EP0000254B1 - Antithrombotisches 2-(Gamma-(1-piperidinyl)1,2-Benzisothiazol-3-on, seine therapeutisch zulässigen Säureadditionssalze, ihre Herstellung und ihre Präparate - Google Patents

Antithrombotisches 2-(Gamma-(1-piperidinyl)1,2-Benzisothiazol-3-on, seine therapeutisch zulässigen Säureadditionssalze, ihre Herstellung und ihre Präparate Download PDF

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Publication number
EP0000254B1
EP0000254B1 EP78300050A EP78300050A EP0000254B1 EP 0000254 B1 EP0000254 B1 EP 0000254B1 EP 78300050 A EP78300050 A EP 78300050A EP 78300050 A EP78300050 A EP 78300050A EP 0000254 B1 EP0000254 B1 EP 0000254B1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
acid addition
pharmaceutically acceptable
propyl
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.)
Expired
Application number
EP78300050A
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English (en)
French (fr)
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EP0000254A1 (de
Inventor
Barbara Nunn
Keith Howard Baggaley
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.)
Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0000254A1 publication Critical patent/EP0000254A1/de
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Expired legal-status Critical Current

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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

  • This invention relates to antithrombotic compounds and in particular to a benzisothiazolone and its acid addition salts having particularly high activity.
  • Arterial thrombosis develops initially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus.
  • the most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting.
  • anti-coagulant therapy has no effect on platelet aggregation and has therefore limited effectiveness in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
  • U.S. Patent Specification 3,227,715 discloses a class of benzisothiazolones of the formula (I): wherein A represents a lower alkylene of 2 to 4 carbon atoms, R 1 and R 2 are hydrogen or halogen, R 3 and R 4 represent hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to 4 carbon atoms, and R 3 and R 4 together with the nitrogen atom on which they are substituted stand for an unsubstituted or lower alkyl substituted heterocyclic ring having from 5 to 6 atoms in the ring; as being useful for the therapy of inflammatory processes.
  • A represents a lower alkylene of 2 to 4 carbon atoms
  • R 1 and R 2 are hydrogen or halogen
  • R 3 and R 4 represent hydrogen, lower alkyl, cycloalkyl, hydroxyalkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to
  • the present invention therefore provides the compound 2 - [y - (1 - piperidinyl)propyl] - 1,2 -benzisothiazol - 3 - one of formula (II), or a pharmaceutically acceptable acid addition salt thereof:-
  • Suitable acid addition salts include inorganic salts such as sulphate, nitrate, phosphate, and borate, hydrohalides e.g. hydrochloride, hydrobromide, and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate.
  • inorganic salts such as sulphate, nitrate, phosphate, and borate
  • hydrohalides e.g. hydrochloride, hydrobromide, and hydroiodide
  • organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate.
  • Preferred salts are the hydrochloride and hydrobromide.
  • the compound of this invention may be prepared by reacting a compound of formula (III): wherein W and Z are the same or different and each is a halogen atom; with a compound of formula (lV):-
  • W is chlorine and Z is chlorine or bromine.
  • Suitable solvents for the reaction include carbon tetrachloride or other halogenated hydrocarbon solvents.
  • a second method for the preparation of the compound of formula (II) comprises reaction of a compound of formula (V) or a salt thereof:- with a compound of formula (VI):- wherein Q is a readily displaceable group.
  • Q is a halogen atom.
  • the compound (VI) is used as its alkali metal salt, for example the sodium salt.
  • a solvent such as dimethyl formamide or dimethylsulfoxide may be used, preferably at elevated temperatures.
  • the corresponding 3-ether is also formed and the desired product may be separated by crystallisation, distillation and chromatographic techniques.
  • Compound of formula (II) may also be prepared by treating a compound of formula (VII):_ with either a base or with chlorine or bromine.
  • Suitable bases include 10% sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temperature or elevated temperatures. If chlorine is employed in this reaction it may be bubbled into a solution of compound (VII) in an inert solvent such as carbon tetrachloride.
  • the compound of formula (11) may also be prepared by treating a compound a formula (VIII) wherein CO Z R e is a carboxylic ester group; with a base.
  • the group R a is an alkyl or aryl group.
  • Suitable bases for the reaction include alkali metal alkoxides, alkali metal hydroxides and tetramethylammonium hydroxide in lower alcohols.
  • the invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above together with at least one pharmaceutically acceptable carrier.
  • composition will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thrombus formation.
  • compositions may be formulated for administration by any route, although an oral administration is preferred.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or gum acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoo
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 1 - 500 mg., of the active ingredient.
  • the dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range 0.01 to 30 mg/kg/day depending on the route and frequency of administration.
  • the preferred dose is 10 to 500 mg., orally 1 to 3 times a day for an adult human.
  • compositions of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis; in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myocardial infarcts and strokes.
  • the compounds of formula (II) may also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
  • reaction mixture was transferred to a separating funnel with dichloromethane and the suspension was washed with 10% aqueous sodium hydroxide solution, water and brine.
  • the organic layer was dried (anhydrous MgS0 4 ), evaporated, and the residue was chromatographed on silica gel (150 g) using dichloromethane-methanol (90:10) as eluant.
  • the compound of the Example was tested for their ability to inhibit platelet aggregation in the guinea pig ex vivo by the method given below, and was compared with two closely related compounds disclosed in U.S. Patent 3,337,715, and also with two compounds disclosed in French Patent Specification No, 2332019 as well as with three known anti-aggregant compounds.
  • the dose ratio represents the ratio of the concentration of aggregating agent to cause aggregation in PRP from drug-treated animals to the concentration of aggregating agent to cause aggregation in PRP from control animals.
  • Table 1 gives the results of this invention (compound A), two compounds disclosed in French Specification 2332019 (compounds B and C), two compounds disclosed in U.S. Patent 3,227,715 (compounds D and E) and three known anti-aggregant agents (compound F,G,H).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (4)

1. Die Verbindung 2 - [gamma - (1 - - Piperidinyl) - propyl] - 1,2 -benzisothiazol - 3 - on oder deren pharmakologisch verträgliches Säureadditionssalz.
2. Die Verbindung wie in Anspruch 1 beansprucht, in Form ihres Hydrochloridsalzes.
3. Verfahren zur Herstellung einer Verbindung wie in Anspruch 1 beansprucht, die Maßnahme einschließend
(a) Umsetzen einer Verbindung der Formel (III) hierin mit einer Verbindung der Formel (IV) hierin;
(b) Umsetzen einer Verbindung der Formel (V) hierin oder deren Salz mit einer Verbindung der Formel (VI) hierin;
(c) Behandeln einer Verbindung der Formel (VII) hierin entweder mit einer Base oder mit Chlor oder Brom; oder
(d) Behandeln einer Verbindung der Formel (VIII) hierin mit einer Base und gegebenenfalls nach Stufe (a), (b), (c) oder (d), Umwandlung in ein Säureadditionssalz.
4. Pharmazeutische Zubereitung, enthaltend eine Verbindung wie in Anspruch 1 beansprucht, zusammen mit mindestens einem pharmakologisch verträglichen Trägerstoff.
EP78300050A 1977-06-20 1978-06-15 Antithrombotisches 2-(Gamma-(1-piperidinyl)1,2-Benzisothiazol-3-on, seine therapeutisch zulässigen Säureadditionssalze, ihre Herstellung und ihre Präparate Expired EP0000254B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2559977 1977-06-20
GB2559977 1977-06-20

Publications (2)

Publication Number Publication Date
EP0000254A1 EP0000254A1 (de) 1979-01-10
EP0000254B1 true EP0000254B1 (de) 1981-06-10

Family

ID=10230306

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300050A Expired EP0000254B1 (de) 1977-06-20 1978-06-15 Antithrombotisches 2-(Gamma-(1-piperidinyl)1,2-Benzisothiazol-3-on, seine therapeutisch zulässigen Säureadditionssalze, ihre Herstellung und ihre Präparate

Country Status (16)

Country Link
US (1) US4186203A (de)
EP (1) EP0000254B1 (de)
JP (1) JPS549283A (de)
AR (1) AR216675A1 (de)
AU (1) AU516003B2 (de)
CA (1) CA1098447A (de)
DE (1) DE2860750D1 (de)
DK (1) DK275478A (de)
ES (3) ES470977A1 (de)
FI (1) FI781956A7 (de)
IE (1) IE46937B1 (de)
IL (1) IL54956A0 (de)
IT (1) IT7849941A0 (de)
NO (1) NO782129L (de)
NZ (1) NZ187628A (de)
ZA (1) ZA783508B (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58177915A (ja) * 1982-04-12 1983-10-18 Green Cross Corp:The 抗血栓剤
FR2583046B1 (fr) * 1985-06-05 1987-07-17 Cird Alkyl ou aralkyl thio-2 cycloalkene-1 carboxamides-1 et leurs sulfoxydes, leurs procedes de preparation et leur application a la synthese de tri et tetramethylene-4,5 isothiazoline-4, ones-3
DE3617976A1 (de) * 1986-05-28 1988-01-14 Alter Sa 1,4-dihydropyridin, verfahren zu dessen herstellung und dessen verwendung in antithrombotischen medikamenten
CA1335289C (en) * 1987-10-26 1995-04-18 Fujio Antoku Piperidinyl benzisoxazole derivatives, their production and pharmaceutical use
JP2581739Y2 (ja) * 1990-12-29 1998-09-24 箱竹 株式会社 多目的ラック

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH395094A (de) * 1960-03-24 1965-07-15 Wander Ag Dr A Verfahren zur Herstellung von 6-Chlor-benzisothiazolon
DE1147947B (de) * 1961-07-25 1963-05-02 Knoll Ag Verfahren zur Herstellung neuer 1, 2-Benzisothiazolone
US3661974A (en) * 1970-04-27 1972-05-09 Sherwin Williams Co 2-carbalkoxy-phenyl sulfenamides
NZ182325A (en) * 1975-11-18 1979-03-16 Beecham Group Ltd 2-substituted-1,2-benzisothiazol-3-ones
DE2602643C2 (de) * 1976-01-24 1984-12-20 Bayer Ag, 5090 Leverkusen 1,2-Benzisothiazolinone-3, Verfahren zu ihrer Herstellung sowie Arzneimittel
ZA776857B (en) * 1976-12-04 1978-09-27 Beecham Group Ltd Heterocyclic compounds

Also Published As

Publication number Publication date
US4186203A (en) 1980-01-29
IL54956A0 (en) 1978-08-31
AR216675A1 (es) 1980-01-15
ES470977A1 (es) 1979-10-01
EP0000254A1 (de) 1979-01-10
IE781226L (en) 1978-12-20
ES478685A1 (es) 1979-07-01
NO782129L (no) 1978-12-21
JPS549283A (en) 1979-01-24
DK275478A (da) 1978-12-21
IT7849941A0 (it) 1978-06-20
IE46937B1 (en) 1983-11-02
NZ187628A (en) 1981-01-23
FI781956A7 (fi) 1978-12-21
CA1098447A (en) 1981-03-31
AU3729478A (en) 1980-01-03
ES478686A1 (es) 1979-07-01
DE2860750D1 (en) 1981-09-17
ZA783508B (en) 1979-06-27
AU516003B2 (en) 1981-05-14

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