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US20110201564A1 - Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof - Google Patents

Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof Download PDF

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Publication number
US20110201564A1
US20110201564A1 US13/001,133 US200913001133A US2011201564A1 US 20110201564 A1 US20110201564 A1 US 20110201564A1 US 200913001133 A US200913001133 A US 200913001133A US 2011201564 A1 US2011201564 A1 US 2011201564A1
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Prior art keywords
cyano
fluorine
hydrogen
hydroxy
methyl
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Inventor
Peter Kolkhoe
Astrid Brüns
Kai Thede
Karl-Heinz Schlemmer
Alexander Hillisch
Dieter Lang
Michael Gerisch
Andreas Göller
Rolf Grosser
Carsten Schmeck
Elisabeth Woltering
Olaf Prien
Holger Paulsen
Armin Kern
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT reassignment BAYER SCHERING PHARMA AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LANG, DIETER, DR., WOLTERING, ELISABETH, DR., SCHMECK, CARSTEN, DR., GERISCH, MICHAEL, DR., BRUNS, ASTRID, DR., GOLLER, ANDREAS, DR., HILLISCH, ALEXANDER, DR., KERN, ARMIN, DR., KOLKHOF, PETER, DR., PAULSEN, HOLGER, DR., PRIEN, OLAF, DR., SCHLEMMER, KARL-HEINZ, DR., THEDE, KAI, DR., GROSSER, ROLF, DR.
Publication of US20110201564A1 publication Critical patent/US20110201564A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present application relates to novel 7-sulfanylmethyl-, 7-sulfinylmethyl- and 7-sulfonylmethylindole derivatives, processes for the preparation thereof, the use thereof alone or in combinations for the treatment and/or prevention of diseases, and the use thereof for the manufacture of medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
  • Aldosterone plays a key part in maintaining fluid and electrolyte homeostasis by promoting, in the epithelium of the distal nephron, sodium retention and potassium secretion, thus contributing to keeping the extracellular volume constant and thus to regulating blood pressure. Besides this, aldosterone displays direct effects on the structure and function of the cardiac and vascular system, but the underlying mechanisms thereof are not yet fully explained [R. E. Booth, J. P. Johnson, J. D. Stockand, Adv. Physiol. Educ. 26 (1), 8-20 (2002)].
  • Aldosterone is a steroid hormone which is formed in the adrenal cortex. Its production is regulated indirectly very substantially depending on the renal blood flow. Any decrease in renal blood flow leads to release in the kidney of the enzyme renin into the circulating blood. This in turn activates the formation of angiotensin II, which on the one hand has a constricting effect on the arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex.
  • the kidney acts as blood pressure sensor, and thus indirect volume sensor, in the circulating blood and counteracts, via the renin-angiotensin-aldosterone system, critical losses of volume by on the one hand increasing the blood pressure (angiotensin II effect), and on the other hand, by rebalancing the state of filling of the vascular system by increased reabsorption of sodium and water in the kidney (aldosterone effect).
  • This control system may be pathologically impaired in diverse ways.
  • a chronic reduction in renal blood flow e.g. as a result of heart failure and the congestion of blood in the venous system caused thereby
  • a chronically excessive release of aldosterone leads to a chronically excessive release of aldosterone.
  • this is followed by an expansion of the blood volume and thereby increases the weakness of the heart through an excessive supply of volume to the heart.
  • Congestion of blood in the lungs with shortness of breath and formation of edema in the extremities, and ascites and pleural effusions may be the result; the renal blood flow falls further.
  • the excessive aldosterone effect leads to a reduction in the potassium concentration in the blood and in the extracellular fluid.
  • cardiac arrhythmias with a fatal outcome may be induced if there is a deviation below a critical minimum level. This is likely to be one of the main causes of the sudden cardiac death which frequently occurs in patients with heart failure.
  • aldosterone is also thought to be responsible for a number of the myocardial remodeling processes typically to be observed in heart failure.
  • hyperaldosteronism is a crucial component in the pathogenesis and prognosis of heart failure which may originally be induced by various types of damage such as, for example, a myocardial infarction, a myocardial inflammation or high blood pressure.
  • This assumption is supported by the fact that there was a marked reduction in overall mortality in wide-ranging clinical studies on groups of patients with chronic heart failure and post acute myocardial infarction through the use of aldosterone antagonists [B. Pitt, F. Zannad, W. J. Remme et al., N. Engl. J. Med.
  • normokalemic hyperaldosteronism a hyperaldosteronism diagnosed in connection with essential hypertension is a starting point for a causal and prophylactically worthwhile therapy.
  • hyperaldosteronism Far less common than the types of hyperaldosteronism detailed above are pathological states in which the impairment either is to be found in the hormone-producing cells of the adrenal itself, or the number or mass thereof is increased through hyperplasia or proliferation.
  • Adenomas or diffuse hyperplasias of the adrenal cortex are the commonest cause of the primary hyperaldosteronism referred to as Conn's syndrome, the leading symptoms of which are hypertension and hypokalemic alkalosis.
  • the priority here too, besides surgical removal of the diseased tissue, is medical therapy with aldosterone antagonists [H. A. kuhn and J. Schirmeister (Editors), Innere Medizin, 4th edition, Springer Verlag, Berlin, 1982].
  • Another pathological state associated typically with an elevation of the plasma aldosterone concentration is advanced cirrhosis of the liver.
  • the cause of the aldosterone elevation in this case is mainly the restricted aldosterone breakdown resulting from the impairment of liver function.
  • Volume overload, edema and hypokalemia are the typical consequences, which can be successfully alleviated in clinical practice by aldosterone antagonists.
  • the effects of aldosterone are mediated by the mineralocorticoid receptor which has an intracellular location in the target cells.
  • a receptor which is closely related to the mineralocorticoid receptor is the glucocorticoid receptor via which the activity of glucocorticoids (e.g. cortisone, cortisol or corticosterone) is mediated.
  • the mineralocorticoid receptor binds not only aldosterone but also endogeneous glucocorticoids [Funder J W. Hypertension. 47, 634-635 (2006)]. This interaction of the mineralocorticoid receptor with glucocorticoids appears likewise to play an important, but mostly unappreciated, role in the pathophysiology of cardiac disorders.
  • aldosterone antagonists available to date have, like aldosterone itself, a basic steroid structure.
  • the utility of such steroidal antagonists is limited by their interactions with the receptors of other steroid hormones, in particular of testosterone and progesterone, which in some cases lead to considerable side effects such as gynecomastia and impotence and to discontinuation of the therapy [M. A. Zaman, S. Oparil, D. A. Calhoun, Nature Rev. Drug Disc. 1, 621-636 (2002)].
  • Indol-3-yl(phenyl)acetic acid derivatives are disclosed as endothelin receptor antagonists in WO 97/43260 and ⁇ -amino(indol-3-yl)acetic acid derivatives with an antidiabetic effect are disclosed in WO 90/05721.
  • WO 2004/067529, WO 2005/092854 and M. G. Bell, J. Med. Chem. 2007, 50 (26), 6443-6445 describe various indole derivatives substituted in position 3 as modulators of steroid hormone receptors.
  • WO 2007/062994 and WO 2005/118539 claim 3-(3-amino-1-arylpropyl)indoles for the treatment of depression and anxiety states.
  • WO 2007/040166 claims fused pyrrole derivatives as glucocorticoid receptor modulators having anti-inflammatory and antidiabetic effects.
  • WO 2007/070892 and WO 2008/019357 describe substituted indoles for the treatment of anxiety, pain, inflammatory disorders and cognitive impairments.
  • WO 2008/157740 describes variously substituted indoles inter alia for the treatment of pain and inflammatory disorders.
  • 3-(Indol-3-yl)-3-phenylpropionitrile derivatives are described inter alia in U.S. Pat. No. 2,752,358, U.S. Pat. No. 2,765,320 and U.S. Pat. No. 2,778,819.
  • the present invention relates to compounds of the general formula (I)
  • A is —S—, —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is (C 1 -C 4 )-alkyl or cyclopropyl
  • R 2 is hydrogen, fluorine or chlorine
  • R 3 is hydrogen, fluorine, chlorine or methyl
  • R 4 is hydrogen or fluorine
  • R 5 is a group of the formula
  • Compounds of the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers).
  • the present invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof.
  • the stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
  • the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed are salts which are themselves unsuitable for pharmaceutical uses but can be used for example for isolating or purifying the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds of the invention include salts of conventional bases such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • Solvates refers for the purposes of the invention to those forms of the compounds of the invention which form, in the solid or liquid state, a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • the present invention additionally encompasses prodrugs of the compounds of the invention.
  • prodrugs encompasses compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example by metabolism or hydrolysis).
  • Alkyl represents in the context of the invention a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • a linear or branched alkyl radical having 1 to 4 carbon atoms is preferred. Mention may be made by way of example and preferably of: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
  • Cycloalkyl represents in the context of the invention a saturated monocyclic carbocycle having 3 to 7 or 3 to 6 ring carbon atoms. Mention may be made by way of example and preferably of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy represents in the context of the invention a linear or branched alkoxy radical having 1 to 4 carbon atoms. Mention may be made by way of example and preferably of: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Heteroaryl represents in the context of the invention a monocyclic or, where appropriate, bicyclic aromatic heterocycle (heteroaromatic system) having a total of 5 to 10 ring atoms which comprises up to three identical or different ring heteroatoms from the series N, O and/or S and is linked via a ring carbon atom or, where appropriate, via a ring nitrogen atom.
  • heterocycle heteromatic system
  • Halogen includes in the context of the invention fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are particularly preferred.
  • radicals in the compounds of the invention are substituted, the radicals may be substituted one or more times, unless specified otherwise.
  • all radicals which occur more than once have a mutually independent meaning. Substitution by one or two identical or different substituents is preferred. Substitution by one substituent is very particularly preferred.
  • A is —S—, —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is (C 1 -C 4 )-alkyl or cyclopropyl
  • R 2 is hydrogen, fluorine or chlorine
  • R 3 is hydrogen, fluorine, chlorine or methyl
  • R 4 is hydrogen or fluorine
  • R 5 is a group of the formula
  • A is —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O)— or —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • A is —S( ⁇ O) 2 —
  • R 1 is methyl
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • radicals indicated specifically in the respective combinations or preferred combinations of radicals are replaced as desired irrespective of the particular combinations indicated for the radicals also by definitions of radicals of other combinations.
  • the invention further relates to a process for preparing the compounds of the invention of the formula (I), characterized in that
  • Solvents suitable for the reactions (I-1) ⁇ (I-2) or (I-3) and (II) ⁇ (II-2) or (II-3) are all organic solvents which are inert under the reaction conditions. These include ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, isopropanol and tert-butanol, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or other solvents such as dimethylformamide (DMF
  • Suitable oxidizing agents for the reactions (I-1) ⁇ (I-2) or (I-3) and (II) ⁇ (II-2) or (II-3) are organic oxidizing agents such as tert-butyl peroxide, meta-chloroperbenzoic acid, and inorganic oxidizing agents such as hydrogen peroxide, OXONE (CAS-RN 37222-66-5) or tetrabutylammonium perruthenate in conjunction with N-methylmorpholine oxide (TPAP/NMO). meta-Chloroperbenzoic acid is preferably used.
  • the oxidizing agent can be employed for the reaction (I-1) ⁇ (I-2) and (II) ⁇ (II-2) in an amount of from 1 to 1.2 mol, preferably from 1 to 1.05 mol, based on 1 mol of the compound of the formula (I-1) or (II).
  • the oxidizing agent can be employed for the reactions (I-1) ⁇ (I-3) and (II) ⁇ (II-3) in an amount of from 2 to 4 mol, preferably from 2 to 2.2 mol, based on 1 mol of the compound of the formula (I-1) or (II).
  • the reactions (I-1) ⁇ (I-2) or (I-3) and (II) ⁇ (II-2) or (II-3) generally take place in a temperature range from ⁇ 78° C. to +50° C., preferably in the range from ⁇ 20° C. to +50° C., in particular at 0° C. to +30° C.
  • the reaction can be carried out under atmospheric, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). It is generally carried out under atmospheric pressure.
  • Solvents suitable for process steps (II-2)+(XI) ⁇ (I-2) and (II-3)+(XI) ⁇ (I-3) are all organic solvents which are inert under the reaction conditions.
  • These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, primary alcohols such as methanol, ethanol, n-propanol and n-butanol, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane and chlorobenzene, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (
  • Acids suitable for process step (II-2)+(XI) ⁇ (I-2) and (II-3)+(XI) ⁇ (I-3) are acetic acid, trifluoroacetic acid, sulfuric acid, para-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid or hydrochloric acid.
  • Trifluoroacetic acid is preferably employed.
  • the acid can be employed in this reaction in an amount of from 0.9 to 2.0 mol, preferably from 1 to 1.2 mol, based on 1 mol of the compound of the formula (II).
  • Lewis acids suitable for process step (II-2)+(XI) ⁇ (I-2) and (II-3)+(XI) ⁇ (I-3) are boron trifluoride-diethyl ether complex, cerium(IV) ammonium nitrate (CAN), tin(II) chloride, lithiumperchlorate, zinc(II) chloride, indium(III) chloride or indium(III) bromide. Indium(III) chloride is preferably used.
  • the Lewis acid can be employed in this reaction in an amount of from 0.2 to 2.0 mol, preferably 0.7 to 1.2 mol, based on 1 mol of the compound of the formula (II).
  • the reactions (II-2)+(XI) ⁇ (I-2) and (II-3)+(XI) ⁇ (I-3) can where appropriate also be carried out using a mixture of acid and Lewis acid, with preference in this case for trifluoroacetic acid and indium(III) chloride.
  • the acid and Lewis acid can be employed in a ratio of from 1:99 to 99:1, preferably 2:1 to 4:3.
  • the reaction takes place when acids are employed generally in a temperature range from ⁇ 40° C. to +40° C., preferably at 0° C. to +30° C., and when Lewis acids are employed generally in a temperature range from +20° C. to +150° C., preferably at +40° C. to +100° C.
  • reaction (II-2) ⁇ (I-2) and (II-3) ⁇ (I-3) can also be carried out using an acetate (XI-A)
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above, and X is a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate, and subsequent substitution reaction with an alkali metal cyanide to give a compound of the invention of the formula (I-1B)
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above.
  • Process step (II)+(III)+(IV) ⁇ (V) can be carried out in one stage as 3-component reaction or else in two stages by initially condensing the aldehyde of the formula (III) with the malonic ester of the formula (IV) by standard methods to give a compound of the formula (VIII)
  • the malonic ester component (IV) preferably used is Meldrum's acid (cycl. isopropylidene malonate).
  • the product of the formula (Va) resulting in this case is Meldrum's acid (cycl. isopropylidene malonate).
  • an acid/base catalyst such as, for example D,L-proline or piperidinium acetate.
  • the reaction (VIII)+(II) ⁇ (V) can where appropriate take place advantageously with the aid of an amine base such as triethylamine or a Lewis acid such as copper(II) or ytterbium trifluoromethanesulfonate.
  • Solvents suitable for process steps (II)+(III)+(IV) ⁇ (V) and (VIII)+(II) ⁇ (V) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to employ mixtures of the solvents mentioned. Acetonitrile is preferably used.
  • DMF dimethyl
  • the reactions generally take place in a temperature range from 0° C. to +120° C., preferably at 0° C. to +60° C.
  • the reactions can be carried out under atmospheric, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). They are generally carried out under atmospheric pressure.
  • the reducing agent suitable in process step (VI) ⁇ (I-1A) is in particular lithium aluminum hydride or lithium borohydride.
  • the reactions are preferably carried out in an ether such as diethyl ether or tetrahydrofuran as inert solvent in a temperature range from 0° C. to +80° C.
  • Inert solvents suitable in particular for process steps (VII) ⁇ (I-1B) are ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to employ mixtures of these solvents. Dimethylformamide is preferably used.
  • the reactions generally take place in a temperature range from +20° C. to +150° C., preferably at +40° C. to +100° C.
  • the indoles of the formula (II) can be prepared by reacting a 6-nitrobenzyl bromide derivative of the formula (IX)
  • R 1 , R 2 , R 3 and R 4 each have the meanings indicated above.
  • Solvents suitable for process step (IX)+(X) ⁇ (XI) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to employ mixtures of the solvents mentioned. Tetrahydrofuran or DMF is preferably used.
  • acyclic and cyclic ethers such as diethy
  • the reaction generally takes place in a temperature range from ⁇ 20° C. to +100° C., preferably at 0° C. to +60° C.
  • the reactions can be carried out under atmospheric, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). They are generally carried out under atmospheric pressure.
  • Solvents suitable for the Grignard reaction (XI) ⁇ (II) are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidinone (NMP) and acetonitrile. It is likewise possible to employ mixtures of the solvents mentioned. Tetrahydrofuran is preferably used.
  • acyclic and cyclic ethers such as diethyl ether,
  • the reaction generally takes place in a temperature range from ⁇ 100° C. to +50° C., preferably at ⁇ 78° C. to +25° C.
  • the reactions can be carried out under atmospheric, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). They are generally carried out under atmospheric pressure.
  • the compounds of the formulae (IX) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • indoles of the formula (II) in which R 2 , R 3 and R 4 are H can each be prepared starting from 7-methylindole, as illustrated by way of example in the synthesis scheme below:
  • R 5 is a group of the formula
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above, and T 4 is hydrogen or (C 1 -C 4 )-alkyl, and subsequently reacting in an inert solvent with a suitable reducing agent such as, for example, lithium aluminum hydride to give a compound of the invention of the formula (I-1C)
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above.
  • R 5 is a group of the formula
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above, and X is a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate, and a subsequent substitution reaction with an alkali metal cyanide to give a compound of the invention of the formula (I-1D)
  • R 1 , R 2 , R 3 , R 4 and R 9 each have the meanings indicated above.
  • the hydrolysis of the nitriles (I-1B) to the carboxylic acids (XII) is preferably carried out with aqueous solutions of alkali metal or alkaline earth metal hydroxides such as lithium, sodium, potassium, calcium or barium hydroxide.
  • Suitable cosolvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, other solvents such as acetone, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), or mixtures of these solvents.
  • the hydrolysis generally takes place in a temperature range from +50° C. to +150° C., preferably at +60° C. to +100° C.
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • R 5 is a group of the formula
  • Process step (II)+(XI) ⁇ (I-1) is carried out under the conditions mentioned for the reaction steps (II-2)+(XI) ⁇ (I-2) and (II-3)+(XI) ⁇ (I-3).
  • R 5 is a group of the formula
  • R 9 , R 11 and T 4 each have the meanings indicated above, and then reacting the latter in an inert solvent in the presence of a Lewis acid or acid with a compound of the formula (II), (II-2) or (II-3) to give a compound of the formula (XVII), (XVII-2) or (XVII-3)
  • R 1 , R 2 , R 3 , R 4 , R 9 , R 11 and T 4 each have the meanings indicated above, and then reducing the latter in an inert solvent with a suitable reducing agent to a compound of the formula (I-1A), (I-2A) or (I-3A), or alternatively reducing a compound of the formula (XVI) in an inert solvent with a suitable reducing agent to a compound of the formula (XVIII)
  • R 9 and R 11 each have the meanings indicated above, and then reacting the latter under the conditions mentioned above with a compound of the formula (II), (II-2) or (II-3) to give a compound of the formula (I-1A), (I-2A) or (I-3A).
  • Inert solvents suitable for process steps (XVII) ⁇ (I-1A), (XVII-2) ⁇ (I-2A), (XVII-3) ⁇ (I-3A) and (XVI) ⁇ (XVIII) are in this case alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane or 1,2-dichloroethane, or other solvents such as dimethylformamide. It is likewise possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferably used.
  • Reducing agents suitable for process steps (XVII) ⁇ (I-1A), (XVII-2) ⁇ (I-2A), (XVII-3) ⁇ (I-3A) and (XVI) ⁇ (XVIII) are borohydrides such as, for example, sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydrides such as, for example, lithium aluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride or diisobutylaluminium hydride or boron-tetrahydrofuran complex.
  • borohydrides such as, for example, sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride
  • aluminum hydrides such as, for example, lithium aluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride or diisobutylaluminium hydride or boron-tetrahydro
  • the reaction (IV-C) ⁇ (V-C) generally takes place in a temperature range from 0° C. to +60° C., preferably from 0° C. to +40° C.
  • Further compounds of the invention can also be prepared where appropriate by conversions of functional groups of individual substituents, in particular those mentioned for A, R 7 , R 8 , R 9 , R 10 and R 11 , starting from compounds of the formula (I) obtained by the above processes.
  • conversions are carried out by conventional methods known to a person skilled in the art and include for example reactions such as nucleophilic, electrophilic or transition metal-catalyzed substitution reactions, oxidation, reduction, hydrogenation, alkylation, acylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides and sulfonamides, and the introduction and removal of temporary protective groups.
  • the compounds of the invention are potent antagonists of the mineralocorticoid receptor which are selective in relation to the androgen (testosterone) and progesterone receptors and are distinguished by a valuable range of pharmacological effects which could not have been predicted, and an advantageous CYP inhibition profile by comparison with compounds disclosed in the prior art. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.
  • the compounds of the invention are suitable for the prophylaxis and/or treatment of various disorders and disease-related conditions, especially of disorders which are characterized either by an elevation of the plasma aldosterone concentration or by a change in the plasma aldosterone concentration relative to the plasma renin concentration, or are associated with these changes.
  • disorders which are characterized either by an elevation of the plasma aldosterone concentration or by a change in the plasma aldosterone concentration relative to the plasma renin concentration, or are associated with these changes.
  • Examples which may be mentioned are: idiopathic primary hyperaldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenomas and/or adrenal carcinomas, hyperaldosteronism associated with cirrhosis of the liver, hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension.
  • the compounds of the invention are also suitable, because of their mechanism of action, for the prophylaxis of sudden cardiac death in patients at increased risk of dying of sudden cardiac death.
  • patients suffering for example from one of the following disorders: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, therapy-resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, dilated cardiomyopathies, congenital primary cardiomyopathies such as, for example, Brugada syndrome, cardiomyopathies induced by Chagas disease, shock, arteriosclerosis, atrial and ventricular arrhythmia, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiac vascular disorders, peripheral blood flow disturbances, arterial occlusive diseases such as intermittent claudication, asymptomatic left-ventricular dysfunction, myocarditis, hypertrophic alterations of the heart, pulmonary hypertension, spasms of the coronary arteries
  • the compounds of the invention can additionally be used for the prophylaxis and/or treatment of edema formation, such as, for example, pulmonary edema, renal edema or heart failure-related edema, and of restenoses such as following thrombolysis therapies, percutaneous transluminal angioplasties (PTA) and coronary angioplasties (PTCA), heart transplants and bypass operations.
  • edema formation such as, for example, pulmonary edema, renal edema or heart failure-related edema
  • restenoses such as following thrombolysis therapies, percutaneous transluminal angioplasties (PTA) and coronary angioplasties (PTCA), heart transplants and bypass operations.
  • PTA percutaneous transluminal angioplasties
  • PTCA coronary angioplasties
  • the compounds of the invention can additionally be employed for the prophylaxis and/or treatment of erectile dysfunction.
  • the compounds of the invention are further suitable for use as potassium-sparing diuretic and for electrolyte disturbances such as, for example, hypercalcemia, hypernatremia or hypokalemia, including genetically related forms such as Gitelman's or Barrter's syndrome.
  • the compounds of the invention are likewise suitable for the treatment of renal disorders such as acute and chronic renal failure, hypertensive kidney disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic renal disorders, for the prevention of kidney damage which may be caused for example by immunosuppressants such as cyclosporin A in association with organ transplants, and for renal cancer.
  • renal disorders such as acute and chronic renal failure, hypertensive kidney disease, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic renal disorders
  • immunosuppressants such as cyclosporin A in association with organ transplants, and for renal cancer.
  • the compounds of the invention can additionally be employed for the prophylaxis and/or treatment of diabetes mellitus and diabetic sequelae such as, for example, neuropathy, nephropathy and cardiomyopathy.
  • the compounds of the invention can additionally be employed for the prophylaxis and/or treatment of eye disorders, especially forms based on angiogenesis and neovascularization, such as, for example, neonatal retinopathy, diabetic retinopathy, and age-related macular degeneration and glaucoma.
  • angiogenesis and neovascularization such as, for example, neonatal retinopathy, diabetic retinopathy, and age-related macular degeneration and glaucoma.
  • the compounds of the invention can further be used for the prophylaxis and/or treatment of microalbuminuria, for example caused by diabetes mellitus or high blood pressure, and of proteinuria.
  • the compounds of the invention are also suitable for the prophylaxis and/or treatment of disorders associated either with an increase in the plasma glucocorticoid concentration or with a local increase in the concentration of glucocorticoids in tissue (e.g. of the heart).
  • disorders associated either with an increase in the plasma glucocorticoid concentration or with a local increase in the concentration of glucocorticoids in tissue e.g. of the heart.
  • Examples which may be mentioned are: adrenal dysfunctions leading to overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumors with resulting overproduction of glucocorticoids, and pituitary tumors which autonomously produce ACTH (adrenocorticotropic hormone) and thus lead to adrenal hyperplasias with resulting Cushing's disease.
  • ACTH adrenocorticotropic hormone
  • the compounds of the invention can additionally be employed for the prophylaxis and/or treatment of obesity, of metabolic syndrome and of obstructive sleep apnea.
  • the compounds of the invention can further be used for the prophylaxis and/or treatment of inflammatory disorders caused for example by viruses, spirochetes, fungi, bacteria or mycobacteria, and of inflammatory disorders of unknown etiology, such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inflammatory disorders caused for example by viruses, spirochetes, fungi, bacteria or mycobacteria
  • inflammatory disorders of unknown etiology such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • the compounds of the invention can further be employed for the treatment of central nervous disorders such as depressions, anxiety states and chronic pain, especially migraine, and for neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
  • central nervous disorders such as depressions, anxiety states and chronic pain, especially migraine
  • neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.
  • the compounds of the invention are also suitable for the prophylaxis and/or treatment of vascular damage, e.g. following procedures such as percutaneous transluminal coronary angioplasty (PTCA), implantations of stents, coronary angioscopy, reocclusion or restenosis following bypass operations, and for endothelial dysfunction, for Raynaud's disease, for thromboangitis obliterans (Buerger's syndrome) and for tinnitus syndrome.
  • PTCA percutaneous transluminal coronary angioplasty
  • the compounds of the invention are also suitable for the prophylaxis and/or treatment of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
  • the present invention further relates to the use of the compounds of the invention for the treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further relates to the use of the compounds of the invention for the manufacture of a medicament for the treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further relates to a method for the treatment and/or prevention of disorders, especially of the aforementioned disorders, by using an effective amount of at least one of the compounds of the invention.
  • the present invention further relates to the compounds of the invention for use in a method for the treatment and/or prophylaxis of aldosteronism, high blood pressure, acute and chronic heart failure, the sequence of the myocardial infarction, cirrhosis of the liver, renal failure and stroke.
  • the compounds of the invention can be employed alone or, if required, in combination with other active ingredients.
  • the present invention further relates to medicaments comprising at least one of the compounds of the invention and one or more further active ingredients, especially for the treatment and/or prevention of the aforementioned disorders.
  • Suitable active ingredients for combinations are by way of example and preferably:
  • the compounds of the invention are administered in combination with a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthal
  • Agents which lower blood pressure preferably mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors, and diuretics.
  • the compounds of the invention are administered in combination with a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds of the invention are administered in combination with an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compounds of the invention are administered in combination with an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds of the invention are administered in combination with an endothelin antagonist such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • the compounds of the invention are administered in combination with an alpha-1 receptor blocker such as by way of example and preferably prazosin.
  • the compounds of the invention are administered in combination with a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol, pin
  • the compounds of the invention are administered in combination with a Rho kinase inhibitor such as by way of example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • a Rho kinase inhibitor such as by way of example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • Antithrombotics preferably mean compounds from the group of platelet aggregation inhibitors, of anticoagulants or of profibrinolytic substances.
  • the compounds of the invention are administered in combination with a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds of the invention are administered in combination with a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, bivalirudin or clexane.
  • a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, bivalirudin or clexane.
  • the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist such as by way of example and preferably tirofiban or abciximab.
  • the compounds of the invention are administered in combination with a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, ML
  • the compounds of the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds of the invention are administered in combination with a vitamin K antagonist such as by way of example and preferably coumarin.
  • Agents which alter lipid metabolism preferably mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.
  • the compounds of the invention are administered in combination with a CETP inhibitor such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapid or CETP vaccine (CETi-1).
  • a CETP inhibitor such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapid or CETP vaccine (CETi-1).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds of the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds of the invention are administered in combination with a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds of the invention are administered in combination with an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds of the invention are administered in combination with an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • the compounds of the invention are administered in combination with a PPAR-delta agonist such as by way of example and preferably GW-501516 or BAY 68-5042.
  • the compounds of the invention are administered in combination with a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds of the invention are administered in combination with a lipase inhibitor such as by way of example and preferably orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as by way of example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • a polymeric bile acid adsorbent such as by way of example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • the compounds of the invention are administered in combination with a lipoprotein(a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein(a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the present invention further relates to medicaments which comprise at least one compound of the invention, normally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.
  • the compounds of the invention may have systemic and/or local effects.
  • they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as implant or stent.
  • the compounds of the invention can be administered in administration forms suitable for these administration routes.
  • Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds of the invention rapidly and/or in a modified manner, and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having coatings which are resistant to gastric juice or are insoluble or dissolve with a delay and control the release of the compound of the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example having coatings which are resistant to gastric juice or are insoluble or dissolve with a delay and control the release of the compound of the invention
  • tablets which disintegrate rapidly in the mouth or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Suitable for the other routes of administration are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants or stents.
  • pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, preparations for the ears and eyes
  • vaginal capsules aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (
  • Oral or parenteral administration are preferred, especially oral and intravenous administration.
  • the compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorings (e.g. inorganic pigments such as, for example, iron oxides) and masking flavors and/or odors.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and very particularly preferably about 0.1 to 10 mg/kg of body weight.
  • MS instrument type Micromass ZQ
  • HPLC instrument type Waters Alliance 2795
  • eluent A 1 l water+0.5 ml 50% formic acid
  • eluent B 1 l acetonitrile+0.5 ml 50% formic acid
  • flow rate 2 ml/min
  • UV detection 210 nm.
  • MS instrument type Micromass ZQ
  • HPLC instrument type HP 1100 Series
  • UV DAD column: Phenomenex Gemini 3 ⁇ 30 mm ⁇ 3.00 mm
  • eluent A 1 l water+0.5 ml 50% formic acid
  • eluent B 1 l acetonitrile+0.5 ml 50% formic acid
  • flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
  • UV detection 210 nm.
  • MS instrument type Waters (Micromass) Quattro Micro
  • HPLC instrument type Agilent 1100 Series
  • column Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm
  • eluent A 1 l water+0.5 ml 50% formic acid
  • eluent B 1 l acetonitrile+0.5 ml 50% formic acid
  • gradient 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.01 min 100% A (Flow 2.5 ml) ⁇ 5.0 min 100% A; flow rate: 2 ml/min; oven: 50° C.; UV detection: 210 nm.
  • Instrument Micromass GCT, GC6890; column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant helium flow rate: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min ⁇ 310° C. (hold for 3 min).
  • MS instrument type Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm; eluent A: 1 l water+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.1 min 100% flow rate: 2.5 ml/min, oven: 55° C.; flow rate: 2 ml/ml; UV detection: 210 nm.
  • the title compound is prepared starting from 2.00 g (10.24 mmol) of the compound from Example 9A and 1.78 g (10.24 mmol) of 4-(trifluoromethyl)benzaldehyde in analogy to the synthesis of the compound from Example 21A. 3.83 g (75% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 1.62 g (91% purity, 3.01 mmol) of the compound from Example 30A in analogy to the synthesis of the compound from Example 27A. 0.89 g (59% of theory) of the title compound was obtained as mixture of diastereomers.
  • the enantiomers were separated by preparative HPLC on a chiral phase [column with chiral selector poly(N-methacryloyl-L-leucine dicyclopropylmethylamide), 10 ⁇ m, 250 mm ⁇ 30 mm; eluent: isohexane/ethyl acetate 82:18; flow rate: 45 ml/min; temperature: RT; UV detection: 260 nm].
  • the separated enantiomers were purified again by preparative HPLC on an achiral phase (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid):
  • the title compound was prepared starting from 3.82 g (7.71 mmol) of the compound from Example 22A in analogy to the synthesis of the compound from Example 47A. 3.05 g (90% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 1.73 g (71% purity, 3.72 mmol) of the compound from Example 23A in analogy to the synthesis of the compound from Example 47A. 1.23 g (81% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 250 mg (0.67 mmol) of the compound from Example 10 in analogy to the synthesis of the compound from Example 54A. 308 mg (100% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 1.24 g (3.46 mmol) of the compound from Example 11 in analogy to the synthesis of the compound from Example 54A. 1.41 g (93% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 1.81 g (4.55 mmol) of the compound from Example 17 in analogy to the synthesis of the compound from Example 66A. 2.20 g of the title compound were obtained as crude product and were reacted further without purification.
  • the title compound was prepared starting from 640 mg (1.74 mmol) of the compound from Example 18 in analogy to the synthesis of the compound from Example 66A. 768 mg of the title compound were obtained as crude product and were reacted further without purification.
  • the title compound was prepared starting from 566 mg (1.44 mmol) of the compound from Example 20 in analogy to the synthesis of the compound from Example 69A. 622 mg (92% of theory) of the title compound were obtained as mixture of diastereomers.
  • the title compound was prepared starting from 202 mg (0.56 mmol) of the compound from Example 21 in analogy to the synthesis of the compound from Example 69A. 221 mg (90% of theory) of the title compound were obtained as mixture of diastereomers.
  • the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo.
  • the crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 1.02 g (66% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 6.00 g (34.29 mmol) of 4-bromofluorobenzene and 5.78 g (41.14 mmol) of 4-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 7.14 g (88% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 1.00 g (4.87 mmol) of 2-bromo-5-chlorotoluene and 0.72 g (5.84 mmol) of 4-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 0.64 g (52% of theory) of the title compound was obtained.
  • the title compound was prepared starting from 1.00 g (5.71 mmol) of 4-bromofluorobenzene and 0.97 g (6.86 mmol) of 2,4-difluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 0.53 g (38% of theory) of the title compound was obtained.
  • the title compound was prepared starting from 4.60 g (26.28 mmol) of 4-bromofluorobenzene and 5.00 g (31.53 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 4.45 g (66% of theory) of the title compound were obtained.
  • the title compound was prepared starting from 2.00 g (11.22 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 4.74 ml (22.45 mmol) of ethyl acetate in analogy to the synthesis of the compound from Example 90A. 2.52 g (84% of theory) of the title compound were obtained.

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US13/001,133 2008-06-25 2009-06-16 Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof Abandoned US20110201564A1 (en)

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