EP0000750A1 - 1,2-Benzisothiazoles and process for their preparation - Google Patents
1,2-Benzisothiazoles and process for their preparation Download PDFInfo
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- EP0000750A1 EP0000750A1 EP78100536A EP78100536A EP0000750A1 EP 0000750 A1 EP0000750 A1 EP 0000750A1 EP 78100536 A EP78100536 A EP 78100536A EP 78100536 A EP78100536 A EP 78100536A EP 0000750 A1 EP0000750 A1 EP 0000750A1
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- benzisothiazole
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- benzisothiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
Definitions
- the invention relates to new 1,2-benzisothiazoles and a process for the preparation of 1,2-benzisothiazoles by reacting o-haloaryl ketones with ammonia and elemental sulfur.
- DOS 25 03 699 relates to a process for the preparation of 1,2-benzisothiazoles of the formula in which R 1 is hydrogen, an aliphatic, cycloaliphatic or an optionally fused aromatic residue, halogen, an alkoxy or nitro group or the rest.
- R 1 is hydrogen, an aliphatic, cycloaliphatic or an optionally fused aromatic residue, halogen, an alkoxy or nitro group or the rest.
- the individual radicals R 2 may be the same or different and each represent hydrogen, an aliphatic, cycloaliphatic, araliphatic or aromatic radical ,. designated; where o-haloaryl aldehydes of the formula in which X represents halogen and R 1 has the abovementioned meaning, reacted with ammonia and elemental sulfur.
- R 1 is hydrogen, an aliphatic, cycloaliphatic or an optionally fused aromatic residue, halogen, an alkoxy group, nitro group or the rest in which the individual radicals R 2 can be identical or different and in each case denote hydrogen, an aliphatic, cycloaliphatic, araliphatic or aromatic radical, and R3 denotes a substituted mono- nuclear or unsubstituted polynuclear or substituted polynuclear, aromatic radical or a heterocyclic radical is found.
- the reaction can be represented as follows:
- the process according to the invention starts from readily accessible starting materials and surprisingly provides 1,2-benzisothiazoles in a better yield and purity in a simple and economical manner.
- the ketones II can also be converted to 1,2-benzisothiazoles which have not been described so far and which are substituted in the 3-position by aromatic or heterocyclic radicals.
- Preferred starting materials II and correspondingly preferred 1,2-benzisothiazoles I are those in the formulas R 1 of which is an alkyl radical with up to 6 carbon atoms optionally substituted by a carbonamide group, a cycloalkyl radical with 5 to 12 carbon atoms, a phenyl or naphthyl radical, each of which also fuses can be a fused naphthoquinone- (1,4) -ylene radical, hydrogen, bromine or especially chlorine, an alkoxy group with 1 to 4 carbon atoms, a nitro group or the rest wherein the individual radicals R 2 are the same or different and each hydrogen represents an alkyl radical with 1 to 6 carbon atoms, an alkenyl radical with 3 to 6 carbon atoms, a cycloalkyl radical with 5 to 8 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical, R 3 denotes an unsubstituted or a through one or more,
- radicals can also be substituted by groups which are inert under the reaction conditions, for example alkyl groups or alkoxy groups each having 1 to 4 carbon atoms, nitro groups, carbonamido groups.
- groups which are inert under the reaction conditions for example alkyl groups or alkoxy groups each having 1 to 4 carbon atoms, nitro groups, carbonamido groups.
- substances which form the starting materials II under the reaction conditions for example the corresponding aldehyde acetals such as o-chlorobenzophenone dimethylacetal.
- Starting materials II, ammonia and elemental sulfur can be used in approximately stoichiometric amounts, but a ratio of 2 to 10 moles of ammonia and / or 0.9 to 1.1 gram atom of sulfur per mole of starting material II is preferably used.
- suitable starting materials II are: 5-nitro-, 4-dimethylamino-, 4-diethylamino-, 4-diallylamino-, 4-di- (2'-methylallyl) -amino-, 4- (N-methyl-N -2-carbonamido-ethylamino) -, 6-methyl, 3-ethyl, 5-hexyl, 6-isobutyl, 5-propyl, 4-tert-butyl, 4-cyclohexyl, 4-cyclopentyl -, 5-phenyl-, 4-phenyl-, 4-nitrophenyl-, 4-p-toluyl-, 4-p-ethoxyphenyl-, 3-di- (2'-ethoxyethyl) -amino-, 4-naphthyl-, 4-bromo, 6-methoxy, 6-dicyclohexylamino, 4-dibenzylamino, 4-diphenylamino, 4-p-xylyl-2-chloro
- the reaction is generally carried out at a temperature of 20 to 250 ° C., advantageously from 20 to 200 ° C., preferably from 40 to 180 ° C., in particular from 40 to 120 ° C., without pressure or under pressure, continuously or batchwise.
- the reaction pressure is generally determined by the total vapor pressure of the components at the reaction temperature.
- organic solvents which are inert under the reaction conditions can be used, for example aromatic hydrocarbons such as toluene, Ethylbenzene, o-, m-, p-xylene, isopropylbenzene; Alkanols and cycloalkanols such as ethanol, n-butanol, isobutanol, methyl glycol, cyclohexanol, propanol, methanol, 2-ethyl hexanol; Ether, for example ethyl propyl ether, diisobutyl ether, methyl tert.
- aromatic hydrocarbons such as toluene, Ethylbenzene, o-, m-, p-xylene, isopropylbenzene
- Alkanols and cycloalkanols such as ethanol, n-butanol, isobutanol, methyl glycol, cyclohexan
- the solvent is expediently used in an amount of 200 to 10,000 percent by weight, preferably 300 to 1,000 percent by weight, based on starting material II.
- the reaction can be carried out as follows: Starting material II, elemental sulfur and ammonia, optionally in the presence of a solvent, are reacted with one another in a pressure reactor for 3 to 10 hours at the aforementioned temperature.
- the 1,2-benzisothiazole I is obtained from the reaction mixture by the usual methods, e.g. by fractional distillation, filtration and, if appropriate, subsequent recrystallization from a suitable solvent, e.g. Ligroin.
- the reaction mixture can also be poured into water after removal of excess ammonia and solvent, the mixture formed with a suitable solvent, e.g. Extract methylene chloride, benzene and work up the extract in the aforementioned manner.
- the compounds which can be prepared by the process of the invention are valuable starting materials for the production of dyes, crop protection agents and pharmaceuticals.
- the 1,2-benzisothiazoles with the preferred meanings of R 3 are advantageously suitable for the abovementioned uses.
- 1,2-benzisothiazoles of the formula L. in which R 1 has the meaning given above by reaction with a diamine of the general formula in the Y a bridge member of the formula represents, and elemental sulfur, advantageously in an inert, organic solvent, compounds of the formula in which R 1 has the abovementioned meaning, in particular a hydrogen atom, an alkyl radical having 1 to 4'C atoms, an alkoxy radical having 1 to 3 C atoms, a halogen atom or a nitro group and Y has the meaning given, and, if appropriate, the Compounds IV thus obtained can be converted into physiologically acceptable acid addition salts.
- R is a hydrogen atom, a halogen atom, especially a chlorine or bromine atom, a nitro group, an alkyl group or an alkoxy group each having 1 to 4 carbon atoms and Y 1 Methyläthylen-1,2 and trimethylene-1 To name 3. Hydrogen and R 1 -methyl-1,2 and trimethylene-1,3 are particularly preferred for R 1 .
- the aforementioned reaction of the compounds IV is advantageously carried out at temperatures from 40 to 150 ° C., preferably at temperatures from 70 to 120 ° C.
- Appropriate solvents for the reaction of the compounds IV are aromatic hydrocarbons, in particular benzene hydrocarbons, such as benzene or toluene, lower alcohols, such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, saturated cyclic or aliphatic ethers, such as dibutyl ether or dioxane, glycol ether, in particular monoalkyl ethers of glycol, such as glycol monomethyl ether or glycol monoethyl ether, or mixtures of the solvents mentioned.
- aromatic hydrocarbons in particular benzene hydrocarbons, such as benzene or toluene
- lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol
- saturated cyclic or aliphatic ethers such as dibutyl ether or dioxane
- glycol ether in particular
- the benzene carbon. wa.sserstoffe advantageously benzene and toluene, and monoalkyl ether of glycol, especially glycol monomethyl ether, preferred.
- the diamine of the formula III calculated on the compound of the formula I or Ib, is used in stoichiometric or in excess amount, optionally up to 3 times the stoichiometric amount.
- the elemental sulfur, calculated on the compound Ib, is used in a stoichiometric or excess amount up to 1.2 times the amount above the stoichiometric amount. turns.
- the stoichiometric amount of elemental sulfur is preferably used.
- the starting compounds of the formula Ib can be obtained, for example, by side chain chlorination of 3- (4-methylphenyl) -1,2-benzisothiazole I with chlorine at about 170 ° C. and under UV radiation.
- 3- [4- (1,3-diazacycloalken-2-yl) phenyl] -1,2-benzisothiazoles IV and their physiologically tolerated acid addition salts have valuable pharmacological properties. They can be used to produce pharmaceutical preparations which, in addition to conventional pharmaceutical carriers and diluents, contain a compound of the formula IV as an active ingredient.
- 3- [4- (Tetrahydropyrimidin-2-yl) -phenyl] -1,2-benzisothiazole, 3- [4- (methylimidazolin-2-yl) -phenyl] -1,2-benzisothiazole and their physiologically tolerable are particularly suitable Acid addition salts.
- Substances IV and their physiologically compatible acid addition salts are characterized by a strong antiarrhythmic effect and are particularly suitable for the pharmacotherapy of cardiac arrhythmias.
- the substances were administered orally to rats (strain: Sprague Dawley, weight: 180-240 g) 45 minutes before the start of anesthesia (thiobutabarbital 100 mg / kg i.p.).
- Aconitin served as the arrhythmogenic substance and was infused intravenously 60 minutes after the substance application (dosage rate: 0.005 mg / kg ⁇ minute).
- dose rate 0.005 mg / kg ⁇ minute.
- the dose was determined, which prolonged the infusion duration by 50% (ED 50%).
- the known substance served as reference substance Antiarrhythmicum procainamide.
- the acute toxicity was determined in groups of 10 or 20 female Swiss mice, weight 20-26 g, with intraperitoneal application.
- the LD 50 was calculated as the dose (probit analysis) after which 50% of the animals died within 7 days.
- Table 1 shows that the compounds of Examples 2 and 3, compared to the antiarrhythmicum procainamide, are around 5 times more antiarrhythmic. Another advantage is that the effect of the maximum dose reaches 114 (example 2) or 73% (example 3) higher values than that of procainamide; i.e. that the aconitine antagonism of the tested compounds is significantly more pronounced than that of procainamide.
- the therapeutic index as the quotient of the lethal dose (LD 50) and the antiarrhythmic dose (ED 50%) is 4 times (example 2) and 2.8 times (example 3). larger than that of procainamide.
- the therapeutic agents or preparations are produced in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage.
- the preferred preparations are in a dosage form which is suitable for oral administration.
- dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
- parenteral forms of preparation such as injection solutions or additives to infusion solutions, can also be used.
- Suppositories may also be mentioned as preparations.
- the corresponding tables can, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn, starch, alginic acid or polyvinylpyrrolidone, binders such as starch or Gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
- auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn, starch, alginic acid or polyvinylpyrroli
- coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. It can also Drageehülle consist of several layers, wherein the excipients mentioned above for the tablets can be used.
- agents conventionally used in tablet coatings for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. It can also Drageehülle consist of several layers, wherein the excipients mentioned above for the tablets can be used.
- Solutions or suspensions with the active ingredients according to the invention can additionally contain taste-improving agents such as saccharin, cyclamate or sugar and, for example, flavoring agents such as vanillin or orange extract. They can also contain suspending aids such as sodium carboxymethyl cellulose or preservatives such as parahydroxybenzoates.
- Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier, such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.
- Suitable suppositories can be produced, for example, by mixing with the carrier material provided, such as neutral fats or polyethylene glycols or their derivatives.
- the single dose of a substance according to the invention in humans is 5 to 100 mg, preferably 10 to 80 mg.
- the parts given in the following examples are parts by weight. They relate to parts by volume like kilograms to liters.
- the crystals formed are suction filtered, dissolved in 300 parts of water, filtered, the filtrate with conc. NaOH made alkaline and extracted with methylene chloride.
- the methylene chloride phase is dried and 20 parts of hydrogen chloride gas are introduced. 17 parts of the desired end product are obtained as colorless crystals with a melting point of 243 ° C. The yield corresponds to 52% of theory.
- the active ingredient is moistened with polyvinylpyrrolidone in a 10 percent aqueous solution, passed through a sieve with a mesh size of 1.0 mm and dried at 50 ° C. These granules are mixed with polyethylene glycol (average M.G. 4000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into tablets of 280 mg each.
- the mixture of the active substance with lactose and corn starch is granulated with an 8% aqueous solution of the polyvinylpyrrolidone through a 1.5 mm sieve, dried at 50 ° C. and again passed through a 1.0 mm sieve.
- the granules thus obtained are mixed with magnesium stearate and pressed to dragee cores.
- the dragee cores obtained are coated in a conventional manner with a casing which consists essentially of sugar and talc.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
Neue 1,2-Benzisothiazole und ein Verfahren zur Herstellung von 1,2-Benzisothiazolen durch Umsetzung von o-Halogen- arylketonen mit Ammoniak und elementarem Schwefel. Die nach dem Verfahren der Erfindung herstellbaren Verbindungen sind wertvolle Ausgangsstoffe für die Herstellung von Farbstoffen, Pflanzenschutzmitteln und Pharmazeutika.New 1,2-benzisothiazoles and a process for the preparation of 1,2-benzisothiazoles by reacting o-halo-aryl ketones with ammonia and elemental sulfur. The compounds which can be prepared by the process of the invention are valuable starting materials for the production of dyes, crop protection agents and pharmaceuticals.
Description
Die Erfindung betrifft neue 1,2-Benzisothiazole und ein Verfahren zur Herstellung von 1,2-Benzisothiazolen durch Umsetzung von o-Halogenarylketonen mit Ammoniak und elementarem Schwefel.The invention relates to new 1,2-benzisothiazoles and a process for the preparation of 1,2-benzisothiazoles by reacting o-haloaryl ketones with ammonia and elemental sulfur.
Es ist aus der Angewandten Chemie, Band 36, Seite 159 (1923) und aus den Berichten der deutschen Chemischen Gesellschaft, Band 58, Seite 2 095 (1925) bekannt, Thio- naphthen-2,3-dion mit Ammoniak und Wasserstoffperoxid zu 3-Carbamyl-1,2-benzisothiazol umzusetzen und daraus durch Hydrolyse und Decarboxylierung 1,2-Benzisothiazol zu gewinnen. Die vorgenannten Berichte, Band 56, Seite 1 630 (1923) und Liebigs Annalen der Chemie, Band 454, Seite 264 (1927) beschreiben die Umsetzung von 2-Formyl-4-nitro- phenylsulfonenylbromid mit Ammoniak zu 5-Nitro-1,2-benzisothiazol. Ebenfalls kann man Benzisothiazole durch Cyclisierung von o-Mercapto-phenyl-carbonyl-verbindungen in Gegenwart von Polyphosphorsäure synthetisieren (Annali di Chimica, Band 53, Nummer 5, Seiten 577 bis 587 (1963)). Es ist aus der deutschen Offenlegungsschrift 1 670 196 bekannt, daß man Dihalogenmethylarylverbindungen mit Ammoniak und Schwefel zu Benzisothiazolen umsetzt. Alle diese Verfahren sind mit Bezug auf leicht zugängliche Ausgangsstoffe Wirtschaftlichkeit, Einfachheit des Betriebs bei gleichzeitig guter Ausbeute an Endstoff unbefriedigend.It is known from Angewandte Chemie, volume 36, page 159 (1923) and from the reports of the German Chemical Society, volume 58, page 2 095 (1925) that thionaphthene-2,3-dione with ammonia and hydrogen peroxide 3 -Carbamyl-1,2-benzisothiazole to implement and to obtain 1,2-benzisothiazole from it by hydrolysis and decarboxylation. The aforementioned reports, volume 56, page 1 630 (1923) and Liebigs Annalen der Chemie, volume 454, page 264 (1927) describe the reaction of 2-formyl-4-nitrophenylsulfonenyl bromide with ammonia to give 5-nitro-1,2 -benzisothiazole. It is also possible to synthesize benzisothiazoles by cyclization of o-mercapto-phenyl-carbonyl compounds in the presence of polyphosphoric acid (Annali di C himica, volume 53, number 5, pages 577 to 587 (1963)). It is known from German Offenlegungsschrift 1 670 196 that dihalomethylaryl compounds are reacted with ammonia and sulfur to give benzisothiazoles. All of these ver driving are unsatisfactory in terms of easily accessible raw materials, economy, simplicity of operation and a good yield of end product.
Gegenstand der DOS 25 03 699 ist ein Verfahren zur Herstellung von 1,2-Benzisothiazolen der Formel
Es wurde nun gefunden, daß man 1,2-Benzisothiazole der Formel
Weiterhin wurden die neuen 1,2-Benzisothiazole der Formel
Die Reaktion läßt sich am Beispiel der Umsetzung von 2-Chlor-5-nitrobenzophenon mit Ammoniak und Schwefel formelmäßig wie folgt wiedergeben:
Bevorzugte Ausgangsstoffe II und dementsprechend bevorzugte 1,2-Benzisothiazole I sind solche, in deren Formeln R1 einen gegebenenfalls durch eine Carbonamidgruppe substituiexten Alkylrest mit bis 6 Kohlenstoffatomen, einen Cycloalkylrest mit 5 bis 12 Kohlenstoffatomen, einen Phenyl- oder Naphthylrest, die jeweils auch anelliert sein können, einen anellierten Naphthochinon-(1,4)-ylenrest, Wasserstoff, Brom oder insbesondere Chlor, eine Alkoxygruppe mit 1 bis 4 Kohlenstoffatomen, eine Nitrogruppe oder den Rest
Als Ausgangsstoffe II kommen beispielsweise in Betracht: 5-Nitro-, 4-Dimethylamino-, 4-Diäthylamino-, 4-Diallylamino-, 4-Di-(2'-methylallyl)-amino-, 4-(N-Methyl-N-2-carbonamido-äthylamino)-, 6-Methyl-, 3-Äthyl-, 5-Hexyl-, 6-Isobutyl-, 5-Propyl-, 4-tert.-Butyl-, 4-Cyclohexyl-, 4-Cyclopentyl-, 5-Phenyl-, 4-Phenyl-, 4-Nitrophenyl-, 4-p-Toluyl-, 4-p-Äthoxyphenyl-, 3-Di-(2'-äthoxyäthyl)-amino-, 4-Naphthyl-, 4-Brom-, 6-Methoxy-, 6-Dicyclohexylamino-, 4-Dibenzylamino-, 4-Diphenylamino-, 4-p-Xylyl-2-chlorbenzo-' phenon; 2-Chlorbenzophenon, 2-Brombenzophenon; l-Chlor-2-benzoyl-, 2-Chlor-3-benzoyl-, 2-Chlor-1-benzoyl-naphthalin; 1-Chlor-2-benzoyl-, 2-Chlor-3-benzoyl-, 2-Chlor-l-benzoyl-anthrachinon; 1-Chlor-2-benzoyl-, 2-Chlor-3-ben zoyl-, 2-Chlor-l-benzoyl-anthrachinon; 1-Chlor-2-benzoyl-, 2-Chlor-3-benzoyl-, 2-Chlor-1-benzoyl-anthracen; 1-Chlor-2-benzoyl-, 2-Chlor-3-benzoyl-, 2-Chlor-1-benzoyl-phenanthren; entsprechend substituierte Bromarylketone; analog mit vorgenannten Substituenten an beiden Phenylkernen substituierte Benzophenone; analoge Aroylbenzole, deren Aroylrest mit Chlor oder,Brom substituiert ist und die am Benzolkern in o-, m- und/oder p-Stellung ein oder zwei Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, sek.-Butyl-, tert.-Butyl-, Chlor-, Brom-, Äthoxy-, Methoxy-, Propoxy-, Isopropoxy-, Butoxy-, Dimethylamino-, Diäthylamino-, Dipropylamino-, Diisopropylamino-gruppen tragen; mit vorgenannten Substituenten am Aroylkern substituierte Aroylnaphthaline, Aroylthiophene, Aroyltetrahydrofurane, Aroylpyrane und entsprechende Aroylverbindungen von Imidazol, 1-Methylimidazol, 1-Propylimidazol, 2-Methylpyridin, 3-Methylpyridin, 4-Methylpyridin, 2,4-Dimethylpyridin, 2,6-Dimethylpyridin, 2,4,6-Trimethylpyridin, Pyridin, Pyrrolidin, Pyrrol, Imidazolidin, Piperidin, Morpholin, Pyridazin, Pyrimidin, Pyrazin, Piperazin.Examples of suitable starting materials II are: 5-nitro-, 4-dimethylamino-, 4-diethylamino-, 4-diallylamino-, 4-di- (2'-methylallyl) -amino-, 4- (N-methyl-N -2-carbonamido-ethylamino) -, 6-methyl, 3-ethyl, 5-hexyl, 6-isobutyl, 5-propyl, 4-tert-butyl, 4-cyclohexyl, 4-cyclopentyl -, 5-phenyl-, 4-phenyl-, 4-nitrophenyl-, 4-p-toluyl-, 4-p-ethoxyphenyl-, 3-di- (2'-ethoxyethyl) -amino-, 4-naphthyl-, 4-bromo, 6-methoxy, 6-dicyclohexylamino, 4-dibenzylamino, 4-diphenylamino, 4-p-xylyl-2-chlorobenzo- 'phenone; 2-chlorobenzophenone, 2-bromobenzophenone; 1-chloro-2-benzoyl-, 2-chloro-3-benzoyl-, 2-chloro-1-benzoyl-naphthalene; 1-chloro-2-benzoyl-, 2-chloro-3-benzoyl-, 2-chloro-l-benzoyl-anthraquinone; 1-chloro-2-benzoyl-, 2-chloro-3-benzoyl-, 2-chloro-l-benzoyl-anthraquinone; 1-chloro-2-benzoyl-, 2-chloro-3-benzoyl-, 2-chloro-1-benzoyl-anthracene; 1-chloro-2-benzoyl-, 2-chloro-3-benzoyl-, 2-chloro-1-benzoyl-phenanthrene; appropriately substituted bromoaryl ketones; Benzophenones substituted analogously with the aforementioned substituents on both phenyl nuclei; Analogous aroylbenzenes, the aroyl radical of which is substituted by chlorine or bromine and which have one or two methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec .-Butyl, tert-butyl, chlorine, bromine, ethoxy, methoxy, propoxy, isopropoxy, butoxy, dimethylamino, diethylamino, dipropylamino, diisopropylamino groups; substituted with the aforementioned substituents at Aroylkern Aroylnaphthaline, Aroylthiophene, Aroyltetrahydrofurane, Aroylpyrane and corresponding aroyl compounds of imidazole, 1-methylimidazole, 1-propylimidazole, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine , 2,4,6-trimethylpyridine, pyridine, pyrrolidine, pyrrole, imidazolidine, piperidine, morpholine, pyridazine, pyrimidine, pyrazine, piperazine.
Die Umsetzung wird in der Regel bei einer Temperatur von 20 bis 250°C, vorteilhaft von 20 bis 200°C, vorzugsweise von 40 bis 180°C, insbesondere von 40 bis 120°C, drucklos oder unter Druck,kontinuierlich oder diskontinuierlich durchgeführt. Der Reaktionsdruck wird im allgemeinen durch den Gesamtdampfdruck der Komponenten bei der Umsetzungstemperatur bedingt..Gegebenenfalls kann man unter den Reaktionsbedingungen inerte, organische Lösungsmittel verwenden, z.B. aromatische Kohlenwasserstoffe wie Toluol, Äthylbenzol, o-, m-, p-Xylol, Isopropylbenzol; Alkanole und Cycloalkanole wie Äthanol, n-Butanol, Isobutanol, Methylglykol, Cyclohexanol, Propanol, Methanol, 2-Äthylhexanol; Äther, z.B. Äthylpropyläther, Diisobutyläther, Methyl-tert. butyläther, n-Butyläthyläther, Di-n-butyläther, Dioxan, Diisoamyläther, Diisopropyläther, Anisol, Phenetol, Cyclohexylmethyläther, Diäthyläther, Tetrahydrofuran, Thioanisol; und entsprechende Gemische. Zweckmäßig verwendet man das Lösungsmittel in einer Menge von 200 bis 10 000 Gewichtsprozent, vorzugsweise von 300 bis 1 000 Gewichtsprozent, bezogen auf Ausgangsstoff II.The reaction is generally carried out at a temperature of 20 to 250 ° C., advantageously from 20 to 200 ° C., preferably from 40 to 180 ° C., in particular from 40 to 120 ° C., without pressure or under pressure, continuously or batchwise. The reaction pressure is generally determined by the total vapor pressure of the components at the reaction temperature. If appropriate, organic solvents which are inert under the reaction conditions can be used, for example aromatic hydrocarbons such as toluene, Ethylbenzene, o-, m-, p-xylene, isopropylbenzene; Alkanols and cycloalkanols such as ethanol, n-butanol, isobutanol, methyl glycol, cyclohexanol, propanol, methanol, 2-ethyl hexanol; Ether, for example ethyl propyl ether, diisobutyl ether, methyl tert. butyl ether, n-butyl ethyl ether, di-n-butyl ether, dioxane, diisoamyl ether, diisopropyl ether, anisole, phenetol, cyclohexylmethyl ether, diethyl ether, tetrahydrofuran, thioanisole; and corresponding mixtures. The solvent is expediently used in an amount of 200 to 10,000 percent by weight, preferably 300 to 1,000 percent by weight, based on starting material II.
Die Reaktion kann wie folgt durchgeführt werden: Ausgangsstoff II, elementarer Schwefel und Ammoniak, gegebenenfalls in Gegenwart eines Lösungsmittels, werden in einem Druckreaktor während 3 bis 10 Stunden bei der vorgenannten Temperatur miteinander umgesetzt. Aus dem Reaktionsgemisch erhält man das 1,2-Benzisothiazol I nach den üblichen Verfahren, z.B. durch fraktionierte Destillation, Filtration und gegebenenfalls anschließender Umkristallisation aus einem'geeigneten Lösungsmittel, z.B. Ligroin. Man kann das Reaktionsgemisch auch nach Entfernung überflüssigen Ammoniaks und Lösungsmittels in Wasser gießen, das gebildete Gemisch mit einem geeigneten Lösungsmittel, z.B. Methylenchlorid, Benzol, extrahieren und den Extrakt in vorgenannter Weise aufarbeiten.The reaction can be carried out as follows: Starting material II, elemental sulfur and ammonia, optionally in the presence of a solvent, are reacted with one another in a pressure reactor for 3 to 10 hours at the aforementioned temperature. The 1,2-benzisothiazole I is obtained from the reaction mixture by the usual methods, e.g. by fractional distillation, filtration and, if appropriate, subsequent recrystallization from a suitable solvent, e.g. Ligroin. The reaction mixture can also be poured into water after removal of excess ammonia and solvent, the mixture formed with a suitable solvent, e.g. Extract methylene chloride, benzene and work up the extract in the aforementioned manner.
Die nach dem Verfahren der Erfindung herstellbaren Verbindungen sind wertvolle Ausgangsstoffe für die Herstellung von Farbstoffe, Pflanzenschutzmitteln und Pharmazeutika.The compounds which can be prepared by the process of the invention are valuable starting materials for the production of dyes, crop protection agents and pharmaceuticals.
Vorteilhaft sind für vorgenennte Verwendungen die 1,2-Benzisothiazole mit den bevorzugten Bedeutungen von Rund R3 geeignet. So können z.B. aus 1,2-Benzisothiazolen der Formel L.
Die vorgenannte Umsetzung der Verbindungen IV wird zweckmäßig bei Temperaturen von 40 bis 150°C, bevorzugt bei Temperaturen von 70 bis 120°C, durchgeführt.The aforementioned reaction of the compounds IV is advantageously carried out at temperatures from 40 to 150 ° C., preferably at temperatures from 70 to 120 ° C.
Zweckmäßige.Lösungsmittel für die Umsetzung der Verbindungen IV sind aromatische Kohlenwasserstoffe, insbesondere Benzolkohlenwasserstoffe, wie Benzol oder Toluol, niedere Alkohole, wie Methanol, Äthanol, Propanol, Isopropanol, Butanol oder Isobutanol, gesättigte cyclische oder aliphatische Äther, wie Dibutyläther oder Dioxan, Glykoläther, insbesondere Monoalkyläther des Glykols, wie Glykolmonomethyläther oder Glykolmonoäthyläther, oder Mischungen der genannten Lösungsmittel.Appropriate solvents for the reaction of the compounds IV are aromatic hydrocarbons, in particular benzene hydrocarbons, such as benzene or toluene, lower alcohols, such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol, saturated cyclic or aliphatic ethers, such as dibutyl ether or dioxane, glycol ether, in particular monoalkyl ethers of glycol, such as glycol monomethyl ether or glycol monoethyl ether, or mixtures of the solvents mentioned.
Von den genannten Lösungsmitteln sind die Benzolkohlen-. wa.sserstoffe, zweckmäßig Benzol und Toluol, und Monoalkyläther des Glykols, insbesondere Glykolmonomethyläther, bevorzugt.Of the solvents mentioned, the benzene carbon. wa.sserstoffe, advantageously benzene and toluene, and monoalkyl ether of glycol, especially glycol monomethyl ether, preferred.
Das Diamin der Formel III wird, berechnet auf die Verbindung der Formel I oder Ib, in stöchiometrischer oder in überschüssiger Menge, gegebenenfalls bis zur 3-fachen stöchiometrischen Menge, verwendet.The diamine of the formula III, calculated on the compound of the formula I or Ib, is used in stoichiometric or in excess amount, optionally up to 3 times the stoichiometric amount.
Der elementare Schwefel wird, berechnet auf die Verbindung Ib, in stöchiometrischer oder in überschüssiger Menge bis zur 1,2-fachen Menge über der stöchiometrischen Menge ver- wendet. Bevorzugt wird die stöchiometrische Menge elementarer Schwefel eingesetzt.The elemental sulfur, calculated on the compound Ib, is used in a stoichiometric or excess amount up to 1.2 times the amount above the stoichiometric amount. turns. The stoichiometric amount of elemental sulfur is preferably used.
Die Umsetzung von beispielsweise 3-(4-Chlormethylphenyl)-1,2-benzisothiazol mit Äthylendiamin und Schwefel kann durch die folgende Reaktionsgleichung beschrieben werden:
Die Ausgangsverbindungen der Formel Ib können beispielsweise durch Seitenkettenchlorierung von 3-(4-Methylphenyl)-1,2-benzisothiazolen I mit Chlor bei etwa 170°C und unter UV-Bestrahlung erhalten werden.The starting compounds of the formula Ib can be obtained, for example, by side chain chlorination of 3- (4-methylphenyl) -1,2-benzisothiazole I with chlorine at about 170 ° C. and under UV radiation.
Die Verbindungen der allgemeinen Formel IV werden gegebenenfalls in an sich üblicher Weise in das Säureadditionssalz einer physiologisch verträglichen Säure überführt. Als übliche physiologiseh verträgliche organische oder anorganische Säuren kommen beispielsweise in Betracht Salzsäure, Bromwasserstoffsäure, Phosphorsäure oder Schwefelsäure und als organische Säuren beispielsweise Oxalsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Salicylsäure, Adipinsäure oder Benzoesäure oder können aus Fortschritte der Arzneimittelforschung, Band 10, Seiten 224 bis 225, Birkhäuser Verlag, Basel und Stuttgart, 1966, entmmmen werden. Als vorteil- hafte Verbindungen der Formel IV sind beispielsweise zu nennen:
- 3-[4-(Imidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 3-[4-(Methylimidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 3-[4-(Tetrahydropyrimidin-2-yl)-phenyl]-1,2-benzisothlazol
- 5-Chlor-3-[4-(imidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 5-Chlor-3-[4-(methylimidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 4-Methoxy-3-[4-(methylimidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 5-Nitro-3- [4-(imidazolin-2-yl)-phenyl]-1,2-benzisothiazol
- 5-Nitro-3-[4-(tetrahydropyrimidin-2-yl)-phenyl]-1,2-benzisothiazol
- 5-Brom-6-chlor-3-[4-(imidazolin-2-yl)-phenyl]-1,2-benzisothiazol.
- 3- [4- (imidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 3- [4- (Methylimidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 3- [4- (tetrahydropyrimidin-2-yl) phenyl] -1,2-benzisothlazole
- 5-chloro-3- [4- (imidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 5-chloro-3- [4- (methylimidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 4-methoxy-3- [4- (methylimidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 5-nitro-3- [4- (imidazolin-2-yl) phenyl] -1,2-benzisothiazole
- 5-nitro-3- [4- (tetrahydropyrimidin-2-yl) phenyl] -1,2-benzisothiazole
- 5-bromo-6-chloro-3- [4- (imidazolin-2-yl) phenyl] -1,2-benzisothiazole.
Die vorgenannten 3-[4-(1,3-Diazacycloalken-2-yl)-phenyl]-1,2-benzisothiazole IV und ihre physiologisch verträglichen Säureadditionssalze weisen wertvolle pharmakologische Eigenschaften auf. Aus ihnen können pharmazeutische Zubereitungen, die neben üblichen pharmazeutischen Träger-und Verdünnungsmitteln eine Verbindung der Formel IV als Wirkstoff enthält, hergestellt werden. Besonders geeignet sind 3-[4-(Tetrahydropyrimidin-2-yl)-phenyl]-1,2-benzisothiazol, 3-[4-(Methylimidazolin-2-yl)-phenyl]-1,2-benzisothiazol und ihre physiologisch verträglichen Säureadditionssalze. Die Stoffe IV und ihre physiologisch verträglichen Säureadditionssalze zeichnen sich durch eine starke antiarrhythmische Wirkung aus und sind besonders zur Pharmakotherapie von Herzrhythmusstörungen geeignet. Zur Bestimmung ihrer antiarrhythmischen Wirksamkeit wurden die Substanzen Ratten (Stamm: Sprague Dawley, Gewicht: 180 - 240 g) 45 Minuten vor Beginn der Narkose (Thiobutabarbital 100 mg/kg i.p.) oral appliziert.The aforementioned 3- [4- (1,3-diazacycloalken-2-yl) phenyl] -1,2-benzisothiazoles IV and their physiologically tolerated acid addition salts have valuable pharmacological properties. They can be used to produce pharmaceutical preparations which, in addition to conventional pharmaceutical carriers and diluents, contain a compound of the formula IV as an active ingredient. 3- [4- (Tetrahydropyrimidin-2-yl) -phenyl] -1,2-benzisothiazole, 3- [4- (methylimidazolin-2-yl) -phenyl] -1,2-benzisothiazole and their physiologically tolerable are particularly suitable Acid addition salts. Substances IV and their physiologically compatible acid addition salts are characterized by a strong antiarrhythmic effect and are particularly suitable for the pharmacotherapy of cardiac arrhythmias. To determine their antiarrhythmic activity, the substances were administered orally to rats (strain: Sprague Dawley, weight: 180-240 g) 45 minutes before the start of anesthesia (thiobutabarbital 100 mg / kg i.p.).
Als arrhythmogene Substanz diente Aconitin, das 60 Minuten nach der Substanzapplikation intravenös infundiert wurde (Dosierungsgeschwindigkeit: 0,005 mg/kg · Minute). Bei nichtbehandelten Tieren (N = 30) treten nach durchschnittlich 3,7 + 0,9 Minuten Arrhythmien auf, deren Eintritt durch Antiarrhythmica dosisabhängig verzögert werden kann.Aconitin served as the arrhythmogenic substance and was infused intravenously 60 minutes after the substance application (dosage rate: 0.005 mg / kg · minute). In untreated animals (N = 30) arrhythmias occur after an average of 3.7 + 0.9 minutes, the onset of which can be delayed by antiarrhythmics depending on the dose.
Zur quantitativen Auswertung der linearen Beziehung zwischen dem Logarithmus der Dosis (mg/kg) der Prüfsubstanzen und der relativen Verlängerung der Aconitininfusionsdauer (Δ%) wurde die Dosis bestimmt, welche die Infusionsdauer um 50 % verlängert (ED 50 %) Als Vergleichssubstanz diente das bekannte Antiärrhythmicum Procainamid.For the quantitative evaluation of the linear relationship between the logarithm of the dose (mg / kg) of the test substances and the relative extension of the aconitine infusion duration (Δ%), the dose was determined, which prolonged the infusion duration by 50% (ED 50%). The known substance served as reference substance Antiarrhythmicum procainamide.
Die akute Toxizität wurde an Gruppen von je 10 oder 20 weiblichen Swiss-Mäusen, Gewicht.20 - 26 g, bei intraperitonealer Applikation ermittelt. Als LD 50 wurde die Dosis berechnet (Probit-Analyse), nach der 50 % der Tiere innerhalb von 7 Tagen starben.The acute toxicity was determined in groups of 10 or 20 female Swiss mice, weight 20-26 g, with intraperitoneal application. The LD 50 was calculated as the dose (probit analysis) after which 50% of the animals died within 7 days.
Die Tabelle 1 zeigt, daß die Verbindungen der Beispiel 2 und 3, verglichen mit dem Antiarrhythmicum Procainamid, rund 5 mal stärker antiarrhythmisch wirksam sind. Ein weiterer Vorteil besteht darin, daß die Wirkung der Maximaldosis um 114 (Beispiel 2) bzw. 73 % (Beispiel 3) höhere Werte erreicht, als die von Procainamid; d.h., daß der Aconitinantagonismus der geprüften Verbindungen deutlich stärker ausgeprägt ist als bei Procainamid.Table 1 shows that the compounds of Examples 2 and 3, compared to the antiarrhythmicum procainamide, are around 5 times more antiarrhythmic. Another advantage is that the effect of the maximum dose reaches 114 (example 2) or 73% (example 3) higher values than that of procainamide; i.e. that the aconitine antagonism of the tested compounds is significantly more pronounced than that of procainamide.
Die therapeutische Breite als Quotient aus der letalen Dosis (LD 50) und der antiarrhythmisch wirkenden Dosis (ED 50 %) ist 4 mal (Beispiel 2) bzw. 2,8 mal (Beispiel 3). größer als beim Procainamid.
Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tab tten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen oder Depotformen.The preferred preparations are in a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
Selbstverständlich kommen auch parenterale Zubereitungsformen, wie Injektionslösungen oder Zusätze zu Infusionslösungen, in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien genannt.Of course, parenteral forms of preparation, such as injection solutions or additives to infusion solutions, can also be used. Suppositories may also be mentioned as preparations.
Die entsprechenden Tabellen können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerte Verdünnungsmittel, wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmittel, wie Mais, Stärke, Alginsäure oder Polyvinylpyrrolidon, Bindemittel, wie Stärke oder Gelatine, Gleitmitteln, wie Magnesiumstearat oder Talkum und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxypolymethylen, Carboxymethylcellulose, Celluloseacetatphthalat oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.The corresponding tables can, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn, starch, alginic acid or polyvinylpyrrolidone, binders such as starch or Gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Kollidon oder Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe-verwendet werden können.Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. It can also Drageehülle consist of several layers, wherein the excipients mentioned above for the tablets can be used.
Lösungen oder Suspensionen mit den erfindungsgemäßen Wirkstoffen können zusätzlich geschmacksverbessernde Mittel, wie Saccharin, Cyclamat oder Zucker sowie beispielsweise Aromastoffe, wie Vanillin oder Orangenextrakt, enthalten. Sie können außerdem Suspendierhilfsstoffe, wie Natriumcarboxymethylcellulose, oder Konservierungsstoffe, wie Parahydroxybenzoate, enthalten. Wirkstoffe enthaltende Kapseln können beispielsweise hergestellt werden, indem man den Wirkstoff mit einem inerten Träger, wie Milchzucker oder Sorbit, mischt und in Geletinekapseln einkapselt.Solutions or suspensions with the active ingredients according to the invention can additionally contain taste-improving agents such as saccharin, cyclamate or sugar and, for example, flavoring agents such as vanillin or orange extract. They can also contain suspending aids such as sodium carboxymethyl cellulose or preservatives such as parahydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier, such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenem Trägermaterial, wie Neutralfetten oder Polyäthylenglykolen bzw. dessen Derivaten, herstellen.Suitable suppositories can be produced, for example, by mixing with the carrier material provided, such as neutral fats or polyethylene glycols or their derivatives.
Die Einzeldosis einer erfindungsgemäßen Substanz am Menschen liegt bei 5 bis 100 mg, vorzugsweise bei 10 bis 80 mg.The single dose of a substance according to the invention in humans is 5 to 100 mg, preferably 10 to 80 mg.
Die in den folgenden Beispielen angebenen Teile sind Gewichtsteile. Sie verhalten sich zu den Volumenteilen wie Kilogramm zu Liter.The parts given in the following examples are parts by weight. They relate to parts by volume like kilograms to liters.
In einem Tantalautoklaven werden 216,5 Teile 2-Chlorbenzophenon, 32 Teile Schwefel und 100 Teile NH3 in 1 000 Teilen Glykolmonomethyläther 6 Stunden bei 160°C umgesetzt. Nach Abkühlen und Entspannen wird das Reaktionsgemisch weitgehend vom Lösungsmittel befreit, mit 500 Teilen Wasser versetzt und mit 3 x 200 Teilen Methylenchlorid extrahiert. Die Methylenchloridlösung wird destillativ aufgearbeitet. Bei Kp1 150 bis 1550C werden 164 Teile 3-Phenyl-1,2-benzisothiazol mit Fp 70°C erhalten. Die Ausbeute entspricht 78 % der Theorie.216.5 parts of 2-chlorobenzophenone, 32 parts of sulfur and 100 parts of NH 3 in 1,000 parts of glycol monomethyl ether are reacted at 160 ° C. in a tantalum autoclave for 6 hours. After cooling and releasing the pressure, the reaction mixture is largely freed from the solvent, 500 parts of water are added and the mixture is extracted with 3 × 200 parts of methylene chloride. The methylene chloride solution is worked up by distillation. At Kp 1 150 to 155 0 C 164 parts of 3-phenyl-1,2-benzisothiazole with mp 70 ° C are obtained. The yield corresponds to 78% of theory.
Man erhält 192 Teile 3-(2',5'-Dimethylphenyl)-1,2-benzisothiazol mit Fp 870C. Die Ausbeute entspricht 80 % der Theorie.This gives 192 parts of 3- (2 ', 5'-dimethylphenyl) -1,2-benzisothiazol with mp 87 0 C. The yield is 80% of theory.
In entsprechender Weise werden unter denselben Bedingungen und Molverhältnissen aus 2,5-Dichlor-4'-methylbenzophenon 5-Chlor-3-(4'-methylphenyl)-1,2-benzisothiazol vom Fp 121°C (85 % der Theorie; aus 2-Chlor-5-nitro-4'-methylbenzo- phenon 5-Nitro-3-(4'-methylphenyl)-12-benzisothiazol vom Fp 1790C (90 % der Theorie) hergestellt.In a corresponding manner, 5-chloro-3- (4'-methylphenyl) -1,2-benzisothiazole of mp 121 ° C. (85% of theory) is obtained from 2,5-dichloro-4'-methylbenzophenone under the same conditions and molar ratios 2-chloro-5-nitro-4'-methylbenzo- phenone 5-nitro-3- (4'-methylphenyl) -12-benzisothiazole manufactured C (90% of theory) of mp 179 0th
In einem Tantalautoklaven werden 28,75 Teile 2-Chlor-4'- diäthylamino-benzophenon, 3,2 Teile Schwefel und 50 Teile NH3 in 400 Teilen Glykolmonoäthyläther 20 Stunden bei 160°C umgesetzt. Der Autoklavenaustrag wird vollständig eingeengt, der Rückstand in 500 Teilen Wasser aufgenommen und 3 mal mit 200 Teilen Methylenchlorid extrahiert. Die organische Phase wird getrocknet und eingeengt. Nach Umkristallisieren aus Methanol erhält man 20 Teile 3-(4'-Diäthylaminophenyl)-1,2-benzisothiazol mit Fp 850C. Die Ausbeute entspricht 71 % der Theorie.28.75 parts of 2-chloro-4'-diethylamino-benzophenone, 3.2 parts of sulfur and 50 parts of NH 3 in 400 parts of glycol monoethyl ether are reacted at 160 ° C. for 20 hours in a tantalum autoclave. The autoclave discharge is completely concentrated, the residue is taken up in 500 parts of water and extracted 3 times with 200 parts of methylene chloride. The organic phase is dried and concentrated. After recrystallization from methanol to obtain 20 parts of 3- (4'-diethylaminophenyl) -1,2-benzisothiazol with mp 85 0 C. The yield corresponds to 71% of theory.
Die vorliegende Erfindung wird durch die nachfolgenden Verwendungsbeispiele näher erläutert.The present invention is illustrated by the following examples of use.
225 Teile 3-(4-Methylphenyl)-1,2-benzisothiazol werden in einer Rührapparatur auf 170°C erhitzt und unter Bestrahlung mit einer UV-Lampe werden innerhalb von 2 Stunden 100 Teile Chlor eingeleitet. Der Endpunkt der Reaktion wird gaschromatographisch bestimmt (Verschwinden des Ausgangsproduktes). Anschließend wird das Reaktionsgemisch abgekühlt, es wird abgesaugt und aus Methanol umkristallisiert. Man erhält 208 Teile 3-(4-Chlormethylphenyl)-1,2-benzisothiazol von einem Schmelzpunkt von 86 bis 89°C, was einer Ausbeute von 80 % der Theorie entspricht.225 parts of 3- (4-methylphenyl) -1,2-benzisothiazole are heated to 170 ° C. in a stirrer apparatus and 100 parts of chlorine are introduced within 2 hours while being irradiated with a UV lamp. The end point of the reaction is determined by gas chromatography (disappearance of the starting product). The reaction mixture is then cooled, it is suctioned off and recrystallized from methanol. 208 parts of 3- (4-chloromethylphenyl) -1,2-benzisothiazole with a melting point of 86 to 89 ° C. are obtained , which corresponds to a yield of 80% of theory.
In entsprechender Weise wird unter denselben Bedingungen und Molverhältnissen 5-Chlor-3-(4'-chlormethylphenyl)-1,2-benzisothiazol mit Fp 116°C hergestellt.In a corresponding manner 5-chloro-3- (4'-chloromethylphenyl) -1,2-benzisothiazole with mp 116 ° C. is produced under the same conditions and molar ratios.
B. Herstellung der Verbindungen IV.B. Preparation of Compounds IV.
-3-[4-(Imidazolin-(2")-yl)-phenyl]-1,2-benzisothiazol
3-[4'-Tetrahydropyrimidin-(2")-yl)-phenyl]-1,2-benz- isothiazolhydrochlorid
3-[4'-(Methylimidazolin-(2")-yl)-phenyl]-1,2-benzisothiazol-hydrochlorid
5-Chlor-3-[4'-(imidazolin-(2")-yl)-phenyl]-1,2-benzisothiazol
44 Teile 5-Chlor-3-(4'-chlormethylphenyl)-1,2-benzisothiazol, 9,6 Teile Schwefel und 18 Teile Äthylendiamin werden in 500 Teilen Toluol 20 Stunden am Rückfluß gekocht. Das Reaktionsgemisch wird heiß filtriert, das Filtrat abgekühlt und die gebildeten Kristalle abgesaugt. Nach Umkristallisieren aus Toluol unter Zusatz von Aktivkohle werden 26 Teile 5-Chlor-3-[4'-(imidazolin-(2")-yl)]-1,2-benzisothiazol vom Schmelzpunkt 195°C erhalten. Die Ausbeute entspricht 55 % der Theorie.44 parts of 5-chloro-3- (4'-chloromethylphenyl) -1,2-benzisothiazole, 9.6 parts of sulfur and 18 parts of ethylenediamine are refluxed in 500 parts of toluene for 20 hours. The reaction mixture is filtered while hot, the filtrate is cooled and the crystals formed are suction filtered. After recrystallization from toluene with the addition of activated carbon, 26 parts of 5-chloro-3- [4 '- (imidazolin- (2 ") - yl)] - 1,2-benzisothiazole of melting point 195 ° C. are obtained. The yield corresponds to 55% of theory.
5-Chlor-3-[4'-(methylimidazolin-(2")-yl)-phenyl]-1,2-benzisothiazol-hydrochlorid
Die gebildeten Kristalle werden abgesaugt und aus Wasser umkristallisiert. Man erhält 31 Teile 5-Chlor-3-[4'-(methylimidazolin-(2")-yl)-phenyl]-1,2-benzisothiazol vom Schmelzpunkt 248°C (Zersetzung). Die Ausbeute entspricht 57 % der Theorie.The crystals formed are suction filtered and recrystallized from water. 31 parts of 5-chloro-3- [4 '- (methylimidazolin- (2 ") - yl) -phenyl] -1,2-benzisothiazole of melting point 248 ° C. (decomposition) are obtained. The yield corresponds to 57% of theory.
Formulierungsbeispiele, die in üblicher Weise hergestellt werden: 6. Tabletten:
Der Wirkstoff wird mit Polyvinylpyrrolidon in 10-prozentiger, wäßriger Lösung befeuchtet, durch ein Sieb mit der lichten Maschenweite 1,0 mm getrieben und bei 50°C getrocknet. Dieses Granulat wird mit Polyäthylenglykol (mittl. M.G. 4000), Hydroxypropylmethylcellulose, Talkum und Magnesiumstearat vermischt und zu Tabletten à 280 mg verpreßt.The active ingredient is moistened with polyvinylpyrrolidone in a 10 percent aqueous solution, passed through a sieve with a mesh size of 1.0 mm and dried at 50 ° C. These granules are mixed with polyethylene glycol (average M.G. 4000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into tablets of 280 mg each.
Die Mischung der Wirkstoffsubstanz mit Lactose und Maisstärke wird mit einer 8-prozentigen, wäßrigen Lösung des Polyvinylpyrrolidons durch Sieb 1,5 mm granuliert, bei 50°C getrocknet und nochmals durch Sieb 1,0 mm getrieben. Das so erhaltene Granulat wird mit Magnesiumstearat gemischt und zu Drageekernen verpreßt. Die erhaltenen Drageekerne werden in üblicher Weise mit einer Hülle überzogen, die im wesentlichen aus Zucker und Talkum besteht.The mixture of the active substance with lactose and corn starch is granulated with an 8% aqueous solution of the polyvinylpyrrolidone through a 1.5 mm sieve, dried at 50 ° C. and again passed through a 1.0 mm sieve. The granules thus obtained are mixed with magnesium stearate and pressed to dragee cores. The dragee cores obtained are coated in a conventional manner with a casing which consists essentially of sugar and talc.
Claims (2)
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DE19772734866 DE2734866A1 (en) | 1977-08-03 | 1977-08-03 | NEW 1,2-BENZISOTHIAZOLES AND THE METHOD FOR PRODUCING THEM |
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EP (1) | EP0000750A1 (en) |
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DE3018108A1 (en) | 1980-05-12 | 1981-11-19 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING 1,2-BENZISOTHHIAZOLES |
US4411901A (en) * | 1981-12-23 | 1983-10-25 | Mead Johnson & Company | Benzisothiazole and benzisoxazole piperazine derivatives |
WO2001079203A1 (en) * | 2000-04-17 | 2001-10-25 | Basf Aktiengesellschaft | Herbicidal 3-heterocyclic substituted benzisothiazole and benzisoxazole compounds |
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US3682941A (en) * | 1967-03-18 | 1972-08-08 | Basf Ag | Production of 1,2-benzoisothiazoles |
DE1915387A1 (en) * | 1969-03-26 | 1970-10-01 | Basf Ag | herbicide |
DE2609864C2 (en) * | 1976-03-10 | 1984-02-16 | Basf Ag, 6700 Ludwigshafen | Process for the preparation of 3-amino-1,2-benzisothiazoles |
DE2734882A1 (en) * | 1977-08-03 | 1979-02-22 | Basf Ag | 3-SQUARE BRACKETS ON 4- (1,3-DIAZACYCLOALKEN-2-YL) -PHENYL SQUARE BRACKETS FOR -1,2-BENZISOTHIAZOLS, THE METHOD FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINED |
US4178451A (en) * | 1978-07-13 | 1979-12-11 | E. R. Squibb & Sons, Inc. | 3-(Substituted hydrazino)benzisothiazole-1,1-dioxides |
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1977
- 1977-08-03 DE DE19772734866 patent/DE2734866A1/en not_active Withdrawn
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1978
- 1978-07-28 EP EP78100536A patent/EP0000750A1/en not_active Withdrawn
- 1978-08-02 JP JP9372578A patent/JPS5436261A/en active Pending
-
1979
- 1979-10-02 US US06/081,059 patent/US4277477A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2503699A1 (en) * | 1975-01-30 | 1976-08-05 | Basf Ag | PROCESS FOR THE PREPARATION OF 1,2-BENZISOTHIAZOLES |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 58, (1963) 11340c, 8 Ric. Sci Rend. Ser. B2 177-8 (1962) * |
Also Published As
Publication number | Publication date |
---|---|
US4277477A (en) | 1981-07-07 |
JPS5436261A (en) | 1979-03-16 |
DE2734866A1 (en) | 1979-02-22 |
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