 10 ⁼ OH,

NC

A mixture of 5 grams of 3-aminopyrazole and 50 ml of 5-ethyl-2-methylpyridine was heated to 175 ° C. A solution of 21 grams of the β-ketoester of the compound of Example 5 in 50 ml of 5-ethyl-2-methylpyridine was added dropwise to the reaction mixture.

The reaction mixture was heated at 175 ° C for 6 hours. A precipitate of 11.9 g was obtained, which was filtered off and identified as a derivative of the compound of Example 18 above.

The concentrated mother liquors were then added to a mixture of water and chloroform. After decanting, the aqueous phase was extracted with chloroform and the combined organic phases were dried and concentrated to give 10.7 g of amorphous crystals. Chromatography on silica gel (eluent: 95% CHCl ₃ /5% methanol) afforded the title compound, i.e. the title compound was collected. 6 - [(2'-Cyanobiphenyl-4-yl) methyl] -5-hydroxy-7-propylpyrazolo [1,5-a] pyrimidine.

Yield: 4.1 g

Melting point: 236 C.

^X H NMR (DMSO-d):

2.99 (t, 2H, propyl _CH2); 3.95 (WITH, 2H, benzyl CH ₂ ), 5.85 (D, 1H, H ₃ , J (H ₂ -H ₃ ): 1.5 Hz), 7.75 (M, 2H, H ₂ , with aromatic proton)

The derivatives listed in the following Examples 20 to 26 were prepared by one of the two procedures described in Examples 18 and 19, using the appropriate β-ketoester compounds shown in Examples 5 to 15.

Example 20

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

Compound of Formula III-a:

R'2 = n-propyl,

X = 2-CH _3,

R ₁₀ = OH,

NC

Melting point: 210 C. C.

¹ H NMR (DMSO-d 6):

2.3 (s, 3H, CH _3),

2.6 (t, 2H, propyl _CH2);

5.9 (s, 1H, H ₃ ).

Example 21

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

Compound of Formula III-a:

R '= R = n-butyl,

X = hydrogen,

_Lo R = OH,

NC

Melting point: 216 C. C.

¹ H NMR (CHCl ₃ ):

2.8 (t, 2H, n-butyl _CH2);

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

6.14 (d, 1H, H ₃ );

7.75 (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2.3 Hz).

Example 22

Preparation of 6- [4- (3-cyano-2-thienyl) benzyl] -7-hydroxy-

5-pyrazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R ' ₃ = n-propyl,

X = hydrogen,

R ₁₀ = OH,

NC

Mp .: 252 ° C.

¹ H NMR (DMSO-d ₆ ):

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

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

6.12 (d, 1H, H ₃ , J (H ₂ -H ₃ ): 1.2 Hz).

Example 23

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

Compound of Formula VIII-b:

R'1 = n-propyl,

X = hydrogen,

R ₁₀ = n-propyl,

NC

IN

Melting point: 125 C. C.

¹ H NMR (CHCl ₃ ):

2.74 (T, 2H, n-propyl CH ₂ ), 3.23 (q Χ- 2H, n-propyl CH ₂ ), 4,21 ίε. 2H, benzyl CH ₂ ), 6.61 (D, 1H, H ₃ , J (H ₂ -H ₃ ): 1.2 Hz), 8.09 (D, 1H, H ₂ , J (H ₂ -H ₃ ): 2.2 Hz).

Example 24

Preparation of 6- [4- (3-cyano-2-pyridyl) benzyl] -7-hydroxy-

5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R'1 = n-propyl,

X = hydrogen,

R ₁₀ = OH,

Melting point: 248 C. C.

^{Χ Η} NMR (DMSO-d):

2.65 (t, 2H, n-propyl _CH2); 3.99 (with, 2H, benzyl CH ₂ ), 6,12 (D, 1H, H ₃ , J (H ₂ -H ₃ ): 1.2 Hz), 7.87 (D, 1H, H ₂ , J (H ₂ -H ₃ ): 1.7 Hz).

Example 25

Preparation of 6 - [- [2'-Cyanobiphenyl-

4-yl) methyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidin-2-yl) carboxylic acid

Compound of Formula III-a:

R ' ₃ = n-propyl,

X = 3-COOCH ₂ CH _3,

R ₁₀ = OH,

Melting point: 160 ’C.

¹ H NMR (DMSO-d 6):

2.83 (t, 2H, n-propyl _CH2); 3.99 (with, 2H, benzyl CH ₂ ), 8.21 (WITH, 1H, h ₂ ).

Example 26

6- [2'-Cyanobiphenyl-4-yl) methyl] -2,7-dihydroxy-5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula III-a:

R'1 = n-propyl,

X = 2-OH,

R ₁₀ = OH,

The following compounds were prepared by reacting β-ketoesters according to Examples 9, 10, 13-13 bis and 14 with 3-aminopyrazole using the method of Example 18 or 19:

6- [2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-methoxymethylpyrazolo [1,5-a] pyrimidine;

5-Benzyloxymethyl-6- [2'-cyanobiphenyl-4-yl) methyl] -7-hydroxypyrazolo [1,5-a] pyrimidine;

6- [4- (3-cyano-2-furyl) benzyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine;

6- [4- (5-bromo-cyano-2-furyl) benzyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine,

6- [2'-cyanobiphenyl-4-yl) methyl] -5,7-dimethylpyrazolo [1,5-a] pyrimidine,

Example 27

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

Compound of Formula VIII-a:

R '= n-propyl,

X = hydrogen,

NC

27 grams of 6- [2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine prepared as described in Example 18 was added portionwise to 540 ml of oxychloride. phosphorus POC1 ₃ . The reaction mixture was then heated at reflux for 3 hours. Next, the reaction mixture was concentrated under vacuum. The resulting oil was then taken up in dichloromethane and washed twice with water and ice. The organic phase was decanted, dried and concentrated. The resulting yellow oil was then taken up in ether to give crystals of the desired 7-chloro-6- [2'-cyanobiphenyl-4-yl) methyl] -5-propylpyrazolo [1,5-a] pyrimidine.

Yield: 25.6 grams

Melting point: 137 C.

¹ H NMR (CDCl ₃ ):

2.8 (t, 2H, propyl _CH2);

6.7 (d, 1H, H ₃ );

8.2 (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2.2 Hz).

Example 28

6- [2'-Cyanobiphenyl-4-yl) methyl] -7- [2- (morpholin-4-yl) ethylamino] -5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ' ₃ = n-propyl,

X = hydrogen,

The reaction mixture contained 5 grams of the chlorinated derivative prepared according to the procedure of Example 27,

1.8 g of 4- (2-aminoethyl) morpholine, 1.5 g of sodium carbonate

Na ₂ CO ₃ and 100 milliliters of ethanol are heated at reflux for 7 hours. Then 1.8 g was added to the next reaction mixture

Of 4- (2-aminoethyl) morpholine and the reaction mixture was heated at reflux for 8 hours. It was then concentrated under vacuum and the resulting product was taken up in a mixture of water and dichloromethane. The aqueous phase was decanted and extracted with dichloromethane. The obtained organic phases were combined and dried. Evaporation of the solvent gave a brown oil which was sufficiently pure to be used for the next step.

Yield: 5.9 g ¹ H NMR (CDCl ₃ ):

2.5 (t, 2H, propyl _CH2);

6.4 (d, 1H, H ₃ );

7.9 (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2.4 Hz).

Example 29

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

5-propyl-pyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

= OCH ₃ ,

X = hydrogen,

R ₂ = n-propyl,

NC

IN

7.7 g of the chlorinated compound prepared according to Example 27 were reacted at room temperature with a solution of sodium methylate and 1,2-dimethoxyethane prepared from 0.6 g of sodium, 25 ml of methanol and 50 ml of 1,2-dimethoxyethane was carried out for 6 hours.

The resulting reaction mixture was concentrated. The resulting concentrate was then added to a mixture of water and ethyl acetate. In this way, a precipitate (1.4 g) was identified as 6- [2'-cyanobiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine, a compound obtained according to the procedure of Example 18. The organic phase was chromatographed on silica gel (eluent: 90% dichloromethane / 10% acetone) to give the desired product.

6- [2'-Cyanobiphenyl-4-yl) methyl] -7-methoxy-5-propyl-pyrazolo [1,5-a] pyrimidine.

Yield: 4 g

Melting point: 110 ° C.

¹ H NMR (CDCl ₃ ):

2.75 (Q » 2H, propyl ch ₂ ), 4.18 (with, 2H, benzyl ch ₂ ), 4.29 (with, 3H, och ₃ ), 6.60 (D, 1H, h ₃ ), 8.07 (d , 1H , h ₂ , Jl (H ₂ - ^H 3

Example 30

Preparation of 6- [2'-cyanobiphenyl-4-yl) methyl] -5-propylpyrazolo [1,5-a] pyrimidin-7-yl] 2-methoxyethyl ether

Compound of formula (X):

R ₁ = OCH ₂ CH ₂ OCH ₃ ,

X = hydrogen,

R ₂ = n-propyl,

According to this example of sodium NaH added after milliliters of 2-methoxyethanol, 0.6 grams of 60% hydride was portioned to a mixture containing 25 and 50 milliliters of 1,2-dimethoxyethane.

After 15 minutes, 5 grams of the chlorinated compound, prepared as described in Example 27, was added in portions, followed by 50 ml of 1,2-dimethoxyethane. The reaction mixture was stirred for 3 hours at room temperature and then concentrated under vacuum and the concentrate was taken up in a mixture of water and ethyl acetate. After decanting, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and evaporated to give 6.3 grams of an oil which was purified by silica gel chromatography (eluent: 90% dichloromethane / 10% acetone) to give the desired product.

6- [2'-cyanobiphenyl-4-yl) methyl] -5-propyl-pyrazolo [1,5-a] pyrimidine

7-yl] 2-methoxyethyl ether.

Yield: 4.2 g

Melting point: 106 C. C.

The compounds of Examples 31 to 34 were obtained by one of the procedures of Examples 28 to 30 using appropriate nucleophilic reagents.

Example 31

6- [2'-Cyanobiphenyl-4-yl) methyl] -7- (N-morpholine) -5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₃ = N-morpholine group,

R ₂ = n-propyl, X = H,

Melting point: 140 ° C.

¹ H NMR (DMSO-d 6):

2.6 (t, 2H, propyl _CH2);

6.6 (d, 1H, H ₃ );

8.1 (d, 1H, H ₂ ), J (H ₂ -H ₃ ): 2.4 Hz).

Example 32

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

7- (2- (pyrrolidin-l-yl) ethylamino] pyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₂ = n-propyl,

X = hydrogen,

The resulting oil was purified by silica gel chromatography (eluent: 90% CHCl 3/10% methanol).

¹ H NMR (CDCl ₃ ):

2.6 (m, 4 H, _{propyl-CH2 CH2} pyrrolidine),

6.4 (d, 1H, H ₃ J (H ₂ -H ₃ ): 2.1 Hz),

7.9 (d, 1H, H ₂ ).

Example 33

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

1-yl) -5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

= n-propyl, = hydrogen.

The product obtained was crystallized from isopropyl ether.

Melting point: 118 ° C.

Example 34

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

Compound of Formula IX:

R 2 -S-CH ₂ COOEt,

X = hydrogen,

R ₂ - n -propyl.

NC

Melting point: 126 C. C.

The compounds of Examples 35 and 36 were obtained according to the procedure of Example 28, except that the reaction was carried out in an autoclave at 100 ° C for hours.

Example 35

Preparation of [6 - [(2'-cyanobiphenyl-4-yl) methyl] -7-N, N-diethylamino-5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₂ = n-propyl,

X = hydrogen,

CH ₂ —CH ₂

CH ₂ —CH ₂

NC

The oil obtained was purified by silica gel chromatography (eluent: 95% CH ₂ Cl ₂ /5% ethyl acetate).

¹ H NMR (DMSO-d 6):

2.6 (t, 2H, propyl _CH2);

6.6 (d, 1H, H ₃ J (H ₂ -H ₃ ): 2.1 Hz),

8.1 (d, 1H, H ₂ ).

Example 36

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

Compound of Formula IX:

R ₁ = NH _2,

R ₂ = n-propyl,

X = hydrogen,

NC

IN

The resulting oil was purified by silica gel chromatography (eluent: 95% CH ₂ Cl ₂ /5% acetone).

Crystallization of the product proceeded slowly.

Melting point: 158 C. C.

¹ H NMR (CDCl ₃ ):

2.7 (t, 2H, propyl _CH2);

6.4 (d, 1H, H ₃ );

7.9 (d, 1 H, ₂ H, J (H ₂ -H _3): 2 Hz);

Example 37

6- [2'-Cyanobiphenyl-4-yl) methyl] -5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula IX:

R ₃ = H,

R ₂ = n-propyl, X = H,

A solution containing 5.4 grams of the chlorinated compound prepared as described in Example 27 in 110 milliliters of sodium acetate,

Of 2-methoxyethanol containing 1.2 grams of anhydrous hydrogenated at atmospheric pressure and at ambient temperature in the presence of activated carbon. The catalyst system was filtered with 2-methoxyethanol. The obtained ether filtrate yielded 5.2

1.4 grams purified on Celite with hydrogen.

545 and palladium The washed was concentrated and loaded into a gram of crude product. This product was then purified by silica gel chromatography (eluent: 90% dichloromethane / 10% acetone) to give the desired 6- [2'-cyanobiphenyl-4-yl) methyl] -5-propylpyrazolo [1,5-a]. ] pyrimidine.

Yield: 4 g

Melting point: 154 C. C.

Example 38

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

Compound of Formula I:

R 6 = OH,

R ₂ = n-propyl,

X = hydrogen,

The mixture contained 0.8 grams

3-aminopyrazole, 3.9 g of the β-ketoester obtained according to the procedure of Example 17 and 25 ml of acetic acid are heated at reflux for 6 hours. An additional 0.4 grams of aminopyrazole was added to the reaction mixture, and the reaction mixture was heated at reflux for 6 hours. The product thus obtained was concentrated under vacuum. The resulting oil was taken up in water to give 3.8 grams of a solid which was purified first by silica gel chromatography (eluent: 80% chloroform / 20% methanol to remove less polar products and then 70% chloroform / 30% methanol). for eluting the pyrazolopyrimidine compound). The resulting solid was treated with normal sodium hydroxide solution. The insoluble matter was removed and the clear solution was acidified to pH 4 by bubbling SO ₂ gas, resulting in a white precipitate. The obtained compound was crystallized from ethanol to give the desired 7-hydroxy-5-propyl-6 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] pyrazolo [1,5-a] pyrimidine.

Yield: 0.6 g

Empirical formula: ^c 23 ^h 21 ^N 7 ° ^{2 h} 2 ° Melting point:> 320 ° C (dec.).

¹ H NMR (DMSO-d 6):

2.5 (m, 2H, propyl _CH2 + DMSO-d), (d, 1 H, ₃ H);

7.8 (d, 1 H, ₂ H, J (H ₂ -H _3): 1.9 Hz).

Example 39

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

Compound of Formula I:

R @ 1 = n-propyl,

R ₂ = OH,

X = hydrogen,

A mixture of 5 grams of the derivative prepared according to Example 19, 150 ml of xylene, 6 ml of dimethylformamide DMF and 7 grams of trimethyltin azide was heated at 115 ° C for 50 hours.

The organic phase was decanted. The resulting precipitate was taken up in tetrahydrofuran THF. Hydrochloric acid gas was then bubbled through until the precipitate had dissolved.

This solution was then concentrated under vacuum and the resulting concentrate was taken up in water and triturated. The gum was crystallized in the presence of acetonitrile. Recrystallization from isopropanol gave the desired 5-hydroxy-7-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] pyrazolo [1,5-a] pyrimidine.

Yield: 0.7 grams Empirical formula: ^C 23 ^H 21 ^N 7 ° Melting point: 260 ° C.

^X H NMR (DMSO-d):

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

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

5.83 (d, 1H, H ₃ );

7.74 (d, 1H, H ₂ , J (H ₂ -H ₃ ): 1.9 Hz).

Example 40

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

Compound of Formula I:

R ₂ = n-propyl,

X = hydrogen,

_{NH-CH2 -CH2} -N

The mixture contained 5.9 grams

6- [2'-cyanobiphenyl-4-yl) methyl] -7- [2- (morpholin-4-yl) -ethylamino] -5-propylpyrazol-1,5-a] pyrimidine, prepared according to the procedure of Example 28, hereinafter 3, 1 gram of trimethyltin azide and 120 ml of xylene brought to reflux. After 15 hours, an additional 3.1 grams of trimethyltin azide was added and the reaction mixture was refluxed for a further 20 hours.

The thick oil obtained was decanted from xylene and then transferred to tetrahydrofuran THF. Acidification with gaseous hydrochloric acid gave a gummy precipitate which was then taken up in acetonitrile to give 4.7 g of a solid.

The base was prepared by treatment with a solution of triethylamine and ethyl acetate. The obtained compound was purified first by silica gel chromatography (eluent: 80% chloroform / 20% methanol).

Recrystallization from ethanol gave the desired 7 - [(N-morpholinoethyl) amino] -5-propyl-6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] pyrazole [1,5- ajpyrimidine in the form of white crystals.

Yield: 2.5 g

Empirical formula: ^C 29 ^H 33 ^N 9 ° * ^{0.1 H} 2 °

Melting point: 210 C. C.

¹ H NMR (DMSO-d 6):

2.6 (t, 2H, n-propyl);

6.3 (d, 1H, H ₃ ), (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2.2 Hz).

The compounds of Examples 41 to 49 were prepared by any of the methods described in Examples 38, 39 or 40.

Example 41

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

Compound of Formula I:

= OH group,

R ₂ = n-propyl,

X = 2-CH _3,

Empirical formula: C 24 H 23 N 7 O. HCl. 0.2 H ₂ O Melting point: 230-232 ° C (dec.).

^X H NMR (DMSO-d):

2.6 (t, 2H, n-propyl CH ₂ ), (s, 1H, H ₃ ).

Example 42

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

Compound of Formula I:

R1 = Cl,

R ₂ = n-propyl,

X = hydrogen,

Empirical formula: C ₂₃ H _{20 O 1} N ₇

Melting point: 234 C. C.

¹ H NMR (DMSO-d ₆ ):

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

6.8 (d, 1 H, H ₃ ),

8.3 (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2.3 Hz).

Example 43

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

Compound of Formula I:

R ₂ = n-propyl,

X = hydrogen,

Empirical formula:? 7? 28? 8 °. HC1 Melting point: 210-212 ° C.

^X H NMR (DMSO-d):

2.8 (t, 2H, n-propyl _CH2); 6.5 (D, 1H, Hj) 8.2 (D, 1H, h ₂ , j (h ₂ -h ₃ )

Example 44

5-Propyl-7 - [(N-pyrrolidinethyl) amino] -6- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] pyrazolo [1,5-a] pyrimidine

Compound of Formula I:

R ₂ = n-propyl,

X = hydrogen,

Empirical formula: C ₂₉ H ₃₃ N ₉

Melting point: 200 - 201 ° C.

¹ H NMR (DMSO-d 6):

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

6.4 (d, 1H, H ₃ ), (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2 Hz).

Example 45

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

Compound of Formula I:

R _x = NH ₂ ,

R ₂ = n-propyl,

X = hydrogen,

Empirical formula: ^C 23 ^H 22 ^N 8

Melting point: 255 ’C.

¹ H NMR (DMSO-d 6):

2.5 (m, 2H, n-propyl _CH2 + DMSO-d?),

6.3 (d, 1H, H ₃ ), (d, 1H, H ₂ , J (H ₂ -H ₃ ): 2 Hz).

Example 46

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

Compound of Formula I:

R ₂ = n-propyl,

X = hydrogen,

CH ₂ —CH ₃ ^R 1 ⁼ N ^Z \

ch ₂ —ch ₃

Empirical formula: ^C 27 ^H 29 ^N 5 ' ^HC 1 Melting point: 192 ° C.

¹ H NMR (DMSO-d 6):

2.68 (t, 2H, n-propyl _CH2); 6.63 (D, 1H, h ₃ ), 8.21 (D, 1H, h ₂ ).

Example 47

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

Compound of Formula I:

R1 = OH,

R ₂ = n-butyl, X = H,

The product thus obtained was purified by silica gel chromatography (eluent: 90% dichloromethane / 10% methanol).

Empirical formula: ^C 24 ^H 23 ^N 7 ° Melting point:> 370 ° C (dec.).

¹ H NMR (DMSO-d ₆ ):

2.51 (m, n-propyl _CH2 / DMSO-d),

5.99 (d, 1H, H ₃ );

7.8 (d, 1 H, ₂ H, J (H ₂ -H _3): 1.8 Hz).

Example 48

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

Compound of Formula I:

R 6 = hydrogen,

R ₂ = n-butyl,

X = hydrogen,

The product thus obtained was purified by crystallization from acetonitrile.

Empirical formula: ^C 23 ^H 21 ^N 7 Melting point: 196 ° C

¹ H NMR (DMSO-d ₆ ):

2.64 (T, 2H, n-propyl CH ₂ ), 4.05 (with, 2H, benzyl CH ₂ ), 6.58 (D, 1H, h ₃ ), 8.11 (D, 1H, H ₂ , J (H ₂ -H ₃ ): 1.8 8.89 (with, 1H, h ₇ ).

Example 49

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

Compound of Formula I:

R = n-propyl,

R ₂ = n-propyl, X = H,

The product thus obtained was purified by crystallization from isopropyl acetate.

Empirical formula: C ₂₆ H ₂₇ N ₇ Melting point: 188 ° C

¹ H NMR (DMSO-d 6):

2.64 (T, 2H, n-propyl ch ₂ ), 3.17 (T, 2H, n-propyl ch ₂ ), 4.16 (WITH, 2H, benzyl CH ₂ ), 6.59 (WITH, 1 H, ₃ H); 8.13 (with, 1 H, ₃ H).

Example 50

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

Compound of Formula I:

= OH group,

R ₂ = n-propyl, X = H,

h ₂ n

A mixture of 7.4 grams of the compound of Example 18 in NaOH, prepared from 29.6 grams of sodium hydroxide pellets and 700 mL of water, was heated at reflux for 3 hours. A white precipitate was obtained, which was filtered and treated with a dilute acetic acid solution. The product was purified by recrystallization from 2-methoxyethanol to give the desired 6- [2'-aminocarbonylbiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine.

Yield: 3.4 g

Empirical formula: ^C 23 ^H 22 ^N 4 ° 4 Melting point: 264 ° C.

¹ H NMR (DMSO-d 6):

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

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

6.09 (s, 1H, H ₃ );

7.85 (d, 1 H, ₂ H, J (H ₂ -H _3): 1.7 Hz).

Example 51

6- [2'-Carboxybiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazolo [1,5-a] pyrimidine

Compound of Formula I:

R @ 1 = OH;

R ₂ = n-propyl,

X = hydrogen,

HOOC

A mixture of 7.4 grams of the compound of Example 18 in sodium hydroxide solution, made up of 40 grams of sodium hydroxide pellets and 500 milliliters of water, was refluxed for 6 hours. A white precipitate was obtained after treatment with a dilute acetic acid solution, the melting point of which was between 230 DEG and 240 DEG C., and the product was re-treated by heating to reflux in a mixture containing 6 g of NaOH, 6 ml of water and 200 ml of ethylene glycol for 18 hours. The resulting reaction mixture was concentrated under vacuum and then taken up in water. Treatment with sodium acetate the precipitate was prepared, which was purified by recrystallization from 2-methoxyethanol to afford the desired 6- [2 ¹ carboxybiphenyl-4-yl) methyl] -7-hydroxy-5-propylpyrazole [1,5-a ] pyrimidine.

Yield: 4 g

Empirical formula: C ₂₃ H ₂₁ N ₃ O ₃ Melting point: 300 ° C.

^X H NMR (DMSO-d):

2.63 (T, 2H, n-propyl CH ₂ ), 3.91 (with, 2H, benzyl CH ₂ ), 6.09 (D, 1H, H ₃ ), 7.85 (D, 1H, H ₂ , J (H ₂ -H ₃ ): 1.9 Hz)

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 incubated using Tyr ¹ , Ile ⁸ -angiotensin rat adrenal homogenate were of one concentration [ ¹²⁵ ] -SIAII (Sar ¹ ,

II), which is an angiotensin II receptor antagonist, and two concentrations of competing agents (10 ^-5 M, 10 ^-7 M) for 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.

Test substance % replacement of labeled ligands 1 E-7 M 1 E-5 m Example 38 65 39 Example 40 70 51 Example 41 68 40 Example 42 68 38 Example 43 65 21 Example 44 72 48 Example 45 64 46 Example 46 72 49

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

The 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 pre-treated for one hour with the test molecule (10 ^"4 M) and then stimulated with an interval of 22 hours growth factor (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 aspirating the reaction medium, separating the 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 ³ H-thymidine incorporation relative to the growth factor effect.

Under the above conditions, the test compounds of the formula I according to the invention had an antiproliferative activity at 100 μΜ.

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 of the compounds of the above examples showed good affinity for angiotensin II receptors. Therefore, the various pathological angiotensin II, especially and cardiac insufficiency, compounds can be advantageously used to treat conditions in which they are involved in the treatment of arterial hypertension at doses ranging from 400 to 400 milligrams for oral administration and in the range of 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 (10)

PATENT CLAIMS 1. Pyrazolopyrimidine derivatives of the general formula wherein: - one of R ^ and R _2: - a lower alkyl group containing 1 to carbon, or - an ether residue of the formula: - (CH ₂ ) _p or wherein p is an integer from 1 to 6 and R is a lower alkyl group containing 1 to 6 carbon or benzyl, and - the second of R 1 or R ₂ means: - a hydrogen atom, - halogen atom, a lower alkyl group containing 1 to carbon, or a residue selected from the group consisting of OR ₄ , SR ₄ , NR ₅ R ₆ and NH (CH ₂ ) _n -NR ₅ R ₆ , in which: atoms atoms group atoms 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 represents an integer from 1 to 4 and R' represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or - the rest of the formula: in which R 'have the same meaning as above, ^r 5 ^and 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 ₅ 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 may be in the 2-position or 3-position of the pyrazolo [1,5-a] pyrimidine ring, representing: - a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or - a group selected from the group consisting of hydroxyl and COOR ', wherein R' has the same meaning as above, and R ₃ is a radical of the formula: in which it means: Z is CH or N and Z 'is sulfur or oxygen, is hydrogen or halogen, and R ₁₂ represents a tetrazole moiety, a CN, COOH or conh _{2 group} and tautomeric forms and addition salts thereof, especially pharmaceutically acceptable addition salts. Compounds of the formula I as claimed in claim 1, in which: - one of the radicals R and R _2: a lower alkyl group having 1 to 6 carbon atoms, and - the other of the radicals R @ 1 or R @ ₂ represents: - a hydrogen atom, - a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a radical selected from the group consisting of OH, NR ₅ R ₆ and NH (CH _{2) n} -NR ₅ R _6, wherein: 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 the group consisting of morpholine and pyrrolidine, and n represents an integer from 2 to 4, X may be in the 2-position or 3-position of the pyrazolo [1,5-a] pyrimidine ring, representing: a hydrogen atom, or a lower alkyl group having 1 to 6 carbon atoms, and R ₃ is one of the following moieties: and tautomeric forms and addition salts thereof, especially pharmaceutically acceptable addition salts. Derivatives according to claim 1 or 2, wherein R 1 represents an n-propyl group, a hydroxyl group, a morpholinoethylamine group, an amino group or an N-diethylamine group. Derivatives according to any one of claims 1 to 3, wherein R ₂ represents an n-propyl group or a hydroxyl group. Compounds according to any one of claims 1 to 4, wherein X represents a hydrogen atom. Derivatives according to any one of claims 1 to 5, wherein R ₃ represents a 2- (1H-tetrazol-5-yl) phenyl group. Derivatives according to claim 1 or 2, selected from the group consisting of derivatives of the following formulas C to G: (C) (D) (E) (F) A process for the preparation of a compound of formula I according to any one of claims 1 to 7, characterized in that it comprises the following steps: (a) preparing a compound of formula I-A: (I-A) wherein: X and R ₃ have the same meaning as set forth in claims 1 or 2, 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 containing C 1 to C 6 or an ether radical of 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, this process being carried out by condensation of the 3-aminopyrazole of formula II: in which X has the same meaning as above, with a derivative of the general formula I-B: in which R '2 represents a lower alkyl group having 1 to 6 carbon atoms or an ether radical of the formula: - (ch ₂ ) _p -or wherein 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, 100 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 is as defined in claims 1 or 2, in an aprotic solvent such as dichlorobenzene or trichlorobenzene or 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 embodiment in pyridine or 2-methyl-5-ethylpyridine in the presence or absence of 4-dimethylaminopyridine, and at a temperature ranging from 50 ° C to 200 ° C. (b) introducing, if necessary, a R ₃ protecting group into the R ₃ substituent using well known methods; (c) heating the derivative thus obtained prepared from the derivative of the general formula IB, if the compound is a ketoester, a suitable reagent, such as POCl ₃ , to convert the hydroxyl group represented by the 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 give a derivative of the general Formula IA in which A and B have the same meaning as R 1 and R ₂ . (e) removing the protecting group attached to R ₃ , if necessary, (e ₃ ) converting this group into an acid group, 101, for example, by hydrolysis when the group is a nitrile group, or (e ₂ ) is converted 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 this group into an amide group, for example when the group is a nitrile group, by reaction with sulfuric acid or by reaction with hydrogen peroxide, or otherwise by reaction with polyphosphoric acid. and (f) if desired, converting the thus obtained derivative 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 disease, comprising a pharmaceutically effective amount of at least one compound of the general formula I as defined in any one of claims 1 to 7, or at least one pharmaceutically acceptable addition salt derived therefrom, which may or may not be incorporated or combined with a pharmaceutically acceptable vehicle, excipient or carrier material. A pharmaceutical composition, in particular having an antiproliferative effect, by which it is possible to successfully treat or prevent diseases of the arterial walls, 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 7 or at least one pharmaceutically acceptable addition salt thereof 102 compounds, which may or may not be combined with a pharmaceutically acceptable substance or carrier. be injected or vehicle, auxiliary