GB2068950A - Pyridine Derivatives - Google Patents

Abstract

Pyridine thromboxane synthetase inhibitors have the formula: <IMAGE> wherein m is 0 or 1; X is O or S; Y is either (a) -(CH2)n- wherein n is 0 or an integer of from 1 to 5 or (b) a 5- or 6-membered heterocyclic group; R<1> is hydrogen or a C1-C4 alkyl group; and R<2> is a polar group, provided that when Y is isoxazolyl, R<2> may also be methyl. The compounds may be converted to their pharmaceutically acceptable acid addition salts and/or formulated as pharmaceutical compositions.

Description

SPECIFICATION Pyridine Derivatives This invention relates to certain pyridine derivatives, and to their use in selectively inhibiting the action of the thromboxane synthetase enzyme, i.e. without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes. The compounds may thus be useful in, for example, the treatment of ischaemic heart disease, stroke, transient ischaemic attack, migraine, and the vascular complications of diabetes.

Thus according to the invention there are provided compounds of the formula

wherein m is O or 1; XisOorS; Y is either (a) (CH2) wherein n is O or an integer of from 1 to 5 or (b) a 5- or 6-membered heterocyclic group; R1 is hydrogen or a C1-C4 alkyl group; and R2 is a polar group, provided that when Y is isoxazolyl, R2 may also be methyl; and the pharmaceutically acceptable acid addition salts thereof.

Suitable polar groups are for example -CO2H, -C02(01-C4 alkyl), -ON, 5-tetrazolyl or -CONHR3 wherein R3 is H, C1-C4 alkyl, a 5- or 6-membered heterocyclic group, --CN, --COR4 or --SO,R4, R4 being C1-C4 alkyl, phenyl or a 5- or 6-membered heterocyclic group.

Suitable 5- or 6-membered heterocyclic groups are for example, furyl, pyridyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl or thiazolyl.

Preferably, Y is -(CH2)2- -(CH2)4-, 2-furyl, 2-thienyl or 5-isoxazolyl, and R2 is -COOH, -COOCH3, -COOC2H5, -CON H2,-CONHCOCH3,-CONHCO . Phenol, or-CONH(2-pyridyl), provided that when Y is 5-isoxazolyl, R2 may also be methyl.

Preferred individual compounds include 6-(pyrid-3-yloxy) hexanoic acid and 4-(3picolylthio)butyrate.

In addition, the invention provides a pharmaceutical composition comprising a compound of the formula (i) or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. The composition is preferably in unit dosage form.

The invention also provides a method of inhibiting the action of the thromboxane synthetase enzyme in an animal, including a human being, without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes, which comprises administering to the animal an effective amount of a compound of the formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising such a compound or salt together with a pharmaceutically acceptable diluent or carrier.

The invention yet further provides a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof for use in treating an animal, including a human being, to inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes.

By the term "unit dosage form" as used herein is meant a physically discrete unit containing an individual quantity of the active component in association with a pharmaceutically acceptable diluent or carrier, the quantity of active component being such that at least one unit or severable fraction of a unit is required for a single therapeutic administration. In the case of severable units, such as scored tablets, at least one severable fraction such as a 1#2 or 1#4 of the unit may be all that is required for a single therapeutic administration.It will be appreciated that the term "unit dosage form" does not include mere solutions except when the solutions are packaged in ingestible containers, e.g. soft capsules, or have been prepared so as to be suitable for parenteral administration, e.g. in vials of solution suitable for parenteral injection.

Pharmaceutically acceptable acid addition salts of the compounds of the invention are salts with acids containing pharmaceutically acceptable anions, e.g. the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, and p-toluene sulphonate salts.

The compounds of the invention may be prepared by a number of routes, including the following: (1) The compounds of the formula (I) may be prepared as follows:

wherein m, X, Y, R1 and R2 are as defined above and Z is CI, Br or I.

Suitable base/solvent combinations are for example sodium hydride/N,N-dimethylformamide, sodium ethoxide/ethanol, sodium hydroxide/water/N,N-dimethylformamide or sodium hydroxide/ethanol.

The reaction and isolation of the end product may be carried out in a conventional manner as illustrated in many of the specific Examples hereinafter.

The starting materials of the formulae (II) and (II) are either known compounds or may be prepared by conventional techniques.

(2) Many of the compounds of the formula (I) may be prepared from other compounds of the formula (I) in a conventional manner.

For example, compounds in which R2 is -COOH may be prepared by the alkaline hydrolysis of the corresponding ester [B2=-COO(C1-C4 alkyl)], using e.g. KOH/H20 or NaOH/H20.

Compounds of the formula (I) in which R2 is a group of the formula --CONHR3, R3 being a 5-or 6membered heterocyclic group or a group of the formula --COR4 or -S02B4, R4 being as defined for formu'a '!), may be prepared by reacting the corresponding acid (R2=COOH), with N,N' carbcnyldiImidazole and then with a compound of the formula R3NH2.

Compounds of the formula (I) in which R2 is a group of the formula -CONH2 may be prepared by the reaction of the corresponding compound in which R2 is -COO (ClC4 alkyl) with ammonia, e.g. as ammonia in ethanol or aqueous ammonia.

(3) The pharmaceutically acceptable acid addition salts may be prepared by conventionaí procedures, e.g. by reacting the free base in a suitable solvent with a solution of the appropriate acid in a suitable solvent thus generally precipitating the desired salt.

The compounds of the invention inhibit the action of the thromboxane synthetase enzyme, but do not significantly inhibit the action of the prostacyclin synthetase or cycio-oxygenase enzymes. Thus the compounds are useful in the treatment of conditions characterised by an imbalance of prostacyclin/thromboxane A2, which may for example include thrombosis, ischaemic heart disease, stroke, transient ischaemic attack, migraine, and the vascular complications of diabetes, as explained below.

Research work has established that in most tissues the major product of the arachidonic acid metabolism is either of two unstable substances, thromboxane A2 (TxA2) or prostacyclin (PG 12). (Proc.

Nat. Acad. Sci. U.S.A., 1975, 72, 2994; Nature, 1 976, 263, 663; Prostaglandins, 1976, 12, 897.) In most cases the prostaglandins PGE2, PG F2 and PGD2 are comparatively minor by-products in this bio syntinetic pathway. The discovery of thromboxane A2 and prostacyclin has significantly increase our understanding of vascular homeostasis; prostacyclin for instance is a powerful vasodilator and inhibitor of platelet aggregation, and in this last respect is the most potent endogenous substance so far discovered. The prostacyclin synthetase enzyme is located in the endothelial layer of the vasculature, and is fed by endoperoxides released by blood platelets coming into contact with the vessel wall.The prostacyclin thus produced is important for prevention of platelet deposition on vessel walls.

(Prostaglandins, 1976, 12.685;Science, 1976,17; Nature, 1978,273,765).

Thromboxane A2 is synthetised by the thromboxane synthetase enzyme which is located in, for example. the blood platelets. Thromboxane A2 is a powerful vasoconstrictor and pro-aggregatory substance. As such its actions are in direct opposition to those of prostacyclin. If, for any reason, prostacyclin formation by the vasculature is impaired, then the endoperoxides produced by platelets coming into contact with the vessel wall are converted into thromboxane, but are not converted effectively into prostacyclin (Lancet,1977,18; Prostaglandins, 1978, 13, 3). Alteration of the prostacyclin/thromboxane balance in favour of the latter substance could result in platelet aggregation, vasospasm (Lancet,1977,479; Science 1 976, 1135; Amer.J. Cardiology,1978,4 787) and an increased susceptibility to atherothrombosis (Lancet (i) 1 977, 1 21 6). It is also known that in experimental atherosclerosis prostacyclin generation is suppressed and thromboxane A2 production is enhanced (Prostaglandins. 1977,14,1025 and 1035).

Thus thromboxane A2 has been implicated as the causative agent in variant angina, myocardial infarction, sudden cardiac death and stroke (Thromb. Haemostasis, 1977, 38, 132). Studies in rabbits have shown that ECG changes typical of these conditions were produced when freshly prepared thromboxane A2 was injected directly into the animal's heart (Biochem. Aspects of Prostaglandins and Thromboxanes, Editors, N. Kharasch and J. Fried, Academic Press 1 977 page 189).

This technique is considered to represent a unique animal model of the heart attacks of coronary patients and has been used to show that administration of a compound believed to antagonise the effects of thromboxane A2 protects the rabbits from the adverse consequences of thromboxane A2 injection.

Another area where a PGl2 /TxA2 imbalance is considered to be a contributory factor is that of migraine. The migraine headache is associated with changes in intra and extra-cerebral blood flow, in particular a pre-headache reduction of cerebral blood flow followed by dilatation in both vascular areas during the headache phase.

Prior to the development of the headache, blood levels of 5-hydroxytryptamine are elevated, and this suggests the occurrence of in vivo aggregation and release of the amine from the platelet stores. It is known that the blood platelets of migraine patients are more prone to aggregate than are those of normal individuals(J. Olin. Pathol., 1971,24,250;J. Headache, 1977,17,101). Furthermore, it has now been postulated that not only is an abnormality of platelet function a major factor in the pathogenesis of migraine attacks but it is in fact their prime cause (Lancet (i), 1978, 501). Thus a drug that selectively modifies platelet function to inhibit thromboxane A2 formation could be of considerable benefit in migraine therapy.

Abnormalities of platelet behaviour have been reported in patients with diabetes mellitus (Metabolism, 1979, 28, 394, Lancet 1978 (i) 235). Diabetic patients are known to be particularly susceptibie to microvascular complications, atherosclerosis and thrombosis and platelet hyperreactivity has been suggested as the cause of such angiopathy. Diabetic platelets produce elevated amounts of TxB2 and malondialdehyde (Symposium "Diabetes and Thrombosis-Implications for Therapy", Leeds U.K. April, 1979). Also it has been shown that in rats with experimental diabetes vascular prostacyclin production is impaired and TxA2 synthesis from the platelets is elevated (IV International Prostaglandin Conference, Washington, D.C. May 1979).

Thus the imbalance between prostacyclin and TxA2 is considered to be responsible for the microvascular complications of diabetes. A TxA2-synthetase inhibitor could therefore find clinical utility in preventing these vascular complications.

Aspirin and most other non-steroidal anti-inflammatory drugs inhibit the cyclo-oxygenase enzyme. The effect of this is to shut down the production of the PGG2/H2 endoperoxides and by so doing to reduce both the prostacyclin and thromboxane A2 levels. Aspirin and aspirin-like drugs have been evaluated clinically for prevention of stroke and heart attack (New England J. Med., 1978, 299, 53; B.M.J., 1978, 1188; stroke, 1977, 8, 301).

Although some encouraging results have been obtained with these drugs, a compound which specifically inhibits-thromboxane A2 formation leaving the biosynthesis of prostacyclin unimpaired would be more valuable in these clinical conditions (Lancet (ii), 1978, 780).

The effect of the compounds of the formula (I) on the thromboxane synthetase enzyme, and the prostacyclin synthetase and cyclo-oxygenase enzyme has been measured by the following in vitro enzyme assays:- 1. Cyclo-oxygenase Ram seminal vesicle microsomes (Biochemistry, 1971, 10, 2372) are incubated with arachidonic acid (100 cm: 1 min.: 220) to produce PGH2 and aliquots of the reaction mixture injected into a stream of Krebs-bicarbonate at 370C (containing a mixture of antagonists (Nature, 1978,218, 1135) and indomethacin (Brit. J. Pharmacol., 1972,45,451)) which is superfusing a spirally-cut rabbit aorta strip (Nature, 1 969, 223, 29).

The ability of a compound to inhibit the enzyme is measured by comparing the increases in isometric tension produced by PGH2 in the absence of the test compound, and following pre-incubation of the enzyme with the test compound for 5 minutes.

2. Prostacyclin (PGI2) Synthetase Pig aorta microsomes (Nature, 1976, 263, 663) are incubated (30 sec.; 220C) with PGH2 produced as in 1) and aliquots bio-assayed as in 1. PGI2 production is assessed indirectly by measuring the decrease in PGH2-induced tension (PGI2 itself does not contract the aorta). This decrease can be prevented completely by pre-incubation of the enzyme with the selective PGI2 synthetase inhibitor, 1 5- hydroperoxy-arachidonic acid (Prostaglandins, 1976, 12, 715). The test compound is then preincubated with the enzyme for 5 minutes, and its ability to prevent the decrease in tension is measured.

3. Thromboxane A2 (TxA2) Synthetase Indomethacin pretreated human platelet microsomes (Science 1976, 193, 163) are incubated (2 min.: OOC) with PGH2 (produced as in 1) and aliquots of the reaction mixture superfused over two rabbit aorta spirals which are separated by a delay coil (2 min.). The latter is required to ailow the selective decay of the more unstable thromboxane A2 (Proc. Nat. Acad. Sci., 1975, 72, 2994) thereby enabling the separate measurement of increased isometric tension due to the TxA2 formed and the PGH2 remaining.

The test compound is pre-incubated with the enzyme for 5 minutes, and its ability to inhibit the thromboxane synthetase enzyme is measured as its reduction of the TxA2 component of the isometric tension.

Compounds of the invention tested in this way have been shown to be capable of selectively inhibiting the thromboxane synthetase enzyme.

In addition to the above an in vitro assay for measuring the inhibition of human blood platelet aggregation has been described and this may be predictive of anti-thrombotic efficacy clinically (Lancet (ii), 1974, 1223: J. Exp. Med., 1967, 126(171). Both the clinically effective agents aspirin and sulphinpyrazone show inhibitory activity in vitro against a variety of aggregaring agents in this test.

A number of in vivo tests in animals have also been described for evaluating potential antithrombotic drugs. Intravenous injection of arachidonic acid causes death in rabbits by causing platelet clumping and embolisation in the lungs. Again both the clinically effective aspirin (Agents and Actions, 1 977, 1.481) and sulphinpyrazone (Pharmacology, 1976, 14, 522) protect the rabbit from the lethal effect of the injection. Sulphinpyrazone has also been shown to prevent the aggregation of platelets in an extra corporeai loop of the abdominal aorta of rats in vivo (Thromb. Diathes. Haem., 1 973,30, 138).

The compounds of the invention are expected to be effective inhibitors of human blood platelet aggregation in the above in vitro assay, to protect rabbits against the lethal effect of arachidonic acid injection, and to prevent aggregation of platelets in the rat aorta.

The compounds may be administered orally in the form of tablets or capsules containing a unit dose of the compound together with such excipients as maize starch, calcium carbonate, dicalcium phosphate, alginic acid. lactose, magnesium stearate, "Primogel" (Trade Mark) or talc. The tablets are typically prepared by granulating the ingredients together and compressing the resulting mixture to tablets of the desired size. The capsules are typically prepared by granulating the ingredients together and filling them into hard gelatine capsules of the appropriate size to contain the ingredients.

The compounds may also be administered parenterally, for example by intramuscular, intravenous or subcutaneous injection. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes such as tonic and pH adjusters. The compounds may e.g. be added to distilled water and the pH adjusted to 3-6 using an acid such as citric, tactic or hydrochloric. Sufficient solutes such as dextrose or saline may be added to render the solution isotonic.

The resulting solution may then be sterilised according to the method of B.P. 1 973 by filtration through a bacteria-prooi filter under aseptic conditions into sterile containers so as to comply with the test for steriiity of Appendix 1 21, B.P. 1 973. Suitable containers are for example sterile glass vials of an appropriate size to contain the desired volume of solution, which volume will typically contain a unit dose of the compound of the formula (I). The compounds of the invention may also be administered by the infusion of a parenteral formulation as described above into a vein.

For oral administration to human patients, it is expected that the daily dosage level of a compound of the invention will be from 0.1 to 20 mg/kg per day for a typical adult patient (70 kg). For parenteral administration, it is expected that the daily dosage level of a compound of the formula (I) will be from 0.01--0.5 mg/kg. per day, for a typical adult patient. Thus tablets or capsules can generally be expected to contain from 5 to 1 50 mg of the active compound for administration orally up to 3 times a day. Dosage units fnr parenteral administration can be expected to contain from 0.5-35 mg of the active compound. A typical viai could be a 10 ml vial containing 5 mg of the active compound in 6-1 0 ml of solution.

It should of course be appreciated that the physician in any event will determine the actual dosage which will be most suitable for the individual and it will vary with the age, weight and response of the patient. The above dosages are exemplary of the average host. There may of course be individual cases where higher or lower dosage ranges are merited.

The following Examples, in which all temperatures are given in C, illustrate the invention: Example 1 Ethyl 6-(Pyrid-3-yloxy!hexanoate Sodium hydride (0.5 g of 50% dispersion in mineral oil) was added in portions to a stirred solution of 3-hydroxypyridine (0.95 g) in dry N,N-dimethylformamide (30 ml) and the mixture was stirred at room temperature for 30 minutes. Ethyl 6-bromohexanoate (2.23 g) was then added and the mixture was stirred at room temperature for 1 8 hours and then evaporated to dryness. Water was then added to the residue and the mixture was extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. The column was eluted with petrol (b.p. 40--600) to remove mineral oil and then with chloroform to give ethyl 6-(pyrid-3-yloxy)hexanoate (1.10 g) as an oil.

Analysis %:- Found: C, 65.81; H, 8.14; N, 6.18.

C13HXgNO3 requires: C, 65.80; H, 8.07; N, 5.90.

Example 2 Ethyl 6-[4-Methylpyrid-3-yloxy]hexa no ate hydrochloride Treatment of 3-hydroxy-4-methylpyridine with sodium hydride followed by ethyl 6bromohexanoate by a procedure similar to that described in Example 1 gave ethyl 6-[4-methylpyrid-3yloxy]hexanoate as an oil.

A portion of the oil was dissolved in ether and the resulting solution was treated with an excess of ethereal hydrogen chloride to give a solid which was crystallised from ethyl acetate to give ethyl 6-[4methylpyrid-3-yloxy]hexanoate hydrochloride, m.p. 130--1310.

Analysis %:- Found: C, 58.20; H, 7.62; N, 4.55.

C14H21NO3HCI requires: C, 58.42; H, 7.71; N, 4.87.

Example 3 6-[4-Methylpyrid-3-yloxy]hexanoic acid Ethyl 6-[4-Methylpyrid-3-yloxy]hexanoate was heated on a steam bath for 22 hours in a solution of potassium hydroxide (0.28 g) in water (20 ml). The resulting solution was just acidified with acetic acid and the precipitate was filtered off, washed with water, dried and crystallised from ethyl acetate/petrol. (b.p. 40--600) to give 6-[4-methylpyrid-3-yloxy]hexanoic acid acid (0.35 g), m.p. 76- 77C, Analysis %:- Found: C, 64.74; H, 7.75; N, 6.08.

C12HNO3 requires: C, 64.55; H, 7.68; N, 6.27.

Example 4 6-(Pyrid-3-yloxy)hexanoic acid Treatment of ethyl 6-(pyrid-3-yloxy)hexanoate with aqueous potassium hydroxide by a procedure similar to that described in Example 3 gave 6-(pyrid-3-yloxy)hexanoic acid, m.p. 89--900 following recrystallisation from ethyl acetate/petrol (b.p. 60--800).

Analysis %:- Found: C, 62.94; H, 7.34; N, 6.94.

Ct1H15NO3 requires: C, 63.13; H, 7.23; N, 6.70.

Example 5 Ethyl 4-(3-Picolylthio)butyrate 3-Pyridinemethanethiol (2.5 g) was dissolved in a solution of sodium hydroxide (0.80 g) in ethanol (70 ml) and ethyl 4-bromobutyrate (3.9 g) was added dropwise and the resulting mixture was heated under reflux for 2 hours. The mixture was then cooled and filtered and the residue was washed with a little ethanol. The combined filtrate and washings were evaporated and the residue was chromatographed on silica gel. Elution with chloroform/methanol (30:1) gave pure 4-(3picolylthio)butyrate as an oil (3.60 g).

Analysis %:- Found: C, 59.91; H, 7.49; N, 5.27.

C12H17NO2S requires: C, 60.22; H, 7.16; N, 5.85.

Example 6 4-(3-Picolylthio)butyric acid Ethyl 4-(3-picolylthio)butyrate (1.2 g) was heated on a steam bath for 4 hours in a solution of sodium hydroxide (0.20 g) in water (20 ml). The resulting solution was cooled to 0 and just acidified with acetic acid. The solid was filtered off and crystallised from water to give 4-(3-picolylthio)butyric acid (0.68 g), m.p. 105106C.

Analysis %:- Found: C, 56.95; H, 6.11; N, 6.65.

C1oH13No2s requires: C, 56.84; H, 6.20; N, 6.63.

Example 7 Methyl 5-(3-Pyridylmethylthiomethyl)-2-furoate hemifumarate 3-Pyridinemethanethiol (4.20 g) was added dropwise with stirring to a solution of sodium (0.685 g) in ethanol (100 ml) and stirring was continued for 10 minutes. A solution of methyl 5-chloromethyl2-furoate (5.87 g) in ethanol (20 ml) was added dropwise with stirring over 10 minutes. The mixture was stirred for 2 hours and then evaporated. The residue was partitioned between chloroform and 2N hydrochloric acid. The chloroform layer was separated and extracted with 2N hydrochloric acid. The combined acidic layers were neutralised with solid sodium bicarbonate and then extracted with chloroform. The combined chloroform extracts were washed with water and dried (Na2SO4).

Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of chloroform and methanol (20:1) gave the product as an oil (3.50 g) pure enough for further reaction.

A sample was dissolved in the minimum volume of ethanol and a slight excess of an ethereal solution of fumaric acid was added. The solid was filtered off and crystallised from isopropanol to give methyl 5-(3-pyridylmethylthio methyl)-2-furoate hemifumarate, m.p. 134135o after partial melting at 94--9 5 OC.

Analysis %: Found: C, 55.72; H, 4.59; N, 4.48.

C13H13N03S.-21C4H4O4requirns: C, 56.07; H, 4.71; N, 4.36.

Example 8 5-(3-Pyridylmethylthio methyl)-2-furoic acid A solution of methyl 5-(3-pyridylmethylthiomethyl)-2-furoate (2.80 g) in ethanol (10 ml) was added to a solution of potassium hydroxide (1.50 g) in water (20 ml) and the mixture was heated under reflux fGr; / hour and then evaporated to small volume. The solution was made just acidic with acetic acid and Lhen evaporated. The residue was crystallised from water to give 5-(3 pyridylmethylthiomethyi)-2-furoic acid (1.80 g), m.p. 164165.5C.

Analysis o:- Found: C, 57.68; H, 4.36; N, 5.19.

C,2Hl,NO3S requires: C, 57.83; H, 4.45; N, 5.62.

Example 9 5-(3-Pyridylmethylth iomethyl)-furan-2-carboxa m ide Methyl 5-(3-pyridylmethyithiomethyl)-2-furoate (0.35 g) was dissolved in a saturated solution of ammonia in ethanol (10 ml) and the solution was allowed to stand for 6 days. It was then evaporated and the residue was triturated with ether to give a solid which was crystallised from water to give 5-(3 pyridylmethylthiomethyl)-furan-2-carboxamide (0.18 g), m.p. 118--1190C.

Analysis %:- Found: C, 57.96; H, 4.99; N, 11.15.

C12H,2N202S requires: C, 58.06; I H, 4.87; N, 11.28.

Example 10 Ethyl 5-(3-Pyridylmethoxymethyl)-2-thenoate Sodium hydride (4.0 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 3-pyridylmethanol (8.72 g) in dry N,N-dimethylformamide. When the initial reaction had subsided the mixture was heated to 500C for 1 5 minutes and then cooled. A solution of ethyl 5bromomethyl-2-thenoate (20.0 g) in dry N,N-dimethylformamide (20 ml) was added with stirring over 10 minutes and the resulting mixture was stirred for 1 hour and then evaporated. The residue was dissolved in chloroform and the solution was extracted with 2N hydrochloric acid (3 x50 ml). The combined acidic extracts were neutralised by the addition of solid sodium bicarbonate and the mixture was extracted with chloroform (3x 100 ml). The combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave some impurity and then elution with a mixture of chloroform and methanol (20:1) gave ethyl 5-(3-pyridylmethoxymethyl)-2-thenoate (9.50 g) as an oil.

Example 11 5-(3-Pyridylmethoxymethyl)-2-thenoic acid Hydrolysis of ethyl 5-(3-pyridylmethoxymethyl)-2-thenoate by a procedure similar to that of Example 8 gave 5-(3-pyridylmethoxymethyl)-2-thenoic acid, m.p. 123--1240 after recrystallisation from water.

Analysis %:- Found: C, 58.25; H, 4.53; N, 5.79.

C,2H11NO3S requires: C, 57.87; H, 4.45; N, 5.62.

Example 12 N-( 2-Pyridyl)-5-(3-pyridyl methoxymethyl )thiophene-2-carboxa mide A mixture of 5-(3-pyridylmethoxymethyl)-2-thenoic acid (0.50 g) and N,N'-carbonyldiimidazole (0.49 g) in dioxan (5 ml) was heated on a steam bath for 30 minutes. 2-Aminopyridine (0.47 g) was then added and the solution was heated on a steam bath for a further 3 hours and then evaporated.

The residue was dissolved in ethyl acetate and the solution was washed with water and dried (Na2SO4).

Evaporation of the solvent gave an oil which solidified on trituration with ether. The solid was crystallised from ethanol/petrol (b.p. 60--800) to give N-(2-pyridyl)-5-(3pyridylmethoxymethyl)thiophene-2-carboxamide (0.17 g), m.p. 1 21--1 22 0.

Analysis %:- Found: C, 62.67; H, 4.72; N, 12.86.

C1gH,5N302S requires: C, 62.76; H, 4.65; N, 12.92.

Example 13 5-(3-Pyridyloxymethyl )fura n-2-carboxa mide 3-Hydroxypyridine (1.35 g) was dissolved in a solution of sodium hydroxide (0.60 g) in water (2 ml) and N,N-dimethylformamide (100 ml) and then methyl 5-chloromethyl-2-furoate (2.6 g) was added.

The solution was stirred at room temperature for 30 minutes, then heated at 1000 for 3 hours and then allowed to stand at room temperature overnight. It was then evaporated to dryness, 2N sodium hydroxide (20 ml) was added and the mixture was extracted with methylene chloride (3x25 ml). The combined organic layers were washed with brine and dried (MgSO4). Evaporation of the solvent gave crude methyl 5-(3-pyridyioxymethyl)-2-furoate as an oil (1.55 g). The oil was stirred with 20 ml of aqueous ammonia (S.G. 0.880) for 2 hours. The solid was filtered off, dried and crystallised from isopropanol to give 5-(3-pyridyloxymethyl)furan-2-carboxamide (0.36 g), m.p. 1530.

Analysis %:- Found: C, 60.27; H. 4.64; N, 13.04.

C"H,oN203 requires: C, 60.54; H, 4.62; N, 12.84.

Example 14 3-Methyl-5-(3-Pyridyloxymethyl)isoxazole hydrochloride 3-Hydroxypyridine (3.80 g) was dissolved in a solution prepared by dissolving sodium (0.92 g) in ethanol (50 ml) and then 5-chloromethyl-3-methylisoxazole (5.50 g) was added. The solution was stirred at room temperature for 2 hours and then evaporated to dryness. 2N Sodium hydroxide (20 ml) was added and the mixture was extracted with ether (2x50 ml). The combined ethereal extracts were washed with water and dried (MgSO4). Evaporation of the solvent gave an oil which was redissolved in a small volume of dry ether and a saturated solution of ethereal hydrogen chloride was added until no further precipitation occurred. The solid was filtered off and crystallised from isopropanol to give 3methyl-5-(3-pyridyloxymethyl)isoxazole hydrochloride (1.20 g), m.p. 158--1590.

Analysis %:- Found: C, 52.66; H, 4.67; N, 12.46.

C10HrON202. HCI requires: C, 52.99; H, 4.89; N, 12.36.

Example 15 5-(3-Pyridyloxymethyl)-2-thenoic acid 3-Hydroxypyridine (1.70 g) was dissolved in dry N,N-dimethylformamide (20 ml) and sodium hydroxide (1.0 g of 50% dispersion in mineral oil) was added portionwise with stirring. The mixture was stirred at room temperature for 30 minutes and then ethyl 5-bromomethyl-2-thenoate (5.0 g) was added. The mixture was stirred for 40 minutes and then poured into water. Extraction with ethyl acetate gave a dark oil which was chromatographed on silica gel. Elution with chloroform gave first some impurity and mineral oil followed by pure product. Evaporation of the product-containing fractions gave ethyl 5-(3-pyridyloxy)-2-thenoate as an oil (1.0 g) which was used directly.

A mixture of the above oil, potassium hydroxide (0.15 g), ethanol (10 ml) and water (1 ml) was heated under reflux for 1 hour and then allowed to stand overnight. The solution was then evaporated and the residue was dissolved in a small volume of water. Addition of acetic acid gave a solid which was filtered off and crystallized from water to give 5-(3-pyridyloxymethyl)-2-thenoic acid (0.15 g), m.p.

183--1840C.

Analysis %:- Found: C, 55.97; H, 3.81; N, 5.90.

C"HgNO3S requires: C, 56.17; H, 3.86; N, 5.95.

Example 16 N-(2-Pyridyl)-5-(3-pyridylmethylthiomethyl)furan-2-carboxa mide Successive treatment of 5-(3-pyridylmethylthiomethyl)-2-furoic acid (see Example 8) with N,Ncarbonyldiimidazole and 2-aminopyridine by the method of Example 12 gave N-(2-pyridyl)-5-(3pyridylmethylthiomethyl)furan-2-carboxamide, m.p. 99-100 C (from methylene chloride/petrol).

Analysis %:- Found: C, 62.32; H, 4.72; N, 12.98.

C1gH,5N302S requires: C, 62.76; H, 4.65; N, 12.92.

Example 17 N-Acetyl-5-(3-pyridylmethoxymethyl)th iophene-2-carboxa mide A mixture of 5-(3-pyridylmethoxymethyl)-2-thenoic acid (0.50 g) (see Example 11), and N,Ncarbonyldiimidazole (0.49 g) in dry dioxan (2.0 ml) was heated under reflux for 45 minutes. The solution was evaporated and acetamide (0.12 g) was added to the residue. The mixture was heated at 1 3000 for 2.5 hours and then cooled. Water was added and the mixture was extracted several times with ethyl acetate. The combined extracts were dried (Na2SO4) and evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave a small amount of inpurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallized from methylene chloride/petrol to give carboxamide (0.07 g), m.p. 11 61180O.

Analysis %:- Found: C, 57.85; H, 4.68; N, 10.01.

C,4H,4N203S requires: C, 57.93; H, 4.86; N, 9.65.

Example 18 N-Benzoyl-5-(3-pyridylmethoxymethyl )thiophene-2-carboxa mide Successive treatment of 5-(3-pyridylmethoxymethyl)-2-thenoic acid (see Example 11) with N,N' carbonyidlimidazole and benzamide by the method of Example 17 gave N-benzoyl-5-(3 pyridylmethoxymethyl)thiophene-2-carboxamide m.p.114.5-115.5 C(from methylene chloride/petrol).

Analysis %: Found: C, 64.4; H, 4.61; N, 8.03.

C19H16N203S requires: C, 64.76; H, 4.58; N, 7.95.

Claims (9)

Claims

1. Pyridines of the formula:

wherein m is 0 or 1; XisOorS; Y is either (a) (OH2) wherein n is O or an integer of from 1 to 5 or (b) a 5- or 6-membered heterocyclic group; R' is hydrogen or a C,C4 alkyl group; and R2 is a polar group, provided that when Y is isoxazolyl, R2 may also be methyl; and the pharmaceutically acceptable acid addition salts thereof.

2. A pyridine as claimed in claim 1 wherein said polar group is -CO2H, -CO2(CiC4 alkyl), -ON, 5-tetrazolyl or --CONHR3 wherein R3 is H, C1C4 alkyl, a 5-or 6-membered heterocyclic group, --CN, --COR4 or SO2R4, R4 being CrC4 alkyl, phenyl or a 5- or 6-membered heterocyclic group.

3. A compound according to claim 1 or 2, wherein the 5- or 6-membered heterocyclic group or groups are selected from furyl, pyridyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl and thiazolyl.

4. A compound as claimed in any one of the preceding claims wherein Y is -(OH2)2-, -(OH2)4-, 24uryl, 2-thienyl or 5-izoxazolyl, and R2 is-COOH,-COOCH-COOC2H5,-CONH2, -CONHCOCH3,-CONHCO. Phenyl or -CONH (2-pyridyl), provided that when Y is 5-isoxazolyl, R2 may also be methyl.

5. 6-(Pyrid-3-yloxy)hexanoic acid or 4-(3-picolylthio)butyrate.

6. A process for preparing a compound of the formula (I) as claimed in claim 1, which comprises reacting a compound of the formula:

wherein R', X and m are as defined in claim 1, with a compound of the formula: ZCH2YR2 (III) wherein Y and R2 are as defined in claim 1 and Z is Cl, Br or I, in the presence of a base; followed by, optionally: (i) conversion of a product in which R2 iS -C02(C1-C4 alkyl) into a compound in which R2 is -CO2H or -CONH2 by, respectively, alkaline hydrolysis or reaction with ammonia; or (ii) conversion of a product in which R2 is -CO2H into a product in which R2 is -CONHB3 where R3 is a 5- or 6-membered heterocyclic group or a group of the formula --COR4 or --SO,R4, R4 being as defined in claim 1, by reaction with N,N'-carbonyldiimidazole and then with a compound of the formula R3NH2, R3 being as defined in this method.

7. A process as claimed in claim 6 substantially as hereinbefore described in any one of Examples 1 to 18.

8. A compound of the formula (I) as claimed in claim 1 or pharmaceutically acceptable acid addition salt thereof which has been prepared by a process as claimed in either of claims 6 and 7.

9. A pharmaceutical composition comprising a compound of the formula (I) or pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims 1 to 5 and 8, together with a pharmaceuticaily acceptable diluent or carrier.