GB2101992A

GB2101992A - Indole derivatives

Info

Publication number: GB2101992A
Application number: GB08218431A
Authority: GB
Inventors: Peter Edward Cross; Roger Peter Dickinson
Original assignee: Pfizer Ltd
Current assignee: Pfizer Ltd
Priority date: 1981-07-07
Filing date: 1982-06-25
Publication date: 1983-01-26
Also published as: ES8305355A1; PT75191A; EP0069513A2; PL240814A1; IL66223A0; YU145482A; ES513765A0; FI822386A0; CS229934B2; AR230056A1; AU8563882A; FI822386L; AU532640B2; PT75191B; NO822360L; DD202714A5; US4451472A; DK297382A; DE3275545D1; EP0069513B1

Description

1

GB2101 992A 1

SPECIFICATION

Indole thromboxane synthetase inhibitors, processes for their preparation, and pharmaceutical compositions containing them

5

This invention relates to indole derivatives, and in particular to certain 3(pyridylmethyl)- or 3-(imidazolylmethyl)- indolyl acrylic acid derivatives. Such compounds are able to selectively inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin sythetase or cyclo-oxygenase enzymes. The compounds may thus be 10 useful in, for example, the treatment of thrombosis, ischaemic heart disease, stroke, transient ischaemic attack, migraine, cancer and the vascular complications of diabetes.

Thus, according to the invention there are provided compounds of the general formula:

wherein

R1 is hydrogen or C,-C4 alkyl;

R2 is hydrogen, C,-^ alkyl, C!-C4 alkoxy or halo;

25 R3 is hydrogen or methyl;

Y is -COOH, -C00(C1-C4 alkyl) or -CONH2;

and

Z is 1-imidazolyl or 3-pyridyl;

and the pharmaceutical^ acceptable salts thereof.

30 "Halo" means F, CI, Br or I.

Alkyl and alkoxy groups of 3 and 4 carbon atoms may be straight or branched chain.

The preferred compounds are in the E (trans) form, i.e. where the group "Y" is trans to the indole ring. R3 is preferably H. Preferably R1 is CH3 and Y is -COOH. R2 is preferably H, CH3, OCH3 or C1. When R2 is a substituent, it is preferably in the 5-position.

35 In the most preferred compounds, R1 is CH3, R2 and R3 are hydrogen and Y is -COOH.

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), or a pharmaceutically acceptable 40 salt thereof, or a pharmaceutical composition comprising such a compound or salt together with a pharmaceutically acceptable diluent or carrier.

The invention further provides a compound of the formula (I), or a pharmaceutically acceptable 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 45 prostacyclin synthetase or cyclo-oxygenase enzymes.

The invention also includes a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The preferred salts are the pharmarceutically acceptable acid addition, and, when Y is 50 -COOH, the pharmaceutically acceptable metal or ammonium salts.

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.

55 The preferred metal salts are the alkali metal salts.

(1) The compounds of the formula (I) may be prepared by a number of different routes, including by the following reaction scheme:-

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GB2101 992A 2

R3 „3

5

R2

CH.Z

R CH-Z

CH=CH.Y

(ii) (hi) (i)

10 10

where FT, RJ, R3, Y and Z are as defined for formula (I).

In a typical procedure, the indole (II) and alkyne (III) are reacted together preferably in the presence of a base (e.g. benzyltrimethylammonium hydroxide or tetrabutylammonium fluoride)

and in a suitable organic solvent, e.g. dioxan or tetrahydrofuran, typically for a few hours, e.g.

15 up to 4 hours, at room temperature, although the reaction mixture may be heated, e.g. at up to 15 100°C, to accelerate the reaction.

The product can be isolated and purified by conventional procedures as are illustrated in the following Examples.

This route prepares products in the E-form: products in the Z (cis) form are generally

20 obtainable by irradiation of the E-form with u.v. light according to conventional procedures. 20

The starting materials of the formulae (II) and (III) are either known compounds or can be prepared by procedures analogous to those of the prior art. For example, the starting materials in which Z is 1-imidazolyl are described in European patent no. 3901. The starting materials in which Z is 3-pyridyl can be prepared by the following routes:-

25 25

i) KOH

H0CH(R3)Z > Compound (II)

"•'-CPki

H

iii) Raney's alloy

35 or 35

i) CH3MgI

40 R2—C |j^ } Compound (II); 40

J! R li) C1.CH(R3)Z H

the starting indoles being described in European patent no. 3901.

45 Pyridyl intermediates in which R3 is C,-C4 alkyl can also be prepared by the following route:-

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60

CH3COOH)

N ^ R H

Z hydrogenation R 1 <

HO .

-h2o v

R

-A'

X '

R1, R2 & R3 are as defined for formula (I).

R4 is the alkylene group having the same number of carbon atoms as R3. For example, the 65 dehydration of the intermediate in which R3 is CH3 yields the compound in which R4 is CH2,

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GB2 101 992A 3

which compound is then hydrogenated (using e.g. Pd/C, C2H5OH, H2 at 2-5-atm.) to the desired end product.

(2) Naturally certain of the groups Y can be obtained by chemical transformation reactions and these possibilities will be well known to those skilled in the art. Thus, for example, compounds 5 of the formula (I) wherein Y is a carboxyl group can be obtained by the hydrolysis, preferably alkaline hydrolysis, of the corresponding esters where Y is -C00(C,-C4 alkyl). The acid may be converted to a variety of derivatives, e.g. formation of the acid chloride or bromide or the imidazolide followed by reaction with ammonia gives the amides where Y is CONH2. Also, the esters in which Y is -000(0,-04 alkyl) can be reacted with ammonia to form the corresponding 10 amides.

All these reactions are entirely conventional and the methods and conditions for their performance will be well known to those skilled in the art, as with other possibilities and variations.

The pharmaceutically acceptable acid addition salts of the compounds of the invention can be 15 prepared by conventional procedures, e.g. by reacting the free base in a suitable solvent, e.g. ethanol, with a solution containing one equivalent of the desired acid in a suitable solvent, e.g. ether. The salt generally precipitates from solution or is recovered by evaporation of the solvent. Similarly the pharmaceutically acceptable metal and ammonium salts can be prepared by conventional procedures.

20 Where the compounds of the invention contain an asymmetric carbon atom the invention includes the racemic mixtures and the separated D- and L- optically active isomeric forms. Such forms should be obtainable by conventional methods, e.g. by fractional crystallisation of a salt with a suitable optically active acid, e.g. tartaric acid.

The compounds of formula (I) and their pharmaceutically acceptable salts have been found to 25 selectively inhibit the action of the thromboxane synthetase enzyme without significantly affecting the action of the prostacyclin synthetase or cyclooxygenase enzymes. Thus the compounds are of value in the treatment of a variety of clinical conditions which are characterised by an imbalance of prostacyclin/thromboxane A2. For the reasons given below these conditions may include thrombosis, ischaemic heart disease, stroke, transient ischaemic 30 attack, migraine, cancer and the vascular complications of diabetes.

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 (PGI2). (Proc. Nat. Acad. Sci. U.S.A., 1975, 72, 2994, Nature, 1976, 263, 663, Prostaglandins, 1976, 12, 897). In most cases the prostaglandins PGE2, PGF2 and PGD2 are comparatively 35 minor by-products in this bio-synthetic pathway. The discovery of thromboxane A2 and prostacyclin has significantly increased 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 syntehtase enzyme is located in the endothelial layer of the vasculature, and may be fed by endoperoxides 40 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 synthesised by the thromboxane synthetase enzyme which is located in, for example, the blood platelets. Thromboxane A2 is a powerful vasoconstrictor and pro-45 aggregatory substance. As such its actions are in direct opposition to those of prostacyclin. If, for any reason, prostacyclin formation by the vasculator is impaired, then the endoperoxides produced by platelets coming into contact with the vessel wall may be 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 50 substance could result in platelet aggregation, vasospasm (Lancet, 1977, 479, Science, 1976, 1135, Amer. J. Cardiology, 1978, 41, 787) and an increased susceptibility to atherothrombosis (Lancet (i) 1977, 1216). 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 55 variant angina, myocardial infarction, sudden cardiac death and stroke (Thromb. Haemostasis, 1 977, 38, 1 32). 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 1977 page 189). This technique is considered to represent a unique 60 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 PGI2/TxA2 imbalance is considered to be a contributory factor is that of migraine.

65 The migraine headache is associated with changes in intra and extracerebal blood flow, in

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GB2101 992A 4

particular a pre-headache reduction of cerebral blood flow followed by dilation 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 5 platelet stores. It is known that the blood platelets of migraine patients are more prone to 5

aggregate than are those of normal individuals (J. Clin. 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

10 inhibit thromboxane As formation could be of considerable benefit in migraine therapy. 10

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 susceptible to microvascular complications, atherosclerosis and thrombosis and platelet hyper-reactivity has been suggested as the cause of such angiopathy. Diabetic platelets

15 produce elevated amounts of TxB2 and malondialdehyde (Symposium "Diabetes and Thrombo- 15 sis-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 Prostaglandiln Conference, Washington, D.C., May 1979).

Thus the imbalance between prostacyclin and TxA2 is considered to be responsible for the

20 microvascular complications of diabetes. A TxA2-synthetase inhibitor could therefore find clinical 20 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 asprin-like

25 drugs have been evaluated clinically for prevention of stroke and heart attack (New England and 25 J. Med. 1978, 299, 53, B.M.J., 1978, 1 188, 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).

30 The ability of primary neopalms to metastasize is a principle cause of failure to cure human 30 cancers. It has been suggested that metastatic tumour cells can alter the critical PGI2-TxA2 balance in favour of thrombosis (Science, 1981, 212, 1270). Prostacyclin has recently been shown to be a powerful anti-metastatic agent by virtue of its platelet antiaggregatory action. This result indicates that a TxA2-synthetase inhibitor would function as an antimetastatic agent in vivo

35 (J. Cell. Biol. 1980, 87 64). 35

The effect of the compounds of the formula (I) on the thromboxane syntehtase enzyme, and the prostacyclin synthetase and cyclooxygenase enzymes has been measured by the following in vitro enzyme assays:-

40 1. Cyclo-oxygenase 40

Ram seminal vesicle microsomes (Biochemistry. 1971, 10, 2372) are incubated with arachidonic acid (100 /xM: 1 min. : 22°) to produce PGH2 and aliquots of the reaction mixture injected into a stream of Krebs-bicarbonate at 37°C containing a mixture of antagonists (Nature,

1978, 218, 1135) and indomethacin (Brit. J. Pharmacol., 1972, 45 451) which is superfusing

45 a spirally-cut rabbit aorta strip (Nature, 1969, 223, 29). 45

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 preincubation of the enzyme with the test compound for 5 minutes (Agents and Actions, 1 981, 11, 274).

50 50

2. Prostacyclin (PGI2) Synthetase

Pig aorta microsomes (Nature, 1976, 263, 663) are incubated (30 sec.: 22°C) with PGH2 produces 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 contact the aorta). This

55 decrease can be prevented completely by pre-incubation of the enzyme with the selective PGI2 55 synthetase inhibitor, 1 5-hydroxy-arachidonic acid (Prostaglandins, 1976, 12, 715). The test compounds is then pre-incubated with the enzyme for 5 minutes, and its stability to prevent the decrease in tension is measured.

60 3. Thromboxane A2 (TxA2) Synthetase 60

Indomethacin pre-treated human platelet microsomes (Science, 1976, 193, 163) are incubated (2 min. : 0°C) 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 allow the selective decay of the more unstable thromboxane A2 (Proc. Nat. Acad.

65 Sci., 1975, 72 2994) thereby enabling the separate measurement of increased isometric 65

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GB2101992A

5

tension due to the TxA2 formed and the PGH2 remaining. The test compound is pre-incubated with 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 formula (I) tested in this way have been shown to be capable of selectively 5 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 clinically effective agents aspirin and sulphinpyrazone show inhibitory activity in vitro against a variety of aggregating 10 agents in this test.

A number of in vivo tests in animals have also been described for evaluating potential antithrombotic drugs.

The method of Patrono et al is adapted to study the generation of TxB2 in whole blood samples removed from animals prior to and following drug treatment. Briefly, blood samples are 15 taken into glass tubes and allowed to clot at 37°C. Serum is separated by centrifugation and the samples stored at -40°C until assayed for TxB2, when appropriate dilutions of ethanol deproteinised samples are analysed by RIA. This technique is used in experiments with the test compounds to determine intravenous potency in anaesthetised rabbits:-

20 Anaesthetised Rabbits

Male New Zealand white rabbits (2.6-5.6 kg) are anaesthetised with sodium pentobarbitone (30 mg/kg i.v.) followed by urethane (500 mg/kg i.p.). After cannulation of the trachea, a carotid artery is catherised for collection of blood samples. The catheter is kept patent by slow infusion (0.2 ml/minute) of sterile saline. Control carotid arterial blood samples are taken 30 25 and 5 minutes prior to administration of the test compound or vehicle (0.9% w/v NaC1, 0.2 ml/kg) via a marginal ear vein. Three groups of rabbits are used. The first group receive 0.03 mg/kg of the test compound followed, one hour later, by 0.1 mg/kg. Similarly, the second group receive 0.3 mg/kg, followed by 1 mg/kg. The third group receive vehicle, followed one hour later by a further vehicle injection. Carotid arterial blood samples are taken at various times 30 after all doses. At each time point, a 1 ml blood sample is taken into a glass test tube, without anticoagulant, for TxB2 determination. For the latter, the blood sample is allowed to clot during a two hour incubation at 37°C (which preliminary experiments had shown to give maximum TxB2 production) and the serum obtained by centrifugation. Serum samples are then processed through the TxB2 RIA after deproteinisation with ethanol and dilution with Isogel Tris buffer. 35 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, 1977, 1, 481) and sulphinpyrazone (Pharmcology, 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 corporeal loop of the abdominal aorta of rats in vivo (Thromb. Diathes, 40 Haem., 1973, 30, 138).

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 45 the resulting mixture to give tablets of the desired size. Capsuels are typically prepared by granulating the ingredients together and filling them into hard gelatine capsules of the appropriate size to contain the desired dosage.

The compounds may also be administered parenterally, for example by intramuscular, intravenous or subcutaneous injection. For parenteral administration, they are best used in the 50 form of a sterile aqueous solution which may contain other solutes such as tonic and pH

adjusters. The compounds may be added to distilled water and the pH adjusted to 3-6 using an acid such as citric, lactic or hydrochloric acid. Sufficient solutes such as dextrose or saline may be added to render the solution isotonic. The resulting solution may then be sterilised and filled into sterile glass vials of an appropriate size to contain the desired volume of solution. The 55 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 formula (I) 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 60 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 150 mg of the active compound for administration orally up to 3 times a day. Dosage units for parenteral administration can be expected to contain from 0.5-35 mg of the active compound A typical vial could be a 10 ml vial containing 5 mg of the active compound in 6-10 ml of solution.

65 It should of course be appreciated that in any event the physician will determine the actual

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GB2101 992A

6

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 patient, there may of course by individual cases where higher or lower dosage ranges are merited.

5 The preparation of the novel compounds of the formula (I) is illustrated by the following 5

Examples. All temperatures are in °C.

EXAMPLE 1

E-3- {1 -[2-methyl-3-(1-imidazolylmethyl)]indolyl} acrylic acid 10 Ethyl propiolate [CH=C.COOC2H5] (0.54 g) was added dropwise to a stirred solution of 2- 10 methy!-3-(1 -imidazolylmethyl)indole (1.05 g) (European patent no. 3901), and benzyltrimethy-lammonium hydroxide (0.5 ml of 40% solution in methanol) in dioxan (12 ml), and the resulting solution was stirred at room temperature for 2 hours and then evaporated. The residue was poured into water and the mixture was extracted several times with ethyl acetate. The 1 5 combined extracts were washed with water and dried (Na2S04). Evaporation of the solvent gave 1 5 an oil which was chromatographed on silica gel. Elution with chloroform gave an oil (1.1 g)

which was shown by n.m.r. to be a mixture of the ethyl and methyl esters of the desired product.

The ester mixture (0.80 g) was dissolved in ethanol (2 ml) and a solution of sodium hydroxide 20 (0.21 g) in water (20 ml) was added. The mixture was heated on a steam bath for 6 hours and 20 then evaporated. The residue was dissolved in a small volume of water and the solution was acidified with acetic acid. The solid was filtered off, washed with water and crystallized from isopropanol to give E-3-{1-[2-methyl-3-(1-imidazolylmethyl)]indolyi}acrylic acid (0.32 g) m.p. 228-230°.

25 25

Analysis %:-

Found: C,68.28; H,5.48; N,14.60. C16H15N302

Requires: C,68.31; H,5.38; N,14.94.

30 EXAMPLE 2 30

E-3- {1 -[2-methyl-3-(3-pyridylmethyl)]indolyl} acrylic acid

Treatment of 2-methyl-3-(3-pyridylmethyl)indole with ethyl propiolate followed by hydrolysis of the intermediate ester by a procedure similar to that described in Example 1, gave E-3-{1 -[2-methyl-3-(3-pyridylmethyl)]indolyl}acrylic acid, m.p. 206-207° (from methanol).

35 35

Analysis %:-

Found: C,73.48; H,5.53; N.9.78. C18H16N202

Requires: C,73.95; H,5.52; N,9.58.

40 E-3-{1-[2-Methyl-3-(1-imidazolylmethyl)indolyl} acrylic acid ethyl ester 40

A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (50 ml) was added dropwise to a stirred solution of 2-methyl-3-(1-imidazolylmethyl)indole (10.55 g) and ethyl propiolate (4.90 g) in dry tetrahydrofuran (1 50 ml) at room temperature. The solution was stirred at room temperature for 2 hours and then poured into water. The mixture was extracted several times

45 with ethyl acetate and the combined extracts were washed well with water and dried (Na2S04). 45 Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform first gave some inpurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallised from chloroform/petrol (b.p. 40-60°) to give E-3-{1-[2-methyl-3-(1-imidazolylmethyl)indolyl}acrylic acid ethyl ester (8.00 g), m.p.

50 121-1 22°C. 50

Analysis %:-

Found: C,69.69; H,6.1 6; N, 1 3.57. C18H18N302

Requires: C,69.88; H,6.59; N,13.58.

55 55

Other esters prepared by the method of Example 3 from appropriate starting materials are listed in Table 1.

table 1

Example No.

Compound

M.P.(°C)

Analysis %

4

'vttra s

C02C2H5

115-116

Found: C.66.48; H.5.92; N.12.57. C18H19N3°3 Required: C.66.44; H.5.89; N.12.92.

5

3iQnOO

N '^CH-

s

C02C2H5

125-126

Found: C.75.20; H.6.43; N.8.34. C21H22N2°2 Required: C.75.42; H.6.63; N.8.38.

6

7

YYTTXj

Is

^°2C2H5 cn^

Co^O

s to2c2H5

126-127

Found: C.67.55; H,5.38; N.8.03. C?0HlgClN2O2 Required: C.67.69; 11,5.40; N.7.90.

Product hydrolysed directly after chromatograpliy

table 2

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GB2101 992A 9

Hydrolysis of the ethyl esters according to the method described in Example 1 gave the carboxylic acids listed in Table 2.

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GB 2 101 992A

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EXAMPLE 12

E-3- {1-[5-Chloro-2-methyl-3-(3-pyridylmethyl)]indolyl} acrylamide

A mixture of E-3-{1-[5-chloro-2-methyl-3-(3-pyridylmethyl)]indolyl} acrylic acid (0.33 g), N,N'-carbonyldi-imidazole (0.20 g) and dry dioxan (5 ml) was heated on a steam bath for 2 hours and 5 then evaporated. An excess of a concentrated solution of ammonia in ethanol was added and 5

the solution was allowed to stand for 30 minutes and then evaporated. The gummy residue was triturated with water to give a solid which was crystallised from methanol to give E-3-{1-[5-chloro-2-methyl-3-(3-pyridylmethyl)]indolyl)acrylamide, m.p. 262-263°C.

10 Analysis %:- 10

Found: C,65.88; H,5.23; N, 1 2.44. C18H16CIN30

Requires: C,66.36; H,4.95; N,12.90.

The following illustrates the preparation of a starting material used in Example 2. All 15 temperatures are in °C:- 15

Preparation 1

Preparation of 2-Mef.hy\-3-(3-pyridylmethyl)indole

25 3-Pyridylmethanol (27.25 g) was added to a suspension of KOH (2.24 g) in exylene (200 ml), 25 and the mixture heated at reflux using a Dean and Stark apparatus to remove the water: After cooling, 2-methylindole (16.4 g) was added and the mixture heated at reflux for 3 hours.

"Raneys Alloy" (1.0 g) was then added to the hot solution and heating at reflux was continued overnight. After cooling, the metallic residue was filtered off and washed with ether (25 mi). The 30 combined organic filtrate was extracted with H20 (2 X 100 ml) and the organic layer separated 30 and cooled to 0°, whereupon a solid precipitated which was filtered off. Crystallisation of the solid from toluene afforded the pure title compound, 14.6 g, m.p. 207-210°.

Analysis %:-

35 Found: C,81.05; H, 6.35; N, 12.6. C15H14N2 35

Required: C,80.6; H,6.3; N,12.15.

Preparation 2

2-Methyl-3-( 1 -[3-pyridyl]ethyl)indole 40 A solution of 1-(2-methyl-3-indolyl)-1-(3-pyridyl)ethylene (prepared according to J. Het Chern., 40 9, 833, 1972) 9.37 g) in ethanol (200 ml) was hydrogenated at 2.5 atm. pressure in the presence of 10% palladium/charcoal). The solution was filtered and evaporated and the residue was crystallised from ethyl acetate/petrol (b.p. 60-80°) to give 2-methyl-3-[1-(3-pyridyl)ethyl]in-dole (5.74 g) m.p. 139-141°C. 45 45

Analysis %:-

Found: C,81.56; H,7.1 1; N, 1 1.65. C16H16N2.

Requires: C,81.32; H,6.83; N,11.86%.

50 ACTIVITY RESULTS

% Inhibition of TxB2 formation after i.v. administration to rabbits:-

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GB2101 992A 11

COMPOUND DOSE

(mg/kg)

% INHIBITION TxB, PRODUCTION

2 MINI 5 MIN30 MIN45 MIN75 MIN

u

oxp

0.3

93

10 S

co2h

1.0

93

96

95

UXHy o o co '->■

95

81 98

82

93

90

20 co2h

1.0

97

94

97

95

10

15

20

Claims

25 1. A compound of the formula:-

„3

30

ch=ch.y where

35 R1 is H or C,-C4 alkyl;

R2 is H, 0,-04 alkyl, 0,-04 alkoxy or halo;

R3 is H or methyl;

Y is -COOH, -000(0,-04 alkyl) or -COHN2;

and

40 Z is 1-imidazolyl or 3-pyridyl;

and their pharmaceutically acceptable salts.
2. A compound as claimed in claim 1, where R3 is hydrogen.
3. A compound as claimed in claim 1 or 2, wherein R1 is methyl and Y is -COOH.
4. A compound as claimed in claim 1, wherein R1 is CH3, R2 and R3 are hydrogen and Y is

45 -COOH.
5. A compound as claimed in any one of the preceding claims, which is in the E form where the group Y is trans to the indole ring.
6. A process for preparing a compound of the formula (I) as claimed in claim 1, which comprises reacting a compound of the formula:-

50

CHCfi0,2.

55

where R1, R2, R3 and Z are as defined in claim 1, with a compound of the formula:-CH^C.Y (III)

60 where Y is as defined in claim 1, followed by, optionally, conversion of the product of the formula (I) into a pharmaceutically acceptable salt; or conversion of a compound of the formula

25

30

35

40

45

50

55

60

12

GB2101992A

12

(I) in which Y is -COOH into a compound in which Y is -CONH2 by formation of an acid chloride or bromide or an imidazolide, followed by reaction with ammonia.
7. A process as claimed in claim 6, which is carried out in the presence of a base.
8. A process as claimed in claim 7, wherein said base is benzyitrimethylammonium

5 hydroxide or tetrabutylammonium fluoride. 5
9. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, together with a pharmaceutically acceptable diluent or carrier.
10. A compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed

10 in any one of claims 1 to 5 for use in treating an animal, including a human being, to inhibit the 10 action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes.

Printed for Her Majesty s Stationery Office by Burgess & Son (Abingdon) Ltd.—1983

Published at The Patent Office 25 Southampton Buildings. London. WC2A 1 AY from which copies may be obtained