HUT72299A - Novel selective aromatase inhibiting heterocyclic compounds, pharmaceutical compositions containing them and process for preparing them - Google Patents

Abstract

The present invention relates to novel compounds of formula (I) wherein R1 is hydrogen, CH3, OCH3, NO2, NH2, CN, CF3, CHF2, CH2F or halogen, R2 is a heterocyclic group which may be 1-imidazolyl, triazolyl, \ t tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, R3 is hydrogen or hydroxy, R4 is hydrogen, R5 is hydrogen or hydroxy; or R 4 is hydrogen and R 3 and R 5 together form a bond, or R 3 is hydrogen and R 4 and R 5 together represent an oxygen atom; R6 is methylene, ethylene, -CHOH, -CH2-CHOH, -CHOH-CH2, -CH = CH- or -C (= O) -; or R 4 is hydrogen and R 5 and together = CH or CH = CH 2, stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof.

Description

The present invention relates to novel compounds having selective aromatase inhibitory activity. The present invention relates to novel heterocyclic diarylalkyl compounds, their stereoisomers and their non-toxic pharmaceutically acceptable acid addition salts, processes for their preparation, pharmaceutical compositions containing them and their use.

The compounds of the invention may be represented by the general formula (I) wherein they are hydrogen, CH3, OCH3, NO2, NH2, CN, CF3,

CHF2, CH2F or halogen,

R ² is a heterocyclic group which may be 1-imidazolyl, triazolyl, preferably 1-1,2,4-triazolyl), tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl,

R ³ is hydrogen or hydroxy,

R ⁴ is hydrogen,

^R5 is hydrogen or hydroxy; obsession

R ⁴ is hydrogen and

R ³ and R ⁵ together form a bond, or

R ³ is hydrogen and

R ⁴ and r 5 together represent oxygen;

R ⁶ is methylene, ethylene, -CHOH, -CH 2 -CHOH, -CHOH-CH 2, -CH = CH- or -C (= O) -; obsession

R ⁴ is hydrogen and r 5 and R ⁶ together form = CH- or = CH-CH 2 -.

The invention also relates to stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof.

Compounds of Formula I and their Stereoisomers ···· · · · · · ·

They form 3 acid addition salts with both organic and inorganic acids. Thus, many pharmaceutically acceptable acid addition salts may be formed, for example, chlorine, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate and the like.

The present invention also relates to pharmaceutical compositions comprising one or more compounds of formula I, stereoisomers or non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier compatible with the compound.

EP-A-0390558. U.S. Pat. No. 4,800,015 discloses certain diphenyl substituted 4 (5) -imidazolyl derivatives as aromatase inhibitors. US 4978672. U.S. Pat. No. 4,800,011 discloses diphenyl-substituted 1-1,2,4 and 1-1,3,4-triazolyl derivatives wherein the carbon chain is preferably methyl, such as 2- [α- (4-chlorophenyl) phenyl]. 1- (1,2,4-triazolyl) methyl] -benzonitrile. U.S. Pat. No. 4,937,250 discloses diphenyl substituted 1-imidazolyl derivatives, U.S. Pat. The derivatives described in the aforementioned U.S. Patents are also disclosed as aromatase inhibitors.

The compounds of the present invention have selective aromatase inhibitory activity on their desmolase inhibitory properties.

- 4 relative to. These compounds are thus useful in the treatment of estrogen-dependent diseases such as breast cancer or benign prostatic hyperplasia (BPH). The selectivity of the compounds of formula (I) can be controlled by stereochemically isomerization.

The absolute stereochemical configuration of the compounds of formula (I) has not been experimentally determined. Conventionally, stereoisomers are designated by the letters a, b and so on without further reference to their absolute stereochemical configuration.

Stereoisomers of the compounds of formula (I) are, of course, within the scope of the invention.

Compounds of formula (I) may be prepared by reacting a halide of formula (II) wherein

Hal is halogen, preferably bromine or chlorine, n is 1 or 2,

R ¹ is as defined above,

R ⁷ is a CN group or other reactive group which can be converted to a cyano group by reaction with a heterocyclic compound of formula R ^2, H wherein

R ² 'is 1-imidazolyl, 1-1,2,4-, 4-1,2,4-, 1-1,2,3- or

2-1,2,3-triazolyl or 1- or 2-tetrazolyl in a suitable solvent and the resulting compound of formula (III) is recovered.

The heterocyclic compound is preferably in the form of a salt, preferably the sodium salt.

may be prepared conventionally from optionally substituted benzaldehyde and a suitable benzene derivative.

The corresponding compound of formula (III) wherein R ² 'is 4-1,2,3- or 3-1,2,4-triazolyl or 5-tetrazolyl may be prepared by the above procedure in the presence of a strong base such as alkyl lithium. in the presence of a suitable protecting group on the nitrogen atom of the starting heterocyclic compound.

The compounds of formula (I) may also be prepared by reacting a compound of formula (IV) wherein R ² and R ⁷ are as defined above and R ^{2 is} optionally protected on a nitrogen atom in a known manner with an appropriate halide of formula (V) wherein Hal is halogen, preferably bromine or chlorine, n is 1 or 2 and R ¹ is as defined above. The reaction is carried out in the presence of a strong base such as alkyl lithium, preferably n-butyllithium, to give compounds of formula III wherein R ² 'has the same meaning as R ² . Such compounds are referred to as (III ').

Alternatively, a compound (IV) is reacted with a (VI) with an aldehyde of formula wherein n and R ¹ are carried out as above, the reaction of a strong base such as alkyl lithium, preferably n-butyl lithium in the presence of to give a compound of formula VII, which can then be dehydrated in a known manner, for example by refluxing in the presence of SOCl2, POCl3 or PCl5, optionally in a suitable solvent such as acetonitrile. This gives the compound of formula (VIII), which may optionally be hydrogenated catalytically to give the corresponding saturated compound.

The compound of formula (I) may also be prepared by reacting a compound of formula (IV) wherein R ² and R ⁷ are as defined above with a suitable ester of formula (IX) wherein R 'is lower alkyl, preferably methyl or an ethyl group in the presence of a strong base such as alkyl lithium, preferably n-butyllithium, to give a compound of formula X which can be further reduced by a known procedure such as sodium borohydride to give the corresponding alcohol of formula VII .

The compounds of formula (I) may also be prepared by reacting a heterocyclic compound of formula R ^2, H wherein R ² 'is as defined above, with a ketone of formula XI in the presence of thionyl chloride to form a compound of formula VIII. wherein R ² is R ²¹ . Such a compound is designated (VIII ¹ ). The starting compound of formula XI can be prepared in a known manner from an optionally substituted benzaldehyde and a suitable benzene derivative.

The compound of formula (I) may also be prepared by reacting a ketone of formula (XII) wherein R ¹ and R ⁷ are as defined above and n 'is 0 or 1 with a heterocyclic compound of formula R ² Ή, wherein R ² 'has the meaning given above. The reaction is known from J. Am. Chem. Soc., Vol. 77 (1955), p. 2572 and Vol. 76 (494) 4933. The reaction provides ketones of formula (XIII) wherein R ² 'is as defined above, which ketones **

7 can be further reduced to give compounds of formula (XIV) which, if desired, are dehydrated to give unsaturated compounds of formula (I).

A further process for the preparation of compounds of formula I is by reacting a compound of formula IV with formamide in the presence of a strong base such as n-butyllithium to give compounds of formula XV. The compounds of formula (XV) are subjected to a condensation reaction of the appropriate acetophenone with aldol to give unsaturated ketones which are further reduced to give the alcohols of formula (I).

Compounds of formula (VIII) may also be prepared by reacting a ketone of formula (XVI) wherein R ² and R ⁷ are as defined above and optionally protecting R ² with a ketone of formula (XVII) or (XVIII). with a compound wherein R 'is lower alkyl, n is 1 or 2, and R ¹ is as defined above. The reaction is carried out in an inert solvent such as tetrahydrofuran according to WO 92/10482. U.S. Patent No. 4,400,198.

Compounds of formula (I) wherein R ³ is hydroxy are prepared by reacting a compound of formula (XIX) wherein R ² 'is 4-1,2,3- or

3- 1,2,4-triazolyl, 5-tetrazolyl, 3- or 4-pyrazolyl, 2-,

4- or 5-pyrimidinyl, 2-, 4- or 5-oxazolyl, 2-, 4- or

5-thiazolyl, 3-, 4- or 5-isoxazolyl or 3-, 4- or 5-isothiazolyl, and Y is hydrogen or a protecting group, is reacted with a compound of formula XI

·. * · ... «• ·. . . 'J. ·. ··· ·· «.

·· * .. · ····

In the presence of 8 bases such as alkyl lithium such as n-butyllithium, the resulting compound of formula XX is optionally dehydrated and hydrogenated.

Compounds of formula (XX) may also be prepared by reacting a ketone of formula (XVI) with a halide of formula (V). The reaction is carried out in a suitable solvent such as tetrahydrofuran in the presence of an alkyl lithium such as n-butyllithium or magnesium.

Compounds of formula (XIV) wherein R ² * is R ² can be prepared by reacting an epoxy derivative of general formula (XXI) wherein R ¹ is as defined above and n ¹ is 0 or 1 with a compound of formula (IV). compound in the presence of a strong base.

Exemplary of R ⁷ which can be converted to a cyano group include nitro, amino, halogen, preferably bromine, formyl or carboxylic acid amide.

Compounds of formula (III), (VII), (VIII), (X), (XIII), (XIV), (XV) and (XX) wherein R ⁷ is nitro can be converted to formula (I). to hydrogenate the compounds and then diazotize the amino group.

Compounds of formula (III), (VII), (VIII), (X), (XIII), (XIV), (XV) and (XX) wherein R ⁷ is a halogen atom, a cyanide salt such as sodium or potassium cyanide to form a compound of formula (I).

Compounds of formula (III), (VII), (VIII), (X), (XIII), (XIV), (XV) and (XX) wherein R ⁷ is

···· ··· «* · * ·» · • · * n t »« ♦ · · ·. · "··· 9" formyl, can be converted to the compound of formula I by methods known in the art.

The compounds of formulas (III), (VII), (VIII), (X), (XIII), (XIV), (XV) and (XX) wherein R ⁷ is a carboxylic acid amide group may be The compounds of formula I are refluxed in the presence of, for example, SOCl2 or PCl5.

When reactive groups, such as NH 2, CN or cyclic NH, are present in the starting compounds or intermediates which are converted to the compounds of the invention by the reactions described above, these reactive groups are protected by methods known in the art to protect non-reactive groups. protected from desired reactions. The nitrogen atom in the heterocyclic ring is preferably protected with a tri- (lower alkyl) silyl group such as trimethylsilyl.

Stereoisomers of the compounds of formula (I) may be prepared by separation techniques known in the art, such as selective crystallization or chromatographic techniques, such as column chromatography or high performance liquid chromatography.

The compounds of formula (I) and their non-toxic pharmaceutically acceptable acid addition salts and mixtures thereof may be administered parenterally, intravenously or orally. Generally, an effective amount of the compound is used in conjunction with a suitable pharmaceutical carrier. As used herein, the term "effective amount" means an amount that provides the desired effect by causing adverse side effects.

- Without 10. The exact amount to be used in a given situation will depend on many factors, such as the mode of administration, the type of mammal, the condition being treated, and of course the structure of the compound.

The pharmaceutical carriers commonly used with the compounds of the invention may be solid or liquid and will generally be selected according to the intended route of administration. For example, solid carriers include lactose, sucrose, gelatin and agar, and liquid carriers include water, syrups, peanut oil, olive oil. Other combinations of the compound and the carrier may also be formulated in a variety of acceptable forms, for example, as tablets, capsules, suppositories, solutions, emulsions or powders.

The compound of the present invention is particularly effective as an aromatase inhibitor and is therefore useful in the treatment of estrogen dependent diseases such as breast cancer or benign prostatic hyperplasia (BPH).

Estrogens are essential steroids in physiology and play an important role in the proper functioning of the breasts and genitals in women. On the other hand, estrogens are known to stimulate the growth of estrogen-dependent cancers, particularly breast and endrometric cancers, and may increase the risk of developing breast cancer when administered at pharmacological doses for prolonged periods. Excessive estradiol production can also cause other benign lesions in hormone-dependent organs. The importance of estrogens as cancer growth stimulators and / or regulators is clearly expressed in the fact that antiestrogens play a central role in the treatment of estrogen receptor rich breast cancers. Antiestrogens act by binding to estrogen receptors and thereby inhibiting the biological action of estrogens. This was clinically achieved with the non-specific steroid synthesis inhibitor, aminoglutethimide. Estrogen synthesis can be specifically blocked by inhibition of the aromatase enzyme, a key enzyme in the biochemical estrogen synthesis pathway. Inhibition of aromatase is extremely important because some breast tumors synthesize estradiol and estrone in situ and thereby continuously stimulate growth (see Alan Lipton et al., Cancer 59: 770-782, 1987).

The compounds of the invention were assayed for aromatase inhibitory activity in vitro by the assay described by M. Pasanen (Biological Research in Pregnancy, Vol. 6, No. 2, 1985, pp. 94-99). Human aromatase enzyme was used. The enzyme was prepared from a human placenta rich in the enzyme. A microsomal fraction (100,000 xg precipitate) was prepared by centrifugation. The enzyme preparation was used without further purification. The test compounds in Table 1 were co-administered with 100,000 dpm of 1,2 [ ³ H] -androstene-3,17-dione and the NADPH generating system. The concentrations of the test compounds were 0.001, 0.01, 0.1 and 1.0 mmol. Incubation was carried out at 37 ° C for 40 minutes. The aromatization of 1,2 [ ³ H] -androstene-3,17-dione results in formation of ³ × 2 <3. The tritium-labeled water and the tritium-labeled substrate can be easily separated on a Sep-Pak mini-column that absorbs the steroid but does not bind the aqueous eluent. THE * · ·· ······ · •· · · · ·· · ·"

- 12 radioactivity was measured with a liquid scintillation counter. The aromatase inhibition was determined by comparing the ³ H ₂ O radioactivity of the inhibitor-treated samples to that of the comparator containing no inhibitor. IC 50 values are calculated which are the concentrations that inhibit the activity of the enzyme by 50%. These concentrations are shown in Table 2.

Cholesterol side chain cleavage (SCC) activity (desmolase) was determined according to the procedure described by Pasanen and Pelkonen, Steroids 43: 517-527, 1984. Incubation was carried out in a 1.5 ml Eppendorf plastic test tube using an Eppendorf shaker funnel, centrifuge and incubator. In a 300 µl incubation volume, the substrate (5 pmol) was prepared according to Hanoguelu and Jefcoate, J. Chromatogr. 190: 256-262, 1980, 100000 dpm of radioactive ³ H-4-cholesterol (purified by TLC), 0.5% Tween 20, 10 mmol MgCl ₂ were added. pmol cyanoketone and 2 mM NADPH. Comparative samples contained all of these materials, but the enzyme preparation was inactivated by addition of 900 µL of methanol prior to incubation. The mitochondrial fraction (1 mg protein) from the human placenta or bovine adrenal gland was used as the enzyme source. After incubation for 30 minutes at 37 ° C, the reaction was quenched by the addition of 900 µL of methanol. For each incubation 1500 dpm ¹⁴ C-

4-pregnenolone is added as a marker and vials are vigorously shaken. After equilibration for 10 minutes, the methanol precipitated protein was separated by centrifugation (8,000 x g for 2 minutes).

The supernatant was aspirated into a 1 ml plastic injection syringe and transferred to a minicolumn pre-equilibrated with 75% methanol. The column was washed with 1 mL of 75% methanol followed by 3 mL of 80% methanol. The 80% methanol eluate was transferred to the counter vial and 10 mL of scintillation fluid was added. Radioactivity was measured using a dual labeled program using a liquid scintillation counter (LKB RackBeta). Typical activity of the placental or bovine adrenal enzyme preparation is 0.5-3 and 50-100 pmol pregnenolone / mg protein / min.

In inhibition assays, the substance (final concentration range 1-1000 μπιόΐ) was usually added to the incubation mixture in the form of a solution of methanol or ethanol in a volume of 10-2 0 μΐ. An equal volume of solvent was added to the comparative incubation vial. IC 50 values (concentration that results in 50% inhibition) are plotted and shown in Table 2.

• ··· ····· * · · · · · · · · · · · · · · · · · · · · · · ·

Song Table 1 Test compounds Name First l- [l- (4-cyanophenyl) -4- (4-fluorophenyl) butyl] - -1H-imidazole Second 1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl] -1H-imidazole a + d diastereomer Third 1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -1-butenyl] -1,2,4-triazole, Isomer b 4th 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -2- -Hydroxypropyl] -1,2,4-triazole a + d diastereomer 5th 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2- -Hydroxybutyl] -1,2,4-triazole a + d diastereomer 6th 1- [3-hydroxypropyl-1- (4-cyanophenyl) -3- (4-fluoro) phenyl] -1,2,4-triazole 7th 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-oxobutyl] -1,2,4-triazole 8th 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] -1,2,4-triazole, Isomer b 9th 5- [l- (4-cyanophenyl) -3- (4-fluorophenyl) -1-hydroxypropyl] thiazole

• · · · · · · · · · · · · · · · · · · · · · · ·

- 15 Table 2

Inhibition of human aromatase and desmolase by test compounds. IC5Q is the concentration that inhibits the enzyme by 50%.

Compound- aromatase Demoláz song IC50 IC50 gmol / L gmol / L First 0.042 17.0 Second 0,180 49.0 3. 0,140 300 4th 0.260 > 1000 5th 0,950 > 1000 6th 0,300 380 7th 0,900 172 8th 0,052 165 9th 0.280 300

Generally, the daily dose administered to the patient will be about. 10-200 mg orally.

Acute toxicity of 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole a + d diastereomer, LD5Q in young NMRI strain female mice. The test compound was administered orally. The highest dose tested was 400 mg / kg, well tolerated by the animals. No adverse effects were observed.

The invention will now be illustrated by the following examples.

The 1 H-NMR spectrum is determined by a Bruker AC-300 P • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 16 needles. The reference material was tetramethylsilane.

Example 1

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) butyl] -1H-imidazole g (0.0054 mol) of 1- (4-cyanobenzyl) imidazole was dissolved in anh. tetrahydrofuran and the solution was cooled to -70 ° C. To the reaction mixture was added dropwise a solution of 0.0054 mol of n-BuLi in hexane. After stirring for 30 minutes at -70 ° C, a solution of 1.5 g (0.0069 mol) of 3- (4-fluorophenyl) propyl bromide in 10 ml of tetrahydrofuran is added and stirring is continued for 2 hours. The reaction mixture was then allowed to warm to room temperature. Saturated aqueous ammonium chloride solution was added, the mixture was shaken and the phases were separated. The tetrahydrofuran phase was dried and evaporated to dryness. The residue is crystallized from isopropanol as the hydrochloride salt. The filtrate was purified by flash chromatography.

¹ H-NMR (HCl salt, MeOH-d ₄ ):

1.5-1.63 (quintet, 2H), 2.3-2.5 (m, 2H), 2.7 (t, 2H),

5.75 (t, 1H), 6.94-7.00 (m, 2H), 7.14-7.19 (m, 2H), 7.62 (d, 2H), 7.63 (s, 1H), 7.78 (s, 1H), 7.8 (d, 2H), 9.6 (s, 1H).

Example 2

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) butyl] -1,2,4-triazole

The compound was prepared according to the procedure described in Example 1 (6.0 g, 0.0272 mole) of 1- (4-cyanobenzyl) -1,2,4-triazole. 0.0272 moles of n-BuLi and 7.6 g (0.035 moles) of 3- (4-fluorophenyl) propyl bromide. The product is purified by first slurrying the residue in a mixture of 2M aqueous hydrochloric acid and petroleum ether. The petroleum ether phase is separated off, the aqueous phase and the separated oil are extracted with diethyl ether. The diethyl ether phase was evaporated and the residue was purified by flash chromatography.

¹ H-NMR (HCl salt, CDCl ₃ ):

1,4- -1.65 (M, 2 H) , 2.2-2.4 (m, 1H), 2.45-2, , 6 (m, 1H), 2.67 (t, 2H), 6.12 (T, 1H), 6.94 (t, 2H), 7.06-7.10 (m, 2H), 7.67 (d, 2H), 7.73 (D, 2 H) , 8.43 (s, 1H), 11.31 (s, 1H).

Example 3 1- [1- (4-Cyanophenyl) -4-phenyl) -1-butenyl] -1,2,4-triazole

a) 1- [1- (4-Cyanophenyl) -2-hydroxy-4-phenylbutyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -2-hydroxy-4-phenylbutyl] -1,2,4-triazole is prepared according to the procedure of Example 1, 2.0 g (0.0108 mol) of (4-cyanobenzyl) -1,2,4-triazole, 0.0108 mol of n-BuLi and 1.74 g (0.013 mol) of 3-phenylpropionaldehyde. The product was purified by flash chromatography.

¹ H-NMR (base, CDCl 3):

1.5-1.75 (m, 2H), 2.6-2.75 (m, 1H), 2.8-2.95 (m, 1H),

4.3-4.5 (m, 1H), 5.25-5.27 (m, 1H), 7.0-7.35 (m, 5H), 7.39 and 7.51 (d, 2H) ), 7.60 (d, 2H), 7.89 and 7.91 (s, 1H), 8.08 and 8.13 (s, 1H).

The following compounds of the present invention were prepared by a similar process:

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl] -1,2,4-triazole a + d and b + c diastereomers ^{X 1} H-NMR base, CDCl ₃ ):

diastereomer a + d:

1.5-1.7 (m, 2H), 2.6-2.73 (m, 1H), 2.8-2.9 (m, 1H), 4.4-.

4.5 (m, 1H), 5.23 (d, 1H), 6.96 (t, 2H), 7.11 (dd, 2H), 7.48 (d, 2H), 7.66 (d) , 2H), 8.05 (s, 1H), 8.08 (s, 1H).

diastereomer b + c:

1.5-1.7 (m, 2H), 2.63-2.73 (m, 1H), 2.8-2.9 (m, 1H), 4.3-.

4.4 (m, 1H), 5.26 (d, 1H), 6.95 (t, 2H), 7.05 (dd, 2H), 7.38 (d, 2H), 7.65 (d) , 2H), 8.07 (s, 1H), 8.12 (s, 1H).

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl] -1H-imidazole a + d and b + c diastereomers a + d diastereomer:

¹ H-NMR (base, CDCl 3):

1.6-1.8 (m, 2H), 2.6-2.75 (m, 1H), 2.81-2.9 (m, 1H),

4.24-4.3 (m, 1H), 5.04 (d, 1H), 6.9-7.0 (m, 4H), 7.08-7.12 (m,

2H), 7.49 (d, 2H), 7.57 (s, 1H), 7.67 (d, 2H), b + c diastereomer:

¹ H-NMR (base, CDCl 3 + MeOH-d ₄ ):

1.6-1.8 (m, 2H), 2.6-2.73 (m, 1H), 2.8-2.89 (m, 1H),

4.21-4.27 (m, 1H), 5.09 (d, 1H), 6.93-7.11 (m, 6H), 7.3 (d, 2H), 7.64 (d, 2H), 7.69 (s, 1H).

b) 1- [1- (4-Cyanophenyl) -4-phenyl-1-butenyl] -1,2,4-triazole

0.42 g (0.00132 mol) of 1- [1- (4-cyanophenyl) -2-hydroxy-44 · · · · · · · · · · · · N-Phenylbutyl] -1,2,4-triazole is dissolved in acetonitrile. To the solution was added phosphorus pentachloride (0.27 g, 0.0013 mol) and the mixture was refluxed for 2 hours.

The acetonitrile was evaporated and the residue was dissolved in 2M sodium hydroxide solution and extracted with methylene chloride.

The methylene chloride phase was dried and the product crystallized from ethyl acetate as the hydrochloride salt (the isomer).

¹ H-NMR (HCl salt, MeOH-d ₄ ):

2.40 (q, 2H), 2.58 (t, 2H), 6.82 (t, 1H), 6.84-7.28 (m,

5H), 7.32 (d, 2H), 7.72 (d, 2H), 8.58 (s, 1H), 8.65 (s, 1H).

The following compounds of the invention were prepared by the same procedure:

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -1-butenyl] -1,2,4-triazole a and b isomer ^{X 1} H-NMR (HCl salt, MeOH) d ₄ ):

isomer: 2.42 (q, 2H), 2.85 (t, 2H), 6.85 (t, 1H), 7.0 (t, 2H), 7.16-7.21 (m, 2H) ), 7.37 (d, 2H), 7.74 (d, 2H), 8.82 (S, 1H), 9.38 (s, 1H);

Isomer b: 2.53 (q, 2H), 2.83 (t, 2H), 6.63 (t, 1H), 6.98 (t, 2H), 7.12-7.17 (m, 2H) ), 7.33 (d, 2H), 7.80 (d, 2H), 8.62 (s, 1H), 9.33 (s, 1H).

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -1-butenyl] -1H-imidazole a and b isomers:

¹ H-NMR (base, CDCl ₃ ):

• ··· «·

2.4 (q, 2H), 2.77 (t, 2H), 6.33 (t, 1H), 6.69 (s, 1H), 7.0 (t, 2H), 7.05-7 , 1 (m, 2H), 7.15 (d, 2H), 7.19 (s, 1H), 7.3 (s, 1H), 7.6 (d, 2H).

Isomer b: 1 H-NMR (HCl salt, CDCl 3):

2.56 (q, 2H), 2.87 (t, 2H), 6.55 (t, 1H), 6.89 (s, 1H), 7.0 (t, 2H), 7.11 (dd) , 2H), 7.19 (d, 2H), 7.44 (s, 1H), 7.72 (d, 2H), 9.64 (s, 1H).

Example 4

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] -1,2,4-triazole

a) 1- (4-Cyanophenyl) -3- (4-fluorophenyl) prop-2-en-1-one

14.5 g (0.1 mol) of 4-acetylbenzonitrile and 12.1 g (0.1 mol) of 4-fluorobenzaldehyde are dissolved in 150 ml of methanol and the solution is made basic with solid sodium hydroxide. After stirring at room temperature for 6 hours, the product was filtered off and washed with methanol.

¹ H-NMR (CDCl 3):

7.14 (t, 2H), 7.40 (d, 1H), 7.66 (dd, 2H), 7.81 (d, 1H),

7.82 (d, 2H), 8.09 (d, 2H)

b) 1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propanone

1- (4-Cyanophenyl) -3- (4-fluorophenyl) prop-2-en-1-one is hydrogenated in ethanol in the presence of 5% Pd-C catalyst.

¹ H-NMR (CDCl 3):

3.05 (t, 2H), 3.29 (t, 2H), 6.98 (t, 2H), 7.20 (dd, 2H),

7.76 (d, 2H), 8.02 (d, 2H)

c) 1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propanol

1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propanone (6.35 g, 25 mmol) was dissolved in methanol (50 mL). Sodium borohydride (0.48 g, 12.6 mmol) was added and the mixture was stirred at 30 ° C for one hour. The reaction mixture was acidified with 2M hydrochloric acid and the solvent was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with dilute sodium hydroxide and water, dried and the solvent was distilled off. The product was used in the next step without purification.

1 H-NMR (CDCl ₃ ):

1.94-2.10 (m, 2H), 2.66-2.74 (m, 2H), 4.74 (dd, 1H), 6.97 (t, 2H), 7.13 (dd, 2H), 7.45 (d, 2H), 7.64 (d, 2H).

d) 1-Chloro-1- (4-cyanophenyl) -3- (4-fluorophenyl) propane

1.43 g (13 mmol) of 1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propanol are dissolved in 20 ml of dichloromethane. Thionyl chloride (1.2 mL, 16 mmol) was added dropwise while the solution was cooled and stirred at room temperature for 2 hours. The reaction mixture was washed with water, dried and the solvent was evaporated. The residue was used for the next step without purification.

1 H-NMR (CDCl 3):

2.20-2.44 (m, 2H), 2.66-2.83 (m, 2H), 4.77 (dd, 1H), 6.99 (t, 2H), 7.13 (dd, 2H), 7.46 (d, 2H), 7.65 (d, 2H)

e) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] -1,2,4-triazole

4.18 g (15 mmol) of 1-chloro-1- (4-cyanophenyl) -3- (4-fluorophenyl) propane and 1.37 g (15 mmol) of 1,2,4-triazole The mixture of sodium derivative in 30 ml of dimethylformamide was heated gently for 4 hours. The residue was dissolved in ethyl acetate and washed with water. The organic phase is dried and the solvent is distilled off. The product was purified by flash chromatography (Silica gel 60, 230-400 mesh, eluent: methylene chloride / methanol 99: 1 by volume).

¹ H-NMR (HCl salt, MeOH-d ₄ ):

2.55-2.65 (m, 3H), 2.78-2.84 (m, 1H), 5.83 (dd, 1H), 7.00 (t, 2H), 1.17 (dd, 2H), 7.68 (d, 2H), 6.78 (d, 2H), 8.75 (s, 1H), 9.69 (s, 1H).

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] -1H-imidazole is prepared according to the same procedure as 1-chloro-1- (4-cyanophenyl) -3- (4-fluorophenyl) propane and 1H-imidazole sodium.

1 H-NMR (HCl salt, MeOH-d ₄ ):

2.59-2.80 (m, 4H), 5.72 (m, 1H), 7.00 (t, 2H), 7.19 (dd, 2H), 7.63 (d, 2H), 7 , 67 (s, 1H), 7.81 (d, 2H), 7.84 (s, 1H),

9.23 (s, 1H).

Example 5

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] -lH-imidazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] -1H-imidazole was prepared according to the procedure of Example 1 using 4-fluorophenethyl bromide as the alkylating agent. The product was purified by flash chromatography.

1 H-NMR (HCl salt, MeOH-d ₄ ):

2.59-2.80 (m, 4H), 5.72 (m, 1H), 7.00 (t, 2H), 7.19 (dd, 2H), 7.63 (d, 2H), 7 , 67 (s, 1H), 7.81 (d, 2H), 7.84 (s, 1H),

9.23 (s, 1H).

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] -1,2,4-triazole is prepared according to the same procedure, starting from 1- (4-cyanophenyl) -1,2,4-triazole and 4-fluorophenethyl bromide are used. The product was purified by flash chromatography.

Example 6

1- [1- (4-cyanophenyl) -3- (4-fluoro-phenyl) propenyl] -1H-imidazole

a) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1H-imidazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1H-imidazole was prepared according to the procedure of Example 1, starting from 1- (4-cyanophenyl) starting material. benzyl) imidazole and 4-fluorophenylacetaldehyde are used. The product was purified by flash chromatography.

1 H-NMR (HCl salt, MeOH-d ₄ ):

2.57-2.70 (m, 1H), 2.75-2.82 (m, 1H), 4.62-4.68 (m, 1H),

5.64-5.66 (m, 1H), 6.97-7.05 (m, 2H), 7.17-7.24 (m, 2H), 7.547.85 (m, 6H), 9, 16 and 9.21 (2s and 1H).

- 24 b) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propenyl] -1H-imidazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1H-imidazole is dehydrated according to the procedure described in Example 3 (b). The product is a 1: 1 mixture of E and Z isomers. The product was purified by flash chromatography.

1 H-NMR (base, CDCl ₃ ):

3.42 and 3.52 (2d, together 2H), 6.16 and 6.50 (2t and 1H), 6.91-7.12 (m, 6H), 7.26 and 7.42 (2d and 2H), 7.55 and 7.59 (2s and 1H), 7.62 and 7.75 (2d and 2H).

Example 7

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -l-propenyl] -lH-imidazole

Imidazole (0.55 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran. The solution was cooled in an ice bath and treated dropwise with 0.16 mL (2 mmol) of SOC12 ^_ t. After stirring for 10 minutes, 1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propanone (0.34 g, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 days. Methylene chloride was added and the mixture was washed with water. The organic phase is dried and the solvent is evaporated. The residue contained 35% product (1 H-NMR) in the form of a 9: 1 mixture of isomers. The product was purified by flash chromatography eluting with a 99: 1 mixture of methylene chloride / methanol.

Isomer b:

¹ H-NMR (HCl salt, MeOH-d ₄ ):

3.62 (d, 2H), 6.65 (t, 1H), 7.05 (t, 2H), 7.26 (dd, 2H),

7.63 (d, 2H), 7.66 (s, 1H), 7.69 (s, 1H), 7.69 (s, 1H), 7.91 (d, 2H), 9.16 (s) , 1H).

Example 8

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -2-propenyl] -1,2,4-triazole

a) 3- (4-Cyanophenyl) -1- (4-fluorophenyl) prop-2-en-1-one

3- (4-Cyanophenyl) -1- (4-fluorophenyl) prop-2-en-1-one was prepared according to the procedure described in Example 4 (a), starting from 4-cyanobenzaldehyde and 4-cyanobenzaldehyde. fluroacetophenone is used.

1 H-NMR (CDCl ₃ ):

7.21 (t, 2H), 7.59 (d, 1H), 7.73 (s, 4H), 7.79 (d, 1H), 8.08 (dd, 2H)

b) 3- (4-Cyanophenyl) -1- (4-fluorophenyl) -3- (1-triazolyl) propanone

2.5 g (10 mmol) of 3- (4-cyanophenyl) -1- (4-fluorophenyl) prop-2-en-1-one, 0.7 g (10 mmol) of 1,2,4- Triazole and 1 drop of Triton B are heated to dissolution. The reaction mixture was cooled, diluted with diethyl ether and the resulting product was filtered. The product was used in the next step without purification.

¹ H-NMR (CDCl 3):

3.61 (dd, 1H), 4.37 (dd, 1H), 6.25 (dd, 1H), 7.15 (t,

2H), 7.55 (d, 2H), 7.68 (d, 2H), 7.95 (s, 1H), 7.99 (m, 2H),

8.23 (S, 1H) • ·

- 26c) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -3-hydroxypropyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -3-hydroxypropyl] -1,2,4-triazole is prepared as described in Example 4, Step c). (4-cyanophenyl) -1- (4-fluorophenyl) -3- (1-triazolyl) -propanonból. The product was purified by flash chromatography as a diastereomeric mixture (a + d, b + c, 2: 1).

1 H-NMR (base, CDCl ₃ ):

2.27-2.37 and 2.54-2.63 (2m and 1H), 2.76-2.88 (m, 1H), 4.26 and 4.41 (2dd and 1H), 5.62 and 5.91 (2dd and 1H), 7.03 and 7.04 (2t and 2H), 7.22-7.31 (m, 2H), 7.50 and 7.55 (2d and 2H),

7.65 and 7.69 (2d and 2H), 7.94 and 8.04 (2s and 1H), 8.05 and 8.22 (2s and 1H).

The diastereomeric mixture was triturated with diethyl ether and filtered. Diastereomer a + d is enriched in insoluble material (> 90%) and diastereomer b + c in the filtrate (> 80%). Both diastereomers are further purified by recrystallization from toluene.

¹ H-NMR (HCl salt, MeOH-d ₄ ):

diastereomer a + d:

2.67 (ddd, 1H), 2.84 (dd, 1H), 4.54 (dd, 1H), 6.13 (dd,

1H), 7.04 (t, 2H), 7.33 (dd, 2H), 7 77 (D, 2H), 7.81 (d, 2 H) , 8.79 (s, 1H), 9.86 (s, 1H); diastereomer b + c: 2.43 (ddd, 1H), 2.94 (ddd, 1H), 4, 33 (dd, 1H), 6.14 (Dd, 1H), 7.05 (t, 2H), 7.34 (dd, 2H), 7 66 (D, 2H), 7.75 (d, 2 H) , 8.69 (s, 1H), 9.62 (s, 1H).

d) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-propenyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -3-hydroxypropyl] -1,2,4-triazole (100 mg) was heated in an oil bath at 400 ° C with 400 mg of potassium bisulfate. At C for 2 hours. Methanol was added to the reaction mixture and the inorganic material was filtered off. The methanol was evaporated to give the product as a mixture of cis and trans isomers.

1 H-NMR (base, CDCl ₃ ): vinyl protons of the cis isomer, 6.22 (m, 1H), 6.56 (m) 6.47 (D) and 6.81 (dd) the trans isomer vinyl protons, 6.09 and 7.12 (2t and 2 H) , 7.29-7.34 (M, 2H), 7, 36 and 7.49 (2d and 2H), 7.69 and 8 02 (2d and 2H), 8, 03 and 8.02 (2s and 1H), 8.26 and 8.12 (2s and 1H).

Example 9

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] -1,2,4-triazole

a) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole was prepared according to the procedure of Example 2, starting from 1- (4-Cyanophenyl) -1,2,4-triazole and 4-fluorophenylacetaldehyde are used. The diastereomers of the product were separated by flash chromatography (ethyl acetate / methanol 95: 5 by volume).

• ·· · ····

- 28 ^{X 1} H-NMR (HCl salt, MeOH-d ₄ ): a + d diastereomer:

2.62 (dd, 1H), 2.72 (dd, 1H), , 4.73 (Ddd, 1H), 5, , 73 (d, 1H), 7.00 (t, 2H), 7.19 (dd, 2 H) , 7.80 (s, 4H) , 8.75 (s, 1H), 9.67 (s, 1H); diastereomer b + c: 2.66-2.70 (m, 2H), 4.67 (Dt, 1H), 5.70 (d , 1H), 6.98 (t, 2 H) , 7.15 (dd, 2H), 7.80 (m, 4H), 8.78 (s, 1H) , 9.78 (s, 1H).

b) 1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] -1,2,4-triazole is prepared according to the procedure of Example 3, step b) using 1- [ from the b + c diastereomer of 1- (4-cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole. The procedure mainly yields the isomer. The products are purified by flash chromatography.

¹ H-NMR (HCl salt of the isomer, MeOH-d 4):

3.47 (d, 2H), 6.97 (t, 1H), 7.04 (t, 2H), 7.26 (dd, 2H),

7.43 (d, 2H), 7.75 (d, 2H), 8.86 (s, 1H), 9.71 (s, 1H).

¹ H-NMR (HCl salt of ab isomer, MeOH-d 4):

3.58 (d, 2H), 6.79 (t, 1H), 7.04 (t, 2H), 7.23 (dd, 2H),

7.62 (d, 2H), 7.90 (d, 2H), 8.62 (s, 1H), 9.39 (s, 1H).

Example 10

1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-oxobutyl] -1,2,4-triazole

1- [1- (4-Cyanophenyl) -4- (4-fluorophenyl) -2-oxo-butyl] 29 · · · · · ··· ······································································ ··· · · ♦ * ·· · ··

-1,2,4-Triazole was prepared according to the procedure of Example 1

1.7 g (0.0092 mol) of 1- (4-cyanobenzyl) -1,2,4-triazole, 0.0108 mol of n-BuLi and 2.3 g (0.0117 mol) of ethyl 3- (4-fluorophenyl) propionate, prepared from 4-fluorocinnamic acid by esterification and hydrogenation. The product was purified by flash chromatography. The eluent was 95: 5 methylene chloride / methanol.

¹ H-NMR (base, CDCl ₃ ):

2.65-2.95 (m, 4H), 6.15 (s, 1H), 6.93 (t, 2H), 7.04 (dd, 2H), 7.37 (d, 2H), 7 , 67 (d, 2H), 7.97 (s, 1H), 8.18 (s, 1H).

II. example

2- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole and

1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole

0.45 g of NaH (as a suspension in 55% mineral oil) was added to anhydrous dimethylformamide under a nitrogen atmosphere. To the mixture was added tetrazole (1.1 g) and heated gently for 20 minutes. The reaction mixture was cooled to room temperature and 1.53 g of 1-chloro-1- (4-cyanophenyl) -3- (4-fluorophenyl) propane was added. After stirring for 6 hours, water was added and the product was extracted into ethyl acetate. After drying and evaporation of the solvent, the products obtained are purified by flash chromatography. Elution was started with pure methylene chloride and continued with increasing volumes of methanol. First, 2- (1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] -tetrazole is obtained with a ¹ H-NMR spectrum as follows:

···· ················································•

- 30 - * - 1 H-NMR (base, CDCl 3):

2.47-2.61 (m, 3H), 2.88-3.01 (m, 1H), 5.93 (dd, 1H), 6.96-7.10 (m, 4H), 7, 51 (d, 2H), 7.67 (d, 2H), 8.57 (s, 1H).

Further elution gave 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole, which had a Th-NMR spectrum as follows:

1 H-NMR (base, CDCl 3):

2.50-2.65 (m, 3H), 2.86-2.93 (m, 1H), 5.54 (dd, 1H), 6.98-7.26 (m, 4H), 7, 44 (d, 2H), 7.71 (d, 2H), 8.54 (s, 1H).

Example 12

5- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] thiazole

a) 5- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-hydroxypropyl] thiazole

5.66 g (10 mmol) of 5-bromothiazole are dissolved in diethyl ether. 4.85 ml (2.5 moles) of n-butyllithium are added very slowly at -60 ° C under a nitrogen atmosphere. After stirring at -60 ° C for 20 minutes, (4-cyanophenyl) -2- (4-fluorophenyl) ethyl ketone (2.5 g, 10 mmol) was added as a solution in diethyl ether. at room temperature and the mixture was stirred for a further 2 hours. The reaction mixture was then allowed to warm to room temperature and quenched with saturated aqueous ammonium chloride. The diethyl ether layer was separated and the solvent was distilled off. Water was added to the residue and the product was extracted with ethyl acetate. After drying and evaporation of the solvent, the residue is mixed with ethanol and the resulting black precipitate is filtered off. The ethanol is evaporated and the product is • 4 «

• 44 ·· · · «

purification by chromatography. The eluent was dichloromethane / methanol (46: 1).

¹ H-NMR (base, CDCl ₃ ):

2.33-2.40 (m, 1H), 2.52-2.67 (m, 2H), 2.68-2.83 (m, 1H),

6.96 (t, 2H), 7.061 (dd, 2H), 7.65 (AB guart, 4H), 7.73 (s, 1H), 8.73 (s, 1H).

b) 5- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] thiazole

5- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] thiazole is prepared according to the procedure described in Example 3, Step b). phenyl) -3- (4-fluorophenyl) -1-hydroxypropyl] thiazole. The product consists mainly of the isomer. The isomers were separated by flash chromatography eluting with ethyl acetate: methanol (99: 1).

¹ H-NMR (base, CDCl 3):

isomer: 3.35 (d, 2H), 6.37 (t, 1H), 6.70 (t, 2H), 7.03 (dd, 2H), 7.33 (s, 1H), 7, 43 (d, 2H), 7.77 (d, 2H), 8.67 (s, 1H);

Isomer b: 3.60 (d, 2H), 6.41 (t, 1H), 7.01 (t, 2H), 7.14 (dd, 2H), 7.39 (d, 2H), 7, 60 (d, 2H), 7.79 (S, 1H), 8.92 (s, 1H).

Claims (28)

Compounds of formula (I) wherein R ¹ is hydrogen, CH 3, OCH 3, NO ₂ , NH ₂ , CN, CF 3, CHF ₂ , CH ₂ F or halogen, R ² is a heterocyclic group which may be 1-imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, R ³ is hydrogen or hydroxy, R ⁴ is hydrogen, ^R5 is hydrogen or hydroxy; obsession R ⁴ is hydrogen and R ³ and R ⁵ together form a bond, or R ³ is hydrogen and R ⁴ and R ⁵ together are oxygen; R ⁶ is methylene, ethylene, -CHOH, -CH ₂ -CHOH, -CHOH-CH ₂ -, -CH = CH- or -C (= O) -; obsession R ⁴ is hydrogen and R ⁵ and R ⁶ together form = CH- or = CH-CH ₂ -, their stereoisomers and their non-toxic pharmaceutically acceptable acid addition salts. Compounds according to claim 1, wherein R ³ and R ⁴ are hydrogen, ^R5 is hydroxy, or R ³ is hydroxy and R ⁴ and R ⁵ are hydrogen, and · ··· ♦ · ♦ · - 33 R ⁶ is methylene or ethylene; obsession R ³ , R ⁴ and R ⁵ are hydrogen and R ⁶ is -CHOH-, -CH ₂ -CHOH-, -CHOH-CH ₂ -; and Of R ¹ and R ² are as defined in claim 1. Compounds according to claim 2, wherein R ³ and R ⁴ are hydrogen, and R ⁵ is hydroxy, and R ⁶ is methylene or ethylene; obsession R ³ , R ⁴ and R ⁵ are hydrogen and R ⁶ is -CHOH-, -CH ₂ -CHOH-, -CHOH-CH ₂ -; and Of ^R1 and ^R2 as described in claim 2. The compound of claim 1, wherein R ⁴ is hydrogen, and R ³ and R ⁵ together form a bond or an oxygen atom, and R ⁶ is methylene or ethylene; obsession R ³ and R ⁴ are hydrogen and R ⁵ and R ⁶ together are = CH- or = CH-CH ₂ -; obsession R ³ , R ⁴ and R ⁵ are hydrogen and R ⁶ is -CH = CH- or -C (= O) -, or R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen; Of R ¹ and R ² are as defined in claim 1. 5. Compounds according to any one of claims 1 to 3, wherein R ² is 1-imidazolyl, triazolyl, tetrazolyl or thiazolyl. '· «« «· <· ·,« «,, • · w · ·. • · · · · · · · · · · · · · · · · · · · · · · · ··· Compounds according to claim 5, wherein R ² is 1-imidazolyl, 1-1,2,4-triazolyl, 1- or 2-tetrazolyl or 5-thiazolyl. The compound according to claim 1, which is 1- (1- (4-cyanophenyl) -4- (4-fluorophenyl) butyl] -1H-imidazole, its stereoisomers and its non-toxic pharmaceutically acceptable acid addition salts. . 8. The compound according to claim 1, which is stereoisomers of 1- (1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl) -1H-imidazole and non-toxic, pharmaceutically acceptable applicable acid addition salts. 9. The compound according to claim 1, which is stereoisomers of 1- (1- (4-cyanophenyl) -4- (4-fluorophenyl) -1-butenyl) -1,2,4-triazole and non-toxic , pharmaceutically acceptable acid addition salts thereof. 10. The compound according to claim 1, which is a stereoisomer of 1- (1- (4-cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl) -1,2,4-triazole; non-toxic pharmaceutically acceptable acid addition salts thereof. 11. The compound according to claim 1, wherein the stereoisomers of 1- (1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl) -1,2,4-triazole and non-toxic pharmaceutically acceptable acid addition salts thereof. · * · 4 * ··· ·· ♦ «··« • · »· ·. · -. ··· ·· · W ·· '·· «, * · *' * · {· \« *; - 35 - 12. The compound according to claim 1, the stereoisomers of 1- (1- (4-cyanophenyl) -3- (4-fluorophenyl) -3-hydroxypropyl] -1,2,4-triazole, and non-toxic pharmaceutically acceptable acid addition salts thereof. 13. The compound according to claim 1, wherein the stereoisomers of 1- (1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-oxobutyl) -1,2,4-triazole and non-toxic pharmaceutically acceptable acid addition salts thereof. 14. The compound according to claim 1, which is stereoisomers of 1- (1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propenyl) -1,2,4-triazole and non-toxic , pharmaceutically acceptable acid addition salts thereof. 15. The compound according to claim 1, which is 5- (1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-hydroxypropyl) thiazole, its stereoisomers and non-toxic pharmaceutically acceptable acid addition salts. salts. 16. The compound according to claim 1, which is 1- (1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole, stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof. 17. The compound of claim 1 which is 2- (1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole, stereoisomeric and non-toxic pharmaceutically acceptable acid addition - 36 J salts. A pharmaceutical composition according to any one of claims 1-17. A compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 19. A method of inhibiting aromatase, wherein a subject for whom such inhibition is desired is in an amount of 1-17. A compound according to any one of claims 1 to 6 which produces the desired inhibition. 20. A compound according to any one of claims 1 to 6 for use in a method of medical treatment. 21. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament having an aromatase inhibitor. 22. A process for the preparation of compounds of formula I wherein R ^x is hydrogen, CH 3, OCH 3, NO ₂ , NH ₂ , CN, CF 3, CHF ₂ , CH ₂ F or halogen, R ² is a heterocyclic group which may be 1-imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, R ³ is hydrogen or hydroxy, R ⁴ is hydrogen, ^R5 is hydrogen or hydroxy; or • · ♦ 37 R ⁴ is hydrogen and R ³ and R ⁵ together form a bond, or R ³ is hydrogen and R ⁴ and R 5 together represent oxygen; R ⁶ is methylene, ethylene, -CHOH, -CH 2 -CHOH, -CHOH-CH2-, -CH = CH- or -C (= O) -; obsession R ⁴ is hydrogen and R ⁵ and R ⁶ together form = CH- or = CH-CH 2 - to form their stereoisomers and their non-toxic pharmaceutically acceptable acid addition salts, characterized in that (a) a halide of formula (θ9Υ) wherein: Hal is halogen, n is 1 or 2, R ¹ is as defined above, R ⁷ is a CN group or other reactive group which can be converted to a cyano group by reaction with a heterocyclic compound R ^2, H wherein r 21 is 1-imidazolyl, 1-1,2,4-, 4-1,2, 4-, 1-1,2,3- or 2-1,2,3-triazolyl or 1- or 2-tetrazolyl and the resulting compound of formula III is recovered, or b) reacting a halide as defined in Reaction a with a nitrogen protected heterocyclic compound R ^2, H wherein R ² 'is 4-1,2,3-, 3- -1,2,4-triazolyl or 5- tetrazolyl, in the presence of a strong base, and recovering the compound of formula (III) wherein R ² ', R ¹ , R ⁷ and n are as defined above, or »· · · · · ······································· (38) c) a compound of formula IV wherein R ² and R ⁷ are as defined above and the nitrogen atom in R ^{2 is} optionally protected with a halide of formula V wherein Hal is halogen, n and R ¹ are reacting in the presence of a strong base as described above, recovering the resulting compound of formula III 'wherein R ² , R ¹ , R ⁷ and n are as defined above, or d) reacting a compound of formula IV wherein R ² and R ⁷ are as defined above, with an aldehyde of formula VI in the presence of a strong base, followed by reacting a compound of formula VII wherein R ¹ , R ² , R ⁷ and n are as defined above, or ^e ) dehydrating a compound of formula VII wherein R ¹ , R ² , R ⁷ and n are as defined above, and then obtaining the compound of formula VIII wherein R ¹ , R ² , R ⁷ and n are as defined above, or f) reacting a compound of Formula IV wherein R ² and R ⁷ are as defined above, with an ester of Formula IX wherein R 'is lower alkyl in the presence of a strong base; R ^1, R ^2, R ⁷ and n are as defined above, is recovered, or g) reducing a compound of formula X and recovering the resulting compound of formula VII wherein R ¹ , R ² , R ⁷ and n are as defined above, or h) ^R2, H, a heterocyclic compound of the formula wherein R ² 'is reacted with a ketone of formula I according to a), (XI) with thionyl chloride in the presence of the resulting (VIII') a compound of formula wherein R ¹ , R ² ', • · · «« · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · - 39 R ⁷ and n are as defined above, or i) (XII) with a ketone of formula wherein ^R1 and ^R7 are as defined above, n 'is 0 or 1, one R ² Ή formula heterocycle, wherein R ^2' are as defined in a), and thereafter yielding a compound of formula (XIII) wherein R ¹ , R ² ', R ⁷ and n' are as defined above, or j) Reducing θ9Υ of formula (XIII) wherein R ¹ , R ² ', R ⁷ and n are as defined in (i), then reducing the resultant compound of formula XIV where R ¹ , R ² ', R ⁷ and n 'are as defined above, or; k) reacting an epoxy derivative of Formula XXI wherein n is 0 or 1 with a compound of Formula IV in the presence of a strong base, followed by reacting a compound of Formula XIV wherein R ¹ , R ² , R ⁷ and n ' has the same meaning as above, or l) reacting a compound (XIV) wherein ^{R1, R2, R7} and n 'are as defined is claim s), or ^R2 identical to ^R2' according to claim meaning as j), dehydrated, and yielded (XII) or recovering a compound of Formula XXIII wherein R ¹ , R ² and R ⁷ are as defined above, or m) hydrogenating a compound of formula (XXII) or (XXIII) wherein R ¹ , R ² and R ⁷ are as defined in (1), and then obtaining the compound of formula (III ') wherein R ¹ , R ² , R ⁷ and n are as defined above, or n) reacting a compound of formula IV wherein R ² and R ⁷ are as defined above, with formamide in the presence of a strong base, and treating the resultant compound of formula XV with 4 ····· 4 * - 40 t of acetophenone and then reduced to the alcohol of formula I, or o) reacting a ketone of formula XVI, wherein R ^{2 is} optionally protected, with a compound of formula XVII or XVIII, wherein R 'is lower alkyl, n is 1 or 2, then reacting the resultant (VIII) ), wherein R ¹ , R ² , R ⁷ and n are as defined above, or P) a compound of Formula XIX wherein R ² 'is 4-1,2,3- or 3-1,2,4-triazolyl, 5-tetrazolyl, 3 or 4-pyrazolyl, 2-, 4 - or 5-pyrimidinyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isoxazolyl or 3-, 4- or 5-isothiazolyl, and Y is a hydrogen atom or a protecting group, is reacted with a ketone of formula XI in the presence of a strong base, and the resulting compound of formula XX, wherein R ¹ , R ² ', R ⁷ and n are as defined above, is recovered, or q) reacting a ketone of formula XVI wherein R ² and R ⁷ are as defined above, with a halide of formula V wherein R ¹ and n are as defined above, in the presence of alkyl lithium or magnesium, followed by ') a compound of formula wherein R ^1, R ^2, R ⁷ and n are as defined above, is recovered, or r) a 'compound), wherein R ^1, R ^2, R ⁷ and n are as defined above, or R ² represents the same as R ^2' (XX according to claim report ap) is dehydrated and the obtained (VIII) wherein R ¹ , R ² , R ^7, and n are as defined above, or · «· · - 41 ^seconds), a formula (VIII) with a compound of formula wherein R ^1, R ^2, R ⁷ and n are as above or R ² represents the same meaning as of R ² 'a), b) or r) point is hydrogenated, then the (III ¹⁾ a compound of formula wherein R ^1, R ^2, R ⁷ and n are as defined above, is recovered, then the R ⁷ substituents, where other than that is not cyano, converting the cyano group, and then optionally removing the heterocyclic group of the nitrogen protecting groups and, if desired, separating and / or isolating the stereoisomers and / or converting the compound obtained by any of the above processes into a non-toxic pharmaceutically acceptable acid addition salt or converting the acid addition salt into the free compound. A process according to claim 22 for the preparation of compounds of formula I, stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof, wherein R ³ and R ⁴ are hydrogen and R ⁵ is hydroxy or R ³ is hydroxy and R ⁴ and R ⁵ is hydrogen and R ⁶ is methylene or ethylene; obsession ^{R3, R4} and ^R5 is hydrogen and ^R6 is -CHOH-, -CH2-CHOH-, -CHOH-CH2-; R ¹ and R ² are as defined in claim 22, characterized by using correspondingly substituted starting compounds. 24. A process according to claim 22 for the preparation of compounds of formula (I), stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof, wherein R ³ 'is 42 t and R ⁴ is hydrogen. and ^R5 is hydroxy, ^R6 is methylene or ethylene; or ^{R3, R4} and R5 is H and ^R6 is -CHOH-, -CH2-CHOH-, -CHOH-CH2-; R ¹ and R ² are as defined in claim 22, characterized by using correspondingly substituted starting compounds. 25. A process according to claim 22 for the preparation of compounds of formula (I), stereoisomers and non-toxic pharmaceutically acceptable acid addition salts thereof, wherein R ⁴ is hydrogen, R ³ and R ⁵ together form a bond or oxygen, R ⁶ is methylene or ethylene; or R ³ and R ⁴ are hydrogen and R ⁵ and R ⁶ together form = CH- or = CH-CH 2 - or R ³ , R ⁴ and R ⁵ are hydrogen and R ⁶ is -CH = CH- or -C (= O) -, or R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen and R ¹ and R ² are as defined in claim 22, wherein the appropriately substituted starting compounds are used. 26. The process of claim 22, 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole, its stereoisomers and non- and pharmaceutically acceptable acid addition salts thereof, wherein the appropriately substituted starting materials are used. 27. The process of claim 22, 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-hydroxypropyl] -1,2,4-triazole, stereoisomers and non- toxic, pharmaceutically acceptable acid addition salts thereof, using appropriately substituted starting materials. The method of claim 22 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) butyl] -lH-imidazole, 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-hydroxybutyl] -1H-imidazole, 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -1-butenyl] -1,2,4-triazole, 1- [3-hydroxypropyl-1- (4-cyanophenyl) -3- (4-fluoro) phenyl] -1,2,4-triazole, 1- [1- (4-cyanophenyl) -4- (4-fluorophenyl) -2-oxobutyl] -1,2,4-triazole, 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-propenyl] -1,2,4-triazole, 5- [1- (4-cyanophenyl) -3- (4-fluorophenyl) -1-hydroxypropyl] thiazole, 1- [1- (4-cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole, 2- [1- (4-Cyanophenyl) -3- (4-fluorophenyl) propyl] tetrazole, its stereoisomers and its non-toxic pharmaceutically acceptable acid addition salts, characterized in that the appropriately substituted starting materials are used.