EP0000727B1 - 3-(4-(1,3-Diazacycloalcen-2-yl)-phenyl)-1,2-benzisothiazole, procédé pour leur préparation et médicaments les contenant. - Google Patents

3-(4-(1,3-Diazacycloalcen-2-yl)-phenyl)-1,2-benzisothiazole, procédé pour leur préparation et médicaments les contenant. Download PDF

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Publication number
EP0000727B1
EP0000727B1 EP78100498A EP78100498A EP0000727B1 EP 0000727 B1 EP0000727 B1 EP 0000727B1 EP 78100498 A EP78100498 A EP 78100498A EP 78100498 A EP78100498 A EP 78100498A EP 0000727 B1 EP0000727 B1 EP 0000727B1
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EP
European Patent Office
Prior art keywords
phenyl
benzisothiazole
general formula
compound
acid
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Expired
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EP78100498A
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German (de)
English (en)
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EP0000727A1 (fr
Inventor
Helmut Dr. Hagen
Dieter Dr Lenke
Gerda Dr. Von Philipsborn
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BASF SE
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BASF SE
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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 3- (4- (1,3-diazacycloalken-2-yl) phenyl] -1,2-benzisothiazoles and their acid addition salts, their preparation and pharmaceutical preparations containing these compounds.
  • Hydrogen is particularly preferred for R and Y is preferred for Y. to emphasize.
  • the compounds of the invention can be prepared by using a compound of general formula II in which R has the meanings given above, with a diamine of the general formula III, in which Y has the meanings given above, and elemental sulfur is advantageously reacted in an inert organic solvent and, if appropriate, the compound obtained in one transferred physiologically acceptable acid addition salt.
  • the reaction is expediently carried out at temperatures from 40 to 150 ° C., preferably at temperatures from 70 to 120 ° C.
  • Appropriate solvents for the reaction are aromatic hydrocarbons, especially 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, especially monoalkyl ether of glycol , such as glycol monomethyl ether or glycol monoethyl ether, or mixtures of the solvents mentioned.
  • aromatic hydrocarbons especially 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 especially monoalkyl ether of glyco
  • the benzene hydrocarbons in particular benzene and toluene, and monoalkyl ethers of glycol, in particular glycol monomethyl ether, are preferred.
  • the diamine of the general formula III calculated on the compound of the general formula 11, is used in a stoichiometric or in excess amount, optionally up to 3 times the stoichiometric amount.
  • the elemental sulfur calculated on the chloromethyl compound used, is used in stoichiometric or in excess amount up to 1.2 times.
  • the stoichiometric amount of elemental sulfur is preferably used.
  • the starting compounds of the general formula II can be obtained, for example, by side chain chlorination of 3- (4-methylphenyl) -1,2-benzisothiazoles with chlorine at about 170 ° C. and under UV radiation.
  • the starting material IV, ammonia and elemental sulfur are used in approximately stoichiometric amounts, but a ratio of 2 to 10 moles of ammonia and 0.9 to 1.1 gram atom of sulfur per mole of starting material IV is preferably used.
  • This 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, e.g.
  • aromatic hydrocarbons such as toluene, ethylbenzene, o-, m-, p-xylene, isopropylbenzene; Alkanols and cycloalkanols, such as ethanol, n-butanol, isobutanol, methylglycol, cyclohexanol, propanol, methanol, 2-ethylhexanol; Ether, e.g.
  • 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 IV.
  • the reaction can be carried out as follows: starting material IV, elemental sulfur and ammonia, optionally in the presence of a solvent, are combined in one Pressure reactor reacted with one another at the aforementioned temperature for 3 to 10 hours.
  • the 1,2-benzisothiazole is obtained from the reaction mixture by the customary methods, for example by fractional distillation, filtration and, if appropriate, subsequent recrystallization from a suitable solvent, for example ligroin.
  • the reaction mixture can also be poured into water, the mixture formed extracted with a suitable solvent, for example methylene chloride, benzene, and the extract worked up.
  • the compounds of general formula 1 according to the invention are optionally converted in a conventional manner into the acid addition salt of a physiologically tolerated acid.
  • suitable physiologically compatible organic or inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, and organic acids are, for example, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzoic acid or can be based on advances in drug research 10, pages 224 to 225, Birkhäuser Verlag, Basel and Stuttgart, 1966.
  • the compounds according to the invention and their physiologically tolerated acid addition salts are distinguished by a strong antriarrhythmic 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 min before the start of anesthesia (thiobuteal barbital 100 mg / kg i.p.).
  • Aconitin was used as the arrhythmogenic substance, which i.v. 60 min after the substance application. was infused (dosing rate: 0.005 mg / kg. min).
  • arrhythmias occur after an average of 3.7 ⁇ 0.9 min, the onset of which can be delayed by antiarrhythmics depending on the dose.
  • 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 range as the quotient of the lethal dose (LD 50) and the antiarrhythmic dose (ED 50%) is 2 times (example 2) and 1.9 times (example 3) greater than that of procainamide.
  • the invention accordingly also relates to therapeutic agents or preparations which, in addition to conventional carriers and diluents, contain a compound of the general formula I or its physiologically tolerable acid addition salt as active ingredient, and the use of the new compounds for therapeutic purposes.
  • the therapeutic agents or preparations are produced in a known manner with the usual carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to 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 of this type are, for example, tablets, film-coated tablets, coated tablets, 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 tablets 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 for achieving 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 polyvinylpyrrol
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet cover can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active compounds according to the invention can additionally contain taste-improving agents such as saccharin, cyclamate or sugar and, for example, flavorings 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 hydrochloride of the compound has a melting point of 318 ° C.
  • the active ingredient is moistened with polyvinylpyrrolidone in 10% strength aqueous solution, passed through a sieve with a mesh size of 1.0 mm and dried at 50.degree. These granules are mixed with polyethylene glycol (average M.G. 4000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into 280 mg tablets.
  • the mixture of the active ingredient 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 rubbed again 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Claims (7)

1. Composés de formule générale I
Figure imgb0028
dans laquelle R est un atome d'hydrogène, un radical alkyle à 1 à 4 atomes de carbone, un radical alcoxy à 1 à 3 atomes de carbone, un atome d'halogène ou un groupe nitro et Y est un pont de formule
Figure imgb0029
et leurs sels d'addition acides tolérés physiologiquement.
2. [(Tétrahydropyrimidine-2-yl)-4-phényl]-3-benzisothiazole-1,2 et ses sels d'addition acides physiologiquement acceptables.
3. [(Méthyl-4-imidazoline-2-yl)-4-phényl]-3-benzisothiazole-1,2 et ses sels d'addition acides physiologiquement acceptables.
4. Procédé de préparation de composés de formule générale I, caractérisé par le fait qu'on fait réagir un composé de formule générale Il
Figure imgb0030
dans laquelle R a le sens indiqué dans la revendication 1, avec une diamine de formule générale III
Figure imgb0031
dans laquelle Y a le sens indiqué dans la revendication 1, et du soufre élémentaire, de préférence dans un solvant organique inerte.
5. Préparations pharmaceutiques caractérisés par le fait qu'elles contiennent, outre des supports et diluants pharmaceutiques usuels, un composé de formule générale I comme matière active.
6. Préparations pharmaceutiques à effet anti-arythmique contenant, outre des supports et diluants pharmaceutiques usuels, le composé [(Tétrahydropyrimidine-2-yl)-4-phényl]-3-benzisothiazole-1,2-ou un sel d'addition acide physiologiquement acceptable de ce composé.
7. Préparations pharmaceutiques à effet anti-arythmique contenant, outre des supports et diluants pharmaceutiques usuels, le composé [(Méthylimidazoline-2-yl)-4-phényl]-3-benzisothiazole-1,2 ou un sel d'addition acide physiologiquement acceptable de ce composé.
EP78100498A 1977-08-03 1978-07-26 3-(4-(1,3-Diazacycloalcen-2-yl)-phenyl)-1,2-benzisothiazole, procédé pour leur préparation et médicaments les contenant. Expired EP0000727B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2734882 1977-08-03
DE19772734882 DE2734882A1 (de) 1977-08-03 1977-08-03 3- eckige klammer auf 4-(1,3-diazacycloalken-2-yl)-phenyl eckige klammer zu -1,2-benzisothiazole, verfahren zu ihrer herstellung und diese enthaltende arzneimittel

Publications (2)

Publication Number Publication Date
EP0000727A1 EP0000727A1 (fr) 1979-02-21
EP0000727B1 true EP0000727B1 (fr) 1980-08-20

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EP78100498A Expired EP0000727B1 (fr) 1977-08-03 1978-07-26 3-(4-(1,3-Diazacycloalcen-2-yl)-phenyl)-1,2-benzisothiazole, procédé pour leur préparation et médicaments les contenant.

Country Status (5)

Country Link
US (1) US4206217A (fr)
EP (1) EP0000727B1 (fr)
AT (1) AT364841B (fr)
DE (2) DE2734882A1 (fr)
IT (1) IT1105391B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ182325A (en) * 1975-11-18 1979-03-16 Beecham Group Ltd 2-substituted-1,2-benzisothiazol-3-ones
DE2734866A1 (de) * 1977-08-03 1979-02-22 Basf Ag Neue 1,2-benzisothiazole und verfahren zu ihrer herstellung
US4957931A (en) * 1987-07-08 1990-09-18 Ciba-Geigy Corporation Certain 1,2-benzisoxazole and 1,2-benzisothiazole derivatives
MX2017000996A (es) * 2016-01-20 2017-07-19 Rehrig Pacific Co Apilador de bandejas de panaderia.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3549624A (en) * 1967-08-17 1970-12-22 Pfizer & Co C 2-substituted-2-delta**2-tetrahydropyrimidines and delta**2-im
US3557115A (en) * 1968-11-29 1971-01-19 Sandoz Ag 2 - (2 - imidazolin and pyrimidin substituted methylthio) - imidazoles and pyrimidines
US4147698A (en) * 1978-07-13 1979-04-03 E. R. Squibb & Sons, Inc. 3-(Heterocyclicalkylamino)benzisothiazole-1,1-dioxides
US4148798A (en) * 1978-02-03 1979-04-10 E. R. Squibb & Sons, Inc. [(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]alkanoic acids and esters thereof

Also Published As

Publication number Publication date
IT1105391B (it) 1985-10-28
DE2734882A1 (de) 1979-02-22
EP0000727A1 (fr) 1979-02-21
US4206217A (en) 1980-06-03
ATA559778A (de) 1981-04-15
AT364841B (de) 1981-11-25
DE2860232D1 (en) 1980-12-04
IT7850533A0 (it) 1978-07-31

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