EP0000727A1 - 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
EP0000727A1
EP0000727A1 EP7878100498A EP78100498A EP0000727A1 EP 0000727 A1 EP0000727 A1 EP 0000727A1 EP 7878100498 A EP7878100498 A EP 7878100498A EP 78100498 A EP78100498 A EP 78100498A EP 0000727 A1 EP0000727 A1 EP 0000727A1
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EP
European Patent Office
Prior art keywords
phenyl
benzisothiazole
formula
acid addition
compounds
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.)
Granted
Application number
EP7878100498A
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German (de)
English (en)
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EP0000727B1 (fr
Inventor
Helmut Dr. Hagen
Dieter Dr Lenke
Gerda Dr. Von Philipsborn
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.)
BASF SE
Original Assignee
BASF SE
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Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP0000727A1 publication Critical patent/EP0000727A1/fr
Application granted granted Critical
Publication of EP0000727B1 publication Critical patent/EP0000727B1/fr
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Classifications

    • 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 present 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, a halogen atom, in particular chlorine or bromine, or a nitro group and Y 1-methyl-1,2 and trimethylene-1,3 are preferred for R.
  • 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 advantageously reacting elemental sulfur in an inert organic solvent and, if appropriate, converting the compound obtained into a physiologically tolerated 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 formula III calculated on the compound of the formula II, is used in 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 reaction of, for example, 3- (4-chloromethylphenyl) -1,2-benzisothiazole with ethylenediamine and sulfur can be described by the following reaction equation:
  • the starting compounds of formula II can be obtained, for example, by side chain chlorination of 3- (4-methylphenyl) -1,2-benziosthiazoles with chlorine at about 170 ° C. and under UV radiation.
  • the 3- (4-methylphenyl) -1,2-benzisothiazoles on which the compounds of the formula II are based can be obtained by using an o-haloaryl ketone of the formula in which R 1 has the meanings given for R in formula I, R 2 represents a 4-methylphenyl radical and X represents a halogen atom, in particular chlorine, with ammonia and elemental sulfur according to the principle of the process of the published German patent application P 25 03 699.
  • R 2 hydrogen (aldehydes).
  • the reaction of a ketone of the formula IV is explained below in Example A.1.
  • a corresponding patent application was filed in the Federal Republic of Germany on August 3, 1977 under file number P 27 34 866.9.
  • a corresponding patent application with the German priority mentioned was also filed in this country under the number on.
  • 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 from 0.9 to 1.1 gram atom of sulfur per mole of starting material IV is preferably used.
  • This reaction is usually 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.
  • inert organic solvents for example 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, 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, tetrahydro
  • aromatic hydrocarbons such as tolu
  • the reaction can be carried out as follows: Starting material IV, 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 is obtained from the reaction mixture by the usual methods, e.g. by fractional distillation, filtration and optionally subsequent recrystallization from a suitable solvent, e.g. Ligroin.
  • the reaction mixture can also be poured into water after the removal of excess ammonia and solvent, the mixture formed with a suitable solvent, e.g. Extract methylene chloride, benzene and work up the extract.
  • the compounds of the general formula I according to the invention are converted into the acid addition salt of a physiologically tolerated acid in a manner which is customary per se.
  • suitable physiologically compatible organic or inorganic acids are hydrochloric acid, hydrobromic acid and LJ Phosphoric acid or sulfuric acid and as organic acids 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 taken from the progress of drug research Volume 10, pages 224 to 225, Birkhäuser Verlag, Basel and Stuttgart, 1966 become.
  • the compounds according to the invention and their physiologically tolerated acid addition salts are distinguished by a strong antiarrhythmic action 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 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 4 times (example 2) and 2.8 times (example 3) greater than that of procainamide.
  • the present invention accordingly also relates to therapeutic agents or preparations which, in addition to conventional carriers and diluents, contain a compound of the formula I or its physiologically tolerable acid addition salts 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 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 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 be mixed, 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 polyvin
  • coated tablets can be coated with cores usually made in analogy to the tablets.
  • Dragee coatings used agents for example Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar, are produced.
  • the coated tablet 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.
  • Example 1 230.5 parts of 2-chloro-4'-methyl-benzophenone, 32 parts of sulfur and 100 parts of NH 3 are reacted in 800 parts of methyl glycol at 160 ° C. in an enamel autoclave for 6 hours. 200 parts of 3- (4'-methylphenyl) -1,2-benzisothiazole with mp 56 ° C. are obtained. The yield corresponds to 89% of theory.
  • 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 (mean MW 4000), hydroxypropylmethyl cellulose, talc and magnesium stearate and pressed into tablets 4,280 mg. r
  • 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)
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
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
DE2734882 1977-08-03

Publications (2)

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

Family

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Family Applications (1)

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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)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170233199A1 (en) * 2016-01-20 2017-08-17 Rehrig Pacific Company Bakery tray stacker

Families Citing this family (3)

* 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

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 58 (1963) 11340c; & Ric. Sci. Rend., Ser. B2, 117-8 (1962) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170233199A1 (en) * 2016-01-20 2017-08-17 Rehrig Pacific Company Bakery tray stacker

Also Published As

Publication number Publication date
DE2860232D1 (en) 1980-12-04
IT1105391B (it) 1985-10-28
US4206217A (en) 1980-06-03
AT364841B (de) 1981-11-25
IT7850533A0 (it) 1978-07-31
DE2734882A1 (de) 1979-02-22
ATA559778A (de) 1981-04-15
EP0000727B1 (fr) 1980-08-20

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