EP0873335A1 - HETEROCYCLYL-CONDENSED BENZOYLGUANIDINES, THEIR PRODUCTION AND USE AS INHIBITORS OF THE CELLULAR Na+/H+-ANTIPORTER - Google Patents

HETEROCYCLYL-CONDENSED BENZOYLGUANIDINES, THEIR PRODUCTION AND USE AS INHIBITORS OF THE CELLULAR Na+/H+-ANTIPORTER

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Publication number
EP0873335A1
EP0873335A1 EP96943131A EP96943131A EP0873335A1 EP 0873335 A1 EP0873335 A1 EP 0873335A1 EP 96943131 A EP96943131 A EP 96943131A EP 96943131 A EP96943131 A EP 96943131A EP 0873335 A1 EP0873335 A1 EP 0873335A1
Authority
EP
European Patent Office
Prior art keywords
dioxide
diaminomethylene
dihydro
carboxamide
carboxylic acid
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.)
Withdrawn
Application number
EP96943131A
Other languages
German (de)
French (fr)
Inventor
Manfred Baumgarth
Rolf Gericke
Klaus-Otto Minck
Norbert Beier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP0873335A1 publication Critical patent/EP0873335A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to cyclic sulfones of the formula I.
  • R2 each independently of one another H, A, CF 3 , CH 2 F, CHF 2 , 5 C 2 F 5 , shark, OH, OA, NH 2 , NHA, NA 2 , N0 2 or CN,
  • Re and R 7 each independently of one another H, A, R3, shark, OH, OA, SH, 5 SA, NH 2 , NHA or NA 2 or else
  • R7 and R ⁇ together also each form a bond, with a maximum of only one such bond being able to occur in each molecule;
  • R ⁇ and R9 are each independently H or A,
  • R3 is phenyl or benzyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, NH 2 , NHA, NA 2 , F, Cl, Br and / or CF 3 and
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the new compounds are inhibitors of the cellular Na + / H + antiporter, ie active substances that inhibit the NaVH + exchange mechanism of the cells (Düsing et al., Med. Klin. 8_Z, 378-384 ( 1992)) and thus represent good antiarrhythmics, which are particularly suitable for the treatment of arrhythmias that occur as a result of lack of oxygen.
  • the best-known active ingredient in the group of acylguanidines is amiloride. However, this substance primarily shows an antihypertensive and saluretic effect, which is particularly undesirable in the treatment of cardiac arrhythmia, while the antiarrhythmic properties are only very weak.
  • Benzoylguanidines are e.g. described in DE 44 04 183. However, the compounds described in the prior art are structurally distinctly different from those claimed here.
  • the invention relates to compounds of the formula I and their physiologically acceptable salts.
  • the substances according to the invention of the present application show a good cardioprotective effect and are therefore particularly suitable for the treatment of infarct, prophylaxis of the infarct and for the treatment of angina pectoris. Furthermore, the substances counteract all pathological hypoxic and ischemic damage, so that the diseases caused primarily or secondarily can be treated.
  • the active ingredients are also well suited for preventive applications.
  • the compounds can also be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, diabetic late complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias.
  • diseases caused by cell proliferation such as arteriosclerosis, diabetic late complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias.
  • the Substances for diagnostic use for the detection of diseases which are accompanied by increased activity of the Na + / H + antiporter for example in erythrocytes, thrombocytes or leukocytes.
  • the effects of the compounds can be determined with the aid of methods known per se, such as e.g. by N. Escobales and J. Figueroa in J. Membrane Biol. 120, 41-49 (1991) or by L Counillon, W. Scholz, HJ. Lang and J. Pouyssegur in Mol. Pharmacol. 44, 1041-1045 (1993).
  • Suitable experimental animals are e.g. Mice, rats, guinea pigs, dogs, cats, monkeys or pigs.
  • the compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediate products for the production of further active pharmaceutical ingredients.
  • A denotes a branched or unbranched alkyl group with 1-6, preferably 1-4, in particular 1, 2 or 3
  • C atoms in particular preferably methyl, further preferably ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methyl- pentyl).
  • Ri preferably denotes A, in particular methyl or ethyl, or hydrogen.
  • R2 is preferably hydrogen, while R3 is preferably phenyl or benzyl.
  • R ⁇ and Rs are preferably independently of one another H, methyl or ethyl.
  • R5 and Re or R? however, and R ⁇ can also each be a bond together, although it applies that only one such bond can be present per molecule.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following formulas Ia to Ig, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • the invention further relates to a process for the preparation of the compounds of the formula I according to claim 1, and of their salts, characterized in that a compound of the formula II
  • Q denotes Cl, Br, OA, O-CO-A, O-CO-Ph, OH or another reactive esterified OH group or easily nucleophilically substitutable leaving group
  • the compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons , Inc., New York; and in the above-mentioned patent application), under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • the starting materials can also be formed in situ, in such a way that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Compounds of the formula I are preferably prepared by reacting an activated carboxylic acid derivative of the formula II, where Q is particularly preferably Cl or -0-CH 3 , with guanidine.
  • Q is particularly preferably Cl or -0-CH 3
  • Methods in which intermediate isolation is unnecessary are, for example, activation with carbonyldiimidazole, dicyclohexylcarbodiimide or the Mukayama variant (Angew. Chem. 91, 788-812 (1979)).
  • the carboxylic acids of formula II and their derivatives used as intermediates can be prepared, for example, by
  • the cyclic sulfones obtained in this way can be further dervated or cyclized by customary methods.
  • Formula II with guanidine is carried out in a manner known per se, preferably in a protic or aprotic polar or non-polar inert organic solvent.
  • Suitable bases are preferably, for example, alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine or pyridine, which are also used in excess and can then simultaneously serve as solvents.
  • Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol are particularly suitable as inert solvents; Ethers such as diethyl ether, diisopropyl ether, THF or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Amides such as phosphoric acid hexamethyl triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1, 2-dichloroethane or carbon tetrachloride; Hydrocarbon
  • Particularly suitable solvents are methanol, THF, dimethoxyethane, dioxane, water or mixtures which can be prepared therefrom.
  • temperatures between 20 ° and the boiling point of the solvent are suitable as the reaction temperature.
  • the reaction times are between 5 minutes and 12 hours.
  • an acid scavenger in the reaction.
  • Any type of base that does not interfere with the reaction itself is suitable for this.
  • the use of inorganic bases such as potassium carbonate or of organic bases such as triethylamine or pyridine or an excess of guanidine is particularly suitable.
  • the compounds of the formula I can be obtained by removing them from their functional derivatives by solvolysis, in particular
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups, correspondingly protected groups
  • Contain amino and / or hydroxyl groups preferably those which, instead of an H atom which is connected to an N atom, carry an amino protecting group, in particular those which, instead of an HN group, have an R'-N- Carry a group in which R 'is an amino protecting group, and / or those which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I but carry an OR "group instead of an OH group, where R" denotes a hydroxyl protective group.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has occurred at another point on the Molecule has been carried out.
  • Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example 2,4-dinitrophenyl (DNP)), aralkoxymethyl (for example benzyloxymethyl (BOM)) or aralkyl groups (for example benzyl, 4-nitrobenzyl) , Triphenylmethyl).
  • acyl group is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular
  • Alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluoyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert.
  • alkanoyl such as acetyl, propionyl, butyryl
  • Aralkanoyl such as phenylacetyl
  • Aroyl such as benzoyl or toluoyl
  • Aryloxyalkanoyl such as phenoxyacetyl
  • Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-t
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule.
  • Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups.
  • the nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • Examples of hydroxyl protecting groups include tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.
  • the functional derivatives of the compounds of the formula I to be used as starting materials can be prepared by customary methods, such as those e.g. are described in the mentioned standard works and patent applications, e.g. by reacting compounds corresponding to formulas II and III, but at least one of these compounds contains a protective group instead of an H atom.
  • the liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - e.g. with strong acids, suitably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid.
  • strong acids suitably with trifluoroacetic acid or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids
  • benzene or p-toluenesulfonic acid strong organic carboxylic acids
  • the presence of an additional inert solvent is possible, but not always necessary.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol and water.
  • carboxylic acids such as acetic acid
  • ethers such as tetrahydrofuran (THF) or dioxane
  • amides such as dimethylformamide (DMF)
  • halogenated hydrocarbons such as dichloromethane
  • Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °; preferably one works between 15 and 30
  • the BOC group can, for example, preferably with 40% ' ⁇ ger trifluoroacetic acid in dichloromethane or using approximately 3 to 5 n HCl in dioxane at 15-60 ° Weden th pickspal-, the FMOC group using an approximately 5-20% solution of
  • the DNP group can be split off, e.g. also with an approximately 3-10% solution of 2-mercaptoethanol in DMF / water at 15-30 °.
  • Hydrogenolytically removable protective groups e.g. BOM, CBZ or
  • Benzyl can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, suitably on a support such as coal).
  • a catalyst e.g. a noble metal catalyst such as palladium, suitably on a support such as coal.
  • Suitable solvents are those given above, in particular e.g. Alcohols like methanol or ethanol or amides like DMF.
  • Hydrogenation is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. good on 5-10% Pd-C in methanol at 20-30 °.
  • a base of the formula I can also be converted into the associated acid addition salt using an acid.
  • Acids which provide physiologically acceptable salts are suitable for this reaction.
  • So inorganic acids can be used, for example sulfuric acid.
  • the compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (e.g. dinitrobenzoylphenylglycine) is also advantageous.
  • an optically active separating agent e.g. dinitrobenzoylphenylglycine
  • optically active compounds of the formula I by the methods described above by using starting materials (for example those of the formula II) which are already optically active.
  • the compounds of formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in a non-chemical way.
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredient (s).
  • the invention furthermore relates to compositions, in particular pharmaceutical preparations, comprising at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly.
  • tablets, dragees, capsules, syrups, juices or drops are used, for rectal use suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use, ointments, creams, pastes, Lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or their mixtures with one another and / or with water) or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.
  • Liposomal preparations are also particularly suitable for topical use.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or flavoring substances. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice and in the therapeutic treatment of the human or animal body and be used in combating diseases, in particular in the therapy and / or prophylaxis of disorders of the cardiovascular system. They are therefore suitable for the treatment of arrhythmias, in particular if they are caused by lack of oxygen, of angina pectoris, infarcts, ischemia of the nervous system such as, for example
  • the substances can also be used as therapeutic agents in diseases in which cell proliferation plays a role, such as arteriosclerosis, late diabetic complications, tumor diseases, fibrosis and organ hypertrophies and hyperplasias, in particular in prostate diseases.
  • the substances according to the invention are generally used in analogy to known antiarrhythmics, e.g. Aprindine administered, preferably in doses between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dosage unit.
  • the daily dosage is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg / kg body weight.
  • the specific dose for each particular patient depends on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on the rate of elimination , Drug combination and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • customary workup means:
  • 6-carbonyl chloride-1,1-dioxide [obtainable by reacting 1.9 g of 2,3-dihydro-3,5-dimethyl-1-benzothiophene-6-carboxylic acid-1,1-dioxide with 10 ml of thionyl chloride under Exclusion of moisture and stirring over 4 hours at the boil], added dropwise in 10 ml EDME. The reaction mixture is then allowed to cool to room temperature and is stirred 1
  • a guanidine solution prepared as described in Example 3 from 547 mg of sodium, 12 ml of methanol and 2.5 g of guanidine hydrochloride is mixed with 1.2 g of 2,3-dihydro-5-methyl-3-methylene-1- methyl benzothiophene-6-carboxylate-1,1-dioxide [prepared by cyclization of methyl 4-acetyl-2-methyl-5-methylsulfonylbenzoate and subsequent dehydration] and the mixture was boiled for one hour and then stirred for a further hour at room temperature and worked up as usual.
  • N-diaminomethylene-6-methyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide from 1,3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide the N-diaminomethylene-1,3-benzoxathiol-5-carboxamide-3,3-dioxide;
  • 1,1-dioxide the 7-N-diaminomethylene-carbamoyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile . Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • Example E tablets
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient .
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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  • Organic Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Cyclic sulphones of formula (I) are disclosed, in which: R?1 and R2¿ each independently of one another stand for H, A, CF¿3?, CH2F, CHF2, C2F5, Hal, OH, OA, NH2, NHA, NA2, NO2 or CN; X stands for CR?4R5¿, C=Z, O, S, NH, NA or NR3; Y stands for CR6R7, C=Z, O, NH, NA, or NR3; Z stands for O, S, NH, NA, NOH, NOA, CH¿2?, CHA or CA2; R?4, R5, R6 and R7¿ each independently of one another stand for H, A, R3, Hal, OH, OA, SH, SA, NH¿2?, NHA or NA2, or alternatively, R?5 and R6 or R7 and R8¿ can together represent a bond, only one such bond being present in each molecule; R?4 and R5¿ together can also stand for O-(CH¿2?)2-O or O-(CH2)3-O; R?8 and R9¿ each independently of one another stand for H or A; A stands for alkyl with 1-6 C atoms; Hal stands for F, Cl, Br or I; and R3 stands for phenyl or benzyl which is unsubstituted or single-, double- or triple-substituted by A, OA, NH¿2?, NHA, NA2, F, Cl, Br and/or CF3; and n is 0 or 1. Also disclosed are the physiologically tolerable salts of these compounds. These compounds and their salts have anti-arrhythmic properties and act as inhibitors of the cellular Na+/H+-antiporter.

Description

HETEROCYCLYLKONDENSIERTE BENZOYLGUANIDINE, DEREN HERSTELLUNG UND DEREN VERWENDUNG ALS INHIBITOREN DES ZELLULÄREN Na+/H+-ANTIPORTERSHETEROCYCLYL-CONDENSED BENZOYLGUANIDINE, THEIR PRODUCTION AND THE USE THEREOF AS INHIBITORS OF THE CELLULAR Na + / H + ANTIPORTER
Die Erfindung betrifft cyclische Sulfone der Formel IThe invention relates to cyclic sulfones of the formula I.
0 worin 0 where
und R2 jeweils unabhängig voneinander H, A, CF3, CH2F, CHF2, 5 C2F5, Hai, OH, OA, NH2, NHA, NA2, N02 oder CN,and R2 each independently of one another H, A, CF 3 , CH 2 F, CHF 2 , 5 C 2 F 5 , shark, OH, OA, NH 2 , NHA, NA 2 , N0 2 or CN,
CR6R7, C=Z, O, NH, NA oder NR3, 0CR6R7, C = Z, O, NH, NA or NR3, 0
O, S, NH, NA, NOH, NOA, CH2, CHA oder CA2l O, S, NH, NA, NOH, NOA, CH 2 , CHA or CA 2l
R4, R5-R 4 , R 5 -
Re und R7 jeweils unabhängig voneinander H, A, R3, Hai, OH, OA, SH, 5 SA, NH2, NHA oder NA2 oder aberRe and R 7 each independently of one another H, A, R3, shark, OH, OA, SH, 5 SA, NH 2 , NHA or NA 2 or else
Rs und R6 oderRs and R 6 or
R7 und Rβ jeweils zusammen auch eine Bindung, wobei in jedem 0 Molekül maximal nur eine derartige Bindung auftreten kann;R7 and R β together also each form a bond, with a maximum of only one such bond being able to occur in each molecule;
5 R4 und Rs zusammen auch O-(CH2)2-O oder O-(CH2)3-0,5 R4 and Rs together also O- (CH 2 ) 2 -O or O- (CH 2 ) 3 -0,
Rβ und R9 jeweils unabhängig voneinander H oder A,R β and R9 are each independently H or A,
A Alkyl mit 1 bis 6 C-Atomen,A alkyl with 1 to 6 carbon atoms,
Hai F, Cl, Br oder I undShark F, Cl, Br or I and
R3 unsubstituiertes oder ein-, zwei- oder dreifach durch A, OA, NH2, NHA, NA2, F, Cl, Br und/oder CF3 substituiertes Phenyl oder Benzyl undR3 is phenyl or benzyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, NH 2 , NHA, NA 2 , F, Cl, Br and / or CF 3 and
n 0 oder 1n 0 or 1
bedeuten,mean,
sowie deren physiologisch unbedenkliche Salze.and their physiologically acceptable salts.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wert- vollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstel¬ lung von Arzneimitteln verwendet werden können.The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
Es wurde gefunden, daß die Verbindungen der Formel I und ihre physio¬ logisch unbedenklichen Salze bei guter Verträglichkeit wertvolle pharma- kologische Eigenschaften besitzen.It has been found that the compounds of the formula I and their physiologically acceptable salts, with good tolerability, have valuable pharmacological properties.
Bei den neuen Verbindungen handelt es sich um Inhibitoren des zellulären Na+/H+-Antiporters, d.h. um Wirkstoffe, die den NaVH+-Austauschmecha- nismus der Zellen hemmen (Düsing et al., Med. Klin. 8_Z, 378-384 (1992)) und die somit gute Antiarrhythmika darstellen, die sich insbesondere zur Behandlung von Arrhythmien eignen, die als Folge von Sauerstoffmangel auftreten. Der bekannteste Wirkstoff der Gruppe der Acylguanidine ist Amilorid. Diese Substanz zeigt jedoch in erster Linie eine blutdrucksenkende und saluretische Wirkung, was insbesondere bei der Behandlung von Herz- Rhythmus-Störungen unerwünscht ist, während die antiarrhythmischen Eigenschaften nur sehr schwach ausgeprägt sind.The new compounds are inhibitors of the cellular Na + / H + antiporter, ie active substances that inhibit the NaVH + exchange mechanism of the cells (Düsing et al., Med. Klin. 8_Z, 378-384 ( 1992)) and thus represent good antiarrhythmics, which are particularly suitable for the treatment of arrhythmias that occur as a result of lack of oxygen. The best-known active ingredient in the group of acylguanidines is amiloride. However, this substance primarily shows an antihypertensive and saluretic effect, which is particularly undesirable in the treatment of cardiac arrhythmia, while the antiarrhythmic properties are only very weak.
Benzoylguanidine sind z.B. in DE 44 04 183 beschrieben. Die im Stand der Technik beschriebenen Verbindungen sind jedoch strukturell deutlich von den hier beanspruchten verschieden.Benzoylguanidines are e.g. described in DE 44 04 183. However, the compounds described in the prior art are structurally distinctly different from those claimed here.
Gegenstand der Erfindung sind Verbindungen der Formel I sowie ihre physiologisch unbedenklichen Salze.The invention relates to compounds of the formula I and their physiologically acceptable salts.
Die erfindungsgemäßen Substanzen der vorliegenden Anmeldung zeigen eine gute kardioprotektive Wirkung und eignen sich daher besonders zur Infarktbehandlung, Infarktprophylaxe und zur Behandlung von Angina pectoris. Ferner wirken die Substanzen allen pathologischen hypoxischen und ischämischen Schädigungen entgegen, so daß die dadurch primär oder sekundär verursachten Krankheiten behandelt werden können. Die Wirkstoffe sind ebenfalls für präventive Anwendungen gut geeignet.The substances according to the invention of the present application show a good cardioprotective effect and are therefore particularly suitable for the treatment of infarct, prophylaxis of the infarct and for the treatment of angina pectoris. Furthermore, the substances counteract all pathological hypoxic and ischemic damage, so that the diseases caused primarily or secondarily can be treated. The active ingredients are also well suited for preventive applications.
Aufgrund der protektiven Wirkungen dieser Substanzen bei pathologi¬ schen, hypoxischen oder ischämischen Situationen resultieren daraus weitere Anwendungsmöglichkeiten bei chirurgischen Eingriffen zum Schutz zeitweilig minderversorgter Organe, bei Organtransplantationen zum Schutz der entnommenen Organe, bei angioplastischen Gefäß- oder Herzeingriffen, bei Ischämien des Nervensystems, bei der Therapie von Schockzuständen und zur präventiven Behandlung der essentiellen Hypertonie.Because of the protective effects of these substances in pathological, hypoxic or ischemic situations, this results in further possible uses in surgical interventions to protect temporarily under-supplied organs, in organ transplants to protect the removed organs, in angioplasty vascular or cardiac interventions, in ischemia of the nervous system, in the Therapy of shock conditions and for the preventive treatment of essential hypertension.
Ferner können die Verbindungen auch als Therapeutika bei durch Zell- proliferation bedingten Erkrankungen wie Arteriosklerose, diabetische Spätkomplikationen, Tumorerkrankungen, fibrotischen Erkrankungen, insbesondere von Lunge, Leber und Nieren sowie Organhypertrophien und -hyperplasien, eingesetzt werden. Darüber hinaus eignen sich die Substanzen zur diagnostischen Anwendung zur Erkennung von Krank¬ heiten, die von einer gesteigerten Aktivität des Na+/H+-Antiporters z.B. in Erythrozyten, Thrombozyten oder Leukozyten begleitet werden.Furthermore, the compounds can also be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, diabetic late complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias. In addition, the Substances for diagnostic use for the detection of diseases which are accompanied by increased activity of the Na + / H + antiporter, for example in erythrocytes, thrombocytes or leukocytes.
Die Wirkungen der Verbindungen können mit Hilfe an sich bekannter Methoden ermittelt werden, wie sie z.B. von N. Escobales and J. Figueroa in J. Membrane Biol. 120, 41-49 (1991) oder von L Counillon, W. Scholz, HJ. Lang und J. Pouyssegur in Mol. Pharmacol. 44, 1041-1045 (1993) angegeben werden.The effects of the compounds can be determined with the aid of methods known per se, such as e.g. by N. Escobales and J. Figueroa in J. Membrane Biol. 120, 41-49 (1991) or by L Counillon, W. Scholz, HJ. Lang and J. Pouyssegur in Mol. Pharmacol. 44, 1041-1045 (1993).
Als Versuchstiere eignen sich z.B. Mäuse, Ratten, Meerschweinchen, Hunde, Katzen, Affen oder Schweine.Suitable experimental animals are e.g. Mice, rats, guinea pigs, dogs, cats, monkeys or pigs.
Die Verbindungen können daher als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin verwendet werden. Ferner können sie als Zwischen¬ produkte zur Herstellung weiterer Arzneimittelwirkstoffe Verwendung finden.The compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediate products for the production of further active pharmaceutical ingredients.
In den angegebenen Formeln bedeutet A eine verzweigte oder unver- zweigte Alkylgruppe mit 1-6, bevorzugt 1-4, insbesondere 1 , 2 oder 3In the formulas given, A denotes a branched or unbranched alkyl group with 1-6, preferably 1-4, in particular 1, 2 or 3
C-Atomen, im einzelnen vorzugsweise Methyl, ferner bevorzugt Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, weiterhin bevorzugt sek.-Butyl, tert.- Butyl, Pentyl, Isopentyl (3-Methylbutyl), Hexyl oder Isohexyl (4-Methyl- pentyl).C atoms, in particular preferably methyl, further preferably ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methyl- pentyl).
Ri bedeutet vorzugsweise A, insbesondere Methyl oder Ethyl, oder Wasserstoff.Ri preferably denotes A, in particular methyl or ethyl, or hydrogen.
R2 ist vorzugsweise Wasserstoff, während R3 vorzugsweise Phenyl oder Benzyl ist. X und Y sind jeweils unabhängig voneinander besonders bevorzugt -CH2-, -CH(CH3)-t -C(=CH2)-, -C(CH3)2-, -CH(OH)-,-COH(CH3)-, -C(OH)R3-, -C(OCH3)CH3-, -CH(OCH3)-, -C(OCH3)R3-, -CHCI-, -CH(NH2)-, -CH(NA2)-, -CH(CN)-, -CO-, -C(=NOH)-, -C(=NOA)-, -C(0-CH2-CH2-0)-, -S-, -O-, -NH-, -NA-, oder aber ferner auch bevorzugt X und Y zusammenR2 is preferably hydrogen, while R3 is preferably phenyl or benzyl. X and Y are each particularly preferably independently of one another -CH 2 -, -CH (CH 3 ) - t -C (= CH 2 ) -, -C (CH 3 ) 2 -, -CH (OH) -, - COH ( CH 3 ) -, -C (OH) R3-, -C (OCH 3 ) CH 3 -, -CH (OCH 3 ) -, -C (OCH 3 ) R 3 -, -CHCI-, -CH (NH 2 ) -, -CH (NA 2 ) -, -CH (CN) -, -CO-, -C (= NOH) -, -C (= NOA) -, -C (0-CH 2 -CH 2 -0 ) -, -S-, -O-, -NH-, -NA-, or further preferably X and Y together
-CH=CH-, -C(CH3)=CH-, -CH=C(CH3)-, =CH-CH2-, =C(CH3)-CH2- oder =CH-CH(CH3)-.-CH = CH-, -C (CH 3 ) = CH-, -CH = C (CH 3 ) -, = CH-CH 2 -, = C (CH 3 ) -CH 2 - or = CH-CH (CH 3 ) -.
Rβ und Rs sind vorzugsweise unabhängig voneinander H, Methyl oder Ethyl.R β and Rs are preferably independently of one another H, methyl or ethyl.
R5 und Re oder R? und Rβ können jedoch auch jeweils zusammen eine Bindung sein, wobei jedoch gilt, daß nur eine derartige Bindung je Molekül vorliegen kann.R5 and Re or R? however, and R β can also each be a bond together, although it applies that only one such bond can be present per molecule.
Hai bedeutet vorzugsweise F, CI oder Br.Shark preferably means F, CI or Br.
Allgemein gilt, daß sämtliche Reste wie z.B. A, die mehrfach im Molekül auftreten können, gleich oder verschieden, d.h. unabhängig voneinander sein können.In general, all residues such as e.g. A that can appear multiple times in the molecule, the same or different, i.e. can be independent of each other.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejeni¬ gen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die nachste¬ henden Formeln la bis Ig ausgedrückt werden, die der Formel I entspre¬ chen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedochAccordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following formulas Ia to Ig, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in la X und Y jeweils CH2 und n = 0 bedeuten;in la X and Y each represent CH 2 and n = 0;
in Ib n = 0 und X oder Y CH(CH3) und der jeweilig andere Restin Ib n = 0 and X or Y CH (CH 3 ) and the respective other radical
CH2 bedeutet; in lc X und Y zusammen -CH=CH-, -CH=C(CH3)-, -C(CH3)=CH-,Represents CH 2 ; in lc X and Y together -CH = CH-, -CH = C (CH 3 ) -, -C (CH 3 ) = CH-,
-CH2-C(=CH2)-, -C(=CH2)-CH2-, -C(CH3)2-CH2- oder -CH2- C(CH3)2- und n = 0 bedeuten;-CH 2 -C (= CH 2 ) -, -C (= CH 2 ) -CH 2 -, -C (CH 3 ) 2 -CH 2 - or -CH 2 - C (CH 3 ) 2 - and n = Mean 0;
in Id Y CH2 und X CHOH, C(CH3)OH, CR3OH, CHOCH3,in Id Y CH 2 and X CHOH, C (CH 3 ) OH, CR 3 OH, CHOCH 3 ,
CA(OCH3), CR3(OCH3), CHCI, CH(NH2), CH(NHA), CH(NA2), CH(CN). C=O, C(0-CH2CH2-0), C(=NOH) oder C(=NOA) sowie n = 0 bedeuten;CA (OCH 3 ), CR3 (OCH 3 ), CHCI, CH (NH 2 ), CH (NHA), CH (NA 2 ), CH (CN). C = O, C (0-CH 2 CH 2 -0), C (= NOH) or C (= NOA) and n = 0;
in le X = O, n = 0 und Y CH2, CH(CH3) oder C(CH3)2 bedeuten;in le X = O, n = 0 and Y are CH 2 , CH (CH 3 ) or C (CH 3 ) 2 ;
in If X = NH, NA oder NR3, Y CH2, CH(CH3) oder C(CH3)2 und n =in If X = NH, NA or NR 3 , Y CH 2 , CH (CH 3 ) or C (CH 3 ) 2 and n =
0 bedeuten;Mean 0;
in Ig die Einheit -(CRβR9)n-Y-X- für -CH2-CH=CH- oder -CH=CH-in Ig the unit - (CR β R9) n -YX- for -CH 2 -CH = CH- or -CH = CH-
CH2- steht.CH 2 - stands.
Ferner sind jene Verbindungen besonders bevorzugt, die die unter la bis If genannten bevorzugten Bedeutungen haben, bei denen aber n = 1 bedeutet und -CRβRs- vorzugsweise CH2, CH(CH3) oder C(CH3)2 ist.Furthermore, particular preference is given to those compounds which have the preferred meanings mentioned under Ia to If, but in which n = 1 and -CR β Rs- is preferably CH 2 , CH (CH 3 ) or C (CH 3 ) 2 .
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung der Verbindungen der Formel I gemäß Anspruch 1 , sowie von deren Salzen, dadurch gekennzeichnet, daß man eine Verbindung der Formel IIThe invention further relates to a process for the preparation of the compounds of the formula I according to claim 1, and of their salts, characterized in that a compound of the formula II
worin Ri, R2, Rβ, R9, x, Y und n die zuvor angegebenen Bedeutungen habenwherein Ri, R2, R β , R9, x, Y and n have the meanings given above
und Q Cl, Br, OA, O-CO-A, O-CO-Ph, OH oder eine andere reaktionsfähige veresterte OH-Gruppe bzw. leicht nucleophil substituierbare Abgangsgruppe bedeutet,and Q denotes Cl, Br, OA, O-CO-A, O-CO-Ph, OH or another reactive esterified OH group or easily nucleophilically substitutable leaving group,
mit Guanidin umsetzt,reacted with guanidine,
oder daß man eine sonst der Formel I entsprechende Verbindung, die jedoch anstelle eines oder mehrerer Wasserstoff atome eine oder mehrere reduzierbare Gruppe(n) und/oder eine oder mehrere zusätzliche C-C- und/oder C-N-Bindung(en) enthält, mit einem reduzierenden Mittel behandelt,or that a compound which otherwise corresponds to the formula I, but which instead of one or more hydrogen atoms contains one or more reducible group (s) and / or one or more additional CC and / or CN bond (s), with a reducing compound Treated means
oder daß man eine sonst der Formel I entsprechende Verbindung, die jedoch anstelle eines oder mehrerer Wasserstoffatome eine oder mehrere solvolysierbare Gruppe(n) enthält, mit einem solvolysierenden Mittel behandeltor that a compound otherwise corresponding to formula I, which, however, contains one or more solvolysable group (s) instead of one or more hydrogen atoms, is treated with a solvolysing agent
und/oder daß man eine erhaltene Base der Formel I durch Behandeln mit einer Säure in eines ihrer Salze umwandelt.and / or that a base of formula I obtained is converted into one of its salts by treatment with an acid.
Die Verbindungen der Formel I werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme- Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; sowie in der oben angegebenen Patentanmeldung) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.The compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons , Inc., New York; and in the above-mentioned patent application), under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe können gewünschtenfalls auch in situ gebildet wer¬ den, derart, daß man sie aus dem Reaktionsgemisch nicht isoliert, son¬ dern sofort weiter zu den Verbindungen der Formel I umsetzt. Vorzugsweise werden Verbindungen der Formel I hergestellt, indem man ein aktiviertes Carbonsäurederivat der Formel II, wobei Q besonders be¬ vorzugt Cl oder -0-CH3 ist, mit Guanidin umsetzt. Besonders geeignet sind auch Reaktionsvarianten, bei denen die freie Carbonsäure II (Q = OH) in an sich bekannter Weise zu dem jeweiligen aktivierten Derivat um¬ gesetzt und dieses dann direkt, ohne Zwischenisolierung, mit Guanidin zur Reaktion gebracht wird. Methoden, bei denen eine Zwischenisolierung entbehrlich ist, sind beispielsweise eine Aktivierung mit Carbonyldiimida- zol, Dicyclohexylcarbodiimid oder die Mukayama-Variante (Angew. Chem. 91, 788-812 (1979)).If desired, the starting materials can also be formed in situ, in such a way that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. Compounds of the formula I are preferably prepared by reacting an activated carboxylic acid derivative of the formula II, where Q is particularly preferably Cl or -0-CH 3 , with guanidine. Also particularly suitable are reaction variants in which the free carboxylic acid II (Q = OH) is converted to the respective activated derivative in a manner known per se and this is then reacted directly with guanidine, without intermediate isolation. Methods in which intermediate isolation is unnecessary are, for example, activation with carbonyldiimidazole, dicyclohexylcarbodiimide or the Mukayama variant (Angew. Chem. 91, 788-812 (1979)).
Die als Zwischenstufen verwendeten Carbonsäuren der Formel II und deren Derivate lassen sich beispielsweise herstellen durchThe carboxylic acids of formula II and their derivatives used as intermediates can be prepared, for example, by
(a) basenkatalysiertee intramolekulare Cyclisierung von 3-Methyl- sulfonylbenzoesäuren oder -derivaten, die in 4-Stellung eine Carbonyl- oder Cyangruppe tragen, z.B.(a) base catalyzed intramolecular cyclization of 3-methylsulfonylbenzoic acids or derivatives bearing a carbonyl or cyano group in the 4-position, e.g.
(b) Heck-Reaktion geeigneter 3-Alkenylsulfonyl-4-brombenzoesäure- derivate, z.B. (b) Heck reaction of suitable 3-alkenylsulfonyl-4-bromobenzoic acid derivatives, for example
Heck-ReaktionHeck reaction
(Heck-Reaktion s. z.B. Org. React. 27, 345 (1982))(Heck reaction see e.g. Org. React. 27, 345 (1982))
(c) intramolekulare nucleophile Substitution von 4-Halogenbenzoe- säuren oder -derivaten, die in 3-Stellung einen geeigneten Hydroxy-, Amino- oder Mercaptoalkylsulfonyl-Rest (R) tragen, z.B.(c) intramolecular nucleophilic substitution of 4-halobenzoic acids or derivatives bearing a suitable hydroxy, amino or mercaptoalkylsulfonyl radical (R) in the 3-position, e.g.
(d) Oxidation cyclischer Sulfide der allgemeinen Formel(d) Oxidation of cyclic sulfides of the general formula
(e) Addition von Carbonylverbindungen an Mercaptophenole oder -an iline und anschließende Oxidation oder(e) addition of carbonyl compounds to mercaptophenols or anilines and subsequent oxidation or
Die angegebenen Reaktionen sind Standardreaktionen der Organischen Chemie und werden beispielsweise in J. March, Adv. Org. Chemistry, 3rd. Ed., John Wiley & Sons (1985) beschrieben.The reactions given are standard reactions in organic chemistry and are described, for example, in J. March, Adv. Org. Chemistry, 3rd. Ed., John Wiley & Sons (1985).
Die so erhaltenen cyclischen Sulfone lassen sich nach üblichen Methoden weiter dervatisieren oder cyclisieren.The cyclic sulfones obtained in this way can be further dervated or cyclized by customary methods.
Die Umsetzung eines reaktionsfähigen Carbonsäurederivates derThe implementation of a reactive carboxylic acid derivative
Formel II mit Guanidin erfolgt in an sich bekannter Weise vorzugsweise in einem protischen oder aprotischen polaren oder unpolaren inerten organischen Lösungsmittel.Formula II with guanidine is carried out in a manner known per se, preferably in a protic or aprotic polar or non-polar inert organic solvent.
Eine bevorzugte Variante besteht allerdings auch darin, daß man dieA preferred variant is, however, that the
Reaktionspartner direkt, ohne Zusatz eines Lösungsmittels, miteinander zur Reaktion bringt.Reacting reactants directly with one another without the addition of a solvent.
Bei der Herstellung von II oder bei der Umsetzung von II mit Guanidin ist es ebenfalls zweckmäßig, in Gegenwart einer Base oder mit einem Über¬ schuß der basischen Komponente zu arbeiten. Als Basen eignen sich bevorzugt z.B. Alkalimetall- oder Erdalkalimetallhydroxide, -carbonate, -alkoholate oder organische Basen wie Triethylamin oder Pyridin, die auch im Überschuß angewendet werden und dann gleichzeitig als Lösungs- mittel dienen können. Als inerte Lösungsmittel eignen sich insbesondere Alkohole wie Methanol, Ethanol, Isopropanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, THF oder Dioxan; Glykolether wie Ethylenglykolmono- methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylen- glykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Nitrile wie Acetonitril; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat; Amide wie Phosphorsäurehexamethyltriamid; Sulfoxide wie Dimethylsulfoxid (DMSO); chlorierte Kohlenwasserstoffe wie Dichlor¬ methan, Chloroform, Trichlorethylen, 1 ,2-Dichlorethan oder Kohlenstoff- tetrachlorid; Kohlenwasserstoffe wie Benzol, Toluol oder Xylol. Weiterhin eignen sich Gemische dieser Lösungsmittel untereinander.In the preparation of II or in the reaction of II with guanidine, it is also expedient to work in the presence of a base or with an excess of the basic component. Suitable bases are preferably, for example, alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine or pyridine, which are also used in excess and can then simultaneously serve as solvents. Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol are particularly suitable as inert solvents; Ethers such as diethyl ether, diisopropyl ether, THF or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Amides such as phosphoric acid hexamethyl triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1, 2-dichloroethane or carbon tetrachloride; Hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.
Besonders geeignete Lösungsmittel sind Methanol, THF, Dimethoxyethan, Dioxan, Wasser oder daraus herstellbare Gemische. Als Reaktions- temperatur sind beispielsweise Temperaturen zwischen 20° und dem Siedepunkt des Lösungsmittels geeignet. Die Reaktionszeiten liegen zwischen 5 Min. und 12 Std.. Es ist zweckmäßig, bei der Reaktion einen Säurefänger einzusetzen. Hierzu eignen sich jeglische Arten von Basen, die die Reaktion selbst nicht stören. Besonders geeignet ist jedoch die Verwendung von anorganischen Basen wie Kaliumcarbonat oder von organischen Basen wie Triethylamin oder Pyridin oder aber ein Überschuß des Guanidins.Particularly suitable solvents are methanol, THF, dimethoxyethane, dioxane, water or mixtures which can be prepared therefrom. For example, temperatures between 20 ° and the boiling point of the solvent are suitable as the reaction temperature. The reaction times are between 5 minutes and 12 hours. It is advisable to use an acid scavenger in the reaction. Any type of base that does not interfere with the reaction itself is suitable for this. However, the use of inorganic bases such as potassium carbonate or of organic bases such as triethylamine or pyridine or an excess of guanidine is particularly suitable.
Weiterhin können die Verbindungen der Formel I erhalten werden, indem man sie aus ihren funktionellen Derivaten durch Solvolyse, insbesondereFurthermore, the compounds of the formula I can be obtained by removing them from their functional derivatives by solvolysis, in particular
Hydrolyse, oder durch Hydrogenolyse in Freiheit setzt.Hydrolysis, or released by hydrogenolysis.
Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die sonst der Formel I entsprechen, aber anstelle einer oder meh- rerer freier Amino- und/oder Hydroxygruppen entsprechende geschütztePreferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups, correspondingly protected groups
Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die an¬ stelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Amino¬ schutzgruppe tragen, insbesondere solche, die anstelle einer HN-Gruppe eine R'-N-Gruppe tragen, worin R' eine Aminoschutzgruppe bedeutet, und/oder solche, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z.B. solche, die der Formel I entsprechen, jedoch anstelle einer OH-Gruppe eine OR"-Gruppe tragen, worin R" eine Hydroxyschutzgruppe bedeutet.Contain amino and / or hydroxyl groups, preferably those which, instead of an H atom which is connected to an N atom, carry an amino protecting group, in particular those which, instead of an HN group, have an R'-N- Carry a group in which R 'is an amino protecting group, and / or those which carry a hydroxyl protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I but carry an OR "group instead of an OH group, where R" denotes a hydroxyl protective group.
Es können auch mehrere - gleiche oder verschiedene - geschützte Amino- und/oder Hydroxygruppen im Molekül des Ausgangsstoffes vorhanden sein. Falls die vorhandenen Schutzgruppen voneinander verschieden sind, können sie in vielen Fällen selektiv abgespalten werden.Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.
Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Umset¬ zungen zu schützen (zu blockieren), die aber leicht entfernbar sind, nach¬ dem die gewünschte chemische Reaktion an einer anderen Stelle des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind insbe¬ sondere unsubstituierte oder substituierte Acyl-, Aryl- (z.B. 2,4-Dinitro- phenyl (DNP)), Aralkoxymethyl- (z.B. Benzyloxymethyl (BOM)) oder Aral- kylgruppen (z.B. Benzyl, 4-Nitrobenzyl, Triphenylmethyl). Da die Amino- schutzgruppen nach der gewünschten Reaktion (oder Reaktionsfolge) entfernt werden, ist ihre Art und Größe im übrigen nicht kritisch; bevorzugt werden jedoch solche mit 1-20, insbesondere 1-8 C-Atomen. Der Ausdruck "Acylgruppe" ist im Zusammenhang mit dem vorliegenden Verfahren im weitesten Sinne aufzufassen. Er umschließt von aliphati¬ schen, araliphatischen, aromatischen oder heterocyclischen Carbon- säuren oder Sulfonsäuren abgeleitete Acylgruppen sowie insbesondereThe term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has occurred at another point on the Molecule has been carried out. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example 2,4-dinitrophenyl (DNP)), aralkoxymethyl (for example benzyloxymethyl (BOM)) or aralkyl groups (for example benzyl, 4-nitrobenzyl) , Triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular
Alkoxycarbonyl-, Aryloxycarbonyl- und vor allem Aralkoxycarbonyl- gruppen. Beispiele für derartige Acylgruppen sind Alkanoyl wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Benzoyl oder Toluoyl; Aryloxyalkanoyl wie Phenoxyacetyl; Alkoxycarbonyl wie Methoxy- carbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, Isopropoxy- carbonyl, tert. -Butoxycarbonyl (BOC), 2-Jodethoxycarbonyl; Aralkyloxy- carbonyl wie Benzyloxycarbonyl (CBZ), 4-Methoxybenzyloxycarbonyl, 9-Fluorenylmethoxycarbonyl (FMOC). Bevorzugte Aminoschutzgruppen sind BOC, DNP und BOM, ferner CBZ, Benzyl und Acetyl. Der Ausdruck "Hydroxyschutzgruppe" ist ebenfalls allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Hydroxygruppe vor chemischen Umsetzungen zu schützen, die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an einer anderen Stelle des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind die oben genannten unsubstituierten oder substituierten Aryl-, Aralkyl- oder Acylgruppen, ferner auch Alkylgruppen. Die Natur und Größe der Hydroxy- schutzgruppen ist nicht kritisch, da sie nach der gewünschten chemischen Reaktion oder Reaktionsfolge wieder entfernt werden; bevorzugt sind Gruppen mit 1-20, insbesondere 1-10 C-Atomen. Beispiele für Hydroxy- schutzgruppen sind u.a. tert.-Butyl, Benzyl, p-Nitrobenzyl, p-Toluol- sulfonyl und Acetyl, wobei Benzyl und Acetyl besonders bevorzugt sind.Alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluoyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert. -Butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl. The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxyl protecting groups include tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.
Die als Ausgangsstoffe zu verwendenden funktionellen Derivate der Verbindungen der Formel I können nach üblichen Methoden hergestellt werden, wie sie z.B. in den genannten Standardwerken und Patent¬ anmeldungen beschrieben sind, z.B. durch Umsetzung von Verbindungen, die den Formeln II und III entsprechen, wobei jedoch mindestens eine dieser Verbindungen eine Schutzgruppe anstelle eines H-Atoms enthält.The functional derivatives of the compounds of the formula I to be used as starting materials can be prepared by customary methods, such as those e.g. are described in the mentioned standard works and patent applications, e.g. by reacting compounds corresponding to formulas II and III, but at least one of these compounds contains a protective group instead of an H atom.
Das In-Freiheit-Setzen der Verbindungen der Formel I aus ihren funktio¬ nellen Derivaten gelingt - je nach der benutzten Schutzgruppe - z.B. mit starken Säuren, zweckmäßig mit Trifluoressigsäure oder Perchlorsäure, aber auch mit anderen starken anorganischen Säuren wie Salzsäure oder Schwefelsäure, starken organischen Carbonsäuren wie Trichloressigsäure oder Sulfonsäuren wie Benzol- oder p-Toluolsulfonsäure. Die Anwesenheit eines zusätzlichen inerten Lösungsmittels ist möglich, aber nicht immer erforderlich.The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - e.g. with strong acids, suitably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.
Als inerte Lösungsmittel eignen sich vorzugsweise organische, beispiels¬ weise Carbonsäuren wie Essigsäure, Ether wie Tetrahydrofuran (THF) oder Dioxan, Amide wie Dimethylformamid (DMF), halogenierte Kohlen¬ wasserstoffe wie Dichlormethan, ferner auch Alkohole wie Methanol, Ethanol oder Isopropanol sowie Wasser. Ferner kommen Gemische der vorgenannten Lösungsmittel in Frage. Trifluoressigsäure wird vorzugs¬ weise im Überschuß ohne Zusatz eines weiteren Lösungsmittels verwen¬ det, Perchlorsäure in Form eines Gemisches aus Essigsäure und 70%iger Perchlorsäure im Verhältnis 9:1. Die Reaktionstemperaturen für die Spal- tung liegen zweckmäßig zwischen etwa 0 und etwa 50°; vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol and water. There are also mixtures of aforementioned solvents in question. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °; preferably one works between 15 and 30 ° (room temperature).
Die BOC-Gruppe kann z.B. bevorzugt mit 40%'ιger Trifluoressigsäure in Dichlormethan oder mit etwa 3 bis 5 n HCl in Dioxan bei 15-60° abgespal- ten weden, die FMOC-Gruppe mit einer etwa 5-20%igen Lösung vonThe BOC group can, for example, preferably with 40% 'ιger trifluoroacetic acid in dichloromethane or using approximately 3 to 5 n HCl in dioxane at 15-60 ° Weden th abgespal-, the FMOC group using an approximately 5-20% solution of
Dimethylamin, Diethylamin oder Piperidin in DMF bei 15-50°. Eine Abspal¬ tung der DNP-Gruppe gelingt z.B. auch mit einer etwa 3-10%igen Lösung von 2-Mercaptoethanol in DMF/Wasser bei 15-30°.Dimethylamine, diethylamine or piperidine in DMF at 15-50 °. The DNP group can be split off, e.g. also with an approximately 3-10% solution of 2-mercaptoethanol in DMF / water at 15-30 °.
Hydrogenolytisch entfernbare Schutzgruppen (z.B. BOM, CBZ oderHydrogenolytically removable protective groups (e.g. BOM, CBZ or
Benzyl) können z.B. durch Behandeln mit Wasserstoff in Gegenwart eines Katalysators (z.B. eines Edelmetallkatalysators wie Palladium, zweck¬ mäßig auf einem Träger wie Kohle) abgespalten werden. Als Lösungs¬ mittel eignen sich dabei die oben angegebenen, insbesondere z.B. Alkohole wie Methanol oder Ethanol oder Amide wie DMF. Die Hydro¬ genolyse wird in der Regel bei Temperaturen zwischen etwa 0 und 100° und Drucken zwischen etwa 1 und 200 bar, bevorzugt bei 20-30° und 1-10 bar durchgeführt. Eine Hydrogenolyse der CBZ-Gruppe gelingt z.B. gut an 5-10%igem Pd-C in Methanol bei 20-30°.Benzyl) can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, suitably on a support such as coal). Suitable solvents are those given above, in particular e.g. Alcohols like methanol or ethanol or amides like DMF. Hydrogenation is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. good on 5-10% Pd-C in methanol at 20-30 °.
Eine Base der Formel I kann ferner mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden. Für diese Umsetzung kommen Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure. Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsaure, Phosphorsäuren wie Orthophosphorsäure, Sulfa- minsäure, ferner organische Säuren, insbesondere aliphatische, alicycli- sche, araliphatische, aromatische oder heterocyclische ein- oder mehr- basige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essig¬ säure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bern¬ steinsäure, Pimelinsäure, Fumarsaure, Maleinsäure, Milchsäure, Wein¬ säure, Äpfelsäure, Benzoesäure, Salicylsäure, 2- oder 3-Phenylpropion- säure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonico- tinsäure, Methan- oder Ethansulf onsäure, Ethandisulf onsäure, 2-Hydroxy- ethansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Naphthalin- mono- und -disulfonsäuren, Laurylschwefelsäure.A base of the formula I can also be converted into the associated acid addition salt using an acid. Acids which provide physiologically acceptable salts are suitable for this reaction. So inorganic acids can be used, for example sulfuric acid. Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly- basic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3 -Phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfonic acid.
Die Verbindungen der Formel I enthalten ein oder mehrere chirale Zentren und können daher in racemischer oder in optisch- aktiver Form vorliegen. Erhaltene Racemate können nach an sich bekannten Methoden mecha¬ nisch oder chemisch in die Enantiomeren getrennt werden. Vorzugsweise werden aus dem racemischen Gemisch durch Umsetzung mit einem optisch-aktiven Trennmittel Diastereomere gebildet. Als Trennmittel eig¬ nen sich z.B. optisch aktive Säuren, wie die D- und L-Formen von Wein¬ säure, Diacetylweinsäure, Dibenzoylweinsäure, Mandelsäure, Äpfelsäure, Milchsäure oder die verschiedenen optisch-aktiven Camphersulfonsäuren wie ß-Camphersulfonsäure. Vorteilhaft ist auch eine Enantiomerentren- nung mit Hilfe einer mit einem optisch aktiven Trennmittel (z.B. Dinitro- benzoylphenyl-glycin) gefüllten Säule.The compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (e.g. dinitrobenzoylphenylglycine) is also advantageous.
Natürlich ist es auch möglich, optisch-aktive Verbindungen der Formel I nach den oben beschriebenen Methoden zu erhalten, indem man Ausgangsstoffe (z.B. solche der Formell II) verwendet, die bereits optisch¬ aktiv sind.Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials (for example those of the formula II) which are already optically active.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können zur Herstellung pharmazeutischer Zubereitungen verwendet werden, insbesondere auf nicht-chemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoff(en) in eine geeignete Dosierungsform ge¬ bracht werden. Gegenstand der Erfindung sind ferner Mittel, insbesondere pharmazeuti¬ sche Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The compounds of formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in a non-chemical way. Here, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredient (s). The invention furthermore relates to compositions, in particular pharmaceutical preparations, comprising at least one compound of the formula I and / or one of its physiologically acceptable salts.
Diese Zubereitungen können als Arzneimittel in der Human- oder Veteri¬ närmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbin¬ dungen nicht reagieren, beispielsweise Wasser, pflanzliche öle, Benzyl- alkohole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlenhydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Lanolin, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugsweise ölige oder wässerige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes, Pasten, Lotionen, Gele, Sprays, Schäume, Aerosole, Lösungen (z.B. Lösungen in Alkoholen wie Ethanol oder Isopropanol, Acetonitril, DMF, Dimethylacetamid, 1,2-Propandiol oder deren Gemischen untereinander und/oder mit Wasser) oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyo- philisate z.B. zur Herstellung von Injektionspräparaten verwendet werden.These preparations can be used as pharmaceuticals in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly. For oral use, tablets, dragees, capsules, syrups, juices or drops are used, for rectal use suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use, ointments, creams, pastes, Lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or their mixtures with one another and / or with water) or powder. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.
Insbesondere für die topische Anwendung kommen auch liposomale Zubereitungen in Betracht. Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabi- lisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotisches Druckes, Puffersubstanzen, Färb-, Geschmacks- und/oder Aromastoffe enthalten. Sie können, falls erwünscht, auch einen oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.Liposomal preparations are also particularly suitable for topical use. The specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or flavoring substances. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.
Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können an Menschen oder Tiere, insbesondere Säugetiere wie Affen, Hunde, Katzen, Ratten oder Mäuse verabreicht und bei der thera¬ peutischen Behandlung des menschlichen oder tierischen Körpers sowie bei der Bekämpfung von Krankheiten verwendet werden, insbesondere bei der Therapie und/oder Prophylaxe von Störungen des cardiovasculären Systems. Sie eignen sich daher zur Behandlung von Arrhythmien, ins¬ besondere wenn diese durch Sauerstoffmangel hervorgerufen werden, von Angina pectoris, Infarkten, Ischämien des Nervensystems wie z.B.The compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice and in the therapeutic treatment of the human or animal body and be used in combating diseases, in particular in the therapy and / or prophylaxis of disorders of the cardiovascular system. They are therefore suitable for the treatment of arrhythmias, in particular if they are caused by lack of oxygen, of angina pectoris, infarcts, ischemia of the nervous system such as, for example
Schlaganfall oder Hirnödeme, von Schockzuständen und zur Präventiv¬ behandlung.Stroke or cerebral edema, from shock and for preventive treatment.
Die Substanzen können ferner als Therapeutika bei Erkrankungen einge- setzt werden, bei denen Zeilproliferationen eine Rolle spielen wie Arterio- sklerose, diabetische Spätkomplikationen, Tumorerkrankunken, Fibrösen sowie Organhypertrophien und -hyperplasien, insbesondere bei Erkran¬ kungen der Prostata.The substances can also be used as therapeutic agents in diseases in which cell proliferation plays a role, such as arteriosclerosis, late diabetic complications, tumor diseases, fibrosis and organ hypertrophies and hyperplasias, in particular in prostate diseases.
Dabei werden die erfindungsgemäßen Substanzen in der Regel in Analo¬ gie zu bekannten Antiarrhythmika, z.B. Aprindin, verabreicht, vorzugs¬ weise in Dosierungen zwischen etwa 0,01 und 5 mg, insbesondere zwi¬ schen 0,02 und 0,5 mg pro Dosierungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,0001 und 0,1 , insbesondere zwischen 0,0003 und 0,01 mg/kg Körpergewicht. Die spezielle Dosis für jeden bestimmten Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbin¬ dung, vom Alter, Körpergewicht, dem allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabfolgungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.The substances according to the invention are generally used in analogy to known antiarrhythmics, e.g. Aprindine administered, preferably in doses between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dosage unit. The daily dosage is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg / kg body weight. However, the specific dose for each particular patient depends on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on the rate of elimination , Drug combination and severity of the respective disease to which the therapy applies. Oral application is preferred.
In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung":In the examples below, "customary workup" means:
Man gibt, falls erforderlich, Wasser hinzu, extrahiert mit einem organi¬ schen Lösungsmittel wie Ethylacetat, trennt die organische Phase ab, trocknet die organische Phase über Natriumsulfat, filtriert, dampft ein und reinigt durch Chromatographie und/oder Kristallisation. Beispiel 1If necessary, water is added, extracted with an organic solvent such as ethyl acetate, the organic phase is separated off, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography and / or crystallization. example 1
Man trägt unter Stickstoff-Atmosphäre, Rühren und Feuchtigkeitsaus¬ schluß 1 ,9 g Natrium in 40 ml getrocknetes Methanol ein. Die erhaltende Lösung wird bei Raumtemperatur mit 8,7 g Guanidin-hydrochlorid versetzt und 30 Minuten gerührt. Die Suspension wird filtiert, das Filtrat mit 4 g 2,3- Dihydro-3-hydroxy-1 -benzothiophen-6-carbonsäuremethylester-1 , 1 -dioxid [erhältlich durch Natriummethylat-Cyclisierung und anschließende Säure¬ behandlung von 3-Methylsulfonyl-4-cyan-benzoesäuremethylester sowie Natriumborhydrid-Reduktion des erhaltenen Ketons] versetzt und 3 Stun¬ den bei 50° gerührt. Anschließend wird die Reaktionsmischung unter Eis¬ kühlung mit Wasser versetzt, mit Natriumchlorid gesättigt und mit Essig¬ saureethylester extrahiert. Nach üblicher Aufarbeitung erhält man das N-Diaminomethylen-2,3-dihydro-3-hydroxy-1-benzothiophen-6-carbox- amid-1 ,1 -dioxid, F. 240-241°. Durch Behandlung mit Methansulfonsäure in1.9 g of sodium are added to 40 ml of dried methanol under a nitrogen atmosphere, with stirring and with the exclusion of moisture. 8.7 g of guanidine hydrochloride are added to the resulting solution at room temperature and the mixture is stirred for 30 minutes. The suspension is filtered, the filtrate with 4 g of 2,3-dihydro-3-hydroxy-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide [obtainable by sodium methylate cyclization and subsequent acid treatment of 3-methylsulfonyl-4 -cyano-benzoic acid methyl ester and sodium borohydride reduction of the ketone obtained] and stirred for 3 hours at 50 °. The reaction mixture is then mixed with water while cooling with ice, saturated with sodium chloride and extracted with ethyl acetate. After the usual work-up, the N-diaminomethylene-2,3-dihydro-3-hydroxy-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 240-241 °. By treatment with methanesulfonic acid in
Methanol erhält man das entsprechende Methansulfonat, F. 204-206 °.Methanol gives the corresponding methanesulfonate, mp 204-206 °.
Analog erhält manYou get analog
aus 2,3-Dihydro-3-hydroxy-5-methyl-1 -benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxy-5-methyl-1 -benzothiophen- 6-carboxamid-1 ,1 -dioxid, Methansulfonat: F. 266-267° (aus Methanol);N-diaminomethylene-2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, methanesulfonate: mp 266-267 ° (from methanol);
aus 2,3-Dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid, F. 243-245°, Methansulfonat: F. 214- 216°.N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 243-245 °, methanesulfonate: mp 214-216 °.
aus 2,3-Dihydro-3-hydroxy-3-ethyl-5-methyl-1-benzothiophen-6- carbonsäure methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-hydroxy-3-ethyl-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxy-3-methyl-5-ethyl-1-benzo- thiophen-6-carboxamid-1 ,1 -dioxid, F. 126-128°, Methansulfonat: 218- 220°; aus 2,3-Dihydro-3-hydroxy-5-ethyl-1 -benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasN-diaminomethylene-2,3-dihydro-3-hydroxy-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 126-128 °, methanesulfonate: 218-220 °; from 2,3-dihydro-3-hydroxy-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxy-5-ethyl-1-benzo- thiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-hydroxy-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-hydroxy-2,2,5-trimethyl-1 -benzothiophen-6- carbonsäure-methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxy-2,2,5-trimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxy-2,2,5-trimethyl-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid, F. 253°, Methansulfonat: 262-263°;N-diaminomethylene-2,3-dihydro-3-hydroxy-2,2,5-trimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 253 °, methanesulfonate: 262-263 °;
aus 2,3-Dihydro-3-chlor-3-methyl-5-ethyl-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-chloro-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,3-dihydro-3-chlor-3-methyl-5-ethyl-1-benzo- thiophen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-chloro-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-chlor-5-ethyI-1 -benzothiophen-6-carbonsäure methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-chloro-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-chlor-5-ethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-chloro-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-chlor-1-benzothiophen-6-carbonsäure methylester-1 ,1 - dioxid dasfrom 2,3-dihydro-3-chloro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 - dioxide the
N-Diaminomethylen-2,3-dihydro-3-chlor-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-chloro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-chlor-3-methyl-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-chloro-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-chlor-3-methyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-chloro-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-cyan-5-methyl-1 -benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-cyan-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-cyan-5-methyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid; aus 2,3-Dihydro-3-cyan-3-methyl-5-ethyl-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasN-diaminomethylene-2,3-dihydro-3-cyan-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3-cyan-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,3-dihydro-3-cyan-3-methyl-5-ethyl-1-benzo- thiophen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-cyan-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-cyan-5-ethyl- 1 -benzothiophen-6-carbonsäure methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-cyan-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-cyan-5-ethyl-1-benzo-thiophen-6- carboxamid-1 ,1-dioxid;N-diaminomethylene-2,3-dihydro-3-cyano-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-cyan-1-benzothiophen-6-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,3-dihydro-3-cyano-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3-cyan-1-benzothiophen-6- carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-cyan-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-cyan-3-methyl-1 -benzothiophen-6-carbonsäure methylester-1, 1 -dioxid dasfrom 2,3-dihydro-3-cyan-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-cyan-3-methyl-1-benzothiophen-6- carboxam id- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-cyano-3-methyl-1-benzothiophene-6-carboxam id-1,1-dioxide;
aus 2,3-Dihydro-3-amino-5-methyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-amino-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-amino-5-methyl-1-benzothiophen- 6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-amino-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-amino-3-methyl-5-ethyl-1-benzothiophen-6- carbonsäuremethylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-amino-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-amino-3-methyl-5-ethyl-1-benzo- thiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-amino-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-amino-5-ethyl-1 -benzothiophen-6-carbonsäure methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-amino-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-amino-5-ethyl-1-benzo-thiophen-6- carboxamid-1 ,1 -dioxid; aus 2,3-Dihydro-3-amino-1-benzothiophen-6-carbonsäure methylester- 1 ,1- dioxid dasN-diaminomethylene-2,3-dihydro-3-amino-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3-amino-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3-amino-1-benzothiophen-6- carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-amino-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-amino-3-methyl-1-benzothiophen-6-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-amino-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-amino-3-methyl-1-benzothiophen- 6- carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-amino-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N-methyl-amino-5-methyl-1 -benzothiophen-6- carbonsäure-methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-N-methylamino-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-N-methyl-amino-5-methyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N-methylamino-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N-methyl-amino-3-methyl-5-ethyl-1-benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-N-methyl-amino-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3-N-methyl-amino-3-methyl-5-ethyl-1- benzo-thiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N-methylamino-3-methyl-5-ethyl-1-benzo-thiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N-methyl-amino-5-ethyl-1 -benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-N-methylamino-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-N-methyl-amino-5-ethyl-1-benzo- thiophen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N-methylamino-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N-methyl-amino-1-benzothiophen-6-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-N-methyl-amino-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-N-methyl-amino-1-benzothiophen-6- carboxam id- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N-methylamino-1-benzothiophene-6-carboxam id-1,1-dioxide;
aus 2,3-Dihydro-3-N-methyl-amino-3-methyl-1 -benzothiophen-6- carbonsäuremethylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-N-methyl-amino-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-N-methyl-amino-3-methyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid; aus 2,3-Dihydro-3-N,N-dimethyl-amino-5-methyl-1-benzothiophen-6- carbonsäuremethylester- 1 ,1 -dioxid dasN-diaminomethylene-2,3-dihydro-3-N-methylamino-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3-N, N-dimethylamino-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-N,N-dimethyl-amino-5-methyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N,N-dimethyl-amino-3-methyl-5-ethyl-1-benzothiophen- 6-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-N, N-dimethylamino-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3-N,N-dimethyl-amino-3-methyl-5- ethyl- 1 -benzothiophen-6-carboxamid- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1, 1-dioxide;
aus 2,3-Dihydro-3-N,N-dimethyl-amino-5-ethyl-1-benzothiophen-6- carbonsäuremethylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-N, N-dimethylamino-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-N,N-dimethyl-amino-5-ethyl-1-benzo- thiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N,N-dimethyl-amino-1-benzothiophen-6-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-N, N-dimethylamino-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-DiaminomethyIen-2,3-dihydro-3-N,N-dimethyl-amino-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-N,N-dimethyl-amino-3-methyl-1-benzothiophen-6- carbonsäuremethylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-N, N-dimethylamino-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-N,N-dimethyl-amino-3-methyl-1 - benzothiophen-6-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-N, N-dimethylamino-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methyl-5-ethyl-1-benzothiophen-6-carbonsäuremethyl- ester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,3-dihydro-3-methyl-5-ethyl-1-benzothiophen-6- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-oxo-5-methy I- 1 -benzothiophen-6-carbonsäure- methylester- 1,1 -dioxid dasfrom 2,3-dihydro-3-oxo-5-methyl I-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-3-oxo-5-methyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid; aus 2,3-Dihydro-3-oxo-5-ethyl-1 -benzothiophen-6-carbonsäure methylester-1, 1 -dioxid dasN-diaminomethylene-2,3-dihydro-3-oxo-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3-oxo-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-oxo-5-ethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-oxo-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-oxo-5-fluor-1 -benzothiophen-6-carbonsäure methylester-1, 1 -dioxid dasfrom 2,3-dihydro-3-oxo-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-oxo-5-fluor-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-oxo-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-oxo-1 -benzothiophen-6-carbonsäure methylester-1 -1 - dioxid dasfrom 2,3-dihydro-3-oxo-1-benzothiophene-6-carboxylic acid methyl ester-1 -1 - dioxide that
N-Diaminomethylen-2,3-dihydro-3-oxo-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-oxo-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-oxo-5-trifluormethyl-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-oxo-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,3-dihydro-3-oxo-5-trifluormethyl-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-oxo-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-ethylendioxy-5-methyl-1 -benzothiophen-6- carbonsäure-methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3,3-ethylenedioxy-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3,3-ethylendioxy-5-methyl-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid, F. 242°, Methansulfonat: 285-287°;N-diaminomethylene-2,3-dihydro-3,3-ethylenedioxy-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 242 °, methanesulfonate: 285-287 °;
aus 2,3-Dihydro-3,3-ethylendioxy-5-ethyl-1-benzothiophen-6-carbonsäure methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3,3-ethylenedioxy-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-diyhdro-3,3-ethylendioxy-5-ethyl-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-ethylenedioxy-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-ethylendioxy-5-fluor-1-benzothiophen-6-carbonsäure methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3,3-ethylenedioxy-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-diyhdro-3,3-ethylendioxy-5-fluor-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid; aus 2,3-Dihydro-3,3-ethylendioxy-1 -benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasN-diaminomethylene-2,3-dihydro-3,3-ethylenedioxy-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3,3-ethylenedioxy-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3,3-ethylendioxy-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-ethylenedioxy-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-ethylendioxy-5-trifluormethyl-1-benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3,3-ethylenedioxy-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3,3-ethyiendioxy-5-trifluormethyl-1 - benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-ethylenedioxy-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-hydroxyimino-5-methyl-1 -benzothiophen-6- carbonsäure-methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-hydroxyimino-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxyimino-5-methyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid, F. 250° (Methansulfonat);N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 250 ° (methanesulfonate);
aus 2,3-Dihydro-3-hydroxyimino-5-ethyl-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxyimino-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxyimino-5-ethyl-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-hydroxyimino-5-fluor-1-benzothiophen-6-carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxyimino-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxyimino-5-fluor-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-hydroxyimino-2,2,5-trimethyl-1-benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxyimino-2,2,5-trimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxyimino-2,2,5-trimethyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid, F. 237-238° (Methansulfonat);N-diaminomethylene-2,3-dihydro-3-hydroxyimino-2,2,5-trimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 237-238 ° (methanesulfonate);
aus 2, 3-Dihydro-3-hydroxyimino-5-trif luormethy 1-1 -benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-hydroxyimino-5-trif luormethy 1-1 -benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-3-hydroxyimino-5-trifluormethyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid; aus 2,3-Dihydro-3-methoxyimino-5-methyl-1 -benzothiophen-6- carbonsäure-methylester-1 ,1 -dioxid dasN-diaminomethylene-2,3-dihydro-3-hydroxyimino-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3-methoxyimino-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-methoxyimino-5-methyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid, F. 284° (Methansulfonat);N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 284 ° (methanesulfonate);
aus 2,3-Dihydro-3-methoxyimino-5-ethyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-methoxyimino-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-diyhdro-3-methoxyimino-5-ethyl-1-benzothio- phen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methoxyimino-5-fluor-1-benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-methoxyimino-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,3-diyhdro-3-methoxyimino-5-fluor-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methoxyimino-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-methoxyimino-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-methoxyimino-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methoxyimino-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methoxyimino-5-trifIuormethyl-1-benzothiophen-6- carbonsäure methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-methoxyimino-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-3-methoxyimino-5-trifluormethyl-1 - benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methoxyimino-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methoxy-1-benzothiophen-6-carbonsäure-methylester-from 2,3-dihydro-3-methoxy-1-benzothiophene-6-carboxylic acid methyl ester
1 ,1 -dioxid das1, 1 -dioxide that
N-Diaminomethylen-2,3-dihydro-3-methoxy-1-benzothiophen-6-carbox- amid-1 ,1 -dioxid, F. 193-194°, Methansulfonat: F. 234-236°.N-diaminomethylene-2,3-dihydro-3-methoxy-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 193-194 °, methanesulfonate: mp 234-236 °.
aus 2,3-Dihydro-3-methoxy-5-methyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-methoxy-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-methoxy-5-methyl-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid, F. 224°, Methansulfonat: F. 249-251 °. Beispiel 2N-diaminomethylene-2,3-dihydro-3-methoxy-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 224 °, methanesulfonate: mp 249-251 °. Example 2
Unter Feuchtigkeitsausschluß, Sticksoff-Atmosphäre und Rühren werden 1 ,24 g Natrium in 20 ml trockenes Methanol eingetragen. Anschließend versetzt man die Lösung bei Raumtemperatur mit 5,64 g Guanidin-hydro- chlorid und rührt 30 Minuten nach. Dann wird filtiert, das Filtrat im Vakuum eingeengt, mit 10 ml Ethylenglykoldimethylether (EDME) versetzt und nochmals vom Lösungsmittel befreit. Der Rückstand wird in 8 ml EDME aufgenommen und unter Rühren bei 5 bis 10° innerhalb von 45 Minuten eine Suspension von 2,1 g des 2,3-Dihydro-3,5-dimethyl-1-benzothiophen-Excluding moisture, a nitrogen atmosphere and stirring, 1.24 g of sodium are introduced into 20 ml of dry methanol. 5.64 g of guanidine hydrochloride are then added to the solution at room temperature and stirring is continued for 30 minutes. The mixture is then filtered, the filtrate is concentrated in vacuo, 10 ml of ethylene glycol dimethyl ether (EDME) are added and the solvent is again removed. The residue is taken up in 8 ml of EDME and, with stirring at 5 to 10 °, a suspension of 2.1 g of 2,3-dihydro-3,5-dimethyl-1-benzothiophene- within 45 minutes.
6-carbon-säurechlorid-1 ,1 -dioxid [erhältlich durch Umsetzung von 1 ,9 g 2,3-Dihydro-3,5-dimethyl-1 -benzothiophen-6-carbonsäure-1 , 1 -dioxid mit 10 ml Thionylchlorid unter Feuchtigkeitsausschluß und Rühren über 4 Stunden in der Siedehitze], in 10 ml EDME zugetropft. Anschließend läßt man die Reaktionsmischung auf Raumtemperatur abkühlen, rührt 16-carbonyl chloride-1,1-dioxide [obtainable by reacting 1.9 g of 2,3-dihydro-3,5-dimethyl-1-benzothiophene-6-carboxylic acid-1,1-dioxide with 10 ml of thionyl chloride under Exclusion of moisture and stirring over 4 hours at the boil], added dropwise in 10 ml EDME. The reaction mixture is then allowed to cool to room temperature and is stirred 1
Stunde nach, versetzt dann unter Eiskühlung mit 60 ml Wasser und saugt den entstandenen Niederschlag ab. Nach Umkristallisation aus Dichlor¬ methan/Methanol erhält man das N-Diaminomethylen-2,3-dihydro-3,5- dimethyl-1-benzothiophen-6-carboxamid-1 ,1 -dioxid, F. 237-238°. Durch Behandlung mit Methansulfonsäure in 30 ml Methanol bei 40° über einenHour after, then mixed with ice cooling with 60 ml of water and suctioned off the resulting precipitate. After recrystallization from dichloromethane / methanol, the N-diaminomethylene-2,3-dihydro-3,5-dimethyl-1-benzothiophene-6-carboxamide-1, 1-dioxide, mp 237-238 °. By treatment with methanesulfonic acid in 30 ml of methanol at 40 ° over a
Zeitraum von 2 Stunden erhält man das entsprechende Methansulfonat: F. 245-248°.The corresponding methanesulfonate is obtained over a period of 2 hours: mp 245-248 °.
Analog erhält manYou get analog
aus 2,3-Dihydro-5-methyl-1-benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-5-methyl-1-benzothiophen-6-carbox- amid-1 ,1 -dioxid, F. 299-301 ° (Methansulfonat);N-diaminomethylene-2,3-dihydro-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 299-301 ° (methanesulfonate);
aus 2,3-Dihydro-5-ethyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1- dioxid dasfrom 2,3-dihydro-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,3-dihydro-5-ethyl-1-benzothiophen-6-carbox- amid-1 ,1 -dioxid; aus 2,3-Dihydro-5-trifluormethyl-1 -benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasN-diaminomethylene-2,3-dihydro-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-5-trifluormethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2, 3-Dihydro-1-benzothiophen-6-carbonsäure-methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-1 -benzothiophen-6-carboxamid-1 , 1 - dioxid, F. 223°, Methansulfonat: F. 264-265°;N-diaminomethylene-2,3-dihydro-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 223 °, methanesulfonate: mp 264-265 °;
aus 2,3-Dihydro-3-methyl-5-fluor-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-methyl-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-methyl-5-fluor-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methyl-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-isopropyl-5-methyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-isopropyl-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-isopropyl-5-methyl-1-benzothiophen-N-diaminomethylene-2,3-dihydro-3-isopropyl-5-methyl-1-benzothiophene-
6-carboxamid-1 ,1 -dioxid, F. 194-196°;6-carboxamide-1,1-dioxide, mp 194-196 °;
aus 2,3-Dihydro-3-methyl-1-benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-methyl-1-benzothiophen-6-carbox- amid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-dimethyl-5-fluor-1-benzothiophen-6-carbonsäure- methyl ester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3,3-dimethyl-5-fluor-1-benzothiophen-N-diaminomethylene-2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophene-
6-carboxamid-1 , 1 -dioxid;6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-dimethyl-5-ethyl-1-benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3,3-dimethyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethyien-2,3-dihydro-3,3,5-trimethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid; aus 2,3-Dihydro-3,3,5-trimethyl-1 -benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasN-diamino-methyl-2,3-dihydro-3,3,5-trimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 2,3-dihydro-3,3,5-trimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3,3-dimethyl-5-fluor-1-benzothiophen- 6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-dimethyl-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-dimethyl-5-trifluormethyl-1 -benzothiophen-6- carbonsäure-methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3,3-dimethyl-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3,3-dimethyl-5-trifluormethyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-dimethyl-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3,3-dimethyl-1 -benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3,3-dimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3,3-dimethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3,3-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2,2-dimethyl-5-fluor-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-2,2-dimethyl-5-fluor-1-benzothiophen-N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophene-
6-carboxamid-1 , 1 -dioxid;6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2,2-dimethyl-5-ethyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-2,2-dimethyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2,2-dimethyl-5-ethyl-1-benzothiophen-N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-ethyl-1-benzothiophene-
6-carboxamid-1 , 1 -dioxid;6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2,2,5-trimethyl-1 -benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-2,2,5-trimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2,2-dimethyl-5-fluor-1-benzothiophen-N-diaminomethylene-2,3-dihydro-2,2-dimethyl-5-fluoro-1-benzothiophene-
6-carboxamid-1 , 1 -dioxid;6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2,2,5-trimethyl-3-methoxy-1-benzothiophen-6- carbonsäure-methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-2,2,5-trimethyl-3-methoxy-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-2,2,5-trimethyl-3-methoxy-1-benzothio- phen-6-carboxamid-1 ,1 -dioxid, F. 245°, Methansulfonat: 284-285°; aus 2,3-Dihydro-2,2-dimethyl-1 -benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasN-diaminomethylene-2,3-dihydro-2,2,5-trimethyl-3-methoxy-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 245 °, methanesulfonate: 284-285 °; from 2,3-dihydro-2,2-dimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2,2-dimethyl-1-benzothiophen-6- carboxam id- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-2,2-dimethyl-1-benzothiophene-6-carboxam id-1,1-dioxide;
aus 2,3-Dihydro-2,5-dimethyl-1 -benzothiophen-6-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-2,5-dimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2,5-dimethyl-1-benzothiophen-6- carboxamid-1 ,1-dioxid;N-diaminomethylene-2,3-dihydro-2,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2-methyl-5-ethyl-1-benzothiophen-6-carbonsäure- methylester- 1,1 -dioxid dasfrom 2,3-dihydro-2-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-2-methyl-5-ethyl-1-benzothiophen-6- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-2-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2-methyl-5-trifluormethyl-1 -benzothiophen-6- carbonsäure-methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-2-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2-methyl-5-trifluormethyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid;N-diaminomethylene-2,3-dihydro-2-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-2-methyl-1-benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-2-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-2-methyl-1-benzothiophen-6-carbox- amid- 1,1 -dioxid.N-diaminomethylene-2,3-dihydro-2-methyl-1-benzothiophene-6-carboxamide 1.1-dioxide.
Beispiel 3Example 3
Unter Stickstoffatmosphäre, Rühren und Feuchtigkeitsausschluß werden 213 mg Natrium in 5 ml Methanol eingetragen. Die erhaltene Lösung wird bei Raumtemperatur mit 975 mg Guanidin-hydrochlorid versetzt und 30 Minuten gerührt. Anschließend filtiert man die Suspension. Danach wird das Filtrat mit 500 mg 4-Acetyl-2-methyl-5-methylsulfonyl-benzoe- säure-methylester versetzt und 1 Stunde refluxiert. Nach einstündigem Nachrühren bei Raumtemperatur wird unter Eiskühlung mit Wasser versetzt, mit Kochsalz gesättigt, mit Essigester extrahiert, die organische Phase mit Wasser gewaschen, getrocknet und eingeengt. Umkristalli¬ sation aus Methanol/Essigester gibt das N-Diaminomethylen-2,3-dihydro- 3-hydroxy-3,5-dimethyl-1-benzothiophen-6-carboxamid-1 ,1-dioxid, F. 243-Under a nitrogen atmosphere, stirring and excluding moisture, 213 mg of sodium are introduced into 5 ml of methanol. The solution obtained is mixed with 975 mg of guanidine hydrochloride at room temperature and stirred for 30 minutes. The suspension is then filtered. The filtrate is then treated with 500 mg of methyl 4-acetyl-2-methyl-5-methylsulfonylbenzoate and refluxed for 1 hour. After one hour After stirring at room temperature, water is added with ice cooling, saturated with sodium chloride, extracted with ethyl acetate, the organic phase is washed with water, dried and concentrated. Recrystallization from methanol / ethyl acetate gives N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1, 1-dioxide, F. 243-
245°. Durch Behandlung mit Methansulfonsäure in Methanol erhält man nach Umkristallisieren aus Methanol/ Aceton das entsprechende Methan¬ sulfonat: F. 214-216°.245 °. By treatment with methanesulfonic acid in methanol, the corresponding methanesulfonate is obtained after recrystallization from methanol / acetone: mp 214-216 °.
Analog erhält manYou get analog
aus 4-Benzoyl-5-methylsulfonyl-benzoesäuremethylester dasfrom 4-benzoyl-5-methylsulfonyl-benzoic acid methyl ester
N-Diaminomethylen-2,3-dihydro-3-phenyl-3-hydroxy-1-benzothiophen- 6-carboxam id- 1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-phenyl-3-hydroxy-1-benzothiophene-6-carboxam id-1,1-dioxide;
aus 4-Benzoyl-2-methyl-5-methylsulfonyl-benzoesäuremethylester das N-Diaminomethylen-2,3-dihydro-3-phenyl-3-hydroxy-5-methyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid.from 4-benzoyl-2-methyl-5-methylsulfonyl-benzoic acid methyl ester the N-diaminomethylene-2,3-dihydro-3-phenyl-3-hydroxy-5-methyl-1-benzothiophene-6-carboxamide-1, 1-dioxide .
Beispiel 4Example 4
Eine - wie in Beispiel 3 beschrieben - aus 547 mg Natrium, 12 ml Methanol und 2,5 g Guanidin-hydrochlorid hergestellte Guanidin-Lösung wird mit 1 ,2 g 2,3-Dihydro-5-methyl-3-methylen-1-benzothiophen-6-carbonsäure- methylester- 1 ,1 -dioxid [hergestellt durch Cyclisierung von 4-Acetyl-2- methyl-5-methylsulfonyl-benzoesäuremethylester und anschließende Dehydratisierung] versetzt und die Mischung eine Stunde gekocht, anschließend eine weitere Stunde bei Raumtemperatur gerührt und wie üblich aufgearbeitet. Man erhält das N-Diaminomethylen-2,3-dihydro-3- methoxy-3,5-dimethyl-1-benzothiophen-6-carboxamid-1 ,1-dioxid. Durch Behandlung mit Methansulfonsäure in Methanol erhält man das entsprech¬ ende Methansulfonat F. 214-215°. Analog erhält manA guanidine solution prepared as described in Example 3 from 547 mg of sodium, 12 ml of methanol and 2.5 g of guanidine hydrochloride is mixed with 1.2 g of 2,3-dihydro-5-methyl-3-methylene-1- methyl benzothiophene-6-carboxylate-1,1-dioxide [prepared by cyclization of methyl 4-acetyl-2-methyl-5-methylsulfonylbenzoate and subsequent dehydration] and the mixture was boiled for one hour and then stirred for a further hour at room temperature and worked up as usual. The N-diaminomethylene-2,3-dihydro-3-methoxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide is obtained. Treatment with methanesulfonic acid in methanol gives the corresponding methanesulfonate F. 214-215 °. You get analog
aus 3-Phenyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1 -dioxid das N-Diaminomethylen-2,3-dihydro-3-phenyl-3-methoxy-1-benzothiophen- 6-carboxamid- 1 ,1 -dioxid;from 3-phenyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-2,3-dihydro-3-phenyl-3-methoxy-1-benzothiophene-6-carboxamide-1, 1 -dioxide;
aus 5-Methyl-3-phenyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1 - dioxid dasfrom 5-methyl-3-phenyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 - dioxide the
N-Diaminomethylen-2,3-dihydro-3-phenyl-3-methoxy-5-methyl-1- benzothiophen-6-carboxamid- 1 ,1 -dioxid.N-diaminomethylene-2,3-dihydro-3-phenyl-3-methoxy-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide.
Beispiel 5Example 5
Analog Beispiel 2 erhält man durch Umsetzung von frisch hergestelltem Guanidin mit 3,5-Dimethyl-1 -benzothiophen-6-carbonsäure-chlorid- 1 ,1- dioxid [erhältlich durch Umsetzung von 1 ,9 g 3,5-Dimethyl-1-benzothio- phen-6-carbonsäure- 1 ,1 -dioxid mit 10 ml Thionylchlorid unter Feuchtig¬ keitsausschluß und Rühren über 4 Stunden in der Siedehitze] das N- Diaminomethylen-3,5-dimethyl-1-benzothiophen-6-carboxamid-1 ,1 -dioxid. Durch Behandlung mit Methansulfonsäure in Methanol erhält man das entsprechende Methansulfonat.Analogously to Example 2, reaction of freshly prepared guanidine with 3,5-dimethyl-1-benzothiophene-6-carboxylic acid chloride 1, 1-dioxide [obtainable by reaction of 1.9 g of 3,5-dimethyl-1 benzothiophene-6-carboxylic acid 1,1-dioxide with 10 ml thionyl chloride with exclusion of moisture and stirring for 4 hours at the boiling point] the N-diaminomethylene-3,5-dimethyl-1-benzothiophene-6-carboxamide-1 , 1 -dioxide. Treatment with methanesulfonic acid in methanol gives the corresponding methanesulfonate.
Analog erhält manYou get analog
aus 5-Methyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1 -dioxid das N-Diaminomethylen-5-methyl-1-benzothiophen-6-carboxamid-1 ,1- dioxid;from 5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-5-methyl-1-benzothiophene-6-carboxamide-1, 1-dioxide;
aus 5-Ethyl-1-benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid dasfrom 5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-5-ethyl-1-benzothiophen-6-carboxamid-1 ,1 -dioxid; aus 5-Trifluormethyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1- dioxid dasN-diaminomethylene-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-5-trifluormethyl-1 -benzothiophen-6-carboxamid-N-diaminomethylene-5-trifluoromethyl-1-benzothiophene-6-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 1-Benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid das N-Diaminomethylen-1-benzothiophen-6-carboxamid-1 ,1-dioxid;from 1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-1-benzothiophene-6-carboxamide-1, 1-dioxide;
aus 3-Methyl-5-ethyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1- dioxid dasfrom 3-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-methyl-5-ethyl-1-benzothiophen-6-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-3-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 3-Methyl-5-f luor- 1 -benzothiophen-6-carbonsäure-methylester- 1 ,1- dioxid dasfrom 3-methyl-5-f luor-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-methyl-5-fluor-1-benzothiophen-6-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-3-methyl-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 3-Methyl-5-trifluormethyl-1 -benzothiophen-6-carbonsäure- methylester- 1 , 1 -dioxid dasfrom 3-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-methyl-5-trifluormethyl-1-benzothiophen-6- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-3-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 3-Phenyl-5-methyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1- dioxid dasfrom 3-phenyl-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-3-phenyl-5-methyl-1-benzothiophen-6-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-3-phenyl-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 3-Phenyl-5-ethyl-1 -benzothiophen-6-carbonsäure-methyiester-1,1 - dioxid dasfrom 3-phenyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1,1 - dioxide the
N-Diaminomethylen-3-phenyl-5-ethyl-1-benzothiophen-6-carboxamid- 1 ,1 -dioxid; aus 3-Phenyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1 -dioxid das N-Diaminomethylen-3-phenyl-1-benzothiophen-6-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-phenyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide; from 3-phenyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-3-phenyl-1-benzothiophene-6-carboxamide-1, 1-dioxide;
aus 3-Methyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1-dioxid dasfrom 3-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-methyl-1-benzothiophen-6-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2, 5-Dimethyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1 -dioxid dasfrom 2, 5-dimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,5-dimethyl-1-benzothiophen-6-carboxamid-1 ,1 - dioxid;N-diaminomethylene-2,5-dimethyl-1-benzothiophene-6-carboxamide-1, 1 - dioxide;
aus 2-Methyl-5-ethyl-1-benzothiophen-6-carbonsäure-methylester-1 ,1- dioxid dasfrom 2-methyl-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2-methyl-5-ethyl-1-benzothiophen-6-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-2-methyl-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2-Methyl-5-trifluormethyl-1-benzothiophen-6-carbonsäure-methyl- ester- 1 , 1 -dioxid dasfrom 2-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2-methyl-5-trifluormethyl-1-benzothiophen-6- carboxamid-1 ,1 -dioxid;N-diaminomethylene-2-methyl-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2-Methyl-5-f luor- 1-benzothiophen-6-carbonsäure-methylester- 1 ,1- dioxid dasfrom 2-methyl-5-fluorous-1-benzothiophene-6-carboxylic acid methyl ester 1, 1-dioxide the
N-Diaminomethylen-2-methyl-5-fluor-1-benzothiophen-6-carboxamid- 1 ,1-dioxid;N-diaminomethylene-2-methyl-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2-Methyl- 1 -benzothiophen-6-carbonsäure-methylester- 1 , 1 -dioxid das N-Diaminomethylen-2-methyl-1-benzothiophen-6-carboxamid-1 ,1 - dioxid; aus 2,3-Dihydro-3-methylen-5-methyl-1-benzothiophen-6-carbonsäure- methylester-1,1 -dioxid dasfrom 2-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-2-methyl-1-benzothiophene-6-carboxamide-1, 1 - dioxide; from 2,3-dihydro-3-methylene-5-methyl-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-3-methylen-5-methyl-1-benzothiophen- 6-carboxamid-1 ,1 -dioxid, F. 208-212°, Methansulfonat: 230-235°;N-diaminomethylene-2,3-dihydro-3-methylene-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 208-212 °, methanesulfonate: 230-235 °;
aus 2,3-Dihydro-3-methylen-5-ethyl-1-benzothiophen-6-carbonsäure- methylester-1 ,1 -dioxid dasfrom 2,3-dihydro-3-methylene-5-ethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-methylen-5-ethyl-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methylene-5-ethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-oxo-2,2,5-trimethyl-1-benzothiophen-6-carbonsäure- methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-oxo-2,2,5-trimethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-oxo-2,2,5-trimethyl-1-benzothiophen- 6-carboxamid-1,1 -dioxid, F. 250-251° (Methansulfonat);N-diaminomethylene-2,3-dihydro-3-oxo-2,2,5-trimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide, mp 250-251 ° (methanesulfonate);
aus2,3-Dihydro-3-methylen-5-fluor-1-benzothiophen-6-carbonsäure- methylester-1,1 -dioxid dasfrom 2,3-dihydro-3-methylene-5-fluoro-1-benzothiophene-6-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,3-dihydro-3-methylen-5-fluor-1-benzothiophen-6- carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methylene-5-fluoro-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2,3-Dihydro-3-methylen-5-trifluormethyl-1 -benzothiophen-6- carbonsäure-methylester-1 , 1 -dioxid dasfrom 2,3-dihydro-3-methylene-5-trifluoromethyl-1-benzothiophene-6-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,3-dihydro-3-methylen-5-trifluormethyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid;N-diaminomethylene-2,3-dihydro-3-methylene-5-trifluoromethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
aus 2, 3-Dihydro-3-methylen-1 -benzothiophen-6-carbonsäure-methylester- 1 ,1 -dioxid dasfrom 2,3-dihydro-3-methylene-1-benzothiophene-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,3-dihydro-3-methylen-1-benzothiophen-6- carboxamid-1 , 1 -dioxid.N-diaminomethylene-2,3-dihydro-3-methylene-1-benzothiophene-6-carboxamide-1,1-dioxide.
Beispiel 6Example 6
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid dasfrom 6-methyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-6-methyl-1 ,3-benzoxathiol-5-carboxamid-3,3-dioxid; aus 1 ,3-Benzoxathiol-5-carbonsäuremethylester-3,3-dioxid das N-Diaminomethylen-1 ,3-benzoxathiol-5-carboxamid-3,3-dioxid;N-diaminomethylene-6-methyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide; from 1,3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide the N-diaminomethylene-1,3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 6-Ethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid das N-Diaminomethylen-6-ethyl-1 ,3-benzoxathiol-5-carboxamid-3,3-dioxid;from 6-ethyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide the N-diaminomethylene-6-ethyl-1, 3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 2,6-Dimethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid dasfrom 2,6-dimethyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-2,6-dimethyl-1 ,3-benzoxathiol-5-carboxamid-3,3- dioxid;N-diaminomethylene-2,6-dimethyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 2-Methyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid das N-Diaminomethylen-2-methyl-1 ,3-benzoxathiol-5-carboxamid-3,3-dioxid;from 2-methyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide the N-diaminomethylene-2-methyl-1, 3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 2-Methyl-6-ethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3- dioxid dasfrom 2-methyl-6-ethyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-2-methyl-6-ethyl-1 ,3-benzoxathiol-5-carboxamid-2- 3,3-dioxid;N-diaminomethylene-2-methyl-6-ethyl-1,3-benzoxathiol-5-carboxamide-2, 3,3-dioxide;
aus 2,2,6-Trimethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid dasfrom 2,2,6-trimethyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-2,2,6-trimethyl-1 ,3-benzoxathiol-5-carboxamid-3,3- dioxid;N-diaminomethylene-2,2,6-trimethyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 2,2-Dimethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3-dioxid dasfrom 2,2-dimethyl-1,3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-2,2-dimethyl-1 ,3-benzoxathiol-5-carboxamid-3,3- dioxid;N-diaminomethylene-2,2-dimethyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide;
aus 2,2-Dimethyl-6-ethyl-1 ,3-benzoxathiol-5-carbonsäuremethylester-3,3- dioxid dasfrom 2,2-dimethyl-6-ethyl-1, 3-benzoxathiol-5-carboxylic acid methyl ester-3,3-dioxide
N-Diaminomethylen-2,2-dimethyl-6-ethyl-1 ,3-benzoxathiol-5-carbox- amid-3,3-dioxid; aus 2,5-Dimethyl-2,3-dihydro-benzothiazol-6-carbonsäuremethylester-1 ,1- dioxid dasN-diaminomethylene-2,2-dimethyl-6-ethyl-1,3-benzoxathiol-5-carboxamide-3,3-dioxide; from 2,5-dimethyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1,1-dioxide
6-N-Diaminomethylencarbamoyl-2,5-dimethyl-2,3-dihydro-benzothiazol-6-N-diaminomethylene carbamoyl-2,5-dimethyl-2,3-dihydro-benzothiazole-
1 ,1 -dioxid;1, 1 dioxide;
aus 2-Methyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester-1 ,1- dioxid dasfrom 2-methyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1-dioxide
6-N-Diaminomethylencarbamoyl-2-methyl-2,3-dihydro-benzothiazol-1 , 1 - dioxid;6-N-diaminomethylene carbamoyl-2-methyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2-Methyl-6-ethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester- 1 , 1 -dioxid dasfrom 2-methyl-6-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2-methyl-6-ethyl-2,3-dihydro-benzo- thiazol- 1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-2-methyl-6-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,3,5-Trimethyl-2,3-dihydro-benzothiazol-6-carbonsäuremethylester- 1,1 -dioxid dasfrom 2,3,5-trimethyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1,1-dioxide
6-N-Diaminomethylencarbamoyl-2,3,5-trimethyl-2,3-dihydro- benzothiazol-1 , 1 -dioxid;6-N-diaminomethylene carbamoyl-2,3,5-trimethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,3-Dimethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,3-dimethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1,1-dioxide
6-N-DiaminomethylencarbamoyI-2,3-dimethyl-2,3-dihydro-benzothiazol-6-N-diaminomethylene carbamoy-2,3-dimethyl-2,3-dihydro-benzothiazole
1 ,1-dioxid;1, 1-dioxide;
aus 2,3-Dimethyl-5-ethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethyl- ester- 1 ,1 -dioxid dasfrom 2,3-dimethyl-5-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1-dioxide the
6-N-Diaminomethylencarbamoyl-2,3-dimethyl-5-ethyl-2,3-dihydro- benzothiazol-1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-2,3-dimethyl-5-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 5-Methyl-2,3-dihydro-benzothiazol-6-carbonsäuremethylester-1 ,1 - dioxid dasfrom 5-methyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1, 1 - dioxide the
6-N-Diaminomethylencarbamoyl-5-methyl-2,3-dihydro-benzothiazol-1 ,1- dioxid; aus 2,3-dihydro-benzothiazoI-5-carbonsäuremethylester-1 , 1 -dioxid das 6-N-Diaminomethylencarbamoyl-2,3-dihydro-benzothiazol-1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-5-methyl-2,3-dihydro-benzothiazole-1,1-dioxide; from 2,3-dihydro-benzothiazoI-5-carboxylic acid methyl ester-1, 1-dioxide the 6-N-diaminomethylene carbamoyl-2,3-dihydro-benzothiazole-1, 1-dioxide;
aus 6-Ethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 6-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-6-ethyl-2,3-dihydro-benzothiazol-1 , 1 - dioxid;6-N-diaminomethylene carbamoyl-6-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 3,5-Dimethyl-2,3-dihydro-benzothiazol-6-carbonsäuremethylester-1 ,1- dioxid dasfrom 3,5-dimethyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1,1-dioxide
6-N-Diaminomethylencarbamoyl-3,5-dimethyl-2,3-dihydro-benzothiazol- 1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-3,5-dimethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 3-Methyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester-1 ,1- dioxid dasfrom 3-methyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1,1-dioxide
6-N-Diaminomethylencarbamoyl-3-methyl-2,3-dihydro-benzothiazol-1 ,1- dioxid;6-N-diaminomethylene carbamoyl-3-methyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 3-Methyl-5-ethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 3-methyl-5-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-3-methyl-5-ethyl-2,3-dihydro- benzothiazol-1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-3-methyl-5-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,2,5-Trimethyl-2,3-dihydro-benzothiazol-6-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2,2,5-trimethyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2,2,5-trimethyl-2,3-dihydro-benzo- thiazol-1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-2,2,5-trimethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,2-Dimethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,2-dimethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1,1-dioxide
6-N-Diaminomethylencarbamoyl-2,2-dimethyl-2,3-dihydro-benzothiazol- 1 ,1 -dioxid; aus 2,2-Dimethyl-6-ethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethyl- ester- 1 ,1 -dioxid das6-N-diaminomethylene carbamoyl-2,2-dimethyl-2,3-dihydro-benzothiazole-1,1-dioxide; from 2,2-dimethyl-6-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2,2-dimethyl-6-ethyl-2,3-dihydro- benzothiazol-1 , 1 -dioxid;6-N-diaminomethylene carbamoyl-2,2-dimethyl-6-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,2,3,5-Tetramethyl-2,3-dihydro-benzothiazol-6-carbonsäuremethyl- ester- 1 ,1 -dioxid dasfrom 2,2,3,5-tetramethyl-2,3-dihydro-benzothiazole-6-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2,2,3,5-tetramethyl-2,3-dihydro- benzothiazol- 1 , 1 -dioxid;6-N-diaminomethylene carbamoyl-2,2,3,5-tetramethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,2,3-Trimethyl-2,3-dihydro-benzothiazol-5-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2,2,3-trimethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2,2,3-trimethyl-2,3-dihydro-benzothia- zol- 1 ,1 -dioxid;6-N-diaminomethylene carbamoyl-2,2,3-trimethyl-2,3-dihydro-benzothiazole-1,1-dioxide;
aus 2,2,3-Trimethyl-5-ethyl-2,3-dihydro-benzothiazol-5-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 2,2,3-trimethyl-5-ethyl-2,3-dihydro-benzothiazole-5-carboxylic acid methyl ester-1, 1 -dioxide
6-N-Diaminomethylencarbamoyl-2,2,3-trimethyl-5-ethyl-2,3-dihydro- benzothiazol-1 , 1 -dioxid.6-N-diaminomethylene carbamoyl-2,2,3-trimethyl-5-ethyl-2,3-dihydro-benzothiazole-1,1-dioxide.
Beispiel 7Example 7
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-6-methyl-thiochroman-7-carboxamid- 1 ,1 -dioxid;from 6-methyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-6-methyl-thiochroman-7-carboxamide-1,1-dioxide;
aus Thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-thiochroman-7-carboxamid- 1 ,1 -dioxid;from thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-thiochroman-7-carboxamide-1,1-dioxide;
aus 6-Ethyl-thiochroman-7-carbonsäuremethylester-1 ,1-dioxid das N-Diaminomethylen-6-ethyl-thiochroman-7-carboxamid-1 ,1 -dioxid; aus 2,6-Dimethyl-thiochroman-7-carbonsauremethylester-1 ,1 -dioxid das N-Diamιnomethylen-2,6-dimethyl-thιochroman-7-carboxamid-1 ,1 -dioxid;from 6-ethyl-thiochroman-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-6-ethyl-thiochroman-7-carboxamide-1, 1-dioxide; from 2,6-dimethyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diamιnomethylene-2,6-dimethyl-thιochroman-7-carboxamide-1, 1-dioxide;
aus 2-Methyl-thιochroman-7-carbonsauremethylester-1 , 1 -dioxid das N-Dιamιnomethylen-2-methyl-thιochroman-7-carboxamιd- 1 ,1 -dioxid,from 2-methyl-thιochroman-7-carboxylic acid methyl ester-1, 1 -dioxide, the N-diminomethylene-2-methyl-thιochroman-7-carboxamιd- 1, 1 -dioxide,
aus 2-Methyl-6-ethyl-thιochroman-7-carbonsauremethylester-1 , 1 -dioxid dasfrom 2-methyl-6-ethyl-thιochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Dιamιnomethylen-2-methyl-6-ethyl-thιochroman-7-carboxamιd-1 , 1 - dioxid;N-diminomethylene-2-methyl-6-ethyl-thioochroman-7-carboxamid-1, 1 - dioxide;
aus 2,2,6-Trιmethyl-thιochroman-7-carbonsauremethylester-1 , 1 -dioxid das N-Dιamιnomethylen-2,2,6-trιmethyl-thiochroman-7-carboxamid-1 ,1- dioxid;from 2,2,6-trιmethyl-thιochroman-7-carboxylic acid methyl ester-1, 1 -dioxide the N-dιamιnomethylene-2,2,6-trιmethyl-thiochroman-7-carboxamide-1, 1-dioxide;
aus 2,2-Dιmethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Dιaminomethylen-2,2-dimethyl-thιochroman-7-carboxamιd- 1 ,1 -dioxid;from 2,2-dimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diminomethylene-2,2-dimethyl-thiochroman-7-carboxamid-1,1-dioxide;
aus 2,2-Dιmethyl-6-ethyl-thιochroman-7-carbonsauremethylester-1 ,1- dioxid dasfrom 2,2-dimethyl-6-ethyl-thιochroman-7-carboxylic acid methyl ester-1, 1-dioxide
N-Dιamιnomethylen-2,2-dιmethyl-6-ethyl-thιochroman-7-carboxamιd- 1 ,1 -dioxid;N-diminomethylene-2,2-dimethyl-6-ethyl-thioochroman-7-carboxamid-1,1-dioxide;
aus 3,6-Dιmethyl-thiochroman-7-carbonsauremethylester- 1 , 1 -dioxid das N-Dιamιnomethylen-3,6-dimethyl-thιochroman-7-carboxamιd-1 ,1 -dioxid;from 3,6-dimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diminomethylene-3,6-dimethyl-thiochroman-7-carboxamid-1,1-dioxide;
aus 3-Methyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid das N-Dιamιnomethylen-3-methyl-thιochroman-7-carboxamιd- 1 ,1 -dioxid;from 3-methyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diminomethylene-3-methyl-thιochroman-7-carboxamid-1, 1 -dioxide;
aus 3-Methyl-6-ethyl-thιochroman-7-carbonsauremethylester-1 ,1 -dioxid dasfrom 3-methyl-6-ethyl-thιochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Dιamιnomethylen-3-methyl-6-ethyl-thιochroman-7-carboxamιd-1 , 1 - dioxid; aus 4,6-Dimethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-4,6-dimethyl-thiochroman-7-carboxamid-1 , 1 - dioxid, F. 204-205°, Methansulfonat: 248-250°;N-diminomethylene-3-methyl-6-ethylthioochroman-7-carboxamid-1, 1 - dioxide; from 4,6-dimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-4,6-dimethyl-thiochroman-7-carboxamide-1,1-dioxide, mp 204-205 °, methanesulfonate: 248-250 °;
aus 4-Methyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid dasfrom 4-methyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-4-methyl-thiochroman-7-carboxamid-1 , 1 -dioxid;N-diaminomethylene-4-methyl-thiochroman-7-carboxamide-1,1-dioxide;
aus 4-Methyl-6-ethyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid das N-Diaminomethylen-4-methyl-6-ethyl-thiochroman-7-carboxamid-1 , 1 - dioxid;from 4-methyl-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-4-methyl-6-ethyl-thiochroman-7-carboxamide-1,1-dioxide;
aus 3,3,6-Trimethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3,3,6-trimethyl-thiochroman-7-carboxamid-1 , 1 - dioxid; aus 3,3-Dimethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3,3-dimethyl-thiochroman-7-carboxamid-1 , 1 - dioxid;from 3,3,6-trimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-3,3,6-trimethyl-thiochroman-7-carboxamide-1,1-dioxide; from 3,3-dimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-3,3-dimethyl-thiochroman-7-carboxamide-1,1-dioxide;
aus 3,3-Dimethyl-6-ethyl-thiochroman-7-carbonsäuremethylester-1 , 1 - dioxid dasfrom 3,3-dimethyl-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1, 1 - dioxide the
N-Diaminomethylen-3,3-dimethyl-6-ethyl-thiochroman-7-carboxamid- 1 , 1 -dioxid;N-diaminomethylene-3,3-dimethyl-6-ethylthiochroman-7-carboxamide-1,1-dioxide;
aus 4,4,6-Trimethyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid dasfrom 4,4,6-trimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-4,4,6-trimethyl-thiochroman-7-carboxamid-1 , 1 - dioxid;N-diaminomethylene-4,4,6-trimethylthiochroman-7-carboxamide-1, 1 - dioxide;
aus 4,4-Dimethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-thiochroman-4,4-dimethyl-7-carboxamid-1 ,1- dioxid;from 4,4-dimethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-thiochroman-4,4-dimethyl-7-carboxamide-1,1-dioxide;
aus 2,2,4,6-Tetramethyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid das N-Diaminomethylen-2,2,4,6-tetramethyl-thiochroman-7-carboxamid-1 , 1 - dioxid, F. 256° (Methansulfonat); aus 4,4-Dimethyl-6-ethyl-thiochroman-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,2,4,6-tetramethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-2,2,4,6-tetramethyl-thiochroman-7-carboxamide-1,1-dioxide, F 256 ° (methanesulfonate); from 4,4-dimethyl-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-4,4-dimethyl-6-ethyl-thiochroman-7-carboxamid-N-diaminomethylene-4,4-dimethyl-6-ethyl-thiochroman-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 6-Methyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 6-methyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-6-methyl-2H-1-benzothiopyran-7-carboxamid-1 ,1 - dioxid;N-diaminomethylene-6-methyl-2H-1-benzothiopyran-7-carboxamide-1, 1 - dioxide;
aus 2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethyien-2H-1-benzothiopyran-7-carboxamid- 1 ,1 -dioxid;from 2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethyien-2H-1-benzothiopyran-7-carboxamide-1, 1 -dioxide;
aus 6-Ethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 6-ethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-6-ethyl-2H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-6-ethyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 2,6-Dimethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,6-dimethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,6-dimethyl-2H-1-benzothiopyran-7-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-2,6-dimethyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 2-Methyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 2-methyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2-methyl-2H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2-methyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 2-Methyl-6-ethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2-methyl-6-ethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2-methyl-6-ethyl-2H-1-benzothiopyran-7- carboxamid-1 ,1 -dioxid; aus 2,2,6-Trimethyl-2H-1-benzothioρyran-7-carbonsäuremethylester-1 ,1- dioxid dasN-diaminomethylene-2-methyl-6-ethyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide; from 2,2,6-trimethyl-2H-1-benzothioρyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,2,6-trimethyl-2H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-2,2,6-trimethyl-2H-1-benzothiopyran-7-carboxamide-
1 , 1 -dioxid;1, 1 dioxide;
aus 2,2-Dimethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,2-dimethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,2-dimethyl-2H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-2,2-dimethyl-2H-1-benzothiopyran-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 2,2-Dimethyl-6-ethyl-2H-1-benzothiopyran-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2,2-dimethyl-6-ethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,2-dimethyl-6-ethyl-2H-1-benzothiopyran-7- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-2,2-dimethyl-6-ethyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 3,6-Dimethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 3,6-dimethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-3,6-dimethyl-2H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-3,6-dimethyl-2H-1-benzothiopyran-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 3-Methyl-2H-1-benzothiopyran-7-carbonsäuremethylester- 1 , 1 -dioxid dasfrom 3-methyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-methyl-2H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-methyl-2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 3-Methyl-6-ethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 3-methyl-6-ethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2H-1-benzothiopyran-7-carboxamid-3-methyl-6- ethyl- 1 ,1 -dioxid;N-diaminomethylene-2H-1-benzothiopyran-7-carboxamide-3-methyl-6-ethyl-1, 1-dioxide;
aus 4,6-Dimethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 4,6-dimethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-4,6-dimethyl-2H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-4,6-dimethyl-2H-1-benzothiopyran-7-carboxamide-
1 ,1 -dioxid; aus 4-Methyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid das1, 1 dioxide; from 4-methyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-4-methyl-2H-1-benzothiopyran-7-carboxamid-1 ,1 - dioxid;N-diaminomethylene-4-methyl-2H-1-benzothiopyran-7-carboxamide-1, 1 - dioxide;
aus 4-Methyl-6-ethyl-2H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 ■ dioxid dasfrom 4-methyl-6-ethyl-2H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 ■ dioxide that
N-Diaminomethylen-4-methyl-6-ethyl 2H-1 -benzothiopyran-7- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-4-methyl-6-ethyl 2H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 6-Methyl-4H-1-benzothiopyran-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 6-methyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-6-methyl-4H-1-benzothiopyran-7-carboxamid-1 ,1 - dioxid;N-diaminomethylene-6-methyl-4H-1-benzothiopyran-7-carboxamide-1, 1 - dioxide;
aus 4H-1-benzothiopyran-7-carbonsäuremethylester- 1,1 -dioxid das N-Diaminomethylen-4H-1-benzothiopyran-7-carboxamid-1 ,1 -dioxid;from 4H-1-benzothiopyran-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-4H-1-benzothiopyran-7-carboxamide-1, 1-dioxide;
aus 6-Ethyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 6-ethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-6-ethyl-4H- 1 -benzothiopyran-7-carboxamid- 1 ,1- dioxid;N-diaminomethylene-6-ethyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 2,6-Dimethyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,6-dimethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,6-dimethyl-4H-1-benzothiopyran-7-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-2,6-dimethyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 2-Methyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 2-methyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2-methyl-4H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid; aus 2-Methyl-6-ethyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasN-diaminomethylene-2-methyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide; from 2-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2-methyl-6-ethyl-4H-1 -benzothiopyran-7-carbox- amid-1 ,1 -dioxid;N-diaminomethylene-2-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 3,6-Dimethyl-4H-1 -benzothiopyran-7-carbonsäuremethylester-1 , 1 - dioxid dasfrom 3,6-dimethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 - dioxide that
N-Diaminomethylen-3,6-dimethyl-4H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-3,6-dimethyl-4H-1-benzothiopyran-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 3-Methyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 3-methyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-methyl-4H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-methyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 3-Methyl-6-ethyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 3-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-methyl-6-ethyl-4H-1-benzothiopyran-7-carbox- amid-1,1-dioxid;N-diaminomethylene-3-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 4,6-Dimethyl-4H-1 -benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 4,6-dimethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-4,6-dimethyl-4H-1-benzothiopyran-7-carboxamid-N-diaminomethylene-4,6-dimethyl-4H-1-benzothiopyran-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 4-Methyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 4-methyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-4-methyl-4H-1-benzothiopyran-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-4-methyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide;
aus 4-Methyl-6-ethyl-4H-1-benzothiopyran-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 4-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-4-methyl-6-ethyl-4H-1 -benzothiopyran-7-carbox- amid- 1 ,1 -dioxid; aus 3-Hydroxy-6-methyl-thiochroman-7-carbonsäuremethylester- 1 ,1 -dioxid dasN-diaminomethylene-4-methyl-6-ethyl-4H-1-benzothiopyran-7-carboxamide-1,1-dioxide; from 3-hydroxy-6-methyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-hydroxy-6-methyl-thiochroman-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-hydroxy-6-methylthiochroman-7-carboxamide-1,1-dioxide;
aus 3-Hydroxy-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 3-hydroxy-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-hydroxy-thiochroman-7-carboxamid-1 , 1 -dioxid;N-diaminomethylene-3-hydroxy-thiochroman-7-carboxamide-1,1-dioxide;
aus 3-Hydroxy-6-ethyl-thiochroman-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 3-hydroxy-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-hydroxy-6-ethyl-thiochroman-7-carboxamid-1 ,1 - dioxid;N-diaminomethylene-3-hydroxy-6-ethylthiochroman-7-carboxamide-1, 1 - dioxide;
aus 4-Hydroxy-6-methyl-thiochroman-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 4-hydroxy-6-methyl-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-4-hydroxy-6-methyl-thiochroman-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-4-hydroxy-6-methylthiochroman-7-carboxamide-1,1-dioxide;
aus 4-Hydroxy-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-4-hydroxy-thiochroman-7-carboxamid-1 ,1 -dioxid;from 4-hydroxy-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-4-hydroxy-thiochroman-7-carboxamide-1,1-dioxide;
aus 4-Hydroxy-6-ethyl-thiochroman-7-carbonsäuremethy lester- 1 , 1 -dioxid dasfrom 4-hydroxy-6-ethyl-thiochroman-7-carbonsäuremethy lester-1, 1 -dioxid das
N-Diaminomethylen-4-hydroxy-6-ethyl-thiochroman-7-carboxamid-1 , 1 - dioxid;N-diaminomethylene-4-hydroxy-6-ethylthiochroman-7-carboxamide-1, 1 - dioxide;
aus 3-Oxo-6-methyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3-oxo-6-methyl-thiochroman-7-carboxamid-1 ,1- dioxid;from 3-oxo-6-methyl-thiochroman-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-3-oxo-6-methyl-thiochroman-7-carboxamide-1,1-dioxide;
aus 3-Oxo-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3-oxo-7-carboxamid-thiochroman- 1 ,1 -dioxid; aus 3-Oxo-6-ethyl-thiochroman-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3-oxo-6-ethyl-thiochroman-7-carboxamid-1 , 1 - dioxid;from 3-oxo-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-3-oxo-7-carboxamide-thiochroman-1, 1 -dioxide; from 3-oxo-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-3-oxo-6-ethyl-thiochroman-7-carboxamide-1, 1-dioxide;
aus 4-Oxo-6-methyl-thiochroman-7-carbonsäuremethylester-1 ,l-dioxid dasfrom 4-oxo-6-methyl-thiochroman-7-carboxylic acid methyl ester-1, l-dioxide that
N-Diaminomethylen-4-oxo-6-methyl-thiochroman-7-carboxamid-1 , 1 - dioxid;N-diaminomethylene-4-oxo-6-methyl-thiochroman-7-carboxamide-1, 1 - dioxide;
aus 4-Oxo-thiochroman-7-carbonsäuremethylester- 1 ,1 -dioxid das N-Diaminomethylen-4-oxo-thiochroman-7-carboxamid-1 ,1 -dioxid;from 4-oxo-thiochroman-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-4-oxo-thiochroman-7-carboxamide-1, 1 -dioxide;
aus 4-Oxo-6-ethyl-thiochroman-7-carbonsäuremethylester-1 , 1 -dioxid das N-Diaminomethylen-4-oxo-6-ethyl-thiochroman-7-carboxamid-1 , 1 - dioxid.from 4-oxo-6-ethyl-thiochroman-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-4-oxo-6-ethyl-thiochroman-7-carboxamide-1, 1-dioxide.
Beispiel 8Example 8
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 7-Methyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid das N-Diaminomethylen-7-methyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;from 7-methyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide the N-diaminomethylene-7-methyl-1, 4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 7-Ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid das N-Diaminomethylen-7-ethyl-1 ,4-benzoxathian-6-carboxamid-4,4-dioxid;from 7-ethyl-1,4-benzoxathiane-6-carboxylic acid methyl ester-4,4-dioxide the N-diaminomethylene-7-ethyl-1,4-benzoxathiane-6-carboxamide-4,4-dioxide;
aus 1 ,4-Benzoxathian-6-carbonsäuremethylester-4,4-dioxid das N-Diaminomethylen-1 ,4-benzoxathian-6-carboxamid-4,4-dioxid; aus 2,7-Dimethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid dasfrom 1,4-benzoxathiane-6-carboxylic acid methyl ester-4,4-dioxide the N-diaminomethylene-1,4-benzoxathiane-6-carboxamide-4,4-dioxide; from 2,7-dimethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2,7-dimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-2,7-dimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 2-Methyl-7-ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 2-methyl-7-ethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2-methyl-7-ethyl-1 ,4-benzoxathian-6-carboxamid-N-diaminomethylene-2-methyl-7-ethyl-1,4-benzoxathian-6-carboxamide
4,4-dioxid;4,4-dioxide;
aus 2-Methyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid das N-Diaminomethylen-1 ,4-benzoxathian-2-methyl-6-carboxamid-4,4- dioxid;from 2-methyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide the N-diaminomethylene-1, 4-benzoxathian-2-methyl-6-carboxamide-4,4-dioxide;
aus 3,7-Dimethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxjd dasfrom 3,7-dimethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxjd das
N-Diaminomethylen-3,7-dimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-3,7-dimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 3-Methyl-7-ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 3-methyl-7-ethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-3-methyl-7-ethyl-1 ,4-benzoxathian-6-carboxamid- 4,4-dioxid;N-diaminomethylene-3-methyl-7-ethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 3-Methyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid dasfrom 3-methyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-3-methyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-3-methyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 2,2,7-Trimethyl- 1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 2,2,7-trimethyl-1,4-benzoxathiane-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2,2,7-trimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid; aus 2,2-DimethyI-7-ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasN-diaminomethylene-2,2,7-trimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide; from 2,2-dimethyI-7-ethyl-1,4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2,2-dimethyl-7-ethyl-1 ,4-benzoxathian-6- carboxamid-4,4-dioxid;N-diaminomethylene-2,2-dimethyl-7-ethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 2,2-Dimethyl-1,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid dasfrom 2,2-dimethyl-1,4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2,2-dimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-2,2-dimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 3,3,7-Trimethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 3,3,7-trimethyl-1,4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-3,3,7-trimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid, F. 243-244° (Methansulfonat);N-diaminomethylene-3,3,7-trimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide, mp 243-244 ° (methanesulfonate);
aus 3,3-Dimethyl-7-ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 3,3-dimethyl-7-ethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-3,3-dimethyl-7-ethyl-1 ,4-benzoxathian-6- carboxamid-4,4-dioxid;N-diaminomethylene-3,3-dimethyl-7-ethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 3,3-Dimethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid dasfrom 3,3-Dimethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-3,3-dimethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-3,3-dimethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 2-Oxo-7-methyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4- dioxid dasfrom 2-oxo-7-methyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2-oxo-7-methyl-1 ,4-benzoxathian-6-carboxamid-N-diaminomethylene-2-oxo-7-methyl-1,4-benzoxathian-6-carboxamide
4,4-dioxid; aus 2-Oxo-7-ethyl-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid das4,4-dioxide; from 2-oxo-7-ethyl-1, 4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide
N-Diaminomethylen-2-oxo-7-ethyl-1 ,4-benzoxathian-6-carboxamid-4,4- dioxid;N-diaminomethylene-2-oxo-7-ethyl-1,4-benzoxathian-6-carboxamide-4,4-dioxide;
aus 2-Oxo-1 ,4-benzoxathian-6-carbonsäuremethylester-4,4-dioxid das N-Diaminomethylen-2-oxo-1 ,4-benzoxathian-6-carboxamid-4,4-dioxid.from 2-oxo-1,4-benzoxathian-6-carboxylic acid methyl ester-4,4-dioxide the N-diaminomethylene-2-oxo-1,4-benzoxathian-6-carboxamide-4,4-dioxide.
Beispiel 9Example 9
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-3, 1 -benzoxathian-7-carbonsäuremethylester-1 , 1 -dioxid das N-Diaminomethylen-6-methyl-3,1-benzoxathian-7-carboxamid-1,1- dioxid;from 6-methyl-3, 1-benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-6-methyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 6-Ethyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-6-ethyl-3,1-benzoxathian-7-carboxamid-1 ,1-dioxid;from 6-ethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-6-ethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 3,1-Benzoxathian-7-carbonsäuremethylester-1 , 1-dioxid das N-Diaminomethylen-3, 1 -benzoxathian-7-carboxamid-1 , 1 -dioxid;from 3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-3, 1-benzoxathian-7-carboxamide-1, 1-dioxide;
aus 2,6-Dimethyl-3,1 -benzoxathian-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 2,6-dimethyl-3,1 -benzoxathian-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,6-dimethyl-3,1-benzoxathian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2,6-dimethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 2-Methyl-6-ethyl-3, 1 -benzoxathian-7-carbonsäuremethylester- 1,1- dioxid dasfrom 2-methyl-6-ethyl-3, 1 -benzoxathian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2-methyl-6-ethyl-3, 1-benzoxathian-7-carboxamid- 1 ,1 -dioxid; aus 2-Methyl-3, 1 -benzoxathian-7-carbonsäuremethylester-1 , 1 -dioxid das N-Diaminomethylen-3, 1 -benzoxathian-2-methyl-7-carboxamid-1 , 1 - dioxid;N-diaminomethylene-2-methyl-6-ethyl-3, 1-benzoxathian-7-carboxamide-1, 1-dioxide; from 2-methyl-3, 1 -benzoxathian-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-3, 1 -benzoxathian-2-methyl-7-carboxamide-1, 1 - dioxide;
aus 4,6-Dimethyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1-dioxid dasfrom 4,6-dimethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-4,6-dimethyl-3,1-benzoxathian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-4,6-dimethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 4-Methyl-6-ethyl-3, 1 -benzoxathian-7-carbonsäuremethylester-1 , 1 - dioxid dasfrom 4-methyl-6-ethyl-3, 1-benzoxathian-7-carboxylic acid methyl ester-1, 1 - the dioxide
N-Diaminomethylen-4-methyl-6-ethyl-3,1-benzoxathian-7-carboxamid- 1 ,1 -dioxid;N-diaminomethylene-4-methyl-6-ethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 4-Methyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 4-methyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3, 1 -benzoxathian-4-methyl-7-carboxamid-1 , 1 - dioxid;N-diaminomethylene-3, 1-benzoxathiane-4-methyl-7-carboxamide-1, 1 - dioxide;
aus 2,2,6-Trimethyl-3, 1 -benzoxathian-7-carbonsäuremethylester- 1 ,1- dioxid dasfrom 2,2,6-trimethyl-3, 1 -benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide that
N-Diaminomethylen-2,2,6-trimethyl-3,1-benzoxathian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2,2,6-trimethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 2,2-Dimethyl-6-ethyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,2-dimethyl-6-ethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,2-dimethyl-6-ethyl-3,1-benzoxathian-6- carboxamid- 1 , 1 -dioxid;N-diaminomethylene-2,2-dimethyl-6-ethyl-3,1-benzoxathian-6-carboxamide-1,1-dioxide;
aus 2,2-Dimethyl-3,1-benzoxathian-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2,2-dimethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2,2-dimethyl-3,1-benzoxathian-7-carboxamid-1 ,1 - dioxid; aus 4,4,6-Trimethyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1- dioxid dasN-diaminomethylene-2,2-dimethyl-3,1-benzoxathian-7-carboxamide-1, 1 - dioxide; from 4,4,6-trimethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-4,4,6-trimethyl-3,1-benzoxathian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-4,4,6-trimethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 4,4-Dimethyl-6-ethyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 4,4-dimethyl-6-ethyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-4,4-dimethyl-6-ethyl-3, 1 -benzoxathian-6- carboxamid-1 ,1-dioxid;N-diaminomethylene-4,4-dimethyl-6-ethyl-3,1-benzoxathian-6-carboxamide-1,1-dioxide;
aus 4, 4-Dimethyl-3,1-benzoxathian-6-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 4, 4-dimethyl-3,1-benzoxathian-6-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-4,4-dimethyl-3, 1 -benzoxathian-6-carboxamid-1 , 1 - dioxid;N-diaminomethylene-4,4-dimethyl-3,1-benzoxathian-6-carboxamide-1,1-dioxide;
aus 4-Oxo-6-methyl-3,1-benzoxathian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 4-oxo-6-methyl-3,1-benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-4-oxo-6-methyl-3,1-benzoxathian-7-carboxamid-N-diaminomethylene-4-oxo-6-methyl-3,1-benzoxathian-7-carboxamide-
1 ,1 -dioxid;1, 1 dioxide;
aus 4-Oxo-6-ethyl-3,1 -benzoxathian-7-carbonsäuremethylester-1 ,1-dioxid dasfrom 4-oxo-6-ethyl-3,1 -benzoxathian-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-4-oxo-6-ethyl-3,1-benzoxathian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-4-oxo-6-ethyl-3,1-benzoxathian-7-carboxamide-1,1-dioxide;
aus 4-Oxo-3, 1-benzoxathian-6-carbonsäuremethylester-1,1-dioxid das N-Diaminomethylen-4-oxo-3,1-benzoxathian-6-carboxamid-1 ,1 -dioxid. from 4-oxo-3, 1-benzoxathian-6-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-4-oxo-3,1-benzoxathian-6-carboxamide-1, 1-dioxide.
Beispiel 10Example 10
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-1,4-benzodithian-7-carbonsäuremethylester-1,1-dioxid dasfrom 6-methyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-6-methyl-1,4-benzodithian-7-carboxamid-1,1- dioxid;N-diaminomethylene-6-methyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus6-Ethyl-1,4-benzodithian-7-carbonsäuremethylester-1,1-dioxid das N-Diaminomethylen-6-ethyl-1,4-benzodithian-7-carboxamid-1,1 -dioxid;from 6-ethyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-6-ethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 1,4-benzodithian-7-carbonsäuremethylester- 1,1 -dioxid das N-Diaminomethylen-1 ,4-benzodithian-7-carboxamid- 1 , 1 -dioxid;from 1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2,6-Dimethyl-1,4-benzodithian-7-carbonsäuremethylester-1,1 -dioxid dasfrom 2,6-dimethyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,6-dimethyl-1,4-benzodithian-7-carboxamid-1,1- dioxid;N-diaminomethylene-2,6-dimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus2-Methyl-6-ethyl-1,4-benzodithian-7-carbonsäuremethylester-1,1- dioxid dasfrom 2-methyl-6-ethyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2-methyl-6-ethyl-1,4-benzodithian-7-carboxamid- 1,1-dioxid;N-diaminomethylene-2-methyl-6-ethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2-Methyl-1,4-benzodithian-7-carbonsäuremethylester- 1,1 -dioxid das N-Diaminomethylen-2-methyl-1,4-benzodithian-7-carboxamid-1,1- dioxid;from 2-methyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide the N-diaminomethylene-2-methyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 3,6-Dimethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1-dioxid dasfrom 3,6-dimethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-3,6-dimethyl-1,4-benzodithian-7-carboxamid-1,1- dioxid; aus 3-Methyl-6-ethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1- dioxid dasN-diaminomethylene-3,6-dimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide; from 3-methyl-6-ethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-methyl-6-ethyl-1 ,4-benzodithian-7-carboxamid-N-diaminomethylene-3-methyl-6-ethyl-1,4-benzodithian-7-carboxamide
1 ,1-dioxid;1, 1-dioxide;
aus 3-Methyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3-methyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;from 3-methyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-3-methyl-1, 4-benzodithian-7-carboxamide-1, 1-dioxide;
aus 2,2,6-Trimethyl- 1 ,4-benzodithian-7-carbonsäuremethylester- 1 , 1 -dioxid dasfrom 2,2,6-trimethyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2,2,6-trimethyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2,2,6-trimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2,2-Dimethyl-6-ethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2,2-dimethyl-6-ethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-2,2-dimethyl-6-ethyl-1 ,4-benzodithian-6- carboxamid- 1 ,1 -dioxid;N-diaminomethylene-2,2-dimethyl-6-ethyl-1,4-benzodithian-6-carboxamide-1,1-dioxide;
aus 2,2-Dimethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1-dioxid dasfrom 2,2-dimethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-2,2-dimethyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2,2-dimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 3,3,6-Trimethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1-dioxid dasfrom 3,3,6-trimethyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-3,3,6-trimethyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3,3,6-trimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 3,3-Dimethyl-6-ethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 3,3-dimethyl-6-ethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3,3-dimethyl-6-ethyl-1 ,4-benzodithian-6- carboxamid- 1 , 1 -dioxid; aus 3,3-Dimethyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1-dioxid dasN-diaminomethylene-3,3-dimethyl-6-ethyl-1,4-benzodithian-6-carboxamide-1,1-dioxide; from 3,3-Dimethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide
N-Diaminomethylen-3,3-dimethyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3,3-dimethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2-Oxo-6-methyl-1,4-benzodithian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 2-oxo-6-methyl-1,4-benzodithian-7-carboxylic acid methyl ester-1,1-dioxide
N-Diaminomethylen-2-oxo-6-methyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2-oxo-6-methyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2-Oxo-6-ethyl-1 ,4-benzodithian-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 2-oxo-6-ethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-2-oxo-6-ethyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-2-oxo-6-ethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 2-Oxo-l , 4-benzodithian-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-2-oxo-1 ,4-benzodithian-7-carboxamid-1 ,1 -dioxid;from 2-oxo-l, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide the N-diaminomethylene-2-oxo-1, 4-benzodithian-7-carboxamide-1, 1-dioxide;
aus 3-Oxo-6-methyl-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1- dioxid dasfrom 3-oxo-6-methyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1-dioxide the
N-Diaminomethylen-3-oxo-6-methyl-1 ,4-benzodithian-7-carboxamid-1 ,1- dioxid;N-diaminomethylene-3-oxo-6-methyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 3-Oxo-6-ethyl-1 ,4-benzodithian-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 3-oxo-6-ethyl-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1 -dioxide
N-Diaminomethylen-3-oxo-6-ethyl-1,4-benzodithian-7-carboxamid-1,1- dioxid;N-diaminomethylene-3-oxo-6-ethyl-1,4-benzodithian-7-carboxamide-1,1-dioxide;
aus 3-Oxo-1 ,4-benzodithian-7-carbonsäuremethylester-1 ,1 -dioxid das N-Diaminomethylen-3-oxo-1 ,4-benzodithian-7-carboxamid-1 , 1 -dioxid. Beispiel 11from 3-oxo-1, 4-benzodithian-7-carboxylic acid methyl ester-1, 1 -dioxide the N-diaminomethylene-3-oxo-1, 4-benzodithian-7-carboxamide-1, 1 -dioxide. Example 11
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäuremethylester-from 6-methyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester
1 ,1 -dioxid das 7-N-Diaminomethylen-carbamoyl-6-methyl-3,4-dihydro-2H-1 ,4-benzo- thiazin-1 ,1 -dioxid;1, 1-dioxide 7-N-diaminomethylene-carbamoyl-6-methyl-3,4-dihydro-2H-1, 4-benzothiazine-1, 1-dioxide;
aus 6-Ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäuremethylester-from 6-ethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester
1,1 -dioxid das 7-N-Diaminomethylen-carbamoyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzo- thiazin-1 ,1 -dioxid;1,1-dioxide the 7-N-diaminomethylene-carbamoyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3,4-Dihydro-2H-1 ,4-benzothiazin-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1 -dioxide
7-N-Diaminomethylen-carbamoyl-3,4-dihydro-2H-1 ,4-benzothiazin-1 , 1 - dioxid;7-N-diaminomethylene-carbamoyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 4,6-Dimethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure-methyl- ester- 1 ,1 -dioxid dasfrom 4,6-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-4,6-dimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-4,6-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 4-Methyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 4-methyl-6-ethyl-3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-4-methyl-6-ethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-4-methyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 4-Methyl-3,4-dihydro-2H- 1 ,4-benzothiazin-7-carbonsäuremethylester-from 4-methyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester
1 , 1 -dioxid das1, 1 -dioxide
7-N-Diaminomethylen-carbamoyl-4-methyl-3,4-dihydro-2H-1 ,4-benzo- thiazin-1 ,1 -dioxid; aus 3,6-Dimethyl-3,4-dihydro-2H- 1 ,4-benzothiazin-7-carbonsäuremethyl- ester- 1 ,1 -dioxid das7-N-diaminomethylene-carbamoyl-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide; from 3,6-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,6-dimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 , 1 -dioxid;7-N-diaminomethylene-carbamoyl-3,6-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3-Methyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 3-methyl-6-ethyl-3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-3-methyl-6-ethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-3-methyl-6-ethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3-Methyl-3,4-dihydro-2H- 1 ,4-benzothiazin-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 3-methyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3-methyl-3,4-dihydro-2H-1 ,4-benzo- thiazin- 1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-3-methyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3,4,6-Trimethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 , 1 -dioxid dasfrom 3,4,6-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,4,6-trimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-3,4,6-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3,4-Dimethyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 3,4-dimethyl-6-ethyl-3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-3,4-dimethyl-6-ethyl-3,4-dihydro-2H-7-N-diaminomethylene-carbamoyl-3,4-dimethyl-6-ethyl-3,4-dihydro-2H-
1 ,4-benzothiazin- 1 , 1 -dioxid;1,4-benzothiazine-1,1-dioxide;
aus 3,4-Dimethyl-3,4-dihydro-2H- 1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 3,4-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,4-dimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 , 1 -dioxid;7-N-diaminomethylene-carbamoyl-3,4-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3,3,6-Trimethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 3,3,6-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3,6-trimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 , 1 -dioxid; aus 3,3-Dimethyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid das7-N-diaminomethylene-carbamoyl-3,3,6-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide; from 3,3-dimethyl-6-ethyl-3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3-dimethyl-6-ethyl-3,4-dihydro-2H-7-N-diaminomethylene-carbamoyl-3,3-dimethyl-6-ethyl-3,4-dihydro-2H-
1 ,4-benzothiazin-1 ,1 -dioxid;1,4-benzothiazine-1,1-dioxide;
aus 3,3-Dimethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester- 1 , 1 -dioxid dasfrom 3,3-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3-dimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-3,3-dimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide;
aus 3,3,4,6-Tetramethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methyl-ester-1 ,1 -dioxid dasfrom 3,3,4,6-tetramethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3,4,6-tetramethyl-3,4-dihydro-2H-7-N-diaminomethylene-carbamoyl-3,3,4,6-tetramethyl-3,4-dihydro-2H-
1 ,4-benzothiazin-1 ,1 -dioxid;1,4-benzothiazine-1,1-dioxide;
aus 3,3,4-Trimethyl-6-ethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbon- säuremethylester-1 ,1 -dioxid dasfrom 3,3,4-trimethyl-6-ethyl-3,4-dihydro-2H-1, 4-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3,4-trimethyl-6-ethyl-3,4-dihydro-2H-7-N-diaminomethylene-carbamoyl-3,3,4-trimethyl-6-ethyl-3,4-dihydro-2H-
1 ,4-benzothiazin-1 , 1 -dioxid;1,4-benzothiazine-1,1-dioxide;
aus 3,3,4-Trimethyl-3,4-dihydro-2H-1 ,4-benzothiazin-7-carbonsäure- methylester-1 ,1 -dioxid dasfrom 3,3,4-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,3,4-trimethyl-3,4-dihydro-2H-1 ,4- benzothiazin-1 , 1 -dioxid.7-N-diaminomethylene-carbamoyl-3,3,4-trimethyl-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide.
Beispiel 12Example 12
Analog Beispiel 1 erhält manAnalogously to Example 1, one obtains
aus 6-Methyl-3,4-dihydro-2H-1 ,3-benzothiazin-7-carbonsäuremethylester- 1 ,1 -dioxid dasfrom 6-methyl-3,4-dihydro-2H-1,3-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-6-methyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 ,1 -dioxid; aus 6-Ethyl-3,4-dihydro-2H-1 ,3-benzothiazin-7-carbonsäuremethylester- 1 ,1 -dioxid das7-N-diaminomethylene-carbamoyl-6-methyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide; from 6-ethyl-3,4-dihydro-2H-1,3-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-6-ethyl-3,4-dihydro-2H-1,3- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-6-ethyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 3,4-Dihydro-2H-1 ,3-benzothiazin-7-carbonsäuremethylester-1 ,1 -dioxid dasfrom 3,4-dihydro-2H-1, 3-benzothiazine-7-carboxylic acid methyl ester-1, 1 -dioxide
7-N-Diaminomethylen-carbamoyl-3,4-dihydro-2H-1 ,3-benzothiazin-1 ,1- dioxid;7-N-diaminomethylene-carbamoyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 3,6-Dimethyl-3,4-dihydro-2H-1 ,3-benzothiazin-7-carbonsäure- methylester-1 ,1 -dioxid dasfrom 3,6-dimethyl-3,4-dihydro-2H-1,3-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3,6-dimethyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 , 1 -dioxid;7-N-diaminomethylene-carbamoyl-3,6-dimethyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 3-Methyl-6-ethyl-3,4-dihydro-2H-1,3-benzothiazin-7-carbonsäure- m ethylester- 1 ,1 -dioxid dasfrom 3-methyl-6-ethyl-3,4-dihydro-2H-1,3-benzothiazine-7-carboxylic acid m ethyl ester-1, 1-dioxide that
7-N-Diaminomethylen-carbamoyl-3-methyl-6-ethyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 , 1 -dioxid;7-N-diaminomethylene-carbamoyl-3-methyl-6-ethyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 3-Methyl-3,4-dihydro-2H- 1 ,3-benzothiazin-7-carbonsäuremethylester- 1,1 -dioxid dasfrom 3-methyl-3,4-dihydro-2H-1,3-benzothiazine-7-carboxylic acid methyl ester-1,1-dioxide
7-N-Diaminomethylen-carbamoyl-3-methyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-3-methyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 4-Oxo-6-methyl-3,4-dihydro-2H-1 ,3-benzothiazin-7-carbonsäure- methylester- 1 , 1 -dioxid dasfrom 4-oxo-6-methyl-3,4-dihydro-2H-1, 3-benzothiazine-7-carboxylic acid methyl ester-1, 1 -dioxide
7-N-Diaminomethylen-carbamoyl-4-oxo-6-methyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 ,1 -dioxid;7-N-diaminomethylene-carbamoyl-4-oxo-6-methyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide;
aus 4-Oxo-6-ethyl-3,4-dihydro-2H-1 ,3-benzothiazin-7-carbonsäure- methylester- 1 ,1 -dioxid dasfrom 4-oxo-6-ethyl-3,4-dihydro-2H-1, 3-benzothiazine-7-carboxylic acid methyl ester-1, 1-dioxide
7-N-Diaminomethylen-carbamoyl-4-oxo-6-ethyl-3,4-dihydro-2H-1 ,3- benzothiazin-1 , 1 -dioxid; aus 4-0x0-3, 4-dihydro-2H-1 , 3-benzothiazin-7-carbonsäuremethylester- 1 ,1 -dioxid das7-N-diaminomethylene-carbamoyl-4-oxo-6-ethyl-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide; from 4-0x0-3, 4-dihydro-2H-1, 3-benzothiazine-7-carboxylic acid methyl ester-1, 1 -dioxide
7-N-Diaminomethylen-carbamoyl-4-oxo-3,4-dihydro-2H-1 ,3-benzothia- zin-1 ,1 -dioxid.7-N-diaminomethylene-carbamoyl-4-oxo-3,4-dihydro-2H-1,3-benzothiazine-1,1-dioxide.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat werden in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abge¬ füllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile . Each injection jar contains 5 mg of active ingredient.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2P04 • 2 H20, 28,48 g Na2HP04 • 12 H20 und 0,1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen. Beispiel E: Tabletten500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kar¬ toffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient .
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatine¬ kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingun¬ gen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims

Patentansprüche claims
1. Cyclische Sulfone der Formel1. Cyclic sulfones of the formula
worinwherein
und R2 jeweils unabhängig voneinander H, A, CF3, CH2F, CHF2, C2F5, Hai, OH, OA, NH2, NHA, NA2, N02 oder CN, and R2 each independently of one another H, A, CF 3 , CH 2 F, CHF 2 , C 2 F 5 , shark, OH, OA, NH 2 , NHA, NA 2 , N0 2 or CN,
CR4R5, C=Z, O, S, NH, NA oder NRs,CR4R5, C = Z, O, S, NH, NA or NRs,
Y CR6R7, C=Z, O, NH, NA oder NRsY CR6R7, C = Z, O, NH, NA or NRs
O, S, NH, NA, NOH, NOA, CH2, CHA oder CA2,O, S, NH, NA, NOH, NOA, CH 2 , CHA or CA 2 ,
und R? jeweils unabhängig voneinander H, A, Rs, Hai, OH, OA, and R? each independently of one another H, A, Rs, Hai, OH, OA,
SH, SA, NH2, NHA oder NA2 oder aberSH, SA, NH 2 , NHA or NA 2 or else
Rs und Re oderRs and Re or
R7 und Rβ jeweils zusammen auch eine Bindung, wobei in jedemR7 and R β together each also form a bond, being in each
Molekül maximal nur eine derartige Bindung auftreten kann; R4 und Rs zusammen auch 0-(CH2)2-0 oder 0-(CH2)3-0,Molecule at most only such a bond can occur; R4 and Rs together also 0- (CH 2 ) 2 -0 or 0- (CH 2 ) 3 -0,
Rβ und Rs jeweils unabhängig voneinander H oder A,R β and Rs are each independently H or A,
A Alkyl mit 1 bis 6 C-Atomen,A alkyl with 1 to 6 carbon atoms,
Hai F, Cl, Br oder I undShark F, Cl, Br or I and
Rs unsubstituiertes oder ein-, zwei- oder dreifach durch A, OA, NH2, NHA, NA2, F, Cl, Br und/oder CF3 substitu¬ iertes Phenyl oder Benzyl undRs unsubstituted or mono-, di- or trisubstituted by A, OA, NH 2 , NHA, NA 2 , F, Cl, Br and / or CF 3 phenyl or benzyl and
n 0 oder 1n 0 or 1
bedeuten, sowie deren physiologisch unbedenkliche Salze.mean, and their physiologically acceptable salts.
2. (a) N-Diaminomethylen-2,3-dihydro-3-hydroxy-1 -benzothiophen-6- carboxamid- 1 ,1 -dioxid;2. (a) N-diaminomethylene-2,3-dihydro-3-hydroxy-1-benzothiophene-6-carboxamide-1,1-dioxide;
(b) N-Diaminomethylen-2,3-dihydro-3-hydroxy-5-methyl-1 - benzothiophen-6-carboxamid-1 , 1 -dioxid;(b) N-diaminomethylene-2,3-dihydro-3-hydroxy-5-methyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
(c) N-Diaminomethylen-2,3-dihydro-3-hydroxy-3,5-dimethyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid;(c) N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
(d) N-Diaminomethylen-2,3-dihydro-3-methoxy-3,5-dimethyl-1- benzothiophen-6-carboxamid-1 ,1 -dioxid;(d) N-diaminomethylene-2,3-dihydro-3-methoxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
(e) N-Diaminomethylen-2,3-dihydro-3,5-dimethyl-1-benzothiophen- 6-carboxam id- 1 , 1 -dioxid; (f) N-Diaminomethylen-2,3-dihydro-3-hydroxy-3,5-dimethyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid;(e) N-diaminomethylene-2,3-dihydro-3,5-dimethyl-1-benzothiophene-6-carboxam id-1,1-dioxide; (f) N-diaminomethylene-2,3-dihydro-3-hydroxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide;
(g) N-Diaminomethylen-2,3-dihydro-3-methoxy-3,5-dimethyl-1- benzothiophen-6-carboxamid-1 , 1 -dioxid(g) N-Diaminomethylene-2,3-dihydro-3-methoxy-3,5-dimethyl-1-benzothiophene-6-carboxamide-1,1-dioxide
gemäß Anspruch 1 , sowie deren physiologisch unbedenkliche Salze.according to claim 1, and their physiologically acceptable salts.
3. Verfahren zur Herstellung von cyclischen Sulfonen der Formel I gemäß Anspruch 1 sowie von deren Salzen, dadurch gekennzeichnet, daß man eine Verbindung der Formel II3. A process for the preparation of cyclic sulfones of the formula I according to claim 1 and of their salts, characterized in that a compound of formula II
worin Ri, R2, Rβ, R9, X, Y und n die zuvor angegebenen Bedeu- tungen habenwhere Ri, R2, R β , R9, X, Y and n have the meanings given above
undand
Q Cl, Br, OA, O-CO-A, O-CO-Ph, OH oder eine andere reaktionsfähige veresterte OH-Gruppe bzw. leicht nucleophil substituierbare Abgangsgruppe bedeutet,Q is Cl, Br, OA, O-CO-A, O-CO-Ph, OH or another reactive esterified OH group or easily nucleophilically substitutable leaving group,
mit Guanidin umsetzt,reacted with guanidine,
oder daß man eine sonst der Formel I entsprechende Verbindung, die jedoch anstelle eines oder mehrerer Wasserstoffatome eine oder mehrere reduzierbare Gruppe(n) und/oder eine oder mehrere zusätz¬ liche C-C- und/oder C-N-Bindung(en) enthält, mit einem reduzieren¬ den Mittel behandelt, oder daß man eine sonst der Formel I entsprechende Verbindung, die jedoch anstelle eines oder mehrerer Wasserstoffatome eine oder mehrere solvolysierbare Gruppe(n) enthält, mit einem solvolysieren- den Mittel behandeltor that a compound which otherwise corresponds to the formula I, but which instead of one or more hydrogen atoms contains one or more reducible group (s) and / or one or more additional CC and / or CN bond (s), with a reducing agents treated, or that a compound otherwise corresponding to formula I, which, however, contains one or more solvolysable groups instead of one or more hydrogen atoms, is treated with a solvolysing agent
und/oder daß man eine erhaltene Base der Formel I durch Behan¬ deln mit einer Säure in eines ihrer Salze umwandelt.and / or that a base of the formula I obtained is converted into one of its salts by treatment with an acid.
4. Verfahren zur Herstellung pharmazeutischer Zubereitungen, dadurch gekennzeichnet, daß man eine Verbindung der Formel I gemäß4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of formula I according to
Anspruch 1 und/oder eines ihrer physiologisch unbedenklichen Salze zusammen mit mindestens einem festen, flüssigen oder halbflüssigen Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.Claim 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary in a suitable dosage form.
5. Pharmazeutische Zubereitung, gekennzeichnet durch einen Gehalt an mindestens einer Verbindung der allgemeinen Formel I gemäß Anspruch 1 und/oder einem ihrer physiologisch unbedenklichen Salze.5. Pharmaceutical preparation, characterized in that it contains at least one compound of the general formula I according to Claim 1 and / or one of its physiologically acceptable salts.
6. Verwendung von Verbindungen der Formel I nach Anspruch 1 oder von deren physiologisch unbedenklichen Salzen zur Herstellung eines Arzneimittels.6. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts for the manufacture of a medicament.
7. Verwendung von Verbindungen der Formel I nach Anspruch 1 oder von deren physiologisch unbedenklichen Salzen bei der Bekämpfung von Krankheiten.7. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts in the control of diseases.
8. Verwendung von Verbindungen der Formel I nach Anspruch 1 zur Herstellung von Arzneimitteln zur Behandlung von Arrhythmien, Angina pectoris, Infarkten sowie zur präventiven Behandlung der genannten Indikationen. 8. Use of compounds of formula I according to claim 1 for the manufacture of medicaments for the treatment of arrhythmias, angina pectoris, infarcts and for the preventive treatment of the indications mentioned.
EP96943131A 1995-12-23 1996-12-16 HETEROCYCLYL-CONDENSED BENZOYLGUANIDINES, THEIR PRODUCTION AND USE AS INHIBITORS OF THE CELLULAR Na+/H+-ANTIPORTER Withdrawn EP0873335A1 (en)

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DE19548708A DE19548708A1 (en) 1995-12-23 1995-12-23 Cyclic sulfones
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TW200614995A (en) * 2004-11-10 2006-05-16 Nicholas Piramal India Ltd Tricyclic guanidine derivatives as sodium-proton exchange inhibitors

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CA2241143A1 (en) 1997-07-03
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CZ199798A3 (en) 1998-10-14
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DE19548708A1 (en) 1997-06-26

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