WO2006005725A2 - N containing condensed heterocycles with antitumor effects - Google Patents

Abstract

The application relates to novel heterocyclic compounds of the general formula (I), in which L, R, R1, R2, W, X, Y, Z and n have the meanings explained in more detail in the description, to a process for their preparation and to the use of these compounds as medicaments, in particular as aromatase inhibitors.

Description

Organic compounds

The invention relates to novel heterocycles, to a process for the preparation of the compounds according to the invention, to pharmaceutical preparations comprising them and to their use as pharmaceutical active substances, in particular as aromatase inhibitors.

The present invention relates first to compounds of the general formula

in which

W represents C or, if Z represents a bond and X represents C, also represents N;

X represents C or, if Z represents a bond, also represents N;

Y represents C or, if Z represents C, also represents N;

Z represents C or a bond;

R represents hydrogen, d-Cβ-alkyl, Ci-C₈-alkoxy-C₀-C₄-alkyl, halogen or trifluoromethyl;

R¹ represents hydrogen, Ci-C₈-alkyl, Co-C₈-alkylcarbonyl, carbamoyl, mono- or di(CrC₈- alkyl)aminocarbonyl, carboxy, carboxy-Ci-C₄-alkyl, halogen, cyano, trifluoromethyl,

Ci-C₈-alkoxy-Ci-C₄-alkyl, Ci-C₈-alkoxycarbonyl, heterocyclyl-Co-C₄-alkyl or aryl-C₀-C₄-alkyl, which radicals are unsubstituted or substituted by 1-4 Ci-C₈-alkyl, C₀-C₈-alkylcarbonyl, C_rC₈- alkylsulphonyl, halogen, cyano, oxo, tri-(CrC₄-alkyl)silyl, trifluoromethoxy, trifluormethyl, C₀-

C₈-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-Ci-C₈-alkylamino, carbamoyl, mono- or di(Ci-C₈- alkyl)aminocarbonyl, carboxy-C₀-C₄-alkyl, Ci-C₈-alkoxy, CrCβ-alkoxycarbonyl, aryl or heterocyclyl, and, in addition, if W represents C, also represents amino, mono- and di(Ci-C₈- alkyl)amino, Co-Cβ-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-CrC₈-alkylamino or C₁-C₈- alkoxy-Co-C₄-alkyl;

R² represents heterocyclyl or aryl, which radicals are unsubstituted or substituted by 1-4

Ci-C₈-alkyl, C₀-C₈-alkylcarbonyl, CrC₈-alkylsulphonyl, halogen, cyano, oxo, tri-(C_rC₄- alkyl)silyl, trifluoromethoxy, trifluoromethyl, Co-Cs-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-

CrCs-alkylamino, carbamoyl, mono- or di(Ci-C₈-alkyl)aminocarbonyl, carboxy-C₀-C₄-alkyl,

Ci-C₈-alkoxy-Co-C₄-alkyl, d-Cs-alkoxycarbonyl, aryl or heterocyclyl; L represents -C(O)-, -C(R³)(R⁴)-O-, -C(R³)(R⁴)-S(O)_m- or -C(R³)(R⁴)-NR⁵- and, in addition, if W represents C, also represents -O-, -NR⁵-, -S(O)_n,-, -O-C(R³)(R⁴)-, -S(O)_m-C(R³)(R⁴)-,

-NR⁵-C(R³)(R⁴)-, -NR⁵-S(O)_m- or -S(O)_m-NR⁵-;

R³ represents hydrogen or Ci-C₈-alkyl;

R⁴ a) represents hydrogen or C_rC₈-alkyl; or b) represents, together with R³, oxo; R⁵ represents hydrogen, Ci-C₈-alkyl or C₀-C₈-alkylcarbonyl; m represents a number 0, 1 or 2; n represents a number 0, 1 or 2; and their salts, preferably their pharmaceutically usable salts, in which, if n = 0, W and Y represent C₁ Z represents a bond, X represents N₁ L represents -HNCO- and R¹ represents hydrogen, R² is not alkoxy-substituted phenyl; or if n = 2, W, X and Z represent C₁ Y represents C or N₁ L represents -NR⁵-S(O)₂- and R¹ represents hydrogen, R² is not optionally substituted phenyl; or if Y represents C, Z represents a bond and L represents -NR⁵-C0-, R² is not amino- substituted phenyl; or if W₁ X₁ Y and Z represent C and L represents -NH-, R¹ is not hydrogen.

The term "aryl" denotes an aromatic hydrocarbon which generally comprises 5-14, preferably 6-10, carbon atoms and is, for example, phenyl, indenyl, e.g. 2- or 4-indenyl, or naphthyl, e.g. 1- or 2-naphthyl. Aryl with 6-10 carbon atoms, in particular phenyl or 1- or 2-naphthyl, is preferred. The abovementioned radicals may be unsubstituted or substituted one or more times, e.g. once or twice, it being possible for the substituent to be in any position, e.g. in the o-, m- or p-position of the phenyl radical or in the 3- or4-position of the 1- or 2-naphthyl radical, and it also being possible for a plurality of identical or different substituents to be present.

Aryl-C₀-C₄-alkyl is, for example, phenyl, naphthyl or benzyl.

The term "heterocyclyl" denotes a saturated or unsaturated, 4-8-membered, particularly preferably 5-6-membered, monocyclic ring system, a saturated or unsaturated, 7-12- membered, particularly preferably 9-10-membered, bicyclic ring system and also a saturated or unsaturated, 7-12-membered, tricyclic ring system, in each case comprising an N, O or S atom in at least one ring, it also being possible for an additional N, O or S atom to be present in one ring. The abovementioned radicals may be unsubstituted or substituted one or more times, e.g. once or twice, it also being possible for a plurality of identical or different substituents to be present.

Unsaturated monocyclic heterocyclyl-C₀-C₄-alkyl is, for example, pyrrolyl, pyridyl, thiophenyl, thiazolyl or oxazolyl.

Saturated monocyclic heterocyclyl-C₀-C₄-alkyl is, for example, pyrrolidinyl.

Unsaturated bicyclic heterocyclyl-C₀-C₄-alkyl is, for example, 4,5,6,7-tetrahydroisobenzofuranyl, 4,5,6,7-tetrahydrobenzothiazolyl, benzofuranyl, benzothiophenyl, indazolyl, indolyl, isoquinolinyl, quinolinyl, 3,4-dihydro-2H- [1 ,6]naphthyridinyl or pyrrolo[3,2-c]pyridin-1-yl.

Ci -C₈-Al kyl may be straight-chain or branched and/or bridged and is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or a pentyl, hexyl or heptyl group.

d-Cβ-Alkoxy is, for example, CrCs-alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or pentyloxy, but can also be a hexyloxy or heptyloxy group.

Ci-C₈-Alkoxy-C₀-C₄-alkyl is, in addition to the meanings mentioned for Ci-C₈-alkoxy, for example, Ci-C₅-alkoxy-CrC₄-alkyl, such as methoxyethyl, ethoxyethyl, propyloxymethyl, isopropyloxybutyl, butyloxymethyl, isobutyloxyethyl, sec-butyloxypropyl, tert-butyloxybutyl or pentyloxymethyl, but can also be a hexyloxymethyl or heptyloxymethyl group.

Ci-C₈-Alkoxycarbonyl is preferably CrCβ-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl or tert-butyloxycarbonyl.

Co-Cs-Alkylcarbonyl is, for example, formyl, acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl or tert-butylcarbonyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine. Carboxy-Ci-C₄-alkyl is, for example, carboxymethyl, 2-carboxyethyl, 2- or 3-carboxypropyl, 2-carboxy-2-methylpropyl, 2-carboxy-2-ethyl butyl or 4-carboxybutyl, in particular carboxymethyl.

Mono- or di(CrC₈-alkyl)amino is, for example, Ci-C₄-alkylamino, such as methylamino, ethylamino, propylamino or butylamino, or di(Ci-C₄-alkyl)amino, such as dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-propylamino or N-butyl-N-methylamino.

Mono- or di(CrC₈-alkyl)aminocarbonyl is, for example, Ci-C₄-alkylaminocarbonyl, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl or butylaminocarbonyl, or di(C_rC₄-alkyl)aminocarbonyl, such as dimethylaminocarbonyl, N-methyl-N-ethylamino- carbonyl, diethylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylamino- carbonyl.

Co-Cβ-Alkylcarbonylamino is, for example, formylamino, acetylamino, propionylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino or tert-butylcarbonylamino.

Co-Cβ-Alkylcarbonyl-CrCs-alkylamino is, for example, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, sec-butylcarbonyl- or tert-butylcarbonyl-methylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, sec-butylcarbonyl- or tert-butylcarbonyl- ethylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, sec-butylcarbonyl- or tert-butylcarbonyl-propylamino or formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, sec- butylcarbonyl- or tert-butylcarbonyl-butylamino.

The compound groups mentioned below are not to be regarded as closed; on the contrary, parts of these compound groups may usefully, e.g. to replace general by more specific definitions, be replaced by one another or by the definitions given above or may be omitted.

Preferred compounds of the formula (I) are compounds of the general formulae

in which the meanings of the substituents L, R, R¹ and R² are as indicated for compounds of the formula (I).

L preferably represents -C(O)-, -O-, -O-C(R³)(R⁴)-, -C(R³)(R⁴)-O- or -C(R³)(R⁴)-NR⁵-, very particularly preferably -C(O)-, -O- or -C(R³)(R⁴)-NR⁵-, in which R⁵ is hydrogen or Ci-C₃-alkyl.

R preferably represents hydrogen, CrC₈-alkyl₍ halogen or trifluoromethyl, very particularly preferably hydrogen or methyl.

R¹ preferably represents hydrogen, d-Cs-alkyl, halogen, heterocyclyl-Co-C₄-alkyl or aryl-Co-C₄-alkyl, very particularly preferably hydrogen, halogen or Ci-C₃-alkyl.

R² preferably represents heterocyclyl or aryl, which radicals can be monosubstituted by halogen, cyano or heterocyclyl in particular.

R³ and R⁴ together preferably represent oxo.

R⁵ preferably represents hydrogen or C_rC₈-alkyl, very particularly preferably hydrogen or Ci-C₃-alkyl.

n preferably represents a number 0 or 1. Preferred substituents for aryl or heterocyclyl are halogen, cyano, trifluoromethyl, heterocyclyl or C₀-C₈-alkylcarbonyl. Very particularly preferred substituents for aryl or heterocyclyl are bromine, cyano, thiophenyl, thiazolyl, oxazolyl or acetyl.

Preference is therefore very particularly given, for example, to compounds of the general formulae (I), (Ia), (Ib), (Ic) and (Id), in which

L represents -C(O)-, -O- or -C(R³)(R⁴)-NR⁵-;

R represents hydrogen, C_rC₈-alkyl, halogen or trifluoromethyl, very particularly preferably hydrogen or methyl;

R¹ represents hydrogen, CrC₈-alkyl, halogen, heterocyclyl-C₀-C₄-alkyl or aryl-Co-C₄-alkyl, very particularly preferably hydrogen, halogen or Ci-C₃-alkyl;

R² represents heterocyclyl or aryl, which radicals can be monosubstituted by halogen, cyano or heterocyclyl in particular;

R³ represents hydrogen or Ci-C₈-alkyl;

R⁴ a) represents hydrogen or d-C₈-alkyl; or, very particularly preferably, b) represents, together with R³, oxo; and R⁵ represents hydrogen or Ci-C₃-alkyl.

The compounds of the formula (I) having at least one asymmetric carbon atom can exist in the form of optically pure enantiomers or mixtures of enantiomers or as racemates. Compounds with a second asymmetric carbon atom can exist in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates or as meso compounds. The invention includes all these forms. Mixtures of enantiomers, racemates, mixtures of diastereomeric isomers, diastereomeric racemates or mixtures of diastereomeric racemates can be separated by conventional methods, e.g. by racemate resolution, column chromatography, thin layer chromatography, HPLC and the like.

The term "pharmaceutically usable salt" includes salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like. Salts of compounds having salt-forming groups are in particular acid addition salts, salts with bases or, in the presence of a plurality of salt-forming groups, optionally also mixed salts or inner salts. The compounds of the formula (I) can be prepared in a manner analogous to preparation methods disclosed in the literature. Details of the specific preparation variants can be taken from the examples.

The compounds of the formula (I) can also be prepared in optically pure form. The separation into antipodes can be carried out by methods known per se, either, preferably, at an early stage in the synthesis by salt formation with an optically active acid, such as, for example, (+)- or (-)-mandelic acid, and separation of the diastereomeric salts by fraction crystallization or, preferably, at a rather late stage by derivatization with a chiral auxiliary component, such as, for example, (+)- or (-)-camphanoyl chloride, separation of the diastereomeric products by chromatography and/or crystallization, and subsequent cleavage of the bond to the chiral auxiliary. The pure diastereomeric salts and derivatives can be analysed using current spectroscopic methods in order to determine the absolute configuration of the compound present, single-crystal X-ray spectroscopy representing a particularly suitable method.

Salts are primarily the pharmaceutically useful or nontoxic salts of compounds of the formula (I). Such salts are, for example, formed from compounds of the formula (I) having an acid group, e.g. a carboxy or sulpho group, and are, for example, their salts with suitable bases, such as non-toxic metal salts derived from metals of Groups Ia, Ib, Na and Nb of the Periodic Table of the Elements, e.g. alkali metal salts, in particular lithium, sodium or potassium salts, alkaline earth metal salts, for example magnesium or calcium salts, furthermore zinc salts or ammonium salts, and also those salts which are formed with organic amines, such as optionally hydroxy-substituted mono-, di- or trialkylamines, in particular mono-, di- or tri(lower alkyl)amines, or with quaternary ammonium bases, e.g. methyl-, ethyl-, diethyl- or triethylamine, mono-, bis- or tris[2-hydroxy(lower alkyl)]amines, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, N,N-di(lower alkyl)-N-[hydroxy(lower alkyl)]amine, such as N,N-dimethyl-N-(2-hydroxy- ethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide. The compounds of the formula (I) having a basic group, e.g. an amino group, can form acid addition salts, e.g. with suitable inorganic acids, e.g. hydrohalic acid, such as hydrochloric acid or hydrobromic acid, sulphuric acid, with replacement of one or both protons, phosphoric acid, with replacement of one or more protons, e.g. orthophosphoric acid or metaphosphoric acid, or pyrophosphoric acid, with replacement of one or more protons, or with organic carboxylic, sulphonic or phosphonic acids or N-substituted sulphamic acids, e.g. acetic acid, propionic acid, glycol ic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid, nicotinic acid, isonicotinic acid, furthermore amino acids, such as, e.g. α- amino acids, as well as methanesulphonic acid, ethanesulphonic acid, 2- hydroxyethanesulphonic acid, ethane-1 ,2-disulphonic acid, benzenesulphonic acid, 4- toluenesulphonic acid, naphthalene-2-sulphonic acid, 2- or 3-phosphoglycerate, glucose 6- phosphate or N-cyclohexylsulphamic acid (with formation of cyclamates), or with other acidic organic compounds, such as ascorbic acid. Compounds of the formula (I) having acidic and basic groups can also form inner salts.

Pharmaceutically unsuitable salts can also be used for isolation and purification.

The compounds of the formula (I) and (la-d) also include those compounds in which one or more atoms are replaced by their stable nonradioactive isotopes; for example a hydrogen atom by deuterium.

Prodrug derivatives of the compounds described above are derivatives thereof which, on in vivo application, release the original compound by a chemical or physiological process. A prodrug can, for example, be converted to the original compound when a physiological pH is reached or by enzymatic conversion. Prodrug derivatives can, for example, represent esters of freely available carboxylic acids or S- and O-acyl derivatives of thiols, alcohols or phenols, the acyl group being as defined above. Preference is given to pharmaceutically useful ester derivatives which are converted to the original carboxylic acid by solvolysis in a physiological medium, such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters or mono- or disubstituted lower alkyl esters, such as lower ω-(amino, mono- or dialkylamino, carboxy or lower alkoxycarbonyl)-alkyl esters or such as lower α-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)-alkyl esters; pivaloyloxymethyl esters and similar esters are conventionally used as such.

Because of the close relationship between a free compound, a prodrug derivative and a salt compound, a particular compound in this invention also includes its prodrug derivative and salt form, provided that this is possible and appropriate. The naturally occurring oestrogens 17β-oestradiol (E2), oestrone (E1) and oestriol (E3) are C18 steroids derived from cholesterol. After cholesterol links up to lipoprotein receptors of steroidogenic cells, it is stored intracellularly and is brought in to sites of steroid synthesis. The aromatization of the A ring in the steroid backbone forms the final synthetic step in the formation of oestrogen. This reaction is catalysed by the P450 aromatase-monooxygenase enzyme complex (Cyp19), which is located in the smooth endoplasmic reticulum and functions as demethylase. Oestrone and oestradiol, originating from the necessary precursors androstenedione and testosterone respectively, are synthesized in three successive hydroxylation reactions.

In women, oestradiol is mainly formed in the theca and granulosa cells of the ovaries and in the placenta. This has given rise to the "two cell theory": the theca cells of the ovary manufacture androgens under the influence of luteinizing hormone (LH) of the pituitary gland and the cells of the egg follicles which surround the actual egg cell (granulosa cells) produce the oestrogens under the influence of follicle-stimulating hormone (FSH) from the pituitary gland. However, it is suspected that theca cells as well as granulosa cells both form androgens and oestrogens. Oestrone and oestrio! are mainly formed in the liver from oestradiol. The activity of the aromatases, however, can also be detected in muscle, fat and nerve tissue as well as in the Leydig ceiis of the testicles. Oestrogen synthesis in nongonadal tissues increases with age and body weight.

In the blood circulation, oestradiol binds reversibly to sex hormone binding giobulin, a β-giobulin, and with relatively weak affinity to albumin; 2-3% of oestradiol is nonbonded in the plasma. Oestrogens are metabolized as sulphates or giucoronides and the conjugates are removed in the gail bladder or urine. The hydrolysis of these conjugates by the intestinai flora and the resulting reabsorption can bring about an enterohepatic circulation of the oestrogens.

Oestrogens stimulate the growth, the blood supply and the enriching in water of the sexual organs. They can accordingly also cause breast cancer and endometrial hyperplasia. Oestrogens increase the expression of lipoprotein receptors in the liver, which results in a reduction in the level of low density lipoprotein cholesterol (LDL-C). However, they also increase the ability of the blood to clot by stimulating the production of clotting factors in the liver. In bone, the osteoclasts and osteoblasts are direct targets of oestrogens, where they exert an antiresorptive effect on the bone mass. In breast tissue, the oestrogens stimulate the growth and the differentiation of the ductal epithelium, they induce the mitotic activity of the columnar cells of the duct and they stimulate the growth of the connective tissue. Oestrogens stimulate above all the growth of breast cancer cells. In postmenopausal women with breast cancer, the local oestradiol concentration in the tumour is increased because of increased in situ aromatase enzyme activity, in spite of low oestradiol plasma levels.

The chemical compounds described in the present invention exhibit useful pharmacological properties by inhibiting the aromatase enzyme (CYP19) in mammals, in particular in man. In this way, the metabolic conversion of the androgens to oestrogens is inhibited. The compounds can accordingly be used for the treatment of oestrogen-dependent diseases, such as, for example, oestrogen-dependent breast cancer, above all in postmenopausal women. The compounds can also, because of the inhibition of steroid aromatization, be used for the treatment of gynecomastia, the development of breast tissue in men.

The aromatase-inhibiting effect of these described compounds can be shown by means of in vitro assays in cell-free or cellular test systems. The inhibition of the aromatase activity in vitro by the compounds described in the present invention can be shown using commercially available Cyp19 assay kits. The Cyp19/Methoxy-4-trifluoromethyl-coumarin (MFC) High Throughput Inhibition Screening Kit (Becton Dickinson Biosciences, San Jose, CA, USA), for example, allows the testing in the 96-well plate format of possible chemical compounds which inhibit the Cyp19 catalytic activity. The kit comprises recombinantly expressed Cyp19 enzyme in the form of supersomes, a fluorescent P450 substrate, an NADPH regenerating system, a reaction buffer and a stop reagent. The MFC fluorogenic substrate is quickly converted by the Cyp19 supersome activity to the highly fluorescent product 7-hydroxy-4- trifluoromethyl-coumarin (7-HFC). This assay is carried out in the presence of a wide range of concentrations of test compound, including the concentrations from 0.2 nanomolar up to 20 millimolar, according to the instructions of the manufacturer of the kit.

The IC₅₀ values for active test compounds are determined by simple linear regression analysis in order to produce inhibition curves free from data weighting. The inhibition curve was calculated by fitting a 4-parameter logistic function with the raw data points using the least squares method. The equation of the 4-parameter logistic function is calculated according to:

Y = (d-a)/((1 + (x/c)-^b)) + a in which: a = minimum data level b = gradient

d = maximum data level x = inhibitor concentration.

The compounds of the present invention show, in the in vitro test systems, inhibitory effects at minimum concentrations of approximately 10^~3 to approximately 10 ^"10 mol/l.

The Cyp19-inhibiting properties of chemical compounds of the present invention can also be shown in a cellular test system. The NCI-H295R cell line was originally derived from an adrenocortical carcinoma and has been characterized in the literature by the stimulable secretion of steroid hormones and the presence of the enzymes essential for steroid genesis. Thus, the NCI-H295R cells have Cyp11 A (cholesterol side-chain cleavage), Cyp11B1 (steroid 11β-hydroxylases), Cyp11B2 (aldosterone synthases), Cyp17 (steroid 17α-hydroxylases and/or 17,20-lyases), Cyp19 (aromatases), Cyp21B2 (steroid 21 -hydroxylases) and 3β-HSD (hydroxysteroid dehydrogenases). The cells show the physiological property of zonal Iy undifferentiated human foetal adrenocortical cells which, however, have the ability to produce those steroid hormones which are formed in the three phenotypically distinct zones in the adult adrenalcortex. The NCI-H295R cells (American Type Culture Collection, ATCC₁ Rockville, MD, USA) are cultured in Dulbecco's Modified Eagle's/Ham's F-12 Medium (DME/F12) in 75 cm² cell culture flasks at 37°C and in a 95% air/5% carbon dioxide atmosphere, the DME/F12 having been supplemented with Ultroser SF serum (Soprachem, Cergy-Saint-Christophe, France), insulin, transferrin, selenite (I-T-S, Becton Dickinson Biosiences, Franklin Lakes, NJ, USA) and antibiotics. The cells are subsequently transferred to a 24-well incubation flask for colony formation. They are cultured there for 24 hours in DME/F12 medium which now is supplemented with 0.1% bovine serum albumin instead of Ultroser SF serum. The experiment is initiated by culturing the cells for 72 hours in DME/F12 medium which is supplemented with 0.1% bovine serum albumin and test compound, in the presence or absence of cell stimulants. The test substance is added in a concentration range of 0.2 nanomolar up to 20 millimolar. Angiotensin Il (10 or 100 nanomolar), potassium ions (16 millimolar), forskolin (10 micromolar) or a combination of two stimulants can be used as cell stimulants. The cellular secretion of oestrone, oestradiol, dihydroepiandrostendione, aldosterone, corticosterone and/or Cortisol in the culture medium can be detected and quantified in radioimmunoassays using commercially available specific monoclonal antibodies according to the manufacturer's instructions. Inhibition of the release of certain steroids can be used as a measure of the respective enzyme inhibition by the test compounds added. The dose-dependent inhibition of the enzyme activity by a compound is plotted by the inhibition curve, which is characterized by an IC₅₀ value.

The IC₅₀ values for active test compounds are determined by simple linear regression analysis in order to produce inhibition curves free from data weighting. The inhibition curve was calculated by fitting a 4-parameter logistic function with the raw data points using the least squares method. The equation of the 4-parameter logistic function is calculated according to:

Y = (d-a)/((1 + (x/c)^"b)) + a

in which: a = minimum data level b = gradient c = IC₅₀ d = maximum data level x = inhibitor concentration.

The compounds of the present invention show, in the in vitro test systems, inhibitory effects at minimum concentrations of approximately 10^"3 to approximately 10^"10 mol/l.

The oestrogen-reducing effect of the compounds described above can be tested in vivo with suitable mammalian models, such as, for example, guinea pigs, mice, rats, cats, dogs or apes.

The inhibition of the aromatase activity by chemical compounds can be monitored by measuring the plasma steroid level, as described in the following protocol: female rats in the sexual cycle are treated with 5 subcutaneous injections, applied on alternating days, of 100 IU of pregnant mare serum gonadotropin (PMSG, Sigma) in 0.1 ml of sterile saline solution. 24 hours after the final injection, the test compound is administered to the animals per os at doses of 0.01 up to 10 mg/kg. Twenty-four hours after treatment, the animals are subjected to a terminal bleed. The heparinized plasma is stored at -20⁰C until analysed. The plasma levels of the steroids 17β-oestradiol, oestrone, oestriol, progesterone, testosterone, aldosterone and corticosterone are determined using commercially available radioimmuno¬ assays in accordance with the instructions of the manufacturer. In this connection, a purification and concentration step is necessary in order to determine plasma testosterone in female rats. For this, the plasma samples are treated with 4 units by volume of diethyl ether, mixed for 15 minutes by gentle rocking and centrifuged at 2000 rpm for 5 minutes. The aqueous phase is frozen with dry ice, the organic phase is separated and the solvent is evaporated using a stream of nitrogen. The dry extract is again taken up in the assay buffer.

The inhibition of the aromatase activity by chemical compounds can also be determined by measuring the oestrogen content of the ovaries according to the following protocol: female rats, aged 21 days, are treated with a subcutaneous injection of 10 IU of pregnant mare serum gonadotropin (PMSG, Sigma). Two days later, 30 IU of human chorionic gonadotropin (hCG, Sigma) are injected subcutaneously into the same rats. On the following day, either 0.2 ml of polypropylene glycol or various doses of the test substance are injected subcutaneously into the rats. One hour later, 2.25 mg of 4-androstene-3,17-dione in 0.1 ml of oil are injected subcutaneously into the rats. Four hours after the injection of the androstenedione, the rats are killed and their ovaries are removed. The ovaries are freed from adhering tissue and stored as pairs at -50⁰C. In order to determine the oestrogen content of the ovaries, the organs are treated with 1.5 ml of a 0.05M aqueous phosphate buffer solution pH 7.4 and with 0.2 ml of a 0.1 M aqueous sodium hydroxide solution, and homogenized. The homogenate is extracted with 15 ml of diethyl ether before aliquots of 5 ml are subjected to a radioimmunoassay. The antiserum used for this radioimmunoassay exhibits a 100% crossreactivity for oestradiol, oestrone and oestriol. The result of the analysis is expressed as ng of oestrogen content per pair of ovaries.

The antitumour effects of the compounds, above all for oestrogen-dependent tumours, can be determined in vivo, for example in female Sprague-Dawley rats in which a breast tumour has been induced using dimethylbenzanthracene (DMBA) (see Proc. Soc. Exp. Biol. Med., 160, 296-301, 1979). Compounds of this invention bring about, after daily application per os of doses from 1 up to 20 mg/kg or even less, a regression of existing tumours and a suppression of the emergence of new tumours.

In order to achieve the desired effects in a patient to be treated, the compounds of the present invention can be administered orally or enterally, for example intravenously, intraperitoneally, intramuscularly, rectally, subcutaneously or also by direct injection of the active substance locally into tissues or tumours. The term "patient" describes warm-blooded animals and mammals, such as, for example, man, primates, cattle, dogs, cats, horses, sheep, mice, rats and pigs. The compounds can be administered as a pharmaceutical preparation or can be incorporated in an administration device which guarantees continuous release of the compound. The amount of substance to be administered can vary over a wide range and can represent any effective dose. Depending on the patient to be treated or the condition to be treated and administration form, the dose of the effective substance can be between approximately 0.005 and 50 milligrams per kilogram of body weight daily; however, it is preferably between approximately 0.05 and 5 milligrams per kilogram of body weight daily.

For oral administration, the compounds can be formulated in solid or liquid pharmaceutical forms, such as, for example, as capsules, pills, tablets, sugar-coated tablets, granules, powders, solutions, suspensions or emulsions. The dose of a solid pharmaceutical form can be a conventional hard gelatin capsule which can be filled with active substances and adjuvants, such as lubricants and fillers, such as, for example, lactose, sucrose and maize starch. A tableting of the active substance of the present invention can represent an additional administration form. The tableting can be carried out with conventional tableting adjuvants, such as, for example, lactose, sucrose or maize starch, combined with binders from gum acacia, maize starch or gelatin, disintegrating agents, such as potato starch or crosslinked polyvinylpyrrolidone (PVPP)₁ and lubricants, such as stearic acid or magnesium stearate.

Examples of excipients suitable for soft gelatin capsules are vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like.

Examples of excipients suitable for producing solutions and syrups are water, polyols, sucrose, invert sugar, glucose, and the like.

For rectal administration, the compounds can be formulated in solid or liquid pharmaceutical forms, such as, for example, suppositories. Examples of excipients suitable for suppositories are natural or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like. For parenteral administration, the compounds can be formulated as injectable doses of the active substance in a liquid or suspension. The preparations generally comprise a physiologically compatible sterile solvent which can comprise a water-in-oil emulsion, with or without surfactant, and other pharmaceutically acceptable adjuvants. Oils which can be used for such preparations are liquid paraffins and triglycerides of vegetable, animal or synthetic origin, such as, for example, peanut oil, soybean oil and mineral oil. Injectable solutions generally comprise liquid carriers, such as, preferably, water, saline, dextrose or related sugar solutions, ethanol and glycols, such as propylene glycol or polyethylene glycol.

The substances can be administered as transdermal patch system, as depot injection or implant, if the formulation makes possible continuous delivery of the active substance. The active substance can be compressed as granules or to narrow cylinders and can be administered subcutaneously or intramuscularly as depot injection or implant.

The pharmaceutical preparations can in addition also comprise preservatives, solubility promoters, viscosity-increasing substances, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, aromatizing agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also comprise yet other therapeutically valuable substances.

The present invention makes possible the use of the compounds of the formula (I) and (la-d) and their pharmaceutically useable salts for the prevention, for slowing down the progression or for the treatment of symtoms or findings which respond to aromatase inhibition, especially proliferative diseases, such as breast cancer or similar types of hormone-sensitive soft tissue cancers, above all oestrogen-dependent findings, such as gynecomastia, tumours of the breast or of the endometrium, endometriosis and premature labour. The compounds can also be used for the treatment or prevention of locally advanced or metastatic breast cancer in postmenopausal women who have been tested hormone receptor-positive or hormone receptor-unknown.

The compounds of the formula (I) and (la-d) and their pharmaceutically useable salts can be used in combination with one or more active substances with an antineoplastic effect, thus, for example, with an active substance exhibiting an antioestrogen activity, such as, for example, described for exemestane, toremifen, fulvestrant, and tamoxifen; with an active substance exhibiting an activity in inhibiting bone resorption, such as, for example, described for pamidronates and zoledronic acid; with an active substance exhibiting an alkylating activity, such as, for example, described for busulfan, temozolomide, melphalan, chlorambucile and mechlorethamine; with an active substance exhibiting an activity in the intercalation of nucleotide bases, such as, for example, described for adriamycin, daunorubicin, dactinomcyin, doxorubicin, epirubicin and idarubicin; with an active substance exhibiting an antimetabolite activity, such as, for example, described for cytarabine, fludarabine, cladribine, mercaptopurine, thioguanine and capecitabine; with an active substance exhibiting an antiandrogen activity, such as, for example, described for abarelix and bicalutamide; with an active substance exhibiting an androgen activity, such as, for example, described for nilutamide and methyltestosterone; with an active substance exhibiting a gonadotropin-releasing hormone activity, such as, for example, described for leuprolide, triptorelin and goserelin; with an active substance exhibiting a progestogen activity, such as, for example, described for medroxyprogesterone; with an active substance exhibiting a nucleoside-analogue activity, such as, for example, described for gemcitabine; with an active substance exhibiting an activity in inhibiting topoisomerase I, such as, for example, described for topotecan and irinotecan; with an active substance exhibiting a kinase-inhibiting activity, such as, for example, described for imatinib; with an active substance exhibiting an activity in inhibiting growth factor, such as, for example, described for gefitinib and trastuzumab; with an active substance exhibiting a growth hormone activity, such as, for example, described for epoetin alfa, sargramostim, filgastrim, pegfilgastrim, oprelvekin and interferon alpha-2b; with an active substance of diverse activity, such as, for example, described for pemetrexed, dacarbazine, procarbazine, oxaliplatin, asparaginase, pegaspargase, altretamine, gemtuzumab, vinorelbine, mitoxantrone, denileukin, rituximab, alitretinoin, arsenic trioxide, bortezomib, tretinoin and docetaxel; or with an active substance exhibiting an antiemetic activity, such as, for example, described for dolasetron, palonosetron, aprepitant, ganisetron, dronabinol and ondansetrone.

The compounds of the invention described above make possible the following methods of use:

- as therapeutic combination in the form of a preparation or of a kit which is composed of individual components comprising a compound described above, in the free form or as a pharmaceutically usable salt, and at least one other pharmaceutical form, the active substance of which has an antineoplastic effect, which can be used either simultaneously or sequentially. The preparation and the kit can include instructions for use. The dose can vary within a wide range and must naturally from case to case be adjusted to the individual conditions. Generally, in oral application, a daily dose of 0.3 mg up to 3 g, however preferably a daily dose of 1 mg up to 1 g, is used, which, for example at a dose of 10 mg for an adult weighing 70 kg, can be administered in 1 to 3 individual daily doses proportioned identically or differently. Children usually receive weaker doses according to their age and body weight.

The following examples illustrate the present invention. All temperatures are given in degrees Celsius and pressures in mbar. Unless otherwise mentioned, the reactions take place at ambient temperature. The abbreviation "Rf = xx (A)" means, for example, that the Rf value xx is determined in the solvent system A. The ratio of the amounts of solvents to one another is always given in proportions by volume. Chemical names for final products and intermediates were generated using the AutoNom 2000 (Automatic Nomenclature) program.

HPLC gradients on Hypersil BDS C-18 (5 μm); column: 4 x 125 mm :

95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* in 10 minutes + 2 minutes

(1 ml/min)

* comprises 0.1% of trifluoroacetic acid

The following abbreviations are used:

Rf ratio of the distance migrated by a substance to the separation of the solvent front from the starting point in thin layer chromatography Rt retention time of a substance in HPLC (in minutes)

M. p. melting point (temperature)

Example 1

5,6,7,8-TetrahvdroimiclazoH ,5-aiPyridine-5-carboxylic acid (methyl)(pyridin-4-v0amide 2.200 mmol of oxalyl chloride are added at 0⁰C to a solution of 2.000 mmol of 5,6,7,8-tetra- hydroimidazo[1,5-a]pyridine-5-carboxylic acid in 10 ml of dichloromethane. A drop of N,N-dimethylformamide is added and the reaction solution is stirred at 0⁰C for 30 minutes. 3.000 mmol of triethylamine are subsequently added to the reaction solution. A solution of 2.000 mmol of 4-methylaminopyridine in 2 ml of dichloromethane is added dropwise at 0⁰C and the solution is subsequently stirred at ambient temperature for a further 1 hour. 10 ml of saturated aqueous sodium hydrogencarbonate solution are added to the reaction solution and extraction is carried out with dichloromethane (2 x). The combined organic phases are washed with 20 ml of aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO₂60F) in the form of a yellow solid. Rf = 0.37 (dichloromethane/methanol/conc. ammonia = 92:8:1); Rt = 3.33.

The starting materials are prepared as follows:

a) 5,6,7,8-Tetrahvdroimidazori ,5-aipyridine-5-carboxylic acid

6 ml of 2M NaOH are added to 5.260 mmol of ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine- 5-carboxyIate. The reaction mixture is heated at reflux for 2 hours, subsequently cooled to ambient temperature and adjusted to neutral pH with 6 ml of 2M HCI. The reaction mixture is evaporated. The crude title compound is obtained from the residue as a white solid. Rt = 2.78.

b) Ethyl 5,6.7,8-tetrahvdroimidazoπ ,5-alpyridine-5-carboxylate

30 ml of cone. HCI and 0.750 g of 10% Pd/C are added to a solution of 15.770 mmol of ethyl imidazo[1,5-a]pyridine-5-carboxylate [76292-67-6] in 100 ml of ethanol. The reaction mixture is subsequently hydrogenated at 58 psi and 60⁰C for 2 hours. The catalyst is filtered off via Hyflo and the filtrate is concentrated. The crude title compound is obtained from the residue as an amber-coloured oil. Rf = 0.37 (toluene/methanol = 85:15); Rt = 4.19. Example 2

5.6.7,8-Tetrahvdroimidazo[1.δ-alpyridine-δ-carboxylic acid (methyl)(thiophen-3-yl)amide A solution of 0.970 mmol of δ.β/.β-tetrahydroimidazoti.δ-alpyridine-δ-carboxylic acid (thiophen-3-yl)amide in 10 ml of anhydrous N,N-dimethylformamide is cooled in an ice bath to 0-5⁰C. 1.260 mmol of sodium hydride (60% dispersion in liquid paraffin) are added portionwise and the reaction mixture is stirred at 0⁰C for 30 minutes. 1.260 mmol of methyl iodide are added at 0°C and the mixture is subsequently heated to ambient temperature and stirred for a further 1 hour. The reaction mixture is poured onto 20 ml of saturated aqueous sodium hydrogencarbonate solution and is extracted with ethyl acetate (3 x). The combined organic phases are washed with 30 ml of aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO₂60F) in the form of a cream-coloured solid. Rf = 0.21 (toluene/methanol = 8δ:1δ); Rt = 4.72.

The starting material is prepared as follows:

a) δ.6,7,8-Tetrahvdroimidazori ,δ-aipyridine-δ-carboxylic acid (thiophen-3-vπamide 2.000 mmol of δ,67_>8-tetrahydroimidazo[1,δ-a]pyridine-δ-carboxylic acid and 2.000 mmol of thiophen-3-ylamine are reacted analogously to Example 1. The title compound is obtained from the crude mixture by triturating with ethyl acetate/tert-butyl methyl ether (1 :1) and subsequently filtering off the solid as a brown solid. Rf = 0.17 (toluene/methanol = 8δ:1δ); Rt = 4.74.

The following compounds are prepared in an analogous way according to the process described in Example 1 :

Examples :

3 (3.4-Dihvdro-2H-f1.61naphthyridin-1-vπ(δ.6.7.8-imidazof1,δ-aipyridin-δ-vπmethanone

4 Pyrrolor3,2-clpyridin-1-yl)(δ,6,7,8-imidazof1,δ-alpyridin-δ-yl)methanone 5 5,6,7,8-Tetrahvdroimiclazori .δ-alpyridine-δ-carboxylic acid (3-methoxyPhenyl)- methyl-amide

Example 6

3-(5,6,7,8-Tetrahvdroimidazori,5-a1pyridin-8-yloxy)benzonitrile 2.120 mmol of triphenylphosphine are added to a solution of 2.120 mmol of 3-hydroxy- benzonitrile in 25 ml of tetrahydrofuran and the mixture is cooled to 0-5⁰C using an ice bath. 2.120 mmol of diisopropyl azodicarboxylate are subsequently added, followed by a solution of 1.770 mmol of 5,6₅7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol in 5 ml of tetrahydrofuran. The ice bath is removed and the reaction solution is stirred overnight at ambient temperature. The reaction mixture is diluted with tert-butyl methyl ether and extracted with 0.1 M HCI (2 x). The aqueous phase is neutralized with 4M NaOH, adjusted to pH 8 with solid sodium hydrogencarbonate and extracted with dichloromethane (3 *). The organic phase is dried over sodium sulphate and evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO₂ 60F) in the form of a yellow oil. Rf = 0.19 (dichloromethane/methanol = 95:5); Rt = 5.17.

The starting material is prepared as follows:

a) 5,6,7,8-Tetrahydroimidazori,5-aiPyridin-8-ol

2.000 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] are introduced into 5 ml of ethanol. 0.800 mmol of sodium borohydride is added to the reaction mixture at ambient temperature and stirring is carried out for a further 2 hours. 0.5M HCI (2 ml) is added to the reaction mixture, which is diluted with water and washed with heptane (2 *). The aqueous phase is evaporated, the residue is dissolved in ethanol (10 ml) and filtered, and the mother liquor is evaporated. The crude title compound is obtained from the residue as a beige solid. Rt = 2.00.

Claims

Claims

1. Compound of the general formula

in which

W represents C or, if Z represents a bond and X represents C, also represents N;

X represents C or, if Z represents a bond, also represents N;

Y represents C or, if Z represents C, also represents N;

Z represents C or a bond;

R represents hydrogen, CrCs-alkyl, CrC₈-alkoxy-C₀-C₄-alkyl, halogen or trifluoromethyl;

R¹ represents hydrogen, CrCs-alkyl, C₀-C₈-alkylcarbonyl, carbamoyl, mono- or Ui(C₁-C₈- alkyl)aminocarbonyl, carboxy, carboxy-Ci-C₄-alkyl, halogen, cyano, trifluoromethyl,

CrC₈-alkoxy-C₁-C₄-alkyl_J Ci-C₈-alkoxycarbonyl, heterocyclyl-C₀-C₄-alkyl or aryl-Co-C₄-alkyl, which radicals are unsubstituted or substituted by 1-4 CrC₈-alkyl, Co-Cβ-alkylcarbonyl,

Ci-C₈-alkylsulphonyl, halogen, cyano, oxo, tri(Ci-C₄-alkyl)silyl, trifluoromethoxy, trifluoromethyl, Co-Cβ-alkylcarbonylamino, Co-C₈-alkylcarbonyl-Ci-C₈-alkylamino, carbamoyl, mono- or di(Ci-C₈-alkyl)aminocarbonyl, carboxy-C₀-C₄-alkyl, CrC₈-alkoxy, C₁-C₈- alkoxycarbonyl, aryl or heterocyclyl, and, in addition, if W represents C, also represents amino, mono- and di(CrC₈-alkyl)amino, Co-Cβ-alkylcarbonylamino, Co-Cs-alkylcarbonyl-Cr

C₈-alkylamino or CrC₈-alkoxy-Co-C₄-alkyl;

R² represents heterocyclyl or aryl, which radicals are unsubstituted or substituted by 1-4

CrC₈-alkyl, Co-Cs-alkylcarbonyl, C_rC₈-alkylsulphonyl, halogen, cyano, oxo, W-(C₁-C₄- alkyl)silyl, trifluoromethoxy, trifluoromethyl, CrC₈-alkoxy-Co-C₄-alkyl, CrCβ-alkoxycarbonyl, aryl or heterocyclyl;

L represents -C(O)-, -C(R³)(R⁴)-O~, -C(R³)(R⁴)-S(O)_m- or -C(R³)(R⁴)-NR⁵- and, in addition, if W represents C₁ also represents -O-, -NR⁵-, -S(O)_n,-, -O-C(R³)(R⁴)-, -S(O)_m-C(R³)(R⁴)-,

-NR⁵-C(R³)(R⁴)-, -NR⁵-S(O)_m- or -S(O)_m-NR⁵-;

R³ represents hydrogen or CrC₈-alkyl;

R⁴ a) represents hydrogen or C_rC₈-alkyl; or b) represents, together with R³, oxo; R⁵ represents hydrogen, C_rC₈-alkyl or C₀-C₈-alkylcarbonyl; m represents a number 0, 1 or 2; n represents a number 0, 1 or 2; and its salt, prodrug or compound in which one or more atoms are replaced by their stable nonradioactive isotopes, in particular pharmaceutically usable salt, in which if n = 0, W and Y represent C₁ Z represents a bond, X represents N₁ L represents -HNCO- and R¹ represents hydrogen, R² is not alkoxy-substituted phenyl; or if n = 2, W₁ X and Z represent C, Y represents C or N, L represents -NR⁵-S(O)₂- and R¹ represents hydrogen, R² is not optionally substituted phenyl; or if Y represents C, Z represents a bond and L represents -NR⁵-CO-, R² is not amino- substituted phenyl; or if W, X₁ Y and Z represent C and L represents -NH-, R¹ is not hydrogen.

2. Compound according to Claim 1, characterized in that it corresponds to the general formula

in which the meanings of the substituents L, R, R¹ and R² are as indicated for compounds of the formula (I) according to Claim 1.

3. Compound according to Claim 1 or 2, in which R represents hydrogen, CrC₈-alkyl, halogen or trifluoromethyl, very particularly preferably hydrogen or methyl.

4. Compound according to any of Claims 1 to 3, in which R¹ represents hydrogen, Ci-C₈-alkyl, halogen, heterocyclyl-C₀-C₄-alkyl or aryl-C₀-C₄-alkyl, very particularly preferably hydrogen, halogen or d-C₃-alkyl.

5. Compound according to any of Claims 1 to 4, in which R² represents heterocyclyl or aryl, which radicals can be monosubstituted by halogen, cyano or heterocyclyl in particular.

6. Compound according to Claim 1, in which n represents a number 0 or 1.

7. Compound according to Claim 1 or 2, in which

L represents -C(O)-, -O-, -O-C(R³)(R⁴)-, -C(R³)(R⁴)-O- or -C(R³)(R⁴)-NR⁵-, very particularly preferably -C(O)-, -O- or -C(R³)(R⁴)-NR⁵-;

R represents hydrogen, Ci-C₈-alkyl, halogen or trifluoromethyl, very particularly preferably hydrogen or methyl;

R¹ represents hydrogen, Ci-C₈-alkyl, halogen, heterocyclyl-C₀-C₄-alkyl or aryl-C₀-C₄-alkyl, very particularly preferably hydrogen, halogen or CrC₃-alkyl;

R² represents heterocyclyl or aryl, which radicals can be monosubstituted by halogen, cyano or heterocyclyl in particular;

R³ represents hydrogen or C_rC₈-alkyl;

R⁴ a) represents hydrogen or Ci-C₈-alkyl; or, very particularly preferably, b) represents, together with R³, oxo; and R⁵ represents hydrogen or C_rC₃-alkyl.

8. Use of a compound of the general formula (I) according to any of Claims 1 to 7 for the preparation of a medicament.

9. Use of a compound of the general formula (I) according to any of Claims 1 to 7 for the preparation of a human medicament for the prevention, for slowing down the progression or for the treatment of syndromes or findings which respond to aromatase inhibition, especially proliferative diseases.

10. Method for the prevention, for slowing down the progression or for the treatment of syndromes or findings which respond to aromatase inhibition, especially proliferative diseases, in which a therapeutically effective amount of a compound of the general formula (I) according to any of Claims 1 to 7 is used.

11. Pharmaceutical preparation comprising a compound of the general formula (I) according to any of Claims 1 to 7 and conventional adjuvants.