GB2101115A - Thromboxane synthetase inhibitors - Google Patents

Thromboxane synthetase inhibitors Download PDF

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GB2101115A
GB2101115A GB08131786A GB8131786A GB2101115A GB 2101115 A GB2101115 A GB 2101115A GB 08131786 A GB08131786 A GB 08131786A GB 8131786 A GB8131786 A GB 8131786A GB 2101115 A GB2101115 A GB 2101115A
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Roger Peter Dickinson
Peter Edward Cross
Geoffrey Noel Thomas
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Pfizer Ltd
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract

Thromboxane synthetase inhibitors of the formula: <IMAGE> or a pharmaceutically acceptable acid addition salt thereof; wherein <IMAGE> Y is -COOH, -COO(C1-C4 alkyl) or -CONH2; and Z is O, S or NH; processes for their preparation, and pharmaceutical compositions containing them.

Description

SPECIFICATION Thromboxane synthetase inhibitors This invention relates to certain benzo-fused heterocycles which are substituted by a carboxy, lower alkoxycarbonyl or carbamoyl group. Such compounds are able to selectively inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes. The compounds are thus useful as therapeutic agents, for example, in 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:
or the pharmaceutically acceptable acid addition salts thereof; wherein R1 is
Y is -COOH, -COO(C1-C4 alkyl) or -CONH2; and Z is O, S or NH.
"Halogen" means F, Cl, Br or Preferred compounds of the formula (I) are:
Y being as defined for formula (I).
The preferred compounds of the formula (II) are:
Y being as defined for formula (II).
Preferred compounds of the formula Ill are:
wherein Y is as defined for formula (III) and Z is O or NH.
The invention also includes a pharmaceutical composition comprising a compound of the formula (I) to (III), or a pharmaceutically acceptable and addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.
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.
(1) The 1-imidazolyZalkyl- and 1-imidazolylalkoxy-benzo-fuzed heterocycles in which Y is -CO2 (C1-C4 alkyl) can be prepared as follows: (a)
[Hal = Br or Cli.
The preferred base is sodium hydride.
In a typical procedure, sodium hydride (dispersion in oil) is added portionwise to a stirred solution of imidazole in a suitable solvent, e.g. dry N,N-dimethylformamide or chloroform. The resulting mixture is then stirred at room temperature, for, say 2 hour, and then the haloalkyl- heterocycle either alone or in a suitable solvent, e.g. dimethylformamide, is added. The reaction may proceed to completion at room temperature but it is sometimes advantageous to heat the reaction mixture at up to 1 00 C to accelerate the reaction. The time taken for the reaction to go substantially to completion will naturally depend on the precise conditions and temperature used and on the nature of the reactants: we have found that a period of up to 6 hours is usually sufficient. The desired product may then be isolated and purified by conventional methods.The above is only a typical procedure, and variations are possible as will be known to those skilled in the art.
Similarly the starting materials are either known compounds or may be prepared by conventional methods, many of these conventional methods being illustrated in the following specific Examples.
(2) The quinolone esters can be prepared as follows:
In a typical procedure, the amine in a suitable solvent, e.g. toluene, is heated at up to 200"C, e.g. at reflux temperature, with the diester, generally for up to about 4 hours. The intermediate anilinomalonate can then be isolated and, if necessary, purified by conventional procedures. The intermediate malonate can then be cyclised to the desired quinolone by heating at up to 100"C, e.g. for up to 2 hours. In a typical procedure, the malonate is dissolved in m-dichlorobenzene, and the resulting solution is warmed on an oil bath with a condenser set for distillation so that the solvent slowsly distils over.When the solution has been concentrated to about 2 volume, it can be cooled, poured into 60 C-80 C pet. ether, and allowed to stand, e.g.
overnight. The product can then be filtered off and recrystallized from e.g. water.
(3) The chromone esters can be prepared as follows:
In a typical procedure, the acetophenone, di-ester and sodium in ethanol are heated at up to 100 C for a few hours, e.g. up to 3 hours. A strong acid such as concentrated hydrochloric acid is then added, and the mixture stirred at this temperature for a short period, e.g. up to 1 hour.
The desired product can then be filtered off and purified by conventional procedures.
(4) The acids and amides of the invention (Y = -COOH or -CONH2) may be obtained by conventional chemical transformation reactions from the corresponding esters wherein Y is -CO2 (C1-C4 alkyl), and these possibilities will be well known to those skilled in the art. Thus for example the compounds of the formula (I) wherein Y is a carboxyl group may be obtained by hydrolysis of the corresponding ester. Such a hydrolysis may be carried out in a conventional manner, e.g. by warming the ester at up to reflux temperature with aqueous alkali, e.g. potassium hydroxide in H2O/methanol, for up to about 3 hours. Acid hydrolysis is also possible and should be used in hydrolysing the chromone esters which are prone to degradation by alkali.
Similarly, treatment of the ester with ammonia, e.g. as ethanolic ammonia at room temperature yields the amides where Y is CONH2. Periods of up to about 4 hours are usually sufficient.
All these reactions are quite conventional and methods for their performance and other possibilities and variations will be well known to those skilled in the art.
(5) The pharmaceutically acceptable salts of the compound of the invention can be prepared by mixing solutions containing equimolar amounts of the free base and appropriate acid and the required salt is collected by filtration, if insoluble, or by evaporation of the solvent.
The compounds of formula (I) to (III) and their pharmaceutically acceptable acid addition salts have been found to selectively inhibit the action of the thromboxane synthetase enzyme without significantly affecting the action of the prostacyclin synthetase or cyclo-oxygenase 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 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 (PGl2). (Proc. Nat. Acad. Sci.
U.S.A., 1975,72,2994, Nature, 1976,263,663, prostaglandins, 1976,12,897.) In most cases the prostaglandins PGE2, PGF2a and PGD2 are comparatively minor by-products in this bio-synthetic pathway.
The discovery of throxboxame 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 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 synthesised 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, 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 varient angina, myocardial infarction, sudden cardiac death and stroke (Throm. 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 1977 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 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 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 platelet stores. It is known that the blood platelets of migraine patients are more prone to 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 inhibit thromboxane A2 formation could be of considerable benefit in migraine therapy.
Abnormalities of platelet behaviour have also 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 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, DC, 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 and J. Med. 1978,299, 53, B.M.J. 1978, 1188, Stroke, 1977,8301) and some encouraging results have been obtained with these drugs, however, it is clear that 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 ability of primary neoplasms to metastasize is a principal cause of failure to cure human cancers. It has been suggested that metastatic tumour cells can alter the critical PC12-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 anti-aggregatory action.This result indicates that a TxA2-synthetase inhibitor would function as an antimetastatic agent in vivo (J. Cell. Biol. 1980,8764).
The ability of primary neoplasms to metastasize is a principal cause of failure to cure human cancers. It has been suggested that metastatic tumour cells can alter the critical PGl2-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 (J. Cell. Biol. 1980,8764).
The effect of the compounds of the invention on the thromboxane synthetase enzyme, and the prostacyclin synthetase and cyclo-oxygenase enzymes have been measured by the following in vitro enzyme assays: 1. Cyclo-oxygenase Ram seminal vesicle microsomes (Biochemistry, 1971, lea, 2372) are incubated with arachidonic acid (100 FM: 1 min: 22"C) 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, 1978,217,1135) and indomethacin (Brit. J. Pharmacol., 1972,45,451) which is superfusing a spirally-cut rabbit aorta strip (Nature 1969,223, 29).
The ability of a compound to in hibit the enzyme is measured by comparing the increases in isometric tension produced by PGH2 in the absence of the test compounds, and following pre-incubation of the enzyme with the test compound for 5 minutes (Agents and Actions, 1981, 11,274).
2. Prostacyclin rPGI2) Synthetase Pig aorta microsomes (Nature, 1976,263,663) are incubated (30 sec.; 22"C) with PGH2 produced as in 1 and the reaction terminated with 5 volumes of ethanol. POl2 production is assessed by measuring its stable breakdown product, 6-keto PG F1 ,,, using a specific radioimmunoassay.PGI2 production can be completely inhibited by pre-incubation of the enzyme with the selective Pig12 synthetase inhibitor, 15-hydroperoxy- arachidonic acid (Prostaglandins, 1976, 12, 715). The test compound is pre-incubated with the enzyme for 5 minutes, and its ability to prevent the production of Pig12 (6-keto PGFaa) is measured.
3. ThromboxaneA2 (TxA2) Synthetase Indomethacin pretreated human platelet microsomes (Science 1976, 193,163) are incubated (2 min.: 0 C) with PGH2 (produced as in 1) and the reaction terminated with 5 volumes of ethanol. TxA2 production is assessed by measuring its stable metabolite TxB2, using a specific radioimmunoassay. The test compound is pre-incubated with the enzyme for 5 minutes, and its ability to inhibit the thromboxane synthetase enzyme measured as reduction of the TxA2 (TxB2) production.
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 clinically effective agents aspirin and sulphinpyrazone show inhibitory activity in vitro against a variety of aggregating agents in this test.
A number of in vivo tests in animals have also been described for evaluating potential anti-thrombotic 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, 1977, 1,481) and su l phi npyrazone (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 corporeal loop of the abdominal aorta of rats in vivo (Throm. Diathes. Haem., 1973,30,137).
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, or talc. The tablets are typically prepared by granulating the ingredients together and compressing the resulting mixture to give tablets of the desired size. Capsules 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 form of a sterile aqueous solution which may contain other solutes such as tonic and pH adjusters. Such solutions are prepared by adding the compounds to distilled water and adjusting the pH 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 sterilized and filled into sterile glass vials of an appropriate size to contain the desired volume of solution. The compounds of the invention may also be administered by the infusion of 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 or salt 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 or salt of the invention will be from 0.01 - 0.5 mg/kg. per day, for a typical adult patient. Thus tablets or capsules can be generally expected to contain for 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.
It should of course be appreciated that in any event the physician 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 patient, there may of course be individual cases where higher or lower dosage ranges are merited.
The preparation of compounds of the invention is illustrated by the following Examples: EXAMPLE 1
Ethyl 6-methyl-chrom-4-one-2-carboxylate (2.3 g), N-bromo-succinimide (1.8 g), and benzoyl peroxide (0.1 g) were added to CCl4 (20 ml) and the mixture was heated at reflux for 4 hours. After filtration the mixture was cooled, whereupon the product crystallized and was filtered and dried to yield ethyl 6-bromomethyl-chrom4-one-2-carboxylate, m.p. 1 20-1 25"C. The product was not purified further and was used directly in the next stage.
Ethyl 6-bromomethyl-chrom-4-one-2-carboxylate (1.55 g) and imidazole (0.68 g) were mixed and warmed at 70"C for 3 hours. After cooling, the solid was added to warm EtOH, filtered, the solvent was removed and H2O (50 ml) was added to the residual solid. The solution was extracted with ether (3 x 50 ml) followed by extraction with CHIC13 (3 x 50 ml). The CHIC13 extracts were combined, dried (MgSO4), filtered and evaporated to give a solid which was recrystallized from toluene to give ethyl 6-(1H-imidazol-1-ylmethyl)-chrom-4-one-2carboxylate, yield 0.35 g, m.p. 148"C.
Analysis %:- C16H14N204 requires C,64.4: H,4.7: N,9.4 found C,64.2: H,4.65: N,9.3 EXAMPLE 2
The ester from Example 1 (0.6 g) was dissolved in glacial AcOH (3 ml) and concentrated hydrochloric acid (3 ml) and the solution heated at reflux for 4 hours. After cooling the solid precipitate was filtered and recrystallized from aqueous EtOH to give 6-(lH4midazol-1-ylmethyl)chrom-4-one-2-carboxyllc acid hydrochloride, yield 0.25 g, m.p. > 250 C.
Analysis%:- C14H10N2O4.HCI requires C,55.4: H,3.7: N,8.95 found C,54.9: H,3.6: N,9.15 EXAMPLE 3
4-(3-Pyridylmethyl)phenol (18.5 g) [see British Patent Application No. 8022660forthe preparation of this phenol] was dispersed in dichloroethane (100 ml) and stirred at room temperature during the addition of acctyl chloride (8.0 g). The mixture was then stirred during the portionwise addition of AICI3 (20.0 g). When the vigorous reaction had subsided, the mixture was maintained at reflux temperature for 6 hours. After cooling the mixture was poured onto ice and the organic layer separated.The aqueous portion was extracted with CH2CI2 (3 x 100 ml) and the combined extracts were washed (H2O), dried (MgSO4), filtered and evaporated to give a solid which was re-crystallized from pet. ether (80-100 C) to hield 2-hydroxy-5-(3 pyridyl-methyl)-acetophenone, 6.6 g, m.p. 73-74.5"C, used directly in the next stage.
(ii)
Na (1.84 g) was dissolved in EtOH (40 ml) and to this was added, with stirring, diethyl oxalate (5.8 g) and the acetophenone from part (i) (6.0 g). The mixture was stirred at 70 C for 2 hours before addition of concentrated hydrochloric acid (11 ml), and the resulting mixture was stirred at this temperature for a further 0.5 hours. After standing at room temperature for 48 hours, the solid precipitate was filtered off and added to 5% NaHCO3 solution. The aqueous solution was then extracted with CH2CL2 (3 x 150 ml) and the combined organic extracts washed (H2O) dried, (MgSO4), filtered and evaporated to give a solid which was re-crystallized from isopropylalcohol to yield ethyl 6-(3-pyridyl methyl)-chrom-4-one-2-carboxylate, 3.1 g, m.p.132"C.
Analysis %:- C18H15NO4 requires C,69.9%: H,4.9: N,4.5 found C,69.3: N,4.8: N,4.25 EXAMPLE 4
The ester of Example 3 (1.0 g) was hydrolysed with AcOH (50 ml) and concentrated HCI (5 ml) to give 6-13-pyridy/methy/l-chrom-4-one-2-carbox acid acid hydrochloride hemihydrate or a white solid crystallizing from EtOH/H2O, yield, 0.75 g, m.p. > 255 C.
Analysis %:- C16H11 NO4HCL.-21H2O requires C,57.4: H,3.9: N,4.2 found C, 57,4: H,4.2: N,4.05 EXAMPLE 5 (i)
Diethyl ethoxymethylene malonate (13.2 g) was dissolved in toluene (100 ml) and 1-(4aminobenzyl)imidazole (10.4 g) was added over a period of 15 minutes. The mixture was heated to reflux for 22 hours, cooled to just below the boiling point, and the ethanol removed by azeotropic distillation. The temperature was then increased and most of the toluene removed by distillation. The residue was cooled in an ice bath and the resultant solid, diethyl[4-(1 H-imidazol-1-ylmethyl)anilino] methylene malonate was filtered and recrystallized from MeOH, yield 12.6 g, m.p. 114-116"C.
Analysis%:- C,8H2,N304 requires C,62.95: H,6.2: N,12.25 found C,62.95: H,6.2: N,11.9
The malonate of part (i) (8.6 g) was dissolved in metadichlorobenzene (200 ml) and warmed on an oil bath with a condenser set for distillation so that solvent slowly distilled over. After the solution had been concentrated to half its original volume, it was allowed to cool, poured into 60-80"C pet. ether and allowed to stand overnight. The precipitate was then filtered off and re-crystallized from H2O to give ethyl 1,4-dihydro-6-(lH-imidazol- 1-ylmethyl)4-oxoquinoline-3-carboxylate, 4.2 g, m.p. > 250 C.
Analysis%:- C16H15N303 requires C,64.6: H,5.1: N,14.15% found C,64.6: H,5.1: N,13.9% EXAMPLE 6
The ester of Examples (ii) (1.0 g) was dissolved in 10% aqueous NaOH (20 ml) and heated at reflux for 12 hours. After cooling, the solution was extracted with CH2CI]2 (3 x 10 ml) and the aqueous portion then acidified with AcOH. An oil separated out from the acidic solution, the AcOH was then carefully decanted off and the oil triturated with ether. The resultant crystalline solid was then filtered, and recrystallized from DMF to give 1 ,4-dihydro-6-(1 H-imidazol-1 -ylmethyl)4-oxoquinoline 3-carboxylic acid, 0.12 g, m.p. > 250 C.
Analysis%:- C14H11N3O3 requires C,62.45: H,4.10: N,15.6% found C,61.85: H,4.3: N,15.1% EXAMPLE 7 Methyl-2-1 lH4midazol- 7-ylmethylJbenzoxazole-4carboxylate
Ethyl 2 chloro-acetimidate.HCI (10.2 g) was added to a solution of methyl 4-hydroxy-3-aminobenzoate (10.8 g) in MeOH (200 ml) and the mixture was heated at reflux for 32 hours. After cooling the solvent was evaporated and the residue dissolved in CHIC13 (15 ml); H2O (150 ml) was then added and the organic layer separated. After further extraction of the aqueous layer with CHCl3 the organic extracts were combined, washed, dried and evaporated to give methyl 2-chloromethylbenzoxazole-4-carboxylate as a solid, yield 13.0 g. This was not purified and was used directly in the next stage.
The benzoxazole (0.7 g) was then mixed with imidazole (0.4 g) and the reactants were fused at a temperature of 75 C for 1 hour. After cooling H2O (50 ml) was added and the mixture was then extracted with CHIC13 (2 x 50 ml). Evaporation of the combined organic extracts then afforded the title compound as a crude product, which was re-crystallized from H2O, yield 250 mg., m.p. 133-135"C.
Analysis%:- C13HllN303 requires C,60.7: H,4.3: N,16.35 found C,60.35: H,4.3: N,16.3 EXAMPLE 8 Methyl 2-( lH4midazolylmeth yl)benzimidazole-5-carboxylate
Ethyl 2-chloroacetimidate. HCI (4.0 g) was added to a solution of methyl 3,4-diaminobenzoate (4.0 g) in MeOH (20 ml) and the mixture heated at reflux for 6 hours. After evaporation of the MeOH, water (50 ml) was added to the residue and the mixture was extracted with CHC13 (3 x 75 ml). The combined organic extracts were washed, dried, filtered and evaporated to give methyl 2-chloromethyl-benzimidazole-5-carboxylate as a solid, 3.2 g. This was not purified further and was used directly in the next stage of the reaction sequence.
The benzimidazole (1.4 g) and imidazole (0.85 g) were then dissolved separately in the minimum amount of CHC13, mixed, and then the solvent evaporated. The residue was then heated to 80"C for - hour, allowed to cool, and then left to stand at room temperature overnight. Water (50 ml) was then added and the solution extracted with CHCl3 (3 x 50 ml). The combined organic extracts were washed, dried, filtered and evaporated to give the title compound as a crude product which was re-crystallized from H2O, yield 0.4 g, m.p. 223-225"C.
Analysis%:- C13H14N402 requires C,60.9: H,4.7: N,21.9 found C,60.4: H,4.7: N,21.8.

Claims (10)

1. A compound of the general formula:
or a pharmaceutically acceptable acid addition salt thereof; wherein R1 is
Y is -COOH, -COO(C1-C4 alkyl) or -CONH2; and Z is O, S or NH.
2. A compound of the formula :-
Yin the above being as defined in claim 1, and Z being 0 or NH.
3. A process for preparing a compound of the formula (I), (II) or (III) as claimed in claim 1 in which R2 is 1-imidazolylalkyl and Y is -CO2(C,-C4 alkyl), which comprises reacting imidazole with, respectively, a compound oftheformula:-
wherein "Hal" is Br or Cl, n and Z are as defined in claim 1 and Y is -CO2(C1-C4 alkyl), the reaction being carried out in the presence of a base.
4. A process for preparing a compound of the formula (II) as claimed in claim 1 in which Y is -COO(C1-C4 alkyl), which comprises reacting a compound of the formula:
where R2 is as defined in claim 1, with a compound of the formula: C2H5OCH = C(COO[C1-C4 alkyl]2) to form an intermediate of the formula:
which is then cyclised to the said product of the formula (II).
5. A process for preparing a compound of the formula (I) as claimed in claim 1 in which Y is -COO(C1-C4 alkyl), which comprises reacting a compound of the formula:
where R2 is as defined in claim 1, with a compound of the formula: COO(C1-C4 alkyl) COO(C1-C4 alkyl) in the presence of sodium in ethanol, followed by the addition of a strong acid.
6. A process for preparing a compound of the formula (I), (II) or (III), as claimed in claim 1 in which Y is -COOH, which comprises the hydrolysis of the corresponding compound in which Y is -COO(C1-C4 alkyl).
7. A process for preparing a compound of the formula (I), (II) or (III) as claimed in claim 1 in which Y is -CON H2, which comprises reacting the corresponding compound in which Y is -COO(C1-C4 alkyl) with ammonia.
8. A process for preparing a compound of the formula (I), (II) or (III) as claimed in claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore defined in any one of the Examples.
9. A compound of the formula (I), (II) or (III) as claimed in claim 1 which has been prepared by a process as claimed in any one of claims 3 to 8.
10. A pharmaceutical composition comprising a compound of the formula (I), (II) or (III) as claimed in claim 1, or a pharmaceutically acceptable acid addition salt thereof, together with pharmaceutically acceptable diluent or carrier.
GB08131786A 1980-10-23 1981-10-21 Thromboxane synthetase inhibitors Withdrawn GB2101115A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0125756A2 (en) * 1983-03-22 1984-11-21 Fujisawa Pharmaceutical Co., Ltd. Fused imidazole compounds, processes for the preparation thereof and pharmaceutical compositions containing them
EP0241003A2 (en) * 1986-04-11 1987-10-14 Hoechst Aktiengesellschaft 4H-1-benzopyran-4-one derivatives, process for their preparation and their use as medicaments
EP0316097A1 (en) * 1987-11-12 1989-05-17 Imperial Chemical Industries Plc Naphtho(2,1-b)furan derivatives
US4855435A (en) * 1982-10-12 1989-08-08 The Upjohn Company Pyridyl-substituted benzothiophenes
EP0371564A2 (en) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. (1H-azol-1-ylmethyl)substituted quinoline, quinazoline or quinoxaline derivatives
US6037350A (en) * 1995-12-08 2000-03-14 Janssen Pharmaceutica, N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quionlinone derivatives

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855435A (en) * 1982-10-12 1989-08-08 The Upjohn Company Pyridyl-substituted benzothiophenes
EP0125756A2 (en) * 1983-03-22 1984-11-21 Fujisawa Pharmaceutical Co., Ltd. Fused imidazole compounds, processes for the preparation thereof and pharmaceutical compositions containing them
EP0125756A3 (en) * 1983-03-22 1987-04-08 Fujisawa Pharmaceutical Co., Ltd. Fused imidazole compounds, processes for the preparation thereof and pharmaceutical compositions containing them
EP0241003A2 (en) * 1986-04-11 1987-10-14 Hoechst Aktiengesellschaft 4H-1-benzopyran-4-one derivatives, process for their preparation and their use as medicaments
EP0241003A3 (en) * 1986-04-11 1988-10-12 Hoechst Aktiengesellschaft 4h-1-benzopyran-4-one derivatives, process for their preparation and their use as medicaments
EP0316097A1 (en) * 1987-11-12 1989-05-17 Imperial Chemical Industries Plc Naphtho(2,1-b)furan derivatives
EP0371564A2 (en) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. (1H-azol-1-ylmethyl)substituted quinoline, quinazoline or quinoxaline derivatives
EP0371564A3 (en) * 1988-11-29 1991-05-29 Janssen Pharmaceutica N.V. (1h-azol-1-ylmethyl)substituted quinoline, quinazoline or quinoxaline derivatives
US6037350A (en) * 1995-12-08 2000-03-14 Janssen Pharmaceutica, N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quionlinone derivatives
US6169096B1 (en) 1995-12-08 2001-01-02 Janssen Pharmacaeutic N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives
US6420387B1 (en) 1995-12-08 2002-07-16 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl) methyl-2-quinolinone derivatives

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