EP0000254A1 - 2-(Gamma-(1-piperidinyl)propyl)1,2-benzisothiazole 3-one antithrombotique, ses sels d'acides pharmaceutiquement acceptables, leur préparation et leurs compositions - Google Patents

2-(Gamma-(1-piperidinyl)propyl)1,2-benzisothiazole 3-one antithrombotique, ses sels d'acides pharmaceutiquement acceptables, leur préparation et leurs compositions Download PDF

Info

Publication number
EP0000254A1
EP0000254A1 EP78300050A EP78300050A EP0000254A1 EP 0000254 A1 EP0000254 A1 EP 0000254A1 EP 78300050 A EP78300050 A EP 78300050A EP 78300050 A EP78300050 A EP 78300050A EP 0000254 A1 EP0000254 A1 EP 0000254A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
acid addition
pharmaceutically acceptable
compositions
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
EP78300050A
Other languages
German (de)
English (en)
Other versions
EP0000254B1 (fr
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
Original Assignee
Beecham Group PLC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0000254A1 publication Critical patent/EP0000254A1/fr
Application granted granted Critical
Publication of EP0000254B1 publication Critical patent/EP0000254B1/fr
Expired legal-status Critical Current

Links

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 intially 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 oculusive 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 (l):- 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 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-[ ⁇ -(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 (IV):-
  • 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 dimethylsulphoxide 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 (II) may also be prepared by treating a compound a formula (VIII):- wherein C0 2 R a is a carboxylic ester group; with a base.
  • the group R 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 acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, porpylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate 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 anesthetic, 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 t6 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 MgSO 4 ), evaporated, and the residue was chromatographed on silica gel (150g) 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 Us Patent 3,337,715, and also with two compounds disclosed in British Patent Application No. 47373/75, 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 the compound of this invention (compound A), two compounds disclosed in Application 47373/75 (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)
EP78300050A 1977-06-20 1978-06-15 2-(Gamma-(1-piperidinyl)propyl)1,2-benzisothiazole 3-one antithrombotique, ses sels d'acides pharmaceutiquement acceptables, leur préparation et leurs compositions Expired EP0000254B1 (fr)

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 true EP0000254A1 (fr) 1979-01-10
EP0000254B1 EP0000254B1 (fr) 1981-06-10

Family

ID=10230306

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300050A Expired EP0000254B1 (fr) 1977-06-20 1978-06-15 2-(Gamma-(1-piperidinyl)propyl)1,2-benzisothiazole 3-one antithrombotique, ses sels d'acides pharmaceutiquement acceptables, leur préparation et leurs compositions

Country Status (16)

Country Link
US (1) US4186203A (fr)
EP (1) EP0000254B1 (fr)
JP (1) JPS549283A (fr)
AR (1) AR216675A1 (fr)
AU (1) AU516003B2 (fr)
CA (1) CA1098447A (fr)
DE (1) DE2860750D1 (fr)
DK (1) DK275478A (fr)
ES (3) ES470977A1 (fr)
FI (1) FI781956A (fr)
IE (1) IE46937B1 (fr)
IL (1) IL54956A0 (fr)
IT (1) IT7849941A0 (fr)
NO (1) NO782129L (fr)
NZ (1) NZ187628A (fr)
ZA (1) ZA783508B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0101786A1 (fr) * 1982-04-12 1984-03-07 Green Cross Corporation Utilisation d'un dérivé de benzoisothiazoline pour la préparation d'un médicament contre la thrombose et l'aggrégation des plaquettes
FR2583046A1 (fr) * 1985-06-05 1986-12-12 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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1335289C (fr) * 1987-10-26 1995-04-18 Fujio Antoku Derives piperidinylbenzisoxazole, leur production et leur utilisation pharmaceutique
JP2581739Y2 (ja) * 1990-12-29 1998-09-24 箱竹 株式会社 多目的ラック

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1020M (fr) * 1960-03-24 1962-01-27 Wander Sa A
US3227715A (en) * 1961-07-25 1966-01-04 Knoll Ag Benzisothiazolones
FR2332019A1 (fr) * 1975-11-18 1977-06-17 Beecham Group Ltd Nouvelles benzisothiazolones
FR2338936A1 (fr) * 1976-01-24 1977-08-19 Bayer Ag Nouvelles 1,2-benzisothiazolinones-3, leur procede de preparation et medicament les contenant
NL7713355A (nl) * 1976-12-04 1978-06-06 Beecham Group Ltd Werkwijze voor het bereiden van nieuwe benziso- thiazolonderivaten met een remmende werking op de aggregatie van bloedplaatjes, alsmede farma- ceutische preparaten die deze verbindingen be- vatten.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3661974A (en) * 1970-04-27 1972-05-09 Sherwin Williams Co 2-carbalkoxy-phenyl sulfenamides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1020M (fr) * 1960-03-24 1962-01-27 Wander Sa A
US3227715A (en) * 1961-07-25 1966-01-04 Knoll Ag Benzisothiazolones
FR2332019A1 (fr) * 1975-11-18 1977-06-17 Beecham Group Ltd Nouvelles benzisothiazolones
FR2338936A1 (fr) * 1976-01-24 1977-08-19 Bayer Ag Nouvelles 1,2-benzisothiazolinones-3, leur procede de preparation et medicament les contenant
NL7713355A (nl) * 1976-12-04 1978-06-06 Beecham Group Ltd Werkwijze voor het bereiden van nieuwe benziso- thiazolonderivaten met een remmende werking op de aggregatie van bloedplaatjes, alsmede farma- ceutische preparaten die deze verbindingen be- vatten.

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0101786A1 (fr) * 1982-04-12 1984-03-07 Green Cross Corporation Utilisation d'un dérivé de benzoisothiazoline pour la préparation d'un médicament contre la thrombose et l'aggrégation des plaquettes
FR2583046A1 (fr) * 1985-06-05 1986-12-12 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
US4782069A (en) * 1986-05-28 1988-11-01 Alter, S.A. 1,4-Dihydropiridines and their use as antithrombotic drugs
EP0253092B1 (fr) * 1986-05-28 1991-09-25 Alter, S.A. 1,4-Dihydropyridines, leurs procédés de préparation et leur utilisation comme médicaments antithrombotiques

Also Published As

Publication number Publication date
FI781956A (fi) 1978-12-21
IL54956A0 (en) 1978-08-31
ES478685A1 (es) 1979-07-01
JPS549283A (en) 1979-01-24
DE2860750D1 (en) 1981-09-17
AR216675A1 (es) 1980-01-15
ES478686A1 (es) 1979-07-01
IT7849941A0 (it) 1978-06-20
IE46937B1 (en) 1983-11-02
CA1098447A (fr) 1981-03-31
ZA783508B (en) 1979-06-27
NZ187628A (en) 1981-01-23
EP0000254B1 (fr) 1981-06-10
US4186203A (en) 1980-01-29
AU3729478A (en) 1980-01-03
DK275478A (da) 1978-12-21
AU516003B2 (en) 1981-05-14
NO782129L (no) 1978-12-21
ES470977A1 (es) 1979-10-01
IE781226L (en) 1978-12-20

Similar Documents

Publication Publication Date Title
US4212872A (en) 2-Substituted benzisothiazolones and use thereof
EP0562599B1 (fr) Dérivés condensés de thiadiazole, procédé pour leur préparation et leur utilisation
JPS6230780A (ja) １，７−ナフチリジン誘導体及びこれを含有する薬剤
JP2001002571A (ja) 医薬組成物
EP0000254B1 (fr) 2-(Gamma-(1-piperidinyl)propyl)1,2-benzisothiazole 3-one antithrombotique, ses sels d'acides pharmaceutiquement acceptables, leur préparation et leurs compositions
JP3408546B2 (ja) 抗喘息剤
IE44873B1 (en) Isothiazolo pyridines
EP0118036A1 (fr) Dérivés de cétone biologiquement actifs, leur préparation et application
JPS6258335B2 (fr)
US3719671A (en) 10-imidoylphenothiazines
US4182768A (en) Prophylaxis or treatment of thromboses and inhibition of platelet aggregation in human blood
WO1994005290A1 (fr) Inhibiteur d'agregation plaquettaire
US2899434A (en) Z-phenylamino-l
US5041554A (en) Novel aryl-or heteroaryl-1-alkyl-pyrrole-2-carboxylic acid compounds useful in treating interleukin-1 mediated conditions
EP0001503B1 (fr) Compositions à effet antithrombotique contenant des benzisothiazolones
JP2962186B2 (ja) ピペリジン誘導体及びそれを含有するセロトニン拮抗薬
JPS632986A (ja) 新規なピペラジン誘導体および該化合物を有効成分とする抗潰瘍薬
PL184904B1 (pl) Zastosowanie związków 3-benzoilo-3Ć7-diazabicyklo-[3Ć3Ć1] nonanu do wytwarzania leku do leczenia zakłóceń rytmu serca
JPS6350355B2 (fr)
US3810991A (en) A method of inducing fibrinolysis
JP2997892B2 (ja) ヒダントイン誘導体を有効成分とする循環器系疾患の予防及び治療剤
EP0034002A2 (fr) Dérivés de carboxamidine
JP2955768B2 (ja) 新規なジアゾシン誘導体
DE2753391A1 (de) Benzisothiazolone, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneipraeparate
JPS6241500B2 (fr)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB NL SE

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): BE CH DE FR GB NL SE

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19810624

Year of fee payment: 4

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19810630

Year of fee payment: 4

Ref country code: BE

Payment date: 19810630

Year of fee payment: 4

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19810731

Year of fee payment: 4

REF Corresponds to:

Ref document number: 2860750

Country of ref document: DE

Date of ref document: 19810917

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: BEECHAM GROUP PLC

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19820615

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19820616

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19820630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19830101

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19830301

GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19830331

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

EUG Se: european patent has lapsed

Ref document number: 78300050.8

Effective date: 19850612

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT