EP1678170A1 - Use of a compound of formula (i) as an inhibitor of aromatase for therapeutic purposes and compounds of formula (1) thereas - Google Patents

Abstract

The invention relates to the use of a compound of formula (I) as an inhibitor of aromatase for the production of a pharmaceutical composition for the treatment of cancer or psoriasis. The invention also relates to compounds of formula (1), particularly the use thereof as active ingredients of a medicament.

Description

 Use of a compound of formula (I) aromatase inhibitor for therapeutic purposes and compounds of formula (I) as such FIELD OF THE INVENTION

The present invention relates to new aromatase inhibitor compounds and to their use in the medical field, and more specifically in the prevention and treatment of cancer, particularly breast cancer, or psoriasis.

PRIOR ART Certain derivatives of benzazolinones and more particularly of benzoxazolinone, have already been described for their gonadotropic, antiproliferative and immunomodulatory properties (BERGER et al. 1981; BUTTERSTEIN, et al. 1988; SCHADLER et al. 1988). Over the past ten years, a class of azole compounds (imidazoles and triazoles) have shown aromatase inhibiting activity which has led to their use in the treatment of certain breast cancers (KUIJPERS et al. 1998; SERALINI et al. 2001; BRODIE et al. 2002).

It has been shown that, in mammals, and in particular humans, estrogens are synthesized from androgens by enzymatic catalysis with aromatase. It is commonly accepted that aromatase inhibition is useful in the prevention or treatment of estrogen-related disorders and conditions in mammals, such as breast cancer. Other estrogen-related diseases that can be treated with an aromatase inhibitor compound include endometriosis, cervical cancer, ovarian cancer, polycystic ovary syndrome. An aromatase inhibitor compound is also considered to be useful for the control of conception. More particularly, in the case of breast cancer, it is said that an aromatase inhibitor compound can be advantageously used, replacing a conventional surgical treatment such as ovariectomy or even adrenalectomy. It is also known that an aromatase inhibitor compound is useful in the prevention or treatment of prostate cancer. The advantage of using an aromatase inhibitor compound for the treatment of psoriasis has also been demonstrated. In particular, aromatase inhibitor olefinic compounds comprising one or more heterocycles have been described in European patent application No. EP-299,683. Other aromatase inhibitor compounds, such as the compound designated "TAN-931" , have been described in European patent application No. ^c EP-342 665. Heterocyclic diarylalkyl aromatase inhibitor compounds are also known, such as those described in PCT application No. WO 94/13645 or in PCT application No. WO 02/087571. Aromatase inhibiting heterocyclic aralkyl derivatives are also known, as described in European patent application No. EP-296,749. Aromatase inhibiting compounds consisting of imidazolyl or triazolyl derivatives of pyridine or have also been described. of phenyl substituted dihydropyridine, as in European patent applications No. EP-755 931 and No. "EP-

533 504, or in PCT application No. WO 90/06923. Condensed tricyclic aromatase inhibitors have also been described in European patent application No. EP-360324. However, there is a need, in the state of the art, for new aromatase inhibitor compounds, useful in therapy, which have good inhibitory properties for this enzyme, and which are devoid of toxicity, as well in vitro than in vivo.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the preparation of new azole derivatives of various benzazolinones (benzoxazolinone, benzothiazoliπone, benzoselenazolinone, benzoxazinone, benzothiazinone and indolinone), which have aromatase inhibiting properties and are endowed with remarkable anticancer properties. and aπtipsoriasis. The subject of the invention is the use of a compound of formula (I) below: (I) in which:. Ri represents a hydrogen atom or an alkyl (Cι-C ₆ ), alkenyl (Cι-C ₆ ), or alkynyl (Cι-C ₆ ) radical, linear or branched,

. X represents an oxygen, sulfur, or selenium atom;

. Y represents a single bond or a CH _2l group optionally substituted by one or two lower alkyl groups,

. Z represents a hydrogen or halogen atom, or a linear or branched hydroxy or alkoxy group,

. A represents an imidazole, triazole or tetrazole ring,. B represents a group chosen from phenyl, naphthyl, biphenyl or else a monocyclic or bicyclic heteroaryl group having from 5 to 10 members and comprising from 1 to 3 heteroatoms, the phenyl, naphthyl, biphenyl and heteroaryl groups being unsubstituted or substituted by 1 to 3 groups chosen from alkyl (d- Cβ), alkoxy (Ci-Cβ), carboxy, formyl, amino, amido, ester, nitro, cyano, trifluoromethyl, or halogen atoms, as well as the enantiomers and diastereoisomers of the compounds of formula (I), as well as the addition salts with a pharmaceutically acceptable acid or base of the compounds of formula (I), for the preparation of a pharmaceutical composition intended for the treatment of cancer or psoriasis. By “heteroaryl” is meant, according to the invention, any mono- or bi-cyclic group containing 5 to 10 links and 1 to 3 heteroatoms chosen from oxygen, nitrogen and sulfur. Included within the meaning of the invention are heteroaryl groups containing 5, 6, 7, 8, 9 or 10 members. Included are heteroaryl groups comprising 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. The aryl and heteroaryl B groups of a compound of formula (I) as defined above can be substituted by 1, 2 or 3 groups chosen from alkyl (CrCβJ.alkoxy (Ci-Ce), carboxy, formyl, amino, amido, ester, nitro, cyano, trifluoromethyl, or halogen atoms. The groups Ci-, C ₂ -, C ₃ -, C ₄ -, C5- and Ce- alkyl are therefore included, within the meaning of the invention , as well as the groups Ci-, C ₂ -, C ₃ -, C -, C5- and C ₆ - alkoxy Part of the invention is any addition salt of a compound of formula (I) with an acid Among the pharmaceutically acceptable acids, mention is preferably made, without limitation, of hydrochloric, hydrobromic, sulfuric, acetic, trifluoroacetic, lactic, succinic, fumaric, citric, oxalic or methane sulfonic acids. invention, any addition salt of a compound of formula (I) to a pharmaceutically acceptable base. ptables, it is preferable to cite, without limitation, sodium hydroxide, potassium hydroxide or triethylamine. It has been shown according to the invention that the compounds of formula (I) defined above are of great safety, both in vitro and in vivo. Thus, it has been shown that the compounds of formula (I) are not cytotoxic in vitro. It has also been shown that a compound of formula (I) does not present any danger, even at high doses, when it is administered to the individual. It has also been shown according to the invention that the compounds of formula

(I) have a good ability to inhibit aromatase. Some of the compounds of formula (I) have an IC ₅₀ inhibitory power of the order of 1 nM. The compounds of formula (I) have also been shown to be active in vivo, as illustrated by their capacity to inhibit and, in certain cases, block, uterine hypertrophy induced by androstenedione. In general, the compounds of formula (I) preferred according to the invention are compounds n ° 1 to 51, described in examples 1 to 51, the structure of which is detailed in Table IV. A first family of compounds of formula (I) preferred according to the invention consists of the compounds for which group B is chosen from: - a benzene which is unsubstituted or substituted in the meta or para position by a group chosen from cyano or nitro groups , by a chlorine atom; - a pyridine heterocycle. A second family of compounds of formula (I) preferred according to the invention consists of the compounds for which the group R1 represents a hydrogen atom or a methyl group. A third family of compounds of formula (I) preferred according to the invention consists of the compounds for which the group Z represents a hydrogen atom or a methoxy group. A fourth family of compounds of formula (I) preferred according to the invention consists of the compounds for which the group A represents a 1,3-imidazolyl group or 1,2,4 triazolyl. A fifth family of compounds of formula (I) preferred according to the invention consists of the compounds for which, simultaneously: (i) group B is chosen from: - a benzene which is unsubstituted or substituted in the meta or para position by a chosen group among the cyano or nitro groups, by a chlorine atom; - a pyridine heterocycle; (ii) the group R1 represents a hydrogen atom or a methyl group; (iii) group Z represents a hydrogen atom or a methoxy group; and (iv) group A represents a 1,3-imidazolyl or 1,2,4 triazolyl group. The invention also relates to an aromatase inhibitor compound, as defined above, for its use as an active principle of a medicament. The invention also relates, as a new compound, to any of the compounds of formula (I) as described in the present description. In their use in therapy, the compounds of formula (I) are particularly useful when they are used for the manufacture of a pharmaceutical composition intended for the prevention or treatment of disorders and pathologies associated with estrogens in mammals, such as breast cancer, endometriosis, cervical cancer, ovarian cancer, prostate cancer, polycystic ovary syndrome. A compound of formula (I) is also advantageously used for the manufacture of a pharmaceutical composition intended for the treatment of psoriasis. The present invention further relates to a pharmaceutical composition characterized in that it comprises at least one compound of general formula (I) described above, in combination with at least one excipient chosen from the group consisting of pharmaceutically acceptable excipients . To formulate a pharmaceutical composition according to the invention, a person skilled in the art may advantageously refer to the latest edition of the European Pharmacopoeia or the Pharmacopoeia of the United States of America (USP). ^{Those skilled} in the art will in particular advantageously be able to refer to the 4 ^th “2002” edition of the European Pharmacopoeia, or even to the USP 25-NF20 edition of the American Pharmacopoeia (US Pharmacopeia). Advantageously, a pharmaceutical composition as defined is suitable for daily administration, preferably by oral or topical route, of an amount of a compound of formula (I) of between 1 μg and 10 mg and preferably between 0.5 mg and 10 mg. Advantageously, a pharmaceutical composition as defined above is suitable for daily systemic administration of an amount of a compound of formula (I) of between 0.5 mg and 10 mg. When the composition according to the invention comprises at least one pharmaceutically acceptable excipient, it is in particular an excipient suitable for administration of the composition by the topical and / or an excipient suitable for administration of the composition by the oral route. Systemic administration of a pharmaceutical composition comprising a compound of formula (I), for example orally, for the prevention or treatment of cancer is preferred. A topical administration of a pharmaceutical composition comprising a compound of formula (I) for the treatment of psoriasis is preferred. The invention also relates to a method for treating cancer in a patient, preferably a cancer associated with estrogens, said method comprising a step during which the patient is administered a therapeutically effective amount of a compound of formula (I) or d 'a pharmaceutical composition containing a compound of formula (I). The invention also relates to a method for preventing cancer in a patient, preferably a cancer associated with estrogens, said method comprising a step during which the patient is administered a therapeutically effective amount of a compound of formula (I) or d 'a pharmaceutical composition containing a compound of formula (I). The invention also relates to a method for treating psoriasis in a patient, said method comprising a step during which the patient is administered a. therapeutically effective amount of a compound of formula (I) or of a pharmaceutical composition containing a compound of formula (I). The present invention also relates to the process for obtaining the compounds of formula (I) characterized in that a compound of formula (II) is used as starting material:

(II) in which Ri, X, Y, Z and B have the same meaning as in formula (I) obtained according to one of the experimental protocols described by BONTE et al. (1974), AICHAOUI et al. (1990, 1991 and 1992), OUSSAVI et al. (1989), SASTRY et al. (1988) and YOUS et al. (1994) which is reduced to obtain a compound of formula (III)

(III) in which Ri, X, Y, Z and B have the same meaning as in formula (I) which is then: - either treated with carbonyldiimidazole in order to obtain a compound of formula (I). - or treated with thionyl chloride to lead intermediately to a compound of formula (IV) not isolated.

(IV) which is reacted with an azole derivative: imidazole, triazole or tetrazole, in order to obtain the compounds of formula (I) The preparative separations of the enantiomers of certain compounds chosen from the most active were carried out using columns of polysaccharide chiral stationary phase (cellulose or amylose) using apolar mobile phases. The optical purity of each isolated enantiomer was then evaluated using the analytical columns of the same chiral stationary phase as that which allowed their preparative separation and under the same operating conditions. The raw materials used in the process described above are either commercial or easily accessible to those skilled in the art from the literature and the preparation examples given below. For example, it is possible to prepare the compounds of formula (IIIa) or (IIIll)

(IIIa) (IIIb) in which Ri, X, Y, Z and B have the same meaning as in formula (I) by reaction of a compound of formula (V)

(V) in which Ri, X, Y and Z have the same meaning as in the formula

(I). either with an acid chloride or anhydride of formula B-COCI or (B-CO) ₂ O, in the presence of aluminum trichloride and dimethylformamide. either with an acid of formula B-COOH, in the presence of polyphosphoric acid to obtain a compound of formula (IIa) or (IIb)

(IIIa) (IIb) in which Ri, X, Y, Z and B have the same meaning as in formula (I) which is reduced by sodium borohydride to obtain a compound of formula (IIIa) or (IIIll) Another example of preparation of the compounds of formula (I) consists in using the 4-acyl 2-aminophenols of formula (VI)

(VI) in which R <ι and B have the same meaning as in formula (I) to access by heterocyclization according to a protocol described by AICHAOUI et al. (1990) to 5-acyl benzoxazolinones of formula (Ile)

(Hc) which are then subjected to the same reaction sequence as above. Other routes of synthesis of the compounds of formula (I) according to the invention are described in the examples and illustrated in FIGS. 4 and 5. The present invention is further illustrated by the following figures and examples.

DESCRIPTION OF THE FIGURES Figure 1 illustrates a first scheme for the synthesis of a compound of formula (I) according to the invention. Figure 2 illustrates a second synthetic scheme of a compound of formula (I) according to the invention. Figure 3 illustrates a third synthetic scheme of a compound of formula (I) according to the invention. FIG. 4 illustrates a diagram of synthesis of a compound of formula (I) according to the invention, of the 5-benzothiazolinone type. FIG. 5 illustrates a scheme for the synthesis of a compound of formula (I) according to the invention, of the 6-benzoselenazolinone type. EXAMPLES The following embodiments illustrate the invention and do not limit it in any way. The following preparations lead to synthesis intermediates useful in the preparation of the invention.

The products described in the "preparations" do not form part of the invention. Their description however facilitates the production of the compounds of formula (I) of the invention.

A. General method of synthesis of the compounds of formula (I) of the invention.

A.1. Preparation 1: 6-Acyl benzazinones and 7-acy! -Benzothiazinon @ (Table 1A) The 6-acyl benzoxazolinones, benzothiazolinones, benzoxazinones, indolinones and 7-acyl-bθnzothîazinones and henzoselenazαlinones are obtained from the corresponding benzazolinones according to two known methods and using either the acid chloride or anhydride in the presence of aluminum trichloride in dimethylformamide (Method B), or the organic acid itself in the presence of polyphosphoric acid (Method A) (AICHAOUI et al, 1992 ; BONTE et al, 1974; SASTRY et al, 1988; YOUS et al, 1994).

A.2. Preparation 2: 5-Acyl benzoxazolinones (Table II). 5-acyl benzoxazolinones are prepared from 4-acyl-2-aminophenols according to the method described by AICHOUI et al, (1990).

A3. Preparation 3: 7-Acyl benzoxazinones (Table II) The 7-acyl benzoxazinones are prepared from 5-acyl-2-aminophenols according to the method described by MOUSSAVI et al. (1989).

A.4. Preparation 4: Hydroxyarylmethy! benzazinones (Table III-A) Solubilize acyl benzazinone in methanol (Ri = alkyl, method A) or in an aqueous solution of sodium hydroxide (Ri =

H, method B). Slowly add 2 equivalents of sodium borohydride with stirring and stir at room temperature for three hours and acidify with 6M hydrochloric acid. Squeeze the precipitate, wash with water, dry and recrystallize from a suitable solvent.

B. Examples of synthesis of the compounds of formula (I)

Example 1: 6-I (4-Cyanophenyl) (1 H-imidazol-1 -yl) methyl] -1, 3-benzoxazol-2 (3H) -one. In 30 ml of acetonitrile, 5 mmol of 6- [1- hydroxy-1- (4-cyanophenyl) methyl] -1,3-benzoxazol-2 (3H) -one and 5 mmol of N, / v-carbonyldiimidazole are heated at reflux for 24 hours. The solvent is then evaporated in vacuo. The residue is triturated with 100 ml of water then acidified with 6M hydrochloric acid and extracted with diethyl ether. The aqueous phase is made alkaline with a saturated sodium carbonate solution and then extracted twice with 00 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by column chromatography. The fractions containing the pure product are evaporated and the residue obtained and triturated with petroleum ether and then drained. F ° C: 122-126 ° C.

Examples 2 to 19: Proceeding as in Example 1, but replacing 6- [1-hydroxy-1- (4-cyanophenyl) methyl] -1, 3-benzoxazol- 2 (3H) -one by Phydroxyarylmethyl benzazinone adequate, the products of Examples 2 to 19 are obtained (Table IV)

Example 20: 6 - [(4-Cyanophenyl) (1H-1,2,4-triazol-1-yl) methyl] -3-methyl-1,3-benzothiazol-2 (3W) -one. Thionyl chloride (15 mmol) is added to a solution of 1 H-1,2,4-triazole (60 mmol) in Pacetonitrile (30 ml). The reaction medium is stirred for 1 hour at ambient temperature before being filtered. The solution obtained is added dropwise to a solution of 6- [1-hydroxy-1- (4-cyanophenyl) methyl] -1,3- benzothiazol-2 (3r) -one (4 mmol) in Pacetonitrile (10 ml ). After 5 h of stirring at room temperature the solvent is evaporated under vacuum. The residue obtained is triturated with 100 ml of water then acidified with 6M hydrochloric acid and extracted with diethyl ether. The aqueous phase is made alkaline with a saturated sodium carbonate solution and then extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by column chromatography. The fractions containing the pure product are evaporated and the residue obtained and triturated with petroleum ether and then drained. F ° C 127-130 ° C.

Examples 21 to 24: Proceeding as in Example 20, but replacing 6- [1-hydroxy-1- (4-cyanophenyl) methyl] -1, 3-benzothiazol- 2 (3H) -one with adequate hydroxyarylmethyl benzazinone, the products of Examples 21 to 24 are obtained (Table IV)

Examples 25 to 43

By proceeding as in the previous examples, we also obtain:

6- [1 H-lmidazol-1-yl (phenyl) methyl] -1, 3-benzoxazol-2 (3H) -one (25). F ° C 193-195 ° C

- 6 - [1 W-lmidazol-1-yl (phenyl) methyl] -3-methyl-1, 3-benzoxazol-2 (3H) -one (26). F "C73-74 ° C - 6 ~ [(4-Chlorophenyl) (1 H-imidazol-1 -yl) methyl] -3-methyl-1, 3-benzoxazol- 2 (3H) -one (27). ° C 76-78 ° C

- 3-Methyl-6- [phenyl (4H-1, 3,4-triazol-4-yl) methyl] -1, 3-benzoxazol-2 (3H) -one (28). F ° C 225-226 ° C

- 3-Methyl-6- [phenyl (1 H-1, 2,4-triazol-1 -yl) methyl] -1, 3-benzoxazol- 2 (3/7) -one (29).

F ° C 76-78 ° C

- 5- [1H-lmidazol-1-yl (phenyl) methyl] -1,3-benzoxazol-2 (3rV) -one (30). F ° C 108-111 ° C

- 3-Methyl-5- [1 H-imidazol-1 -yl- (phenyl) methyl] -1, 3-benzoxazol-2 (3H) -one (31). F ° C 133-135 ° C

- 3 -Methyl-5- [phenyl (1H-1, 2,4-triazol-1-yl) methyl] -1, 3-benzoxazol-2 (3f) - one (32). F ° C 135-138 ° C 5 - [(4-Chlorophenyl) (1 H-1,2,4-triazol-1-yl) methyl] -3-methyl-1,3-benzoxazol-2 (3H) -one (33). F ° C 70-74 ° C 5 - [(4-Cyanophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -6-methoxy-1, 3-benzoxazol-2 (3H) -one ( 34). F ° C 125-130 ° C

- 6- [1 H-lmidazol-1-yl (phenyl) methyl] -1, 3-benzothiazol-2 (3r /) - one (35) .F ° C 55-60 ° C 6- [1 tf-lmidazol -1-yl (phenyl) methyl] -3-methyl-1, 3-benzothiazol-2 (3H) -one (36). F ° C 65-68 ° C

- 3-Methyl-6- [phenyl (1H-1, 2,4-triazol-1-yl) methyl] -1, 3-benzothiazol-2 (3f /) - one (37).

F ° C 150-154 ° C - 6 - [(4-Chlorophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzothiazol- 2 (3H) -one (38). F ° C 106-112 ° C

- 6- [1 H-lmidazol-1-yl (4-nitrophenyl) methyl] -1, 3-benzothiazol-2 (3H) -one (39). F ° C 238-241 - 4-Methyl-7- [1 H-imidazol-1-yl (phenyl) methyl] -1, 4-benzoxazin-3 (4H) -one (40). F ° C 66-68 ° C

- 4-Methyl-7- [phenyl (1 HA, 2,4-triazol-1-yl) methyl] -1, 4-benzoxazin-3 (4H) - one (41). F ° C 160-164 ° C

- 4-Methyl-6- [phenyl (1 HA, 2,4-triazol-1-yl) methyl] -1, 4-benzoxazin-3 (4tf) - one (42).

F ° C 140-150 ° C

- 7- [1H-lmidazol-1-yl (phenyl) methyl] -1, 4-benzothiazin-3 (4H) -one (43). F -C 187-189 ° C PREPARATION OF THE COMPOUNDS OF EXAMPLES 44 to 49 (Tables Ib, III-B, IV)

^R ef RXYZ Isomer B

6- (4-Nitrobezoyl) -1,3-benzothiazol-2 (3H) -one (1; Table 1B). In a 100 ml flask containing 35.0 g (265 mmol) aluminum chloride, add dropwise and with magnetic stirring 5.9 m I of dimethylformamide (76 mmol). To follow stirring for 25 minutes, slowly add 5.0 g (33 mmol) of 2 (3 /) - benzothiazolone and heat to 90 ^C C. Add drop by drop 7.36 g of 4-nitrobenzoyl chloride (40 mmol) and continue d '' stir at 100-110 ° C for 4 hours. Versel slowly the reaction medium on ice while stirring vigorously. Add 15 ml of 37% hydrochloric acid and continue stirring for 15 minutes. Squeeze the precipitate and then wash with water until the washings are neutral. Dry the product obtained and recrystallize it from dioxane (5.85 g, 59%). Rf = 0.39 (EtOAc / Cyclohexane = 4/6): mp 260-265 ° C; ir γ NH 3369 cm ^-1 , CO 1682 cm ^"1 , 1651 cm ^'1 , NO ₂ 1521 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 7.26 (d, 1 H, H ₄₎ D4 .5 = 7.8 Hz), 7.72-7.74 (m, 1H, H ₅ ), 7.92 (d, 2H, H ₃ -, H ₅ -, J = 9.0 Hz), 8.09 (s, 1 H, H ₇ ), 8.36 (d, 2H, H ?, H ₆ -, J = 9.0 Hz), 12.3 (br s, 1 H, NH, exchangeable with D ₂ O) .Anal. (C ₁₄ H ₈ N ₂ O ₄ S) 3-Ethyl-6- (4-nitrobezoyl) -1,3-benzothiazol-2 (3H) -one (2). In a 100 ml flask, dissolve 2.5 g (8.3 mmol) of 6- (4-nitrobezoyl) -1,3- benzothiazol-2 (3H) -one in 25 ml of acetone. Add 3.5 g (25 mmol) of potassium carbonate and heat at 60 ° C for 1 hour. Add 0.08 ml (10 mmol) of iodoethane dropwise and with magnetic stirring. Shake at room temperature for 6 hours. The reaction medium evaporate the acetone. Add 70 ml of water and 6 N HCI until an acid pH is obtained. Squeeze the precipitate formed, wash with water, dry it and recrystallize it with Pacetonitrile (2.33 g, 85%). Rf = 0.69 (EtOAc / Cyclohexane = 5/5): mp 148-152 ° C; ir γ CO 1678 cm ^'1 , 1622 cm ^{' 1} , NO ₂ 1518 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-de) δ 1.20 (t, 3H, CH ₃ ), 4.00 (q, 2H, CH ₂ ), 7.54 (d, 1H, H ₄ , J _4-5 = 8.1 Hz), 7.77 (dd, 1H, H ₅ , J _{5. 4} = 8.1 Hz, J ₅ -? = 1.8 Hz), 7.93 (d, 2H, H ₃ ', H _5. , J = 9 Hz), 8.17 (d, 1H, H ₇ , 1.8 Hz), 8.35 (d, 2H, H ₂ -, H _ff , J = 9 Hz). Anal. (Cι ₆ Hι ₂ N ₂ O ₄ S)

4 - [(2-Oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) carbonyl] benzonitrile (3). It is identical to that described for obtaining (1) page 2. 2 (3 H) - benzoselenazolone (5 g, 25 mmol), dimethylformamide (4.5 ml, 58 mmol), aluminum chloride (26.9 g, 202 mmol) and 4 -cyanobenzoyl chloride (6.58 g, 30 mmol), product 3 obtained and recrystallize it in Pacetonitrile (4.1 g, 50%). Rf = 0.41 (EtOAc / Cyclohexane = 4/6): mp 230-232 ° C; ir γ NH 3248 cm ^'1 , CN 2229 cm ^{' 1} , CO 1701 cm ^'1 , 1678 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 7.22 (d, 1H, H ₄ , J _4-5 = 9.0 Hz), 7.67-7.70 (m, 1H, H ₅ ), 7.82 (d, 2H, H ₃ -, H *, J = 8.1 Hz), 8.00 (d, 2H, H ₂ -, H ₆ -, J = 8.1 Hz), 8.16 (s, 1H, H ₇ ), 12.18 (br s, 1H, NH , exchangeable with D ₂ O). Anal. (Cι ₅ Hι ₈ N ₂ O ₂ Se)

4 - [(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) carbonyl] benzonitrile (4). It is identical to that described for obtaining (1) page 2. 3-methyl-2 (3H) -benzoselenazolone (5 g, 24 mmol), dimethylformamide (4.2 ml, 54 mmol), aluminum chloride (25 g, 189 mmol) and 4-cyanobenzoyl chloride (4.7 g, 28 mmol), product 4 obtained and recrystallize it from Pacetonitrile (6.4 g, 80%). Rf = 0.51 (EtOAc / Cyclohexane = 4/6): mp 205-210 ° C; ir γ CN 2231 cm ^'1 , CO 1699 cm ^{' 1} , 1658 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.45 (s, 3H, CH ₃ ), 7.45 (d, 1H, H ₄ , J _4-5 = 8.1 Hz), 7.76- 7.78 (m, 1 H, H ₅ ), 7.83 (d, 2H, H ₃ -, H ₅ -, J = 8.1 Hz), 8.02 (d, 2H, H ₂ -, H ₆ -, J = 8.1 Hz), 8.25 (s, 1H, H ₇ ). Anal. (C ₁₆ Hι ₀ N ₂ O ₂ Se)

4 - [(3-Ethyl-2-oxo-2,3-dihydro-1,3-benzosθlenazol-6-yl) carbonyl] benzonitrile (5). It is identical to that described for obtaining (2) page 2. 4 - [(2-oxo-2,3-dihydro-1, 3-benzoselenazol-6-yl) carbonyl] benzonitrile (1.2 g, 3.7 mmol ), acetone (50 ml), potassium carbonate (1.52 g, 11 mmol) and iodoethane (0.35 ml, 4.4 mmol), the product 5 obtained and recrystallize it from Pacetonitrile (1.1 g, 87%). Rf = 0.55 (EtOAc / Cyclohexane = 4/6): mp 130-135 ° C; ir γ CN 2231 cm ^'1 , CO 1697 cm ^{' 1} , 1674 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.19 (t, 3H, CH ₃ ), 4.00 (q, 2H, CH ₂ ), 7.50 (d, 1 H, H ₄ , J _-5 = 8.4 Hz) , 7.76 (dd, 1 H, H ₅ , J ₅ -4 = 8.4 Hz, J _5-7 = 1.5 Hz), 7.85 (d, 2H, H ₃ -, H _ff , J = 8.4 Hz), 8.02 (d , 2H, H ₂ -, H ₆ -, J = 8.4 Hz), 8.27 (s, 1H, H ₇ ). Anal. (Cι ₇ Hι ₂ N ₂ O ₂ Se)

6- (4-Nitrobezoyl) ~ 1,3-benzoselenazol-2 (3H) -one (6). It is identical to that described for obtaining (1) page 2. 3-methyl-2 (3H) - benzoselenazolone (5 g, 24 mmol), dimethylformamide (4.2 ml, 54 mmol), aluminum chloride (25 g, 189 mmol) and 4-nitrobenzoyl chloride (5.62 g, 30 mmol), the product 6 obtained and recrystallize it from acetonitrile (6.2 g, 70%). Rf = 0.45 (EtOAc / Cyclohexane = 4/6): mp 241- 245 ° C; ir γ NH 3250 cm ^'1 , CO 1695 cm ^{' 1} , 1647 cm ^'1 , NO ₂ 1520 cm ^'1; ¹ H- NMR (300MHz, DMSO-d ₆ ) δ 7.25 (d, 1 H, H ₄ , J _-5 = 8.4 Hz), 7.70 (dd, 1 H, H ₅ , J _M = 8.4 Hz, J ₅ - 7 = 1 -5 Hz), 7.91 (d, 2H, H _3. , H _ff , J = 9.0 Hz), 8.18 (d, 1 H, H ₇ , J _7-5 = 1.5 Hz), 8.35 (d, 2H, H ?, H ₆ -, J = 9.0 Hz), 12.2 (br s, 1 H, NH, exchangeable with D ₂ O) . Anal. (Ci ₄ H ₈ N ₂ O ₄ Se)

3-Methyl-6- (4-nitrophenyl) -1,3-benzoselenazol-2 (3H) -one (7). It is identical to that described for obtaining (2) page 2. 6- (4-Nitrobezoyl) - 1, 3-benzoselenazol-2 (3H) -one (2.5 g, 7.2 mmol), acetone (100 ml) , potassium carbonate (2.99 g, 22 mmol) and iodomethane (0.54 ml, 8.6 mmol), the product 7 obtained and recrystallize it from acetonitrile (2.42 g, 93%). Rf = 0.37 (EtOAc / Cyclohexane = 3/7): mp 151-155 ° C; ir γCO 1680 cm ^'1 , 1655 cm ^{' 1} , NO ₂ 1 520 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.45 (s, 3H, CH ₃ ), 7.44 (d, 1H, H ₄ , J = 8.7 Hz), 7.78 (dd, 1H, H ₅ , J ₅ - 4 = 8.7 Hz, J ₅ -7 = 1 -8 Hz), 7.92 (d, 2H, H ₃ -, H _ff , J = 9.0 Hz), 8.28 (d, 1 H, H ₇ , J _7-5 = 1.8 Hz), 8.36 (d, 2H, H ?, H _ff , J = 9.0 Hz). Anal. (C ₁₅ H ₁₀ N ₂ O ₄ Se)

3-Ethyl-6- (4-nitrobezoyl) -1,3-benzoselenazol-2 (3H) -one (8). It is identical to that described for obtaining (2) page 2. 6- (4-Nitrobezoyl) - 1, 3-benzoselenazol-2 (3H) -one (2.5 g, 7.2 mmol), acetone (100 ml) , potassium carbonate (2.99 g, 22 mmol) and iodoethane (0.69 ml, 8.6 mmol), the poroduct 8 obtained and recrystallize it from methanol (2.2 g, 82%). Rf = 0.60 (EtOAc / Cyclohexane = 4/6): mp 97-102 ° C; ir γ CO 1678 cm ^'1 , 1657 cm ^{' 1} , NO ₂ 1520 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.20 (t, 3H, CH ₃ ), 4.01 (q, 2H, CH ₂ ), 7.51 (d, 1H, H ₄ , J ₄ - ₅ = 8.4 Hz) , 7.78 (dd, 1H, H ₅ , J5-4 = 8.4 Hz, Js. ₇ = 1.5 Hz), 7.94 (d, 2H, H ₃ -, H _s , J = 8.7 Hz), 8.30 (d, 1H, H ₇ , J _7-5 = 1.5 Hz), 8.37 (d, 2H, H _2. , H _ff , J = 8.7 Hz). Anal. (Cι ₆ Hι ₂ N ₂ O ₄ Se)

Reduction (Table II l-B)

Method A: NaBH MeOH Method B: NaBH4, NaOH, H2 <

Ref Ri XYZ Isomer B Method la CÏÏ2CÏI3 S - H 6 - £> ^N ° 2 A

3-Ethyl-6- [hydroxy (4-nitrophenyl) methyl] -1,3-benzothiazol-2 (3H) -one (1a). To a 100 ml flask containing 2.3 g (7 mmol) of 3-ethyl-6- (4-nitrobezoyl) -1, 3-benzothiazol-2 (3H) -one (2.3 g, 7 mmol), add 30 ml of methanol. Then add little by little and with magnetic stirring, 0.3 g (7 mmol) of sodium borohydride. Continue stirring for 2 hours at room temperature. Evaporate all the solvent on a rotary evaporator, then take up the residue in 50 ml of slightly acidic water. Squeeze the precipitate formed, wash with water, until the washings are neutral. Dry the product obtained and recrystallize it from ethyl acetate (2.2 g, 96%). Rf = 0.4 (EtOAc / Cyclohexane =

5/5); mp 160-162 ° C; irγ OH 3423cm ^'1 , CO 1647cm ^{' 1} , NO ₂ 1520 cm ^"1 ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.14 (t, 3H, CH ₃ ), 3.90 (q, 2H, CH ₂ ) , 5.89 (s, 1H, CH), 6.30 (s, 1H, OH, exchangeable with D ₂ O), 7.30 (d, 1H, H ₄ , J ₄ - ₅ = 8.1 Hz), 7.37-7.40 (m. 1H , H ₅ ), 7.66-7.68 (m, 3H, H ₇ , H ₃ -, H ₅ -), 8.16 (d, 2H, H ₂ ', H ₆ ', J = 8.1 Hz). Anal. (Cι ₆ Hι ₄ N ₂ O ₄ S) 4- [Hydroxy (2-oxo-2,3-dihydro-1, 3-benzoselenazol-6- yl) methyl] ben- zonitrile (2a). It is identical to that described for obtaining (1a) page 4. 4 - [(2-oxo-2,3-dihydro-1, 3-benzoselenazol-6-yl) carbonyl] benzonitrile (2 g, 6.1 mmol ), methanol (30 ml) and sodium borohydride (0.5 g, 6.1 mmol), the poroduct 2a obtained and recrystallize it from Pacetonitrile. (1.4 g, 70%). Rf = 0.37 (EtOAc / Cyclohexane = 5/5): mp 209-213 ° C; ir γOH 3506 cm ^'1 , NH 3146 cm ^{' 1} , CN 2227 cm ^'1 , CO 1695 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 5.76 (s, 1H, CH), 6.17 (s, 1H, OH,, exchangeable with D ₂ O), 7.02 (d, 1H, H ₄ , 8.1 Hz), 7.25 (dd, 1H, H ₅ , J ₅ -4 = 8.1 Hz, J5-7 = 1.5 Hz), 7.54 (d, 3H, H ₃ -, H ₅ -, J = 8.1 Hz), 7.66 (d, 2H, H ₂ -, H ₆ -, J = 8.1 Hz), 7.43 (d, 1H, H ₇ , J _{7. 5} = 1.5 Hz), 11.85 (br s, 1H, NH, exchangeable with D ₂ O). Anal. (Cι ₅ Hι ₀ N ₂ O ₂ Se)

4- [Hydroxy (3-methyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) methyl] benzonitrile (3a). It is identical to that described for obtaining (1a) page 4. 4 - [(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) carbonyl] benzonitrile (2.0 g, 5.9 mmol), methanol (50 ml) and sodium borohydride (1.2 g, 32 mmol), the poroduct 3a obtained and recrystallize it from ethyl acetate (1.8 g, 90%). Rf = 0.38 (EtOAc / Cyclohexane = 5/5); mp 205-208 ° C; ir γ OH 3472 cm ^"1 , CN 2224 cm ^'1 , CO 1651 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.30 (s, 3H, CH ₃ ), 5.80 (s, 1H, CH ), 5.82 (s, 1H, OH, exchangeable with D ₂ O), 7.19 (d, 1H, H ₄ , J ₄ -5 = 8.4 Hz), 7.34-7.36 (m, 1H, H ₅ ), 7.55 (d , 2H, H ₃ -, H ₅ -, J = 7.8 Hz), 7.73-7.77 (m, 3H, H ₇ , H ₂ -, H _ff ). Anal. (Cι ₆ H ₁₂ N ₂ O ₂ Se)

4 - [(3-Ethyl-2-oxo-2,3-dïhydro-1,3-benzoselenazol-6-yl) (hydroxy) methyl] benzonitrile (4a).

It is identical to that described for obtaining (1a) page 4. 4 - [(3-ethyl-

2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) carbonyl] benzonitrile (1.1 g, 3.0 mmol), methanol (15 ml) and sodium borohydride (0.06 g, 1.5 mmol), the poroduct 4a obtained and recrystallize it from ethyl acetate (0.92 g, 86%). Rf = 0.31 (EtOAc / Cyclohexane = 4/6): mp 132-134 ° C; irγ OH 3427 cm ^'1 , CN 2227 cm ^{' 1} , CO 1641 cm ^'1 ; ¹ H-NMR (300MHz, DMSO- d ₆ ) δ 1.13 (t, 3H, CH ₃ ), 3.89 (q, 2H, CH ₂ ), 5.80 (d, 1H, CH, J = 3.9 Hz), 6.19 (d , 1 H, OH, J = 3.6 Hz,, exchangeable with D ₂ 0), 7.26 (d, 1 H, H ₄ , J _4-5 = 8.1 Hz), 7.34 (dd, 1H, H ₅ , J ₅ - ₄ = 8.1 Hz, J _5-7 = 1.8 Hz), 7.57 (d, 2H, H _3. , H ₅ ', J = 8.4 Hz), 7.75-7.79 (m, 3H, H ₇ , H ₂ -, H ₆ ). Anal. (C ₁₇ H ₁₄ N ₂ O ₂ Se)

6- [Hydroxy (4-nitrophenyl) methyI] -3-methyI-1,3-benzoselenazol- 2 (3H) -one (5a). It is identical to that described for obtaining (1a) page 4. 3-Methyl-6- (4-nitrophenyl) -1, 3-benzoselenazol-2 (3H) -one (2.3 g, 6.4 mmol), methanol (30 ml) and sodium borohydride (0.3 g, 6.4 mmol), the poroduct 5a obtained and recrystallize it from Pacetonitrile (1.9 g, 84%). Rf = 0.31 (EtOAc / Cyclohexane = 4/6); mp 182-183 ° C; ir γ OH 3406 cm ¹ , CO 1645 cm ^'1 , NO ₂ 1512 cm ^'1; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.35 (s, 3H, CH ₃ ), 5.88 (s, 1 H, CH), 6.29 (s, 1 H, OH, exchangeable with D ₂ O), 7.21 (d, 1 H, H ₄ , J4.5 = 8.1 Hz), 7.37 (dd, 1 H, H ₅ , Js-4 = 8.1 Hz, J _5- = 1.8 Hz), 7.64 (d, 2H, H ₃ -, H ₅ -, J = 8.7 Hz), 7.75 (d, 1 H, H ₇ , J _7-5 = 1.8 Hz), 8.16 (d, 2H, H ₂ >, H ₆ -, J = 8.7 Hz) . Anal. (Cι ₅ Hι ₂ N ₂ O ₄ Se)

3-Ethyl-6- [hydroxy (4-nitrophenyl) methyl] -1,3-benzoselenazol-2 (3H) - one (6a). ). It is identical to that described for obtaining (1a) page 4. 3-Ethyl-6- (4-nitrobezoyl) -1, 3-benzoselenazol-2 (3H) -one (2.2 g, 5.8 mmol), methanol (30 ml) and sodium borohydride (0.3 g, 5.8 mmol), the poroduct 6a obtained and recrystallize it from ethyl acetate (1.2 g, 57%). Rf = 0.35 (EtOAc / Cyclohexane = 4/6); mp 135-137 ° C; ir γ OH 3420 cm ^'1 , CO 1653 cm ^{' 1} , NO ₂ 1514 cm ^"1 ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.13 (t, 3H, CH ₃ ), 3.89 (q, 2H, CH ₂ ), 5.87 (s, 1H, CH), 6.28 (s, 1H, OH, exchangeable with D ₂ O), 7.27 (d, 1H, H ₄ , J - ₅ = 8.4 Hz), 7.36 (dd, 1H , H ₅ , 1.8 Hz), 7.65 (d, 2H, H ₃ -, H _ff , J = 9 Hz), 7.76 (d, 1H, H ₇ , J _{7. 5} = 1.8 Hz), 8.17-8.20 (m, 2H, H ₂ -, H ₆ -). Anal. (Cι ₆ Hι ₄ N ₂ O ₄ Se)

Substitution

Ref Rj XY z Triazole isomer g lt CH ₂ CH ₃ S - H 6, 4 - ^"N ° 2

5b CH ₃ Se - H 6 1,2,4 -Q-NO,

EXAMPLE 44:

3-Ethyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzothiazol-2 (3H) -one.

In a 100 ml flask dissolve 4.83 g (70 mmol) of 1 / - / - 1,2,4-triazol in 35 ml of acetonitrile then slowly add 1.3 ml (18 mmol) of thionyl chloride. To follow stirring for 30 minutes at room temperature. Wring out the filtrate obtained. The filtrate add dropwise to a solution of 1.5 g (4.5 mmol) of 3-ethyl-6- [hydroxy (4-nitrophenyl) methyl] -1,3-benzothiazol-2 (3H) -one and 10 ml of acetonitrile. Continue stirring for 5 hours at room temperature. Evaporate the solvent on a rotary evaporator: Add 100 ml of water and add to 6 N HCI until an acid pH is obtained. Extract with 150 ml of ethyl acetate. The aqueous phase alkalized with a potassium carbonate solution until neutral. Extract with 150 ml of ethyl acetate, dry the organic phase over MgS04 then evaporate and purify it by chromatography on silica gel (eluent: EtOAc) (0.34 g, 20%). Rf = 0.28 (EtOAc): mp 79-83 ° C; ir γ CO 1676 cm ^'1 , 1602 cm ^{' 1} , NO ₂ 1520 cm ^'1 ; ¹ H-NMR (300MHz, CDCI ₃ ) δ 1.17 (t, 3H, CH ₃ ), 3.93 (q, 2H, CH ₂ ), 7.30-7.35 (m, 2H, CH, H ₄ ), 7.40-7.47 (m , 3H, H ₅ , H ₃ -, H ₅ '), 7.62 (s, 1 H, H ₇ ), 8.12 (s, 1 H, H, ** "), 8.23 (d, 2H, H ₂ -, H _ff , J = 8.1 Hz), 8.69 (s, 1 H, Htriaziœ). Anal. (Cι ₇ Hι ₃ N ₅ O ₃ S)

EXAMPLE 45:

4 - [(2-oxo-2,3-dihydro-1, 3-benzoselenazol-6-yl) (1 HA, 2,4-triazoM - yl) methyl] benzonitrile. It is identical to that described for obtaining

(1b) page 6. 4- [Hydroxy (2-oxo-2,3-dihydro-1, 3-benzoselenazol-6- yl) methyl] benzonitrile (1.5 g, 4.6 mmol), thionyl chloride (1.3 ml, 18 mmol), 1H-1, 2,4-triazol (4.84 g, 70 mmol) and THF (35 ml), the poroduct 2b obtained and purify it by chromatography on silica gel (eluent: EtOAc) (0.17 g, 10% ). Mp = 0.46 (EtOAc): mp 223-226 ° C; ir γ NH 3435 cm ^"1 , CN

2229 cm ^'1 , CO 1685 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 7.09 (d, 1 H,

H ₄ , J4-5 = 8.1 Hz), 7.13 (dd, 1H, H ₅ , J ₅ -4 = 8.1 Hz, J _5. = 1.5 Hz), 7.20 (s,

1 H, CH), 7.33 (d, 2H, H ₃ -, H ₅ -, J = 7.8 Hz), 7.56 (d, 1H, H ₇ , J _7-5 = 1.5 Hz),

7.83 (d, 2H, H ₂ -, Hep, J = 7.8 Hz), 8.08 (s, 1H, H _Maz , ₀ β), 8.62 (s, 1 H, Htriazbe), 11.83 (br s, 1H, NH, exchangeable with D ₂ O). Anal.

(C ₁₇ HnN ₅ OSe)

EXAMPLE 46:

4 - [(3-Methyl-2-oxo-2,3-dihydro-1, 3-benzoselenazol-6-yl) (1 HA, 2,4-triazol-1-yl) methyl] benzonitrile. It is identical to that described for obtaining (1b) on page 6. 4- [Hydroxy (3-methyl-2-oxo-2,3-dihydro-1, 3- benzoselenazol-6-yl) methyl] benonitrile (1.5 g, 4.4 mmol), thionyl chloride (1.3 ml, 18 mmol), 1H-1,2,4-triazol (4.65 g, 67 mmol) and acetonitrile (40 ml) , the poroduct 2b obtained and purify it by chromatography on silica gel (eluent: EtOAc) (0.35 g, 20%). Rf = 0.42 (EtOAc): mp 154-158 ° C; ir γ CN 2229 cm ^'1 CO 1657 cm ^'1; ¹ H-NMR (300MHz, DMSO-de) δ 3.37 (s, 3H, CH ₃ ), 7.25-7.30 (m, 3H, CH, H ₄ , H ₅ ), 7.34 (d, 2H, H ₃ >, H ₅ >, J = 8.7 Hz), 7.66 (s, 1H, H ₇ ), 7.84 (d, 2H, H ?, H ₆ -, J = 8.7 Hz), 8.09 (s, 1H, Hwazioe), 8.64 (s , 1 H, Hwazioe). Anal. (Cι ₈ Hι ₃ N ₅ OSe)

EXAMPLE 47:

4 - [(3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzoselθnazol-6-yl) (1 HA, 2,4-triazol-1-yl) methyl] benzonitrile. It is identical to that described for obtaining (1b) page 6. 4 - [(3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) (hydroxy) methyl] benzonitrile (0.9 g, 2.5 mmol), thionyl chloride (0.7 ml, 10 mmol), 1H-1,2,4-triazol (2.68 g, 39 mmol) and acetonitrile (35 ml), the poroduct 2b obtained and purifying it by chromatography on silica gel (eluent: EtOAc) (0.2 g, 19%). Rf = 0.44 (EtOAc); mp 95-98 ° C; ir γ CN 2229 cm ^'1 , CO 1670 cm ^"1 ; ¹ H NMR (300 MHz, DMSO-de) δ 1.15 (t, 3H, CH ₃ ), 3.91 (q, 2H, CH ₂ ), 7.26 (m, 2H, CH, H ₄ ), 7.35-7.39 (m, 3H, H ₅ , H _3. , H ₅ ), 7.69 (s, 1 H, H ₇ ), 7.86 (d, 2H, H ₂ -, ₆ ; J = 8.1 Hz), 8.11 (s, 1 H, Htriazoïe), 8.67 (s, 1H, _WazC Λo). Anal. (Cι ₉ H ₁₅ N ₅ OSe)

EXAMPLE 48

3-Methyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazo -yl) methyl] -1, 3-benzoselenazol-2 (3ft) -one. It is identical to that described for obtaining (1b) page 6. 6- [Hydroxy (4-nitrophenyl) methyl] -3-methyl-1,3- benzoselenazol-2 (3rV) -one (1.5 g, 4.1 mmol), thionyl chloride (l.γ ml, 17 mmol), 1 / V-1, 2,4-triazol (4.39 g, 64 mmol) and acetonitrile (40 ml), the poroduct 2b obtained and purify it by chromatography on silica gel (eluent: EtOAc) (0.29 g, 17%). Rf = 0.46 (EtOAc); mp 190-195 ° C; ir γ CO 1651 cm ^'1 , NO ₂ 1520 cm ^"1 ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.36 (s, 3H, CH ₃ ), 7.30-7.35 (m, 3H, CH, H ₄ , H ₅ ), 7.44 (d, 2H, H ₃ -, H ₅ -, J = 8.7), 7.69 (s, 1 H, H ₇ ), 8.12 (s, 1 H, H ^ goose), 8.24 (d, 2H, H *, H ₆ -, J = 8.7), 8.68 (s, 1 H, Htriazoïθ). Anal. (C-ι ₇ Hι ₃ N ₅ 0 ₃ Se)

EXAMPLE 49

3-Ethyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzoselenazol-2 (3H) -one. It is identical to that described for obtaining (1b) page 6. 3-ethyl-6- [hydroxy (4-nitrophenyl) methyl] - 1, 3-benzoselenazol-2 (3 /) -one (1.2 g, 3.2 mmol), thionyl chloride (0.9 ml, 13 mmol), 1H-1,2,4-triazol (3.38 g, 49 mmol) and acetonitrile (35 ml), the poroduct 2b obtained and purify it by chromatography on gel silica (eluent: EtOAc) (0.28 g, 21%). Rf = 0.44 (EtOAc): mp 79-82 ° C; ir γ CO 1670 cm ^'1 , NO ₂ 1520 cm ^"1 ; ¹ H-NMR (300MHz, CDCI ₃ ) δ 1.13 (t, 3H, CH ₃ ), 3.91 (q, 2H, CH ₂ ), 7.27-7.39 ( m, 3H, CH, H ₄ , H ₅ ), 7.45 (d, 2H, H ₃ >, H ₅ -, J = 8.7 Hz), 7.70 (s, 1 H, H ₇ ), 8.12 (s, 1 H , Htπazbθ), 8.24 (d, 2H, H _2. , H ₆ -, J = 8.7 Hz), 8.69 (s, 1 H, Hwazbe) Anal. (Cι ₈ Hι ₅ N ₅ O ₃ Se)

PREPARATION OF THE COMPOUNDS OF EXAMPLES 50 AND 51 (Tables l-B. Ill-B. IV)

Methyl 4-chloro-3-nitrenzoate (1). Dissolve 4-chloro-3-nitro-benzoic acid (5.0 g, 24.8 mmol) in 200 ml of methanol and add 4.15 ml (29.8 mmol) of triethylamine. Cool in an ice-salt bath and add 3.19 ml (44.7 mmol) of acetyl chloride dropwise. Shake at reflux for e hours. Evaporating under pressure reduces the solvent. Take up the residue in 100 ml of water and extract twice with ethyl acetate (100 ml). Dry the organic phase on MgSO4 and evaporate it under reduced pressure and purify it with ether (10 ml) (4.81 g, 92%). Rf = 0.55 (EtOAc / Cyclohexane = 7/3); mp 79-80 ° C; ir. CO 1716 cm ^"1 ; ¹ H- NMR (300MHz, DMSO-d ₆ ) δ 3.90 (s, 3H, OCH ₃ ), 7.90 (d, 1H, H ₅ , J _5-6 = 8.1 Hz), 8.15 (dd , 1H, H ₆ , J ₆ - ₅ = 8.1 Hz, J5-2 = 1.5 Hz), 8.49 (d, 1H, H ₂ , J _2-6 = 1.5 Hz) .Anal. (C ₈ H ₆ CINO ₄ ) .

Methyl-3-nitro-4-sulfanylbenzoate (2). In a 250 ml flask, suspend sodium sulfate (2.7 g, 34 mmol) and methyl 4-chloro-3-nitrobenzoate (5 g, 23 mmol) in 150 ml of absolute ethanol. Shake at room temperature for 7 hours. Pour the reaction medium onto ice (200 ml). Add acetic acid to pH 2 and extract 3 times with CH ₂ CI ₂ (100 ml). Dry the organic phase on MgSO4 and evaporate it under reduced pressure and purify it with ether (3.9 g, 80%). Rf = 0.31 (EtOAc / Cyclohexane = 3/7); mp 98-101 ° C; ir SH 2546, CO 1722 cm ^'1 ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 381 (s, 3H, OCH ₃ ), 4.31 (brs, 1H, SH, exchangeable with D ₂ O), 7.82 (d, 1H, H ₅ , J ₅ . ₆ = 8.2 Hz), 8.17 (dd, 1H, H ₆ , J _6-5 = 8.2 Hz,, J _5-2 = 1.5 Hz), 8.41 (d, 1H, H ₂ , J _{2. 6} = 1.5 Hz ). Anal. (C ₈ H ₇ NO ₄ S).

3-Amino-4-sulfanyl benzoic acid hydrochloride (3). In a 250 ml flask, suspend thin (ll) chloride (17.3 g, 91.4 mmol) and methyl-3-nitro-4-sulfanylbenzoate (3.9 g, 18.3 mmol) in 50 ml of 6 N HCI. Shake at reflux for 4 hours. Versel the reaction medium on ice (200 ml). Squeeze the precipitate formed, dry it and recrystallize it with ether (3.3 g, 81%). Rf = 0.32 (EtOAc / Cyclohexane 5 = 5/5); mp 215-217 ° C (decomposition); ir NH ₂ 3331 cm ^'1 , SH 2511 cm ^{' 1} , CO 1711 cm ^'1 ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 4.42 (br s, 1H, SH, exchangeable with D ₂ O), 7.76 (d, 1H, H ₅ , J5-e = 8.2 Hz), 8.31 (dd , 1H, H ₆ , J ₆ - ₅ = 8.1 Hz, J ₅ - ₂ = 1.5 Hz), 8.44 (d, 1H, H ₂ , J _{2. 6} = 1.5 Hz), 12.2 (br s, 1H, OH, exchangeable with D ₂ O). Anal. (C ₈ Hι ₀ NO ₂ CIS).

10

2-Oxo-2,3-dihydro-1,3-benzothiazolone-5-carboxylic acid (4).

15 Mix 5 g (24.3 mmol) of 3-amino-4-sulfanyl benzoic acid HCI knows and 14.6 g (243 mmol) of urea. Stir at 140-145 ° C for 4 hours. Versel the reaction medium on ice (200 ml) and add 6N acetic acid until pH 2. Squeeze the precipitate formed, dry it and recrystallize with ether (2.9 g, 49%). Rf = 0.65 (MeOH / EtOH / Cyclohexane = 3/5/2),

20 mp 275-277 ° C; ir OH 3099 cm ^"1 , CO 1718 cm ^{" 1} , NCO 1682 cm ^"1 ; ¹ H- NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (s, 1H, H ₄ ), 7.69-7.72 (m, 2H , H ₅ , ₆ ), 12.10 (br s, 1 H, NH, exchangeable with D ₂ O), 13.06 (br s, 1H, exchangeable with D ₂ O) Anal. (C ₉ H ₇ NO ₃ S).

Methyl-2-oxo-2,3-benzothiazolone-5-carboxylate (5). Add 2-oxo 2,3-dihydro-1,3-benzothiazolone-5-carboxylic acid (5.0 g, 24.8 mmol) to 200 ml of methanol. Cool in an ice-salt bath at 0 ° C and add 9.34 ml (128.1 mmol) of thionyl chloride dropwise. 5 Shake at reflux for 5 hours. Evaporating under pressure reduces the solvent. Take up the residue in 100 ml of water and extract twice with ethyl acetate (100 ml). Dry the organic phase on MgSO and evaporate it under reduced pressure and purify it with ether (10 ml) (4.0 g, 75%). Rf = 0.58 (EtOAc / Cyclohexane = 5/5); mp 217-219 "C; ir CO 1695o cm ^{" 1} , NCO 1684 cm ^"1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.85 (s, 3H, OCH ₃ ), 7.60 (d, 1H, H ₄ , J ₄ -e = 2.7 Hz), 7.67-7.69 (m, 2H, H ₆ , ₇ ), 12.13 (br s, 1H, NH, exchangeable with D ₂ O). Anal. (C ₉ H ₇ NO ₃ S).

5 5- (Hydroxymethyl) -1,3-benzothiazol-2 (3H) -one (6). Dissolve methyl-2-oxo-2,3-benzothiazolone-5-carboxylate (5.0 g, 23.9 mmol) in 100 ml of THF. Cool in an ice-salt bath and gradually add 1.1 g (28.7 mmol) of LiAIH. Stir at room temperature for 3Q> hours. Slowly add 100 ml of water to the reaction medium and add 1 N acetic acid to pH 7. Extract twice with CH ₂ CI ₂ (100 ml). Dry the organic phase on MgSO4 and evaporate it under reduced pressure and purify it with ether (10 ml) (3.4 g, 79%). Rf = 0.33 (EtOAc / Cyclohexane = 3/7); mp 178-181 ° C; ir OH 3319 cm ^"1 , NCO5 1684 cm ^"1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 4.49 (d, 2H, CH ₂ OH, J = 5.7 Hz), 5.26 (t, 1H, CH ₂ OH, J = 5.7 Hz, exchangeable with D ₂ O) , 7.02 (d, 1H, H ₆ , J ₆ -7 = 8.1 Hz), 7.09 (s, 1H, H ₄ ), 7.45 (d, 1H, H ₇ , J _{7. 6} = 8.1 Hz), 11.85 (s , 1H, NH, exchangeable with D ₂ O). Anal. (C ₈ H ₇ NO ₂ S).

2-Oxo-2,3-dihydro-1,3-benzothiazol-5-carbaldehyde (7). Dissolve 5- (hydroxymethyl) -1,3-benzothiazol-2 (3H) -one (1 g, 5.5 mmol) in 100 ml of CH ₂ CI ₂ . Add 10 g (177 mmol) of manganese dioxide and stir at room temperature for 4 hours. The reaction medium drain and evaporate the solvent under reduced pressure and purify it with ether (10 ml) (0.69 g, 69%). Rf = 0.56 (EtOAc / Cyclohexane = 5/5); mp 211-215 ° C; ir CO 1730 cm ^'1 , NCO 1691 cm ^'1; ¹ H-NMR (300MHz, DMSO- de) δ 7.53 (s, 1 H, H ₄ ), 7.65 (d, 1 H, H ₆ , J _6-7 = 8.1 Hz), 7.80 (d, 1 H, H ₇ , J _7-6 = 8.1 Hz), 9.95 (s, 1H, COH), 12.22 (br s, 1H, NH, exchangeable with D ₂ O). Anal. (C ₈ H ₅ NO ₂ S).

Ref R ield 8a CH _{3 84} o _o 8b CH ₂ CH ₃ 87%

3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-carbaldehyde (8a).

In a 100 ml flask, dissolve 1.0 g (5.6 mmol) of 2-oxo-2,3-dihydro-1, 3-benzothiazol-5-carbaldehyde in 50 ml of acetone. Add 2.3 g (16.7 mmol) of potassium carbonate and 0.42 ml (6.7 mmol) of iodomethane. Shake at room temperature for 3 hours. The reaction medium evaporate the acetone. Add 100 ml of water and extract it twice with ethyl acetate (100 ml). Dry the organic phase on MgSO ₄ and evaporate it under reduced pressure and purify it with ether (10 ml) (0.91 g, 84%). Rf = 0.59 (EtOAc / Cyclohexane = 5/5); mp 140-142 ° C; ir CO1682 cm ^'1 , NCO 1674 cm ^'1; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.46 (s, 3H, NCH ₃ ), 7.73-7.75 (m, 2H, H ₄ , ₆ ), 7.90 (d, 1H, H, J _7-6 = 8.1 Hz), 9.99 (s, 1H, COH). Anal. (C ₉ H ₇ NO ₂ S).

3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-carbaldehyde (8b). It is identical to that described for obtaining (8a). 2-Oxo-2,3-dihydro- 1, 3-benzothiazol-5-carbaldehyde (2 g, 11.1 mmol), potassium carbonate (4.6 g, 33.3 mmol), iodoethane (1.1 ml, 13.3 mmol) and acetone (50 ml), product 8b obtained and purify it with ether (2.01 g, 87%). Rf = 0.63 (EtOAc / Cyclo-hexane = 5/5); mp 155-156 ° C; ir CO 1689 cm ^'1 , NCO 1664 cm ^"1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.23 (t, 3H, CH ₂ CH ₃ , J = 6.7 Hz), 4.03 (q, 2H, CH ₂ CH ₃ , J = 6.7 Hz), 7.74 (dd, 1H, H ₆ , J ₆ - ₇ = 8.1 Hz, J _{6- 4} = 2.1 Hz), 7.85 (d, 1H, H ₄ , J _4-6 = 2.1 Hz), 7.91 (d, 1H, H ₇ , J _7-6 = 8.1 Hz), 10.04 (s, 1 H, COH) .Anal. (Cι ₀ H _g NO ₂ S).

Ref R yield 9a CH, 18% 9b CH2CH3 29%

4- [Hydroxy (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl) methyl] benzonitrile (9a).

Dissolve 4-bromobenzonitrile (1.9 g, 10.4 mmol) in 20 ml of THF and add 5.2 ml (10.4 mmol) of / -propyl magnesium chloride 2M solution in THF. Shake at room temperature for 2 hours. Then pour 2 g (10.4 mmol) of 3-methyl-2-oxo-2,3-dihydro- 1, 3-benzothiazol-5-carbaldehyde (2 g, 10.4 mmol) previously diluted in 20 ml of THF. Slowly add 100 ml of water to the reaction medium and extract 2 times with ethyl acetate (100 ml). Dry the organic phase on MgSO4 and evaporate it under reduced pressure and purify it by chromatography on silica gel, (eluent: EtOAc / C-hexane = 3/7) (0.55 g, 18%) Rf = 0.29 (EtOAc / Cyclohexane = 5/5); mp 183-186 ° C; ir OH 3398 cm ^"1 , CN 2224 cm ^{" 1} , CO 1658 cm ^"1 ; ¹ H-NMR (300MHz, DMSO-de) δ 3.38 (s, 3H, NCH ₃ ), 5.84 (d, 1H, CH, J = 3.9 Hz), 6.28 (d, 1H, OH, J = 3.9 Hz, exchangeable with D ₂ O), 7.16 (d, 1H, H ₇ , J _{7. 6} = 8.1 Hz), 7.36 (s, 1H, H ₄ ), 7.54 (d, 1 H, H ₆ , J ₆ - = 8.1 Hz), 7.60 (d, 2H, H _{2> 6} ', J _{2 -3} - = 8.1 Hz), 7.75 (d, 2H, H _{3 (5} ", Jy-z = 8.1 Hz). Anal. (Cι ₆ Hι ₂ N ₂ O ₂ S).

4- [Hydroxy (3-ethyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yl) methyl] benzonitrile (9b). It is identical to that described for obtaining (9a). 3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-carbaldehyde (2g, 9.7 mmol), 4-bromobenzonitrile (1.7 g, 9.7 mmol), / -propyl magnesium chloride 2M solution in THF (4.8 ml, 9.7 mmol) and THF (40 ml), the poroduit 9b obtained and purify it by chromatography on silica gel (eluent: EtOAc / C-hexane = 3/7) (0.87 g, 29%). Rf = 0.31 (EtOAc / Cyclohexane = 5/5); mp 156-158 ° C; ir OH 3433 cm ^"1 , CN 2227 cm ^{" 1} , NCO 1674 cm ^'1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.80 (t, 3H, CH ₂ CH ₃ , J = 7.2 Hz), 3.93 (q, 2H, CH ₂ CH ₃ , J = 7.2 Hz), 5.97 (d , 1H, CH, J = 3.9 Hz), 6.30 (d, 1 H, OH, J = 3.9 Hz, exchangeable with D ₂ O), 7.17 (d, 1 H, H ₇ , J _{7. 6} = 8.0 Hz) , 7.45 (s, 1H, H ₄ ), 7.56 (d, 1H, H ₆ , Je- ₇ = 8.0 Hz), 7.62 (d, 2H, H _{2 d6} -, J '-3' = 8.1 Hz), 7.77 (d, 2H, H ₃ -, ₅ ', J ₃ ' -2- = 8.1 Hz). Anal. (C ₁₇ H ₁₄ N ₂ O ₂ S).

Ref R yield 10a CH ₃ 32% 10b CH ₂ CH ₃ 21%

EXAMPLE 50:

4 - [(3-Methyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-yl) (1 H-1, 2,4-triazol-1-yl) methyl] benzonitrile. In a 100 ml flask dissolve 1.3 g (18.8 mmol) of 1 HA, 2,4-triazol in 20 ml of acetonitrile then slowly add 0.37 ml (5.1 mmol) of thionyl chloride. To follow stirring for 30 minutes at room temperature. Wring out the filtrate obtained. The filtrate add dropwise to a solution of 0.38 g (1.3 mmol) of 4- [hydroxy (3-methyl-2-oxo-2,3-dihydro-1, 3-benzothiazol -5- yl) methyl] benzonitrile and 10 ml of acetonitrile. Continue stirring for 5 hours at room temperature. Evaporate the solvent on a rotary evaporator: Add 100 ml of water and add to 6 N HCl until an acid pH is obtained. Extract with 150 ml of ethyl acetate. The aqueous phase alkalized with a potassium carbonate solution until neutral. Extract with 150 ml of ethyl acetate, dry the organic phase over MgS04 then evaporate and purify it by chromatography on silica gel (eluent: EtOAc / MeOH = 9/1) (0.14 g, 32%) . Rf = 0.54 (EtOAc / MeOH = 9/1): mp 122-125 ° C; ir. CN 2229 cm ^'1 , NCO 1680 cm ^"1 ; ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.34 (s, 3H, NCH ₃ ), 7.10 (dd, 1H, H ₆ , Je-7 = 8.1 Hz , J _{6. 4} = 1.5 Hz), 7.27-7.28 (m, 2H, CH, H ₄ ), 7.35 (d, 2H, H _{2. > 6} ', J ₂ - 3 = 8.4 Hz), 7.66 (d , 1 H, H ₇ , J _7-6 = 8.1 Hz), 7.84 (d, 2H, H ₃ - _{, 5} -, J _{3 -2} = 8.4 Hz), 8.11 (s, 1 H, Hfriazoïθ), 8.66 ( s, 1 H, H _biβZ0 te). Anal. (C ₁₈ H ₁₃ N ₅ OS). EXAMPLE 51:

4 - [(3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-yl) (1 H-1, 2,4-triazol-1-yl) methyl] benzonitrile. It is identical to that described for obtaining (10a). 4- [Hydroxy (3-ethyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-yl) methyl] benzonitrile) (0.87 g, 2.8 mmol), 1, 2,4-triazole (2.9 g, 42.0 mmol), thionyl chloride (0.82 ml, 1.1 mmol) and acetonitrile (100 ml), the poroduct 2b obtained and purify it by chromatography on silica gel (eluent: EtOAc / MeOH = 9/1) (0.21 g , 21%). Rf = 0.58 (EtOAc / MeOH = 9/1); mp 125-127 ° C; ir CN 2229 cm ^"1 , NCO 1674 cm ^"1; ¹ H- NMR (300MHz, DMSO-d ₆ ) δ 1.12 (s, 3H, CH ₂ CH ₃ , J = 7.5 Hz), 3.88 (q, 2H, CH ₂ CH ₃ , J = 7.5 Hz), 7.10 (dd , 1H, H ₆ , J ₆ - ₇ = 8.1 Hz, J ₆ - ₄ = 1.5 Hz), 7.29 (s, 1 H, CH), 7.35 (d, 2H, H ₂ , ₆ ', J ₂ -3- = 8.1 Hz), 7.40 (s, 1 H, H ₄ ), 7.68 (d, 1 H, H ₇ , J _7-6 = 8.1 Hz), 7.86 (d, 2H, H _2. , ₆ -, J2- -3- = 8.1 Hz), 8.12 (s, 1 H, Htπazolθ), 8.69 (S, 1 H, Hfiazol _θ ). Anal. (C19H15N5OS). The above examples illustrate the invention and do not limit it in any way. The above preparations also lead to synthesis intermediates useful in the preparation of the compounds of formula (I) of the invention.

PHARMACOLOGICAL STUDY (Table V)

Example A: Study of acute toxicity

Acute toxicity was assessed after oral administration to lots of

8 mice (26 g). The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment. The dose for which 50% mortality in animals is observed (LD50) was evaluated and showed the low toxicity of the compounds of the invention.

EXAMPLE B Study of the Inhibitory Power of Aromatase in Vitro The IC ₅₀ , concentrations inhibiting 50% of the activity of the enzyme, were determined using microsomes of human placenta as a source of the enzyme according to the tritiated water method described by PURBA et al (1990). The most active compounds have an IC50 close to 1 nanomolar.

Example C: Cell Cytotoxicity Study The protocol for studying cell cytotoxicity is adapted from

MOSMANN (1983).

It is based on the transformation of MTT into formazan by mitochondrial succinate dehydrogenase. This test is carried out on E293 cells of human embryonic kidney which do not express aromatase. The results showed that the compounds are not cytotoxic.

Example D Study of the In Vivo Activity The in vivo activity of inhibiting aromatase by the compounds of formula (I) according to the invention was tested according to the model established by

Bharnagar et al. (1990). Generally speaking, immature female rats of the line

Sprague-Dawley weighing 40 to 50 g were treated with a dose of androstene dione of 30 mg / kg for 4 days, in the absence or in the presence of various doses of the compounds of formulas (I). Four hours after administration of the aromatase inhibitor, the rats were killed. Their uterus was removed, stripped of fat and adherent connective tissue, and then the uterus was weighed (wet weight). The dry weight of the uterus was determined the following day after an overnight drying step at 80 ° C. The detailed results of the in vitro and in vivo activity of various aromatase inhibitors of formula (I) according to the invention are presented in Table V, in the present description. The results show that the compounds of formula (I) according to the invention induce a reduction of the uterine hypertrophy induced by Pandrostenedione which is dependent on the dose of the compound of formula (I) used, with, for some of the compounds of formula ( I), an almost complete inhibition of uterine hypertrophy induced by Pandrostenedione.

Table I - A: 6-ACYL-BENZAZINONES AND 7-ACYL-BEZOTHIAZINONES 6-Acyl-benzoxazolinones, 6-acyl-benzothiazolinones, 6-acyl-benzoxaziπones, 6-acyl-benzothiazinones and 7-acyl-benzothiazinones

Table I-A (continued) -BENZAZINQNES AND 7-ACYL-BEZOTHIAZINONES 6-Acyl-benzoxazolinones, 6-acyI-benzothiazoIinones, 6-acyI-beπzoxazinones, 6-acyl-benzothiazinones and 7-acyl-benzothiazinones

Table I-A (continued) -BENZAZINONES AND 7-ACYL-BEZQTHIAZINONES 6-Acyl-benzoxazoliπones, 6-acyl-benzothiazolinones, 6-acyl-beπzoxazinoπes, 6-acyl-benzothiazinones and 7-acyl-benzothiazinoπes

Table I-A (continued) -BENZAZINQNES AND 7-ACYL-BEZOTHIAZINONES 6-Acyl-benzoxazolinones, 6-acyl-benzothiazoIinon

Table I-A (continuedVBENZAZINONES AND 7-ACYL-BEZOTHIAZINONES 6-Acyl-benzoxazoIinones, 6-acyl-benzothiazoliπones, 6-acyl-benzoxaziπoπes, 6-acyl-benzothiazinones and 7-acyI-benzothiazinones

Table 1-B: 6-ACYL-BENZAZINQNES 6-acyl-beπzothiazolinones, 6-acyl-benzoselenazolinones

TABLE II: 5 and 7-ACYL-BENZAZINONES 5-Acyl-benzoxazoIinones, 7-acyl-benzoxazinones

TABLE II (continued): 5 and 7-ACYL-BENZAZINQNES 5-Acyl-benzoxazolinones, 7-acyl-benzoxazinones

Table III-A: REDUCED DERIVATIVES Hydroxyarylmethyl benzazinones

Table III-A (continued): REDUCED DERIVATIVES Hydroxyarylmethyl benzazinones

Table III-A (continued): REDUCED DERIVATIVES Hydroxyarylmethyl benzazinones

Table III-B: REDUCED DERIVATIVES Hydroxylmethyl benzazinone

Table IV

Table IV (continued)

Table IV (continued)

TABLE IV (continued)

Table IV (continued)

TABLE IV (continued)

TABLE IV (continued)

Table IV (continued)

TABLE IV (continued)

TABLE V Results of the in vitro and in vivo tests of the compounds of formula (I) according to the invention

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

TABLE V (continued)

REFERENCES

AICHAOUI, H., LESIEUR, I., HENICHART, J.-P. Synthesis (1990), 8, 679-680.

AICHAOUI, H., POUPAERT, J.-H., LESIEUR, D., HENICHART, J.-P. Tetrahedron (1991), 47, 6649-6654.

AICHAOUI, H., LESIEUR, D., HENICHART, J.-P. Journal of Heterocyclic Chemistry (1992), 29: 171-175.

BERGER, P.-J .; NEGUS, N.-C; SANDERS, E.-H .; GARDNER, P.-D. Science (1981), 214: 69-70.

BONTE, J.-P.; LESIEUR D.; LESPAGNOL, C.; CAZIN, J.-C. European Journal of Medicinal Chemistry (1974), 9: 491-496.

BRODIE, A.

Trends in Endocrinology and Metabolism (2002), 13: 61-65.

BUTTERSTEIN, G.-M .; SCHADLER,.-H. Biology of Reproduction (1988), 39: 465-471.

KUIJPERS, A.-L; VAN PELT, J.-P .; BERGERS, M .; BOEGHEIM, P.-J.; DEN BAKKER, J.-E.; SIEGENTHALER, G .; VAN DE KERKHOF, P.-C.; SCHALK IJK, J.

The British Journal of Dermatology (1998), 139: 380-389.

MOSMANN, T. Journal of Immunology Methods (1983), 65, 5-63.

MOUSSAVI, Z .; LESIEUR, D .; LESPAGNOL, O; SAUZIERES, J.; OLIVIER, P. European Journal of Medicinal Chemistry (1989), 24, 55-58.

PURBA, H.-S., Bhatnagar, A.-S.

Journal of Enzyme Inhibition (1990), 4, 169-178. SCHADLER, MH; BUTTERSTEIN, GM; FAULKNER, BJ; RICE, S. C; WEISINGER, THE

Biology of Reproduction (1988), 38: 817-820.

SERALINI, G. E .; MOSLEMI, S.

Molecular and Cellular Endocrinology (2001), 178: 117-131.

SASTRY, C.V .; REDDY, RAO, K.; SRINIVASA, RASTOGI, K .; JAIN, M. L. Indian Journal Chemistry Section B (1988) 27; 871 -873.

YOUS, S.; POUPAERT, J. H.; LESIEUR, I.; DEPREUX, P.; LESIEUR, D. Journal of Organic Chemistry (1994), 59. 1574-1576.

Claims

1. Use of a compound of formula (I) below:

(I) in which:

. Ri represents a hydrogen atom or an alkyl (CrC ₆ ), alkenyl radical

(d-Cβ), or alkynyl (C Cβ), linear or branched,

. X represents an oxygen, sulfur or selenium atom; . Y represents a single bond or a CH ₂ group, optionally substituted by one or two lower alkyl groups,

. Z represents a hydrogen or halogen atom, or a linear or branched hydroxy or alkoxy group,

. A represents an imidazole, triazole or tetrazole ring,. B represents a group chosen from phenyl, naphthyl, biphenyl or else a monocyclic or bicyclic heteroaryl group having from 5 to 10 members and comprising from 1 to 3 heteroatoms, the phenyl, naphthyl, biphenyl and heteroaryl groups being unsubstituted or substituted by 1 to 3 groups chosen from alkyl (Ci-Ce), alkoxy (Ci-Ce), carboxy, formyl, amino, amido, ester, nitro, cyano, trifluoromethyl, or halogen atoms, as well as the enantiomers and diastereoisomers of the compounds of formula (I), as well as the addition salts with a pharmaceutically acceptable acid or base of the compounds of formula (I), for the preparation of a pharmaceutical composition intended for the treatment of cancer or psoriasis.

2. Use according to claim 1, characterized in that, for the compound of formula (I), group B is chosen from: - a benzene which is unsubstituted or substituted in the meta or para position by a group chosen from cyano groups or nitro, by a chlorine atom; - a pyridine heterocycle.

3. Use according to one of claims 1 or 2, characterized in that, for the compound of formula (I), R1 represents a hydrogen atom or a methyl group.

4. Use according to one of claims 1 to 3, characterized in that, for the compound of formula (I), Z represents a hydrogen atom or a methoxy group.

5. Use according to one of claims 1 to 4, characterized in that, for the compound of formula (I), A represents a 1,3-imidazolyl or 1,2,4 triazolyl group.

6. Use according to claim 1, characterized in that the compound of formula (I) is chosen from the following compounds: - 5 - [(4-Cyanophenyl) (1 H-imidazol-1 -yl) methyl] -1 , 3-benzoxazol-2 (3H) -one;

- 6 - [(4-Cyanophenyl) (1H-imidazol-1-yl) methyl] -1, 3-benzothiazol-2 (3H) -one;

- 6 - [(4-Cyanophenyl) (1H-imidazol-1-yl) methyl] -3-methyl-1, 3-benzothiazol-2 (3H) -one;

- 6 - [(4-CyanophényI) (1 HA, 2,4-triazol-1-yl) methyl] -1, 3-benzothiazol-2 (3H) - one;

- 6 - [(4-Cyanophenyl) (1H-1, 2,4-triazol-1-yl) methyl] -3-methyl-1, 3-benzothiazol- 2 (3H) -one;

- 6 - [(4-Cyanophenyl) (1H-1,2,4-triazol-1-yl) methyl] -3-ethyl-1, 3-benzothiazol-2 (3H) -one; - 6 - [(4-Cyanophenyl) (1 H-imidazol-1 -yl) methyl] -1, 4-benzoxazin-3 (4 /) - one; 6 - [(4-Cyanophenyl) (1H-imidazol-1-yl) methyl] -4-methyl-1, 4-beπzoxazin- 3 (4H) -one; and

- 7 - [(4-Cyanophenyl) (1H-imidazol-1-yl) methyl] -4-methyl-1,4-benzothiazin-3 (4H) -one;

- 3-Ethyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzothiazol-2 (3H) -one;

- 4 - [(2-oxo-2,3-dihydro-1, 3-benzoselenazol-6-yl) (1 HA, 2,4-triazol-1 - yl) methyl] benzonitrile; - 4 - [(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoselenazol-6-yl) (1H-1,2,4-triazol-1-yl) methyl] benzonitrile;

- 4 - [(3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzoselenazoi-6-yl) (1 HA, 2,4-triazol-1 - yl) methyl] benzonitrile; - 3-Methyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzoselenazol-2 (3) -one;

- 3-Ethyl-6 - [(4-nitrophenyl) (1 HA, 2,4-triazol-1 -yl) methyl] -1, 3-benzoselenazol-2 (3H) -one; - 4 - [(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-5-yI) (1H-1,2,4-triazol-1-yl) methyl] benzonitrile; and

- 4 - [(3-Ethyl-2-oxo-2,3-dihydro-1, 3-benzothiazol-5-yl) (1 H-1, 2,4-triazol-1 - yl) methyl] benzonitrile

7. Aromatase inhibitor compound of formula (I), as defined in any one of claims 1 to 6, for its use as an active principle of a medicament.

8. As a new compound, a compound of formula (I) as defined in any one of claims 1 to 6.