EP2297099A1 - 3-cyanoalkyl- et 3-hydroxyalkyl-indoles et leur utilisation - Google Patents

3-cyanoalkyl- et 3-hydroxyalkyl-indoles et leur utilisation

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Publication number
EP2297099A1
EP2297099A1 EP09768940A EP09768940A EP2297099A1 EP 2297099 A1 EP2297099 A1 EP 2297099A1 EP 09768940 A EP09768940 A EP 09768940A EP 09768940 A EP09768940 A EP 09768940A EP 2297099 A1 EP2297099 A1 EP 2297099A1
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EP
European Patent Office
Prior art keywords
compound
formula
alkyl
phenyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP09768940A
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German (de)
English (en)
Inventor
Kai Thede
Elisabeth Woltering
Peter Kolkhof
Carsten Schmeck
Elisabeth Pook
Alexander Hillisch
Lars BÄRFACKER
Klemens Lustig
Dieter Lang
Martin Radtke
Rolf Grosser
Astrid BRÜNS
Michael Gerisch
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication of EP2297099A1 publication Critical patent/EP2297099A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to novel, 3-cyanoalkyl- and 3-hydroxyalkyl-substituted indole derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or disease prevention, in particular for the treatment and / or prevention of cardiovascular diseases.
  • Aldosterone plays a key role in the maintenance of fluid and electrolyte homeostasis by promoting sodium retention and potassium secretion in the epithelium of the distal nephron, thereby helping to maintain extracellular volume and thus regulate blood pressure.
  • aldosterone has direct effects on the structure and function of the cardiovascular system, although the underlying mechanisms have not yet been exhaustively clarified [R.E. Booth, J.P. Johnson, J.D. Stockand, Adv. Physiol. Educ. 26 (1), 8-20 (2002)].
  • Aldosterone is a steroid hormone that is produced in the adrenal cortex. Its production is indirectly regulated quite significantly depending on the kidney perfusion. Any decrease in renal blood flow in the kidney leads to a release of the enzyme renin into the bloodstream. This in turn activates the formation of angiotensin II, which on the one hand narrows the arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex.
  • the kidney acts as a blood pressure and thus an indirect volume sensor in the bloodstream and counteracts the critical volume losses via the renin-angiotensin-aldosterone system by increasing the blood pressure on the one hand (angiotensin U effect) on the other hand by increasing the reabsorption of Sodium and water in the kidney of the filling state of the vascular system is compensated again (aldosterone effect).
  • This control system can be disturbed in many ways pathologically.
  • a chronic reduced blood flow to the kidneys eg due to cardiac insufficiency and the resulting blood backflow in the venous system
  • a chronically excessive release of aldosterone leads to an expansion of the blood volume and hereby strengthens the heart failure by a volume oversupply to the heart.
  • Stagnation of blood in the lungs with shortness of breath and edema in the extremities as well as ascites and pleural effusions may result; Kidney circulation continues to drop.
  • the exaggerated aldosterone effect leads to a reduction in the potassium concentration in the blood and in the extracellular fluid.
  • hyperaldosteronism is a crucial component in the pathogenesis and prognosis of heart failure, which may initially be elicited by differential injury, such as a myocardial infarction, myocarditis, or hypertension.
  • Hyperaldosteronism Much rarer than the forms of hyperaldosteronism listed above are those diseases in which the disorder is found either in the hormone-producing cells of the adrenal gland itself or their number or mass is increased by hyperplasia or proliferation.
  • Adenoma or diffuse hyperplasia of the adrenal cortex is the most common cause of the also called Conn syndrome primary hyperaldosteronism, whose guiding symptoms are hypertension and hypokalemic alkalosis.
  • drug therapy with aldosterone antagonists is in the foreground [H.A. kuhn and J. Schirmeister (ed.), Internal Medicine, 4th ed., Springer Verlag, Berlin, 1982].
  • aldosterone antagonists Another condition typically associated with elevation of plasma aldosterone concentration is advanced cirrhosis of the liver.
  • the cause of the increase in aldosterone is mainly due to the impaired breakdown of aldosterone due to liver dysfunction.
  • Volume overload, edema and hypokalaemia are the typical consequences that can be successfully alleviated in clinical practice by aldosterone antagonists.
  • the effects of aldosterone are mediated by the mineralocorticoid receptor located intracellularly in the target cells.
  • the object of the present invention is therefore to provide novel compounds which act as potent and selective mineralocorticoid receptor antagonists and can thus be used for the treatment of diseases, in particular of cardiovascular diseases.
  • WO 2004/067529, WO 2005/092854 and M.G. Bell, J. Med. Chem. 2007, 50 (26), 6443-6445 describe various indole derivatives substituted in the 3-position as modulators of steroid hormone receptors.
  • Indole-3-yl (phenyl) acetic acid derivatives as endothelin receptor antagonists are disclosed in WO 97/43260 and ⁇ -amino (indol-3-yl) acetic acid derivatives having anti-diabetic activity are disclosed in WO 90/05721.
  • WO 2007/062994 and WO 2005/118539 3- (3-amino-1-arylpropyl) -indoles are claimed for the treatment of depression and anxiety.
  • WO 2007/040166 claims fused pyrrole derivatives as glucocorticoid receptor modulators which have anti-inflammatory and anti-diabetic activity.
  • WO 2007/070892 describes substituted indoles for the treatment of anxiety, pain and cognitive disorders.
  • the present invention relates to compounds of the general formula (I)
  • A is CR 5 or N
  • R 5 represents hydrogen, fluorine, chlorine or (C r C 4) alkyl
  • R 1 represents halogen, cyano, nitro, (C, -C 6) alkyl, (C r C 6) alkoxy, amino, mono-CQ-C ⁇ alkyl amino, di- (Ci-C 6) - alkylamino or a group of the formula - (CH 2 ) p -NR 6 -SO 2 -R 7 ,
  • p is the number 0, 1 or 2
  • R 6 is hydrogen or (C r C 4) -alkyl
  • R 7 is (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, phenyl, benzyl or 5- or 6-membered heteroaryl,
  • phenyl, benzyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, (Ci-C 4 ) alkyl, trifluoromethyl, hydroxy, (C r C 4 ) alkoxy , Trifluoromethoxy and amino may be substituted,
  • R 2 represents hydrogen, fluorine, chlorine or (C r C 4) alkyl
  • R 3 is phenyl or naphthyl
  • phenyl and naphthyl having 1 to 3 substituents independently of one another are selected from the group consisting of halogen, cyano, nitro, (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, and mono- (C 1 -C 4 ) -alkylamino, di (C 1 -C 4 ) -alkylamino, aminocarbonyl, mono- (C 1 -C 4 ) -alkylaminocarbonyl and di- (C 1 -C 4 ) -alkylaminocarbonyl,
  • n is the number 2 or 3
  • R 4A represents hydrogen, fluorine or (C r C 4) -alkyl
  • R 4B represents hydrogen, fluorine or (C r C 4) -alkyl
  • Z is hydroxy or cyano
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example 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 according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also comprises prodrugs of the compounds according to the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 or 3 to 6 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a linear or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.
  • Di-alkylamino in the context of the invention is an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms.
  • Preferred are linear or branched dialkylamino radicals each having 1 to 4 carbon atoms.
  • Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • Di-alkylaminocarbonyl is in the context of the invention an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-butyl-N-methylaminocarbonyl, N-tert-butyl-N -methylaminocarbonyl, Nn-pentyl-N-methylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series ⁇ , O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples include: Furyl, Pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • A is CR 5 ,
  • R 5 is hydrogen
  • R 1 represents chlorine, bromine, cyano, nitro, (Ci-C 4) alkyl, (C 1 -C 4) alkoxy, amino, mono- (C r C 4) - alkylamino, di- (C iC 4) alkylamino or a group of the formula - (CH 2 ) p -NR 6 -S ⁇ 2 -R 7 ,
  • p is the number 0 or 1
  • R 6 is hydrogen or methyl
  • R 7 is (C r C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, phenyl, benzyl or 5- or 6-membered heteroaryl,
  • phenyl, benzyl and 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, (C r C 4 ) alkyl, trifluoromethyl, hydroxy, (C r C 4 ) alkoxy,
  • Trifluoromethoxy and amino may be substituted
  • R 2 is hydrogen, fluorine or methyl
  • R 3 is phenyl or naphthyl
  • phenyl and naphthyl with 1 or 2 substituents independently of one another are selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, (C 1 -C 4 ) -alkyl,
  • Trifluoromethyl, (C 1 -C 4 ) -alkoxy and trifluoromethoxy may be substituted
  • n is the number 2 or 3
  • R 4A is hydrogen, fluorine or methyl
  • R 4B is hydrogen, fluorine or methyl
  • Z is hydroxy or cyano
  • A is CR 5 ,
  • R 5 is hydrogen
  • R 1 is bromine, cyano, methyl, ethyl, trifluoromethyl or a group of the formula - (CH 2 ) P - NR 6 -SO 2 -R 7 ,
  • R 7 is methyl or ethyl
  • R 2 is hydrogen or fluorine
  • R 3 is phenyl or naphthyl
  • phenyl having 1 or 2 substituents independently of one another can be substituted from the group fluoro, chloro, methyl or trifluoromethyl,
  • n is the number 2 or 3
  • R 4A is hydrogen
  • R 4B is hydrogen
  • Z is hydroxy or cyano
  • Another object of the invention is a process for the preparation of the compounds of the formula (I) according to the invention, characterized in that
  • T 1 and T 2 are identical or different and are (C 1 -C 4 ) -alkyl or both together form a> C (CH 3 ) 2 bridge,
  • T 3 is hydrogen or (Q -C 4 ) -alkyl
  • X is a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,
  • X is a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,
  • transformations are carried out by customary methods known to those 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, as well as the introduction and removal of temporary protecting groups [cf. also the following synthesis schemes 2-7].
  • 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, as well as the introduction and removal of temporary protecting groups [cf. also the following synthesis schemes 2-7].
  • the process step (ET) + (ET) + (IV) - »(V) can be carried out in one stage as a 3-component reaction or in two stages, by first the benzaldehyde of the formula (DI) with the malonic acid ester of the formula (FV) according to standard methods to a benzylidene compound of the formula (X)
  • the single-stage process variant (IT) + (HI) + (IV) -> (V) and - in two-stage reaction - the condensation (IH) + (IV) - »(X) are preferably in the presence of an acid / base catalyst, such as D, L-proline or piperidinium acetate.
  • the reaction (X) + (E) -> (V) may optionally be carried out advantageously with the aid of an amine base such as triethylamine or a Lewis acid such as copper (II) or ytterbium trifluoromethanesulfonate.
  • Suitable solvents for process steps (II) + (Iu) + (IV) ⁇ (V) and (X) + (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 ( ⁇ MP) and acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, acetonitrile is used.
  • the reactions are generally carried out in a temperature range of 0 0 C to +120 0 C, forthcoming Trains t at 0 0 C to +60 0 C.
  • the reactions can be carried out at atmospheric, elevated or reduced pressure (for example in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • Lithium aluminum hydride or lithium borohydride suitable.
  • the Reactions are preferably carried out as the inert solvent in a temperature range of 0 0 C to +80 0 C in an ether such as diethyl ether or tetrahydrofuran.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, or dipolar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidinone ( ⁇ MP) and acetonitrile, as inert solvents. It is also possible to use mixtures of these solvents. Preference is given to using dimethylformamide.
  • the reactions are generally carried out in a temperature range of +20 0 C to +150 0 C, preferably at +40 0 C to +100 0 C.
  • the hydrolysis of the ⁇ itriles (1-2) to the carboxylic acids (Vm) 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 is generally carried out in a temperature range of +50 0 C to +150 0 C, preferably at +60 0 C to +100 0 C.
  • the compounds of the invention are potent and selective antagonists of the mineralocorticoid receptor and show an unpredictable, valuable pharmacological activity spectrum. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular of diseases which are characterized either by an increase in the plasma aldosterone concentration or by a change in the aldosterone plasma concentration relative to the plasma renin concentration or go along with these changes.
  • diseases which are characterized either by an increase in the plasma aldosterone concentration or by a change in the aldosterone plasma concentration relative to the plasma renin concentration or go along with these changes.
  • diseases include: idiopathic primary hyperaldosteronism, hyperaldosteronism in adrenal hyperplasia, adrenal adenomas and / or adrenal carcinomas, hyperaldosteronism in liver cirrhosis hyperaldosteronism in heart failure and (relative) hyperaldosteronism in essential hypertension.
  • the compounds of the present invention are also useful for the prophylaxis of sudden cardiac death in patients at increased risk of dying from sudden cardiac death.
  • patients e.g. suffer from any of the following conditions: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, treatment-resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, dilated cardiomyopathies, congenital primary cardiomyopathies, e.g.
  • Brugada syndrome cardiomyopathies caused by Chagas' disease, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular Dysfunction, myocarditis, hypertrophic changes of the heart, pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders and vasculitis.
  • the compounds of the invention may also be used for the prophylaxis and / or treatment of edema, such as pulmonary edema, renal edema or heart failure-related edema, and restenoses, such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA) and coronary angioplasties (PTCA ), Heart transplants and bypass surgery.
  • edema such as pulmonary edema, renal edema or heart failure-related edema
  • restenoses such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA) and coronary angioplasties (PTCA ), Heart transplants and bypass surgery.
  • PTA percutaneous transluminal angioplasties
  • PTCA coronary angioplasties
  • the compounds of the invention can be used for the prophylaxis and / or treatment of erectile dysfunction.
  • the compounds of the present invention are useful as a potassium-sparing diuretic and in electrolyte disorders such as hypercalcemia, hypernatremia or hypokalemia, including genetically engineered forms such as Gitelman or Barrter syndrome.
  • the compounds of the present invention are also useful in the treatment of renal diseases such as acute and chronic renal failure, hypertensive renal disease, atherosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal insufficiency and cystic kidney disease for the prevention of renal damage caused, for example, by immunosuppressive agents such as cyclosporin A can be caused by organ transplants, as well as kidney cancer.
  • the compounds according to the invention can be used for the prophylaxis and / or treatment of diabetes mellitus and diabetic secondary diseases such as neuropathy, nephropathy and cardiomyopathy.
  • the compounds according to the invention can be used for the prophylaxis and / or treatment of ocular diseases, in particular forms based on angiogenesis and neovascularization, such as e.g. Neonatal retinopathy, diabetic retinopathy, as well as age-related macular degeneration and glaucoma.
  • ocular diseases in particular forms based on angiogenesis and neovascularization, such as e.g. Neonatal retinopathy, diabetic retinopathy, as well as age-related macular degeneration and glaucoma.
  • the compounds according to the invention can furthermore be used for the prophylaxis and / or treatment of microalbuminuria, for example due to diabetes mellitus or high blood pressure, as well as proteinuria.
  • the compounds of the invention are also useful in the prophylaxis and / or treatment of diseases associated with either an increase in plasma glucocorticoid concentration or a local concentration increase of glucocorticoid tissue (e.g., heart).
  • diseases associated with either an increase in plasma glucocorticoid concentration or a local concentration increase of glucocorticoid tissue e.g., heart.
  • Examples include adrenal function disorders leading to the overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumors resulting in the overproduction of glucocorticoids, and pituitary tumors that autonomously produce ACTH (adrenocorticotropic hormone) leading to adrenal hyperplasia resulting in Cushing's disease.
  • ACTH adrenocorticotropic hormone
  • the compounds according to the invention can be used for the prophylaxis and / or treatment of obesity, of the metabolic syndrome and of obstructive sleep apnea.
  • the compounds of the invention may also be used for the prophylaxis and / or treatment of inflammatory diseases, e.g. are caused by viruses, spirochetes, fungi, bacteria or mycobacteria, as well as inflammatory diseases of unknown aetiology, such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • inflammatory diseases e.g. are caused by viruses, spirochetes, fungi, bacteria or mycobacteria
  • inflammatory diseases of unknown aetiology such as polyarthritis, lupus erythematosus, peri- or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.
  • the compounds according to the invention can be used for the treatment of central nervous disorders such as depression, anxiety and chronic pain, in particular migraine, as well as in neurodegenerative diseases such as Alzheimer's disease and Parkinson's syndrome.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of vascular damage, eg after interventions such as percutaneous transluminal coronary angioplasty (PTCA), implantations of stents, coronary angioscopy, reocclusion or Restenosis following bypass surgery, endothelial dysfunction, Raynaud's disease, thrombangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.
  • PTCA percutaneous transluminal coronary angioplasty
  • implantations of stents eg., coronary angioscopy, reocclusion or Restenosis following bypass surgery
  • endothelial dysfunction eg., Raynaud's disease, thrombangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of gynecological diseases such as endometriosis, uterine leiomyomas, dysfunctional bleeding and dysmenorrhoea.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of aldosteronism, hypertension, acute and chronic heart failure, the consequences of myocardial infarction, cirrhosis, renal insufficiency and stroke.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists,
  • Renin inhibitors alpha-receptor blockers, beta-receptor blockers and rho-kinase inhibitors
  • Diuretics especially loop diuretics and thiazides and thiazide-like diuretics
  • Antithrombotic agents by way of example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists;
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;
  • Positive inotropic compounds such as cardiac glycosides (digoxin), beta adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sildenafil sildenafil
  • Vardenafil tadalafil
  • PDE 3 inhibitors such as amrinone and milrinone
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • Guanylate cyclase NO- and heme-independent activators in particular cinaciguat, and the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular riociguat, and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • adenosine receptors in particular adenosine Al antagonists, such as KW-3902, SLV-320 or BG-9928 (Adentri);
  • Vasopressin receptor antagonists such as conivaptan (vaprisol), tolvaptan, satavaptan, lixivaptan, relcovaptan, RWJ-339489 or RWJ-351647.
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gef ⁇ tinib and erlotinib; and or
  • the energy metabolism of the heart affecting compounds such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
  • the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumetiazide, methyclothiazide, polythiazide, trichloromethiazide, 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, chlorothiazide, hydrochlorothiazide, hydroflumetiazide, methyclothiazide, polythiazide, trichloromethia
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, Rho-kinase inhibitors and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an angiotensin AH antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • angiotensin AH antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds according to 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.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for 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, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI- 23095 or BA-1049.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPUb / UIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as, by way of example and by way of preference, rovoxaban (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.
  • rovoxaban BAY 59-7939
  • DU-176b DU-176b
  • apixaban otamixaban
  • fidexaban fidexaban
  • razaxaban fondaparinux
  • Idraparinux Idraparinux
  • PMD-3112 YM-150
  • KFA-1982 KFA-1982
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-I).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-I).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to 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 according to 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 according to 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 MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to 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 according to 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 according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for 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 by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds according to 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.
  • compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, among others, excipients (for example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyols).
  • ethylene glycols ethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes for example inorganic pigments such as, for example, iron oxides
  • flavor and / or odor remedies for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes for example inorganic pigments such as, for example, iron oxides
  • flavor and / or odor remedies for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight.
  • Method 2 Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith RP18e, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 210 nm.
  • Method 3 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C 18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A; Flow: 2 ml / min; Oven: 4O 0 C; UV detection: 208-400 nm.
  • Method 5 Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml HClO 4 (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 6.5 min 90% B ⁇ 6.7 min 2% B ⁇ 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.
  • Method 6 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 8 Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50mm x 1mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; Flow: 0.33 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
  • Method 9 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • the preparation of the title compound was carried out starting from 1.00 g (4.76 mmol) of the compound from Example 9A analogously to the synthesis of the compound from Example IA.
  • the crude product was first purified by flash chromatography on silica gel (eluent: toluene / ethyl acetate gradient) and then by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% formic acid). This gave 1.59 g (63% of theory) of the title compound.
  • the title compound was prepared starting from the compound from Example 9 analogously to the synthesis of the compound from Example 2.
  • the title compound was prepared starting from the compound from Example 17 analogously to the synthesis of the compound from Example 3.
  • the title compound was prepared starting from the compound from Example 33 analogously to the synthesis of the compound from Example 2.
  • the title compound was prepared starting from 985 mg (2.09 mmol) of the compound from Example 17A analogously to the synthesis of the compound from Example 1. However, tetrahydrofuran was used as solvent and stirred at 60 0 C for 2 h.
  • the crude product was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with addition of 0.1% formic acid) to give 630 mg (70% of theory) of the title compound.
  • the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 1% formic acid).
  • the intermediate product was dissolved in DMF, combined with 160 mg (2.46 mmol) of potassium cyanide and the solution was stirred at 80 ° C. for 4 h.
  • the reaction mixture was concentrated, the residue taken up in ethyl acetate and washed successively with sat. Sodium bicarbonate solution, water and sat. Sodium chloride solution washed.
  • the organic phase was dried over magnesium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 1% formic acid). 439 mg (23% of theory) of the title compound were obtained.
  • MR mineralocorticoid receptor
  • CHO Kl cell line an established chimera system is used in which the ligand-binding domains of human steroid hormone receptors are fused to the DNA binding domain of the yeast transcription factor GAL4.
  • the resulting GAL4 steroid hormone receptor chimeras are co-transfected in the CHO cells with a reporter construct and stably expressed.
  • the GAL4 DNA binding domain (amino acids 1-147) from the vector pFC2-dbd (Stratagene) with the PCR amplified ligand-binding domains of the mineralocorticoid receptor (MR , Amino acids 734-
  • glucocorticoid receptor amino acids 443-777
  • progesterone receptor PR
  • Amino acids 680-933) and the androgen receptor (AR, amino acids 667-919) are cloned in the vector pIRES2 (Clontech).
  • the reporter construct which contains five copies of the GAL4 binding site, upstream of a thymidine kinase promoter, leads to the expression of the firefly Luciferase (Photinus pyralis) after activation and binding of the GAL4 steroid hormone receptor chimeras by the respective specific agonists aldosterone (MR), dexamethasone (GR), progesterone (PR) and dihydrotestosterone (AR).
  • MR aldosterone
  • GR dexamethasone
  • PR progesterone
  • AR dihydrotestosterone
  • the MR, GR, PR and AR cells are transplanted into medium (Optimem, 2.5% FCS, 2 mM glutamine, 10 mM HEPES) in 96- (or 384- or 1536-) wells the day before the test. Plated microtiter plates and kept in a cell incubator (96% humidity, 5% v / v CO 2 , 37 ° C). On the test day, the substances to be tested are taken up in the above-mentioned medium and added to the cells. About 10 to 30 minutes after addition of the test substances, the respective specific agonists of the steroid hormone receptors are added. After a further incubation period of 5 to 6 hours, the luciferase activity is measured by means of a video camera. The measured relative light units result in a sigmoidal stimulation curve as a function of the substance concentration. The IC 50 values are calculated using the computer program GraphPad PRISM (version 3.02).
  • Table A shows the IC 50 values of representative example compounds:
  • Wistar rats 250-350 g body weight are kept with free access to feed (Altromin) and drinking water. From about 72 hours before the start of the test, the animals are replaced by the normal fodder exclusively cooking salt-reduced feed with a content of 0.02% sodium chloride (ssniff R / MH, 10 mm with 0.02% Na, S0602-E081, Fa. ssniff Spezialdi decisiven GmbH, D-59494 Soest). During the experiment, the animals are kept individually for about 24 hours in suitable metabolic cages for rats of this weight class (Tecniplast Germany GmbH, D-82383 Hohenpeissenberg) with free access to salt-reduced feed and drinking water.
  • the substance to be tested is administered to the animals in a volume of 0.5 ml / kg body weight of a suitable solvent in the stomach by means of a gavage.
  • Control animals receive only solvents.
  • Controls and substance tests are carried out in parallel on the same day.
  • Control groups and substance dose groups each consist of 6 to 8 animals.
  • the urine excreted by the animals is continuously collected in a container on the floor of the cage.
  • the urine volume per unit of time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by means of standard flame photometric methods. From the measured values, the sodium / potassium quotient is calculated as a measure of the substance effect.
  • the measuring intervals are typically the period up to 8 hours after the start of the test (day interval) and the period from 8 to 24 hours after the start of the test (night interval).
  • the urine is collected and measured every two hours during the day interval. To obtain a sufficient amount of urine, the animals at the beginning of the test and then at intervals of two hours by gavage a defined amount of water supplied.
  • DHA desoxycorticosterone acetate
  • a high-salt diet and unilateral kidney removal induces hypertension in the rat, characterized by relatively low renin levels.
  • endocrine hypertension (DOCA is a direct precursor of aldosterone)
  • cardiac hypertrophy and other end organ damage occurs, depending on the DOCA concentration chosen, e.g. the kidney, the u.a. characterized by proteinuria and glomerulosclerosis.
  • DOCA concentration chosen, e.g. the kidney, the u.a. characterized by proteinuria and glomerulosclerosis.
  • test substances can thus be examined for existing antihypertrophic and end organ protective effect.
  • Uninephrectomized SD rats receive 1% sodium chloride in drinking water and once weekly a subcutaneous injection of desoxycorticosterone acetate (dissolved in sesame oil, Sigma) injected between the shoulder blades (high dose: 100 mg / kg / week sc, normal dose: 30 mg / kg / week sc).
  • the substances that are to be tested for their protective effect in vivo are administered by gavage or via the diet (Ssniff).
  • the substances are administered once a day for 4-8 weeks by gavage or by food.
  • the placebo group used is animals that are treated in exactly the same way, but receive either only the solvent or the feed without the test substance.
  • the effect of the test substances is determined by measuring hemodynamic parameters [blood pressure, heart rate, inotropy (dp / dt), relaxation time (tau), maximum left ventricular pressure, left ventricular end-diastolic pressure (LVEDP)], weight determination of heart, kidney and lung Protein excretion and by measuring the gene expression of biomarkers (eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide) by RT / TaqMan PCR after RNA isolation from cardiac tissue determined.
  • biomarkers eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide
  • the statistical evaluation is done with Student's t-test after checking the variances for homogeneity.
  • the primary aim of the study is to investigate the influence of test compounds with anti-mineralocorticoid receptor activity on aldosterone-induced sodium retention. This procedure is analogous to a published method (Rosenthale, ME, Schneider, F., Kassarich, J. & Datko, L. (1965)., Determination of antialdosterone activity in normal dogs.) Proc Soc Exp Biol Med, 118, 806-809. et al, 1965).
  • the treatment with the test substances leads after 5 hours to an increase of the sodium-potassium ratio in the urine (the sodium and potassium determination is carried out by flame photometry).
  • the sodium and potassium determination is carried out by flame photometry.
  • a positive control serves spironolactone, which also increases the sodium / potassium ratio in the urine dose-dependent
  • a negative control is the treatment with an empty capsule.
  • the evaluation is made by comparing the sodium / potassium ratio in the urine between day 1 and 3.
  • the sodium / potassium ratio between placebo and substance on day 3 can be compared.
  • Male Wistar rats (280-300 g body weight, Harlan- Winkelmann) are anesthetized with 5% isoflurane in the anesthesia cage, intubated, connected to a ventilation pump (ugo basile 7025 rodent, 50 strokes / min, 7 ml) and treated with 2% Isoflurane / N 2 O / O 2 ventilated.
  • the body temperature is maintained at 37-38 ° C by a heat mat.
  • As analgesic 0.05 mg / kg of Temgesic are given subcutaneously. The thorax is opened laterally between the third and fourth ribs and the heart is exposed.
  • the coronary artery of the left ventricle is punctured with an occlusion suture (Prolene 1 metric 5-0 EthiconlH) just below its origin (below the left atrium) and permanently tied.
  • the occurrence of myocardial infarction is monitored by ECG measurement (Cardioline, Remco, Italy).
  • the thorax is closed again and the muscle layers are sutured with Ethibond excel 1 metric 5/0 695 IH and the epidermis with Ethibond excel 3/0 6558H.
  • the surgical suture is wetted with a spray plaster (eg Nebatinin ® N spray dressing, active substance: neomycin sulfate) and the anesthesia is then stopped.
  • a spray plaster eg Nebatinin ® N spray dressing, active substance: neomycin sulfate
  • the size of the myocardial infarction is estimated by echocardiography (Sequoia 512, Acuson).
  • the animals are randomized and divided into individual treatment groups and a control group without substance treatment.
  • a "sham" group in which only the surgical procedure, but not the LAD occlusion was performed, carried along.
  • the substance treatment takes place over 8 weeks by gavage or by adding the test compound to the feed or drinking water.
  • the animals are weighed weekly and the water or feed consumption is determined every 14 days.
  • the animals are anaesthetized again (2% isoflurane / N 2 O / air) and a pressure catheter (Miliar SPR-320 2F) introduced via the carotid artery in the left ventricle. It includes heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), contractility (dp / dt), and relaxation rate ( ⁇ ) using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and the Chart 5 software (SN 425-0586) recorded and evaluated. Subsequently, a blood sample is taken to determine the substance plasma levels and plasma bioparks and the animals are killed. Heart (ventricles, left ventricle with septum, right ventricle), liver, lung and kidney are removed and weighed.
  • LVP left ventricular pressure
  • LVEDP left ventricular end-diastolic pressure
  • dp / dt contractility
  • ⁇ relaxation rate
  • SP-SHR stroke-prone spontaneously hypertensive rat
  • hypertension in the SP-SHR animals is characterized by a relatively high renin level.
  • end organ damage of the heart and kidney which u.a. characterized by proteinuria and glomerulosclerosis, as well as general vascular changes.
  • cerebrovascular lesions may lead to strokes ("stroke-prone") leading to high mortality of untreated animals.
  • test substances can thus be tested for blood pressure-lowering and end organ-protective action.
  • test substances The effect of the test substances is monitored by historical measurements of systolic blood pressure (via a tail cuff) as well as urinary protein excretion.
  • biomarkers eg, ANP, atrial natriuretic peptides, and BNP, brain natriuretic peptides, KIM-I, kidney induced molecule 1, osteopontin-1 are isolated by RT / TaqMan PCR after RNA isolation from cardiac and renal tissue or serum or Plasma determined.
  • the statistical evaluation is done with Student's t-test after checking the variances for homogeneity.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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  • Indole Compounds (AREA)

Abstract

La présente invention porte sur de nouveaux dérivés d'indole à substitution 3-cyanoalkyle- et 3-hydroxyalkyle-, sur des procédés pour les préparer, sur leur utilisation à titre individuel ou en combinaison pour le traitement et/ou la prévention de maladies, ainsi que sur leur utilisation pour préparer des médicaments destinés au traitement et/ou à la prévention de maladies, en particulier au traitement et/ou à la prévention de maladies cardiovasculaires.
EP09768940A 2008-06-25 2009-06-18 3-cyanoalkyl- et 3-hydroxyalkyl-indoles et leur utilisation Withdrawn EP2297099A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008030206A DE102008030206A1 (de) 2008-06-25 2008-06-25 3-Cyanoalky- und 3-Hydroxyalkyl-Indole und ihre Verwendung
PCT/EP2009/004392 WO2009156091A1 (fr) 2008-06-25 2009-06-18 3-cyanoalkyl- et 3-hydroxyalkyl-indoles et leur utilisation

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EP2297099A1 true EP2297099A1 (fr) 2011-03-23

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EP (1) EP2297099A1 (fr)
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CA (1) CA2729057A1 (fr)
DE (1) DE102008030206A1 (fr)
WO (1) WO2009156091A1 (fr)

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WO2015020953A1 (fr) 2013-08-05 2015-02-12 Darin Schaeffer Dispositifs médicaux possédant un organe tubulaire libérable et procédés permettant leur utilisation
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JP2011525507A (ja) 2011-09-22
DE102008030206A1 (de) 2009-12-31
CA2729057A1 (fr) 2009-12-30
US20110183928A1 (en) 2011-07-28

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