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  • 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
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
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• • A—HUMAN NECESSITIES
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • C07D409/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to substituted isoindolone derivatives of the formula I,
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings given below, which are valuable active pharmaceutical ingredients for the therapy and prophylaxis of diseases, for example cardiovascular diseases such as high blood pressure, angina pectoris, heart failure, thrombosis or atherosclerosis.
• cardiovascular diseases such as high blood pressure, angina pectoris, heart failure, thrombosis or atherosclerosis.
• the compounds of formula I have the ability to modulate the body's production of cyclic
• cGMP Guanosine monophosphate
• the invention further relates to processes for the preparation of compounds of the formula I, their use for the therapy and prophylaxis of the specified disease states and for the production of medicaments therefor, and pharmaceutical preparations which contain compounds of the formula I.
• cGMP is an important intracellular messenger that triggers a number of pharmacological effects through the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are
• cGMP will produced by particulate and soluble guanylate cyclases (GC) in response to a number of extracellular and intracellular stimuli.
• GC particulate and soluble guanylate cyclases
• the stimulation takes place essentially by peptide signal substances, such as the atal natriuretic peptide or the cerebral natriuretic peptide.
• sGC soluble guanylate cyclases
• the most important stimulant is nitrogen monoxide (NO) or a closely related species. The importance of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear.
• NO nitrogen monoxide
• Activation mechanism of the activation by NO the connection of NO to the heme is discussed with the formation of a pentacoordinated heme-nitrosyl complex.
• the associated release of the histidine bound to the iron in the basal state converts the enzyme into the activated conformation.
• Active soluble guanylate cyclases consist of an ⁇ and a ⁇ subunit.
• Several subtypes of the subunits have been described, which differ from one another in terms of sequence, tissue-specific distribution and expression at different stages of development.
• the subtypes ⁇ 1 and ⁇ are mainly expressed in the brain and lungs, while ⁇ 2 is mainly found in the liver and kidneys.
• the subtype ⁇ 2 could be detected in human fetal brain.
• the subunits designated as ⁇ 3 and ß 3 were isolated from the human brain and are homologous to oc, and ß ⁇
• Recent studies indicate an ⁇ 2j subunit that contains an insert in the catalytic domain. All subunits show great homologies in the area of the catalytic domain.
• the enzymes presumably contain one heme per heterodimer, which is bound via ß r Cys-78 and / or ß r His-105 and is part of the regulatory center.
• guanylate cyclase activating factors can be reduced or it can be increased by the The occurrence of free radicals leads to an increased breakdown of the same.
• the resulting reduced activation of sGC leads, for example, to an increase in blood pressure, platelet activation or increased cell proliferation and cell adhesion by weakening the respective cGMP-mediated cell response.
• endothelial dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thrombosis, myocardial infarction, strokes or erectile dysfunction develop.
• the pharmacological stimulation of sGC offers a way to normalize cGMP production and thus allows the treatment and prevention of such diseases.
• the present invention thus relates to compounds of the formula I
• R 1 stands for (C 3 -C 7 ) cycloalkyl, phenyl or the residue of a 5-membered or 6-membered aromatic heterocycle which contains one or two identical or different heteroatoms from the series N, O, S, where the Phenyl radical and the heterocyclic radical are unsubstituted or by one or more identical or different radicals from the group (C r C 4 ) -alkyl, Halogen, hydroxy, (C 1 -C 4 ) alkoxy, benzyloxy, phenoxy, benzyl, phenyl, trifluoromethyl, cyano, hydroxycarbonyl, ((C 1 -C 4 ) alkoxy) carbonyl, aminocarbonyl, nitro, amino, (C r C 4 ) alkylamino, di - ((C 1 -C 4 ) alkyl) amino and ((C r C 4 ) alkyl) carbonylamino are substituted; R 2 , R 3
• R 6 represents phenyl which is unsubstituted or by one or more identical or different radicals from the series (C 1 -C 4 ) -alkyl, halogen, hydroxy, (CC 4 ) -alkoxy, benzyloxy, phenoxy, benzyl, phenyl, Trifluoromethyl, cyano, hydroxycarbonyl, ((C 1 -C 4 ) alkoxy) carbonyl, aminocarbonyl, nitro, amino, (C r C 4 ) alkylamino, di - ((C r C 4 ) alkyl) amino and (( C 1 -C 4 ) alkyl) carbonylamino is substituted;
• R 7 has one of the meanings of R 6 independently of R 6 or represents hydrogen; in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts; where if R 1 is unsubstituted phenyl and R 2 , R 3 , R 4 , R 5 and R 7 are hydrogen, then R 6 cannot simultaneously represent unsubstituted phenyl or 3,4-dimethoxyphenyl.
• Alkyl radicals can be straight-chain or branched. This also applies if they are contained in other groups, for example in alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
• alkyl here also means unsaturated alkyl radicals, in particular alkyl radicals which have a double bond or a
• radicals are the vinyl radical, the 2-propenyl radical (allyl radical), the 2-butenyl radical, the 2-methyl-2-propenyl radical, the ethynyl radical, the 2-propynyl radical (propargyl radical) or the 3-butynyl radical.
• cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, all of which are also exemplified by one or more identical or different (C r C 4 ) -alkyl radicals, in particular by Methyl, may be substituted.
• substituted cycloalkyl radicals are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl.
• Phenyl radicals can be unsubstituted or carry one or more, for example two, three or four, identical or different substituents.
• the substituents can be in any position.
• Substituted phenyl radicals are preferably substituted once or twice.
• Monosubstituted phenyl radicals can be substituted in the 2-position, the 3-position or the 4-position, in disubstituted phenyl radicals the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6 -Position, 3.4-position or 3.5-position.
• Examples of 5-membered and 6-membered aromatic heterocycles are furan, thiophene, pyrrole, pyrazole, imidazole, 1, 3-oxazole, 1, 3-thiazole, pyridine, pyridazine, pyrimidine and pyrazine.
• the residues derived from these heterocycles can be bound via any carbon atom.
• a thienyl radical can be present as a 2-thienyl radical or a 3-thienyl radical, a furyl radical as a 2-furyl radical or 3-furyl radical, a pyridyl radical as a 2-pyridyl radical, 3-pyridyl radical or 4-pyridyl radical.
• heterocycles can be unsubstituted or carry one or more, for example two, three or four, identical or different substituents.
• Heterocyclic radicals are preferably unsubstituted or substituted by one or two identical or different radicals, in particular unsubstituted.
• the substituents in heterocycles can be located in any position, for example in a thienyl radical bonded via the 2-position or furyl radical in the 3-position, the 4-position and / or the 5-position, in a thienyl radical bonded via the 3-position or furyl radical in the 2-position, the 4-position and / or the 5-position, in a 2-pyridyl radical in the 3-position, the 4-position, the 5-position and / or the 6-position, in one 3-pyridyl radical in the 2-position, the 4-position, the 5-position and / or the 6-position, in a 4-pyridyl radical in the 2-position, the 3-position, the 5-position and / or the 6- 7
• heterocyclic radicals are (C 1 -C 4) alkyl radicals, in particular methyl, and / or halogen atoms, in particular chlorine and / or fluorine.
• Nitrogen heterocycles can also be present as N-oxides or as quaternary salts, for example pyridyl radicals as pyridine N-oxides.
• nitro groups are present as substituents in phenyl radicals and / or heterocyclic radicals, only a total of up to two nitro groups can be present in the molecule in the compounds of the formula I.
• the benzene ring may in turn also be unsubstituted in them or by one or more, for example two, three or four, identical or different radicals from the Series (C 1 -C 4 ) alkyl, halogen, hydroxy, (C r C 4 ) alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, ((CC 4 ) alkoxy) carbonyl, aminocarbonyl, nitro, amino, (CC 4 ) Alkylamino, di - ((C r C 4 ) alkyl) amino and ((C r C 4 )
• Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
• the present invention encompasses all stereoisomeric forms of
• Asymmetry centers contained in the compounds of the formula I can all independently of one another have the S configuration or the R configuration.
• the invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereomers, in all ratios. Enantiomers are therefore the subject of the invention in all ratios in enantiomerically pure form, both as left-handed and as right-handed antipodes, in the form of racemates and in the form of mixtures of the two enantiomers.
• the cis form as well as the trans form and mixtures of these forms are the subject of the invention in all proportions.
• the production of individual stereoisomers can 8 if desired by separating a mixture by customary methods, for example by chromatography or crystallization, by using stereochemically uniform starting substances in the synthesis or by stereoselective synthesis. If necessary, derivatization can take place before separation of stereoisomers.
• a stereoisomer mixture can be separated at the stage of the compounds of the formula I or at the stage of an intermediate in the course of the synthesis.
• the present invention also includes all tautomeric forms of the compounds of the formula I. Furthermore, it also includes all ring-chain tautomers of the compounds of the formula I, for example the compounds of the formula Ia.
• the corresponding physiologically or toxicologically tolerable salts are also an object of the invention, in particular the pharmaceutically usable salts.
• the compounds of the formula I which contain acidic groups can be present on these groups as alkali metal salts, alkaline earth metal salts or as ammonium salts and can be used according to the invention.
• Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts, salts with physiologically compatible quaternary ammonium ions or acid addition salts with ammonia or physiologically compatible organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
• Compounds of the formula I which contain one or more basic, that is to say protonatable, groups can be in the form of their 9
• Acid addition salts with inorganic or organic acids are present and are used according to the invention, for example as salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, propionic acid, benzoic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, azoic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, benzoic acid, acetic acid, acetic acid, acetic acid, benzoic acid, acetic acid, acetic acid, benzoic acid, acetic acid, acetic acid, benzoic acid, acetic acid, acetic acid, benzoic acid, acetic acid, acetic
• salts can be obtained from the compounds of the formula I by customary processes known to those skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or else by anion exchange or cation exchange from other salts.
• the present invention also encompasses all salts of the compounds of the formula I which, because of their low physiological tolerance, are not directly suitable for use in medicaments, but are, for example, suitable as intermediates for chemical reactions or for the preparation of physiologically tolerable salts.
• the present invention further comprises all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I such as esters, and pro-drugs and active metabolites.
• R 1 preferably represents unsubstituted phenyl or phenyl which is substituted by one or two identical or different radicals from the series (CC 4 ) -alkyl and halogen.
• R 1 particularly preferably represents unsubstituted phenyl or phenyl which is substituted by one or two identical or different halogen atoms.
• R 1 is particularly preferably unsubstituted 10
• R 2 , R 3 , R 4 and R 5 are preferably independently of one another hydrogen, halogen or (C r C 4 ) -alkyl, particularly preferably independently of one another are hydrogen, fluorine, chlorine or methyl. In a particularly preferred embodiment, all R 2 , R 3 , R 4 and R 5 are hydrogen.
• R 6 preferably represents phenyl which is unsubstituted or substituted by one or two identical or different radicals from the series (C r C 4 ) -alkyl, halogen and (C r C 4 ) -alkoxy, in particular in positions 2 and /Or 3.
• R 6 is particularly preferably phenyl which is substituted by one or two identical or different radicals from the halogen and (C 1 -C 4 ) alkoxy group.
• R 6 particularly preferably represents methoxyphenyl, in particular 3-methoxyphenyl, or chlorophenyl, in particular 2-chlorophenyl.
• R 7 preferably represents hydrogen.
• Preferred compounds of the formula I are those in which one or more of the radicals contained therein have preferred meanings, all combinations of preferred substituent definitions being the subject of the present invention. Also of all preferred compounds of formula I, the present invention encompasses all of their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.
• a group of preferred compounds of the formula I are those compounds in which R 1 is unsubstituted phenyl or fluorophenyl, in particular 4-fluorophenyl; R 2 , R 3 , R 4 and R 5 are hydrogen; R 6 represents methoxyphenyl, in particular 3-methoxyphenyl, or chlorophenyl, in particular 2-chlorophenyl; R 7 represents hydrogen; in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts. 1 1
• the present invention also relates to processes for the preparation of the compounds of the formula I, which are explained below and by which the compounds according to the invention can be obtained.
• the compounds can be prepared, for example, by analogously Delcey et al., Heterocycles 41 (1995) 1721, benzoic acids of the formula II which are substituted in the 2-position by a keto group, or activated derivatives of the benzoic acids of the formula II with primary amines of the Formula 111 implemented.
• the radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings given above.
• the 2-ketobenzoic acids of the formula II and the amines of the formula III used as starting substances are commercially available or can be prepared by or analogously to standard processes described in the literature. If the carboxylic acid group in the compounds of the formula II is to be converted into an activated derivative with higher reactivity, this can be done by standard methods.
• the acid group can be converted, for example, into an ester, for example into an alkyl ester such as a methyl ester or ethyl ester or into an aryl ester such as a phenyl ester, chlorophenyl ester or nitrophenyl ester, or it can be converted into an acid halide such as an acid chloride or acid bromide, or it can be converted to an azolide, for example with carbonyldiimidazole to an imidazolide, or it can be converted into a mixed anhydride, for example by reaction with an alkyl chloroformate.
• an ester for example into an alkyl ester such as a methyl ester or ethyl ester or into an aryl ester such as a phenyl ester, chlorophenyl ester or nitrophenyl ester
• an acid halide such as an acid chloride or acid bromide
• azolide for example with carbonyldiimi
• the activation of the carboxylic acid group for the reaction with the amine of formula III can 12 can also be carried out, for example, with activation reagents such as carbodiimides or other reagents customary in peptide chemistry.
• the activation can be carried out in a separate step or in situ.
• a particularly simple and inexpensive process is the activation of carboxylic acids of the formula II, in particular those in which R 1 is an aromatic radical, for example a phenyl radical, by conversion into the carboxylic acid chlorides.
• This chlorination of the benzoic acids to the benzoyl chlorides can be carried out by standard processes for the production of acid chlorides, for example using thionyl chloride, phosphorus chlorides or oxalic acid dichloride in an inert solvent or dispersant or without a solvent.
• reaction of compounds of formula II or their activated derivatives with compounds of formula III can be carried out according to standard methods for the reaction of carboxylic acids or carboxylic acid derivatives with amines under reaction conditions which are well known to the person skilled in the art.
• the reaction is preferably carried out in an inert solvent or dispersant. If, for example, according to a preferred variant of this production process, the acid chloride of a compound of the formula II is used, it is preferred to work in an aprotic solvent or dispersant.
• solvents or dispersants are, for example, ethers such as diethyl ether, dipropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethylene glycol ether and di- and triethylene glycol ethers such as ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, esters such as ethyl acetate or
• amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acid amide, nit le such as acetonitrile, sulfoxides and sulfones such as dimethyl sulfoxide or sulfolane, hydrocarbons and chlorinated hydrocarbons such as gasoline fractions, benzene, t ⁇ luol, xylene or chlorobenzene, methylene chloride, methylene chloride, dichloromethane, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethane, methylene chloride, dichloromethan
• Water or alcohols such as methanol, ethanol, n-propanol, isopropanol or butanols. In general, mixtures of two or more solvents can also be used.
• a base for example a tertiary amine such as ethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine, which binds the hydrogen chloride formed.
• reaction time depends on the individual case, in general the reaction is complete after 1 to 10 hours.
• the course of the reaction can be monitored, for example, by chromatographic analysis of the reaction mixture.
• the resulting compounds of formula I can be isolated from the reaction mixture by customary work-up methods, for example by extraction, and, if desired, can be purified by means of customary purification methods, for example by crystallization, sublimation or by chromatography.
• phthalimides of the formula IV are reacted with organometallic compounds of the formula V, for example with organolithium compounds or with Grignard compounds.
• organometallic compounds of the formula V for example with organolithium compounds or with Grignard compounds.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings given above, M stands for example for Li or for MgCl, MgBr or Mgl. 14
• the starting substances of the formula IV can be prepared by or analogously to standard processes described in the literature, for example according to the information in Bahajaj and Vernon, J. Chem. Soc. Perkin Trans. 1 (1996) 1041, Boykin et al., J. Heterocycl. Chem. 28 (1991) 609 or Wanag, Chem. Ber. 75 (1942) 719.
• the organometallic compounds of the formula V are commercially available or can be known to those skilled in the art
• Methods are prepared, for example, by reacting an organic halogen compound with a metal such as magnesium or lithium or by Ummetallierung.
• the reaction of the phthalimides of the formula IV with the organometallic compounds of the formula V is generally carried out in an inert solvent or dispersant.
• Preferred solvents or dispersants are ethers such as diethyl ether, dipropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethylene glycol ether and di- and triethylene glycol ethers such as ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.
• other inert solvents can also be used, for example hydrocarbons such as pentane, hexane, heptane, benzene or toluene. Mixtures of two or more solvents can also be used.
• the compounds of the formulas IV and V are generally reacted at temperatures from -75 ° C. to +80 ° C.
• the cheapest reaction temperature 15 depends on the individual case, for example on the reactivity of the organometallic compound. In many cases it is favorable to first bring the reactants together at a lower temperature, for example at about -70 ° C. or at about 0 ° C., and then to complete the reaction, the reaction mixture to a higher temperature, for example room temperature or about 40 ° C. to heat.
• the resulting compounds of formula I can in turn be isolated from the reaction mixture by customary work-up processes, for example aqueous work-up with phase separation and / or extraction, and, if desired, can be purified by customary purification methods, for example by crystallization, sublimation or by chromatography.
• the compounds of the formula I according to the invention bring about an increase in the cGMP by activating the soluble guanylate cyclase (sGC). 16
• the activation of the sGC by the compounds of formula I can be examined, for example, in the activity assay described below.
• Cardiovascular diseases such as endothelial dysfunction , diastolic dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thrombosis, restenosis, myocardial infarction, strokes, heart failure or pulmonary hypertension, or for example erectile dysfunction, bronchial asthma, chronic renal failure and diabetes.
• cardiovascular diseases such as endothelial dysfunction , diastolic dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thrombosis, restenosis, myocardial infarction, strokes, heart failure or pulmonary hypertension, or for example erectile dysfunction, bronchial asthma, chronic renal failure and diabetes.
• Compounds of the formula I can also be used in the therapy of cirrhosis of the liver and to improve a reduced ability to learn or memory.
• the compounds of the formula I and their physiologically tolerable salts can thus be used on animals, preferably on mammals, and in particular on humans, as medicaments on their own, in mixtures with one another or in the form of pharmaceutical preparations.
• the present invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts for use as medicaments, their use for the normalization of a disturbed cGMP household and in particular their use in the therapy and prophylaxis of the above-mentioned clinical pictures, and their use for the preparation of medication for it.
• the present invention furthermore relates to pharmaceutical preparations which, as an active ingredient, contain an effective dose of at least one compound of the formula I and / or one physiologically 17 compatible salt and a common pharmaceutically acceptable carrier.
• the present invention also relates to the compounds of the formula I which are already known per se and in which R 1 is unsubstituted phenyl, R 2 , R 3 , R 4 , R 5 and R 7 are hydrogen and R 6 is unsubstituted phenyl or 3,4-Dimethoxyphenyl stands as activators of soluble guanylate cyclase. All of the above and the following statements regarding the pharmacological action and the use of the compounds of the formula I apply accordingly to these two compounds.
• the invention therefore also relates, for example, to these compounds in all their stereoisomeric forms and mixtures thereof in all ratios, and to their physiologically tolerable salts as pharmaceuticals and pharmaceutical preparations which contain an effective dose of at least one of these compounds and / or a physiologically acceptable salt and a conventional pharmaceutically acceptable carrier as active ingredient.
• the medicaments can be administered orally, for example in the form of pills, tablets, film-coated tablets, dragées, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories .
• administration can also take place parenterally, for example subcutaneously, intramuscularly or intravenously in the form of injection solutions or infusion solutions.
• Further possible forms of application are, for example, percutaneous or topical application, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or inhalative application in the form of nasal sprays or aerosol mixtures 1 or for example microcapsules, implants or rods.
• the preferred form of administration depends, for example, on the disease to be treated and its strength.
• the pharmaceutical preparations normally contain 0.5 to 90 percent by weight of the compounds of the formula I and / or their physiological content 18 compatible salts.
• the pharmaceutical preparations can be produced in a manner known per se. For this purpose, one or more compounds of formula I and / or their physiologically tolerable salts together with one or more solid or liquid galenic carriers and / or auxiliaries and, if desired, in combination with other active pharmaceutical ingredients with a therapeutic or prophylactic effect in a suitable administration form or Brought dosage form, which can then be used as a medicine in human medicine or veterinary medicine.
• Pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 200 mg, of active ingredient of the formula I and / or its physiologically tolerable salts per dose.
• Lactose, starch, for example corn starch, or starch derivatives, talc, stearic acid or its salts, etc. can be used for the production of, for example, pills, tablets, dragées and hard gelatin capsules.
• Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
• solutions for example injection solutions, or emulsions or syrups, for example, water, physiological saline, alcohols such as Ethanol, glycerin, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils etc.
• the compounds of the formula I and their physiologically tolerable salts can also be lyophilized and the lyophilisates obtained can be used, for example, for the production of injection preparations or infusion preparations.
• copolymers of glycolic acid and lactic acid are suitable as carriers for microcapsules, implants or rods.
• the pharmaceutical preparations according to the invention can also contain conventional additives, for example fillers, explosives, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colors, and flavors - Or flavoring, thickening, diluting agents, buffer substances, further solvents or 19
• conventional additives for example fillers, explosives, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colors, and flavors - Or flavoring, thickening, diluting agents, buffer substances, further solvents or 19
• Solubilizers or agents for achieving a depot effect salts for changing the osmotic pressure, coating agents or antioxidants.
• the dosage of the active ingredient of formula I to be administered and / or a physiologically tolerable salt thereof depends on the individual case and, as usual, must be adapted to the individual circumstances for an optimal effect. So it depends on the type and strength of the disease to be treated as well as on gender, age, weight and individual responsiveness of the person or animal to be treated, on the potency and duration of action of the compounds used, whether acute or chronic therapy or prophylaxis is, or whether in addition to compounds of formula I other active ingredients are administered.
• a daily dose of about 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, in particular 0.3 to 5 mg / kg (each mg per kg body weight) when administered to an approximately 75 kg adult to achieve the desired Effect appropriate.
• the daily dose can be administered in a single dose or, in particular when larger amounts are applied, divided into several, for example two, three or four, single doses. Depending on individual behavior, it may be necessary to deviate upwards or downwards from the specified daily dose.
• the compounds of formula I activate the soluble guanylate cyclase. Because of this property, they can be used not only as active pharmaceutical ingredients in human medicine and veterinary medicine, but also as a scientific tool or as an aid for biochemical investigations in which such an influencing of guanylate cyclase is intended, as well as for diagnostic purposes, for example in the in vitro diagnosis of Cell samples or tissue samples. Furthermore, as already mentioned above, the compounds of the formula I and their salts can serve as intermediates in the synthesis of further compounds, in particular for the preparation of further active pharmaceutical ingredients. 20th
• the oil obtained was purified by chromatography. It was eluted with a dichloromethane-methanol gradient (0 to 2% methanol). The product obtained as a colorless oil was foamed by co-evaporation with diethyl ether. Yield: 0.32 g. Mp: 119 ° C.
• sGC soluble guanylate cyclase
• GTP guanosine triphosphate
• cGMP cyclic guanosine monophosphate
• EIA enzyme immunoassay
• the sGC used had been isolated from bovine lung (see Methods in Enzymology, Volume 195, p. 377).
• the test solutions (100 ⁇ l per well) contained 50 mM triethanolamine (TEA) buffer (pH 7.5), 3 mM MgCl 2 , 3 mM reduced glutathione (GSH), 0.1 mM GTP, 1 mM 3-isobutyl-1-methylxanthine (IBMX ), suitably diluted enzyme solution as well as the test substance or solvent in the control tests.
• the test substances were dissolved in dimethyl sulfoxide (DMSO) and the solution was diluted with DMSO / water so that the final concentration of test substance in the test mixture was 50 ⁇ M.
• DMSO dimethyl sulfoxide
• DMSO concentration in the test mixture was 5% (v / v).
• the reaction was started by adding the sGC. The reaction mix was incubated for 15 to 20 minutes at 37 ° C. and then the reaction was stopped by ice cooling and addition of the stop reagent (50 mM EDTA, pH 8.0). An aliquot of 50 ⁇ l was removed and used to determine the cGMP content using the acetylation protocol of the Amersham cGMP-EIA kit. The absorption of the samples was measured at 450 nm (reference wavelength 620 nm) in a microtiter plate 30th
• Reading device measured.
• the cGMP concentration was determined using a calibration curve which was obtained under the same test conditions.
• Example 20 50 ⁇ M 8.2 fold B example 2299 5 500 ⁇ ⁇ MM 11.8 fold
• Example 33 50 ⁇ M 9.5 times A (comparison) 50 ⁇ M 2-fold

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• 1998
  • 1998-02-21 DE DE19807423A patent/DE19807423A1/de not_active Withdrawn
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