DE102005009705A1 - Use of naphthalene derivatives for the treatment of hyperaldosteronism, heart failure, myocardial fibrosis, hypercortisolism and diabetes mellitus - Google Patents

Abstract

Use of naphthalene derivatives (I) or their salts for the treatment of hyperaldosteronism, heart failure, myocardial fibrosis, hypercortisolism and diabetes mellitus. Use of naphthalene derivatives of formula (I) or their salts for the treatment of hyperaldosteronism, heart failure, myocardial fibrosis, hypercortisolism and diabetes mellitus. Y1>(=C(R9>)2), (=N(R10>)), (=O) or (=S); T1>, U1>, V1>, W1>, X1>C or N; R1>, R2>H, halo, CN, OH, nitro, alkyl, alkoxy, alkyl carbonyl, alkylcarbonyloxy, alkylaminocarbonyl, alkylaminosulfonyl, thioalkyl, alkylsulfinyl or alkyl sulfonyl; R3>nitrogenous mono- or bicyclic heteroaryl residue (where partially or completely saturated equivalents and substituted) and N atom which is not substituted; R4>-R9>H, halo, CN, OH, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkylaminocarbonyl, lower alkyaminosulfonyl, lower thioalkyl, lower alkylsulfinyl, lower alkylsulfonyl, arylalkyloxy, heteroarylalkyloxy; and n : 0-2. Full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are included for (1) a pharmaceutical composition comprising (I); (2) a naphthalene derivative (I) (with provisos); and (3) the preparation of (I). Provided that (in composition): when T1>, U1>, V1>, W1> and X1> are C, n is 1, and Y1> is O, CH2 or -CH, then R3> is not 1-imidazolyl; when T1>, U1>, V1>, W1>, X1> are C, n is 1, R1>, R2>, R4>-R9> is H, and R6> is H or methyl, then R3> is not 3-pyridyl; when T1>, U1>, V1> and Y1> are C, n is 1, R2>, R4>-R8> and R9> are H atom, and R1> is carboxylic acid, then R3> is not 4-pyridyl; when T1>, U1>, V1>, W1> and Y1> are C atom, X1> is N, n is 1, R1>, R2>, R4>, R5> and R7> are H atom, R9> is H or methyl and R8> with Y1> forms a double bond, then R3> is not pyridyl; when T1>, U1>, V1>, W1> and X1> are C, Y1> is N, n is 1, R1>, R2>, R4>-R7> are H and R8> with Y1> forms a double bond, then R3> is not 4-carboxy-2-pyridyl. Provided that: when T1>, U1>, V1>, W1> and X1> are C, n is 1, and Y1> is O, CH2 or -CH, then R3> is not 1-imidazolyl; when T1>, U1>, V1>, W1>, X1> are C, n is 1, R1>, R4>-R9> are H, R2> is H or methoxy and R6> is H or methyl, then R3> is not pyridyl, imidazolyl or oxazolyl; when T1>, U1>, V1>, W1>, X1> are C, n is 1, R2>, R4>-R9> are H and R1> is carboxylic acid, then R3> is not 4-pyridyl; when T1>, U1>, V1>, W1>, X1> are C, n is 1, R1>, R2>, R4>, R5> and R7> are H, R9> is H or methyl and R8> with Y1> forms double bond, then R3> is not pyridyl or quinolyl; when T1>, U1>, V1>, W1> and X1> are C, Y is N, n is 1, R1>, R2>, R4>-R7> are H and R8> with Y1> forms a double bond, then R3> is not 4-carboxy-2-pyridyl, 5-bromo-2-pyridyl, 6 -bromo-2-pyridyl, 5-bromo-3-pyridyl, 2-pyridyl, 3-pyridyl, 2-pyridazinyl, 2-pyrimidinyl or quinolyl; and when T1>, U1>, V1> and W1> are C, n is 1, R1>, R2>, R4>, R5> and R7> are H and R8> with Y1> forms a double bond, then R3> is not pyridyl or 2-quinolyl. [Image] ACTIVITY : Cardiant; Antiinflammatory; Antidiabetic. MECHANISM OF ACTION : Mammalian- P450-oxygenase inhibitor; Human or mammalian-aldosterone synthase or steroid-11beta -hydroxylase inhibitor; Human steroid-11beta -hydroxylase CYP11B1 or aldosterone synthase CYP11B2 inhibitor.

Description

The The invention relates to compounds for the selective inhibition of human Corticoid synthases CYP11B1 and CYP11B2, their preparation and use for the treatment of hypercortisolism and diabetes mellitus Hyperaldosteronism, heart failure and myocardial fibrosis.

Background of the invention

The Adrenal glands of humans are divided into two areas, the adrenal medulla and the adrenal cortex. The latter secretes a number of hormones, which are known as corticoids and fall into two categories. glucocorticoids (especially hydrocortisone or cortisol) act primarily on the Carbohydrate and glucose metabolism, secondarily, they can promote wound healing Intervention in the inflammatory process and delay the formation of fibrosed tissue. The second category, the mineral corticoids, are primary involved in the retention of sodium and the excretion of potassium. The most important and effective mineral corticoid is aldosterone.

The Glucocorticoid biosynthesis is u. a. of adrenocorticotropin (ACTH) controlled. Steroid-11β-hydroxylase (CYP11B1) is the key enzyme the biosynthesis of glucocorticoids in humans. In all diseases, those with elevated Cortisol formation could go along with it thus play a key role in this enzyme. These diseases include Hypercortisolismus, in particular the Cushing syndrome as well as a Special form of diabetes mellitus caused by an extreme morning Increase in cortisol plasma level is characterized.

in the In the case of Cushing's disease, therapy is usually dependent from the cause of the disease. One distinguishes between pituitary hypothalemic or adrenal Cushing syndrome, which is due to Corticoid-producing tumors of the adrenal cortex developed. For the treatment of hypophyseal-hypothalemic Cushing's syndrome is usually neuromodulatory used, such as bromocriptine, cyproheptin, somastatin or valproic acid, the reduce cortisol production through their influence on ACTH release should. This therapy proved to be only in the past not very effective.

At the adrenal Cushing syndrome occurs especially when one surgical removal of the primary tumor not possible is a therapy with inhibitors of steroid biosynthesis. For use come the nonspecific CYP enzyme inhibitors Aminoglutethimide, metyrapone, ketoconazole and mitotane, which are common in Form of a combination therapy. The effect on However, steroidogenesis is due in the case of aminoglutethimide an attack on CYP11A1, the desmolase, or in the case of ketoconazole on the inhibition of CYP17. Also the other mentioned connections act nonspecifically. Both the combination of several unselective Inhibitors of the steroidogenic CYP enzymes as well as the high doses, that need to be used are therapeutically not safe. This is especially with regard to important that the therapy be carried out lifelong must and because of the lack of selectivity of said compounds with serious side effects (Nieman, L.K., Pituitary 5: 77-82 (2002)). An approach here is the therapy with highly selective inhibitors of the key enzyme of glucocorticoid biosynthesis, CYP11B1. So it does not matter how described in the past, to side effect in particular Androgen formation in men (ketoconazole) or mineralcorticoid biosynthesis comes, here is a selectivity of the compounds desired.

Increased cortisol levels are also associated with neurodegenerative diseases brought. The decrease of the ability to remember and learn Exposure to increased Concentrations of both exogenous and endogenous glucocorticoids (Cortisol) has been described (Heffelfinger et al., Dev. Psychopathol. 13: 491-513 (2001)).

In a special form of stress-dependent diabetes mellitus, there is a rapid morning increase in the plasma cortisol concentration. This so-called "dawn phenomenon" is common in type 2 diabetics and is characterized by reduced glucose tolerance and a decrease in insulin sensitivity in the early morning hours, and the dawn phenomenon complicates the diabetes setting, which often requires insulin pump therapy There are findings in the pathologically altered circadian rhythm of the glucose metabolism in type 2 diabetes, which clearly indicate that this disorder is based on an elevation of nocturnal cortisol concentrations (Bolli et al., N. Engl. J. Med. 310 (1984) 746-750; Shapiro et al, J. Clin. Endocrinol. Metab. 72 (1991) 444-454; Schultes and Fehm, The Internist 9 (2004) 983-993).

Farther are elevated in diabetes mellitus Cortisol levels with the emergence of insulin resistance and a impairment glucose tolerance (Phillips et al., J. Biol. Clin. Endocrinol. Metab. 83: 757-760 (1998)). The liver plays one central role in the adjustment of the glucose balance and in the development of glucose intolerance and type 2 diabetes mellitus. Under physiological conditions, the glucose supply is too 25% by gluconeogenesis (synthesis of glucose from lactate, pyruvate, Glycerol and amino acids) in the liver while in diabetes mellitus type 2 patients 90% of glucose in the liver be generated by gluconeogenesis. Antagonize glucocorticoids the insulin action, regulate hepatic glucose release and lead to an increase the blood glucose level in diabetes mellitus. Their effect exists in the control of the transcription of several genes involved in the regulation of hepatic gluconeogenesis (DeFronzo et al., Diabetes Rev. 5 (1997) 177-269).

The tissue-specific response is by the glucocorticoid receptor and the intracellular Synthesis of active glucocorticoids by 11beta-hydroxysteroid dehydrogenase Type 1 (11β-HSD-1) regulated. 11β-HSD-1 catalyzes the formation of cortisol from cortisone in the liver as well in adipocytes and the beta cells of the pancreas and thus controls the glucocorticoid effect in the respective target tissues (Stewart and Krozowski, Vitam. Standard. 57: 249-324 (1999)).

At present becomes the use of inhibitors of 11β-HSD-1 to regulate blood sugar levels tested. Alberts et al. describe in this context that the selective 11β-HSD-1 Inhibitor BVT.2733 in hyperglycemic and hyperinsulinic mice both for reducing blood glucose levels and insulin levels led (Alberts et al., Diabetologica 45 (2002) 1528-1532). Here as well could be selective CYP11B1 inhibitors the increased Cortisol release, leading to the increase in blood glucose concentration and reduce insulin sensitivity.

The use of inhibitors of 11β-HSD-1 for the regulation of blood sugar levels is described, for example, in US Pat EP 1461333 described. The indications for 11β-HSD-1 inhibitors apply accordingly to the use of CYP11B1 inhibitors.

Also could be here the inhibition of glucocorticoid biosynthesis by direct and selective inhibition of the key enzyme CYP11B1 represent a therapeutic alternative.

The Aldosterone secretion is regulated by a variety of signals: the plasma concentrations of sodium and potassium and that over several Stepping renin-angiotensin-aldosterone system (RAAS). This system is used in response to low blood pressure from the Kidneys renin which releases angiotensin I from a precursor peptide. Angiotensin I is in turn cleaved to angiotensin II, which comprises 8 amino acids and a potent vasoconstrictor. It also acts as a hormone for stimulating the release of aldosterone (Weber, K. T. & Brilla, C.G. Circulation 83: 1849-1865 (1991)).

The key enzyme mineral corticoid biosynthesis, CYP11B2 (aldosterone synthase), a mitochondrial cytochrome P450 enzyme catalyzes the formation of the most potent mineral corticosteroid aldosterone from its steroidal Substrate 11-deoxycorticosterone (Kawamoto, T. et al., Proc Natl Acad Sci., USA 89: 1458-1462 (1992)). Excessive plasma aldosterone concentrations are associated with conditions such as congestive heart failure and congestive heart failure, myocardial fibrosis, ventricular arrhythmia, Stimulation of cardiac fibroblasts, cardiac hypertrophy, renal Mild perfusion and hypertension, and they are in the process of progression involved in these diseases (Brilla, C.G., Herz 25: 299-306 (2000)). Especially in patients with chronic heart failure or renal perfusion or renal artery stenosis occurs in the Contrary to the physiological effect of the renin-angiotensin system (RAAS) its pathophysiological activation (Young, M., Funder, J.W. Trends Endocrinol. Metab. 11: 224-226 (2000)). mediated angiotensin II Vasoconstriction and those occurring due to increased levels of aldosterone Water and sodium restriction lead to an additional Additional burden of the primary already inadequate myocardium. In the sense of a "circulus vitiosus" one results further reduction of renal perfusion and increased renin secretion. Additionally induce both the elevated Plasma aldosterone and angiotensin II levels as well as cardially local secreted aldosterone fibrotic structural changes of the myocardium, in the consequence of which is the development of myocardial fibrosis into another Reduction in cardiac output leads (Brilla, C.G., Cardiovasc. Res. 47: 1-3 (2000); Lijnen, P. & Petrov, V.J. Mol. Cell. Cardiol. 32: 865-879 (2000)).

Fibrotic structural changes are characterized by the formation of tissue, the characterized by an abnormally high amount of fibrotic material (especially collagen strands). Such fibroses are useful in some situations, such as wound healing, but may be harmful, inter alia, if they interfere with the function of internal organs. In myocardial fibrosis, the heart muscle is traversed by fibrotic strands that make the muscle stiff and inflexible, thereby impairing its function.

There even in patients with mild heart failure mortality 10-20 %, It is urgently necessary here with a suitable drug therapy intervene. Despite long-term therapy with digitalis glycosides, diuretics, ACE inhibitors or AT II antagonists remain the plasma aldosterone levels increased in the patients, and the medication has no effect on the fibrotic Structural changes.

Mineralocorticoid receptor antagonists, especially aldosterone-blocking agents, are already the subject numerous patents.

Thus, the steroidal mineralocorticoid receptor antagonist spironolactone blocks (17-hydroxy-7-alpha-mercapto-3-oxo-l7-α-pregn-4-ene-2l-carboxylic acid γ-lactonacetat; Aldactone ^®) aldosterone receptors competitively aldosterone and thus prevents the receptor-mediated aldosterone effect. US 2002/0013303, US 6,150,347 and US 6,608,047 describe the dosage of spironolactone for the treatment or prevention of cardiovascular diseases and myocardial fibrosis while maintaining the patient's normal electrolyte and water balance.

The "Randomized Aldactone Evaluation Study (RALES)." (Pitt, B. et al, New Engl J Med 341:.. 709-717 (1999)) showed clearly that with the gift of aldosterone antagonist spironolactone (Aldactone ^® ) in addition to the basic therapy with ACE inhibitors and loop diuretics, the survival rate of severely heart failure patients could be significantly improved, since the effect of aldosterone was inhibited to a sufficient extent (Kulbertus, H., Rev. Med. Liege 54: 770-772 (1999)) However, the use of spironolactone has been associated with serious side effects such as gynaecomastia, dysmenorrhea and chest pain, which are due to the steroidal structure of the substance and the consequent interactions with other steroid receptors (Pitt, B. et al., New Eng. Med. 341: 709-717 (1999); MacFadyen, RJ et al., Cardiovasc. Res. 35: 30-34 (1997); Soberman, JE & Weber, KT, Curr. Hypertens. Rep. 2: 451-456 (2000)).

mespirenone (15,16-methylene-17-spirolactones) and its derivatives were considered to be promising Alternatives to spironolactone, as they only have a low percentage of the antiandrogenic action of spironolactone (Losert, W. et al., Drug Res. 36: 1583-1600 (1986); Nickisch, K. et al., J Med Chem 30 (8): 1403-1409 (1987); Nickisch, K. et al., J. Med. Chem. 34: 2464-2468 (1991); Agarwal, M.K., Lazar, G., Renal Physiol. Biochem. 14: 217-223 (1991)). Mespirenone blocks aldosterone biosynthesis as part of a complete Mineral Corticoid Biosynthesis Inhibition (Weindel, K. et al., Arzneimittelforschung 41 (9): 946-949 (1991)). Mespirenone, like spironolactone, inhibits aldosterone biosynthesis but only in very high concentrations.

WHERE 01/34132 describes methods of treatment, prevention or blocking of pathogenic changes as a result of vascular injuries (Restenoses) in mammals by the administration of an aldosterone antagonist, eplerenone (an aldosterone receptor antagonist) or related structures that are partially epoxysteroidal and all of them can be derived from 20-spiroxanes.

WHERE 96/40255, US 2002/0123485, US 2003/0220312 and US 2003/0220310 therapeutic methods for the treatment of cardiovascular diseases, Myocardial fibrosis or cardiac hypertrophy using combination therapy from an angiotensin II antagonist and an epoxy-steroidal Aldosterone receptor antagonists such as Eplerone or Epoxymexrenone.

The recently published EPHESUS ("Eplerenone's Heart Failure Efficacy and Survival Study", 2003) was able to substantiate the results of RALES and, in addition to the baseline therapy, the first selective steroidal mineral corticosteroid receptor antagonist Eplerone (Inspra ^® ) significantly reduces morbidity and mortality in patients with acute myocardial infarction as well as the incidence of complications, eg, decrease in left ventricular ejection fraction and heart failure (Pitt., B. et al., N. Eng. J. Med. 348: 1390-1382 (2003)).

RALES and EPHESUS have clearly demonstrated that aldosterone antagonists represent a treatment option that should not be underestimated. However, the requirement arises from their side effect profile for substances that differ in their structure and their mechanism of action of spironolactone. A promising alternative here is nonsteroidal inhibitors of mineral corticoid biosynthesis; because it is better to reduce the pathologically increased aldosterone concentration than to block only the receptors. CYP11B2 as a key enzyme in this context lends itself as a target for specific inhibitors and has already been proposed in previous studies as a target for specific inhibitors (Hartmann, R. et al., Eur. J. Med. Chem. 38: 363-366 (2003 Ehmer, P. et al., J. Steroid Biochem., Mol. Biol. 81: 173-179 (2002)). Thus, excessive generalized aldosterone release and, in particular, cardiac aldosterone production can be reduced by targeted inhibition of biosynthesis, which in turn reduces structural changes in the myocardium.

selective Aldosterone synthase inhibitors could also represent a promising material class, which after a Myocardial infarction with the healing of the impaired myocardial tissue with reduces scarring thus reducing the incidence of serious complications.

WHERE 01/76574 describes a pharmaceutical which is an inhibitor of Aldosterone formation or one of its pharmaceutically acceptable salts, optionally in combination with other active substances. WO 01/76574 refers to the use of at that time commercially available nonsteroidal Inhibitors of aldosterone formation, in particular on the (+) - enantiomer of fadrozole, a 4- (5,6,7,8-tetrahydroimidazo (1,5-a) pyridin-5-yl) benzonitrile, and its synergistic Effect with angiotensin II receptor antagonists.

Anastrozole (Arimidex ^® ) and Exemestane (Coromasin ^® ) are other nonsteroidal aromatase inhibitors. Their field of application is the treatment of breast cancer by inhibiting aromatase, which converts androstenedione and testosterone into estrogen.

The human steroid 11β-hydroxylase CYP11B1 shows more than 93% homology to human CYP11B2 (Kawamoto, T. et al., Proc Natl Acad Sci. USA 89: 1458-1462 (1992); Taymans, S.E. et al., J. Clin. Endocrinol. Metab. 83: 1033-1036 (1998)). Despite the high structural and functional similarity these two enzymes are allowed strong inhibitors of aldosterone synthase the steroid 11β-hydroxylase do not influence and need therefore on their selectivity checked become. In addition, nonsteroidal inhibitors of aldosterone synthase preferably be used as therapeutics because fewer side effects to be expected on the endocrine system. It was already in earlier Investigations pointed out, as well as that development selective CYP11B2 inhibitors that do not affect CYP11B1, by the high similarity of the both enzymes is difficult (Ehmer, P. et al., J. Steroid Biochem. Mol. Biol. 81: 173-179 (2002); Hartmann, R. et al., Eur. J. Med. Chem. 38: 363-366 (2003)).

The Inhibitors should also include other P450 (CYP) enzymes as possible little affect. The only active substance known today, the Corticoidsynthese Affected in humans is the aromatase (estrogen synthase, CYP19) inhibitor Fadrozole used in breast cancer therapy. He can also aldosterone and cortisone levels affect, but only at ten times the therapeutic dose (Demvers, L.M. et al., J. Clin. Endocrinol. Metabol. 70: 1162-1166 (1990)).

For inhibitors of human aldosterone synthase CYP11B2, a test system has already been developed for screening chemical compounds with Schizosaccharomyces pombe cells stably expressing human CYP11B2 and subsequently testing selectivity with V79MZ cells stably expressing either CYP11B2 or CYP11B1 (Ehmer, et al. P. et al., J. Steroid Biochem., Mol. Biol. 81: 173-179 (2002)). With the help of the S. pombe system, 10 substances were tested, one of them as a potent and selective non-steroidal inhibitor of human CYP11B2 (and strong aromatase inhibitor) and four others as non-selective, but with respect to CYP11B1 using the V79MZ system stronger inhibitors were identified (A: CYP11B2 inhibitor, BD: non-selective CYP11B1 inhibitors):

These publication However, it has focused on providing an effective test system focuses on the search for selective CYP11B2 inhibitors and gives except the very general reference to the aromatic N atom and the three structures shown above only a few indications of which Finally, substance classes could be particularly effective. Of It should also be noted that most of this publication structures were strong CYP11B1 inhibitors and therefore not for immediate use as selective CYP11B2 inhibitors should be considered.

The screening of a P450 inhibitor library of over 100 substances for inhibitors of bovine aldosterone synthase (CYP18, CYP11B) (partly published in Hartmann, RW et al., Arch. Pharm. Pharm. Med. 339, 251-61 (1996 )) with the aid of Ehmer et al. (Ehmer, P. et al., J. Steroid Biochem. Mol. Biol. 81: 173-179 (2002)) revealed a high number of compounds that inhibited CYP11B2 (Hartmann, R. et al. Eur. J. Med. Chem. 38: 363-366 (2003)). These substances were also tested for oral availability in the cited study and further for in vitro inhibition of stable in yeast and, if these tests showed strong inhibition of CYP11B2, human CYP11B2 expressed in V79MZ cells. Also, comparisons were made with the inhibition of other CYPs, including CYP11B1 expressed in V79MZ cells, to determine the selectivity of the test substances. Structural variation eventually yielded CYP11B2 inhibitors exhibiting low nanomolar IC ₅₀ values, namely, cyclopropane tetrahydronaphthalene derivatives and arylmethyl substituted indanes. It was found that the CYP11B inhibition is strongly influenced by the substituent on the benzene ring and by the heteroaryl radical. As promising lead structures, the compounds E and F were found:

The the aforementioned scientific publications point to this hints that the presence of an aromatic nitrogen atom essential for the complexation of the iron atom in the target enzyme is (Ehmer, P. et al., J. Steroid Biochem. Mol. Biol. 81: 173-179 (2002); Hartmann, R. et al., Eur. J. Med. Chem. 38: 363-366 (2003)). In addition, this must be N atom unsubstituted and sterically accessible (Ehmer, P. et al., J. Steroid Biochem. Mol. Biol. 81: 173-179 (2002)).

A few heteroaryl-substituted dihydronaphthalenes have already been tested for their action as inhibitors of nonspecific bovine CYP11B in advance of the invention presented here (Hartmann, RW et al., Arch. Pharm. Pharm. Med. Chem. 329: 251-261 (1996) ):

Your Effect on CYP17 and CYP19 is also reported in this publication described. However, they proved too unspecific to be as Therapeutics for targeted inhibition of CYP11B2 in question. In addition, the bovine enzyme is not optimal for evaluating the therapeutic Suitability of compounds to inhibit human CYP11B enzymes, as the Homology between this bovine and the human enzymes is not is high (75%) (Mornet, E. et al., J. Biol. Chem. 264: 20961-20967 (1989)).

Furthermore, the effect of the following compound on CYP17, CYP19 and TxA2 (thromboxane A2 synthase) is described, but an inhibitory effect on CYP11B is not mentioned (Jacobs, C. et al., J. Med. Chem. 43: 1841- 1851 (2000)):

werden als TxA2-Inhibitoren beschrieben (Cozzi, P. et al., Eur. J. Med. Chem. 26:423-433 (1991)).Other 1-imidazolyl and 4-pyridyl-substituted naphthalenes, dihydronaphthalenes, quinolines and their oxa analogs of the formula

are described as TxA2 inhibitors (Cozzi, P. et al., Eur. J. Med. Chem. 26: 423-433 (1991)).

ist bereits als Inhibitor von CYP17 genannt worden (Bencze, W.L. und Barsky, L.I., J. Med. Pharm. Chem. 5:1298-1306 (1962)).Also

has already been named as an inhibitor of CYP17 (Bencze, WL and Barsky, LI, J. Med. Pharm. Chem. 5: 1298-1306 (1962)).

als Werkzeug zur Diagnose von primärem und sekundärem Aldosteronismus und Diabetes mellitus in Alternative zu Metyrapon vorgeschlagen (Johnson, A.L. et al., J. Med. Chem. 12(5):1024-1028 (1969)).Furthermore was

as a tool for diagnosis of primary and secondary aldosteronism and diabetes mellitus in alternative to metyrapone (Johnson, AL et al., J. Med. Chem. 12 (5): 1024-1028 (1969)).

some Pyridine-substituted quinolines is attributed to spasmolytic activity (Hey, D.H., and Wllliams, J.M., J. Chem. Soc., 1678-83 (1950)).

All hitherto known inhibitors of aldosterone or glucocorticoid formation have considerable disadvantages: etomidate and metyrapone inhibit glucocorticoid formation stronger as the aldosterone formation. Etomidate is a powerful narcotic and Metyrapone is a relatively unselective CYP inhibitor, therefore only used as a diagnostic agent. At fadrozole is described that it makes aldosterone production stronger inhibits glucocorticoid formation (Bhatnagar, A.S. et al., J. Biol. Steroid Biochem. Biol. 37: 1021-1027 (1990); Hausler, A. et al., J. Steroid Biochem. 34: 567-570 (1989); Dowsett, M. et al. Clin. Endocrinol. (Oxf.) 32: 623-634 (1990); Santen, R.J. et al., J. Clin. Endocrinol. Metabol. 73: 99-106 (1991); Demers, L.M. et al., J. Clin. Endocrinol. Metabol. 70: 1162-1166 (1990)). These too Substance comes for an application as an inhibitor of aldosterone or glucocorticoid formation not in Question, because it is a very strong aromatase inhibitor and therefore highly potent in sex hormone formation engages. In the light In the above prior art, there was a need for potent and selective inhibitors of the 11β-hydrolase CYP11B1 and the aldosterone synthase CYP 11B2.

3-pyridyl-substituted Quinolines and quinoxalines have already been prepared by a Fe (salen) Cl-catalyzed cross-coupling reaction of the corresponding chlorinated heteroaryl with a pyridyl Grignard compound (Fürstner, A. et al., JACS 124: 13856-13863 (2002)).

The 3-Pyridyl Grignard also reacts with ethyl 2-quinolinyl sulfoxide to 2-pyridin-3-yl-quinoline 20 (Furukawa, N. et al., Tet. Lett. 28 (47): 5845-8 (1987)). Another synthesis method for this compound is the Treatment of o-aminobenzaldehyde with 3-pyridyl methyl ketone (Hey, D.H. and Williams, J.M., J. Chem. Soc. 1678-83 (1950)).

3-pyridine-3-yl-quinoline 19 can be obtained by a palladium-catalyzed crosscoupling reaction of tri (quinolinyl) magnesate with 6-bromopyridine (Dumouchel, 5th et al., Tetrahedron 59: 8629-8640 (2003)). 2-pyridin-3-yl-quinoxaline 21 is characterized by sales of O-phenylenediamine with brominated 3-pyridylmethyl ketones available (Sarodnick G. and Kempter G., Pharmacia 40 (6): 384-7 (1985)).

All mentioned cross-coupling reactions with iron or palladium complexes have disadvantages: For the production of the iron complex is an additional Synthesis step necessary, and the coupling of Arylmagnesaten requires the expensive ligand dppf (1,1'-bis (diphenylphosphino) ferrocene). The safe handling of the reagents is also difficult, a dry atmosphere and low temperatures are indispensable.

The called reaction of 3-pyridyl methyl ketone with o-aminobenzaldehyde or o-phenylenediamine results in low yields (maximum 20%).

The Synthesis of 4- (6-methoxy-2-naphthyl) pyridine 31 is described (Kelley, C.J., J.Het. Chem. 38 (1): 11-23 (2001)), however, is involved very many individual steps.

It There was therefore a need for a simple synthesis process for heteroaryl-substituted naphthalenes, 3,4-dihydroxynaphthalenes and indanes, which cover a wide range of heteroaryls is applicable.

Summary of the invention

It It has been found that certain aromatic compounds are selective Inhibition of 11β-hydroxylase CYP11B1 and / or the aldosterone synthase CYP11B2 are suitable. their biological activity in terms of inhibition of human CYP11B2 and CYP11B1, and for detection the selectivity of human CYP17 (17α-hydroxylase C17,20-lyase, key enzyme of androgen biosynthesis) and CYP19 has been studied. Compared to previously described CYP11B2 inhibitors (Hartmann, R.W. et al., Eur. J. Med. Chem. 38: 363-366 (2003)) and known inhibitors corticoid biosynthesis (fadrozole) or steroid biosynthesis (ketoconazole) For example, the compounds presented below are more potent and selective.

Farther became a suitable synthesis method for these aromatic compounds, their main representatives are 3-pyridyl-substituted naphthalenes, 3,4-dihydronaphthalenes and Indans are developed.

• (1) Verwendung einer Verbindung mit der Struktur der Formel (I)
  
  worin Y ausgewählt ist aus
  
  T, U, V, W, X unabhängig voneinander ausgewählt sind aus C und N; R¹ und R² unabhängig voneinander ausgewählt sind aus H, Halogen, CN, Hydroxy, Nitro, Alkyl, Alkoxy, Alkylcarbonyl, Alkylcarbonyloxy, Alkylcarbonylamino, Alkylsulfonylamino, Alkylthio, Alkylsulfinyl und Alkylsulfonyl (worin die Alkylreste geradkettig, verzweigt oder cyclisch, gesättigt oder ungesättigt und mit 1 bis 3 Resten R¹² substituiert sein können), Arylalkyl-, Heteroarylalkyl-, Aryl- und Heteroarylresten und deren partiell oder vollständig gesättigten Äquivalenten, welche mit 1 bis 3 Resten R¹² substituiert sein können, Arylalkyloxy-, Heteroarylalkyloxy-, Aryloxy- und Heteroaryloxyresten, wobei Aryl und Heteroaryl die vorstehend angegebene Bedeutung aufweist, -COOR¹¹, -CON(R¹¹)₂, -SO₃R¹¹, -CHO, -CHNR¹¹, -N(R¹¹)₂, -NHCOR¹¹ und -NHS(O)₂R¹¹, sowie, wenn U oder V ein N-Atom ist, einem freien Elektronenpaar, oder R¹ mit R² oder R⁴ bzw. R² mit R⁵ des benachbarten Ringatoms und den dazugehörigen C-Atomen einen gesättigten oder ungesättigten anellierten Aryl- oder Heteroarylring bildet, wobei die Atome des anellierten Aryl- oder Heteroarylrings mit 1-3 Resten R¹² substituiert sein können; R³ ausgewählt ist aus stickstoffhaltigen monocyclischen oder bicyclischen Heteroarylresten und deren partiell oder vollständig gesättigten Äquivalenten, welche mit 1 bis 3 Resten R¹² substituiert sein können und zumindest ein Stickstoffatom aufweisen, das nicht substituiert ist, und/oder R³ über R¹² mit R⁶ oder R⁷ bzw. R⁸ des benachbarten Ringatoms und den dazugehörigen C-Atomen einen gesättigten oder ungesättigten anellierten Aryl- oder Heteroarylring bildet, wobei die Atome des anellierten Aryl- oder Heteroarylrings mit 1-3 Resten R¹² substituiert sein können; R⁴, R⁵, R⁶, R⁷, R⁸ und R⁹ unabhängig voneinander ausgewählt sind aus H, Halogen, CN, Hydroxy, Nitro, Niederalkyl, Niederalkoxy, Niederalkylcarbonyl, Niederalkylcarbonyloxy, Niederalkylcarbonylamino, Niederalkylsulfonylamino, Niederalkylthio, Niederalkylsulfinyl und Niederalkylsulfonyl (worin die Niederalkylreste geradkettig, verzweigt oder cyclisch, gesättigt oder ungesättigt und mit 1 bis 3 Resten R¹² substituiert sein können), Arylalkyl-, Heteroarylalkyl-, Aryl- und Heteroarylresten und deren partiell oder vollständig gesättigten Äquivalenten, welche mit 1 bis 3 Resten R¹² substituiert sein können, Arylalkyloxy-, Heteroarylalkyloxy-, Aryloxy- und Heteroaryloxyresten, wobei Aryl und Heteroaryl die vorstehend angegebene Bedeutung aufweist, -COOR¹¹, -CON(R¹¹)₂, -SO₃R¹¹, -CHO, -CHNR¹¹, -N(R¹¹)₂, -NHCOR¹¹ und -NHS(O)₂R¹¹, oder R⁴, R⁵ und R⁶ ein freies Elektronenpaar ist, wenn T, W oder X ein N-Atom ist, oder R⁷ oder R⁸ mit R⁹ oder R¹⁰ und/oder mit R⁷ oder R⁸ des benachbarten Ringatoms eine oder zwei Doppelbindungen bilden, oder R⁵ und/oder R⁷ (und R⁸) mit R⁹ (und R¹⁰) des benachbarten Ringatoms und den dazugehörigen C-Atomen einen gesättigten oder ungesättigten anellierten Aryl- oder Heteroarylring bilden, wobei die Atome des anellierten Aryl- oder Heteroarylrings mit 1-3 Resten R¹² substituiert sein können; R¹⁰ ausgewählt ist aus aus H, Niederalkyl, Niederalkylcarbonyl (worin die Niederalkylreste geradkettig, verzweigt oder cyclisch, gesättigt oder ungesättigt und mit 1 bis 3 Resten R¹² substituiert sein können), Arylalkyl-, Heteroarylalkyl-, Aryl- und Heteroarylresten und deren partiell oder vollständig gesättigten Äquivalenten, welche mit 1 bis 3 Resten R¹² substituiert sein können, und -COOR¹¹, oder ein freies Elektronenpaar ist, oder mit R⁷ oder R⁸ des benachbarten C-Atoms eine Doppelbindung bildet, oder mit R⁷ (und R⁸) des benachbarten C-Atoms und den dazugehörigen C-Atomen einen gesättigten oder ungesättigten anellierten Heteroarylring bildet, wobei die Atome des anellierten Heteroarylrings mit 1-3 Resten R¹² substituiert sein können; R¹¹ unabhängig vom Auftreten weiterer R¹¹-Reste ausgewählt ist aus H, Niederalkyl (das geradkettig, verzweigt oder cyclisch, gesättigt oder ungesättigt und mit 1 bis 3 R¹² substituiert sein kann) und Aryl, das mit 1 bis 3 R¹² substituiert sein kann; R¹² unabhängig vom Auftreten weiterer R¹²-Reste ausgewählt ist aus H, Hydroxy, Halogen, -CN, -COOH, -CHO, Nitro, Amino, mono- und bis-(Niederalkyl)amino, Niederalkyl, Niederalkoxy, Niederalkylcarbonyl, Niederalkylcabonyloxy, Niederalkylcarbonylamino, Niederalkylthio, Niederalkylsulfinyl, Niederalkylsulfonyl, Hydroxy-Niederalkyl, Hydroxy-Niederalkoxy, Hydroxy-Niederalkylcarbonyl, Hydroxy-Niederylkylcarbonyloxy, Hydroxy-Niederalkylcarbonylamino, Hydroxy-Niederalkylthio, Hydroxy-Niederalkylsufinyl, Hydroxy-Niederalkylsufonyl, mono- und bis-(Hydroxy-Niederalkyl)amino und mono- und polyhalogeniertes Niederalkyl (worin die Niederalkylreste geradkettig, verzweigt oder cyclisch, gesättigt oder ungesättigt sein können); n eine ganze Zahl von 0 bis 2 ist; oder eines pharmazeutisch geeigneten Salzes derselben zur Behandlung von Hyperaldosteronismus, Herzinsuffizienz, Myocardfibrose, Hypercortisolismus und Diabetes mellitus;
• (2) eine pharmazeutische Zusammensetzung, enthaltend eine Verbindung der Formel (I) worin T U V W X Y R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R¹¹ und R¹² die in (1) angegebene Bedeutung aufweisen, oder ein pharmazeutisch geeignetes Salz derselben, vorausgesetzt dass
• (a) wenn T, U, V, W und X C-Atome sind, n = 1 ist und Y ausgewählt ist aus O, CH₂ und -CH=, dann R³ nicht 1-Imidazolyl ist;
• (b) wenn T, U, V, W, X und Y C-Atome sind, n = 1 ist, R¹, R², R⁴, R⁵, R⁷, R⁸ und R⁹ H-Atome sind und R⁶ H oder Methyl ist, dann R³ nicht 3-Pyridyl ist;
• (c) wenn T, U, V, W, X und Y C-Atome sind, n = 1 ist, R², R⁴, R⁵, R⁶, R⁷, R⁸ und R⁹ H-Atome sind und R¹ COOH ist, dann R³ nicht 4-Pyridyl ist;
• (d) wenn T, U, V, W und Y C-Atome sind, X = N ist, n = 1 ist, R¹, R², R⁴, R⁵ und R⁷ H-Atome sind, R⁹ = H oder Methyl ist und R⁸ mit Y eine Doppelbindung bildet, dann R³ nicht Pyridyl ist; und
• (e) wenn T, U, V, W und X C-Atome sind, Y = N ist, n = 1 ist, R¹, R², R⁴, R⁵, R⁶ und R⁷ H-Atome sind und R⁸ mit Y eine Doppelbindung bildet, dann R³ nicht 4-Carboxy-2-pyridyl ist;
• (3) eine Verbindung der Formel (I), worin T, U, V, W, X, Y, R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹ und R¹² die in (1) angegebene Bedeutung aufweisen, oder ein pharmazeutisch geeignetes Salz derselben, vorausgesetzt dass
• (a) wenn T, U, V, W und X C-Atome sind, n = 1 ist und Y ausgewählt ist aus O, N, CH₂ und -CH=, dann R³ nicht 1-Imidazolyl ist;
• (b) wenn T, U, V, W, X und Y C-Atome sind, n = 1 ist, R¹, R⁴, R⁵, R⁷, R⁸ und R⁹ H-Atome sind, R² H oder Methoxy und R⁶ H oder Methyl ist, dann R³ nicht Pyridyl, Imidazolyl oder Oxazolyl ist;
• (c) wenn T, U, V, W, X und Y C-Atome sind, n = 1 ist, R², R⁴, R⁵, R⁶, R⁷, R⁸ und R⁹ H-Atome sind und R¹ COOH ist, dann R³ nicht 4-Pyridyl ist;
• (d) wenn T, U, V, W und Y C-Atome sind, X = N ist, n = 1 ist, R¹, R², R⁴, R⁵ und R⁷ H-Atome sind, R⁹ = H oder Methyl ist und R⁸ mit Y eine Doppelbindung bildet, dann R³ nicht Pyridyl oder Chinolyl ist;
• (e) wenn T, U, V, W und X C-Atome sind, Y = N ist, n = 1 ist, R¹, R², R⁴, R⁵, R⁶ und R⁷ H-Atome sind und R⁸ mit Y eine Doppelbindung bildet, dann R³ nicht 4-Carboxy-2-pyridyl, 5-Brom-2-pyridyl, 6-Brom-2-pyridyl, 5-Brom-3-pyridyl, 2-Pyridyl, 3-Pyridyl, 2-Pyridazinyl, 2-Pyrimidinyl oder Chinolyl ist; und
• (f) wenn T, U, V und W C-Atome sind, X und Y N-Atome sind, n = 1 ist, R¹, R², R⁴, R⁵ und R⁷ H-Atome sind und R⁸ mit Y eine Doppelbindung bildet, dann R³ nicht Pyridyl oder 2-Chinolyl ist;
• (4) ein Verfahren zur Synthese der Verbindungen gemäß (3), umfassend
• (i) die Suzuki-Kupplung der Verbindung (III)
  
  worin (p)Hal ein Halogenatom oder Pseudohalogenid, bevorzugt Br oder OTf ist, mit der Verbindung (II) R3-B(OH)₂ II; und/oder
• (ii) die Bromierung der Verbindung (VI)
  
  zum entsprechenden α-Bromketon, eine daran anschliessende Reduktion zum entsprechenden Alkohol, Dehydrierung und eine daran anschliessende Kupplung mit der Verbindung (II), wobei die Variablen die in (3) angegebene Bedeutung haben, und funktionelle Gruppen in R¹-R¹⁰ optional mit geeigneten Schutzgruppen versehen sein können; und
• (5) die Verwendung der in (1) definierten Verbindungen zur selektiven Hemmung von Säugetier-P450-Oxygenasen, zur Hemmung der humanen oder Säugetier-Aldosteronsynthase oder Steroid-11β-Hydroxylase, besonders zur Hemmung der humanen Steroid-11β-Hydroxylase CYP11B1 oder Aldosteronsynthase CYP11B2, insbesondere zur selektiven Hemmung der CYP11B2 bei gleichzeitiger geringer Beeinträchtigung der humanen CYP11B1.

The invention thus provides

• (1) Use of a compound having the structure of the formula (I)
  
  where Y is selected from
  
  T, U, V, W, X are independently selected from C and N; R ¹ and R ^{2 are} independently selected from H, halo, CN, hydroxy, nitro, alkyl, alkoxy, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkylsulfinyl and alkylsulfonyl (wherein the alkyl radicals are straight, branched or cyclic, saturated or unsaturated and may be substituted by 1 to 3 radicals R ¹² ), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partially or completely saturated equivalents, which may be substituted by 1 to 3 radicals R ¹² , arylalkyloxy, heteroarylalkyloxy, aryloxy and heteroaryloxy radicals, where aryl and heteroaryl have the abovementioned meaning, -COOR ¹¹ , -CON (R ¹¹ ) ₂ , -SO ₃ R ¹¹ , -CHO, -CHNR ¹¹ , -N (R ¹¹ ) ₂ , -NHCOR ¹¹ and -NHS (O) ₂ R ¹¹ , and, when U or V is an N atom, a lone pair of electrons, or R ¹ with R ² or R ⁴ or R ² with R ^{5 of} the adjacent ring atom and the associated C Atoms a saturated or unsaturated anel lierten aryl or heteroaryl ring, wherein the atoms of the fused aryl or heteroaryl ring with 1-3 radicals R ¹² may be substituted; R ^{3 is} selected from nitrogen-containing monocyclic or bicyclic heteroaryl radicals and their partially or fully saturated equivalents, which may be substituted by 1 to 3 radicals R ¹² and have at least one nitrogen atom which is unsubstituted, and / or R ³ via R ¹² with R ⁶ or R ⁷ or R ^{8 of} the adjacent ring atom and the associated carbon atoms forms a saturated or unsaturated fused aryl or heteroaryl ring, wherein the atoms of the fused aryl or heteroaryl ring with 1-3 radicals R ¹² may be substituted; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently selected from H, halo, CN, hydroxy, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylsulfonylamino, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl ( wherein the lower alkyl radicals may be straight-chain, branched or cyclic, saturated or unsaturated and may be substituted by 1 to 3 radicals R ¹² ), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partially or fully saturated equivalents containing from 1 to 3 radicals R ¹² can be substituted, arylalkyloxy, Heteroarylalkyloxy-, aryloxy and Heteroaryloxyresten, wherein aryl and heteroaryl has the meaning given above, -COOR ¹¹ , -CON (R ¹¹ ) ₂ , -SO ₃ R ¹¹ , -CHO, -CHNR ^11th , -N (R ¹¹ ) ₂ , -NHCOR ¹¹ and -NHS (O) ₂ R ¹¹ , or R ⁴ , R ⁵ and R ^{6 is} a lone pair of electrons when T, W or X is an N atom, or R ⁷ or R ⁸ with R ⁹ or R ¹⁰ and / or with R ⁷ or R ^{8 of} the adjacent ring atom one or two double form R ⁵ and / or R ⁷ (and R ⁸ ) with R ⁹ (and R ¹⁰ ) of the adjacent ring atom and the associated C atoms form a saturated or unsaturated fused aryl or heteroaryl ring, wherein the atoms of the fused aryl - or heteroaryl can be substituted by 1-3 radicals R ¹² ; R ^{10 is} selected from H, lower alkyl, lower alkylcarbonyl (wherein the lower alkyl radicals may be straight, branched or cyclic, saturated or unsaturated and substituted with 1 to 3 R ¹² radicals), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partial or fully saturated equivalents, which may be substituted with 1 to 3 R ¹² radicals, and is -COOR ¹¹ , or a lone pair, or forms a double bond with R ⁷ or R ^{8 of} the adjacent C atom, or with R ⁷ (and R ⁸ ) of the adjacent C atom and the associated C atoms forms a saturated or unsaturated fused heteroaryl ring, wherein the atoms of the fused heteroaryl ring may be substituted by 1-3 R ¹² radicals; R ^{11 is selected} independently of the occurrence of further R ¹¹ radicals from H, lower alkyl (which may be straight, branched or cyclic, saturated or unsaturated and substituted with 1 to 3 R ¹² ) and aryl which may be substituted by 1 to 3 R ¹² can; R ¹² is selected from H, hydroxy, halogen, -CN, -COOH, -CHO, nitro, amino, mono- and bis- (lower alkyl) amino, lower alkyl, lower alkoxy, lower alkylcarbonyl, lower alkylcabonyloxy, independently of the occurrence of further R ¹² radicals, Lower alkylcarbonylamino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, hydroxy-lower alkyl, hydroxy-lower alkoxy, hydroxy-lower alkylcarbonyl, hydroxy-lower alkylcarbonyloxy, hydroxy-lower alkylcarbonylamino, hydroxy-lower alkylthio, hydroxy-lower alkylsilinyl, hydroxy-lower alkylsulfonyl, mono- and bis- (hydroxy-lower alkyl) amino and mono- and polyhalogenated lower alkyl (wherein the lower alkyl groups may be straight chain, branched or cyclic, saturated or unsaturated); n is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof for the treatment of hyperaldosteronism, cardiac insufficiency, myocardial fibrosis, hypercortisolism and diabetes mellitus;
• (2) a pharmaceutical composition containing a compound of the formula (I) in which TUVWXYR ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ R ¹⁰ R ¹¹ and R ^{12 have} the meaning given in (1), or a pharmaceutically-acceptable salt thereof, provided that
• (a) when T, U, V, W and X are C-atoms, n = 1 and Y is selected from O, CH ₂ and -CH =, then R ^{3 is} not 1-imidazolyl;
• (b) when T, U, V, W, X and Y are C atoms, n = 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{6 is} H or methyl, then R ^{3 is} not 3-pyridyl;
• (c) when T, U, V, W, X and Y are C atoms, n = 1, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{1 is} COOH, then R ^{3 is} not 4-pyridyl;
• (d) when T, U, V, W and Y are C atoms, X = N, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms, R ⁹ = H or methyl and R ⁸ forms a double bond with Y, then R ^{3 is} not pyridyl; and
• (e) when T, U, V, W and X are C-atoms, Y is N, n is 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} H atoms and R ⁸ forms a double bond with Y, then R ^{3 is} not 4-carboxy-2-pyridyl;
• (3) a compound of formula (I) wherein T, U, V, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 have} the meaning given in (1), or a pharmaceutically acceptable salt thereof, provided that
• (a) when T, U, V, W and X are C-atoms, n = 1 and Y is selected from O, N, CH ₂ and -CH =, then R ^{3 is} not 1-imidazolyl;
• (b) when T, U, V, W, X and Y are C atoms, n = 1, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ^{9 are} H atoms, R ^{2 is} H or methoxy and R ^{6 is} H or methyl, then R ^{3 is} not pyridyl, imidazolyl or oxazolyl;
• (c) when T, U, V, W, X and Y are C atoms, n = 1, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{1 is} COOH, then R ^{3 is} not 4-pyridyl;
• (d) when T, U, V, W and Y are C atoms, X = N, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms, R ⁹ = H or methyl and R ⁸ forms a double bond with Y, then R ^{3 is} not pyridyl or quinolyl;
• (e) when T, U, V, W and X are C-atoms, Y is N, n is 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} H atoms and R ⁸ forms a double bond with Y, then R ³ does not form 4-carboxy-2-pyridyl, 5-bromo-2-pyridyl, 6-bromo-2-pyridyl, 5-bromo-3-pyridyl, 2-pyridyl, 3 Pyridyl, 2-pyridazinyl, 2-pyrimidinyl or quinolyl; and
• (f) when T, U, V and W are C atoms, X and Y are N atoms, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms and R ⁸ with Y forms a double bond, then R ^{3 is} not pyridyl or 2-quinolyl;
• (4) a process for the synthesis of the compounds according to (3), comprising
• (i) Suzuki coupling of compound (III)
  
  in which (p) Hal is a halogen atom or pseudohalide, preferably Br or OTf, with the compound (II) R3-B (OH) ₂ II; and or
• (ii) the bromination of the compound (VI)
  
  to the corresponding α-bromoketone, followed by a reduction to the corresponding alcohol, dehydrogenation and subsequent coupling with the compound (II), wherein the variables have the meaning given in (3), and functional groups in R ¹ -R ¹⁰ optionally with may be provided with appropriate protecting groups; and
• (5) the use of the compounds defined in (1) for the selective inhibition of mammalian P450 oxygenases, for the inhibition of human or mammalian aldosterone synthase or steroid 11β-hydroxylase, in particular for the inhibition of the human steroid 11β-hydroxylase CYP11B1 or aldosterone synthase CYP11B2, in particular for the selective inhibition of CYP11B2 with a simultaneous low impairment of human CYP11B1.

Brief description of the figures

1 : Steroid secretion of H295R cells when treated with inhibitors of steroid biosynthesis as a function of the inhibitor concentration after 6 h incubation (Example 9); 1A: fadrozole, 1B: ketoconazole, 1C: compound 2.

Detailed description the invention

In the compounds of formula (I) of the invention, the variables and the terms used to characterize them have the following meaning:
"Alkyl radicals" and "alkoxy radicals" in the context of the invention may be straight-chain, branched or cyclic and be saturated or (partially) unsaturated. Preferred alkyl radicals and alkoxy radicals are saturated or have one or more double and / or triple bonds. In the case of straight-chain or branched alkyl radicals, preference is here given to those having 1 to 10 C atoms, especially those having 1 to 6 C atoms, very particularly those having 1 to 3 C atoms. In the cyclic alkyl radicals, mono- or bicyclic alkyl radicals having 3 to 15 C atoms, in particular monocyclic alkyl radicals having 3 to 8 C atoms, are particularly preferred.

"Lower alkyl" and "lower alkoxy" in the context of the invention are straight-chain, branched or cyclic saturated lower alkyl radicals and Lower alkoxy or those with a double or triple bond. The straight-chain are those having 1 to 6 carbon atoms, in particular with 1 to 3 C atoms particularly preferred. The cyclic ones are those having 3 to 8 C atoms are particularly preferred.

"Aryls" for the purposes of the present invention include mono-, bi- and tricyclic aryl radicals having 3 to 18 ring atoms, which may optionally be fused with one or more saturated rings. Especially be Preferred are anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, indanyl, indenyl, naphthyl, naphthenyl, phenanthrenyl, phenyl and tetralinyl.

"Unless otherwise stated, 'heteroaryl radicals' are mono- or bicyclic heteroaryl radicals having 3 to 12 ring atoms, which preferably have 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur and which may be fused with one or more saturated rings. The preferred nitrogen-containing monocyclic and bicyclic heteroaryls include benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnolinyl, dihydroindolyl, dihydroisoindolyl, dihydropyranyl, dithiazolyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isoindolyl, isothiazolidinyl, isothiazolyl , Isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl, pteridinyl, purinyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, tetrazinyl , Tetrazolyl, tetrahydropyrrolyl, thiadiazolyl, thiazinyl, thiazolidinyl, thiazolyl, triazinyl and triazolyl. Particular preference is given to mono- or bicyclic heteroaryl radicals having from 5 to 10 ring atoms, which preferably have from 1 to 3 nitrogen atoms, very particular preference to oxazolyl, imidazolyl, pyridyl and pyrimidyl. R ³ is the bevorzugtesten 3-pyridyl.

"Fused Aryl or heteroaryl rings "im The meaning of the present invention includes such monocyclic Rings with 5 to 7 ring atoms, which have two adjacent ring atoms are finned with the neighboring ring. They can be saturated or unsaturated. The fused heteroaryl rings comprise 1 to 3 heteroatoms, preferably nitrogen, sulfur or oxygen atoms, especially preferably oxygen atoms. Preferred fused aryl rings are Cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl and benzyl, preferred heteroaryl rings are furanoyl, dihydropyranyl, pyranyl, Pyrrolyl, imidazolyl, pyridyl and pyrimidyl.

"Pharmaceutically suitable Salts "in the sense The present invention includes salts of the compounds with organic acids (like lactic acid, Acetic acid, Amino acid, oxalic acid etc.), inorganic acids (such as HCl, HBr, phosphoric acid etc.) and, if the compounds have acid substituents, also with organic or inorganic bases. Preference is given to salts with HCl.

• (i) Y entweder N oder C ist; und/oder
• (ii) T, U, V und W C-Atome sind; und/oder
• (iii) die Alkylreste und Alkoxyreste gesättigt sind oder eine oder mehrere Doppel- und/oder Dreifachbindungen aufweisen, die geradkettigen oder verzweigten Alkylreste bevorzugt 1 bis 10 C-Atome, besonders bevorzugt 1 bis 6 C-Atome, ganz besonders bevorzugt 1 bis 3 C-Atmone aufweisen, und die cyclischen Alkyl reste mono- oder bicyclische Alkylreste mit 3 bis 15 C-Atomen, besonders bevorzugt monocyclische Alkylreste mit 3 bis 8 C-Atomen sind; und/oder
• (iv) Aryl ein mono-, bi- und tricyclischer Arylrest mit 3 bis 18 Ringatomen ist, der optional mit einem oder mehreren gesättigten Ringen anelliert sein kann, insbesondere Anthracenyl, Dihydronaphthyl, Fluorenyl, Hydrindanyl, Indanyl, Indenyl, Naphthyl, Phenanthrenyl, Phenyl, Tetralinyl ist; und/oder
• (v) die Heteroarylreste mono- oder bicyclische Heteroarlyreste mit 3 bis 12 Ringatomen sind, die vorzugsweise 1 bis 5 Heteroatome aus Stickstoff, Sauerstoff und Schwefel aufweisen und die mit einem oder mehreren gesättigten Ringen anelliert sein können; und/oder
• (vi) die Niederalkylreste und Niederalkoxyreste gesättigt sind oder eine Doppel- oder Dreifachbindung aufweisen, die geradkettigen insbesondere 1 bis 6 C-Atome, besonders bevorzugt 1 – 3 C-Atome aufweisen, die cyclischen insbesondere 3 bis 8 C-Atome aufweisen; und/oder
• (vii) die stickstoffhaltigen monocyclischen oder bicyclischen Heteroarylreste ausgewählt sind aus Benzimidazolyl, Benzothiazolyl, Benzoxazolyl, Chinazolinyl, Chinolyl, Chinoxalinyl, Cinnolinyl, Dihydroindolyl, Dihydroisoindolyl, Dihydropyranyl, Dithiazolyl, Homopiperidinyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, Indazolyl, Indolyl, Isochinolyl, Isoindolyl, Isothiazolidinyl, Isothiazolyl, Isoxazolidinyl, Isoxazolyl, Morpholinyl, Oxadiazolyl, Oxazolidinyl, Oxazolyl, Phthalazinyl, Piperazinyl, Piperidyl, Pteridinyl, Purinyl, Pyrazolidinyl, Pyrazinyl, Pyrazolyl, Pyrazolinyl, Pyridazinyl, Pyridyl, Pyrimidyl, Pyrrolidinyl, Pyrrolidin-2-onyl, Pyrrolinyl, Pyrrolyl, Tetrazinyl, Tetrazolyl, Tetrahydropyrrolyl, Thiadiazolyl, Thiazinyl, Thiazolidinyl, Thiazolyl, Triazinyl und Triazolyl; und/oder
• (viii) anellierte Aryl- oder Heteroarylringe monocyklische Ringe mit 5 bis 7 Ringatomen sind, die über zwei benachbarte Ringatome mit dem Nachbarring anelliert sind, gesättigt oder ungesättigt sein können und als Heteroarylringe 1 bis 3 Heteroatome, bevorzugt Stickstoff-, Sauerstoff- oder Schwefelatome umfassen können, und besonders bevorzugt ausgewählt sind aus Cyclohexyl, Cyclohexenyl, Cyclopentyl, Cyclopentenyl, Benzyl, Furanoyl, Dihydropyranyl, Pyranyl, Pyrrolyl, Imidazolyl, Pyridyl und Pyrimidyl.

Preference is given to compounds of the formula (I) as defined above under (1) and (2), in which

• (i) Y is either N or C; and or
• (ii) T, U, V and W are C atoms; and or
• (iii) the alkyl radicals and alkoxy radicals are saturated or have one or more double and / or triple bonds, the straight-chain or branched alkyl radicals preferably 1 to 10 C atoms, particularly preferably 1 to 6 C atoms, very particularly preferably 1 to 3 C -Atmone have, and the cyclic alkyl radicals mono- or bicyclic alkyl radicals having 3 to 15 carbon atoms, particularly preferably monocyclic alkyl radicals having 3 to 8 carbon atoms; and or
• (iv) Aryl is a mono-, bi- and tricyclic aryl radical having 3 to 18 ring atoms, which may optionally be fused with one or more saturated rings, in particular anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, indanyl, indenyl, naphthyl, phenanthrenyl, phenyl , Tetralinyl is; and or
• (v) the heteroaryl radicals are mono- or bicyclic heteroaryl radicals having 3 to 12 ring atoms, which preferably have 1 to 5 heteroatoms of nitrogen, oxygen and sulfur and which may be fused with one or more saturated rings; and or
• (vi) the lower alkyl radicals and lower alkoxy radicals are saturated or have a double bond or triple bond which have straight-chain, in particular 1 to 6 C atoms, particularly preferably 1 to 3 C atoms, which have cyclic, in particular 3 to 8, C atoms; and or
• (vii) the nitrogen-containing monocyclic or bicyclic heteroaryl radicals are selected from benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnolinyl, dihydroindolyl, dihydroisoindolyl, dihydropyranyl, dithiazolyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isoindolyl, Isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl, pteridinyl, purinyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, Pyrrolyl, tetrazinyl, tetrazolyl, tetrahydropyrrolyl, thiadiazolyl, thiazinyl, thiazolidinyl, thiazolyl, triazinyl and triazolyl; and or
• (viii) fused aryl or heteroaryl rings are monocyclic rings having 5 to 7 ring atoms which are fused via two adjacent ring atoms with the adjacent ring, saturated or unsaturated, and as heteroaryl comprise 1 to 3 heteroatoms, preferably nitrogen, oxygen or sulfur atoms may be, and more preferably selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, benzyl, furanoyl, dihydropyranyl, pyranyl, pyrrolyl, imidazolyl, pyridyl and pyrimidyl.

• (i) n 0 oder 1 ist; und/oder
• (ii) R¹ oder R² unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus H, Halogen, CN, Hydroxy, O-Niederalkyl, O-Niederalkenyl, O-Niederalkinyl, Niederalkyl, Niederalkenyl, Niederalkinyl, -COOR¹¹, -CON(R¹¹)₂ und Arylalkyloxyresten, und besonders bevorzugt H, 0-Niederalkyl und Arylalkoxyreste sind; und/oder
• (iii) R³ ausgewählt ist aus stickstoffhaltigen monocyclischen Heteroarylresten mit 5-10 Ringatomen und 1 bis 3 Stickstoffatomen, insbesondere ausgewählt ist aus Isochinolyl, Imidazolyl, Oxazolyl, Pyrazinyl, Pyrazolyl, Pyridyl, Pyrimidyl, Pyrrolyl, Thiazolyl, Triazinyl und Triazoyl; und/oder
• (iv) R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ unabhängig voneinander ausgewählt sind aus H, Halogen, CN, Hydroxy, Heteroaryl und C_1-6-Alkyl- und C_1-6-Alkoxyresten, die mit 1 bis 3 Resten R¹² substituiert sein können; und/oder
• (v) R¹⁰ ausgewählt ist aus H, Heteroaryl und C_1-6-Alkylresten, die mit 1 bis 3 Resten R¹² substituiert sein können; und/oder
• (vi) R¹² ausgewählt ist aus H, Halogen, Hydroxyl, CN, C_1-3-Alkyl und C_1-3-Alkoxy.

Particularly preferred are those compounds in which

• (i) n is 0 or 1; and or
• (ii) R ¹ or R ^{2 are} independently selected from the group consisting of H, halogen, CN, hydroxy, O-lower alkyl, O-lower alkenyl, O-lower alkynyl, lower alkyl, lower alkenyl, lower alkynyl, -COOR ¹¹ , -CON ( R ¹¹ ) ₂ and arylalkyloxy radicals, and more preferably H, O-lower alkyl and arylalkoxy radicals; and or
• (iii) R ^{3 is} selected from nitrogen-containing monocyclic heteroaryl radicals having 5-10 ring atoms and 1 to 3 nitrogen atoms, especially selected from isoquinolyl, imidazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, triazinyl and triazoyl; and or
• (iv) R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^{9 are} independently selected from H, halogen, CN, hydroxy, heteroaryl, and C _1-6 alkyl and C _1-6 alkoxy, which may be substituted by 1 to 3 radicals R ¹² ; and or
• (v) R ^{10 is} selected from H, heteroaryl and C _1-6 alkyl radicals which may be substituted with 1 to 3 R ¹² radicals; and or
• (vi) R ^{12 is} selected from H, halogen, hydroxyl, CN, C _1-3 alkyl and C _1-3 alkoxy.

• (i) X und Y C-Atome sind; und/oder
• (ii) R¹ oder R² Wasserstoff ist und der andere der Substituenten R¹ oder R² ausgewählt ist aus H, Fluor, Chlor, Brom, CN, COOR¹¹, Hydroxy, C_1-3-Alkyl und C_1-3-Alkoxy; und/oder
• (iii) R³ ausgewählt ist aus Oxazolyl, Pyridyl, Imidazolyl und Pyrimidyl; und/oder
• (iv) R⁵ und R⁶ unabhängig voneinander ausgewählt sind aus H, Fluor, Chlor, Brom; und/oder
• (v) R⁷ ausgewählt ist aus H, C_1-3-Alkyl und C_1-3-Alkoxyl; und/oder
• (vi) R⁴, R⁸, R⁹, R¹⁰ H sind; und/oder
• (vii) R¹¹ H oder C_1-3-Alkyl ist.

Of these, particular preference is given to those compounds in which

• (i) X and Y are C atoms; and or
• (ii) R ¹ or R ^{2 is} hydrogen and the other of the substituents R ¹ or R ^{2 is} selected from H, fluoro, chloro, bromo, CN, COOR ¹¹ , hydroxy, C _1-3 alkyl and C _1-3 alkoxy; and or
• (iii) R ^{3 is} selected from oxazolyl, pyridyl, imidazolyl and pyrimidyl; and or
• (iv) R ⁵ and R ^{6 are} independently selected from H, fluoro, chloro, bromo; and or
• (v) R ^{7 is} selected from H, C _1-3 alkyl and C _1-3 alkoxyl; and or
• (vi) R ⁴ , R ⁸ , R ⁹ , R ^{10 are} H; and or
• (vii) R ^{11 is} H or C _1-3 alkyl.

The compounds of formula (I) may have chiral centers (e.g., the C atoms substituted with R ⁹ and R ⁷ / R ⁸ ). Here, both the isomer mixtures and the isolated individual compounds of the invention are included.

wobei R³ besonders bevorzugt ausgewählt ist aus 3- und 4-Pyridyl, 1-Imidazolyl, 4-Imidazolyl und 5-Pyrimidyl, und deren pharmazeutisch geeignete Salze.Preferred compounds of embodiments (1) and (2) of the invention are those of formulas (Ia) to (Id):

wherein R ^{3 is more} preferably selected from 3- and 4-pyridyl, 1-imidazolyl, 4-imidazolyl and 5-pyrimidyl, and pharmaceutically acceptable salts thereof.

worin R¹ und R² bevorzugt unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus H, Halogen, CN, Hydroxy, O-Niederalkyl, O-Niederalkenyl, O-Niederalkinyl, Niederalkyl, Niederalkenyl, Niederalkinyl, -COOR¹¹, -CON(R¹¹)₂ und Arylalkyloxyresten, und besonders bevorzugt H, O-Niederalkyl und Arylalkoxy sind;
R⁵ ausgewählt ist aus der Gruppe bestehend aus H, Halogen, Heteroaryl;
R⁶ ausgewählt ist aus H und Halogen;
R⁸ und R⁹ ausgewählt sind aus H und Alkyloxy, oder miteinander einen anellierten Arylring bilden, bevorzugt einen Benzylring;
und deren pharmazeutisch geeignete Salze.Preferred embodiments of the compound (Ia) are the compounds of the following formulas (Ie) to (Ii):

wherein R ¹ and R ^{2 are} preferably independently selected from the group consisting of H, halogen, CN, hydroxy, O-lower alkyl, O-lower alkenyl, O-lower alkynyl, lower alkyl, lower alkenyl, lower alkynyl, -COOR ¹¹ , -CON (R ¹¹ ) ₂ and arylalkyloxy, and more preferably H, O-lower alkyl and arylalkoxy;
R ^{5 is} selected from the group consisting of H, halogen, heteroaryl;
R ^{6 is} selected from H and halogen;
R ⁸ and R ^{9 are} selected from H and alkyloxy, or together form an annulated aryl ring, preferably a benzyl ring;
and their pharmaceutically acceptable salts.

worin X und Y ausgewählt sind aus N und C, das Naphthalingerüst jedoch bevorzugt mindestens ein Stickstoffatom enthält;
R³ ausgewählt ist aus Pyridyl, Pyrimidyl, Imidazolyl, Oxazolyl, bevorzugt Pyridyl und Imidazolyl;
R² ausgewählt ist aus H, Halogen, CN, O-Niederalkyl, O-Niederalkenyl, O-Niederalkinyl, Niederalkyl, Niederalkenyl oder Niederalkinyl, und bevorzugt H oder O-Niederalkyl ist und deren pharmazeutisch geeignete Salze.Preferred embodiments of the compound (Ib) are the compounds of the following formulas (Ij) and (Ik):

wherein X and Y are selected from N and C, but the naphthalene skeleton preferably contains at least one nitrogen atom;
R ^{3 is} selected from pyridyl, pyrimidyl, imidazolyl, oxazolyl, preferably pyridyl and imidazolyl;
R ^{2 is} selected from H, halo, CN, O-lower alkyl, O-lower alkenyl, O-lower alkynyl, lower alkyl, lower alkenyl or lower alkynyl, and is preferably H or O-lower alkyl and pharmaceutically acceptable salts thereof.

worin R¹ und R² bevorzugt ausgewählt sind aus H und O-Niederalkyl;
R³ Pyridyl oder Imidazolyl ist;
R⁶, R⁸ und R⁹ H oder Niederalkyl sind, wobei bevorzugt einer dieser Substituenten Niederalkyl, besonders bevorzugt Methyl, und die anderen beiden H sind;
und deren pharmazeutisch geeignete Salze.Preferred embodiments of the compound (Ic) are the compounds of the following formulas (II) to (In):

wherein R ¹ and R ^{2 are} preferably selected from H and O-lower alkyl;
R ^{3 is} pyridyl or imidazolyl;
R ⁶ , R ⁸ and R ^{9 are} H or lower alkyl, preferably one of these substituents is lower alkyl, more preferably methyl, and the other two are H;
and their pharmaceutically acceptable salts.

Preferred embodiments of the compound (Id) are compounds in which R ² and R ^{5 are} independently H or O-lower alkyl;
R ^{3 is} pyridyl or imidazolyl, preferably 3-pyridyl or 1-imidazolyl; and their pharmaceutically acceptable salts.

Most preferably, R ³ in all embodiments of the invention is 3-pyridyl.

Preferred compounds of formula (I) for embodiment (1) and (2) are in particular the following compounds:
3- (2-naphthyl) pyridine
3- (1-chloro-7-methoxy-2-naphthyl) pyridine
3- (1,5-dichloro-6-methoxy-2-naphthyl) pyridine
3- (3-methoxy-2-naphthyl) pyridine
3- (5-chloro-6-methoxy-2-naphthyl) pyridine
3- (5-bromo-6-methoxy-2-naphthyl) pyridine
3- (6-methoxy-2-naphthyl) pyridine
3- (6-ethoxy-2-naphthyl) pyridine
3- (6-bromo-2-naphthyl) pyridine
3- (7-methoxy-2-naphthyl) pyridine
5- (6-methoxy-2-naphthyl) pyrimidine
Methyl-6-pyridin-3-yl-2-naphthoate
6-pyridin-3-yl-2-naphthonitrile
6-Pyridin-3-yl-2-naphthol
2-pyridin-3-yl-quinolin
3-pyridine-3-yl-quinoline
1- (2-naphthyl) -1H-imidazole
1- (3-methoxy-2-naphthyl) -1H-imidazole
5- (2-naphthyl) -1H-imidazole
3- (3,4-dihydronaphthalene-2-yl) pyridine
3- (1-methyl-3,4-dihydronaphthalene-2-yl) pyridine
3- (3-methyl-3,4-dihydronaphthalene-2-yl) pyridine
3- (4-methyl-3,4-dihydronaphthalene-2-yl) pyridine
3- (6-methoxy-3,4-dihydronaphthalene-2-yl) pyridine
3- (7-Methoxy-3,4-dihydronaphthalene-2-yl) pyridine
3- (1H-inden-2-yl) pyridine
3- (6-methoxy-1H-inden-2-yl) pyridine and
3- (1-ethyl-3,4-dihydronaphthalene-2-yl) pyridine.

These are particularly preferred
3- (2-naphthyl) pyridine
3- (6-methoxy-2-naphthyl) pyridine
3- (6-bromo-2-naphthyl) pyridine
3- (6-ethoxy-2-naphthyl) pyridine
6-pyridin-3-yl-2-naphthonitrile
3- (1,5-dichloro-6-methoxy-2-naphthyl) pyridine
Methyl-6-pyridin-3-yl-2-naphthoate
3- (1H-inden-2-yl) pyridine
3- (3,4-dihydronaphthalene-2-yl) pyridine
3- (6-methoxy-1H-inden-2-yl) pyridine
3- (6-methoxy-3,4-dihydronaphthalene-2-yl) pyridine
3- (1-methyl-3,4-dihydronaphthalene-2-yl) pyridine
3- (3-methyl-3,4-dihydronaphthalene-2-yl) pyridine
3- (1-ethyl-3,4-dihydronaphthalen-2-yl) pyridine and especially
3- (6-methoxy-2-naphthyl) pyridine
3- (6-bromo-2-naphthyl) pyridine
3- (6-ethoxy-2-naphthyl) pyridine
6-pyridin-3-yl-2-naphthonitrile
3- (1H-inden-2-yl) pyridine
3- (3,4-dihydronaphthalene-2-yl) pyridine
3- (6-methoxy-1H-inden-2-yl) pyridine
3- (6-methoxy-3,4-dihydronaphthalene-2-yl) pyridine
3- (1-Methyl-3,4-dihydronaphthalen-2-yl) pyridine and
3- (3-methyl-3,4-dihydronaphthalene-2-yl) pyridine.

At the most preferred are 3- (6-methoxy-2-naphthyl) pyridine, 6-pyridin-3-yl-2-naphthonitrile, 3- (6-methoxy-1H-inden-2-yl) pyridine, 3- (6-Methoxy-3,4-dihydronaphthalen-2-yl) pyridine, 3- (1-methyl-3,4-dihydronaphthalen-2-yl) pyridine and 3- (3-methyl-3,4-dihydronaphthalen-2-yl) pyridine.

• Reaktionsbedingungen: (a) (CF₃SO)₂O, Pyridin, 30 min bei 0°C, über Nacht bei RT (b) PdP(Ph₃)₄, Na₂CO₃, Toluol oder DME, 80°C (c) TBABr₃, CH₂Cl₂, RT; (d) 1) NaBH₄, MeOH, 0°C 2) pTSA, Toluol, Reflux.

The chemical compounds according to the invention can be synthesized in one aspect of the process according to embodiment (4) by Suzuki coupling of compound (III) with compound (II) (compare Examples 1 and 2). The process preferably takes place according to the following general synthesis scheme:

• Reaction conditions: (a) (CF ₃ SO) ₂ O, pyridine, 30 min at 0 ° C, overnight at RT (b) PdP (Ph ₃ ) ₄ , Na ₂ CO ₃ , toluene or DME, 80 ° C (c ) TBABr ₃ , CH ₂ Cl ₂ , RT; (d) 1) NaBH ₄ , MeOH, 0 ° C 2) pTSA, toluene, reflux.

Key step of this synthesis is the Suzuki coupling of various heterocyclic boronic acids with bromo- or triflate-substituted bicyclic compounds. The triflates (III) are synthesized in a first step starting from the corresponding alcohols (IV) by reaction with trifluoromethanesulfonic anhydride and pyridine. In the second step, the bromo or triflate compounds (III) and the herterocyclic boronic acids (II) are coupled by a suzuki reaction with PdP (Ph ₃ ) ₄ as catalyst, Na ₂ CO ₃ as base and toluene or DME as solvent. After workup, the products are purified by column chromatography and characterized by NMR.

In a further aspect of the process according to embodiment (4), the compounds (III) required for the synthesis of the chemical compounds according to the invention can be prepared by TBABr ₃ treatment of the ketones (VI) which converts these into the corresponding α-bromoketones (V) ( Ex. 2). After reduction with NaBH ₄ , the resulting alcohols are refluxed in toluene with the addition of a catalytic amount of pTSA, resulting in the dehydrated bromine compounds (III). The last step is the above-described Suzukikopplung the bromine compounds (III) with the compounds (II).

The Reaction products can be converted into their stable salts, preferably in HCl salts or pharmaceutically acceptable salts.

The syntheses according to the invention can be used for the preparation of the compounds according to the invention and similar compounds. The yields are significantly increased by the synthesis of the invention compared to previously known methods in some cases (by up to 40%). Thus, the yield of 4- (6-methoxy-3,4-dihydronaphthalen-2-yl) pyridine 43 in the literature is 21% (Kelley, CJ et al., J. Het. Chem. 38 (1): 11-23 (2001)), while it is 61% using the synthesis of the present invention.

For the synthesis (4) for the preparation of compounds with deprotonatable substituents or functional groups of the heterocyclic compounds it is necessary to provide them with suitable protective groups. Suitable protecting groups and their removal are known to those skilled in the art e.g. from T.W. Green, Protective Groups in Organic Synthesis, Harvard University, John Wiley & Sons (1981). That means of course when using such protective groups in the process according to the invention (4) a downstream deprotection step necessary is.

The exam the compounds of the invention for use according to embodiment (1) and (5) are performed on in vitro test systems, preferably on more as an in vitro test system. The first stage includes the exam with human CYP11B enzymes, preferably human CYP11B1 and CYP11B2. These human enzymes can either expressed recombinantly, especially in Schizosaccharomyces pombe or V79 cells, or in a tested human cell line, in particular be included in the adrenocortical tumor cell line NCI-H295R (see. Ex. 4 and 8). Particular preference is given to substances for use according to the invention used according to (1) or (5), which has an effect on human CYP11B enzymes demonstrate. To identify new therapeutically active compounds according to embodiment (1) for In particular, humans are fission yeast and V79MZh cells which Express CYP11B1 and CYP11B2 recombinantly, and NCI-H295R cells suitable.

Particularly suitable compounds of the invention for inhibiting human CYP11B2 are those whose selectivity factor (IC ₅₀ CYP11B1 / IC ₅₀ CYP11B2) is greater than 50, especially those whose IC ₅₀ CYP11B2 is less than 20 nM.

In particular, the 3-pyridyl-substituted naphthalene derivatives and 3,4-dihydronaphthalenes according to embodiment (1) are suitable for use in (1) and (5). For selective inhibition of CYP11B2 according to embodiment (5), these are especially the naphthalene derivatives 2, 4, 5 and 10 as well as the dihydronaphthalene derivatives 24, 33, 35 and 38 (compare examples 6-7). Most preferred are 3- (6-methoxy-2-naphthyl) pyridine 2 and 3- (6-methoxy-3,4-dihydronaphthalen-2-yl) pyridine 35 (Ex. 6); the latter is a highly potent CYP11B2 inhibitor (IC ₅₀ : 2 nM), which has a hundredfold selectivity compared to CYP11B1 (IC ₅₀ : 213 nM). This compound also represents a promising lead for other therapeutic agents.

For the selective inhibition of CYP11B1 according to embodiment (5), compounds 27, 29, 45 and 46 are particularly suitable (compare Examples 5-6). These compounds show very low CYP11B2 inhibition in S. pombe (Example 4A) (see Examples 5-6). With IC ₅₀ values of 206 to 805 nM in V79MZh 11B1 cells, they show good inhibitory properties. Very particularly preferred is 4 (5) - (2-naphthyl) -1-H-imidazole 27. It has the strongest CYP11B1 inhibition with moderate ICP11B2 inhibition (41%) with an IC ₅₀ value of 206 nM.

to Determination of inhibition of human CYP11B2 by the test compounds may be a screening test in recombinant 5th pombe, in particular CYP11B2 expressing S. pombe P1) (Example 4A). For another Examination for use according to use (5) are then selected especially those compounds that a higher one show inhibitory effect as the reference fadrozole.

In the second stage can Compounds for use according to (5) in V79 MZh cells (hamster lung fibroblasts), expressing either CYP11B1 or CYP11B2, tested for activity and selectivity become (example 4B). There are different inhibition profiles found: inhibitors that are either selective for CYP11B1 or for CYP11B2 and inhibitors that can inhibit both CYP11B enzymes.

The inhibition of CYP19 by the test compounds can be carried out in vitro using human placental microsomes and [1β, 2β- ³ H] testosterone as substrate (modified according to: Thompson, EA Jr. & Siterii, PK, J. Biol. Chem. 249: 5364-5372 (1974)) (Ex. 3).

The Inhibition of CYP 17 by the test substances may be in vitro with a CYP17-containing membrane fraction from E. coli, the CYP17 recombinant and progesterone can be determined as a substrate (Example 3).

The NCI-H295R cell line is commercially available and is often used as a model for the human adrenal cortex. The cells were first isolated in 1980 (Gazdar, AF et al., Cancer Res. 50: 5488-5496 (1990)) and contain 5 steroidogenic CYP450 enzymes, including 17-alpha-hydroxylase, CYP11B1 and CYP11B2. Because all steroidogenic CYP enzymes found in the adrenal cortex are expressed in this cell line, it is an important tool in estimating the selectivity of inhibitors in vitro. Thus, not only is it essential to distinguish it from the V79 cells NCI-H295R is human cells, but also that in V79MZh11B1 or V79MZh11B2 only one target enzyme is recombinantly expressed in an otherwise completely CYP-enzyme-free system, while NCI-H295R represents a much more complex model. With the help of this new model, the prediction of effects and side effects of compounds on the complex enzymes of the adrenal cortex can become significantly more precise.

The Influence of human CYP11B1 and CYP11B2 in NCI-H295R cells by the substances found in the present invention first tested on the basis of a few compounds (Ex. 8).

Under Use of the NCI-H295R cell line became another test system established for the evaluation of the substances according to the invention (Ex. 9). Background of this test system is that H295R is all steroidogenic CYP enzymes necessary for the synthesis of adrenal steroids expressed within the cell. In the intact human adrenal cortex whereas the formation of mineral corticosteroids takes place in the zona glomerolosa, glucocorticoids in the zona fasciculata and adrenal ones Androgens in the reticular zone. This zoning is in H295R not yet, the concentrations of steroids, which are secreted by H295R, qualitatively and quantitatively the levels released by the intact human adrenal cortex to compare.

Cortisol formation is more strongly inhibited in this model than aldosterone formation when compound 2 is used as the test substance (Ex. 9, Tab. 5). This circumstance can be used to also use indirect inhibitors of CYP11B1 according to embodiment (5) for the preparation of medicaments according to embodiment (2) for the therapy of hypercortisolism and diabetes mellitus. The reason for indirect inhibition by compound 2, which is highly selective for CYP11B2 in the V79MZ system, may be the affinity of this compound for CYP17, which is highly active in H295R. The inhibition of CYP17 may lead to an accumulation of its substrates progesterone and pregnenolone. As a result, degradation of these steroids may result through the CYP21 and CYP11B2 metabolic pathways, which in turn leads to increased levels of the CYP11B2 substrate DOC. CYP11B2 inhibitors then compete with these increased levels of DOC for binding sites at the active site of the protein, resulting in higher IC ₅₀ values. In addition, inhibition of CYP17 results in addition in lowering of the CYP11B1 substrate RSS and in reduced IC ₅₀ values of this enzyme. This cascade can thus sequester selective CYP11B2 inhibition in this assay system. From a systemic point of view, therefore, the compounds according to the invention can considerably influence steroidogenesis beyond the direct effect on individual enzymes.

The in vivo activity The compounds presented here could in the first attempts on Rat model will be shown. Fadrozole lowers the aldosterone and Corticosterone concentrations in ACTH-stimulated rats (Häusler et al., J. Steroid Biochem. 34: 567-570 (1989)). Some of the ones presented here Compounds showed a similar behavior in vivo as fadrozole.

The for use according to embodiment (5) suitable substances of formula (I) may be used to develop a A pharmaceutical substance containing a pharmaceutical preparation according to the embodiment (2) serve the quality of life improved in patients with heart failure or myocardial fibrosis and the mortality can reduce decisively. The results of the present invention clearly show that it is possible is for to develop the target enzyme CYP11B2 inhibitors that are highly active However, the CYP11B1, which is a large structural and functional Homology to CYP11B2, little influence, and vice versa.

The Pharmaceutical composition according to embodiment (2) preferably contains one of those compounds of formula (I) which are preferred for use according to embodiment (1) can be used. It is for the treatment of hyperaldosteronism, Heart failure or myocardial fibrosis, hypercortisolism or Diabetes mellitus in mammals and especially suitable for people.

The compounds of the invention are as individual compounds and in combination with other active ingredients and excipients z. To inhibit human and mammalian P450 oxygenases, particularly to inhibit human or mammalian aldosterone synthase, more particularly to inhibit human aldosterone synthase CYP11B2 with concomitant minor impairment of human CYP11B1 and vice versa reversed to inhibit CYP11B1 with concomitant low impairment of CYP11B2 in vitro and in vivo. CYP11B2-selective compounds can be used in the preparation of medicaments for the treatment of heart failure, (myo) cardiac fibrosis, (congestive heart failure), hypertension, and primary hyperaldosteronism in humans and mammals. The compounds selective for CYP11B1 can be used for the preparation of medicaments for the therapy of hypercortisolism and diabetes mellitus, in particular diabetes mellitus type II.

These Pharmaceutical or pharmaceutical compositions according to the embodiment (2) of the invention in addition to the compounds of the invention even more active ingredients and suitable excipients and carriers contain. Suitable excipients and carriers are those skilled in the art in dependence of Application and application form determined.

The Invention encompasses this addition, a method or the use of the compound of the invention to prevent, slow down the course or therapy of any of following diseases or clinical pictures: diabetes mellitus, Hyperaldosteronism, hypercortisolism, hypertension, congestive heart failure, Renal failure, especially chronic renal failure, restenosis, Atherosclerosis, nephropathy, coronary heart disease, increased Formation of collagen, fibrosis, each linked to or not connected with the onset of hypertension, by administering a pharmaceutical according to the invention Preparation.

In a preferred embodiment This method is used to prevent, slow down the course or therapy of hyperaldosteronism, myocardial fibrosis, congestive heart failure or congestive heart failure and comprising the administration of an effective dose of an aldosterone synthase inhibitor according to the invention or a pharmaceutically acceptable salt thereof to the affected human or the affected mammal.

In a further preferred embodiment This method is used to prevent, slow down the course or therapy of the stress-dependent therapy-resistant diabetes mellitus, in particular type II, or hypercortisolism and includes the gift of a effective dose of a steroid hydroxylase inhibitor of the invention, in particular steroid 11β-hydroxylase inhibitors, or a pharmaceutically acceptable salt thereof to the affected Humans or the affected mammal.

The preferred application for the above-mentioned methods is oral administration, wherein the content of active ingredient by a person skilled in the respective therapy and to be adapted to the patient.

The Invention will be explained in more detail with reference to the following examples, which however, the inventive method do not restrict.

Materials and Methods of Analysis: IR spectra were recorded on a Bruker Vector 33 FT infrared spectrometer. ¹ H NMR spectra were recorded on a Bruker DRX-500 (500 MHz) instrument. Chemical shifts are reported in parts per million (ppm). All coupling constants (J) are given in Hz. Reagents and solvents were from commercial sources and were used without further purification. Column chromatography (CC) was carried out over silica gel (70-200 μm) and the course of the reaction was monitored by thin-layer chromatography over ALUGRAM SIL G / UV ₂₅₄ plates (Macherey-Nagel, Düren).

Example 1: Synthesis of Compounds 1 to 31

• Reaktionsbedingungen: (a) (CF₃SO)₂O, Pyridin, 30 min bei 0°C, über Nacht bei RT (b) PdP(Ph₃)₄, Na₂CO₃, Toluol oder DME, 80°C

The synthesis was carried out according to the general synthesis scheme:

• Reaction conditions: (a) (CF ₃ SO) ₂ O, pyridine, 30 min at 0 ° C, overnight at RT (b) PdP (Ph ₃ ) ₄ , Na ₂ CO ₃ , toluene or DME, 80 ° C

Key step of the synthesis was the Suzuki coupling of various heterocyclic boronic acids with bromine or triflate compounds. The triflates (III) were synthesized in a first step starting from the corresponding alcohols (IV) by reaction with trifluoromethanesulfonic anhydride and pyridine. The bromine compounds were commercially available or were prepared as described under (A). In the second step, the bromo or triflate compounds (III) and the heterocyclic boronic acids (II) were coupled by a suzuki reaction with PdP (Ph ₃ ) ₄ as the catalyst, Na ₂ CO ₃ as the base, and toluene or DME as the solvent. The mixture obtained after the reaction was purified by column chromatography. The products were characterized by NMR.

A) Synthesis of not commercially available precursors:

• Reaktionsbedingungen: (a) RBr, K₂CO₃, DMF, 3h, Reflux

The following compounds were prepared by new or known synthetic methods:
2-bromo-6-ethoxynaphthalene 5i, 2-bromo-6-propoxynaphthalene 6i and 2-bromo-6-phenoxynaphthalene 7i were prepared analogously to Huisgen et al. (slightly modified) (Huisgen, R. and Sorge, G., Liebigs Ann. Chem. 566: 162-184 (1950)):

• Reaction conditions: (a) RBr, K ₂ CO ₃ , DMF, 3h, reflux

• Reaktionsbedingungen: (a) NBS oder NCS, THF, 3h Reflux, über Nacht bei RT

6-bromo-1-chloro-2-methoxynaphthalene 9i and 1,6-dibromo-2-methoxynaphthalene 10i (new synthetic method):

• Reaction conditions: (a) NBS or NCS, THF, 3h reflux, overnight at RT

• Reaktionsbedingungen: (a) NCS, ACN, über Nacht bei RT

1,5-Dichloro-6-methoxy-2-naphthol 12ii was prepared in an anologous manner to WO 03/051805:

• Reaction conditions: (a) NCS, ACN, overnight at RT

• Reaktionsbedingungen: (a) NCS, ACN, über Nacht bei RT

1-Chloro-7-methoxy-2-naphthol 14ii was synthesized in one step (new synthetic method):

• Reaction conditions: (a) NCS, ACN, overnight at RT

• Reaktionsbedingungen: (a) Trifluormethansulfonsäureanhydrid, Pyridin, 30 min bei 0-5°C, über Nacht bei RT

6-Cyano-2-naphthyl trifluoromethanesulfonate 8i, 1,5-dichloro-6-methoxy-2-naphthyl trifluoromethanesulfonate 12i (WO 03/051805), 7-methoxy-2-naphthyl trifluoromethanesulfonate 13i (WO 03/051805) and 1 Chloro-7-methoxy-2-naphthyl trifluoromethanesulfonate 14i:

• Reaction conditions: (a) Trifluoromethanesulfonic anhydride, pyridine, at 0-5 ° C for 30 min, at RT overnight

• Reaktionsbedingungen: (a) POBr₃, 4h, 150°C

2-Bromoquinoline 20i (Young, TE and Amstutz, ED, JACS, 4773-5 (1951)) and 2-bromoquinoxaline 21i were prepared by reaction of the corresponding alcohol with POBr ₃ :

• Reaction conditions: (a) POBr ₃ , 4h, 150 ° C

• Reaktionsbedingungen: (a) 1) nBuLi, THF, –20°C 2) B(OMe)₃, THF, –78°C

O-Methoxynaphthylboronic acid 24i was prepared by a known synthetic method (Chowdhury, S. et al., Tet. Lett. 40 (43): 7599-7603 (1999)):

• Reaction conditions: (a) 1) nBuLi, THF, -20 ° C 2) B (OMe) ₃ , THF, -78 ° C

• Reaktionsbedingungen: (a) MeNH₂, EtOH, Reflux, 1h.

N-Benzylidenemethylamine 28i was prepared as described (H.Dahn and P. Zoller, Helv. Chim. Acta 35: 1348-1351 (1952)):

• Reaction conditions: (a) MeNH ₂ , EtOH, reflux, 1h.

B) Synthesis of the compounds 1-31:

General Synthesis of Compounds 1-2,4-10,12-16,19-22,30-31:

A mixture of substituted 2-bromonaphthalene or 2-trifluoromethanesulfonate (1eq), heterocyclic boronic acid (1.3eq), sodium carbonate (2.1eq) and tetrakis (triphenylphosphine) palladium (0.02eq) in ethylene glycol dimethyl ether or toluene was added Stirred overnight at 80 ° C under a nitrogen atmosphere. After cooling to room temperature (RT), water was added. The mixture was extracted with ethyl acetate, dried over MgSO ₄ , filtered and the solvent removed in vacuo. After purification by column chromatography, the yields were up to 94%.

Synthesis of 6-pyridin-3-yl-2-naphthol 3:

• Reaktionsbedingungen: (a) BBr₃, CH₂Cl₂, –78°C

Demethylation of compound 2 by BBr ₃ in dichloromethane at -78 ° C gave the hydroxylated compound 3:

• Reaction conditions: (a) BBr ₃ , CH ₂ Cl ₂ , -78 ° C

BBr ₃ (0.85 mL, 0.85 mmol) was added slowly to Compound 2 (50 mg, 0.21 mmol) in 6 mL of dry CH ₂ Cl ₂ at -78 ° C under a nitrogen atmosphere. After stirring for 30 minutes, the cooling was stopped and the mixture was stirred at RT overnight. The reaction was then completed by slow addition of methanol. The mixture was washed with a saturated sodium bicarbonate solution, the organic phase was dried over MgSO ₄ , filtered off and the solvent removed in vacuo.

Synthesis of 3- (5-bromo-6-methoxy-2-naphthyl) pyridine 10 and 3,3 '- (2-methoxynaphthalene-1,6-diyl) dipyridine 11:

• Reaktionsbedingungen: (a) PdP(Ph₃)₄, Na₂CO₃, DME, 80°C

The Suzuki coupling of 10i with two equivalents (eq.) Of 3-pyridylboronic acid (catalyst: PdP (Ph ₃ ) ₄ ; base: Na ₂ CO ₃ ) gave a mixture of mono (10) - and di (11) pyridyl-substituted ones Naphthalene:

• Reaction conditions: (a) PdP (Ph ₃ ) ₄ , Na ₂ CO ₃ , DME, 80 ° C

A mixture of 1,6-dibromo-2-methoxynaphthalene 10i (223 mg, 0.71 mmol), 3-pyridinboronic acid (260 mg, 2.12 mmol), sodium carbonate (299 mg, 2.82 mmol) and tetrakis (triphenylphosphine ) Palladium (16 mg) in ethylene glycol dimethyl ether was stirred overnight at 80 ° C under a nitrogen atmosphere. The mixture was cooled to RT and water added. After extraction with ethyl acetate, the organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was purified by column chromatography eluting with CH ₂ Cl ₂ / MeOH (98: 2).

Synthesis of the compounds 17, 18:

• Reaktionsbedingungen: (a) RNHCHO, NaOMe, DMF, 100°C

According to a literature method (Jagdmann, GE et al., Synth. Comm. 20 (8): 1203-1208 (1990)), the carboxylic acid ester 16 was converted into primary or secondary amides with the corresponding formamides and NaOMe as base in anhydrous DMF:

• Reaction conditions: (a) RNHCHO, NaOMe, DMF, 100 ° C

A stirred mixture of methyl 6-bromo-2-naphthoate 16 (1 eq) and formamide (3.3 eq) under nitrogen was added with anhydrous DMF (2 ml) and heated to 100 ° C. Methanolic sodium methoxide (0.7 eq) was added and the mixture further stirred for 1 h. After cooling and adding water (2 ml), the mixture was extracted with ethyl acetate, the organic phase dried over MgSO ₄ , filtered and the solvent removed in vacuo.

Synthesis of the compounds 23-25:

• Reaktionsbedingungen: (a) Imidazol, Cu(OAc)₂, Pyridin, CH₂Cl₂, RT; oder Imidazol, CuI, 2h, Reflux

The 1-imidazolyl-substituted naphthalenes 23-25 were prepared by coupling the naphthylboronic acid with imidazole in the presence of a catalytic amount of a copper salt (Lam, PYS et al., Tet. Lett. 39: 2941-4 (1998); Lan, J. -B. et al., Chem. Commun., 188-9 (2004)):

• Reaction conditions: (a) imidazole, Cu (OAc) ₂ , pyridine, CH ₂ Cl ₂ , RT; or imidazole, CuI, 2h, reflux

A Mixture of naphthalene boronic acid 23i or 25i (2 eq.), Imidazole (1 eq.), Copper (II) acetate (1.5 eq.), Pyridine (2 eq.) And a 4 Å molecular sieve in anhydrous dichloromethane was stirred at RT for two days. The Mixture was filtered off and the solvent removed in vacuo. The product was purified by column chromatography cleaned.

A Mixture of naphthalene boronic acid 24i (1 eq.), Imidazole (1.2 eq.) And copper iodide (5 mol%) in anhydrous Methanol was under air atmosphere Refluxed for 2 hours. The solvent was removed in vacuo. The product was purified by column chromatography.

Synthesis of the compound 26:

• Reaktionsbedingungen: (a) Imidazol, CuO, K₂CO₃, Nitrobenzol, 24h, Reflux

3- (1H-Imidazol-1-yl) quinoline 26 was prepared as described by Kauffmann et al. (Kauffmann, T. et al., Chem. Ber. 115: 452-8 (1982)):

• Reaction conditions: (a) imidazole, CuO, K ₂ CO ₃ , nitrobenzene, 24h, reflux

Synthesis of the compound 27:

• Reaktionsbedingungen: (a) NH₂CHO, 185°C, 2h

Treatment of α-bromoketone 27i with formamide at high temperature gave 4 (5) - (2-naphthyl) -1H-imidazole 27 according to a method of Bredereck and Theilig (Bredereck, H. and Theilig, G., Chem : 88-96 (1953)):

• Reaction conditions: (a) NH ₂ CHO, 185 ° C, 2h

Synthesis of the compounds 28, 29:

• Reaktionsbedingungen: (a) Tosmic, K₂CO₃, RT

Reaction of N-benzylidene methylamine 28i or 2-naphthaldehyde 29i and tosylmethyl isocyanide (Tos mic) with K ₂ CO ₃ as the base gave 1-methyl-5- (2-naphthyl) -1H-imidazole 28 or 5- (2-naphthyl) -1,3-oxazole 29:

• Reaction conditions: (a) Tosmic, K ₂ CO ₃ , RT

A mixture of N-benzylidenemethylamine 28i or 2-naphthaldehyde 29i (1 eq.), Tosylmethyl isocyanide (1.7 eq.) And potassium carbonate (2 eq.) In absolute methanol was stirred at RT overnight. Methanol was removed in vacuo and dichloromethane added to the crude product. After washing with water, the organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was purified by column chromatography.

C) cleaning conditions, Yield and characterization of the title compounds:

3- (2-naphthyl) pyridine (1). Purification: Column Chromatography (CC) (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 16%. ¹ H NMR (500 MHz, _CDCl3): 6 7.44 (dd, 1H, ³ J = 8.2 Hz, J = ⁴ Hz, Pyr-H. 5), 7.51-7.56 (m, 2H, Ar H), 7.71 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.88 to 7.90 (m, 2H, Ar H), 7.96 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.03 to 8.05 (m, 2H, Ar H, Pyr. H-4), 8.63 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.99 (dd, 1H, ⁴ J = 1.6 Hz, Pyr.H-2). IR cm ^-1 : v _max 3392, 3051, 3029, 1599, 1484. MS m / z 206 (MH ⁺ ), 178, 151, 77, 51.

3- (6-Methoxy-2-naphthyl) pyridine (2). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 77%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.95 (s, 1H, OCH ₃ ), 7.17 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.22 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.2 Hz dd, Ar H), 7.45-7.47 (m, 1H, Pyr. H-5), 7.67 (, 1H, ³ J = 8.5 Hz, ⁴ J = 1.8 Hz, Ar H), 7.81 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.85 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.98 (s, 1H, Ar H), 8.04 to 8.06 (m, 1H, Pyr. H-4), 8.61 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.3 Hz, Pyr. H-6), 8.97 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3058, 2938, 1605, 1489. MS m / z 236 (MH ⁺ ).

6-pyridin-3-yl-2-naphthol (3). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 65%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.20 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.2 Hz, Ar H), 7.23 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 7.62 (m, 1H, Pyr. H-5), 7.83 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.87 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.92 (d, 1H, ³ J = 8.8 Hz, Ar H), 8.24 (s, 1H , Ar H), 8.29 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.9 Hz, Pyr. H-4), 8.65 (d, 1H, ³ J = 4.7 Hz, Pyr. H-6), 9.08 (d, 1H, ⁴ J = 1.6 Hz, Pyr. H-2), 9.95 (s, 1H, OH). IR cm ^-1 : v _max 3634, 3021, 1594, 1509, 1489, 793. MS m / z 222 (MH ⁺ ).

3- (6-Bromo-2-naphthyl) pyridine (4). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 21%. ¹ H NMR (500 MHz, CDCl _3): δ 7.53 (. M, 1H, Pyr H-5), 7.62 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz , Ar H), 7.73 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.79 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.89 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.02 (d, 1H, ⁴ J = 1.5 Hz, Ar H), 8.06 (d, 1H , ⁴ J = 1.5 Hz, Ar H), 8.11 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr H-4), 8.65 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.99 (d, 1H, ⁴ J = 1.6 Hz, Pyr. H-2). IR Cm ^-1 : v _max 3032, 2963, 1482. MS m / z 286 (M + 2H ⁺ ) 284 (MH ⁺ ).

3- (6-Ethoxy-2-naphthyl) pyridine (5). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 4%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.51 (t, 3H, ³ J = 6.9 Hz, CH ₃ ), 4.18 (q, 2H, ³ J = 6.9 Hz, CH ₂ ), 7.17 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.21 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.5 Hz, Ar H), 7.55 (m, 1H, Pyr. H-5), 7.66 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.82 (d, 1H , ³ J = 8.8 Hz, Ar H), 7.85 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.98 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 8.16 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr H-4), 8.61 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.99 (d, 1H, ⁴ J = 2.5 Hz, Pyr. H-2). IR cm ^-1 : v _max 302.1, 2995, 1601, 1489, 1252, 821. MS m / z 250 (MH ⁺ ), 221.

3- (6-propoxy-2-naphthyl) pyridine (6). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 84%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.10 (t, 3H, ³ J = 7.2 Hz, CH ₃ ), 1.89 (q, 2H, ³ J = 6.6 Hz, CH ₂ ), 4.07 (t, 2H, ³ J = 6.6 Hz, CH ₂ ), 7.17 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.21 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.5 Hz, Ar H), 7.39 (m, 1H, Pyr. H-5), 7.67 (dd, 1H, ³ J = 8.5 Hz , ⁴ J = 1.9 Hz, Ar H), 7.82 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.83 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.97 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 7.98 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr. H -4), 8.60 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr H-6), 8.96 (d, 1H, ⁴ J = 2.5 Hz , Pyr. H-2). IR cm ^-1 : v _max 2967, 2934, 2878, 1629, 1604, 1491, 1389, 1254. MS m / z 264 (MH ⁺ ).

3- (6-Benzyloxy-2-naphthyl) pyridine (7). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 76%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.22 (s, 2H, CH ₂ ), 7.26 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.30 (dd, 1H, ³ = 8. 7 Hz, ⁴ J = 2.5 Hz, Ar H), 7.36 (t, 1H, ³ J = 7.2 Hz, Ar H), 7.42 (t, 2H, ³ J = 7.6 Hz, Ar H), 7.48-7.51 (m, 1H, Pyr. H-5, Ar H), 7.67 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.84 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.85 (d, 1H, ³ J = 8.5 Hz, Ar H) , 7.99 (s, 1H, Ar H), 8.10 (dt, 1H, ³ J = 7.8 Hz, 4 J = 1.6 Hz, Pyr. H-4), 8.62 (dd, 1H , ³ J = 5.0 Hz, ⁴ J = 1.3 Hz, Pyr. H-6), 8.98 (d, 1H, ⁴ J = 2.2 Hz, Pyr. H-2). IR cm ^-1 : v _max 3040, 1604, 1490. MS m / z 312 (MH ⁺ ), 221.

6-pyridin-3-yl-2-naphthonitrile (8). Reaction time only 2.5 h. Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 71%. ¹ H NMR (500 MHz, CDCl _3): δ 7.55 (. M, 1H, Pyr H-5), 7.68 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.5 Hz , Ar H), 7.84 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.8 Hz, Ar H), 8.01 (d, 1H, ³ 7 = 8.5 Hz, Ar H), 8.04 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.10 (d, 1H, ⁴ J = 1.2 Hz, Ar H), 8.12 (dt, 1H , ³ J = 7.9 Hz, ⁴ 7 = 1.5 Hz, Pyr H-4), 8.28 (s, 1H, Ar H), 8.70 (dd, 1H, ³ J = 4.9 Hz, ⁴ J = 1.5 Hz, Pyr. H-6), 9.01 (d, 1H, ⁴ J = 2.4 Hz, Pyr. H-2). IR cm ^-1 : v _max 3032, 2224 (CN), 1629, 1469, 1424. MS m / z 231 (MH ⁺ ).

3- (5-chloro-6-methoxy-2-naphthyl) pyridine (9). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 93%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 4.07 (s, 3H, OCH ₃ ), 7.39 (d, 1H, ³ J = 9.1 Hz, Ar H), 7.64 (m, 1H, Pyr. H-5), 7.79 (dd, 1H, ³ J = 9.1 Hz, ⁴ J = 2.2 Hz, Ar H), 7.89 (d, 1H, ³ J = 8, 8 Hz, Ar H), 8.04 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 8.26 (dt, 1H, ³ J = 8.1 Hz, ⁴ J = 1.6 Hz , Pyr. H-4), 8.36 (d, 1H, ³ J = 8.8 Hz, Ar H), 8.65 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 9.02 (d, 1H, 4J = 2.2 Hz, Pyr. H-2). IR cm ^-1 : v _max 3033, 2955, 2844, 1602, 1490, 1275. MS m / z 272 (M + 2H ⁺ ), 270 (MH ⁺ ), 255, 227, 192.

3- (5-Bromo-6-methoxy-2-naphthyl) pyridine (10). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 66%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 4.07 (s, 3H, OCH ₃ ), 7.36 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.61 (m, 1H, Pyr. H-5), 7.79 (dd, 1H, ³ J = 9.1 Hz, ⁴ J = 2.2 Hz, Ar H), 7.92 (d, 1H, ³ J = 8, 8 Hz, Ar H), 8.02 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 8.22 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 2.2 Hz , Pyr. H-4), 8.36 (d, 1H, ³ J = 8.8 Hz, Ar H), 8.65 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 9.01 (d, 1H, ⁴ J = 2.2 Hz, Pyr. H-2). IR cm ^-1 : v _max 3045, 2955, 2832, 1601, 1488, 1272. MS m / z 317, 316, 315, 314, 270, 227, 191, 163.

3,3 '- (2-methoxynaphthalene-1,6-diyl) dipyridine (11). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 5%. ¹ H NMR (500 MHz, CDCl _3): δ 3.89 (s, 3H, OCH _3), 7.43-7.46 (m, 2H, Ar H, Pyr-H. 5), 7,54- 7.56 (m, 2H, Ar H, Pyr. H-5), 7.62 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 1.9 Hz, Ar H), 7.86 ( dt, 1H, ³ J = 7.9 Hz, 4 J = 1.9 Hz, Pyr. H-4), 8.01-8.04 (m, 2H, Ar H, Pyr.H-4), 8, 07 (d, 1H, ⁴ J = 1.6 Hz, Ar H), 8.62 (d, 1H, ³ J = 5.0. Hz, Pyr H-6), 8.68 (s, 1H, Pyr H-2), 8.70 (d, 1H, ³ J = 5.0 Hz, Pyr H-6), 8.97 (s, 1H, Pyr H-2). IR cm ^-1 : v _max 3031, 2950, 2842, 1599, 1488, 1258. MS m / z 313 (MH ⁺ ),

3- (1,5-dichloro-6-methoxy-2-naphthyl) pyridine (12). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 41%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 4.10 (s, 3H, OCH ₃ ), 7.48 (d, 1H, ³ J = 9.1 Hz, Ar H), 7.50 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.70 (m, 1H, Pyr. H-5), 8.18 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1, 6 Hz, Pyr. H-4), 8.30 (d, 1H, ³ J = 8.8 Hz, Ar H), 8.37 (d, 1H, ³ J = 9.1 Hz, Ar H), 8.73 (dd, 1H, ³ J = 5.3 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.85 (d, 1H, ⁴ J = 1.6 Hz, Pyr. H -2). IR cm ^-1 : v _max 3060, 2940, 2830, 1617, 1487. MS m / z 307, 306, 305, 304, 270, 227, 191, 163.

3- (7-Methoxy-2-naphthyl) pyridine (13). Reaction time: 8 h. Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 31%. ¹ H NMR (500 MHz, CDCl _3): δ 3.95 (s, 3H, OCH _3), 7.18-7.21 (m, 2H, Ar H), 7.48 (m, 1H, Pyr. H-5), 7.54 (dd, 1H, ³ J = 8.2 Hz, ⁴ J = 1.6 Hz, Ar H), 7.78 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.88 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.95 (d, 1H, ⁴ J = 1.8 Hz, Ar H), 8.08 (dt, 1H , ³ J = 7.8 Hz, ⁴ J = 1.6 Hz, Pyr H-4), 8.63 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.99 (d, 1H, ⁴ J = 2.5 Hz, Pyr. H-2). IR cm ^-1 : v _max 3030, 2973, 2835, 1626. MS m / z 236 (MH ⁺ ), 221.

3- (1-Chloro-7-methoxy-2-naphthyl) pyridine (14). Purification: CC (hexane / EtOAc, 8: 2) Yield 18%. ¹ H NMR (500 MHz, CDCl _3): δ 4.00 (s, 3H, OCH _3), 7.26-7.29 (m, 2H, Ar H), 7.59 (m, 1H, Pyr. H-5), 7.64 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.80 (d, 1H, ³ J = 8.8 Hz, Ar H), 7.82 (d , 1H, ³ J = 8.8 Hz, Ar H), 8.06 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.70 ( d, 1H, ³ J = 5.0 Hz, Pyr. H-6), 8.82 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3020, 2932, 2878, 1677, 1506, 1225. MS m / z 272 (M + 2H ⁺ ), 270 (MH ⁺ ), 255, 191.

3- (3-methoxy-2-naphthyl) pyridine (15). Purification: CC (CH ₂ Cl / MeOH, 98: 2) Yield 31%. ¹ H NMR (500 MHz, CDCl _3): δ 3.94 (s, 3H, OCH _3), 7.25 (s, 1H, Ar H), 7.35-7.40 (m, 2H, Ar H , Pyr. H-5), 7.48 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.3 Hz, Ar H), 7.77 (s, 1H, Ar H), 7, 78 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.81 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.93 (dt, 1H, J = 7 ³ , 9 Hz, ⁴ J = 1.9 Hz, Pyr. H-4), 8.60 (dd, 1H, ³ J = 4.9 Hz, ⁴ J = 1.8 Hz, Pyr. H-6), 8.85 (s, 1H, Pyr. H-2). IR cm ^-1 : _{vmax *} 3054, 2962, 2832, 1631, 1599, 1504, 1466, 1410, 1254. MS m / z 236 (MH ⁺ ).

Methyl 6-pyridin-3-yl-2-naphthoate (16). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 10%. ¹ H NMR (500 MHz, CDCl _3): δ 3.93 (s, 3H, OCH _3), 7.35-7.37 (. M, 1H, Pyr H-5), 7.71 (dd, 1H , ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.89 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.94 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.00 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.01 (s, 1H, Ar H), 8.05 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 8.58 (s, 1H, Ar H), 8.59 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.92 (d, 1H, ⁴ J = 2.2 Hz, Pyr. H-2). IR cm ^-1 : _{vmax *} 3052, 2952, 1718 (CO), 1598, 1499, 1292. MS m / z 264 (MH ⁺ ).

6-pyridin-3-yl-2-naphthamide (17). Purification: CC (hexane / ethyl acetate, 84:15) Yield 61%. ¹ H NMR (500 MHz, CDCl _3): δ 7.42-7.45 (. M, 1H, Pyr H-5), 7.75 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.90 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.96 (d, 1H, ³ J = 8, 8 Hz, Ar H), 8.01-8.04 (m, 2H, Ar H, Pyr. H-4), 8.06 (d, 1H, ⁴ J = 1.3 Hz, Ar H), 8 , 38 (d, 1H, ⁴ J = 1.3 Hz, Ar H), 8.59 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.92 (d, 1H, ⁴ J = 1.9 Hz, Pyr. H-2). IR cm ^-1 : v _{max *} MS m / z 249 (MH ⁺ ).

N-methyl-6-pyridin-3-yl-2-naphthamide (18). N-methylformamide was used. Purification: CC (CH ₂ Cl ₂ / MeOH, 95: 5) Yield 83%. ¹ H NMR (500 MHz, CDCl _3): δ 3.10 (s, 3H, OCH _3), 6.33 (s, 1H, NH), 7.42-7.44 (m, 1H, Pyr H. -5), 7.77 (dd, 1H, ³ J = 8.5 Hz, ³ J = 1.8 Hz, Ar H), 7.87 (dd, 1H, ³ J = 8.5 Hz, 4J = 1.5Hz, ArH), 7.96-8.07 (m, 4H, 3xArH, Pyr. H-4), 8.33 (s, 1H, ArH), 8.65 (dd, 1H , ³ J = 4.6 Hz, ⁴ J = 1.5 Hz, Pyr. H-6), 8.98 (d, 1H, ⁴ J = 1.5 Hz, Pyr. H-2). IR cm ^-1 : v _max 3316, 3059, 2929, 1644, 1549, 1313. MS m / z 263 (MH ⁺ ).

3-pyridin-3-ylquinoline (19). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 3%. ¹ H NMR (500 MHz, CDCl _3): δ 7.46 (. M, 1H, Pyr H-5), 7.62 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.3 Hz , Ar H), 7.77 (td, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.91 (d, 1H, ³ J = 7.6 Hz, Ar H), 8.02 (dt, 1H, ³ J = 7.9 Hz, 4 J = 2.2 Hz, Pyr. H-4), 8.16 (d, 1H, ³ J = 8.2 Hz, Ar H), 8.33 (d, 1H, ⁴ J = 2.2 Hz, Ar H), 8.69 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.3 Hz, Pyr. H -6), 8.98 (d, 1H, 4J = 2.5Hz, Pyr. H-2), 9.16 (d, 1H, 4J = 2.2Hz, Ar H). IR cm ^-1 : _{vmax *} 3055, 2930, 1494. MS m / z 207 (MH ⁺ ).

2-pyridin-3-ylquinoline (20). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1). The product was taken up in 4 ml of diethyl ether and treated with one equivalent of HCl in diethyl ether (1M). The precipitate was filtered off and washed thoroughly with diethyl ether. Yield 43%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.68 (td, 1H, ³ J = 7.9 Hz, ⁴ J = 0.9 Hz, Ar H), 7.86 (td, 1H, ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.95 (dd, 1H, ³ J = 8.2 Hz, ⁴ J = 0.9 Hz, Ar H), 8.12 ( m, 1H, Pyr. H-5), 8.17 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.34 (d, 1H, ³ 7 = 8.5 Hz, Ar H) , 8.57 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.87 (d, 1H, ³ J = 5.4 Hz, Pyr. H-4), 9.34 (d, 1H, ³ J = 8.2 Hz, Pyr. H-6), 9.67 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3053, 2931, 1596, 1548, 1506. MS m / z 207 (MH ⁺ ).

2-pyridin-3-yl-quinoxaline (21). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1). The product was taken up in 4 ml of diethyl ether and treated with one equivalent of HCl in diethyl ether (1M). The precipitate was filtered off and washed thoroughly with diethyl ether. Yield 44%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.79-7.82 (m, 2H, Ar H), 8.07-8.12 (m, 2H, Ar H), 8.14-8, 17 (m, 1H, Pyr. H-5), 8.92 (d, 1H, ³ J = 5.0 Hz, Pyr. H-4), 9.33 (d, 1H, ³ J = 7.9 Hz, Pyr. H-6), 9.46 (s, 1H, Pyr. H-2), 9.71 (s, 1H, Ar H). IR cm ^-1 : v _max 3066, 1604, 1547, 1499, 1313. MS m / z 208 (MH ⁺ ), 181, 102, 75, 51.

3- (9-phenanthryl) pyridine (22). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 94%. ¹ H NMR (500 MHz, CDCl _3): δ 7.56-7.61 (. M, 2H, Ar H, pyr H-5), 7.66 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.3 Hz, Ar H), 7.70-7.74 (m, 3H, Ar H), 7.77 (dd, 1H, ³ J = 8.2 Hz, ⁴ J = 0.9 Hz, Ar H), 7.92 (dd, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Ar H), 8.03 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.9 Hz, Pyr. H-4), 8.73 to 8.76 (m, 2H, Ar H, Pyr. H-6), 8.81 (d, 1H, ³ J = 8, 5 Hz, Ar H), 8.85 (d, 1H, ⁴ J = 2.2 Hz, Pyr. H-2). IR cm ^-1 : v _max 3055, 1659, 1535, 1456, 1247. MS m / z 256 (MH ⁺ ).

1- (2-naphthyl) -1H-imidazole (23). Purification: CC (CH ₂ Cl ₂ / MeOH, 95: 5) Yield 34%. ¹ H NMR (500 MHz, CDCl _3): δ 7.26 (s., 1 H, Im H-4), 7.40 (s., 1 H, Im H-5), 7.51-7.58 ( m, 3H, Ar H), 7.82 (d, 1H ⁴ J = 1.5 Hz, Ar H), 7.88 (t, 2H, ³ J = 7.6 Hz, Ar H), 7.96 (d, 1H, ³ J = 7.6 Hz, Ar H), 8.05 (s, 1H, Im. H-2). IR cm ^-1 : v _max 3116, 3058, 1688, 1602, 1493. MS m / z 195 (MH ⁺ ), 167, 139, 115, 77, 51.

1- (3-methoxy-2-naphthyl) -1H-imidazole (24). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 13%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.97 (s, 3H, OCH ₃ ), 7.21 (s, 1H, Im. H-4), 7.30 (s, 2H, Ar H, In. H-5), 7.24 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.3 Hz, Ar H), 7.51 (td, 1H, ³ J = 8.2 Hz , ⁴ J = 1.3 Hz, Ar H), 7.74 (s, 1H, Ar H), 7.79 (d, 2H, ³ J = 8.5 Hz, Ar H), 7.87 (s , 1H, Im. H-2). IR cm ^-1 : v _max 3059, 2940, 2839, 1506. MS m / z 225 (MH ⁺ ).

1- (6-methoxy-2-naphthyl) -1H-imidazole (25). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 13%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.95 (s, 3H, OCH ₃ ), 7.18 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.24 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 2.5 Hz, Ar H), 7.28 (s, 1H, Im. H-4), 7.38 (s, 1H, Im. H-5 ), 7.48 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 2.5 Hz, Ar H), 7.76 (s, 1H, Ar H), 7.77 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.85 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.07 (s, 1H, Im. H-2). IR cm ^-1 : v _max 3113, 3003, 2962, 2842, 1607. MS m / z 225 (MH ⁺ ), 210, 126.

3- (1H-imidazol-1-yl) quinoline (26). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 18%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.34 (t, 1H, ⁴ J = 1.3 Hz, Im H-4), 7.44 (t, 1H, ⁴ J = 1.5 Hz , Im. H-5), 7.66 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.3 Hz, Ar H), 7.79 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.5 Hz, Ar H), 7.90 (dd, 1H, ³ J = 8.2 Hz, ⁴ J = 1.6 Hz, Ar H), 8.17 (s, 1H, Im. H-2), 8.18-8.19 (m, 2H, Ar H), 9.04 (d, 1H, ⁴ J = 1.8 Hz, Ar H). IR cm ^-1 : v _max 3102, 2962, 1608, 1497. MS m / z 196 (MH ⁺ ), 169, 77, 51.

4 (5) - (2-naphthyl) -1H-imidazole (27). Purification: CC (CH ₂ Cl ₂ ) Yield 9%. ¹ H NMR (500 MHz, CDCl3): δ 7.38 (s, 1H, Im. H-4), 7.39-7.45 (m, 2H, Ar H), 7.73 (dd, 1H, ³ J = 8.5 Hz, 4J = 1.9 Hz, Ar H), 7.74-7.81 (m, 4H, ArH + Im. H-2), 8.13 (s, 1H, Ar H). IR cm ^-1 : v _max 3125, 3044, 2852. MS m / z 195 (MH ⁺ ), 168, 141.

1-methyl-5- (2-naphthyl) -1H-imidazole (28). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 18%. ¹ H NMR (500 MHz, CDCl _3): δ 3.75 (s, 3H, CH _3), 7.22 (s, 1H, H-In. 4), 7.49-7.53 (m, 3H , Ar H), 7.68 (s, 1H, Im. H-2), 7.85 to 7.87 (m, 3H, Ar H), 7.91 (d, 1H, ³ J = 8.5 Hz, Ar H). IR cm ^-1 : v _max 3083, 3053, 2952, 1600, 1490. MS m / z 209 (MH ⁺ ), 167, 139, 115.

5- (2-naphthyl) -1,3-oxazole (29). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3). Yield 28%. ¹ H NMR (500 MHz, CDCl _3): δ 7.47 (s., 1 H, Im H-4), 7.49-7.54 (m, 2H, Ar H), 7.73 (dd, 1H , ³ J = 8.5 Hz, ⁴ J = 1.6 Hz, Ar H), 7.83-7.90 (m, 3H, Ar H), 7.97 (s, 1H, Im. H-2 ), 8.14 (s, 1H, ArH). IR cm ^-1 : v _max 3128, 3055, 2952, 1630, 1497. MS m / z 196 (MH ⁺ ), 167, 139, 115.

5- (6-Methoxy-2-naphthyl) pyrimidine (30). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 24%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.96 (s, 3H, OCH ₃ ), 7.19 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.24 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.5 Hz, Ar H), 7.67 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.84 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.90 (d, 1H, ³ J = 8.5 Hz, Ar H), 8.02 (d, 1H, 4J = 1.9Hz, ArH), 9.15 (s, 2H, Pyr. H-4, Pyr. H-6), 9.26 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3034, 2940, 1694, 1626, 1606, 1487, 1210. MS m / z 237 (MH ⁺ ).

4- (6-Methoxy-2-naphthyl) pyridine (31). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 60%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.97 (s, 3H, OCH ₃ ), 7.19 (d, 1H, ⁴ J = 2.5 Hz, Ar H), 7.25 (dd, 1H, ³ J = 8.8 Hz, ⁴ J = 2.5 Hz, Ar H), 7.76 (dd, 1H, ³ J = 8.5 Hz, ⁴ J = 1.9 Hz, Ar H), 7.86 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.90 (d, 1H, ³ J = 8.5 Hz, Ar H), 7.94 (dd, 1H, ³ J = 6.6 Hz, ⁴ J = 1.6 Hz, Pyr. H-3, Pyr. H-5), 8.15 (d, 1H, ⁴ J = 1.9 Hz, Ar H), 8.75 (dd, 1H, ³ J = 6.3 Hz, ⁴ J = 1.3 Hz, Pyr. H-2, Pyr. H-6). IR cm ^-1 : v _max 3040, 2938, 2840, 1699, 1621, 1488, 1210. MS m / z 236 (MH ⁺ ).

Example 2: Synthesis of indanes and 3,4-dihydronaphthalenes 32 to 46.

A) Synthesis of the compounds 32 to 46:

General Synthesis of Compounds 32-33, 35, 37, 43:

• Reaktionsbedingungen: (a) TBABr₃, CH₂Cl₂, RT; (b) 1) NaBH₄, MeOH, 0°C 2) pTSA, Toluol, Reflux; (c) 3- oder 4-Pyridylboronsäure, PdP(Ph₃)₄, Na₂CO₃, DME, 80°C.

The general procedure for synthesizing the pyridyl-substituted compounds 32-33, 35, 37, 43 was as shown in the following scheme:

• Reaction conditions: (a) TBABr ₃ , CH ₂ Cl ₂ , RT; (b) 1) NaBH ₄ , MeOH, 0 ° C 2) pTSA, toluene, reflux; (c) 3- or 4-pyridylboronic acid, PdP (Ph ₃ ) ₄ , Na ₂ CO ₃ , DME, 80 ° C.

To a solution of the substituted ketone (1 eq) in dichloromethane / methanol (2.5: 1) was added TBABr ₃ (1.1 eq) at RT. The mixture was stirred until the orange solution decolorized. The solvent was removed in vacuo and the precipitate extracted with diethyl ether. The ether phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo.

A solution of the α-bromoketone (1 eq) in anhydrous methanol / tetrahydrofuran (1: 1) was stirred under a nitrogen atmosphere in an ice bath. NaBH ₄ (0.7 eq) was added portionwise. After stirring at 0 ° C. for 15 minutes and stirring at RT for 30 minutes, the mixture was poured into water and extracted with diethyl ether. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo.

A mixture of the resulting alcohol (1 eq) and p-toluenesulfonic acid (0.1 eq) in toluene was refluxed (with a Dean-Stark trap) for 2 hours to remove any water. The mixture was washed with saturated sodium bicarbonate solution and water. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo.

After purification, a mixture of bromine compound (1 eq), 3- or 4-pyridylboronic acid (1.3 eq), sodium carbonate (2.1 eq) and tetrakis (triphenylphosphine) palladium (0.02 eq) in ethylene glycol dimethyl ether overnight at 80 ° C held. After cooling to RT and adding water, the mixture was extracted with dichloromethane, the organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The final product was purified by column chromatography and characterized.

General Synthesis of Compounds 34, 36, 40-42:

• Reaktionsbedingungen: (a) 3-Pyridylacetonitril, NaNH₂, DMF; (b) NaOH, EtOH, Reflux; (c) PPA, 110°C; (d) NaBH₄, MeOH, 0°C; (e) CH₃COOH/H₂SO₄, 100°C.

The synthesis of the 3-pyridyl-substituted compounds 34, 36, 40-42 was carried out as follows:

• Reaction conditions: (a) 3-pyridylacetonitrile, NaNH ₂ , DMF; (b) NaOH, EtOH, reflux; (c) PPA, 110 ° C; (d) NaBH ₄ , MeOH, 0 ° C; (e) CH ₃ COOH / H ₂ SO ₄ , 100 ° C.

These The method has already been used by Bencze and Barsky for the synthesis of 3- (3,4-dihydronaphthalene-2-yl) pyridine 33 (Bencze, W. L. and Barsky, L.I., J. Med. Pharm. Chem. 5: 1298-1306 (1962)), but not for the connections 34, 36, 40-42, which are new.

To a NaNH ₂ (1.2 eq) suspension in 20 ml of anhydrous DMF (three-necked flask, reflux condenser, gas inlet and dropping funnel with septum) under nitrogen atmosphere was added dropwise 3-pyridylacetonitrile (1.07 eq) with stirring and ice bath cooling. After 1 h of stirring at RT and 1 h at 80 ° C, the mixture was cooled with an ice bath and the bromine compound (1 eq) was added dropwise. The reaction mixture was then stirred at RT for 3 h and at 80 ° C for 1 h. After cooling, an excess of water was added and the mixture was extracted with diethyl ether. The organic phase was washed with water, dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was purified by column chromatography (elution with CH ₂ Cl ₂ / MeOH (99: 1)).

To a solution of the resulting nitrile (1 eq) in a few ml of ethanol was added NaOH (11 eq) in water. After 24 h reflux, water was added and adjusted to pH 5 with 2 N HCl and aqueous acetic acid. The mixture was extracted with ethyl acetate, the organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The resulting acid was used in the next reaction step without further purification.

A mixture of polyphosphoric acid (2.2 g) and the acid thus prepared (0.53 g, 2.05 mmol) was stirred at 110 ° C for 20 min. The mixture was poured into ice-water and neutralized with 6% NaOH. With sodium bicarbonate pH 8 was adjusted and the solution extracted with diethyl ether. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was acidified purified by chromatography.

A solution of the ketone (1 eq) in anhydrous methanol was stirred under a nitrogen atmosphere in an ice bath. NaBH ₄ (2 eq) was added portionwise. After stirring at RT for 1 h, the mixture was poured into water and extracted with dichloromethane. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The resulting alcohol was used for the next reaction step without further purification.

A mixture of 1 ml of acetic acid, 0.14 ml of conc. Sulfuric acid and the alcohol (0.30 mmol) was stirred at 100 ° C for 1 h. The mixture was poured into ice-water and basified with a 6% NaOH. After extraction with dichloromethane, the organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was purified by column chromatography (elution with CH ₂ Cl ₂ / MeOH (98: 2)).

Synthesis of compounds 38 and 39:

• Reaktionsbedingungen: (a) R'MgHal, Toluol, Reflux; (b) HCl, 100°C, 2 h.

The synthesis of 3- (1-methyl-3,4-dihydronaphthalen-2-yl) pyridine 38 has also been described by Bencze and Barsky (Bencze, WL and Barsky, LI, J. Med. Pharm. Chem. 5: 1298- 1306 (1962)); 3- (1-Ethyl-3,4-dihydronaphthalen-2-yl) pyridine 39 has not been described so far:

• Reaction conditions: (a) R'MgHal, toluene, reflux; (b) HCl, 100 ° C, 2 h.

General Synthesis of Compounds 44-46:

• Reaktionsbedingungen: (a) TBABr₃, CH₂Cl₂, RT; (b) Imidazol, DMF, RT; (C) 1) NaBH₄, MeOH, 0°C 2) CH₃COOH/H₂SO₄, 120°C.

The procedure for the synthesis of 1-imidazolyl-substituted compounds 44-46 was as follows:

• Reaction conditions: (a) TBABr ₃ , CH ₂ Cl ₂ , RT; (b) imidazole, DMF, RT; (C) 1) NaBH ₄ , MeOH, 0 ° C 2) CH ₃ COOH / H ₂ SO ₄ , 120 ° C.

These This method has already been described by Cozzi et al. for the synthesis of 1- (3,4-dihydronaphthalen-2-yl) -1H-imidazole 45 and 1- (6-methoxy-3,4-dihydronaphthalen-2-yl) -1H-imidazole 46 (Cozzi, P. et al., Eur. J. Med. Chem. 26: 423-433 (1991)), but not for connection 44th

To a solution of the substituted ketone (1 eq) in dichloromethane / methanol (2.5: 1) was added TBABr ₃ (1.1 eq) at RT. The mixture was stirred until the orange solution was decolorized. The solvent was removed in vacuo and the precipitate extracted with diethyl ether. The ether phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo.

A solution of α-bromoketone (1 eq) and imidazole in DMF was stirred at RT overnight. The mixture was poured into ice-water and extracted with dichloromethane. The organic phase was washed thoroughly with water, dried over MgSO ₄ , filtered and the solvent removed in vacuo. The product was purified by column chromatography.

A solution of the 1-imidazolyl substituted ketone (1 eq) in anhydrous MeOH was stirred in an ice bath under a nitrogen atmosphere and NaBH ₄ (2 eq) added portionwise. After 1 h of stirring at RT, the mixture was poured into water and extracted with dichloromethane. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The resulting alcohol was used for the next reaction step without further purification.

The alcohol was dissolved in a mixture of glacial acetic acid and concentrated sulfuric acid and heated at 100 ° C for 4 h. After cooling to RT, the mixture was poured onto ice, neutralized with NaOH and extracted with dichloromethal. The organic phase was dried over MgSO ₄ , filtered and the solvent removed in vacuo. The end product was purified by column chromatography.

B) cleaning conditions, Yield and characterization of the title compounds:

3- (1H-inden-2-yl) pyridine (32). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1) Yield 51%. ¹ H NMR (500 MHz, CDCl ₃ ): δ = 3.81 (s, 2H, H-3), 7.23 (td, 1H, ³ J = 7.2 Hz, ⁴ j = 0.9 Hz, Ar H), 7.29-7.32 (m, 3H, Ar H, Pyr H-5), 7.44 (d, 1H, ³ J = 7.2 Hz, Ar H), 7.50 ( d, 1H, ³ J = 7.2 Hz, Ar H), 7.89 (dt, 1H, ³ J = 8.1 Hz, ⁴ J = 1.9 Hz, Pyr. H-4), 8.50 (s, 1H, Pyr. H-6), 8.90 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3054, 2916, 1533. MS m / z 194 (MH ⁺ ).

3- (3,4-dihydronaphthalen-2-yl) pyridine (33). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 62%. ¹ H NMR (500 MHz, CDCl ₃ ) δ 2.73 (t, 2H, ³ J = 8.3 Hz, H-4), 2.97 (t, 2H, ³ J = 7.8 Hz, H 3), 6.89 (s, 1H, H-1), 7.13-7.19 (m, 4H, ArH), 7.32-7.34 (m, 1H, Pyr. H-5) , 7.85 (td, 1H, ³ J = 8.1 Hz, ⁴ J = 1.5 Hz, Pyr. H-4), 8.49 (dd, 1H, ³ J = 4.9 Hz, ⁴ J = 1.5 Hz, Pyr. H-2), 8.79 (d, 1H, ⁴ J = 1.9 Hz, Pyr. H-6). IR cm ^-1 : v _max 3022, 2935, 2885, 2831, 1485, 1421. MS m / z 208 (MH ⁺ ), 179, 101, 79.

3- (6-Methoxy-1H-inden-2-yl) pyridine (34). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 45%. ¹ H NMR (500 MHz, _CDCl3) δ 3.77 (s, 2H, H-3), 3.85 (s, 3H, OCH _3), 6.86 (dd, 1H, ³ J = 8.2 Hz, ⁴ J = 2.2 Hz, Ar H), 7.09 (d, 1H, ⁴ J = 1.5 Hz, Ar H), 7.30 (s, 1H, H-1), 7.34 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.36-7.39 (m, 1H, Pyr. H-5), 7.94 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.5 Hz, Pyr. H-4), 8.46 (dd, 1H, ³ J = 4.9 Hz, ⁴ J = 1.5 Hz, Pyr. H-6), 8, 85 (d, 1H, ⁴ J = 1.8 Hz, Pyr. H-2). IR cm ^-1 : v _max 3059, 2905, 2836, 1685, 1607, 1493, 1259. MS m / z 224 (MH ⁺ ).

3- (6-Methoxy-3,4-dihydronaphthalen-2-yl) pyridine (35). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 89%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.73 (t, 2H, ³ J = 8.5 Hz, H-3), 2.96 (t, 2H, ³ J = 8.5 Hz, H -4), 3.82 (s, 3H, OCH _3), 6.73 to 6.75 (m, 2H, Ar H), 6.88 (s, 1H, H-1), 7.10 (d , 1H, ³ J = 8.2 Hz, Ar H), 7.32-7.35 (m, 1H, Pyr. H-5), 7.86 (dt, 1H, ³ J = 8.2 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.48 (dd, 1H, ³ J = 4.7 Hz, ⁴ 7 = 1.6 Hz, Pyr. H-6), 8.79 (d, 1H, ⁴ J = 2.5 Hz, Pyr. H-2). IR Cm ^-1 : v _max 3021, 2936, 2834, 1607, 1570, 1499, 1250. MS m / z 238 (MH ⁺ ), 223, 194,165.

3- (7-Methoxy-1H-inden-2-yl) pyridine (36). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1) Yield 34%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.73 (t, 2H, ³ J = 8.5 Hz, H-3), 2.96 (t, 2H, ³ J = 8.5 Hz, H -4), 3.82 (s, 3H, OCH _3), 6.73 to 6.75 (m, 2H, Ar H), 6.88 (s, 1H, Ar H), 7.10 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.32-7.35 (m, 1H, Pyr. H-5), 7.86 (dt, 1H, ³ J = 8.2 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.48 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.79 (d , 1H, ⁴ J = 2.5 Hz, Pyr. H-2). IR cm ^-1 : v _max 3034, 2938, 2836, 1595, 1483, 1263, 1088. MS m / z 224 (MH ⁺ ).

3- (7-Methoxy-3,4-dihydronaphthalen-2-yl) pyridine (37). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 79%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.74 (t, 2H, ³ J = 8.2 Hz, H-3), 2.92 (t, 2H, ³ J = 8.2 Hz, H-4), 3.81 (s, 3H, OCH _3), 6.73 to 6.75 (m, 2H, Ar H), 6.87 (s, 1H, H-1), 7.09 ( d, 1H, ³ J = 8.2 Hz, Ar H), 7.35-7.38 (m, 1H, Pyr. H-5), 7.88 (dt, 1H, ³ J = 7.8 Hz , ⁴ J = 1.9 Hz, Pyr. H-4), 8.51 (dd, 1H, ³ J = 5.0. Hz, ⁴ J = 1.6 Hz, Pyr H-6), 8.80 (d, 1H, ⁴ J = 1.6 Hz, Pyr. H-2). IR cm ^-1 : v _max 3025, 2934, 2833, 1604, 1571, 1497, 1255, 1040. MS m / z 238 (MH ⁺ ).

3- (1-Methyl-3,4-dihydronaphthalen-2-yl) pyridine (38). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 63%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.05 (s, 3H, CH ₃ ), 2.57 (td, 1H, ³ J = 8.2 Hz, ⁴ J = 1.6 Hz, H 3), 2.92 (t, 1H, ³ J = 8.2 Hz, H-4), 7.19-7.23 (m, 2H, Ar H), 7.27 (t, 1H, ³ J = 7.6 Hz, Ar H), 7.38 (d, 1H, ³ J = 7.6 Hz, Ar H), 7.41-7.45 (m, 1H, Pyr. H-5), 7 , 72 (td, 1H, ³ J = 7.92 Hz, ⁴ J = 1.6 Hz, Pyr H-4), 8.54 (dd, 1H, ³ J = 5.0 Hz, ⁴ J = 1 , 6Hz, Pyr. H-6), 8.57 (s, 1H, Pyr. H-2). IR cm ^-1 : v _max 3024, 2937, 2831, 1602, 1487, 1408, 1250. MS m / z 222 (MH ⁺ ).

3- (1-Ethyl-3,4-dihydronaphthalen-2-yl) pyridine (39). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1) Yield%. ¹ H NMR (500 MHz, CDCl _3): δ 1.05 (t, ³ J = 7.6 Hz, CH ₃ 3H), 2.47 to 2.54 (m, 4H, CH _2, H-3 ), 2.87 (t, 2H, ³ J = 7.6 Hz, H-4), 7.18-7.20 (m, 2H, Ar H), 7.24-7.27 (m, 1H , Ar H), 7.30-7.33 (m, 1H, Pyr. H-5), 7.38 (d, 1H, ³ J = 7.6 Hz, Ar H), 7.56 (dt, 1H, ³ J = 7.6 Hz, ⁴ J = 1.8 Hz, Pyr. H-4), 8.51 to 8.53 (m, 2H, Pyr. H-6, Pyr. H-2). IR cm ^-1 : v _{max ·} MS m / z (MH ⁺ ).

3- (3-Methyl-3,4-dihydronaphthalen-2-yl) pyridine (40). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 63%. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.03 (d, 3H, ³ J = 6.9 Hz, CH ₃ ), 2.76 (dd, 1H, ² J = 15.4 Hz, ³ J = 2.2 Hz, H-4), 3.00-3.06 (m, 1H, H-3), 3.23 (dd, 1H, ² J = 15.4 Hz, ³ J = 6.9 Hz , H-4 '), 6.86 (s, 1H, H-1), 7.16-7.22 (m, 2H, ArH), 7.36 (m, 1H, Pyr. H-5) , 7.92 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.52 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.9 Hz, Pyr. H-6), 8.85 (d, 1H, ⁴ J = 1.9 Hz, Pyr. H-2). IR cm ^-1 : v _max 3020, 2962, 2924, 1564, 1453, 1216. MS m / z 222 (MH ⁺ ).

3- (4-Methyl-3,4-dihydronaphthalen-2-yl) pyridine (41). Purification: CC (CH ₂ Cl ₂ / MeOH, 99: 1) Yield 51% ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.32 (d, 3H, ³ J = 6.9 Hz, CH ₃ ), 2 , 54 (ddd, 1H, ² J = 16.1 Hz, ³ J = 7.6 Hz, ⁴ J = 0.9 Hz, H-3), 2.87 (ddd, 1H, ² J = 16.1 Hz, ³ J = 6.6 Hz, ⁴ J = 1.6 Hz, H-3 ') 3.11-3.17 (m, 1H, H-4), 6.89 (s, 1H, H- 1), 7.16-7.24 (m, 4H, ArH), 7.33-7.35 (m, 1H, Pyr. H-5), 7.86-7.85 (td, 1H, ³ J = 8.1 Hz, ⁴ J = 1.5 Hz, Pyr. H-4), 8.52 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr. H -6), 8.82 (d, 1H, ⁴ J = 2.0 Hz, Pyr. H-2). IR cm ^-1 : v _{max *} MS m / z 222 (MH ⁺ ), 203, 178, 77.

3- (4-Ethyl-3,4-dihydronaphthalen-2-yl) pyridine (42) Purification: Yield 55%. ¹ H NMR (CDCl ₃ ) δ 0.92 (t, 3H, ³ J = 7.6 Hz, CH ₃ ), 1.56-1.69 (m, 2H, CH ₂ ), 2.68 (dd, 1H, ² 7 = 16.4 Hz, ³ J = 3.8 Hz, H-3), 2.83 to 2.86 (m, 1H, H-4), 2.93 (dd, 1H, ² J = 16.4 Hz, ³ J = 2.5 Hz, H-3 '), 6.86 (d, 1H, ⁴ J = 2.5 Hz, H-1), 7.16-7.22 (m , 4H, ArH), 7.32-7.34 (m, 1H, Pyr. H-5), 7.84 (dt, 1H, ³ J = 7.9 Hz, ⁴ J = 1.6 Hz, Pyr. H-4), 8.52 (dd, 1H, ³ J = 4.7 Hz, ⁴ J = 1.6 Hz, Pyr. H-6), 8.82 (d, 1H, ⁴ J = 1 , 9 Hz, Pyr H-2). IR cm ^-1 : v _max 3035, 2962, 2931, 1682, 1569, 1486, 1456, 1022. MS m / z 236 (MH ⁺ ).

4- (6-methoxy-3,4-dihydronaphthalen-2-yl) pyridine (43). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 51%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.66 (t, 2H, ³ J = 8.5 Hz, H-3), 2.91 (t, 2H, ³ J = 8.5 Hz, H -4), 3.77 (s, 3H, OCH _3), 6.69 to 6.71 (m, 2H, Ar H), 7.09-7.11 (m, 2H, H-1, H Ar ), 7.53 (dd, 1H, ³ J = 6.6 Hz, ⁴ J = 1.6 Hz, Pyr. H-3, Pyr. H-5), 8.49 (dd, 1H, J = ³ 6.6 Hz, ⁴ J = 1.6 Hz, Pyr. H-2, Pyr. H-6). IR cm ^-1 : v _max 3040, 2939, 2835, 1599, 1504, 1209. MS m / z 238 (MH ⁺ ).

1- (1H-inden-2-yl) -1H-imidazole (44). Purification: CC (CH ₂ Cl ₂ / MeOH, 97: 3) Yield 70%. ¹ H NMR (500 MHz, CDCl _3): δ 3.87 (s, 2H, H-3), 6.78 (s, 1H, H-1), 7.22-7.24 (m, 2H, In. H-4, Ar H), 7.30-7.33 (m, 2H, Ar H, Im. H-5), 7.38 (d, 1H, ³ J = 7.6 Hz, Ar H ), 7.45 (d, 1H, ³ J = 7.6 Hz, Ar H), 8.09 (s, 1H, Im. H-2). IR cm ^-1 : v _max 2940, 1707, 1616, 1498, 1264, 1238. MS m / z 183 (MH ⁺ ).

1- (3,4-dihydronaphthalen-2-yl) -1H-imidazole (45). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 96%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.83 (t, 2H, ³ J = 8.2 Hz, H-4), 3.08 (t, 1H, ³ J = 8.2 Hz, H -3), 6.57 (s, 1H, H-1), 7.12 (d, 1H, ³ J = 7.8 Hz, Ar H), 7.18-7.22 (m, 4H, Im H-4, Ar H), 7.28 (s, 1H, Im. H-5), 7.95 (s, 1H, Im. H-2). IR cm ^-1 : v _max 3006, 3990, 1650, 1484, 1295, 1045. MS m / z 197 (MH ⁺ ).

1- (6-methoxy-3,4-dihydronaphthalen-2-yl) -1H-imidazole (46). Purification: CC (CH ₂ Cl ₂ / MeOH, 98: 2) Yield 54%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.79 (t, 2H, ³ J = 8.2 Hz, H-4), 2.96 (t, 2H, ³ J = 8.2 Hz, H -3), 3.75 (s, 3H, OCH _3), 6.76 to 6.77 (m, 2H, Ar H), 6.82 (s, 1H, H-1), 7.04 (s , 1H, Im. H-4), 7.07 (d, 1H, ³ J = 8.2 Hz, Ar H), 7.64 (s, 1H, Im. H-5), 8.10 (s , 1H, Im. H-2). IR cm ^-1 : v _max 2924, 1729, 1646, 1604, 1495, 1459, 1298, 1253. MS m / z 227 (MH ⁺ ).

Example 3: Enzyme Test Systems for testing compounds for inhibition of CYP enzymes in vitro

It the following CYP enzymes were prepared according to described methods and tested: human CYP17 (expressed recombinantly in E. coli) (Hutschenreuter, T.U. et al., J. Enzyme Inhib. Med. Chem. 19: 17-32 (2004)) and human placental CYP19 (Hartmann, R.W. & Batzl, C., J. Med. Chem. 29: 1362-1369 (1986)).

A) Isolation of the CYP 17-containing Membrane fraction from E, coli pJL17 / OR

The recombinantly altered E. coli strain pJL17 / OR, in which the human CYP17 and the rats NADPH-P450 reductase were co-expressed, was prepared according to the method of Ehmer et al. and stored (Ehmer, PB et al., J. Steroid Biochem. Mol. Biol. 75: 57-63 (2000)). For isolation of the membrane fraction, 5 ml of the bacterial cell suspension with an OD ₅₇₈ of 50 was washed with phosphate buffer (0.05 M, pH 7.4, 1 mM MgCl ₂ , 0.1 mM EDTA and 0.1 mM DTT). The bacteria were spun down and resuspended in 10 ml of ice-cold TES buffer (0.1 M Tris-acetate, pH 7.8, 0.5 mM EDTA, 0.5 M sucrose). 4 mg of lysozyme in 10 ml of ice-cold water was added to give a final concentration of 0.2 mg / ml has been. This was followed by a thirty-minute incubation with constant shaking on ice. The spheroplasts were recovered by a new centrifugation step at 12,000 g for 10 min and resuspended in 3 ml of ice-cold phosphate buffer (composition thus, plus 0.5 mM PMSF).

To The cells were frozen and thawed on ice with an ultrasonic wand open minded. The whole cells and cell debris were at 3,000 g for 7 min centrifuged. The supernatant was again at 50,000 g for 20 min at 4 ° C centrifuged. In the process, the membrane pellet settled down, which in 2ml Phosphate buffer (composition see above) with 20% glycerol with the help an Ultra Turrax rod was resuspended. The protein concentration was determined by the method by Lowry et al. determined (Lowry, O.H. et al., J. Biol. Chem. 193: 265-275 (1951)). Aliquots with an approximate protein concentration of 5 mg / ml were stored at -70 ° C until use.

B) Isolation of CYP19 (Aromatase)

The Enzyme became fresh human from the microsome fraction Placenta (St. Joseph's Hospital, Saarbrücken-Dudweiler, Germany) obtained by the method of Thompson and Siiteri (Thompson, E. A. & Siiteri, P.K., J. Biol. Chem. 249: 5364-5372 (1974)). The isolated microsomes were incubated in a minimal volume of phosphate buffer (0.05 M, pH 7.4; 20% glycerol). In addition, DTT (10 mM) and EDTA (1mM) was added to protect the enzyme from degradation reactions. The Protein concentration was determined according to Lowry et al. determined (Lowry, O. H. et al., J. Biol. Chem. 193: 265-275 (1951)) and should be used according to the Workup be about 35 mg / ml.

C) Determination of the percentage Inhibition of CYP17

A solution of 6.25 nmol of progesterone (in 5 μl of MeOH) was dissolved in 140 μl of phosphate buffer (0.05 M, pH 7.4, 1 mM MgCl ₂ , 0.1 mM EDTA and 0.1 mM DTT) and combined with 50 .mu.l NADPH regenerating system (phosphate buffer with 10 mM NADP ⁺ , 100 mM glucose-6-phosphate and 2.5 units of glucose-6-phosphate dehydrogenase) and inhibitor (in 5 ul DMSO) preincubated at 37 ° C for 5 min. Control incubations were performed in parallel with 5 μl of DMSO without inhibitor. The reaction was started by adding 50 μl of a 1 to 5 diluted membrane suspension in phosphate buffer (0.8-1 mg protein per ml). After mixing the batch was incubated for 30 min at 37 ° C. The reaction was stopped by adding 50 μl 1N HCl.

The steroids were extracted with 1 ml EtOAc. After a centrifugation step (5 min at 2500 g), 900 μl of the organic phase were transferred to an Eppendort vessel with 250 μl of the incubation buffer and 50 μl of 1 N HCl and shaken again. After centrifugation, 800 μl of the organic phase was taken, placed in a new vessel and evaporated to dryness. The samples were dissolved in 50 μl of a water-methanol mixture (1: 1) and analyzed by HPLC. The substrate turnover was calculated from the ratio of the areas of product peaks (17α-hydroxyprogesterone and 16α-hydroxyprogesterone) to that of the substrate peak. The activity of the inhibitors was calculated from the reduced substrate conversion after addition of inhibitors according to the following formula:

D) Determination of the IC ₅₀ value of CYP19

The assay was performed approximately analogously to that of Foster et al. A detailed description can be found in Hartmann and Batzl 1986 (Foster, AB et al., J Med Chem 26: 50-54 (1983); Graves, PE & Salhanick, HA, Endocrinology 105: 52 Hartmann, RW & Batzl, C., J. Med. Chem. 29: 1362-1369 (1986)). The enzyme activity was monitored by measuring the ³ H ₂ O formed during the aromatization from [1β- ³ H] androstenedione. Each reaction vessel contained 15 nM radiolabeled [1β- ³ H] androstenedione (equivalent to 0.08 uCi) and 485 nM unlabelled androstenedione, 2 mM NADP ^⊕, 20 mM glucose-6-phosphate, 0.4 units glucose-6-phosphate dehydrogenase and inhibitor (0-100 μM) in phosphate buffer (0.05 M, pH 7.4). The compounds to be tested were dissolved in DMSO and diluted with buffer to the desired concentration. The final DMSO concentration of the control and inhibitor incubation was about 2%. Each tube was preincubated for 5 min in a water bath at 30 ° C. Addition of the microsomal protein (0.1 mg) started the reaction. The total volume of each batch was 200 μl. By addition of 200 .mu.l ice-cold 1 mM HgCl ₂ solution, the reaction was stopped after 14 min. There were 200μl of a 2% aqueous suspension of dextran coated charcoal (dextran-coated charcoal, DCC) was added to absorb the steroids, and the vessels were shaken for 20 minutes. Thereafter, the activated carbon was centrifuged off at 1,500 g for 5 min. The radioactive water ( ³ H ₂ O) in the supernatant was determined by scintillation measurement by means of an LKB-Wallac β-counter. The IC ₅₀ values were calculated by a semilogarithmic plot of percent inhibitor inhibition inhibition. From this, the molar concentration at which 50% inhibition occurs was read.

Example 4: Biological Test systems for testing compounds for selective inhibition of human CYP11B1 and CYP11B2 in vitro

A) Screeninq test in transgenic fission yeast:

A fission yeast suspension (S.pombe PE1) with a cell density of 3 x 10 ⁷ cells / ml was prepared from a freshly grown cuticle using fresh EMMG (pH 7.4) modified according to Ehmer et al. (Ehmer, PB et al., J. Steroid, Biochem Mol. Biol. 81, 173-179 (2002)). 492.5 μl of this cell suspension were admixed with 5 μl of inhibitor solution (50 μM of the compound to be tested in ethanol or DMSO) and incubated at 32 ° C. for 15 min. Controls were added with 5 μl of ethanol. The enzyme reaction was started by adding 2.5 μl 11-deoxycorticosterone (20 μM, containing 1.25 nCi [4- ¹⁴ C] 11-deoxycorticosterone, in ethanol), then shaking horizontally at 32 ° C for 6 h. The assay was stopped by extraction of the sample with 500 μl EtOAc. After centrifugation (10,000 g, 2 min), the EtOAc phase was removed and evaporated to dryness. The residue was taken up in 10 μl of chloroform. The conversion of the substrate to corticosterone was analyzed by HPTLC (see below).

%P

Konversion (prozentualer Anteil des Produktes an Gesamtsteroid)

PSL

Phospho Stimulated Luminescence (Lumineszenzwert)

PSL_B

PSL für Corticosteron (B)

PSL_DOC

PSL für Deoxycorticosteron (DOC)

PSL_HG

PSL des Hintergrundes

The quantification of the spots for the substrate deoxycorticosterone and the products formed corticosterone (and, if detectable, 18-hydroxycorticosterone and aldosterone) was carried out with the associated evaluation program AIDA. For the human aldosterone synthase expressed in S. pombe, only corticosterone and the substrate deoxycorticosterone were detected as product. 18-Hydroxycorticosterone and aldosterone were not formed in detectable concentrations at an incubation time of 6 hours and therefore were not included in the evaluation. The conversion was calculated according to equation 1. Equation 1:

% P

Conversion (percentage of product to total steroid)

PSL

Phospho Stimulated Luminescence

PSL _B

PSL for corticosterone (B)

PSL _DOC

PSL for Deoxycorticosterone (DOC)

PSL _HG

PSL of the background

%H

prozentuale Hemmung

%P

Prozentwert der Konversion des Substrates zu Produkten

%P_H

Prozentuale Konversion in Anwesenheit eines Hemmstoffs

%P_K

Prozentuale Konversion der Kontrolle

The percent inhibition caused by an inhibitor at the concentration used was calculated according to equation 2. Equation 2:

%H

percent inhibition

% P

Percent value of the conversion of the substrate to products

% P _H

Percent conversion in the presence of an inhibitor

% P _K

Percent conversion of control

B) Test for selective CYP11B1 and CYP11B2 inhibitors:

Maintenance of the cells: V79 MZh11B1 and V79 MZh11B2, which recombinantly express the human aldosterone synthase or steroid 11-β-hydroxylase and according to Denner et al. (Denner, K. et al., Pharmacogenetics 5: 89-96 (1995)) were incubated in a CO ₂ incubator at 37 ° C and in a water vapor saturated atmosphere containing 5% CO ₂ in 60 or 90 mm diameter cell culture dishes cultured. Both cell lines were cultured in DMEM ⁺ containing 10% FCS and the antibiotics penicillin and streptomycin (1%) to protect against bacterial contamination. The cells were passaged every 2-3 days after treatment with trypsin / EDTA, since the doubling density was 1-2 days depending on the cell number. The cells were passaged a maximum of 12-15 times to exclude possible cell changes. If needed further, freshly thawed cells were used. DMEM ⁺ medium DMEM powder medium 13.4 g NaHCO ₃ 3.7 g L-glutamine (200mM) 20.0 ml Penicillin (100 units / ml) / streptomycin (0.1 mg / ml) 10.0 ml Sodium pyruvate (100 mM) 10.0 ml Fetal Calf Serum (FCS) 100 ml H ₂ O bidist. ad 1l

Of the pH of the medium was adjusted to 7.2-7.3. FCS was first added after sterile filtration.

Inhibition test: V79 MZh 11B1 and V79 MZh 11B2 cells (8 x 10 ⁵ cells per well) were grown to confluency on 24-well cell culture plates with 1.9 cm ² culture area per well (Nunc, Roskilde, Denmark). Prior to testing, the existing DMEM culture medium was removed and 450 μl of fresh DMEM with inhibitor added in at least three different concentrations to each well to determine the IC ₅₀ value. After preincubation (60 min, 37 ° C), the reaction was monitored by addition of 50 μl DMEM with 2.5 μl solution of substrate 11-deoxycorticosterone (20 μM, containing 1.25 nCi [4- ¹⁴ C] 11-deoxycorticosterone) Ethanol) started. Thereafter, the plate was stored at 37 ° C and 5% CO ₂ in the CO ₂ incubator. The V79 MZh 11B1 cells were incubated for 120 min, the V79 MZh 11B2 cells for 40 min. Controls without inhibitor were treated in the same way. The enzyme reactions were stopped by extraction of the supernatant with 500 μl EtOAc. The samples were centrifuged (10000 xg, 2 min), the solvent was removed and evaporated. The residue was taken up in 10 μl of chloroform and analyzed by HPTLC (see below).

PSL_B

PSL für Cortisol bzw. Corticosteron

PSL_DOC

PSL für Deoxycortisol (RSS) bzw. Deoxycorticosteron

The conversion for V79 MZh11B1 was calculated in accordance with Equation 1 (Example 4A), where:

PSL _B

PSL for cortisol and corticosterone

PSL _DOC

PSL for deoxycortisol (RSS) or deoxycorticosterone

%P

Konversion (Anteil des Produktes an Gesamtsteroid

PSL

Phospho Stimulated Lumineszence (Lumineszenzwert)

PSL_B

PSL für Corticosteron (B)

PSL_18OHB

PSL für 18-Hydroxycorticosteron (18OHB)

PSL_Aldo

PSL für Aldosteron

PSL_DOC

PSL für 11-Deoxycorticosteron (DOC)

PSL_{H G}

PSL des Hintergrundes

For V79 MZh11B2, the conversion was according to Equation 3: Equation 3:

% P

Conversion (Proportion of the product to total steroid

PSL

Phospho Stimulated Luminescence (luminescence value)

PSL _B

PSL for corticosterone (B)

PSL _18OHB

PSL for 18-hydroxycorticosterone (18OHB)

PSL _Aldo

PSL for aldosterone

PSL _DOC

PSL for 11-deoxycorticosterone (DOC)

PSL _{H G}

PSL of the background

The Percent inhibition by an inhibitor in each used Concentration was calculated according to equation 2 (Example 4A).

Determination of the IC ₅₀ value: The IC ₅₀ value is defined as the concentration of the inhibitor at which the enzyme is inhibited to 50%. It was calculated by determining the percent inhibition at at least 3 different inhibitor concentrations, all of which must be in the linear range of the IC ₅₀ sigmoid curve (log C /% inhibition).

The Calculation was done by linear regression. The specific values were only used when with a probability of r <0.95 a straight line formed.

C) HPTLC analysis and phospho-imaging radioactively labeled steroids:

The resuspended residue from Example 4A or 4B - containing the radiolabeled steroids - was applied to an HPTLC plate (20 x 10 cm, silica gel 60F ₂₅₄ ) with concentration zone (Merck, Darmstadt, Germany). The plate was developed twice with the eluent chloroform: methanol: water (300: 20: 1). Unlabeled 11-deoxycorticosterone and corticosterone were used as reference for the CYP11B1 reaction. For the CYP11B2 reaction, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone and aldosterone were used as reference. The unmarked references were detected at 260 nm. Subsequently, imaging plates (BAS MS2340, for ¹⁴ C samples, Raytest, Straubenhardt, Germany) were exposed for 48 h to the HPTLC plates. The imaging plates were scanned with the phosphoimager system Fuji FLA 3000 (Raytest, Straubenhardt, Germany) and the steroids quantified.

Example 5: Inhibition adrenal CYP11B enzymes in vitro by heteroaryl-substituted naphthalenes

Heteroaryl-substituted naphthalenes were tested as inhibitors as described in Examples 3 and 4. The results of the tests are summarized in Tab. Table 1: Heteroaryl-substituted naphthalenes: inhibition of adrenal CYP11B enzymes, CYP17 and CYP19 in vitro.

• ^a Mean of 4 determinations, standard deviation <10%. ^b S. pombe cells expressing human CYP11B2; Substrate deoxycorticosterone, 100nM; Inhibitor, 500nM. ^c mean of 4 determinations, standard deviation <20%. ^d hamster fibroblasts expressing human CYP11B1; Substrate deoxycorticosterone, 100nM. ^e hamster fibroblasts expressing human CYP11B2; Substrate deoxycorticosterone, 100nM. ^f E. coli expressing the human CYP17; 5 mg / ml protein; Substrate progesterone, 2.5 μM; Inhibitor 2.5 μM. ^g mean of 4 determinations, standard deviation <5%. ^h human placental CYP19, 1 mg / ml protein; Substrate Androstenedione, 2.5 μM. (nd = not determined)

Example 6: Inhibition adrenal CYP11B enzymes in vitro by heteroaryl-substituted 3,4-dihydronaphthalenes and indanes

Heteroaryl-substituted 3,4-dihydronaphthalenes and indanes were tested as inhibitors as described in Examples 3 and 4. The results of the tests are summarized in Tab. Table 2: Heteroaryl-substituted 3,4-dihydronaphthalenes and indanes: inhibition of adrenal CYP11B enzymes, CYP17 and CYP19 in vitro.

• ^a Mean of 4 determinations, standard deviation <10%. ^b S. pombe cells expressing human CYP11B2; Substrate deoxycorticosterone, 100nM; Inhibitor, 500nM. ^c mean of 4 determinations, standard deviation <20%. ^d hamster fibroblasts expressing human CYP11B1; Substrate deoxycorticosterone, 100nM. ^e hamster fibroblasts expressing human CYP11B2; Substrate deoxycorticosterone, 100nM. ^f E. coli expressing human CYP17; 5 mg / ml protein; Substrate progesterone, 2.5 μM; Inhibitor 2.5 μM. ^g mean of 4 determinations, standard deviation <5%. ^h human placental CYP19, 1 mg / ml protein; Substrate Androstenedione, 2.5 μM. (nd = not determined)

Example 7: Inhibition of CYP enzymes in vitro by the reference compounds ketoconazole and fadrozole

Ketocoanzol or fadrozole were tested as inhibitors as described in Examples 3 and 4. The results of the tests are summarized in Tab. Tab.3: ketoconazole and fadrozole: inhibition of adrenal CYP11B enzymes, CYP17 and CYP19 in vitro

^a mean of 4 determinations, standard deviation <10%; ^b S. pombe cells expressing human CYP11B2; Substrate deoxycorticosterone, 100 nM; Inhibitor, 500 nM. ^c mean of 4 determinations, standard deviation <20%. ^d hamster fibroblasts expressing human CYP11B1; Substrate deoxycorticosterone, 100 nM. ^e Haster fibroblasts expressing human CYP11B2; Substrate deoxycorticosterone, 100 nM. ^f mean of 4 determinations, standard deviation <10%; E. coli expressing human CYP17; 5 mg / ml protein; Substrate progesterone, 2.5 μM; Inhibitor, 2.5 μM. ^g mean of 4 determinations, standard deviation <5%; human placental CYP19, 1 mg / ml protein; Substrate testosterone, 2.5 μM; (nd = not determined)

Example 8: Test of Selected Compounds with NCI-H295R cells

Of the compounds presented in Examples 5 and 6, some were studied on the NCI-H295R system. For comparison, fadrozole was used as a reference. The exemplary results obtained are not directly comparable with the IC ₅₀ values and percentage inhibition values achieved in V79 cells, since the test inhibitors on NCI-H295R used, inter alia, other test parameters and a different substrate (see Table 4 for explanation) ).

in the Comparison with fadrozole could be a rough correlation between the Both test systems are determined, the compounds 1 and 2 affect the CYP11B1 to a much lesser extent.

Tab. 4: Comparison inhibition data NCI-H295R, V79 MZ

• ^a : Inhibition of CYP11B1 activity in HCI-H295R, inhibitor concentration 2.5 μM, [ ³ H] deoxycortisol (RSS, 500 nM); Quantification of the products after HPLC separation
• ^b : Inhibition of CYP11B2 activity in NCI-H295R, inhibitor concentration 2.5 μM, [ ³ H] -corticosterone (B, 500 nM) or [ ¹⁴ C] -deoxycorticosterone (DOC, 500 nM); Quantification of the products after HPTLC separation using Phosphoimager system
• ^c : Determination of IC ₅₀ values for CYP11B1 and CYP11B2 in V79 MZh11B1 and V79 MZh11B2, [ ¹⁴ C] deoxycorticosterone (DOC, 100 nM); Quantification of the products after HPLC separation by means of phosphoimager system. To determine IC ₅₀ values, the compounds were tested in at least 3 different concentrations. nt: not tested, RSS = deoxycortisol; B = corticosterone; DOC = deoxycorticosterone, represented are MW (± SD) of at least three independent tests.

to Investigation of the effect of various inhibitors on NCI-H295R A test procedure in 24-well format was developed. For inhibitor testing was first a one-hour Pre-incubation carried out, before the enzyme reactions were started by addition of substrate (500 nM) were.

A) Sowing:

Cultivation and passage of the cell lines took place until a confluent cell lawn had been formed. By trypsin treatment, the cell material was obtained from at least two culture dishes and the cell count using a CASY TT cell counter (150 ul capillary) was determined. By diluting the cell suspension with DMEM: Ham's F12, a cell density of 1 × 10 ⁶ cells / ml was set. Of the cell suspensions thus obtained, 1 ml each was placed on a well of a 24-well plate so that each well was coated with 1 x 10 ⁶ cells. Two 24-well plates could be coated with the cell material from two confluent culture dishes. After 24 hours, the cells were grown and after a further 24-hour stimulation phase with potassium ion-containing solution (final concentration: 20 mM KCl) used for the test.

B) Substrate solutions:

Tritium-labeled deoxycortisol ([ ³ H] -RSS) was used as the substrate for testing the influence of the inhibitors on CYP11B1. To prepare the substrate stock solution, 60 μl of [ ³ H (G)] deoxycortisol (3 Ci / mmol, 1 mCi / ml) in ethanol (Hartmann Analytik, Braunschweig, Germany) were diluted with 140 μl ethanol. 2.5 μl per sample of this solution were used, which corresponded to a final concentration of 500 nM in a test volume of 500 μl in the test.

In the substrate solutions for the studies on CYP11B2, the corticosterone substrate solution (final concentration in the assay 500 nM) consisted of 38.4 [1.2- ³ H (N)] -corticosterone (1 mCi / ml, 76.5 Ci / mmol ; NEN-Perkin-Elmer) in ethanol, 39.0 μl of unlabeled corticosterone solution (0.5 mM in ethanol) and 122.6 μl of ethanol. Deoxycorticosterone, which was also used at a final concentration of 500 nM, was composed of 18 μl of [ ¹⁴ C] -labeled deoxycorticosterone (60.0 mCi / mmol, 0.5 nCi / μl) in ethanol in admixture with 54 μl unlabeled substance (0.5 mM in ethanol) and 228 μl of ethanol.

C) Inhibitor Solutions:

The concentrations required to determine the IC ₅₀ values were adjusted by 1:40 dilution of the stock solution (10 mM) with ethanol. From this solution, 5 μl was added to each of the samples.

D) Implementation of the Testing:

Pre-incubation: The existing medium was aspirated and replaced by 450 .mu.l DMEM: Ham's F12, in the inhibitor added in the appropriate concentration (Final concentration of inhibitor in the final volume (500 μl) of the test: 2.5 μM), Thereafter, it was pre-incubated for 1 h.

Test start: The reaction was carried out by adding 50 μl of DMEM: Ham's F12, 2.5 μl of the respective substrate mix (Final concentration of the substrate: 0.5 μM) initiated.

The 24-well plate was then stored at 37 ° C and 5% CO ₂ in the CO ₂ incubator. The incubation period was 3 hours using deoxycorticosterone as substrate, 24 hours for corticosterone and 48 hours for deoxycortisol.

Test stop: After the incubation period was after a short pan of the Content of the wells as possible taken quantitatively and by mixing with 1000 ul of dichloromethane inactivated in a 2ml Eppendorf tube. After 10 minutes shake was centrifuged for phase separation and the upper organic Phase into a 1.5 ml Eppendorf tube.

To Evaporation of the solvent overnight under the deduction was the residue in 10 μl Chloroform taken and in the middle of the concentration zone applied to an HPTLC plate. The steroids were doubled Developing with a superplasticizer, from chloroform, methanol and water in a ratio of 300: 20: 1 composed, separated. For the detection of steroids on the TLC became the exposed film in the phosphoimager after two days Scanned FLA 3000.

in the In the case of deoxycortisol as a substrate, the separation was carried out Reconstitution in 50 μl Methanol, the deoxycortisol unlabelled as internal standards, Cortisol and cortisone were added by HPLC via RP18 column the flow agent Methanol: water 1: 1 and a flow rate of 0.25 ml / min, the detection was carried out with the help of a Berthold radio monitor 509.

%P

Konversion (Anteil des Produktes an Gesamtsteroid in %)

A

Area (Fläche) in [Units·sec]

A_Cortisol

Fläche für Cortisol

A_Cortison

Fläche für Cortison

A_RRS

Fläche für Deoxycortisol (RSS)

According to Equation 4, the conversion for the substrate deoxycortisol was calculated after HPLC separation: Equation 4:

% P

Conversion (proportion of product to total steroid in%)

A

Area in [Units · sec]

A _cortisol

Area for cortisol

A _cortisone

Area for cortisone

A _RRs

Surface for deoxycortisol (RSS)

For the substrate Deoxycorticosterone gave the conversion according to equation 3 (Example 4B).

%P

Konversion (Anteil des Produktes an Gesamtsteroid in %

PSL

Phospho Stimulated Lumineszence (Lumineszenzwert)

PSL_B

PSL für Corticosteron (B)

PSL_18OHB

PSL für 18-Hydroxycorticosteron (18OHB)

PSL_Aldo

PSL für Aldosteron

PSL_HG

PSL des Hintergrundes

For the substrate corticosterone, equation 5 was: Equation 5:

% P

Conversion (share of product in total steroid in%

PSL

Phospho Stimulated Luminescence (luminescence value)

PSL _B

PSL for corticosterone (B)

PSL _18OHB

PSL for 18-hydroxycorticosterone (18OHB)

PSL _Aldo

PSL for aldosterone

PSL _HG

PSL of the background

The Percent inhibition by an inhibitor in each used Concentration was calculated according to equation 2 (Example 4A).

The determination of the IC ₅₀ value was carried out as described in Example 4B.

Example 9: Quantification of steroids in the supernatant a cell culture of NCI-H295R cells

H295R cells (see example 8) were subcultured at a cell density of 1 × 10 ⁶ cells / ml in a volume of 1 ml / well in a 24-well plate and incubated for 48 hours. The medium was then replaced with 500 μl Ultroser SF-free DMEM: Ham's F12, in which the inhibitor to be tested was present in the corresponding concentration and 1% Etahnol. Control incubations contained only 1% ethanol. After incubation at 37 ° C and 5% CO ₂ for 6 hours, the supernatant was removed and frozen until further analysis. The inhibitor activities were calculated on the basis of the difference between the steroid concentrations in the presence or absence of the test substances used. The aldosterone concentration was determined according to the manufacturer's instructions with an RIA kit (DRG, Marburg, Germany). For the determination of androgens (DHEA and androstenedione) and of cortisol, specific ELISA kits (ibl-Hamburg, Hamburg, Germany) or the cortisol ELISA kit from Cayman Chemical (Ann Arbor, USA) were used according to the manufacturer's instructions.

to Measurement of the total protein content, the cells were washed with PBS, in a lysis buffer (8M urea, 4% (w / v) CHAPS) and frozen at -70 ° C. After three freeze-thaw cycles, the cells were lysed and their protein content was determined by the method of Bradford. The results The steroid determinations were made in pg / mg cell proteins for aldosterone and ng / mg cell proteins for Androgens and cortisol expressed.

Within 6 hours, a clear concentration-dependent decrease in aldosterone secretion could be detected using compound 2 and ketoconazole ( 1B and 1C ). Fadrozole reduced the formation of aldosterone with a 9-fold lower IC ₅₀ compared to cortisol production (39.4 nM versus 363.8 nM; 1A , Table 5), while the formation of adrenal androgens was reduced less (IC ₅₀ > 3900 nM in androstenedione and 150 nM in DHEA). Ketoconazole showed IC ₅₀ values of 59.6 nM and 51.8 nM for the inhibition of androstenedione and DHEA production. Compound 2 proved to be a potent suppressor of the formation of cortisol and adrenal androgens (IC ₅₀ values <1 nM), while aldosterone formation was only weakly inhibited ( 1C , Tab. 5).

Tab. 5: Inhibition of steroid production in H295R cells, determined on the basis of the steroid concentration in the supernatant

• ^a Quantification after 6 h incubation with an inhibitor concentration of 2.5 μM. The supernatant of the cell cultures was used, the determination was carried out by specific immunoassays. Mean values (± SD) from at least three independent experiments.

Claims (16)

Use of a compound having the structure of the formula (I)

where Y is selected from

T, U, V, W, X are independently selected from C and N; R ¹ and R ^{2 are} independently selected from H, halo, CN, hydroxy, nitro, alkyl, alkoxy, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkylsulfinyl and alkylsulfonyl (wherein the alkyl radicals are straight, branched or cyclic, saturated or unsaturated and may be substituted by 1 to 3 radicals R ¹² ), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partially or completely saturated equivalents, which may be substituted by 1 to 3 radicals R ¹² , arylalkyloxy, heteroarylalkyloxy, aryloxy and heteroaryloxy radicals, where aryl and heteroaryl have the abovementioned meaning, -COOR ¹¹ , -CON (R ¹¹ ) ₂ , -SO ₃ R ¹¹ , -CHO, -CHNR ¹¹ , -N (R ¹¹ ) ₂ , -NHCOR ¹¹ and -NHS (O) ₂ R ¹¹ , and, when U or V is an N atom, a lone pair of electrons, or R ¹ with R ² or R ⁴ or R ² with R ^{5 of} the adjacent ring atom and the associated C Atoms a saturated or unsaturated anel lierten aryl or heteroaryl ring, wherein the atoms of the fused aryl or heteroaryl ring with 1-3 radicals R ¹² may be substituted; R ^{3 is} selected from nitrogen-containing monocyclic or bicyclic heteroaryl radicals and their partially or fully saturated equivalents, which may be substituted by 1 to 3 radicals R ¹² and have at least one nitrogen atom which is unsubstituted, and / or R ³ via R ¹² with R ⁶ or R ⁷ or R ^{8 of} the adjacent ring atom and the associated carbon atoms forms a saturated or unsaturated fused aryl or heteroaryl ring, wherein the atoms of the fused aryl or heteroaryl ring with 1-3 radicals R ¹² may be substituted; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently selected from H, halo, CN, hydroxy, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkyl sulfonylamino, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl (wherein the lower alkyl radicals may be straight, branched or cyclic, saturated or unsaturated and substituted with 1 to 3 R ¹² radicals), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partially or fully saturated equivalents which can be substituted by 1 to 3 radicals R ¹² , arylalkyloxy, heteroarylalkyloxy, aryloxy and heteroaryloxy radicals, where aryl and heteroaryl have the abovementioned meaning, -COOR ¹¹ , -CON (R ¹¹ ) ₂ , -SO ₃ R ¹¹ , -CHO, -CHNR ¹¹ , -N (R ¹¹ ) ₂ , -NHCOR ¹¹ and -NHS (O) ₂ R ¹¹ , or R ⁴ , R ⁵ and R ^{6 is} a lone pair of electrons when T, W or X. is an N-atom, or R ⁷ or R ⁸ with R ⁹ or R ¹⁰ and / or with R ⁷ or R ^{8 of} the adjacent ring atom form one or two double bonds, or R ⁵ and / or R ⁷ (and R ⁸ ) with R ⁹ (and R ¹⁰ ) of the adjacent ring atom and the associated carbon atoms is a saturated ode form unsaturated fused aryl or heteroaryl ring, wherein the atoms of the fused aryl or heteroaryl ring with 1-3 radicals R ¹² may be substituted; R ^{10 is} selected from H, lower alkyl, lower alkylcarbonyl (wherein the lower alkyl radicals may be straight, branched or cyclic, saturated or unsaturated and substituted with 1 to 3 R ¹² radicals), arylalkyl, heteroarylalkyl, aryl and heteroaryl radicals and their partial or fully saturated equivalents, which may be substituted with 1 to 3 R ¹² radicals, and is -COOR ¹¹ , or a lone pair, or forms a double bond with R ⁷ or R ^{8 of} the adjacent C atom, or with R ⁷ (and R ⁸ ) of the adjacent C atom and the associated C atoms forms a saturated or unsaturated fused heteroaryl ring, wherein the atoms of the fused heteroaryl ring may be substituted by 1-3 R ¹² radicals; R ^{11 is selected} independently of the occurrence of further R ¹¹ radicals from H, lower alkyl (which may be straight, branched or cyclic, saturated or unsaturated and substituted with 1 to 3 R ¹² ) and aryl which may be substituted by 1 to 3 R ¹² can; R ¹² is selected from H, hydroxy, halogen, -CN, -COOH, -CHO, nitro, amino, mono- and bis- (lower alkyl) amino, lower alkyl, lower alkoxy, lower alkylcarbonyl, lower alkylcabonyloxy, independently of the occurrence of further R ¹² radicals, Lower alkylcarbonylamino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, hydroxy-lower alkyl, hydroxy-lower alkoxy, hydroxy-lower alkylcarbonyl, hydroxy-lower alkylcarbonyloxy, hydroxy-lower alkylcarbonylamino, hydroxy-lower alkylthio, hydroxy-lower alkylsilinyl, hydroxy-lower alkylsulfonyl, mono- and bis- (hydroxy-lower alkyl) amino and mono- and polyhalogenated lower alkyl (wherein the lower alkyl groups may be straight chain, branched or cyclic, saturated or unsaturated); n is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof for the treatment of hyperaldosteronism, cardiac insufficiency, myocardial fibrosis, hypercortisolism and diabetes mellitus. Use according to claim 1, wherein in the compound of formula (I) (i) Y is either N or C; and / or (ii) T, U, V and W are C atoms; and / or (iii) the alkyl radicals and alkoxy radicals are saturated or have one or more double and / or triple bonds, the straight-chain or branched alkyl radicals preferably 1 to 10 C atoms, particularly preferably 1 to 6 C atoms, very particularly preferably 1 have up to 3 C-atoms, and the cyclic alkyl radicals mono- or bicyclic alkyl radicals having 3 to 15 carbon atoms, particularly preferably monocyclic alkyl radicals having 3 to 8 carbon atoms; and / or (iv) aryl is a mono-, bi- and tricyclic aryl radical having 3 to 18 ring atoms which may optionally be fused with one or more saturated rings, in particular anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, indanyl, indenyl, naphthyl, Phenanthrenyl, phenyl, tetralinyl; and / or (v) the heteroaryl radicals are mono- or bicyclic heteroaryl radicals having 3 to 12 ring atoms, which preferably have 1 to 5 heteroatoms of nitrogen, oxygen and sulfur and which may be fused with one or more saturated rings; and / or (vi) the lower alkyl radicals and lower alkoxy radicals are saturated or have a double bond or triple bond which have straight-chain, in particular 1 to 6, carbon atoms, more preferably 1-3 carbon atoms, which have cyclic, in particular 3 to 8, carbon atoms ; and / or (vii) the nitrogen-containing monocyclic or bicyclic heteroaryl radicals are selected from benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnolinyl, dihydroindolyl, dihydroisoindolyl, dihydropyranyl, dithiazolyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl , Isoindolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl, pteridinyl, purinyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl , Pyrrolinyl, pyrrolyl, tetrazinyl, tetrazolyl, tetrahydropyrrolyl, thiadiazolyl, thiazinyl, thiazolidinyl, thiazolyl, triazinyl and triazolyl; and / or (viii) fused aryl or heteroaryl rings are monocyclic rings having 5 to 7 ring atoms which can be fused via two adjacent ring atoms to the adjacent ring, saturated or unsaturated, and as Ne teroaryl rings may comprise 1 to 3 heteroatoms, preferably nitrogen, oxygen or sulfur atoms, and more preferably are selected from cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, benzyl, furanoyl, dihydropyranyl, pyranyl, pyrrolyl, imidazolyl, pyridyl and pyrimidyl. Use according to claim 2, wherein in the compound of formula (I) (i) n is 0 or 1; and / or (ii) R ¹ or R ^{2 are} independently selected from the group consisting of H, halogen, CN, hydroxy, O-lower alkyl, O-lower alkenyl, O-lower alkynyl, lower alkyl, lower alkenyl, lower alkynyl, -COOR ¹¹ , -CON (R ¹¹ ) ₂ and arylalkyloxy, and more preferably H, O-lower alkyl and arylalkoxy; and / or (iii) R ^{3 is} selected from nitrogen-containing monocyclic heteroaryl radicals having 5-10 ring atoms and 1 to 3 nitrogen atoms, especially selected from isoquinolyl, imidazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, triazinyl and triazoyl ; and / or (iv) R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^{9 are} independently selected from H, halo, CN, hydroxy, heteroaryl, and C _1-6 alkyl and C _1-6 Alkoxy radicals which may be substituted by 1 to 3 radicals R ¹² ; and / or (v) R ^{10 is} selected from H, heteroaryl and C _1-6 alkyl radicals which may be substituted with 1 to 3 R ¹² radicals; and / or (vi) R ^{12 is} selected from H, halogen, hydroxyl, CN, C _1-3 alkyl and C _1-3 alkoxy. Use according to claim 3 wherein in the compound of formula (I) (i) X and Y are C atoms; and / or (ii) R ¹ or R ^{2 is} hydrogen and the other of the substituents R ¹ or R ^{2 is} selected from H, fluoro, chloro, bromo, CN, COOR ¹¹ , hydroxy, C _1-3 alkyl and C _{1 -3-} alkoxy; and / or (iii) R ^{3 is} selected from oxazolyl, pyridyl, imidazolyl and pyrimidyl; and / or (iv) R ⁵ and R ^{6 are} independently selected from H, fluoro, chloro, bromo; and / or (v) R ^{7 is} selected from H, C _1-3 alkyl and C _1-3 alkoxyl; and / or (vi) R ⁴ , R ⁸ , R ⁹ , R ^{10 are} H; and / or (vii) R ^{11 is} H or C _1-3 alkyl. Use according to one or more of claims 1 to 4, wherein the compound of formula (I) is a compound of the following formulas (Ia) to (Id)

wherein all variables have the meaning given above and R ^{3 is} preferably selected from 3- and 4-pyridyl, 1-imidazolyl, 4-imidazolyl and 5-pyrimidyl. Use according to one or more of claims 1 to 5, wherein R ^{3 is} 3-pyridyl. Use according to one or more of claims 1 to 6, wherein the compound of formula (I) is selected from 3- (2-naphthyl) pyridine 3- (6-methoxy-2-naphthyl) pyridine 3- (6-Bromo-2-naphthyl) pyridine 3- (6-Ethoxy-2-naphthyl) pyridine 6-Pyridin-3-yl-2-naphthonitrile 3- (1,5-dichloro-6-methoxy-2- naphthyl) pyridine Methyl 6-pyridin-3-yl-2-naphthoate 3- (1H-inden-2-yl) pyridine 3- (3,4-Dihydronaphthalen-2-yl) pyridine 3- (6-Methoxy-1H -inden-2-yl) pyridine 3- (6-Methoxy-3,4-dihydronaphthalen-2-yl) pyridine 3- (1-Methyl-3,4-dihydronaphthalen-2-yl) pyridine 3- (1-ethyl 3,4-dihydronaphthalen-2-yl) pyridine and 3- (3-methyl-3,4-dihydronaphthalen-2-yl) pyridine. Pharmaceutical composition containing a compound of formula (I)

wherein T, U, V, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} the in Claim 1, or a pharmaceutically-acceptable salt thereof, provided that (a) when T, U, V, W and X are C-atoms, n = 1 and Y is selected from O, CH ₂ and -CH = , then R ^{3 is} not 1-imidazolyl; (b) when T, U, V, W, X and Y are C atoms, n = 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{6 is} H or methyl, then R ^{3 is} not 3-pyridyl; (c) when T, U, V, W, X and Y are C atoms, n = 1, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{1 is} COOH, then R ^{3 is} not 4-pyridyl; (d) when T, U, V, W and Y are C atoms, X = N, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms, R ⁹ = H or methyl and R ⁸ forms a double bond with Y, then R ^{3 is} not pyridyl; and (e) when T, U, V, W and X are C-atoms, Y is N, n is 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} H atoms and R ⁸ forms a double bond with Y, then R ^{3 is} not 4-carboxy-2-pyridyl. A pharmaceutical composition according to claim 8, wherein the variables T, U, V, W are as defined in claim 2, variables X and Y are as defined in claim 2 or 4 and variables R ¹ to R ¹² and n are as defined in claim 3 or 4 and preferably containing one of the compounds defined in claim 5, 6 or 7. Pharmaceutical composition according to claim 8 or 9, used to treat hyperaldosteronism, heart failure or myocardial fibrosis, hypercortisolism or diabetes mellitus in mammals and people is suitable. Compound of the formula (I)

wherein T, U, V, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} the in Claim 1 specified meaning or their pharmaceutically acceptable salts, provided that (a) when T, U, V, W and X are C atoms, n = 1 and Y is selected from O, N, CH ₂ and -CH =, then R ^{3 is} not 1-imidazolyl; (b) when T, U, V, W, X and Y are C atoms, n = 1, R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ^{9 are} H atoms, R ^{2 is} H or methoxy and R ^{6 is} H or methyl, then R ^{3 is} not pyridyl, imidazolyl or oxazolyl; (c) when T, U, V, W, X and Y are C atoms, n = 1, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} H atoms and R ^{1 is} COOH, then R ^{3 is} not 4-pyridyl; (d) when T, U, V, W and Y are C atoms, X = N, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms, R ⁹ = H or methyl and R ⁸ forms a double bond with Y, then R ^{3 is} not pyridyl or quinolyl; (e) when T, U, V, W and X are C-atoms, Y is N, n is 1, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} H atoms and R ⁸ forms a double bond with Y, then R ³ does not form 4-carboxy-2-pyridyl, 5-bromo-2-pyridyl, 6-bromo-2-pyridyl, 5-bromo-3-pyridyl, 2-pyridyl, 3 Pyridyl, 2-pyridazinyl, 2-pyrimidinyl or quinolyl; and (f) when T, U, V and W are C atoms, X and Y are N atoms, n = 1, R ¹ , R ² , R ⁴ , R ⁵ and R ^{7 are} H atoms and R ⁸ forms a double bond with Y, then R3 is not pyridyl or 2-quinolyl. A compound according to claim 11, wherein the variables T, U, V, W are as defined in claim 2, the variables X and Y are as defined in claim 2 or 4 and the variables R ¹ to R ¹² and n are as defined in claim 3 or 4 , and which are preferably the compounds defined in claim 5, 6 or 7. A compound according to claim 12 wherein in the compound of formula (I) (i) X and Y are C atoms; and / or (ii) R ¹ or R ^{2 is} hydrogen and the other of the substituents R ¹ or R ^{2 is} selected from H, fluoro, chloro, bromo, CN, COOR ¹¹ , hydroxy, C _1-3 alkyl and C _{1 -3-} alkoxy; and / or (iii) R ^{3 is} selected from oxazolyl, pyridyl, imidazolyl and pyrimidyl; and / or (iv) R ⁵ and R ^{6 are} independently selected from H, fluoro, chloro, bromo; and / or (v) R ^{7 is} selected from H, C _1-3 alkyl and C _1-3 alkoxyl; and / or (vi) R ⁴ , R ⁸ , R ⁹ , R ^{10 are} H; and / or (vii) R ^{11 is} H or C _1-3 alkyl. Process for the synthesis of the compounds according to claim 11, comprising (i) the Suzuki coupling of the compound (III)

in which (p) Hal is a halogen atom or pseudohalide, preferably Br or OTf, with the compound (II) R3-B (OH) ₂ II; and / or (ii) the bromination of the compound (VI)

to the corresponding α-bromoketone, a subsequent reduction to the corresponding alcohol, dehydrogenation and subsequent coupling with the compound (II), wherein the variables have the meaning given in claim 11, and functional groups in R ¹ -R ¹⁰ op tional be provided with suitable protective groups. Use of the compounds defined in claims 1 to 7 for the selective inhibition of mammalian P450 oxygenases, for the inhibition of human or mammalian aldosterone synthase or steroid 11β-hydroxylase, especially for the inhibition of the human steroid 11β-hydroxylase CYP11B1 or aldosterone synthase CYP11B2, in particular for the selective inhibition of CYP11B2 at the same time low impairment the human CYP11B1. Use according to claims 1 to 7 and 15, wherein the mentioned compounds (i) as individual compounds or (Ii) as a component of mixtures containing one or a combination of two and more of the compounds mentioned under claims 1 to 7 or (iii) in combination with other pharmacologically active Connections are used.