WO2006005726A2 - Heterocyclic compounds - Google Patents

Abstract

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

Description

Organic compounds

The invention relates to novel heterocycles, to a process for preparing the compounds of the invention, to pharmaceutical products containing them, and to their use as active pharmaceutical ingredients, in particular as aldosterone synthase inhibitors.

The present invention relates firstly to compounds of the general formula

in which

V is C or, if X is C, it is also N;

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

Y is C;

Z is C or a bond; where V and Y form, with inclusion of X, a 5-9-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, d-C₈-alkoxy or Ci-C₈-alkoxycarbonyl; R¹ is d-Cβ-alkyl, Ca-Cβ-cycloalkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-C₄-alkyl, which radicals are unsubstituted or substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, C₀-C₈- alkylcarbonylamino, Co-Cβ-alkylcarbonyl-d-Cβ-alkylamino, carbamoyl, mono- or di-C_rC₈- alkylaminocarbonyl, carboxy-Co-C₄-alkyl, Ci-C₈-alkoxy, Ci-C₈-alkoxycarbonyl, heterocyclyl or aryl, where heterocyclyl or aryl may be substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, d-C₈-alkylsulfonyl, cyano, oxo, tri-Ci-C₄-alkylsilyl, trifluoromethoxy, trifluoromethyl, Co-Cβ-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-Ci-C₈-alkylamino, carbamoyl, mono- or di-Ci- C₈-alkylaminocarbonyl, carboxy-Co-C₄-alkyl, Ci-C₈-alkoxy or Ci-Cβ-alkoxycarbonyl; R² a) is hydrogen; or b) is Ci-C₈-alkyl, C₃-C₈-cycloalkyl, halogen, carboxy-Ci-C₄-alkyl, d-C₄-alkoxycarbonyl- Co-C₄-alkyl, C₀-C₄-alkylcarbonyl, aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-d-alkyl, which radicals are unsubstituted or substituted by 1-4 d-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, Co-Cβ-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-Ci-C₈- alkylamino, carbamoyl, mono- or di-CrCβ-alkylaminocarbonyl, carboxy-Co-C₄-alkyl, d-C₈- alkoxy, Ci-C₈-alkoxycarbonyl, heterocyclyl or aryl, where heterocyclyl oraryl may be substituted by 1-4 Ci-C₈-alkyl, Co-Cs-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, Co- Cβ-alkylcarbonylamino, Co-Cβ-alkylcarbonyl-Ci-Cg-alkylamino, carbamoyl, mono- or di-Ci-C₈- alkylaminocarbonyl, carboxy-Co-Cα-alkyl, Ci-C₈-alkoxy or Ci-C₈-alkoxycarbonyl; n is a number 0, 1 or 2; and the salts thereof, preferably the pharmaceutically usable salts thereof.

The term aryl stands for an aromatic hydrocarbon radical which generally comprises 5-14, preferably 6-10, carbon atoms and is, for example, phenyl, indenyl, e.g. 2- or4-indenyl, or naphthyl, e.g. 1- or 2-naphthyl. Aryl having 6-10 carbon atoms is preferred, especially phenyl or 1- or 2-naphthyl. Said 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 or 4 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-Co-C₄-alkyl is, for example, phenyl, naphthyl or benzyl.

The term heterocyclyl stands for a saturated or unsaturated, 4-8-membered, particularly preferably 5-membered, monocyclic ring system, for a saturated or unsaturated, 7-12- membered, particularly preferably 9-10-membered, bicyclic ring system and also fora 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. Said 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 heterocydyl-C₀-C₄-alkyl is, for example, pyrrolyl, pyridyl, thiophenyl, thiazolyl or oxazolyl.

Saturated monocyclic heterocydyl-C₀-C₄-alkyl is, for example, pyrrolidinyl. Unsaturated bicyclic heterocyclyl-C₀-C₄-alkyl is for example 4,5,6,7-tetrahydro- isobenzofuranyl, 4,5,6,7-tetrahydrobenzothiazolyl, indazolyl, indolyl, benzofuranyl, benzothiophenyl, isoquinolinyl or quinolinyl.

C₃-C₈-CyClOaI kyl-Co-C₄-alkyl is preferably 3-, 5- or 6-membered cycloalkyl-C₀-C₄-alkyl, such as cyclopropyl, cyclopentyl, cyclohexyl.

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

C₂-C₈-Alkenyl is, for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, secondary butenyl, tertiary butenyl or a pentenyl, hexenyl or heptenyl group.

C₂-C₈-Alkynyl is, for example, ethynyl, propynyl, butynyl, or a pentynyl, hexynyl or heptinyl group.

C₁-C₈-AIkOXy is, for example, Ci-C₅-alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyl oxy, isobutyloxy, secondary butyloxy, tertiary butyloxy or pentyloxy, but may also be a hexyloxy or heptyloxy group.

Ci-Cβ-Alkoxycarbonyl is preferably Ci-Cs-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, secondary butyloxycarbonyl or tertiary butyloxycarbonyl.

Co-Cβ-Alkylcarbonyl is, for example, formyl, acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, secondary butylcarbonyl or tertiary butylcarbonyl.

Carboxy-Ci-C₄-alkyl is, for example, carboxymethyl, 2-carboxyethyl, 2- or 3-carboxypropyl, 2-carboxy-2-methyl-propyl, 2-carboxy-2-ethyl-butyl or 4-carboxy butyl, in particular carboxymethyl.

Mono- or di-Ci-C₈-alkylaminocarbonyl is, for example, Ci-Gralkylaminocarbonyl, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl or butylaminocarbonyl, or di-Ci-C₄-alkylaminocarbonyl, such as dimethylaminocarbonyl, N-methyl-N- ethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N- methylaminocarbonyl.

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

Co-C₈-Alkylcarbonyl-Ci-C₈-alkylamino is, for example, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary butylcarbonyl- or tertiary butylcarbonyl-methylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary butylcarbonyl- or tertiary butylcarbonyl-ethylamino, formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary butylcarbonyl- or tertiary butylcarbonyl-propylamino or formyl-, acetyl-, propionyl-, propylcarbonyl-, isopropylcarbonyl-, butylcarbonyl-, isobutylcarbonyl-, secondary butylcarbonyl- or tertiary butylcarbonyl-butylamino.

Halogen is, for example, fluorine, chlorine, bromine or iodine.

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

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

(Ib),

where the meanings of the substituents R¹ and R² are as indicated for compounds of the formula (I), and R is hydrogen, Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, Ci-C₈-alkoxy or Ci-C₈-alkoxycarbonyl, m is a number 1, 2 or 3, and p is a number 1 or 2.

R is preferably hydrogen or oxo.

R¹ is preferably aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-C₀-C₄-alkyl, which radical may be substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, Ci-C₈-alkylsulfonyl, cyano, oxo, tri-Ci-C₄-alkylsilyl, trifluoromethoxy, trifluoromethyl, Co-Cβ-alkylcarbonylamino, Co-C₈- alkylcarbonyl-Ci-Cs-alkylamino, carbamoyl, mono- or di-Ci-Cβ-alkylaminocarbonyl, carboxy- C₀-C₄-alkyl, Ci-Cβ-alkoxy, CrC₈-alkoxycarbonyl, heterocyclyl or aryl, particularly preferably aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-C₀-C₄-alkyl, which radicals may be substituted by 1-4 cyano, Co-Cβ-alkylcarbonyl, oxazolyl, thiazolyl, thiophenyl, pyrrol id inyl or furyl.

R² is preferably hydrogen, halogen, Ci-C₈-alkyl, aryl-Co-C₄-alkyl or unsaturated heterocyclyl- Co-C₄-alkyl, particularly preferably hydrogen, halogen or d-C₃-alkyl.

n is preferably a number 0 or 1.

Very particularly preferred compounds of the general formulae (I), (Ia), (Ib), (Ic) and (Id) are therefore those in which

R is hydrogen or oxo;

R¹ is aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-C4-alkyl, which radicals may be substituted by 1-4 cyano, Co-Cβ-alkylcarbonyl, oxazolyl, thiazolyl, thiophenyl, pyrrolidinyl or furyl; and

R² is hydrogen, halogen or Ci-C₃-alkyl. The compounds of the formula (I) which have at least one asymmetric carbon atom can exist in the form of optically pure enantiomers, mixtures of enantiomers or as racemates. Compounds having a second asymmetric carbon atom can exist in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates or as meso compounds. The invention includes all these forms. Mixtures of enantiomers, racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates can be fractionated by conventional methods, e.g. by racemate resolution, column chromatography, thin-layer chromatography, HPLC and the like.

The term "pharmaceutically usable salts" 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, if a plurality of salt-forming groups is present, optionally also mixed salts or inner salts.

The compounds of the formula (I) can be prepared in a manner analogous to preparation processes disclosed in the literature. Details of the specific preparation variants can be found in the examples.

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

Salts are primarily the pharmaceutically usable or nontoxic salts of compounds of the formula (I). Such salts are formed for example by compounds of the formula (I) having an acidic group, e.g. a carboxy or sulpho group, and are, for example, salts thereof with suitable bases, such as nontoxic metal salts derived from metals of group Ia, Ib, Ma and Hb of the Periodic Table of Elements, e.g. alkali metal, in particular lithium, sodium or potassium salts, alkaline earth metal salts, for example magnesium or calcium salts, also zinc salts or ammonium salts, and those salts formed with organic amines such as optionally hydroxy- substituted mono-, di- or trialkylamines, in particular mono-, di- or tri-lower-alkylamines, or with quaternary ammonium bases, e.g. methyl-, ethyl-, diethyl- or triethylamine, mono-, bis- ortτis(2-hydroxy-lower-alkyl)amines such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tertiary-butylamine, N,N-di-lower-alkyl-N- (hydroxy-lower-alkyl)amine, such as N,N-dimethyl-N-(2-hydroxyethyl)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, 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, sulphoic or phosphonic acids or N-substituted sulphamic acids, e.g. acetic acid, propionic acid, glycolic 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, embonic acid, nicotinic acid, isonicotinic acid, also amino acids such as, for example, the above mentioned α-amino acids, and 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, N-cyclohexylsulphamic acid (to form cyclamates) or with other acidic organic compounds such as ascorbic acids. 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) also include 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 use in vivo release the original compound through a chemical or physiological process. A prodrug may be converted into the original compound for example when a physiological pH is reached or by enzymatic conversion. Examples of possible prodrug derivatives are esters of freely available carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or phenols, where the acyl group is as defined above. Preference is given to pharmaceutically usable ester derivatives which are converted by solvolysis in physiological medium into the original carboxylic acid, such as, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters, such as lower ω-(amino, mono- or dialkylamino, carboxy, 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 defined compound in this invention also includes its prodrug derivative and salt form where this is possible and appropriate.

Aldosterone is a steroidal hormone which is synthesized in the zona glomerulosa cells of the adrenal cortex by the enzyme aldosterone synthase (CYP11B2). Aldosterone production and secretion is controlled by the adrenocorticotropic hormone (ACTH), angiotensin II, potassium and sodium ions. The primary biological function of aldosterone is to regulate the salt balance, since aldosterone controls the reabsorption of sodium ions from the renal filtrate and the secretion of potassium ions into the renal filtrate. The state of excessive aldosterone secretion, also called hyperaldosteronism, may lead to high blood pressure, hypokalaemia, alkalosis, muscle weakness, polyuria, polydipsia, oedemas, vasculitis, increased collagen formation, fibrosis and endothelial dysfunction.

The chemical compounds described in this invention inhibit the cytochrome P450 enzyme aldosterone synthase (CYP 11B2) and can therefore be used to treat states induced by aldosterone. The described compounds can be employed for the prevention, for delaying the progression, or for the treatment of states such as hypokalaemia, hypertension, congestive heart failure, acute and, in particular, chronic renal failure, cardiovascular restenosis, atherosclerosis, metabolic syndrome (syndrome X), adiposity (obesity), vasculitis, primary and secondary hyperaldosteronism, proteinuria, nephropathy, diabetic complications, such as diabetic nephropathy, myocardial infarction, coronary heart disease, increased collagen formation, fibrosis, vascular and coronary tissue changes (remodelling) secondary to hypertension, endothelial dysfunction and oedemas secondary to cirrhosis, nephrosis and congestive heart failure.

Cortisol is a steroidal hormone which is synthesized almost exclusively in the zona fasciculate cells of the adrenal cortex by the cytochrome P450 enzyme 11-β-hydroxylase (CYP11B1). Cortisol production is controlled by ACTH. The primary biological function of Cortisol is to regulate the production and the availability of carbohydrates for the brain and other metabolically active tissues. Increased Cortisol production and secretion is a normal physiological response to stress and leads to the essential mobilization of fats, proteins and carbohydrates to meet an increased demand for energy by the body. Chronically excessive Cortisol release describes the condition of Cushing's syndrome. Cushing's syndrome may be produced on the one hand by hypersynthesis of Cortisol, which may be generated by an adrenocortical tumour, or be produced on the other hand as the consequence of excessive stimulation of the adrenal cortex by ACTH. The first form is referred to as primary hypercortisolism, and the second form as secondary hypercortisolism. An excessive and persistent Cortisol secretion may also accompany a stress response, which may lead to depression, hyperglycemia and to suppression of the immune system.

The chemical compounds described in this invention inhibit the enzyme 11-β-hydroxylase (CYP11B1) and can therefore, due to the inhibition of Cortisol synthesis, be employed for the prevention, delaying the progression or treatment of Cushing's syndrome and of the physical and mental consequences of excessive and persistent Cortisol secretion in states of stress. As a consequence, the compounds can additionally be employed in conditions such as the ectopic ACTH syndrome, the change in adrenocortical mass, primary pigmented nodular adrenocortical disease (PPNAD) Carney complex (CNC), anorexia nervosa, chronic alcoholic poisoning, nicotine or cocaine withdrawal syndrome, the post-traumatic stress syndrome, the cognitive impairment after a stroke and the cortisol-induced mineralocorticoid excess.

Inhibition of aldosterone synthase (Cyp11B2), and of 11-β-hydroxylase (Cyp11B1) and of aromatase (Cyp19), by the compounds described above can be determined by the following in vitro assay:

The cell line NCI-H295R was originally isolated from an adrenocortical carcinoma and has been characterized in the literature through the stimulable secretion of steroid hormones and the presence of the enzymes essential for steroidogenesis. Thus, the NCI-H295R cells have Cyp11A (cholesterol side-chain cleavage), Cyp11B1 (steroid 11 β-hydroxylase), Cyp11B2 (aldosterone synthase), Cyp17 (steroid 17α-hydraxylase and/or 17,20-lyase), Cyp19 (aromatase), Cyp21B2 (steroid 21 -hydroxylase) and 3β-HSD (hydroxysteroid dehydrogenase). The cells show the physiological property of zonally undifferentiated human foetal adrenocortical cells which, however, have the capacity to produce the steroid hormones which are formed in the three, phenotypically distinguishable zones in the adult adrenal cortex.

The NCI-H295R cells (American Type Culture Collection, ATCC, Rockville, MD, USA) are grown in Dulbecco's Modified Eagle'Ham F-12 Medium (DM BF 12), which has been supplemented with Ulroser SF Serum(Soprachem, Cergy-Saint-Christophe, France), insulin, transferrin, selenite (I-T-S, Becton Dickinson Biosiences, Franklin lakes, NJ, USA) and antibiotics in 75 cm² cell culture vessels at 37°C and in a 95% air - 5% carbon dioxide atmosphere. The cells are subsequently transferred for colony formation into a 24-well incubation vessel. They are cultivated there in DME/F12 medium, which is now supplemented with 0.1% bovine serum instead of Ultroser SF for 24 hours. The experiment is initiated by cultivating the cells in DME/F12 medium which is supplemented with 0.1% bovine serum albumin and test compound, in the presence or absence of cell stimulants, for 72 hours. The test substance is added in a concentration range from 0.2 nanomolar to 20»millimolar. Cell stimulants which can be used are angiotensin Il (10 or 100 nanomolar), potassium ions (16 millimolar), forskolin (10 micromolar) or a combination of two stimulants. The excretion of aldosterone, Cortisol, corticosterone and estradiol/estrone into the culture medium can be detected and quantified by commercially available, specific monoclonal antibodies in radioimmunoassays in accordance with the manufacturer's instructions. Inhibition of the release of certain steroids can be used as a measure of the respective enzyme inhibition by the added test compounds. The dose-dependent inhibition of enzymic activity by a compound is calculated by means of an inhibition plot which is characterized by an IC50.

The IC₅₀ values for active test compounds are ascertained by a simple linear regression analysis in order to construct inhibition plots without data weighting. The inhibition plot is calculated by fitting a 4-parameter logistic function to the raw data points using the least squares method. The equation of the 4-parameter logistic function is calculated as follows:

Y = (d-a) / ((1 + (x/c)^"b)) + a where: a = minimum data level b = gradient c = IC50 d = maximum data level x = inhibitor concentration.

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

The aldosterone-reducing effect of the compounds described herein can be tested in vivo by the following protocol:

Adult male Sprague Dawley rats, weighing between 125 and 150 grams, are kept, housed singly, under the usual conditions of light and temperature. At 16.00 h on the first day of the experiment, the animals receive a subcutaneous injection of the depot ACTH product in a dose of 1.0 mg/kg of weight (SYNACTEN-Depot, Novartis, Basel, CH). Pilot studies showed that this ACTH dose increased plasma aldosterone and corticosterone significantly by respectively 15-fold and 25-fold over a period of at least 18 hours. At 8.00 h in the morning of the second day, the animals, divided into test groups of 5 animals, receive administration either of water orally or of a compound in a variable dose range of 0.01-10 mg/kg orally by gavage. Two hours later, blood is taken in EDTA-treated Eppendorf vessels. Plasma samples are obtained by centrifugation of the blood and can be stored at -20⁰C. An alternative method for stimulating aldosterone synthesis is for adult male, catheterized Wistar rats, weighing between 250 and 350 grams, to be subjected to a low-salt diet for 48 hours and additionally be treated 16 hours, and possibly with additional repetition 2 hours, before the start of the experiment with 10 mg/kg furosemide, administered subcutaneoously or intraperitoneally. Pilot studies showed that this pretreatment increases the plasma aldosterone level by 5 to 20-fold over a period of 12-24 hours. The catheters are chronically implanted into the animals' carotid and thus permit periodic blood sampling of a volume of up to 0.2 ml using an AccuSampler (DiLab Europe, Lund Sweden). The experiment starts with the oral administration of the test substances in a dose range of 0.01 - 10 mg/kg. The blood samples are taken with the AccuSampler 1 hour before administration of the test substances and subsequently after 2, 4, 6, 8, 12, 16 and 24 hours. The blood samples are anticoagulated with heparin and centrifuged. The plasma samples of both protocols are tested for the steroid content in previously described radioimmunoassays. The reduction in the steroid levels, such as, for example, aldosterone, serves as a measure of the in vivo bioavailability and enzyme inhibition activity of the compounds described herein.

The reduction in damage to the heart through the inhibition of aldosterone synthase with compounds described herein can be shown in vivo by the following protocol. The protocol corresponds in large part to the publication (Rocha et al, Endocrinology, Vol. 141 , pp 3871- 3878, 2000). Adult male Wistar rats are housed individually and receive freely available drinking water which contains 0.9% sodium chloride during the experiment. Three days later, the animals are subjected to one of the three following treatments. Group I (control group of 8 animals) is treated for 14 days which the chemical L-NAME (N-nitro-L-arginine methyl ester, Sigma, St. Louis, MO, USA) which inhibits nitric-oxide synthase. On day 11 of this treatment, an osmotic minipump charged with sodium chloride solution is subcutaneously implanted into each animal. Gruppe Il (L-NAME/Angll of 8 animals) is treated with L-NAME for 14 days. On day 11 of this treatment, an osmotic minipump charged with angiotensin Il (Angll) solution is subcutaneously implanted into each animal. Group III (L-NAM E/Ang I I/test substance of 8 animals) is treated similarly to group Il but receives the test substance in a daily dose range from 0.2 to 10 mg/kg of rat weight. The test substance is for this purpose dissolved in distilled water and administered orally by gavage. Groups I and Il receive only the vehicle without test substance. The experiment is stopped on day 14 of L-NAME treatment. L-NAME is administered in a concentration of 60 mg/100 rtiL in the 0.9% NaCI drinking water, leading to a daily intake of about 60 mg/kg. Angiotensin Il is administered by means of an Alzet osmotic minipump (model 2001; Alza Corp, Palo Alto, CA). The minipump is implanted subcutaneously in the back of the neck. Angiotensin Il (human and with a peptide purity of 99%) is purchased from Sigma Chemical Co., St. Louis, MO and administered in a dose of 225 μg/kg/day in sodium chloride solution. The concentration of angiotensin Il for charging the pumps is calculated on the basis of of: a) the average pumping rate stated by the manufacturer; b) the body weight of the animals on the day before implantation of the pumps; and c) the planned dose.

The rats are sacrificed on day 14. The hearts are removed and the ventricles/atria are sliced like a "loaf of bread" in order to obtain three samples from the following approximate regions of the heart: superior, middle and inferior. The samples are fixed in 10% buffered formalin. Paraffin sections are cut and stained with hematoxylin/eosin. The sections are assessed by a single scientist unaware of the assignment to groups. One section from each region of the heart is analysed for each rat. Specific parts of the heart (left and right ventricle, and the septum) are evaluated separately. The whole section is examined histologically for myocardial damage (irrespective of severity) manifested by myocyte necrosis, inflammatory cells, haemorrhages and general tissue damage. The histological data are assessed on the basis of a comparison of groups Il and III, i.e. angiotensin Il with and without test substance. Evaluation of the samples can take place semiquantitatively and be represented in the form of a point table.

The reduction in hypertension and the diminution in damage to the heart and kidneys through inhibition of aldosterone synthase with compounds described herein can be shown in vivo by the following protocol.

The investigations take place in 4-week old, male doubly transgenic rats (dTGR), which overexpress both human angiotensinogen and human renin and consequently develop hypertension. Age-matched Sprague-Dawley (SD) rats serve as non-hypertensive control animals. The animals are divided into treatment groups and receive test substance or vehicle (control) each day for 3-4 weeks. Throughout the study, the animals receive standard feed and tap water ad libitum. ._...

The systolic and diastolic blood pressure, and the heart rate, are measured telemetrically by means of implanted transducers, allowing the animals free and unrestricted movement. The animals are placed once a week in metabolism cages in order to determine the 24-hour urinary excretion of albumin. Heart dimensions (left ventricular mass, end-diastolic diameter and wall thickness, septum thickness, shortening fraction) and the diastolic filling are measured by echocardiography at the start and at the end of the treatment under isoflurane anaesthesia (M mode recording in the short axis and tissue doppler imaging by means of a commercial echocardiography instrument which is equipped with a 15 MHz probe). At the end of the study, the animals are sacrificed and the kidneys and hearts are removed for determining the weight and immunohistological investigations (fibrosis, macro phage/T cell infiltration, etc).

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, such as, for example, intravenously, intraperitoneally, intramuscularly, rectally, subcutaneously or else by direct injection of the active substance locally in tissues or tumours. The term patient encompasses warm-blooded species and mammals such as, for example, human, primate, bovine, dog, cat, horse, sheep, mouse, rat and pig. The compounds can be administered as pharmaceutical product or be incorporated into an administration device which ensures permanent release of the compound. The amount of substance to be administered can vary over a wide range and represent every effective dose. Depending on the patient to be treated or the condition to be treated and mode of administration, the dose of the effective substance each day can be between about 0.005 and 50 milligrams per kilogram of body weight, but is preferably between about 0.05 and 5 milligrams per kilogram of body weight each day.

For oral administration, the compounds can be formulated in solid or liquid pharmaceutical forms such as, for example, as capsules, pills, tablets, coated tablets, granules, powders, solutions, suspensions or emulsions. The dose of a solid pharmaceutical form can be one usual hard gelatin capsule which may be filled with active ingredients and excipients such as lubricants and fillers, such as, for example, lactose, sucrose and maize starch. Another form of administration may be represented by tableting of the active substance of the present invention. The tableting can take place with conventional tableting excipients such as, for example, lactose, sucrose, maize starch, combined with binder from gum acacia, maize starch or gelatin, disintegrants such as potato starch or crosslinked polyvinylpyrrolidone (PVPP) and lubricants such as stearic acid or magnesium stearate.

Examples of excipients suitable for soft gelatin capsules are vegetable oils, waxes, fats, semisolid and liquid polyols etc.

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

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, semiliquid or liquid polyols etc.

For parenteral administration, the compounds can be formulated as injectable dosage of the active ingredient in a liquid or suspension. The preparations usually comprise a physiologically tolerated sterile solvent which may comprise a water-in-oil emulsion, with or without surfactant, and other pharmaceutically acceptable excipients. Oils which can be used for such preparations are paraffins and triglycerides of vegetable, animal or synthetic origin, such as, for example, peanut oil, soya 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 may be administered as transdermal patch system, as depot injection or implant if the formulation makes sustained delivery of the active ingredient possible. The active substance can be compressed as granules or to narrow cylinders and be administered subcutaneously or intramuscularly as depot injection or implant.

The pharmaceutical products may in addition also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, aromatizing agents, salts to change the osmotic pressure, buffers, coating agents or antioxidants. They may also comprise other therapeutically valuable substances too.

The compounds of the invention described herein permit the following methods of use:

- as therapeutic combination in the form of a product or of a kit which is composed of individual components consisting of a compound described herein, in free form or as pharmaceutically usable salt, and at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, an antidiabetic, an obesity-reducing or a lipid- lowering effect, which can be used either simultaneously or sequentially. The product and the kit may comprise instructions for use.

- as method for combined use, such as, for example, in simultaneous or sequential succession, of a therapeutically effective amount of a compound described herein, in free or in pharmaceutically usable salt form, and of a second active ingredient with blood pressure- lowering, inotropic, antidiabetic, obesity-reducing or lipid-lowering effect.

The compounds described herein and their pharmaceutically usable salts can be used in combination with

(i) one or more blood pressure-lowering active ingredients, as such for example: renin inhibitors such as aliskiren; angiotensin Il receptor blockers such as candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan etc.;

ACE inhibitors such as quinapril, ramipril, trandolapril, lisinopril, captopril, enalapril etc.; calcium antagonists such as nifedipine, nicardipine, verapamil, isradipine, nimodipine, amlodipine, felodipine, nisoldipine, diltiazem, fendiline, flunarizine, perhexiline, gallopamil etc.; diuretics such as hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, etacrynic acid, furosemide, indacrinone, metolazone, triamterene, chlortalidone, etc.; aldosterone receptor blockers such as spironolactone, eplerenone; endothelin receptor blockers such as bosentan; phosphodiesterase inhibitors such as amrinone, sildenafil; direct vasodilators such as dihydralazine, minoxidil, pinacidil, diazoxide, nitroprusside, flosequinan etc., α- and β-receptor blockers such as phentolamine, phenoxybenzamine, prazosin, doxazosin, terazosin, carvedilol, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol etc.; neutral endopeptidase (NEP) inhibitors; sympatholytics such as methyldopa, clonidine, guanabenz, reserpine (ii) one or more agents having inotropic activity, as such for example: cardiac glycosides such as digoxin; β-receptor stimulators such as dobutamine thyroid hormone such as thyroxine (iii) one or more agents having antidiabetic activity, as such for example: insulins such as insulin aspart, insulin human, insulin lispro, insulin glargine and further fast-, medium- and long-acting insulin derivatives and combinations insulin sensitizers such as rosiglitazone, pioglitazone; sulphonylureas such as glimepiride, chlorpropamide, glipizide, glyburide etc.; biguanides such as metformin; glucosidase inhibitors such as acarbose, miglitol; meglitinides such as repaglinide, nateglinide; (iv) one or more obesity-reducing ingredients, as such for example: lipase inhibitors such as orlistat; appetite suppressants such as sibutramine, phentermine; (v) one or more lipid-lowering active ingredients, such as, for example,

HMG-CoA reductase inhibitors such as lovastatin, fluvastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin etc.; fibrate derivatives such as fenofibrate, gemfibrozil etc.; bile acid-binding active ingredients such as colestipol, colestyramine, colesevelam cholesterol absorption inhibitors such as ezetimibe nicotinic acid such as niacin and other agents which are suitable for the treatment of high blood pressure, heart failure or vascular disorders associated with diabetes and renal disorders, such as acute or chronic renal failure, in humans and animals. Such combinations can be used separately or in products which comprise a plurality of components.

The compounds described herein and their pharmaceutically usable salts can additionally be used in combination with

(i) a diagnostic test system which permits quantitative determination of the plasma aldosterone level (PAC, plasma aldosterone concentration) (ii) a diagnostic test system which permits quantitative determination of the plasma renin level (PRC, plasma renin concentration) (iii) a diagnostic test system which permits quantitative determination of the plasma renin activity (PRA, plasma renin activity) (iv) a diagnostic test system which permits quantitative determination of the plasma aldosterone / renin level (ARC, aldosterone renin concentration) (v) a diagnostic test system which permits quantitative determination of the plasma aldosterone / renin activity (ARR, aldosterone to renin activity ratio) (vi) a diagnostic test system which permits quantitative determination of the plasma

Cortisol level (PCC, plasma Cortisol concentration)

Such diagnosis-therapy combinations can be used separately or in products which comprise a plurality of components.

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

* contains 0.1% trifluoroacetic acid

The following abbreviations are used:

Rf ratio of the distance migrated by a substance to the distance of the solvent 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

4-(5.6,6a.7.8,9-HexahydrO-4H-imidazor4.5.1.iπαuinolin-4-yl)-benzonitrile

7.740 mmol potassium tert-butoxide are added to a solution of 3.870 mmol of 4-[7-(2-chloro- ethyl)-4.5,6,7-tetrahydrobenzoimidazol-1-ylmethyl]benzonitrile in 20 ml of tetrahydrofuran at room temperature. The reaction mixture is stirred for 30 minutes. Saturated aqueous ammonium chloride solution is added, and the mixture is extracted with dichloromethane (3X). The organic phase is separated off, dried with sodium sulphate and evaporated. The title compound is obtained from the residue as a brownish foam by flash chromatography (SiO₂60F). Rf = 0.38 (toluene:methanol = 85:15); Rt = 5.64.

The starting materials are prepared as follows:

a) 4-r7-(2-Chloroethyl)-4,5.6,7-tetrahydrObenzoimidazol-1-ylmethyllbenzonitrile hydrochloride

7.460 mmol of thionyl chloride are added to a solution of 3.730 mmol of 4-[7-(2-hydroxy- ethylH.S.βJ-tetrahydrobenzoimidazol-i-ylmethylJberizonitrile in 30 ml of chloroform. The reaction mixture is heated to reflux for 3 hours and then cooled to room temperature and evaporated. The crude title compound is obtained from the residue as brown foam. Rf (free base) = 0.38 (toluene:methanol = 85:15); Rt = 6.04.

b) 4-r7-(2-Hydroxy-ethyl)-4.5.6.7-tetrahvdrobenzoimidazol-1-ylmethvπbenzonitrile 14.250 mmol of 4-bromomethylbenzonitrile are added to a solution of 5.700 mmol of 4-[2- (tert-butyldimethylsilanyloxy)ethyl]-1 -trityl-4,5,6,7-tetrahydro-1 H-benzoimidazole and 8.550 mmol of triethylamine in 100 ml of acetonitrile. The reaction mixture is then heated to reflux for 4 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in a tetrahydrofuran/water mixture (5:1), mixed with 4 ml of 4M HCI and stirred at 50⁰C for 4 hours. The reaction mixture is cooled, diluted with water and washed with diethyl ether (2X). The ether phase contains impurities and is discarded. The aqueous phase is made alkaline with 2M NaOH and extracted with ethyl acetate (3X). The organic phase is separated off, dried with sodium sulphate and evaporated. The title compound is obtained as white foam from the residue by flash chromatography (SiO₂60F). Rf = 0.30 (toluene:methanol = 85:15); Rt = 4.59.

c) 4-f2-(tert-Butyl-dimethylsilanyloxy)ethvn-1-trityl-4.5,6.7-tetrahvdro-1 H-benzoimidazole 8.800 mmol of tert-butyldimethylchlorosilane are added to a solution of 7.300 mmol of 2-(1- trityl-4,5,6,7-tetrahydro-1H-benzoimidazol-4-yl)ethanol and 8.8 mmol of triethylamine in 50 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. The solution is washed with water (2X). The organic phase is dried with sodium sulphate and evaporated. The crude title compound is obtained as yellowing oil from the residue. Rf = 0.93 (ethyl acetate); Rt = 10.44.

d) 2-(1-Trityl-4.5.6.7-tetrahvdro-1H-benzoimidazol-4-yl)ethanol

23.700 mmol of (1-trityl-4,5,6,7-tetrahydro-1H-benzoimidazol-4-yl)acetic acid are added in portions to a suspension of 17.800 mmol of lithium aluminium hydride in 100 ml of tetrahydrofuran while cooling in ice. The mixture is stirred at room temperature for 1 hour. The reaction mixture is cooled in ice while being quenched cautiously with a water/tetrahydrofuran mixture, followed by aqueous sodium hydroxide solution. The suspension is filtered through kieselguhr. The filtrate is concentrated, and the residue is taken up in ethyl acetate and again filtered through kieselguhr. The filtrate is washed with water (2X), dried over sodium sulphate and evaporated. The title compound is obtained as a white foam from the residue by flash chromatography (SiO₂60F). Rf = 0.44 (toluene:methanol = 85:15); Rt = 7.78. e) (1-Trityl-4.5.6.7-tetrahvdro-1 H-bβnzoimidazol-4-vnacetic acid

A solution of 24.290 mmol of (1-trityl-4,5,6,7-tetrahydro-1H-benzoimidazol-4-yl)acetonitrile in a mixture of 60 ml of ethanol and 60 ml of 4M NaOH is stirred at an oil bath temperature of 100⁰C for 16 hours. The reaction mixture is evaporated and the residue is suspended in water. The aqueous phase is adjusted to pH 5 and extracted with dichloromethane several times. The organic phase is separated off, dried with sodium sulphate and evaporated. The crude title compound is obtained as a pale brown foam from the residue. Rf = 0.35 (toluene:methanol = 85:15); Rt = 7.64.

f) (1 -Trityl-4.5,6.7-tetrahvdro-1 H-benzoimidazol-4-vOacetonitrile

31.240 mmol of methanesulphonyl chloride are added to a suspension of 28.400 mmol of (1-trityl-4,5,6,7-tetrahydro-1H-benzoimidazol-4-yl)methanol and 42.600 mmol of triethylamine in 100 ml of dimethyl sulphoxide at room temperature. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 500 ml of water and extracted with dichloromethane (3X). The organic phase is dried with sodium sulphate and evaporated. The residue is taken up in 100 ml of dimethyl sulphoxide and, after addition of 284.000 mmol of sodium cyanide, stirred at 100°C for 16 hours. The reaction mixture is cooled to room temperature, mixed with water and extracted with toluene (3X). The organic phase is dried with sodium sulphate and evaporated. The crude title compound is obtained as a white foam from the residue. Rf = 0.40 (toluene:methanol = 85:15); Rt = 7.75.

g) (1 -Trityl-4,5.6.7-tetrahvdro-1 H-benzoimidazol-4-vDmethanol

A solution of 91.630 mmol of 1 -trityM.S.ej-tetrahydro-i H-benzoimidazol-4-carboxylic acid ethyl ester in 100 ml of tetrahydrofuran is added dropwise to a suspension of 68.720 mmol of lithium aluminium hydride in 300 ml of tetrahydrofuran at room temperature. After the addition is complete, the mixture is stirred at room temperature for 2 hours. While cooling in ice, 3.0 ml of a water/tetrahydrofuran mixture (1:1) are added dropwise to the reaction mixture, followed by 6.0 ml of 15% strength NaOH and 9.0 ml of water. The mixture is stirred at room temperature for 30 minutes. The suspension is filtered, the filtercake is washed with tetrahydrofuran, and the filtrate is evaporated. The crude title compound is obtained as a white crystalline solid from the residue. Rf = 0.40 (toluene:methanol = 85 : 15); Rt = 7.47.

h) 1-Trityl-4.5.6J-tetrahvdro-1 H-benzoimidazol-4-carboxylic acid ethyl ester 657.600 mmol of pyridine and 219.200 mmol of triphenylchloromethane are added to a solution of 219.200 mmol of 4,5,6,7-tetrahydro-3H-benzoimidazole-4-carboxylic acid ethyl ester [58729-56-9] in 400 ml of N,N-dimethylformamide. The reaction mixture is stirred at a bath temperature of 50⁰C for 16 h. The reaction mixture is cooled to room temperature and poured into ice-water while stirring. The aqueous phase is extracted several times with ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The crude title compound is obtained as a brown oil from the residue. Rf = 0.15 (heptane:ethyl acetate = 1:1); Rt = 8.22.

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

Examples:

2 4-(3A5.5a.6J.8.9-Octahvdro-1 ,2a-diazabenzo|c.dlazulen-3-yl)-benzonitrile starting from 1,4,5,6,7,8-hexahydrocycloheptaimidazolθ^-carboxylic acid ethyl ester [58729- 58-1].

3 4-(3.4.4a.5.6.7-Hexahvdro-2.7a-diazacvclopentarcdlinden-7-yl)-benzonitrile starting from 3,4,5,6-tetrahydrocyclopentaimidazole-4-carboxylic acid ethyl ester.

The starting material is prepared as follows:

a) 3.4.5,6-Tetrahvdrocvclopentaimidazole-4-carboxylic acid ethyl ester

A solution of 2 mmol of 3-bromo-2-oxocyclopentancarboxylicacid ethyl ester [42593-13-5] in

26 mmol freshly distilled formamide is heated to reflux for 1.5 hours. The excess formamide is evaporated off and the residue is taken up in water. The aqueous solution is washed with diethyl ether, adjusted to pH 8-9 with aqueous sodium carbonate solution and extracted with chloroform (3X). The combined organic phases are dried with sodium sulphate and evaporated.

The crude title compound is obtained from the residue.

4 4-(4.5.5a.7.8.9-Hexahvdro-3H-6-oxa-1.2a-diazabenzofcd1azulen-3-yl)-benzonitrile starting from 4-bromo-3-oxooxepane-2-carboxylic acid ethyl ester.

The starting material is prepared as follows:

a) 4-Bromo-3-oxooxepane-2-carboxylic acid ethyl ester

2.5 mmol of bromine are added dropwise to 1.97 mmol of 3-oxooxepane-2-carboxylic acid ethyl ester [115399-66-1] at 0⁰C. After the addition is complete, the reaction mixture is stirred at 0⁰C for 15 minutes. The mixture is taken up in diethyl ether and washed successively with water, saturated aqueous sodium bicarbonate solution and again with water. The organic phase is dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

Example 5

4-(3.4.5.5a.7.8-HexahydrO-6-oxa-1,2a-diazaacenaphthylen-3-yl)-benzonitrile

28.400 mmol of (i-trityl-i^.^β.Z-tetrahydropyranoβΛ-dJimidazoM-ylJmethanol are reacted in analogy to Example 1 (starting from 1f). The title compound is identified on the basis of the

Rf.

The starting materials are prepared as follows:

a) (1 -Tritγl-1 ,4.6.7-tetrahydro-pyranor3.4-d1imidazol-4-yl)-methanol 219.200 mmol of (1,4,6_l7-tetrahydro-pyrano[3,4-d]imidazol-4-yl)methanol [100650-76-8] are reacted in analogy to Example 1, method 1h. The title compound is identified on the basis of the Rf.

The following compound is prepared in an analogous manner to the process described in Example 5:

6 4-(5.6.7.7a-Tetrahvdro-2H-1-oxa-3.4a-diazacvclopentarcd1inden-5-yl)-benzonitrile 28.400 mmol of 1-trityl-4,6-dihydro-1H-furo[3,4-d]imidazole-4-carboxylic acid ethyl ester are reacted in analogy to Example 1 (starting from 1g). The title compound is identified on the basis of the Rf. The starting materials are prepared as follows:

a) i-TritvM.β-dihvdro-IH-furorS^-dlimidazole^-carboxylic acid ethyl ester

250 mmol of triethylamine are added to a solution of 49 mmol of hydroxy-(5-hydroxymethyl- 1-trityl-1H-imidazol-4-yl)acetic acid ethyl ester in 500 ml of dichloromethane under an argon atmosphere, and cooled to 0⁰C. 49 mmol of methanesulphonyl chloride are added dropwise. The reaction mixture is stirred at 0⁰C for 1 hour and diluted with dichloromethane. The mixture is washed with 1 M aqueous citric acid solution and then with brine, dried with sodium sulphate and evaporated. The residue is dissolved in 200 ml of dimethylformamide under an argon atmosphere, and 49 mmol of sodium hydride dispersion (60%) are added in portions. The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with water and extracted with ethyl acetate (3X). The combined organic phases are washed with 1 M aqueous sodium bisulphate solution and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

b) Hvdroxy-re-hvdroxymethyl-i-trifyl-IH-imidazoM-vOacetic acid ethyl ester

24 mmol of sodium borohydride are added in portions to a solution of 23 mmol of [(tert- butyldimethylsilanyl)methoxy]-(5-formyl-1-trityl-1H-imidazol-4-yl)acetic acid ethyl ester in 55 ml of methanol at 0⁰C. After the addition is complete, the mixture is stirred at room temperature for 1 hour. It is evaporated, and the residue is taken up with ethyl acetate and washed with 1 M aqueous sodium bicarbonate solution, dried with sodium sulphate and evaporated. The residue is taken up in 50 ml of tetrahydrofuran, and 27.6 mmol of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) are added. The reaction solution is stirred at room temperature for 8 hours, diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

c) rftert-ButyldimethylsilanvDmethoxyKS-formyl-i-trityl-IH-imidazoM-vQacetic acid ethyl ester A solution of 7 mmol [(tert-butyldimethylsilanyl)methoxy]-(1-trityl-5-vinyl-1H-imidazol-4- yl)acetic acid ethyl ester and 8.4 mmol of N-methylmorpholine N-oxide in 200 ml of a tetrahydrofuran-tert-butanol-water solvent mixture (4:4:1) is stirred at room temperature for

30 minutes. Then 2.7 mmol of osmium tetroxide are added, and the reaction mixture is stirred at room temperature for 16 hours. It is diluted with 2 M aqueous sodium thiosulphate solution and ethyl acetate and stirred for 3 hours. The phases are separated, and the organic phase is washed with brine, dried with sodium sulphate and evaporated. The residue is dissolved in 200 ml of ethyl acetate, and 10 mmol of lead tetraacetate are added. The reaction mixture is stirred at room temperature for 10 minutes. It is filtered through silica gel and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

d) r(tert-Butyl-dimethylsilanv0methoxyK1-trityl-5-vinyl-1 H-imidazol-4-yl)acetic acid ethyl ester 4 mmol of tetrakistriphenylphosphinepalladium are added to a solutiom of 80 mmol of (S-bromo-i-trityl-IH-imidazoM-yOKtert-butyldimethylsilanyOmethoxylacetic acid ethyl ester and 96 mmol of vinyl-tri-n-butyltin in 500 ml of dimethylformamide under an argon atmosphere. The reaction mixture is stirred at 85°C for 12 hours and cooled to room temperature. The reaction mixture is diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

e) (S-Bromo-i-trityl-IH-imidazoM-vDrftert-butyldimethylsilanvDmethoxyiacetic acid ethyl ester A solution of 90 mmol of [(tert-butyldimethylsilanyOmethoxyHI-trityl-IH-imidazoM-ylJacetic acid ethyl ester in 200 ml of acetonitrile is cooled to 0⁰C under an argon atmosphere, and

90 mmol of N-bromosuccinimide are added. The reaction mixture is stirred for 3 hours, and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂ 60F) on the basis of the Rf.

f) fftert-Butyldimethylsilanvπmethoxyld-trityl-IH-imidazoM-vDacetic acid ethyl ester

100 mmol of hydroxy-(1-trityl-1H-imidazol-4-yl)acetic acid ethyl ester are reacted in analogy to Example 1c. The title compound is identified on the basis of the Rf.

g) Hvdroxy-π-trityl-IH-imidazol^-vDacetic acid ethyl ester

0.12 mol of 4-tributylstannanyl-1-trityl-1H-imidazole [208934-35-4] is added to a solution of 0.1 mol of glyoxylic acid ethyl ester and 20 mmol of [Rh(COd)(MeCN)₂]BF₄ in 100 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is heated at 60⁰C for 20 hours. The reaction mixture is cooled to room temperature, quenched with a little water and stirred at room temperature for 1 hour. 2 I of diethyl ether are added to the mixture, and the precipitated solid is filtered off. The filtrate is evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf. Example 7

4-(6-Oxo^.5.6JΛ9-hexahvdro-3H-1,2a.5a-triazabenzorcx.lazulen-3-yl)-benzonitrile 3.12 mmol of 4-[2-(tert-butyldimethylsilanyloxy)ethyl]-1 -trityl-4,6,7,8-tetrahydro-1 H-1 ,3,4- triazaazulen-5-one are reacted in analogy to Example 1 (starting from 1 b). The title compound is identified on the basis of the Rf.

The starting materials are prepared as follows:

a) 4-f2-(tert-Butyldimethylsilanyloxytethyll-1 -tritvM,6,7,8-tetrahydro-1 H-1 ,3,4-triazaazulen-5-one 1.43 mmol of sodium hydride dispersion (60%) are added in portions to a solution of

1.36 mmol of i-trityM.βJ.β-tetrahydrO-IH-I.S^-triazaazulen-S-one in 2.5 ml of dimethylformamide. The solution is stirred at room temperature for 30 minutes. 1.56 mmol of (2-bromoethoxy)-tert-butyldimethylsilane [86864-60-0] are slowly added to the reaction mixture, which is then stirred at room temperature for 4 hours. Water and diethyl ether are added to the reaction mixture, and the phases are separated. The aqueous phase is extracted with diethylether (2X). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

b) 1-Trityl-4.6.7.8-tetrahvdro-1 H-1 ,3.4-triaza-azulen-5-one

2 mmol of p-toluenesulphonyl chloride and a catalytic amount of dimethylaminopyridine are added to a solution of 1 mmol of 1-trityl-1,5,6,7-tetrahydrobenzoimidazol-4-one oxime in 5 ml of anhydrous pyridine. The solution is stirred at 20⁰C for 24 hours. Water is added, and the mixture is extracted with dichloromethane (3X). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf. c) 1-Trityl-1 ■S.ΘJ-tetrahvdrobenzoimidazoM-one oxime

2.21 mmol of sodium acetate and 2.16 mmol of hydroxylamine hydrochloride are added to a solution of 0.71 mmol of 1-trityl-1_l5_l6_l7-tetrahydrobenzoimidazol-4-one in 5 ml of methanol. The reaction mixture is stirred for 20 hours and quenched by adding 10 ml of buffer solution of pH 7. Methanol is removed by concentration, and the residue is diluted with 10 ml of dichloromethane. The phases are separated, and the aqueous phase is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

d) 1 -Trityl-1.5.6.7-tetrahvdrobenzoimidazol-4one

4.1 mmol of 1,5,6,7-tetrahydrobenzoimidazol-4-one [70500-91-3] are reacted in analogy to Example 1h. The title compound is identified on the basis of the Rf.

The following compound is prepared in an analogous manner to the process described in Example 7: .

8 4-(6-Oxo-4.5.7.8-tetrahvdro-3H.6H-1.2a.5a-triazaacenaphthylen-3-yl)benzonitrile starting from 5,6-dihydro-1 H-cyclopentaimidazol-4-one.

The starting materials are prepared as follows:

a) δ.e-Dihvdro-IH-cvclopentaimidazoM-one

A mixture of 193 mmol of N-(2-hydroxy-5-oxocyclopent-1-enyl)formamide with 140 ml of formic acid and 560 ml of formamide is heated at 150⁰C for 30 minutes. The solution is evaporated and the residue is heated in 450 ml of a freshly prepared solution of acetic formic anhydride in acetic acid (prepared according to L. F. Fieser & M. Fieser, 'Reagents for Organic Synthesis', 1, 4, D. Wiley & Sons 1967) at 100^βC for 1 hour. The solution is evaporated and dehydrated with toluene (2X). The title compound is identified from the residue by flash chromatography (SiO₂ 60F) on the basis of the Rf.

b) N-(2-Hvdroxy-5-oxocvclopent-1-envπformamide

A solution of 382 mmol of 2-amino-3-hydroxycyclopent-2-enone [22351-59-3] in 2.3 I of glacial acetic acid is hydrogenated with 250 ml of a freshly prepared solution of acetic formic anhydride in acetic acid over 35 g of palladium on carbon (5%) under an atmosphere of 4 bar of hydrogen for 72 hours. The catalyst is filtered off, and the filtrate is concentrated and dehydrated twice with toluene. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf.

Example 9

4-(4.5.5a.6.8.9-HexahvdrO-3H-7-oxa-1.2a-diazabenzorcdlazulen-3-vhbenzonitrile 3.12 mmol of 8-[2-(tert-butyldimethylsilanyloxy)ethyl]-1 -trityM.SJ.β-tetrahydro-i H-6-oxa-1 ,3- diazaazulene are reacted in analogy to Example 1b. The title compound is identified on the basis of the Rf.

The starting materials are prepared as follows:

a) 8-r2-(tert-Butyldimethylsilanyloxy)ethyll-1 -trityl-4.5.7.8-tetrahydrO-1 H-6-oxa-1.3- diazaazulene

5 mmol of 4-(tert-butyldimethylsilanyloxy)-2-[5-(2-hydroxyethyl)-3-methyl-3H-imidazol-4- yl]butan-1-ol are reacted in analogy to Example 6a. The title compound is identified on the basis of the Rf.

b) 4-(tert-Butyldimethylsilanyloxy)-2-r5-(2-hvdroxyethyl)-3-trityl-3H-imidazol-4-yllbutan-1-ol A solution of 6.6 mmol of 4-(tert-butyldimethylsilanyloxy)-2-[3-methyl-5-(2- triethylsilanyloxyethyl)-3H-irnidazol-4-yl]butan-1-ol in 500 ml of a solution of 2% hydrogen fluoride in acetonitrile is stirred at room temperature for 2 hours. The reaction solution is diluted with tert-butyl methyl ether, washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂60F) on the basis of the Rf. c) 4-(tert-Butyldinnethylsilanyloxy)-2-r5-(2-triethylsilanyloxyethvn-3-trityl-3H-imiclazol- 4yllbutan-1-ol

10 mmol of 3-(tert-butyldimethylsilanyloxy)-1-[3-methyl-5-(2-triethylsilanyloxyethyl)-3H- imidazol-4-yl]-propan-1-ol are reacted in analogy to Example 1, methods 1f, 1e and 1d. The title compound is identified on the basis of the Rf.

d) 3-(tert-Butyldimethylsilanyloxy)-1-r5-(2-triethylsilanyloxyethyl)-3-trityl-3H-imidazoM-yll- propan-1-ol

A crystal of iodine is added to a mixture of 63.6 mmol of magnesium turnings in 30 ml of tetrahydrofuran. 53.0 mmol of (2-bromoethoxy)-tert-butyldimethylsilane [86864-60-0] are added dropwise in such a way that the reaction mixture refluxes gently. The mixture is stirred at 40⁰C for 1 hour. The supernatant Grignard solution is added dropwise to a solution of 63 mmol of 5-(2-methoxyethyl)-3-trityl-3H-imidazol-4-carbaldehyde in 480 ml of tetrahydrofuran at 0⁰C. After the addition, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. It is extracted with tert-butyl methyl ether (2X). The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂ 60F) on the basis of the Rf.

e) 5-(2-MethoxyethvD-3-trityl-3H-imidazole-4-carbaldehvde

70 mmol of 4-(2-triethylsilanyloxyethyl)-1-trityl-1H-imidazole are reacted in analogy to Example 6, methods 6e, 6d and 6c. The title compound is identified on the basis of the Rf.

f) 4-(2-Triethylsilanyloxyethyl)-1 -trityl-1 H-imidazole

88 mmol of triethylchlorosilane are added to a solution of 73 mmol of 2-(1 -trityl-1 H-imidazol- 4-yl)ethanol [127607-62-9] and 88 mmol of triethylamine in 500 ml of dichloromethane, and the mixture is stirred at room temperature for 1 hour. It is washed with water (2X), and the organic phase is dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.

The following compoud is prepared in an analogous manner to the process described in Example 9:

10 4-(4.5.5a.8-Tetrahvdro-3H.6H-7-oxa-1.2a-diazaacenaphthylen-3-yl)benzonitrile starting from (1 -trityl-1 H-imidazol-4-yl)-methanol [33769-07-2]. Examplθ 11

4-(6-Oxo-3A5.5a.6.7.8.9<)ctahvdro-1.2aJ-triazabertzofcdlazulen-3-v0benzonitrile A solution of 4 mmol of 3-(4-cyanophenyl)-6-oxo-4,5,5a,6,8,9-hexahydro-3H-1 ,2a,7- triazabenzo[cd]azulene-7-carboxylic acid tert-butyl ester in 50 ml of dichloromethane is cooled to 0⁰C, and 18 ml of trifluoroacetic acid are added. The reaction mixture is stirred at 0^βC for 2 hours, and the solvent is evaporated. The title compound is identified from the residue by flash chromatography (SiO₂ 60F) on the basis of the Rf.

The starting materials are prepared as follows:

a) S^-CvanophenvD-β-oxo^.S.δa.β.S.Q-hexahvdro-SH-i^a.T-triazabenzorcdiazulene-Z- carboxylic acid tert-butyl ester

5.5 mmol of 8-[2-(tert-butyldimethylsilanyloxy)ethyl]-7-oxo-1-trityl-4,5,7,8-tetrahydro-1 H- imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester are reacted in analogy to Example 1 (starting from 1b). The title compound is identified on the basis of the Rf.

b) 8-r2-(tert-Butyldimethylsilanyloxy)ethvH-7-oxo-1-trityl-4.5.7.8-tetrahvdro-1H-imidazor4,5- dlazepine-6-carboxylic acid tert-butyl ester

10 mmol of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride are added to a solution of 5 mmol of 2-[5-(2-aminoethyl)-3-trityl-3H-imidazol-4-yl]-4-(tert-butyldimethylsilanyloxy)- butyric acid, 25 mmol of triethylamine and 10 mmol of 1-hydroxybenzotriazole hydrate in 40 ml of dichloromethane. The solution is stirred at room temperature for 12 hours, diluted with tert-butyl methyl ether and washed with 0.1 M HCI. The phases are separated, and the aqueous phase is extracted with tert-butyl methyl ether (2X). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The residue is dissolved in 100 ml of dichloromethane and cooled to 0⁰C. 0 mmol of diisopropylethylamine and 10 mmol of di-tert-butyl dicarbonate are added. The reaction mixture is slowly warmed to room temperature and stirred for 10 hours. The reaction mixture is poured into water, and the phases are separated, and the aqueous phase is extracted with dichloromethane (2X). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO₂ 60F) on the basis of the Rf.

c) 2-r5-(2-Aminoethyl)-3-trityl-3H-imidazol-4-vn-4-(tert-butyldimethylsilanyloxy)butyric acid 6.3 mmol of 2-[5-(2-aminoethyl)-3-trityl-3H-imidazol-4-yl]-4-(tert-butyldimethylsilanyloxy)- butyronitrile are reacted in analogy to Example 1e. The title compound is identified on the basis of the Rf.

d) 2-r5-(2-Aminoethyl)-3-trityl-3H-imidazol-4-vn-4-(tert-butyldimethylsilanyloxy)butyronitrile 10 ml of an aqueous methylamine solution (40%) are added to a solution of 8.04 mmol of 4-(tert-butyldimethylsilanyloxy)-2-{5-[2-(1,3-dioxo-1_l3-dihydroisoindol-2-yl)ethyl]-3-trityl-3H- imidazol-4-yl}butyronitrile in 100 ml of ethanol. The crude title compound is obtained by evaporation after 3 hours.

e) 4-(tert.-Butyldimethylsilanyloxy)-2-f5-r2-(1.3-dioxo-1.3-dihvdroisoindol-2-yl)ethvn-3-trityl- 3H-imidazol-4-yl)butyronitrile

9.5 mmol of 2-(2-{5-[3-(tert-butyldimethylsilanyloxy)-1-hydroxypropyl]-1-trityl-1 H-imidazol-4- yl}ethyl)isoindole-1,3-dione are reacted in analogy to Example 1f. The title compound is identified on the basis of the Rf.

f) 2-(2-f5-f3-(tert-ButyldimethylsilanyloxyV1 -hydroxypropylM -trityl-1 H-imidazol-4-yl}-ethyl)- isoindole-1 ,3-dione

20 mmol of 2-[2-(1-trityl-1H-imidazol-4-yl)ethyl]isoindole-1,3-dione are reacted in analogy to Example 9, methods 9f, 9e and 9d. The title compound is identified on the basis of the Rf.

g) 2-r2-(1 -Trityl-1 H-imidazol-4-yl)ethyllisoindole-1 ,3-dione

74.8 mmol of phthalimide and 74.8 mmol of triphenylphosphine are added to a solution of 50 mmol of 2-(1-trityl-1H-imidazol-4-yl)ethanol [127607-62-9] in 480 ml of tetrahydrofuran at 0⁰C. A solution of 106.9 mmol of diisopropyl azodicarboxylate in 500 ml of tetrahydrofuran is added dropwise over the course of 1.5 hours. The reaction mixture is concentrated, and the precipitated product is filtered off and washed with tetrahydrofuran (3X). The title compound is identified on the basis of the Rf.

The following compound is prepared in an analogous manner to the process described in Example 11 :

12 4-(6-Oxo-4.5.5a.6,7,8-hexahvdro-3H-1.2a.7-triazaacenaphthylen-3-yl)benzonitrile starting from (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2].

Claims

Claims

1. Compound of the general formula

in which

V is C or, if X is C, it is also N;

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

Y is C;

Z is C or a bond; where V and Y form, with inclusion of X, a 5-9-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted by 1-4 Ci-C₈-alkyl, C₀-C₈-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, Ci-C₈-alkoxy or Ci-Cβ-alkoxycarbonyl; R¹ is Ci-Cβ-alkyl, C₃-C₈-cycloalkyl, C₂-C_β-alkenyl, C₂-C₈-alkynyl, aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-C₄-alkyl, which radicals are unsubstituted or substituted by 1-4 Ci-Qβ-alkyI, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, C₀-C₈- alkylcarbonylamino, Co-C₈-alkylcarbonyl-Ci-C₈-alkylamino, carbamoyl, mono- or di-Ci-C₈- alkylaminocarbonyl, carboxy-Co-C4-alkyl, Ci-C₈-alkoxy, Ci-C₈-alkoxycarbonyl, heterocyclyl or aryl, where heterocyclyl or aryl may be substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, Ci-C₈-alkylsulfonyl, cyano, oxo, tri-Ci-C₄-alkylsilyl, trifluoromethoxy, trifluoromethyl, Co-Cβ-alkylcarbonylamino, Co-Cβ-alkylcarbonyl-Ci-Cβ-alkylamino, carbamoyl, mono- or di-d- Cβ-alkylaminocarbonyl, carboxy-C₀-C₄-alkyl, Ci-C₈-alkoxy or Ci-Cβ-alkoxycarbonyl; R² a) is hydrogen; or b) is d-Cβ-alkyl, C₃-C₈-cycloalkyl, halogen, carboxy-Ci-C₄-alkyl, C₁-C₄-alkoxycarbonyl- Co-C₄-alkyl, C₀-C₄-alkylcarbonyl, aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-C₄-alkyl, which radicals are unsubstituted or substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, Co-Cβ-alkylcarbonylamino, C₀-C₈-alkylcarbonyl-Ci-C₈- alkylamino, carbamoyl, mono- or di-d-Cβ-alkylaminocarbonyl, carboxy-C₀-C₄-alkyl, CrC₈- alkoxy, Ci-Cβ-alkoxycarbonyl, heterocyclyl or aryl, where heterocyclyl or aryl may be substituted by 1-4 Ci-C₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, C₀- Cβ-alkylcarbonylamino, Co-Cβ-alkylcarbonyl-Ci-Cβ-alkylamino, carbamoyl, mono- or di-Ci-C₈- alkylaminocarbonyl, carboxy-C₀-C₄-alkyl, Ci-C₈-alkoxy or Ci-Cs-alkoxycarbonyl; n is 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, especially pharmaceutically usable salt.

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

where the meanings of the substituents R¹ and R² are as stated in Claim 1 for compounds of the formula (I), and

R is hydrogen, C_rC₈-alkyl, Co-Cβ-alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, C₁-C₈- alkoxy or Ci-C₈-alkoxycarbonyl; m is a number 1, 2 or 3; and p is a number 1 or 2.

3. Compound according to Claim 2, where R is hydrogen or oxo.

4. Compound according to any of Claims 1 to 3, where R¹ is aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-Co-C₄-alkyl, which radical may be substituted by 1-4 Ci-C₈-alkyl, C₀-C₈- alkylcarbonyl, halogen, CrCβ-alkylsulfonyl, cyano, oxo, tri-Ci-C₄-alkylsilyl, trifluoromethoxy, trifluoromethyl, Co-Cβ-alkylcarbonylamino, Co-Cβ-alkylcarbonyl-CrCs-alkylamino, carbamoyl, mono- or di-Ci-Cβ-alkylaminocarbonyl, carboxy-Co-C₄-alkyl, Ci-C₈-alkoxy, CrC₈- alkoxycarbonyl, heterocyclyl or aryl, particularly preferably aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-C₀-C4-alkyl, which radicals may be substituted by 1-4 cyano, C₀-C₈- alkylcarbonyl, oxazolyl, thiazolyl, thiophenyl, pyrrolidinyl orfuryl.

5. Compound according to any of Claims 1 to 4, where R² is hydrogen, halogen, Ci-C₈-alkyl, aryl-C₀-C₄-alkyl or unsaturated heterocyclyl-C₀-C₄-alkyl, particularly preferably hydrogen, halogen or d-C₃-alkyl.

6. Compound according to Claim 1, where n is a number 0 or 1.

7. Compound according to Claim 1 or 2, where R is hydrogen or oxo;

R¹ is aryl-Co-C₄-alkyl or unsaturated heterocyclyl-C₀-C₄-alkyl, which radicals may be substituted by 1-4 cyano, Co-C₈-alkylcarbonyl, oxazolyl, thiazolyl, thiophenyl, pyrrolidinyl or fury I; and R² is hydrogen, halogen or CrQralkyl.

8. Use of a compound of the general formula (I) according to Claim 1 for producing a medicament.

9. Use of a compound of the general formula (I) according to Claim 1 for producing a human medicament for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism.

10. Use of a compound of the general formula (I) according to Claim 1 for producing a human medicament for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive Cortisol release.

11. Method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism, where a therapeutically effective amount of a compound of the general formula (I) according to Claim 1 is used.

12. Method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive Cortisol release, where a therapeutically effective amount of a compound of the general formula (I) according to Claim 1 is used.

13. Pharmaceutical product comprising a compound of the general formula (I) according to Claim 1, and conventional excipients.

14. Pharmaceutical combination in the form of a product or of a kit composed of individual components consisting a) of a compound of the general formula (I) according to Claim 1, and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.