EP1345941A1 - Cyclin-dependent kinase (cdk) and glycolene synthase kinase-3 (gsk-3) inhibitors - Google Patents

Abstract

The invention concerns novel cyclin-dependent kinase (CDK) and glycolene synthase kinase-3 (GSK-3) inhibitors, corresponding to general formula (I), wherein: A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol)-3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or a -L-NR1R2 radical wherein L represents an alkylene radical and R?1 and R2¿ are selected independently among a hydrogen atom and an alkyl radical or R?1 and R2¿ together with the nitrogen bearing them form a heterocycle with 5 to 7 members optionally substituted; X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralkylthioxo radical, or a NR4R5 radical wherein R4 represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted, an aralkyl radical whereof the aryl radical is optionally substituted, or R4 represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted; Y represents NH or an oxygen atom; Z represents a bond or an alkyl or alkylthioalkyl radical; and Ar represents a carbocyclic aryl radical optionally substituted, a heterocyclic aryl radical optionally substituted or a piridiniumolate radical; or are pharmaceutically acceptable salts of said compounds.

Description

 Cyclin-dependent kinase (CDK) and glycogen svnthase kinase-3 (GSK-3) inhibitors

The subject of the present invention is new inhibitors of cyclin-dependent kinases, and in particular of cyclin B1 / cdc2, and of glycogen synthase kinase-3 (GSK-3).

Control of the transition between the different phases of the cell cycle of mitosis or meiosis is ensured by a set of proteins whose enzymatic activities are associated with different states of phosphorylation. These states are controlled by two main classes of enzymes: kinases and phosphatases.

The synchronization of the different phases of the cell cycle thus allows the reorganization of the cellular architecture at each cycle throughout the living world (microorganisms, yeasts, higher organisms, plants). Among kinases, cyclin-dependent kinases (CDKs) play a major role in this control of the cell cycle. CDKs are complexes where the kinases carry the enzymatic activity and the cyclins associated a regulatory activity of the latter. The association between these proteins is not permanent, these associations vary during the cycle in precise windows of time. Several cyclins and CDKs coexist in the cell, but the associations between cyclins and CDKs are specific. At this date, at least ten CDKs have been described (CDK1-X) (Detivaud et al., Eur. J. Biochem. (1999), 264, 55-66). The enzyme cdc2 is also called CDK1 (Meijer et al., Ewr. /. Biochem. (1997), 243, 527-536). With the exception of CDK3, each of the CDKs is specifically associated with one or more members of the cyclin family:

- cyclin A: CDK1 and CDK2;

- cyclins B1-B3: CDK1;

- cyclin C: CDK8;

- cyclins D1-D3: CDK1, CDK2, CDK4, CDK5 and CDK6; - cyclin Ε: CDK2;

- cyclin H: CDK7;

- cyclin T: CDK9. The CDK partners of cyclins F, G and I have not yet been identified. Other kinases close to cdc2 and other cyclins have been identified and the characterization of their functions is in progress, for example in parasites (Le Roch et al., /. Biol. Chem. (2000), 275, 8952 -8958) or in herpes viruses (Card et al., EMBO (2000), 19, 2877-2888).

Furthermore, the enzymatic activity of these different CDKs is controlled by two other families of enzymes which work in opposition (Jessus and Ozon, Prog. Cell Cycle Res. (1995), 1, 215-228). The first groups kinases such as Weel and Mikl which deactivate CDKs by phosphorylating certain amino acids (Den Haese et al., Mol. Biol. Cell (1995), 6, 371-385). The second groups together phosphatases such as the Cdc25 family which activates certain CDKs by dephosphorylating the tyrosine and threonine residues of CDKs (Gould et al., Science (1990), 250, 1573-1576). It should be noted that entry into cells can occur without activation of the cdc2 kinase in cells treated with okadaic acid, suggesting that phosphatase cdc25C and other kinases may play a role in this process (Gowdy and coll., /. Cell Sci. (1998), 111, 3401-3410).

To complete this control of the cell cycle, different endogenous CDK inhibitors have been identified: pl6ink4A, pl5ink4B, pl8ink4C, p27kipl, p57kip2, p21cipl (Linares-Cruz et al., Proc. Natl. Acad. Sci. USA (1998), 95 , 1131-1135; Goubin and Ducommun, Oncogene (1995), 10, 2281-2287). The expression of these endogenous inhibitors is very often altered in tumor cells.

Many compounds blocking the kinase activity of CDKs are known (Meijer and Kim, Methods Enzymol. (1997), 283, 113-128). they are being studied in several therapeutic fields such as oncology to prevent the division of tumor cells (McDonald and el-Deiry, Int. J. Oncol. (2000), 16, 871-886), neurobiology to prevent natural apoptosis or chemo-induced normal cells (e.g. neurons) (Maas et al., J. Neurochem. (1998), 70, 1401-1410; Park et al., J. Neurosci. (1997), 17, 1256- 1270), nephrology to restore impaired renal function in the event of glomerulonephritis (Pippin et al., /. Clin. Invest. (1997), 100, 2512-2520) and parasitology to block the reproductive cycle of parasites (Knockaert et al., Chem. Biol. (2000), J, 411-422; Le Roch et al., J. Biol. Chem. (2000), 275, 8952-8958).

Cyclin-dependent kinase inhibitors are therefore likely to be used as drugs, in particular in the treatment of the diseases / disorders described. in Meijer et al., Pharmacol. Ther. (1999); 82, 279-284, and in particular:

• to inhibit tumor proliferation when used alone or in combination with other treatments;

• to inhibit the proliferation of normal cells when used alone or in combination with other treatments (for example: atherosclerosis, angiogenesis, psoriasis or restenosis);

• in the prevention of spontaneous alopecia;

• in the prevention of alopecia induced by exogenous products;

• in the prevention of radiation-induced alopecia; • in the prevention of spontaneous or induced apoptosis of normal cells (ischemia);

• in the prevention of meiosis and fertilization;

• in the prevention of oocyte maturation;

• in the treatment of viral or retroviral infections (herpes, AIDS, cytomegalovirus);

• in the prevention and treatment of neurodegenerative diseases (for example tauopathies and in particular Alzheimer's disease);

• in the prevention and treatment of parasites (proliferation of protozoa, for example Trypanosomes, Toxoplasmas or Plasmodium); • in the treatment of myopathies;

• and more generally in the treatment of all diseases / disorders corresponding to reported uses for CDK inhibitors.

The glycogen synthase kinase-3 (GSK-3) enzyme (Parker et al., Eur. J. Biochem. (1983), 130, 227-234) is a serine / threonine kinase enzyme. There are two isoforms α and β from two distinct genes. The α isoform encodes a 51 kd polypeptide. The β isoform codes for a 47 kd polypeptide having an amino acid homology of 85% with GSK-3 α (Woodgett, EMBO (1990), 9, 2431-2438).

The levels of messenger expression for the α and β isoforms of GSK-3 are predominant in the testes, thymus, prostate and ovaries but low in the lung and kidney. Analysis of protein detection in different tissues shows a lack of correlation between transcription and translation (Lau et al., J. Pept. Res. (1999), 54, 85-91).

GSK-3 is in an activated form in cells where it inhibits Glycogen synthase by direct phosphorylation (Eldar-Finkelman et al., Proc. Natl. Acad. Sci. USA (1996), 93, 10228-10233) (3) . Insulin inhibits GSK-3 and activates glycogen synthase. The inhibition of GSK-3 can be observed with other growth factors such as Y Insulin-like Growth Factor-I (IGF-I) or VEpidermal Growth Factor (EGF).

In addition, GSK-3 participates in other biological processes including cell cycle control (Diehl et al., Geπes & Dev. (1998), 12, 3499-3511), the cellular distribution of β-catenin (Yost et al., Genes & Dev. (1996), 10, 1443-1454), cell survival and activation of Nf-kappaB in the control of apoptosis (Hoeflich et al., Nature (2000), 406, 86-90), glucose metabolism (Summers et al., /. Biochem. (1999), 274,17934-17940), phosphorylation of the tau protein (Spittaels et al., J. Biol. Chem., 27 September 2000), or the dynamics of microtubules (Krylova et al., /. Cell Biol. (2000), 151 (1), 83-94).

The study of the role of GSK-3 is still in progress and many interventions are probably still to be described.

Among the molecules now reported as inhibitors of GSK-3, we can mainly cite:

• lithium, a therapeutic agent used in the treatment of depression for many years, which is a direct inhibitor of GSK-3; in addition to these effects on depression, lithium can modulate the proliferation of normal or tumor cells (Cui et al., Brain Res. Dev. Brain Res. (1998), 111 (2), 177-88);

• the compounds SB-216763 and SB-415286 which specifically inhibit GSK-3α and GSK-3β in vitro with Ki of the order of nM. They stimulate the synthesis of glycogen in human liver cells by inhibiting the cellular activity GSK-3 measured by the activation of glycogen synthase which is the direct target of GSK-3 (Coghlan et al., Chem. Biol. ( 2000), 7 (10), 793-803);

• most CDK inhibitors, except those derived from purines, which are reported to be potent inhibitors of GSK-3 (Meijer, Supplement to Cancer Clinical Research (November 2000), 6, Proceedings of the NCI-EORTC - ACCR Symposium, 043). There are also inhibitors of CDKs which are not inhibitors of GSK-3, such as derivatives of purines (roscovitine, olomucine, purvalanol ...) and butyrolactone. The specific inhibition values of different products on the two classes of enzymes are reported in Leclerc et al., /. Biol. Chem., September 2000.

There are many potential therapeutic applications for GSK-3 inhibitors (Ferkey et al., Dev. Biol. (2000), 225 (2), 471-479):

the Depression ;

mood disorders (Maηji et al., J. Clin. Psychiatry (2000), 61 (Suppl. 9), 82-96);

• neurodegenerative disorders such as Parkinson's disease;

tauopathies, pathologies where the tau protein is hyperphosphorylated as in Alzheimer's disease or certain dementias;

proliferative diseases, and in particular cancer; and

diabetes (Nikoulina et al., Diabetes (2000), 49 (2), 263-71).

Certain triazolopyrazine derivatives of simpler structures were already used in therapy, for example as phosphodiesterase inhibitors (US patents 3,846,423 and US 3,865,824), as corticotropin releasing factor (CRF) antagonists (patent applications). PCT WO 98/08847 and WO 99/67247) or also in the treatment of respiratory disorders (US patent 3,995,039), gastrointestinal disorders (US patent 4,565,815) or cardiovascular and circulatory disorders (US patent 5,356,894).

The compounds corresponding to the general formula (I)

(D in racemic, enantiomeric or any combination of these forms, in which

A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1, 3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or a radical

1 9 1

-L-NR R in which L represents an alkylene radical and R and R are chosen

1 9 independently from a hydrogen atom and an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of - CH ₂ -, -NR -, -S- and -O-, R representing independently each time it intervenes a hydrogen atom or an alkyl radical;

X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralkylthioxo radical, or also a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more chosen radicals among the alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom, the cyano radical, the nitro radical and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R represents a hydrogen atom, or then R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of -CH ₂ -, -NR ⁶ -, -S- and -O-, R ⁶ independently representing each time that it intervenes a hydrogen atom or an alkyl or hydroxyalkyl radical;

Y represents NH or an oxygen atom;

Z represents a bond or an alkyl or alkylthioalkyl radical; and

Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom, the cyano radical, the nitro radical, an alkyl or alkoxy radical and a NR ⁷ R ⁸ radical in which R ⁷ and R ⁸ independently represent a hydrogen atom or an alkyl radical or R ⁷ and R ⁸ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of - CH ₂ -, -NR ⁹ -, -S- and -O-, R ⁹ independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or Ar represents a heterocyclic aryl radical with 5 or 6 members and whose heteroatom (s) are chosen from nitrogen, oxygen or sulfur atoms, said heteroatoms possibly being oxidized (Ar can represent, for example, the oxidopyridyl radical ) and said heterocyclic aryl radical which may be optionally substituted by one or more radicals independently chosen from alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl radicals;

or the pharmaceutically acceptable salts of the compounds of general formula (I) can be used to prepare a medicament for inhibiting cyclin dependent kinases (CDK).

According to a preferred variant of the invention, the compounds of general formula (I) can be used to prepare a medicament intended to inhibit both cyclin-dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) .

By alkyl, when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms. By cycloalkyl, when it is not given more precision, is meant a cycloalkyl radical having 3 to 7 carbon atoms. By carbocyclic or heterocyclic aryl, when it is not given more precision, is meant a carbocyclic or heterocyclic system comprising from one to three condensed rings of which at least one is an aromatic ring, a system being said to be heterocyclic when l 'at least one of the cycles which compose it includes one or more heteroatoms (O, N or S). By aryl, when it is not given more precision, one understands a carbocyclic aryl radical. By heteroaryl is meant a heterocyclic aryl radical.

By alkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkylthio, aralkylthio, alkylthioxo, aralkylthioxo, hydroxyalkyl, alkylthioalkyl, aralkyl, heteroaralkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl meant respectively the alkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkylthio, aralkylthio, alkylthioxo, aralkylthioxo, hydroxyalkyl , alkylthioalkyle, aralkyle, heteroaralkyle, aminoalkyle, alkylaminoalkyle and dialkylaminoalkyle whose radicals aryl, heteroaryl and alkyl have the meanings indicated previously.

By linear or branched alkyl having from 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. Cycloalkyl is understood to mean in particular the cyclopropyl and cyclohexyl radicals. By carbocyclic aryl is meant in particular the phenyl and naphthyl radicals. By heterocyclic aryl is meant in particular the pyrrolyl, furannyl, thienyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, indolyl and quinolyl. Finally, by halogen is meant the fluorine, chlorine, bromine or iodine atoms.

The term “pharmaceutically acceptable salt” means in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Knows selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

In some cases, the compounds according to the present invention may contain asymmetric carbon atoms. Consequently, the compounds according to the present invention have two possible enantiomeric forms, that is to say the "R" and "S" configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS" racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.

In particular, the compounds of general formula (I) defined above, or their pharmaceutically acceptable salts, can be used to prepare a medicament intended to treat the following diseases / disorders / natural phenomena: tumor proliferation, proliferation of normal cells, l alopecia, alopecia induced by exogenous products, radio-induced alopecia, spontaneous or induced apoptosis of normal cells (ischemia), meiosis, fertilization, oocyte maturation, viral or retroviral infections ( herpes, AIDS, cytomegalo virus), neurodegenerative diseases (for example tauopathies including Alzheimer's disease), proliferation of parasites (proliferation of protozoa, for example Trypanosomes, Toxoplasmas or Plasmodium) and myopathies. More particularly, the compounds of general formula (I) defined above, or their pharmaceutically acceptable salts, can be used to prepare a medicament intended to treat the following diseases / disorders / natural phenomena: tumor proliferation, proliferation of normal cells, in particular especially restenosis, and tauopathies including Alzheimer's disease. Preferably, the compounds according to the invention will be such that they have at least one of the following characteristics:

• A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl or aralkylcarbonyl radical, or also a radical -L- NR R in which L

1 9 represents an alkylene radical and R and R are independently chosen from a

1 9 hydrogen atom and an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of -CH ₂ - , -NR -, -S- and -O-, R representing independently each time it intervenes a hydrogen atom or an alkyl radical;

• X represents a hydrogen atom, an alkylthio or alkylthioxo radical, or also a NR R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more amino radicals, an aralkyl radical the aryl radical of which is optionally substituted by one or more radicals chosen from a halogen atom and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or then R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group composed of -CH ₂ -, -NR ⁶ -, -S- and -O-, R ⁶ independently representing each time that it intervenes a hydrogen atom o u an alkyl or hydroxyalkyl radical.

More preferably, the compounds according to the invention will be such that they have at least one of the following characteristics:

• A represents a halogen atom, a formyl radical, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidènemethyl or alkylcarbonyl, or a radical -L-NR ^ ² in which L represents a methylene radical and R ¹ and R ² are chosen independently from a hydrogen atom and an alkyl radical or R ¹ and R ² taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH ₂ -, -NR ³ - and -O-, R ³ representing independently each time it intervenes a hydrogen atom or an alkyl radical; • X represents an alkylthio or alkylthioxo radical, or also a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more amino radicals, or alternatively R represents a heteroaryl radical or heteroarylalkyl, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or then R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being independently chosen from the group consisting of -CH ₂ -, -NR ⁶ - and -O-, R ⁶ representing independently each time that a hydrogen atom or an alkyl radical is involved or hydroxyalkyl;

• Z represents a bond or an alkyl radical;

• Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals independently chosen from a halogen atom and a radical NR ⁷ R ⁸ in which R ⁷ and R ⁸ independently represent a hydrogen atom or an alkyl or R radical ⁷ and R ⁸ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group composed of -CH ₂ -, -NR ⁹ - and -O-, R ⁹ independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical having 5 or 6 members and the heteroatom (s) of which are chosen from nitrogen atoms and d oxygen, said heteroatoms possibly being oxidized and said heterocyclic aryl radical possibly being substituted by one or more radicals chosen independently from alkyl, amine radicals oalkyl, alkylaminoalkyl and dialkylaminoalkyl.

Even more preferably, the compounds according to the invention will be such that they have at least one of the following characteristics:

• A represents a halogen atom, a formyl radical, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidènemethyl or alkylcarbonyl, or also a radical -L-NR ^J R ² in which L represents a methylene radical and R ¹ and R ² are chosen

1 9 independently from a hydrogen atom and an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of - CH ₂ -, -NR ³ - and -O-, R ³ representing independently each time it intervenes a hydrogen atom or an alkyl radical; • X represents an alkylthio (and preferably methylthio) or alkylthioxo (and preferably methylthioxo) radical, or also a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical (and preferably cyclohexyl ) optionally substituted by one or more amino radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or else R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group composed of -CH ₂ - and -NR -, R independently representing each time it involves a hydrogen atom or an alkyl or hydroxyalkyl radical;

• Y represents NH;

• Z represents a bond or a radical -CH ₂ -;

• Ar represents a carbocyclic aryl radical (said carbocyclic aryl radical preferably being a phenyl radical) optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom and a radical NR ⁷ R ⁸

7 o in which R and R independently represent a hydrogen atom or an alkyl radical or R ⁷ and R ⁸ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH ₂ - and -NR ⁹ -, R ⁹ representing independently each time it involves an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical containing 5 or 6 members and of which the heteroatom (s) are chosen from nitrogen and oxygen atoms (said heterocyclic aryl radical preferably being a pyridyl radical), said heteroatoms possibly being oxidizable and said heterocyclic aryl radical possibly being optionally substituted by one or more radicals chosen independently from the radicals alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl.

Particularly preferred are the compounds described in Examples 1 to 33 below. Even more particularly preferred will be the compounds of Examples 1 to 8, 11, 12, 15, 18, 26 and 33. A further subject of the invention is, as medicaments, the compounds of general formula (II)

(II) in racemic form, enantiomer or any combination of these forms, in which

A represents a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or a radical -L-NR ^ ² in which L represents a

1 9 alkylene radical and R and R are independently chosen from a hydrogen atom and an alkyl radical or R ¹ and R ² taken together with the nitrogen atom which carries them form a 5- to 7-membered heterocycle, the members complementary being independently selected from the group consisting of -CH ₂ -, -NR ³ -, -S- and -O-, R ³ representing independently each time it intervenes a hydrogen atom or an alkyl radical;

X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralkylthioxo radical, or also a NR ⁴ R radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more radicals chosen from alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom, the cyano radical, the nitro radical and the alkyl or alkoxy radicals, or alternatively R represents a heteroaryl radical or heteroarylalkyl, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or then R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a 5- to 7-membered heterocycle, the complementary members being independently selected from the group consisting of -CH ₂ -, - NR ⁶ -, -S- and -O-, R ⁶ independently representing each time that it intervenes a hydrogen atom or an alkyl or hydroxyalkyl radical; Y represents NH or an oxygen atom;

Z represents a bond or an alkyl or alkylthioalkyl radical; and

Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom, the cyano radical, the nitro radical, an alkyl or alkoxy radical and a NR ⁷ R ⁸ radical in which R ⁷ and R ⁸ independently represent a hydrogen atom or an alkyl radical or R ⁷ and R ⁸ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of - CH ₂ -, -NR ⁹ -, -S- and -O-, R ⁹ independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical having 5 or 6 links and the heteroatom (s) of which are chosen from nitrogen, oxygen or sulfur atoms, said heteroatoms possibly being oxidized (Ar may represent, for example, the oxidopyridyl radical) and said aryl radical heterocyclic which may be optionally substituted by one or more radicals independently chosen from alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl radicals;

it being understood however that when A does not represent a cyano, nitro or guanidinoaminomethylenyl radical then:

- either Z represents an alkyl or thioalkyl radical;

- either X represents a radical NR ⁴ R ⁵ in which R ⁴ represents an aralkylthio, aralkylthioxo or hydroxyalkyl radical, one of the alkyl, alkylthio or alkylthioxo radicals containing from 2 to 5 carbon atoms, a cycloalkyl radical optionally substituted by one or radicals chosen from alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or else R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group consisting of -CH ₂ -, -NR ⁶ -, -S- and -O-, R ⁶ repr having independently each time a hydrogen atom or an alkyl or hydroxyalkyl radical is involved;

or the pharmaceutically acceptable salts of the compounds of general formula (II). In particular, the invention relates, as medicaments, to the compounds of Examples 3 to 33.

It also relates to pharmaceutical compositions comprising, as active principle, at least one compound of general formula (II), one of the compounds of Examples 3 to 33 or a pharmaceutically acceptable salt of one of the latter. Finally, as new industrial products, it relates to the compounds of general formula (II) or their salts or one of the compounds of Examples 3 to 33 or a salt of one of these.

In general, the same preferences as those indicated above for the uses of the compounds of general formula (I) are applicable mutatis mutandis to the compounds of general formula (II) of the drugs, pharmaceutical compositions and products according to the invention.

The pharmaceutical compositions containing a compound of the invention can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.

The administration dose envisaged for a medicament according to the invention is between 0.1 mg to 10 g depending on the type of active compound used.

According to the invention, the compounds of general formula (I) can be prepared by the methods described below. Preparation of the compounds of general formula (I):

A number of triazolopyrazines of general formula (I) can be easily prepared according to the procedures described in US Patent 4,565,815.

The other compounds of general formula (I) according to the invention can be prepared in a few steps, scheme 1, from the compounds of general formula (III) in which A 'represents a hydrogen atom or a halogen atom and X' represents a hydrogen atom or an alkylthio radical. The preparation of the compounds of general formula (III) is described in US Patent 4,565,815 or in Kobe et al., J. Het. Chem. (1974), 11 (2), 199 and s.

(III) (I)

Diagram 1

Different cases must be considered depending on the nature of the substituents A, X and Y-Z-Ar of the compounds of general formula (I).

Preparation of the compounds of general formula (I) in which A represents a hydrogen atom or a halogen atom:

In this case, the starting compound of general formula (III) is such that X represents H or alkylthio and A represents H or a halogen atom Hal. The synthesis strategy is summarized in diagram 2 below.

(III) Ar (D

Diagram 2

The compound of general formula (III) is subjected to a nucleophilic substitution reaction with the compound of general formula (IV) to give the compound of general formula (I). The reaction can, if necessary, be carried out in a solvent such as chloroform.

radical NR ⁴ R ⁵ :

In this case, the starting compound of general formula (III) is such that X 'represents alkylthio and preferably methylthio. The synthesis strategy is summarized in diagram 3 below.

(III) Àr (V)

1) m-chloroperbenzoic acid

2) R + NH ⁵

Diagram 3 The compound of general formula (III) is first subjected to a substitution reaction with alcohol or the amine of general formula (IV) to give the compound of general formula (V). The compound of general formula (V) is then treated with rnetβ-chloroperbenzoic acid and then with the amine of general formula R ⁴ NHR ⁵ to finally give the compound of general formula (I). These reactions are preferably carried out in a solvent such as chloroform.

Prej? _. QLQtiçn..des_ co radical alkylthioxo,: _

This preparation is carried out in a similar manner to that described in scheme 3, the only difference being that the thioxo derivative is isolated during the second step instead of being substituted with the amine of general formula R ⁴ NHR ⁵ (cf. diagram 3bis).

m-chloroperbenzoic acid

Ar (D

Diagram 3bis Preparation of the compounds of general formula (I) in which A does not represent a hydrogen atom or a halogen atom:

When A represents a radical -L-ΝR ^ ² in which L represents -CΗ ₂ -, the compound of general formula (VI) represented in scheme 4 is used as starting material. This compound is a compound of general formula (I) in which A represents H and its synthesis has therefore been described previously. The compound of general formula (VI) is for example first treated with an excess of (chloromethylene) -dimethylammonium chloride in an aprotic polar solvent such as an acetonitrile-dimethylformamide mixture. This makes it possible to obtain compounds of general formula (I) in which A represents the formyl radical. These compounds allow a person skilled in the art to construct, by conventional chemical reactions, different compounds of general formula (I) with various A radicals.

1 9 In the particular case where A represents a radical -L-ΝR R in which L represents -CH - and R ¹ and R ² are methyl groups, the compound of general formula (I) can be obtained directly from the compound of general formula (VI) by reaction with excess (chloromethylene) -dimethylammonium chloride followed by the action of ΝaBH „.

Ar (D

(NI) Ar

Ar (D Ar (D

Diagram 4

Pr _. epαrαtion__des_ com ^ radical -LN ^ R ² :

These compounds can be prepared in a conventional manner from the compound of general formula (VI), for example according to the process represented in scheme 5. The compound of general formula (VI) can for example be treated at low temperature (for example at -78 ° C) successively with butyllithium in a polar aprotic solvent such as ethyl ether or tetrahydrofuran then the compound of general formula (VII) in which Hal represents a halogen atom, before being hydrolyzed with water slightly acidified to give the compound of general formula (I) in which A represents a radical -L-NR ^ ² .

I Ar (VI) Ar (I)

Diagram 5

r _. j? βtion__des_ œ ^^^ radical alkylçw

When it is desired to obtain a compound of general formula (I) in which A is a -CO-Δ radical in which Δ represents an alkyl, aralkyl or heteroaralkyl radical, the compound of general formula (VI) is treated, scheme 6, with the compound of general formula Δ-COC1 in the presence of A1C1 ₃ in a suitable solvent, for example in dichloromethane.

A ι r (VI) A ι rm ^w

Diagram 6

Pj _{. W.} grgtion of _. coi ^^ V & diçal guqnidinoamin ^

The compound of general formula (I) in which A represents a formyl radical is converted into the compound of general formula (I) in which A represents a guanidinoaminomethylenyl radical, scheme 7, by reaction with the aminoguanidine bicarbonate in a solvent such as ethanol and in the catalytic presence of a base like piperidine. The compound of general formula (I) in which A represents a formyl radical is converted into the compound of general formula (I) in which A represents a (1,3-dihydro-2-oxoindol) -3-ylidenemethyl radical by the same type of reaction, oxoindole replacing bicarbonate of aminoguanidine.

Ar (D Ar (D

t

Ar (D

Diagram 7

Pj.W.dI.Q-ÛQn_ des _ co ^ radical [cyano

The compound of general formula (I) in which A represents a formyl radical is converted into the compound of general formula (I) in which A represents a cyano radical, scheme 8, by reaction with hydroxylamine in a mixture of sodium formate and d formic acid. The reaction is preferably carried out with heating.

Ar (D Ar (D

Diagram 8

Preparation, radicals, nitro _. :

These compounds are easily prepared from compounds of general formula (I) in which A represents a hydrogen atom by various nitration methods, for example by reacting the latter with a mixture of nitric acid and sulfuric acid or with inorganic nitrate salts in the presence of an acid such as sulfuric acid (cf. Cao et al., Synthesis (1998), 1724). The introduction of the other groups (X and Y-Z-Ar) is carried out, preferably afterwards, using methods analogous to those described above.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by an ordinary specialist in the field to which this invention belongs. Likewise, all publications, patent applications, all patents and all other references mentioned herein are incorporated by reference.

The following examples are presented to illustrate the above procedures and should in no way be taken as limiting the scope of the invention. EXAMPLES

Example 1: 8-bromo-4- [2- (5-methyl-4-imidazolylmethylthio) -ethylamino] - 2-methylthiopyrazolo [1-5-a] -1-3.5-triazine

This compound was prepared according to the method described in American patent 4,565,815. Mass spectrometry (Electrospray): 416.0.

Example 2: 8-bromo-4- {2 - {[5- (dimethylamino) methyl-2-furannyI] - methyl} thio} ethylamino-2-methylthiopyrazolo [1,5-a] -1, 3-5-triazine

This compound was prepared according to the method described in American patent 4,565,815. Mass spectrometry (Electrospray): 459.1.

Example 3: 8-bromo-4- (3- (l-imidazolyl-propylamino) -2-methylthio-pyrazolo [1-5-a] -1,3,5-triazine

To a solution of 8-bromo-4-chloro-2-methylthiopyrazolo [1,5-a] -1,3,5-triazine (50 mg) in a mixture of 2 ml of chloroform and 2 ml of methanol, the following is added 60 μ \ of l- (3-aminopropyl) imidazole and the mixture is stirred overnight at room temperature. After evaporation of the solvents, the residue is partitioned between chloroform and water. The organic phase is then dried over MgSO ₄ , then, after evaporation of the solvents, the residue is subjected to preparative chromatography on silica gel using a chloroform / methanol 4/1 mixture as eluent. The appropriate fraction is isolated, extracted with a chloroform-methanol mixture and the solvents are evaporated to dryness under vacuum. A white solid is obtained. Chromatography on Thin Layer (silica gel; chloroform / methanol in 4/1 mixture): R _f = 0.32. Mass spectrometry (Electrospray): 368.4; 370.1.

The compounds of Examples 4 to 11 are prepared according to a procedure analogous to that of Example 3.

Example 4: 8-bromo-4 - [(3-pyridyl) methylamino] -2-methylthio-pyrazolo [1,5-a] -1,5-5-triazine

Mass spectrometry (Electrospray): 351.0; 353.0.

Example 5: 8-bromo-4- (3-chloroanilino) -2-methylthio-pyrazolo [1,5-a] -1, 3-5-triazine

Mass spectrometry (Electrospray): 369.9; 371.9. Example 6: 8-bromo-2-methylthio-4- (4-pyridylmethyamino) pyrazolo [1,5-a] - 1-3,5-triazine

Mass spectrometry (Electrospray): 351.0; 352.9.

Example 7: 8-bromo-2-methylthio-4- (2-pyridylethylamino) pyrazolo [1,5-a] - 1,3,5-triazine

Mass spectrometry (Electrospray): 365.0; 366.9.

Example 8: 8-bromo-2-methylthio-4- (2-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine

Solid white. Mass spectrometry (Electrospray): 351.0; 352.9.

Example 9: 8-bromo-2-methylthio-4- (4-fluorophenylmethylamino) - pyrazolo [1-5-a] -1,3,5-triazine

Solid white. Mass spectrometry (Electrospray): 367.9; 369.9.

Example 10: 8-bromo-2-methylthio-4- (3-fluorophenylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine

Solid white. Mass spectrometry (Electrospray): 367.9; 369.8.

Example 11: 8-bromo-2-methylthio-4- [4-N-methylpiperazinyl) anilino] - pyrazolo [1,5-a] -1,5-triazine

White powder. Melting point: 223-224 ° C.

Example 12: 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-chloroanilino) -pyrazolo [1,5-a] -1-3-5-triazine

12.1) 8-bromo-4- (3-chloroanilino) -2-methylthioxo-pyrazolo [1,5-a] -1,3,5-triazine

To a solution of 8-bromo-4- (3-chloroanilino) -2-methylthio-pyrazolo [1,5-a] - 1,3,5-triazine (200 mg; prepared analogously to that used for the compounds examples 3 to 5 from 8-bromo-4-chloro-2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine and 3-chloroaniline) in 5 ml of chloroform are added 280 mg of m-chloroperbenzoic acid. The mixture is stirred overnight at room temperature. The reaction medium is diluted with chloroform (10 ml) and is washed with an aqueous solution of NaHSO ₃ then an aqueous solution of NaHCO ₃ . We dry the phase organic on MgSO ₄ and evaporate the solvents to dryness under vacuum. 200 mg of a brown solid are obtained. Mass spectrometry (Electrospray): 402.0; 404.0.

12.2) 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-chloroanilino) - pyrazolo [1,5-a] -1,3,5-triazine

To a partial suspension of intermediate 12.1 (130 mg) in 5 ml of chloroform, 2 ml of a solution of R-Nalinol in propanol (50 mg / ml) is added. The resulting mixture is stirred overnight at room temperature. After evaporation of the solvents, the residue is subjected to preparative chromatography on silica gel using a chloroform / acetone mixture (9: 1) as eluent. The appropriate fraction is isolated, extracted with a chloroform-acetone mixture and the solvents are evaporated to dryness under vacuum. A brown solid is obtained. TLC (silica gel; chloroform / acetone in 9/1 mixture): R _f = 0.28. Mass spectrometry (Electrospray): 425.1; 427.0.

The compounds of Examples 13 to 17 are prepared according to a procedure analogous to that of Example 12.

Example 13: 8-bromo-2- (2-aminocyclohexylamino) -4- (3-chloroanilino) - pyrazolo [1,5-a] -1,3,5-triazine

Solid pale yellow. Mass spectrometry (Electrospray): 436.1; 438.1.

Example 14: 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-oxido-pyridylmethylamino) -pyrazolo [1,5-a] -1, 3-5-triazme

Pale yellow-brown liquid. Mass spectrometry = 422, 1.

Example 15: 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-fluorophenylmethylamino) -pyrazoIo [1-5-a] -1, 3-5-triazine

Mass spectrometry (Electrospray): 424.9.

Example 16: 8-bromo-2- (4 '-hydroxy ethylpiperazinyl) -4- (3-oxido-pyridylmethylamino) -pyrazolo [1-5-a] -1, 3-5-triazme

Mass spectrometry (Electrospray): 451.0.

Example 17: 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1, 3-5-triazine

Mass spectrometry (Electrospray): 435.0. Example 18: 2,4-bis- (3-pyridyImethylamino) -8-bromo-pyrazoIo [1,5-a] - 1,3,5-triazine

To a solution of 8-bromo-4-chloro-2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine (270 mg) in 10 ml of chloroform are added 430 mg of acid m- chloroperbenzoic. The mixture is stirred for one hour at room temperature. 4 equivalents of 3-aminomethylpyridine are added and the mixture is stirred overnight at room temperature. After dilution with chloroform (20 ml) and washing with water, the organic phase recovered is dried over MgSO ₄ . After evaporation of the solvents, the residue is subjected to preparative chromatography on silica gel using a chloroform / methanol 95/5 mixture as eluent. The appropriate fraction is isolated, extracted with a chloroform-methanol mixture and the solvents are evaporated to dryness under vacuum. A yellow solid is obtained. TLC (silica gel; chloroform / methanol in 9/1 mixture): R _f = 0.33. Mass spectrometry (Electrospray): 411.2; 413.2.

Example 19: 2,4-bis- (2-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] - 1,3,5-triazine

This compound is prepared according to a procedure analogous to that described for Example 17. Yellow solid. Mass spectrometry (Electrospray): 383.1; 385.1.

Example 20: 8-acetyl-4- (3-pyridylmethyIamino) -2-methyIthiopyrazolo [1,5-a] - 1,3,5-triazine

213 mg A1C1 ₃ are successively added to a solution of 2-methylthio-4- (3-pyridylmethylamino) -pyrazolo- [1,5-a] - 1,3,5-triazine (110 mg) in 15 ml of dichloromethane then 90 μl of acetyl chloride. The mixture is brought to reflux for 4 hours. After dilution with chloroform (20 ml), the mixture is acidified with dilute HCl, then basified with an aqueous solution of NaHCO ₃ and the organic phase recovered is dried over MgSO ₄ . The solvents are removed by dry evaporation under vacuum. The residue is subjected to preparative chromatography on silica gel using a chloroform / acetone mixture (9: 1) as eluent. The appropriate portions are isolated, extracted with a chloroform-methanol mixture and the solvents are eliminated by evaporation to dryness under vacuum. 65 mg of a white solid are obtained. TLC (silica gel; chloroform / acetone in 9/1 mixture): R _f = 0.18. Mass spectrometry (Electrospray): 315.1. Example 21: 8-dimethylaminomethyl-4- (3-pyridylmethylamino) - 2-methylthiopyrazolo [1,5-a] - 1, 3,5-triazine

A solution of 2-methylthio-4- (3-pyridylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine (50 mg) and (chloromethylene) -dimethylammonium chloride (2 equivalents) mixture of acetonitrile and dimethylformamide (4: 1; 10 ml) brought to reflux for 4 hours. The solvents are removed by dry evaporation under vacuum. The residue is dissolved in 20 ml of ethanol and treated with an excess of NaBH ₄ . After 2 hours of stirring at room temperature, acetic acid is added to the reaction mixture to decompose the excess reagent. After removing the solvents under vacuum, the residue is partitioned between CHC1 ₃ and water. The organic phase recovered is dried over MgSO ₄ . After removing the solvents, the residue is subjected to preparative chromatography on silica gel using a chloroform-methanol mixture (3: 1) as eluent. The appropriate portions are isolated and extracted with a chloroform-methanol mixture and the solvents are removed by evaporation to dryness under vacuum. 19 mg of an ocher powder are obtained. TLC (silica gel; chloroform / methanol in a 3/1 mixture): R _f = 0.19. Mass spectrometry (Electrospray): 330.1.

Example 22: 8-formyl-4- (3-pyridylmethylamino) -2-methylthiopyrazoIo [1,5-a] - 1,3-5-triazine

2-methylthio-4- (3-pyridylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine (100 mg) and (chloromethylene) -dimethylammonium chloride (4 equivalents) acetonitrile-dimethylformamide (4: 1; 50 ml) is brought to reflux for 2 hours. After evaporation of the solvents, the residue is dissolved in tetrahydrofuran (50 ml) and 25 ml of a 0.5 aqueous solution of sodium acetate. After 4 hours of stirring at room temperature, most of the tetrahydrofuran is removed in vacuo. The concentrated residue is partitioned between chloroform and water. The organic phase recovered is then dried over MgSO ₄ and the solvents are under vacuum to give 8-formyl-2-methylthio-4- (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5- triazine. TLC (silica gel; chloroform / methanol mixture = 9/1): R _f = 0.5. Mass spectrometry (Electrospray): 301.0.

Example 23: 8-morpholinomethyl-4- (3-pyridylmethylamino) - 2-methylthiopyrazolo [1,5-a] -1,3,5-triazine

To a solution of 8-formyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine (90 mg) and morpholine (52 mg) in 40 ml of dichloroethylene containing 1% acetic acid, molecular sieves 3 A (0.5 g) and Na (OAc) ₃ BH (134 mg) are added. The mixture obtained is stirred overnight at room temperature. The reaction mixture is filtered and the filtrate diluted with chloroform (50 ml). The resulting solution is then washed with an aqueous solution of NaHCO ₃ and an aqueous solution of NaCl before being dried over MgSO ₄ . After evaporation of the solvents, the residue is subjected to preparative chromatography on silica gel using a chloroform / methanol mixture (9: 1) as eluent. The appropriate portions are isolated and extracted with a chloroform-methanol mixture and the solvents are removed by evaporation to dryness under vacuum. 26 mg of a whitish solid are obtained. TLC (silica gel; chloroform / methanol mixture = 9/1): R _f = 0.19. Mass spectrometry (Electrospray): 372.2.

Example 24: 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3-pyridylmethylammo) pyrazolo [1,5-a] -1-3-5-triazine

A mixture of 8-formyl-2-methylthio-4- (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5-triazine (70 mg), oxoindole (64 mg) and a drop of piperidine in 50 ml of ethanol is brought to reflux for 7 hours. After returning to ambient temperature, a yellow solid is recovered by filtration and dried. TLC (silica gel; chloroform / methanol mixture = 9/1: R _f = 0.49). Mass spectrometry (Electrospray): 416.2.

Example 25: 8- (guanidmoammomethylene) -2-methylthio- 4- (3-pyridylmethylamino) pyrazoIo [1-5-a] -1-3.5-triazine

This compound is prepared according to a procedure analogous to that described for Example 24, the oxoindole being replaced by the bicarbonate of aminoguanidine. Solid brown. Mass spectrometry (Electrospray): 359.2.

Example 26: 8-bromo-2-methylthioxo-4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine

This compound is prepared according to a procedure analogous to that described for intermediate 12.1. Dark yellow powder. Melting point: 70-71 ° C.

Example 27: 8-bromo-2-methylthioxo-4- (3-chloroanilino) pyrazolo [1,5-a] -1,3,5-triazine

This is intermediary 12.1. Example 28: 8 - [(1,3-dihydro-2-oxoindol) -3-ylidèneméthyI] -2-methylthio- 4- [3- (l-imidazoIyI) propylammo] pyrazolo [1,5-a] -1, 3-5-triazine

This compound is prepared according to a procedure analogous to that described for Example 24, 8-formyl-2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine being replaced by 8-formyl-2-methylthio-

4- (3- (l-imidazolyl) propylamino) pyrazolo [l, 5-a] -l, 3,5-triazine. Solid yellow.

Mass spectrometry (Electrospray): 433.2.

Example 29: 8-cyano-2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1-3,5-triazine

This compound is prepared by heating at reflux a mixture containing the compound of Example 22 (1 equivalent), hydroxylamine hydrochloride (2 equivalents), sodium formate (10 equivalents) and formic acid (100 equivalents) ) (cf. /. Chem. Soc. (1965), 1564). Solid pale yellow. Mass spectrometry (Electrospray): 298.2.

Example 30: 8- (N-methylpiperazinomethyl) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,5-triazine

This compound is prepared according to a procedure analogous to that described for Example 23, the morpholine being replaced by N-methylpiperazine. Solid brown. Mass spectrometry (Electrospray): 385.4; 386.4.

Example 31: 2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine

To a solution of 4-chloro-2-methylthiopyrazolo [1,5-a] -1,3,5-triazine (2.0 g) in 40 ml of chloroform and 14 ml of methanol, 3-aminomethylpyridine is added (3.0 g). The mixture obtained is stirred overnight at room temperature. After evaporation of the solvents to dryness under vacuum, the residue is partitioned between chloroform and water. The organic phase is dried over MgSO ₄ and the solvents are evaporated to dryness under vacuum. The residual mixture is subjected to chromatography on silica gel using a chloroform / methanol mixture (19: 1) as eluent. The appropriate portions are isolated and the solvents are removed by dry evaporation under vacuum. 1.47 g of a white solid are obtained. TLC (silica gel; chloroform / methanol mixture = 19/1): R _f = 0.58. Mass spectrometry (Electrospray): 273.1. Example 32: 2-methylthio-8-nitro-4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1-3,5-triazine

Cupric nitrate (70 mg) is added to a suspension of 2-methylthio- 4- (3-pyridylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine (50 mg; compound of the example 31) in 6 ml of acetic anhydride. The mixture is stirred at ambient temperature overnight before being partitioned between chloroform and a saturated aqueous solution of NaHCO ₃ . The organic phase is dried over MgSO ₄ and the solvents are evaporated to dryness under vacuum. The residue is subjected to preparative chromatography on silica gel using a chloroform-methanol mixture (15: 1) as eluent. The appropriate fraction is isolated and extracted with the chloroform methanol mixture. Once the solvents have been evaporated to dryness under vacuum, the expected product is obtained in the form of a whitish solid. Thin layer chromatography (silica gel; chloroform-methanol mixture 9: 1): R _f = 0.46. Mass spectrometry (Electrospray): 318.1.

Example 33: 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine

33.1) 8 ~ bromo-2-methylthioxo-4 ~ (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5-triazine

To a solution of 8-bromo-2-methylthio-4- (3-pyridylmethylamino) - pyrazolo hydrochloride [1,5-a] -1,3,5-triazine (100 mg) in an ethanol-water mixture (1 : 1; 50 ml), 100 mg of oxone are added. After 15 minutes, the mixture is diluted with water (20 ml), NaHCO ₃ is added in order to make the medium basic and extraction is carried out with a chloroform-methanol mixture (9: 1). The organic phase is dried (MgSO ₄ ) and the solvents are removed to give the expected product in the form of a pale yellow solid (100 mg). Mass spectrometry (Electrospray): 367.2; 369.2.

33.2) 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine

A mixture of intermediate 33.1 (100 mg) and R-valinol (2 eq .; 60 mg) in 3 ml of CH.CN is brought to reflux for 3 hours. After evaporation of the solvents, the residue is taken up in a chloroform-methanol mixture (9: 1; 30 ml), washed with a saturated aqueous NaCl solution and then dried over MgSO ₄ . The solvents are removed by evaporation to dryness under vacuum and the residue is subjected to preparative chromatography on silica gel using a chloroform-methanol mixture (19: 1) as eluent. The appropriate fraction is isolated and extracted using the chloroform-methanol mixture. The solvents are removed by dry evaporation under vacuum. The expected product is obtained in the form of a whitish amorphous solid (50 mg). Thin layer chromatography (silica gel; chloroform-methanol mixture 9: 1): R _f = 0.32. Mass spectrometry (Electrospray): 406.2; 408.2.

Pharmacological study of the compounds of the invention

Methods used

Measurement of the phosphorylation state of histone H1 by the cyclin Bl / cdc2 complex:

The activity of the cyclin B / cyclin dependent kinase 1 complex (CDK1 = cdc2) is evaluated by the phosphorylation of a histone H1 by ATP-33 and no longer by ATP-32 as previously (Alessi et al. ., Exp. Cell Res. (1998), 245, 8-18; Baratte et al., Anticancer Res. (1992), 12, 873-880; Glab et al., EE5S Lett. (1994), 353, 207 -211). The appearance of phosphorylated histone H1 in the presence of inhibitors of the CDK1 enzyme is determined by counting the radioactivity. The cyclin B / CDK1 complex, isolated from starfish oocytes (Marthasterias glacialis) is purified by affinity chromatography and then is eluted with 0.2 M NaCl. Glycerol at a final concentration of 20%, v / v is added to the purified enzyme before storage at -80 ° C (Meijer and Kim, Methods Enzymol. (1997), 283, 113-128). The reaction is carried out in 96-well plates with a final volume of 30 μ \. Each reaction contains 5 μl of histone Hl at 5 mg / ml in final concentration (Sigma, H5505, Saint Quentin en Yvelines, France), 16 μ \ of buffer composed of β-glycerophosphate 60 mM (Sigma, G6251, Saint Quentin in Yvelines, France), p-nitrophenyl phosphate 30 mM (Sigma, N6260, Saint Quentin en Yvelines, France), MOPS 25 mM (Sigma M5789, Saint Quentin en Yvelines, France), dithiothreitol 1 mM (Sigma D9779, Saint Quentin en Yvelines , France), ΕGTA 5 mM (Sigma Ε8145, Saint Quentin en Yvelines, France), sodium orthovanadate 0, lmM (Sigma S6508, Saint Quentin en Yvelines, France), MgCl ₂ 15 mM (Sigma M8286, Saint Quentin en Yvelines, France) and 1 μ \ of the Cycline B / CDK1 complex (final activity: 1.5 pmol of ATP incorporated in 1 minute per 1 μl of kinase). The inhibitor in increasing concentration is added in a volume of 3 μl. The reaction starts with the addition of 5 μl of an ATP solution containing 4 μl of ATPy33 (370 MBq / mmol, Amersham BFIOOO, Les Ulis, France), 90 μl of cold ATP 1 mM (Sigma A7699, Saint Quentin en Yvelines, France) diluted in 906 μl of the buffer described above.

The plates are incubated for 10 minutes at 30 ° C. The reaction medium is recovered on 96-well phosphocellulose P81 filtration plates (Unifilter Polyfiltronics Whatman 7700-0512, Rungis, France) and washed with 1% TCA on a collector (Filtermate Harvester, Packard, Rungis, France). After the filter has dried, Microscint ^® 0 scintillant (Packard, 6016311, Rungis, France) is distributed to all wells. The radioactivity is read in a scintillation counter for Topcount ^® microplates (Packard, Rungis, France). The results are expressed as the value of the concentration of inhibitor inhibiting 50% of the enzymatic reaction.

Measurement of the inhibitory activity of glycogen synthase kinase-3β:

This test can be performed as described in Leclerc et al., /. Biol. Chem., September 2000.

Characterization of antiproliferative activity:

By way of example, the effect of a treatment on two human cell lines Mia-Paca2 and DU145 will be studied with the compounds of examples 1 to 33 described above. The DU145 (human prostate cancer cells) and Mia-PaCa2 (human pancreatic cancer cells) cell lines were acquired from the American Tissue Culture Collection (Rockville, Maryland, USA). The cells placed in 95 μl of modified Eagle medium from Dulbecco (Gibco-Brl, Cergy-Pontoise, France) supplemented with 10% fetal calf serum inactivated by heating (Gibco-Brl, Cergy-Pontoise, France), 100 units / 1 of penicillin and 100 μg / ml / l streptomycin (Gibco-Brl, 10378-057, Cergy-Pontoise, France), and 2 mM of glutamine (Gibco-Brl, Cergy-Pontoise, France) were seeded on a 96-plate wells on day 0. The cells were treated on day 1 for 96 hours with 5 μl of each of the compounds at increasing concentrations from 0 to 25 μM in final concentration. At the end of this period, the quantification of cell proliferation is evaluated by colorimetric test based on the cleavage of the tetrazolium salt WST1 by mitochondrial dehydrogenases in viable cells leading to the formation of formazan (Boehringer Mannheim, Meylan, France ). These tests are carried out in duplicate with 8 determinations per concentration tested. For each compound to be tested, the values included in the linear part of the sigmoid were used for a linear regression analysis and used to estimate the inhibitory concentration IC ₅₀ . The products are dissolved in dimethylsulfoxide (DMSO) at 10 ^"2 M and used in culture with 0.5% DMSO in the end. Results:

The compounds of the present invention were tested according to the cyclin B / cyclin-dependent kinase 1 test described above. All the compounds tested showed a significant inhibition of the activity of cyclin B / cyclin-dependent kinase 1 (CDK1 = cdc2).

The compounds of the present invention were further tested according to the tests relating to the antiproliferative activity described above, their activities being compared to that of Roscovitine. All the compounds tested of the present invention showed an antiproliferative activity superior to that of Roscovitine with regard to Mia-PaCa2 cells. In addition, while no antiproliferative activity with respect to DU-145 cells was observed with Roscovitine, many of the compounds tested of the present invention showed antiproliferative activity against these cells as well.

Claims

claims 1. Use of a compound of general formula (I) I Ar (D in racemic form, enantiomer or any combination of these forms, in which A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or also a radical -L -NR ^ ² in which L represents an alkylene radical and R ¹ and R ² are independently chosen from a hydrogen atom and an alkyl radical or R ¹ and R ² taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group composed of -CH ₂ -, -NR ³ -, -S- and -O-, R ³ representing each time an atom d hydrogen or an alkyl radical; X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralkylthioxo radical, or also a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more chosen radicals among the alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom, the cyano radical, the nitro radical and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or then R ⁴ and R ⁵ taken together with the nitrogen atom which carries them forms a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH -, -NR ⁶ -, -S- and -O-, R ⁶ representing independently each time it involves a hydrogen atom or an alkyl or hydroxyalkyl radical; Y represents NH or an oxygen atom; Z represents a bond or an alkyl or alkylthioalkyl radical; and Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom, the cyano radical, the nitro radical, an alkyl or alkoxy radical and a NR ⁷ R ⁸ radical in which R ⁷ and R ⁸ independently represent a hydrogen atom or an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently selected from the group consisting of -CH ₂ -, -NR ⁹ -, -S- and -O-, R ⁹ representing independently each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical having 5 or 6 members and in which the heteroatom (s) are chosen from nitrogen, oxygen or sulfur atoms, the said heteroatoms possibly being oxidized and the said heterocyclic aryl radical possibly being substituted by u n or radicals independently chosen from alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl radicals; or a pharmaceutically acceptable salt of such a compound for preparing a medicament for inhibiting cyclin dependent kinases (CDK). 2. Use according to claim 1, characterized in that: • A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl or aralkylcarbonyl radical, or also a radical -L- ISER ^ R ² in which L represents an alkylene radical and R ¹ and R ² are independently chosen from a hydrogen atom and an alkyl radical or R ¹ and R ² taken together with the nitrogen atom which carries them form a 5 to 7 membered heterocycle, the complementary members being independently selected from the group consisting of -CH ₂ -, -NR ³ -, -S- and -O-, R ³ representing independently each time it intervenes a hydrogen atom or an alkyl radical; • X represents a hydrogen atom, an alkylthio or alkylthioxo radical, or also a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more amino radicals, a radical aralkyl in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or alkyl radicals and R ⁵ represents a hydrogen atom, or else R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group composed of -CH ₂ -, -NR -, -S- and -O-, R representing independently each time it intervenes a hydrogen atom or an alkyl or hydroxyalkyl radical. 3. Use according to claim 1, characterized in that the compound used is chosen from the following compounds: - 8-bromo-4- [2- (5-methyl-4-imidazolylmethylthio) -ethylamino] - 2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-4- {2 - {[5- (dimethylamino) methyl-2-furannyl] -methyl} thio} ethylamino-2-methylthiopyrazolo [1, 5-a] - 1, 3, 5-triazine; - 8-bromo-4- (3- (1-imidazolyl-propylamino) -2-methylthio-pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-4 - [(3-pyridyl) methylamino] -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-4- (3-chloroanilino) -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-pyridylmethylamino) pyrazolo [1, 5-a] - 1, 3, 5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (3-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- [4-N-methylpiperazinyl) anilino] -pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-2- (2-aminocyclohexylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-fluorophenylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 2,4-bis- (3-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 2,4-bis- (2-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 8-acetyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-dimethylaminomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8-formyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-morpholinomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8- (guanidinoaminomethylene) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-chloroanilino) pyrazolo [1,5-a] -1,3,5-triazine; - 8 - [(1,3-dihydro-2-oxoindol) -3-ylidèneméthyl) -2-methylthio- 4- (3- (l-imidazolyl) propylamino) pyrazolo [1, 5-a] - 1, 3, 5-triazine; - 8-cyano-2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8- (N-methylpiperazinomethyl) -2-methylthio-4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 2-methylthio-8-nitro-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; and the pharmaceutically acceptable salts of these compounds. 4. Use according to one of claims 1 to 3, characterized in that the medicament prepared is intended to treat a disease / disorder / a natural phenomenon chosen from the group consisting of the following diseases / disorders / natural phenomena: tumor proliferation, proliferation of normal cells, spontaneous alopecia, alopecia induced by exogenous products, radiation-induced alopecia, spontaneous or induced apoptosis of normal cells, meiosis, fertilization, maturation of oocytes, viral or retroviral infections, neurodegenerative diseases, proliferation of parasites and myopathies. 5. Use according to claim 4, characterized in that the drug prepared is intended to treat a pathology chosen from the group consisting of the following pathologies: tumor proliferation, proliferation of normal cells and tauopathies. 6. As a medicament, a compound of general formula (II) ι Ar (II) in racemic form, enantiomer or any combination of these forms, in which A represents a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or a radical -LN ^ ² in which L represents a 1 alkylene radical and R and R are chosen independently from a hydrogen atom and an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH ₂ -, -NR ³ -, -S- and -O-, R ³ representing independently each time a hydrogen atom or an alkyl radical intervenes; X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralkylthioxo radical, or alternatively a NR ⁴ R ⁵ radical in which R ⁴ represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more selected radicals among the alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom, the cyano radical, the nitro radical and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or then R ⁴ and R ⁵ taken together with the nitrogen atom which carries form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group composed of -CH ₂ -, - NR ⁶ -, -S- and -O-, R ⁶ independently representing each time that it intervenes a hydrogen atom or an alkyl or hydroxyalkyl radical; Y represents NH or an oxygen atom; Z represents a bond or an alkyl or alkylthioalkyl radical; and Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom, the cyano radical, the nitro radical, an alkyl or alkoxy radical and a NR ⁷ R ⁸ radical in which R ⁷ and R ⁸ 7 R independently represent a hydrogen atom or an alkyl radical or R and R taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently chosen from the group consisting of - CH ₂ -, -NR ⁹ -, -S- and -O-, R ⁹ independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical having 5 or 6 chain links and in which the heteroatom (s) are chosen from nitrogen, oxygen or sulfur atoms, said heteroatoms possibly being oxidized and said heterocyclic aryl radical possibly being substituted by one or more radicals chosen independently from alkyl radicals, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl; it being understood however that when A does not represent a cyano, nitro or guanidinoaminomethylenyl radical then: either Z represents an alkyl or thioalkyl radical; - either X represents a radical NR ⁴ R in which R ⁴ represents an aralkylthio, aralkylthioxo or hydroxyalkyl radical, one of the alkyl, alkylthio or alkylthioxo radicals containing from 2 to 5 carbon atoms, a cycloalkyl radical optionally substituted by one or more radicals chosen from alkyl, hydroxy and amino radicals, an aralkyl radical in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom and the alkyl or alkoxy radicals, or alternatively R ⁴ represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R ⁵ represents a hydrogen atom, or else R ⁴ and R ⁵ taken together with the nitrogen atom which carries them form a heterocycle of 5 with 7 links, the complementary links being chosen independently from the group consisting of -CH ₂ -, -NR ⁶ -, -S- and -O-, R represented being independently each time it involves a hydrogen atom or an alkyl or hydroxyalkyl radical; or a pharmaceutically acceptable salt of such a compound. 7. Medicinal product, characterized in that it is a compound chosen from the following compounds: - 8-bromo-4- (3- (l-imidazolyl-propylamino) -2-methylthio-pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-4 - [(3- pyridyl) methylamino] -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-4- (3-chloroanilino) -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-pyridylmethylarnino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (3-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- [4-N-methylpiperazinyl) anilino] -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-2- (2 - mιinocyclohexylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hyα oxyethylamino) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-fluorophenylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4 '-hydroxyethylpiperazinyl) -4- (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 2,4-bis- (3-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 2,4-bis- (2-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 8-acetyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8-dimethylaminomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8-formyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-morpholinomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine; - 8- (guanidinoaminomethylene) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-chloroanilino) pyrazolo [1,5-a] -1,3,5-triazine; - 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3- (1-imidazolyl) propylamino) pyrazolo [1,5-a] -1,3 5-triazine; - 8-cyano-2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8- (N-methylpiperazinomethyl) -2-methylthio-4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 2-methylthio-8-nitro-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; and the pharmaceutically acceptable salts of these compounds. 8. As a new industrial product, a compound of general formula (II) as defined in claim 6 or a salt of such a compound. 9. Product characterized in that it is a compound chosen from the following compounds: - 8-bromo-4- (3- (1-imidazolyl-propylamino) -2-methylthio-pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-4 - [(3-pyridyl) methylamino] -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-4- (3-chloroanilino) -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylethylamino) pyrazolo [1, 5-a] - 1, 3, 5-triazine; - 8-bromo-2-methylthio-4- (2-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (4-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- (3-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthio-4- [4-N-methylpiperazinyl) anilino] -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 8-bromo-2- (2-aminocyclohexylamino) -4- (3-chloroanilino) -pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-fluorophenylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4 '-hydroxyethylpiρérazinyl) -4- (3-oxido-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-pyridylmethylamino) -pyrazolo [1,5-a] - 1,3,5-triazine; - 2,4-bis- (3-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 2,4-bis- (2-pyridylmethylamino) -8-bromo-pyrazolo [1,5-a] -1,3,5-triazine; - 8-acetyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-dimethylaminomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8-formyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] -1,3,5-triazine; - 8-mo holinomethyl-4- (3-pyridylmethylamino) -2-methylthiopyrazolo [1,5-a] - 1,3,5-triazine; - 8- [(1, 3 -dihydro-2-oxoindol) -3 -ylidenemethyl) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8- (guanidinoaminomethylene) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2-methylthioxo-4- (3-chloroanilino) pyrazolo [1,5-a] -1,3,5-triazine; - 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3- (1-imidazolyl) propylamino) pyrazolo [1,5-a] -1,3 5-triazine; - 8-cyano-2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8- (N-methylpiperazinomethyl) -2-methylthio-4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; - 2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1, 5-a] - 1, 3, 5-triazine; - 2-methylthio-8-nitro-4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine; - 8-bromo-2- (1R-isopropyl-2-hydroxyethylanΗ ^ o) -4- (3-pyridylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine; and the salts of these compounds. 10. Pharmaceutical composition comprising, as active principle, a compound of general formula (II) as defined in claim 6, or a pharmaceutically acceptable salt of one of these.