IE44873B1

IE44873B1 - Isothiazolo pyridines

Info

Publication number: IE44873B1
Application number: IE847/77A
Authority: IE
Original assignee: Beecham Group Ltd
Priority date: 1976-04-28
Filing date: 1977-04-27
Publication date: 1982-04-21
Also published as: NZ183755A; AU2451277A; ZA771963B; FR2349591B1; GB1560726A; FI771236A; IE44873L; ES457993A1; IL51812A0; HU174416B; BE853779A; DK185577A; JPS52131597A; DE2718707A1; NL7704542A; ATA291977A; CA1073461A; FR2349591A1; SE7704800L; AT359063B

Abstract

A class of isothiazolopyridines having an optionally substituted alkyl group attached to the nitrogen of the isothiazolo moiety, are effective in inhibiting platelet aggregation.

Description

This invention relates to a class of isothiazolopyridines which are of value in the prophylactic and therapeutic treatment of thrombotic diseases. The invention also relates to a method for the preparation of such compounds and to pharmaceutical compositions comprising them.

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. However, although effective in. venous thrombosis, where the thrombus is formed mainly of fibrin, 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.

I With the increasing recognition of the primary role of platelets in thrombosis, attention had turned to drugs which . are capable of inhibiting the aggregation of platelets.

It has now been found that a class of isothiazoiopyridines are effective in inhibiting platelet aggregation.

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof: · wherein R is an alkyl group optionally substituted with an aryl group, with a heterocyclic group, or with a group of formula (II): IS 2 wherein R and R are fhe same or different and each is hydrogen, a C^_galkyl or phenyl group; and Z is the residue of a fused pyridine ring which is optionally substituted with up to three groups selected from C1_6alkyl, heterocyclyl, phenyl and substituted phenyl.

Suitable acid addition salts of the compounds of formula (I) include inorganic salts such as the sulphate, nitrate, phosphate,. borate and hydrohalides such as hydrochloride, hydrobromide and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate,ascorbate, methanesulphonate and p-toluenesulphonate.

The alkyl group R may be straight or branched and may suitably have from 1 to 10 carbon atoms, especially from 1 to 6 carbon atoms. When the group R is an aryl-substituted alkyl group, the aryl moiety may be, for example, optionally substituted phenyl. Suitable substituents for the phenyl group include halogen, especially chlorine.

When the group R is an alkyl group substituted with a heterocyclic ring, such a ring may be aromatic or non-aromatic mono- or polycyclic and may contain up to four heteroatoms selected from oxygen, sulphur and nitrogen. The attachment to the alkyl group may be via a carbon or nitrogen atom which is present in the ring. Examples of such rings include pyrimidyl, - 3 25 2-, 3-,· or 4-pyridyl, thiazolyl, thiazolinyl, diazolyl, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyrinyl, benzimidazolyl, benzoxazolyl, benzisothiazelonyl, piperidinyl, pytrolidinyl, morpholinyl, piperazinyl, azabieyclo [3.2.2.]-non-yl, azabicyclo[3.3.1]non-yl, homopiperidinyl and asabicyclo[2.2.2Joct-yl. 2 Suitable groups for the substituents R and R in formula (II) include methyl, ethyl, n- and iso-propyl, η-, sec, iso12 and tert-butvl. Suitably, R and R are methyl or ethyl.10 . The nitrogen atom in the pyridine moiety Z-may be at any one of the four possible positions. Suitably the nitrogen is present at position 7 of. the nucleus. For example, the moiety Z is unsubstituted or substituted with C, . alkyl. Thus, 1—6 ϊ one sub-class of compounds falling within the scope of this 15 invention comprises compounds of formula (III) and pharmaceutically acceptable non-toxic acid addition salts thereof: 2N - R (HI) 6 wherein R , R and R are hydrogen, C^^alkyl or phenyl and R is as defined above with respect to formula (I). Preferably R4, R^ and R.6 are an hydrogen.

A specific compound of formula (III), wherein R is a.

C1_5alkyl group, is: 4 8 7 3 2-n-butylisothiazolyl£5,4-b]pyridin-3-one.

A specific compound of formula (III) wherein R is an aryl substituted alkyl group is 2-(p-chlorobenzyl) isothiazolyl£5,4-b]pyridin-3-one.

Specific compounds of formula (III) and tneir salts wherein R is a heterocyclyl-substituted alkyl group and wherein the alkyl chain has from 2 to 6 carbon atoms include the following: 2-(2-pyrrolidin-l-ylethyl)-isothiazolo[5,4-b]pyridin-3-one; 2-(2-pyrrolidin-l-yl-ethyl)-isothiazolo[5,4-b]pyridin-3-onedihydrochloride: 2-(3-morpholin-l-ylpropyl)-isothiazolo[5,4-b]pyridin-3-one; 2-(2-pyrid -2-ylethyl)isothiazolo[5,4-b]pyridin-3-one; 2-[2-(3-axabicyclo(3.2.2)non-3-yl)-ethyl]isothiazolo[5,4-b]pyridin-3-one; 2-[ 2-(4-methylthiazol-2-yl)ethyl]-5-phenylisothiazolo[ 5, 4-b]-pyridin-3-one; 2-(2-pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo[5,4-b]pyridin-3-one; 2-(2-pyrrolidin-l-ylethyl)-4,5,6-trimethylisothiazolo[ 5,4-b] -pyridm- 3-one.

Another sub-group of compounds within the present invention is represented by formulae(IVA), (IVB), and (IVC) and pharmaceutically acceptable non-toxic acid addition salts thereof: (IVC) (IVA) (IVB) - 5 5 4873 in which formulae tl is as defined with respect to formula (I) above, and the groups R to R each represent hydrogen, C^_galkyl, heterocyclyl, phenyl-or substituted phenyl.

Specific compounds within formulae (IVA)> (IVB), and (IVC) include: 2- (2-pyrrolidin-l-ylethyl) -isothiazolo[ 4,5-b]pyrid in-3-one. 2-( 2-pyrrolidin-l-ylethyl)-isothiazolo[ 5,4-c]pyridin-3-one. 2-( 2-piperidin-l-ylethyl )-isothiazolo[ 5,4-c]pyriiin-3-one. 2-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]isothiazolo[5,4-c]pyridin-3-one. 2-(2-piperidin-l-ylethyl)isothiazolo[4,5-c]pyridin-3-one.

A further sub-class of compounds is represented by formula (V) and pharmaceutically acceptable non-toxic acid addition salts thereof: . wherein Z is as defined with respect to formula (I) above, A and B each represent a straight or branched chain alkylene 16 group each having from 1 to 6 carbon atoms and R represents a heterocyclyl group or a group of formula (II) above.

Specific compound^ of formula (v) include: 2-[2-( diethylamino)ethyl]-5-phenyl-isothiazolo[5,4-b]pyridin-3-one. 2-[ 3-(dimethylamino )propyl]-isoth.iazolo[4,5-b]pyridin-3-one 2-[6-( dimethylamino)hexyl]-isothiazolo[5,4-b]pyridin-3-one.

~ A still further sub-class of compounds within the scope of this invention is represented by formula (VI) and pharmaceutically acceptable non-toxic acid addition salts thereof: (VI) z wherein Z is as defined with respect to formula (I) above, R ,, , , „18 . , , is hydrogen or a alkyl group, and R is a heterocyclic ring attached via a carbon atom in the ring.

One example of a compound of formula (VI) is: 2-(1-methylpyrrolidin-2-ylmethyl)-i sothi azolo[5,4-b]pyrid-3-one.

The compounds of this invention may be prepared by cyclising a compound of formula (VII): (VII) II wherein R and Z are as defined above with respect to formula (I) The reagents for such a cyclisation are generally compounds which halogenate the sulphur atom in structure (VII) and allow subsequent dehydrohalogenation, Ά preferred reagent is iodine in the presence of a base such-as sodium-bicarbonate or anhydrous potassium carbonate but other possibilities include chlorine, bromine, phosphorus pentachloride and thionyl chloride. The reaction may be performed in a solvent which does not react with the intermediate or reagents employed. For example in the case of the reagent iodine/sodium bicarbonate, a lower alkanol, especially ethanol, may be used as a solvent but for more reactive halogenating agents such as phosphorus pentachloride a more inert solvent is employed, such as a halogenated hydrocarbon, or a higher ether or dimethylformamide.

The reaction is conveniently carried out at ambient temperature.

. The intermediate compounds of formula (VII) may be conveniently prepared by the route shown in Scheme 1: S SCHEME I mercuric acetate (VII) XV R‘MH2 wherein R and Z areas defined above with respect to formula (I).

The intermediate (VII) may conveniently be prepared and cyclised in situ to produce the corresponding compound of formula (i) A second method for the preparation of compounds of this invention comprises treating a compound of formula (VIII) with a base: ίο (VIII) C ^co2rj II ^s/NH-R -β44873 wherein R and Z are as defined above with respect to formula (I) and R is an alkyl group, preferably lower alkyl group.

Suitable bases for the reaction include alkali metal alkoxides, alkali metal hydroxides, and tetramethylammonium hydroxide in lower alcohols.

The compounds of formula (I) may also be prepared by reacting a compound of formula (IX): wherein X and Y are the same or different and each represents chlorine or branine, and wherein Z is as defined above with respect to formula (I); with an amine of formula R.NE^z wherein R is as defined above with respect to formula (1).

Suitable solvents include carbon tetrachloride and other halogenated hydrocarbons.

A fourth method for the preparation of catpounds of formula (I) cotprises treating a diner of formula (X): (X) .*4873 wherein R and Z are as defined above with respect to formula (I); with either chlorine or a base.

Suitable bases include 10% sodium hydroxide or other aqueous alkalis and the reaction may be carried out at room temperature or elevated temperature. If chlorine is employed in this reaction- it may be bubbled into a solution of compound (X) in an inert solvent such as carbon tetrachloride.

Compounds of this invention wherein R represents an alkyl group substituted with either a nitrogen - containing heterocyclic ring attached via the ring nitrogen; or with a group of formula (II), may be prepared by reacting a compound of formula (XI); (XI) .

Alk - U wherein Z is as defined with respect to formula (I) above, Alk represents a straight or branched alkylene chain and U represents a readily displaceable atom or group; with a catpound Of formula (XIIA) or (XIIB): , (XIIA) (XIIB) 448 7 3 2 wherein R and R are as defined with reference to formula (IX) and Q is the residue of a heterocyclic ring.

Suitably U is a halogen atom, for example chlorine or bromine; or a substituted sulphonyloxy group, for example £~toluenesulphonyloxy or methanesulphonyloxy.

The reaction may suitably be carried out in a hydrocarbon solvent such as toluene at an elevated temperature, for example 100° - 120°.

The invention also provides a pharmaceutical composition 10 which comprises a compound of formula (I) as defined above or a pharmaceutically acceptable, non-toxic, acid addition salt thereof together with at least one pharmaceutically acceptable carrier.

As is common practice, such compositions will usually be 15 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.

The compositions may be formulated for administration by 20 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 25 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, mag30 nesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch or acceptable wetting agents such as sodium-lauryl- su'lphate. ~ The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations maybe 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 another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, ' 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, propylene glycol, or ethyl alcohol; pre15 servatives, for exampel methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. The compound may also, if desired, be incorporated in a foodstuff, for example in the form of a biscuit.

For parenteral administration, the compound is presented in ' ' a unit dosage form as a solution or suspension in a sterile liquid vehicle, water being preferred. Parenterally administrable compositions may be prepared by dissolving the compound in water for injection, filter sterilising the solution and thereafter filling it into a suitable vial or ampoule which is then sealed.

Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be freeze-dried after it has been put Into the vial. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid before use.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the Sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The 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 l-S00mg. 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 of 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.

The compositions of the invention are useful for administration to humans and other 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 (I) may also have application 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. the heart, and kidneys, which have been removed from a cadaver and prior to.transplant.

Accordingly, this invention also provides a process for inhibiting platelet aggregation in vitro comprising the addition of a compound of the formula (I) or a pharmaceutically acceptable,' non-toxic, acid addition salt, of such a octtpound to whole blood or platelet-rich concentrates. .--The dosage for such an addition is preferably from 0.01 to 50 micrograms/ml of whole blood, The invention also provides a composition comprising whole blood and a compound of formula (I) above or a pharmaceutically acceptable, ηαη-toxic, .acid addition salt of such a compound. ' The, following Examples illustrate the preparation of some of the compounds of this invention. _ 14 4 8 7 3 Example 1 2- (2-Pyrrolidin-l-vl-ethyl) isothiazolof 5,4-b) pyridin-3-on·..·1 (a) 1,2-Dithiolor 5,4-b1pyridin-3-thiqne 2-Mercaptonicotinic acid (17.65g., O.llmole) and phosphorus pentasulphide (15g., 0.06 mole) in pyridine (150ml) were heated under reflux for 2 hours. The reaction mixture was then cooled, diluted with water and the product filtered off. Recrystallisation from ethanol yielded l,2-dithiolo[5,4-b]~ pyridin-3-thione (7.89g; 37%), red needles m.p. 185-6°c. (b) 1,2-Dithiolor 5,4-b1pyridtn-3-one To a stirred suspension of mercuric acetate (17.0g„, 0.053 mole) in glacial acetic acid (200 ml), a solution of l,2-dithiolo[5,4-b]pyridin-3-thione (5g; 0.025mole) in chloroform (100ml) was added and the mixture stirred at room temperature, for 3 days. Celite (ca,25g.) v/as added to the mixture, which was filtered and tiie filtrate evaporated. The word Celite is a Registered Trade Mirk. The residue was treated with dichlorcnethane (ca. lOCml.), the solid filtered off and the filtrate evaporated. This latter process was repeated several tines. The product was then taken up in dichlorcnethane (2Qnl) and filtered -through a short column of silica-gel made up in dichloromethane. The column was washed with sufficient dichloromethane to recover all the product and the combined filtrates evaporated. Recrystallisation of the residue from ethanol yielded 1,2-dithiolo[5,4-b]pyridin-3-one (3.21g., 70%), pale yellow needles, m.p. 96-97°C. (c) N-(2-Pvrrolidin-l-vl-ethvB-2-mercaptonicotinamida l,2-Dithiolo[5,4-b]pyridin-3-one (,l,5g; j0.009mgle), ^(^-aminoethyl)-pyrrolidine (l.lg., 0.01 mole) and ethanol (30ml) were 15 heated under reflux for 1.5' hours. The mixture was filtered hot and the filtrate evaporated to dryness. The oily residue was triturated with dichloromethane and the resulting tan solid recrystallised from ethanol to yield the product (0.75g., 34%) tan prisms, m.p. 202-205°C. - (d) 2-(2-Pyrrolidin-l-yl-ethyl)isothiazoloT 5,4-b]pyridin-3-one A stirred suspension of N-( 2-pyrrolidin-l-yl-ethyl ).-2meroaptonicotinamide (13g. 0.05 mole] and sodium bicarbonate (8.7g., 0.105 mole) in ethanol (130ml) was treated portionwise with iodine (12.35g., 0.049 mole) oyer 2.5 hours, and then stirred at room temperature for a further 8 hours. The mixture was then filtered and the filtrate evaporated to dryness. ί The solids from the filter and the residue from the filtrate were suspended in water (200ml) and extracted thoroughly^with chloroform.(3 x 50 ml) and dried (anhyd. MgSO^). Evaporation of the dried solution yielded 8.8g of crude product which was crystallised from diisopropyl ether (including charcoal treatment) yielding pure 242-pyrrolidin-l-yl-ethyl)isothiazolof5,4-b]pyridin-3-one (4.7g, 37%) as tan needles, m.p. 67-69°C. •3 4 8 Examples 2-6 From 1,2-dithiolo[5,4-b]pyridin-3-one, the intermediate prepared in Example 1(b), the following compounds were prepared by the method of Example 1(c) and 1(d) respectively: Example No. 2. (a) N-(3-Morpholin-l-ylpropyl)-2-mercaptpni-cotinamide, m.p. 139-140°C. (b) 2-(3-Morpholin-l-ylpropyl)-i sothi azolo[5,4-b]pyridin-3-one hydrochloride, m.p. 258-259°C. 3. (a) N-p-chlorobenzyl-2-mercaptonicotinamide, m.p. 216-219°C. (b) 2-(p-Chlorobsnzyl)isothiazolo[5,4-b]-pyridin3-one, m.p. 160-162°C. 4. (a) N-n-Butyl-2-mercaptonicotinamide, m.p. 129-131°C. (b) 2-n-Butylisothiazolo[5,4-b]-pyridin-3-one, m.p. 62-64°C. . (a) N-(2-Pyrid-2-ylethyl)-2-mercaptonicotinamide, m.p. 188-190°C. (b) 2-(2-Pyrid-2-ylethyl)isothiazolo[5,4-b]pyridin-3-one, m.p. 85-86°C. 6. (a) N-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]2-mercaptonicotinamide hydrochloride, m.p. 237-240°C. (b) 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo[5.4-b]pyridin-3-one, m.p. 133-135°C. 4873 - Example 7 ' (a) . 1,Z-Dithiolof5,4-c]pyridin-3-thione, m.p. 155-156°C was prepared by the method of Example 1(a). (b) 1,2-Dithiolor5,4-c]pyridin-3-one, m.p. 142-142.5°C was prepared from the above thione by the method of Example 1(b). (c) 2-(2-piperidin-l-ylethvl)iSothiazolof 5,4-clpyriclin3-one A solution of N-(2-pipefidin-l-yl)ethylamine (1.4g; O.Ollmole) in ethanol (50ml) was treated with l,2-dithiolo[5,4-c]-pyridine-one (1.69g; O.Olmole) and heated under reflux until solution was complete (ca. 15 minutes). The reaction mixture ' · O -was-cooled to 25 and anhydrous potassium carbonate (2g; 0.014mole) was added, ...The resulting suspension was stirred and. treated dropwise with;a solution of iodine (2.54g; O.Olmole) in methanol (15ml) ever 1 hour and then allowed to stand at room ! - temperature over night. The reaction mixture.was evaporated, to dryness under reduced pressure and the residue suspended in water and extracted with dichloromethane (3x50ml). The organic extract was washed with a solution of. sodium thiosulphate (50 ml - IOS), and then saturated brine (50ml) and dried over anhydrous MgS04. Removal of the drying agent and solvent yielded a gummy solid which after chromatography on silicagel, eluting with 10% MeOH/CB^Cl^,and reerystallisation from CH2Cl2/di-isopropylether yielded pure 2-(2-piperidin-l-ylethyl)isothiazolo[5,4-c]pyridin-3-one, 0.78g, m.p. 101-103°C, yield 29%. - 18 4 4 873 Examples 8-9 From 1,2-dithiolo[5,4-c]pyridin-3-one (Example 7(b), the following compounds were prepared by the method of Example 7(c): Example Ho. 8. 2-(2-Pyrrolidin-l-ylethyl)isothiazolo[5;4-c]pyridin-3-one, m.p. 75-77°C. 9. 2-(2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo[5,4-c]pyridin-3-one, m.p. 117-119°C.

Example 10. (a) Γ,2-Dithiolor4,5-b1pyridin-3-thione, m.p. 174-176°C was prepared by the method of Example 1(a). (b) 1,2-Dithiolor4,5-b1pyridin-3-one, m.p. 133-135°C was prepared from the above thione by the method of Example Kb). (c) 2-(2-Pyrrolidin-l-ylethylHsothiazoloT 4,5-blpyridin3-one, m.p. 93-95°C was prepared from l,2-dithiolo[4,5-b]pyridin-3-one and 2-pyrrolidin-l-ylethylamine by the method of Example 7(c).

Example 11. 2- (3-Dimethylaminopropyl)isothiazolof 4,5-blpyridin-3-one, m.p. 59-60°C was prepared from 1,2-dithiolo-(4,5-b]pyridin3- one, (Example 10(b))and 3-dimethylaminopropylamine by the method of Example 7(c).

Example 12. (a) 1,2-Dithiolor4,5-C~l pyridin-3-thione, m.p. 206-208° was prepared by the method of Example 1(a) 44.87 3 (b) 1,2-Dithiolor4,5-c]pyridin-3-one, m.p.157-160° was prepared from the above thione by the method of Example· 1(b). (c) . . 2-(2-Piperidin-l-ylethyl) isothiazolof4,5-c~|5 pyridin-3-one, m.p. 96-98°c, was prepared from l,2-dithiolo[4,5-c]pyridin-3-one and 2-piperidin-l-ylethylamine by the method of Example 1(c) and (d) .

Example 13. _ _ (a) 5-Phenyl-l,2-dithiolof5,4-blpyridin-3-thione, m.p,135° was prepared by the method of Example 1(a) (b) 5-Phertyl-l, 2-dithiolor 5,4-blpyridin-3-one. m.p. 149-150.'5 was prepared from the above thione by the method of Example 1(b). · (c) 2-(2-Diethylaminoethyl)-5-phenylisothiazolor 5,4-bl15 pyridin-3-one, m.p. 85-87° was prepared from 5-phenyl-l,2dithiolo[5,4-b]pyridin-3-one and 2-diethylaminoethylamine by t the method of Example 7(c).

Example 14. 2-f 2-(4-Methyl thiazol-·2-yJ.) ethyll-5-phenylisothi azoio20 ί 5,4-bipyridin-3-one, m.p.. 115-116° was prepared from -phenyl-l,2-dithiolo[5,4-b]pyridin-3-one (Example 13(b) ) and 2-(4-methylthiazol-2-yl)ethylamine by the method of Example 7(c). •ι 18 7 3 Examples 15-16 Following the procedure of Examples 1(a) - 1(d), respectively, the following compounds were prepared: Example No. 15. (a) 4,5,6-Trimethyl-l,2-dithiclo[5,4-b]pyridin3-thione, m.p. 155-157°C. (b) 4,5,6-Trimethyl-l,2-dithiolo[5,4-b]pyridin3-one, m.p. 182-184°C, (c) N-(2-Pyrrolidin-l-ylethyl)-2-mercapto-4,5,6- trimethyl-nicotinamide, m.p. 158-160°C. (d) 2-(2-Pyrrolidin-l-ylethyl)-4,5,6-trimethyl- isothiazolo[5,4-b]pyridin-3-one. dihydrochloride monohydrate, m.p. 198-203°C (dec). 16. (a) 4,6-Dimethyl-l,2-dithiolo[5,4-b]pyridin-3-thione, m.p. 140-141°C. (b) 4,6-Dimethyl-l,2-dithiolo[5,4-b]pyridin-3-one, m.p. 168-169°C. (c) N- (2-Pyrrolidin-l-ylethyl)-4,6-dimethyl-2-mercaptonicotinamide, m.p. 181-183°C. (d) 2-(2-Pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo[5,4-b]-pyridin-3-one dihydrochloride, m.p. 193196°C.

BIOLOGICAL DATA The compounds of Examples 1-16 above were treated for their ability to inhibit platelet aggregation in vitro as follows:5 Human blood (20ml) is drawn into a plastic syringe and immediately anti-coagulated by mixing with 0.1 volume of 3.8% (w/v) trisodium citrate dihydrate. Platelet-rich-plasma (PEP) is prepared by centrifuging the anti-coagulated blood at 180g., for 12 min·., at room temperature. Collagen (ex bovine achilles tendon) is suspended in 0.9% (w/v) saline, using a commercially' available mixer emulsifier. PEP was mixed with 0.1 volume saline ( control) or compound dissolved in saline and incubated at 37° for 3 min., before the addition of collagen. Water-insoluble compounds were added to PRP dissolved in 0.005 volume dimethylformamide, the solvent being included in controls when appropriate. The final concentration of each compound was ΙΟΟμΜ.

Platelet aggregation in response to collagen was measured photometrically (Born, G.V.R., 1962, Nature, 194, 927) in a Bryston aggregometer coupled to a Vitatron C Trade Mark) linear pen recorder. The activity of each ccmpound was expressed as percentage inhibition' of the aggregation response to a dose of collagen producing a just-maximal change in light transmission in control PRP. •ϊ ·4 8 7 3 Results Table I lists % inhibition of platelet aggregation in response to collagen by ΙΟΟμΜ solutions of several compounds of this invention.

Claims

1. CLAIMS :1. An isothiazolopyridine of formula (I) (I) R or a pharmaceutically acceptable non-toxic acid addition 5 salt thereof, .wherein R is an alkyl group optionally substituted with an aryl group, with a heterocyclic group, or with a group of formula (II); R (II) 1 2 wherein R and R are the same or different. and each is hydrogen or a alkyl or phenyl group; and Z is the residue of a fused pyridine ring which is optionally substituted with up to three, groups selected from 0^_θ alkyl, heterocyclyl, phenyl and substituted phenyl.

2. An isothiazolopyridine as claimed in claim 1 of formula. (Ill): · ' (III) - 24 448 73 or a pharmaceutically acceptable non-toxic acid addition salt thereof: 4 5 6 wherein R , R , and R are hydrogen, C^_g3lkyl or phenyl and R is as defined in claim 1.

3. An isothiazolopyridine as claimed in claim 2 wherein 4. 5 6 R , R and R are all hydrogen.

4. An isothiazolopyridine as claimed in claim 2 wherein R is a C^_ 6 alkyl group.

5. 2-n-Butylisothiazolo[5,4-h]pyridin-3-one.

6. An isothiazolopyridine as claimed in claim 2 wherein R is an aryl-suhsti tuted alkyl group.

7. 2-(£-Chlorobenzyl)isothiazolo[5,4-b]pyridin-3-one.

8. An isothiazolopyridine as claimed in claim 2 wherein R is a heterocyclyl-substituted alkyl group in which the alkyl chain has from 2-6 carbon atoms.

9. 2-(2-Pyrrolidin-l-ylethyl)-isothiazolo[5,4-h]pyridin3-one.

10. 3-(2-Pyrrolidin-l-ylethyl)-isothiazolo[5,4-b]pyridin3-one dihydrochloride.

11. 2-(3-Morpholin-l-ylpropyl)-isothiazolo[5,4-b]pyridin3-one.

12. 2-(2-Pyrid-2-ylethyl)isothiazolo[5,4-b]pyridin-3-one.

13. 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)-ethyl]isothiazolo[5,4-b]pyridin-3-one.

14. 2-[2-(4-Methylthiazol-2-yl)ethyl]-5-phenylisothiazolo· [5,4-b]pyridin-3-one. 25 4 43 7 3

15. ·. 2-(3-Morpholin-l-ylpropyl)-isothiazolo[5,4~b]pyridin3-one hydrochloride. .

16.. 2-(2-Pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo- [5,4-b]pyridin-3-one. 5

17. 2-(2-Pyrrolidin-l-ylethyl)-4,5,6-trimethylisothiazolo[5,4-b]pyridin-3-one.

18. An isothiazolopyridine as claimed in claim 1 wherein Z is one of the formula (A), (B), or (C): (C) 14873 in which the groups /, /, /, R^, R^\ R^, R^, r^ an( j 15 R each represent hydrogen, C^_g alkyl, heterocyclyl, phenyl or substituted phenyl.

19. 2-(2-Pyrrolidin-l-ylethyl)-isothiazolo[4,5-b]pyrid in-3-one.

20. 2-(2-Pyrrolidin-l-ylethyl)-isothiazolo[5,4-c]pyrid in-3-one.

21. 2-( 2-Piperidin-l-ylethyl) -isothiazolof 5,4-c]pyridin-3-one.

22. 2-(2-Piperidin-l-ylethyl)isothia2olo[4,5-c]pyridin-3-one.

23. 2-[2-(3-Azabicyclor 3.2.2]non-3-yl) ethyl]isothiazolo[5,4-c]pyridin-3-one.

24. An isothiazolopyridine as claimed in claim 1 of the formula (V): cr a pharmaceutically acceptable non-toxic acid addition salt thereof; wherein Z is as defined in claim 1, A and B each represent a straight or branched alkylene group each having 16 from 1 to 6 carbon atoms; and R represents a heterocyclic group or a group of formula (II) as defined in claim 1.

25. 2-[2-(Diethylamino)ethyl]-5-phenyl-isothiazolo[5,4-b]pyridin-3-one.·

26. 2 6. 2-[3-(Dimethylamino)propyl]-isothiazolo[4,5-b]pyridin-3-one.

27. 2-[ 6-(Dimethylamino) hex/1 ]-isothiazolo[5,4-b]pyridin-3-ona

28. An isothiazolopyridine as claim in claim 1 of formula (VI) -CH-R' - 27 3 or a pharmaceutically acceptable non-toxic acid addition salt 17 thereof; wherein Z is as defined m claim 1, R is hydrogen 18 or a alkyl, group, and R is a heterocyclic ring attached.via a carbon atom in the' ring.

29. 2-(l-Methylpyrrolid-2-ylmethyl)-isothiazolo[5,4-b]pyridin3-one.

30. A process for the preparation of an isothiazolopyridine as claimed in claim 1 which process comprises: (a) cyclising a compound of formula (VII): II (VII) wherein R and Z are as defined in claim 1; or (b) treating a compound of formula (VIII): ,3 co 2 R . 3 wherein R and Z are as defined in claim '1; and R is an alkyl 15 group with a base; or (c) reacting a compound of formula(IX): (IX)- 28 148 7 3 wherein Z is as defined in claim 1, and X and Y are the same or different and each represents chlorine er bromine; with an amine of formula R.NH^; or (d) treating a dimer of formula (X): S-- S wherein R and Z are as defined with respect to formula (I) with either chlorine or a base; or (e) when R represents an alkyl group substituted either with a nitrogen-containing ring attached via the ring 10 nitrogen; or with a group of formula (II) as defined in claim 1, reacting a compound of formula (XI) as hereinbefore defined with a compound of formula (XIIA) or (XIIB) as hereinbefore defined.

31. A process as claimed in claim 30(a) substantially 15 as described in either Example 1(d) or 7(c).

32. A pharmaceutical composition which comprises an isothiazolopyridine or a pharmaceutically acceptable nontoxic acid addition salt thereof as claimed in any one of claims 1 to 29 together with at least one pharmaceutically 20 acceptable carrier.

33. An isothiazolopyridine whenever prepared by a process as claimed in either claim 30 or 31. 443 73

34. A process for inhibiting platelet aggregation in vitro comprising the addition of an isothiazolopyridine or a pharmaceutically acceptable non-toxic acid addition salt thereof as claimed inany one of claims 1 to 29 or 5 33 to whole blood or platelet-rich concentrates.

35. A composition comprising whole blood and an isothiazolopyridine or a pharmaceutically acceptable nontoxic acid addition salt thereof as claimed in any one of claims 1 to 29, or 33.