CS235050B2 - Method of thromboxan-synthetase's naphalene and benzo-heterocyclic inhibitors production - Google Patents

Abstract

The invention discloses a method of making certain naphthalenes and benzo-condensed heteirocycles, namely benzothiophenes, benzofurans and indoles which are substituted with a carboxylic acid lower alkoxycarbonyl or a carbamoyl group. These compounds are capable of selectively inhibiting the effect of the enzyme thromboxane synthetase without significant inhibition of enzyme effects prostacyclin synthetase or cyclooxygenase. Thus, said compounds are useful as therapeutic agents, e.g. treatment of thrombosis, coronary heart disease, stroke, transient ischemia attacks migraine, peripheral vascular disease, vascular disease complications of diabetes, malignant tumors and endotoxin shock. The importance of thromboxane synthetase enzyme various diseases have been identified and confirmed until recently (see, for example, Lancet March 21, 1981, pp. 643 and 644). On knowledge based on the existing state of the art was by no means in any way the new compounds can be expected to of the invention will act as enzyme inhibitors thromboxane synthetase, how about it data summarized in the table below. Thus, the novel compounds produced by the process of the invention are significant enrichment of the prior art. Accordingly, it is an object of the invention a process for the preparation of compounds of formula (I) in which R1 is bonded to any of the carbon atoms of ring B and is hydrogen, atom halogen, an alkyl group of 1 to 4 carbon atoms or alkylthio groups having 1 to 1 carbon atoms; 4 carbon atoms, Y is attached to ring A and represents carboxyl, alkoxycarbonyl C 1 -C 4 -alkoxy in alkoxy parts or carbamoyl group, X represents oxygen, sulfur, N-alk, wherein alk is an alkyl group of 1 to 1 4 carbon atoms, or represents a group -CH = CH- and imidazol-1-ylmethyl is bound to any of the carbon and

Description

SOCIALISTIC C8SHIELD TIRE 8 L 1 RA (18) DESCRIPTION OF THE INVENTION 235050 fllj (M) *> OftAD FOR SURFACE (22) Registered 25 08 82 (21) (PV 9978-83) (32) (31) (33) ) Priority from 26 08 81 (8125976) United Kingdom (40) Published 13 08 84 (45) Published 15 02 87 (51) Int. Cl.5 C 07 D 209/14 C 07 D 233/60 C 07 D 307/81 C 07 D 333/58 * AND DISCOVERIES (72)

CROSS PETER EDWARD, CANTERBURY, DICKINSON ROGER PETER, DOVER (United Kingdom) (73)

Patent proprietor of PFIZER CORPORATION, COLON (Panama) with its registered office in BRUSSELS (Belgium) (54) Method for producing naphthalene and bis-heterocyclic thromboxane synthetase inhibitors

The present invention provides a process for the preparation of certain naphthalenes and benzo-fused heteirocycles, namely, benzothiophenes, benzofurans and indoles which are substituted by a carboxy group, a lower alkoxycarbonyl group or a carbamoyl group. without significant inhibition of the enzymes lipostacycline synthetase or cyclooxygenase.

Accordingly, the compounds are useful as therapeutic agents, for example, thrombosis, ischemic heart disease, stroke, transient attacks of ischemia, migraine, peripheral vascular disease, vascular complications of diabetes, and malignant tumors of aendotoxin shock. The importance of the enzyme thromboxane synthetase in various diseases has only been found and confirmed recently (see, for example, Lanet of March 21, 1981, pages 643 and 644). Based on the prior art knowledge, the new compounds of the invention would not in any way be expected to act as inhibitors of the enzyme thromboxane synthetase, as evidenced by the data summarized in the table below. Accordingly, the novel compounds produced by the process of the invention represent a significant improvement in the prior art.

Accordingly, the present invention provides a process for the preparation of compounds of formula I R1

wherein R 1 is bonded to one of the carbon atoms of ring B and is hydrogen, halo, C 1 -C 4 alkyl, or C 1 -C 4 alkylthio, Y is attached to ring A and is carboxyl, alkoxycarbonyl is 1 to 1, 4 is carbon in alkoxy or carbamoyl, X is oxygen, sulfur, N-alk, wherein alk is (C 1 -C 4) alkyl, or is -CH = CH- and imidazol-1-ylmethyl; - is bonded to one of the carbon a - 235030 235050 4 o

The ring B, and the pharmaceutically acceptable salts thereof.

Halogen means fluorine, chlorine, thunder or iodine. The preferred halogen is chlorine or bromine.

Alkyl groups having 3 or 4 carbon atoms may have a straight or branched chain.

As noted above, the imidazol-1-yl-methyl group and the radical R 1 are attached to one of the carbon atoms of the B ring. If X is a group —CH = CH—, these may be either one or only one. also linked to the carbon atom of the group. In one preferred group of compounds according to the invention, the following general meanings have the following meanings: a) X represents sulfur, Y represents a methoxycarbonyl, ethoxycarbonyl, carboxy or carbamoyl group attached at the 5, 6 or 7 position of the ring A and R 1 represents a hydrogen atom, a methyl group, a chloro atom, a bromine atom or a methylthio group; b) X represents oxygen, Y represents a carbonyl or methoxycarbonyl group attached at the 5 or 6 position of the ring A and R 1 represents a methyl group, an ethyl group, a chlorine atom or a bromine atom; c) X is N (CH 3), Y is a carboxyl or ethoxycarbonyl group attached at the 5-position of A and R 1 is a methyl group, or d) X is -CH = CH-, Y is a carboxyl group and R 1 is a hydrogen atom or methyl group.

Even more preferably

I. Even the radical of the formula is attached at the 2-position, Y is the carboxyl group attached at the 5 or 6 position when X is oxygen, sulfur or N-alk, and at the 6 or 7 position when X is a radical --CH.dbd.CH-- and R @ 1 is C1 -C4 alkyl, C1 -C4 alkylthio, chloro or bromo, and is attached in the 3 position when X is oxygen, sulfur or N- alk, and in position 1 when X is - CH = CH. Preferred alkyl groups are methyl and ethyl, and the preferred alkylthio group is methylthio.

The most preferred compounds according to the invention are

In accordance with the invention, the compounds of the above formula (I) may be prepared according to the following reaction scheme:

(imidazole other base, organic solvent or imidazole metal salt) wherein Q is a readily cleavable group such as halogen, alkylsulfonyloxy of 1 to 4 carbon atoms or arylsulfonyloxy, wherein aryl is phenyl optionally substituted by one or two substituents y taken from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms and halogen atoms, the following general symbols being as defined above. Preferred metal salts are the alkali metal and silver salt imidazole salts. The most preferred salt is the sodium salt, which is prepared from imidazole and sodium hydride.

Q is preferably chlorine or bromine. A preferred further base is bicarbonate, in which case it is desirable to use this base in a 10-fold excess of imidazole. Preferred solvents are dimethylformamide (using sodium hydride) and 8 acetone (using sodium bicarbonate). The reaction is generally completely carried out at room temperature, although in some cases the reaction mixture may be heated to, for example, 100 ° C or, if desired, refluxed to accelerate the reaction. The product can be isolated and cleaned in a conventional manner. Some of the compounds of formula (I) may be prepared from the corresponding other compounds of formula (I). For example, acids may be prepared by acidic (e.g., hydrochloric acid) or base (e.g., hydroxypotassium) hydrolysis of the corresponding esters in conventional manner. . Similarly, by reacting the esters with ammonia, amides are formed which can also be prepared by reacting the corresponding acids first with carbonyl-imidazole or thionyl chloride, and then with ammonia. The starting materials used in the reaction described are either known or obtainable in a conventional manner. These preparations are detailed in the Examples. Some illustrative procedures are set forth below. Starting materials of the general formula

where Y 1 is bromo or C 1 -C 4 alkoxycarbonyl in the alkoxy moiety and X is oxygen or sulfur, the following reaction sequence may be prepared:

CO ^ H i '! n-euLi / EWLi> hcho BH * / THFn & lao

Sr

THF in THF

CHgOH

i} n-BuLL (2 α-ki / J b H coz {R 1 * BrT 1 9 eg 30α / C§HsN'GI = Ci;

PB1R1GL-BH

Et ^ N IQ ^ OSCLMq.} Í. r ·

CfC ^ AlkAnol / H * I naho CH ^ Br ΊίΙΊΖIpouza. ma.thyt. "astar) & U Ozc

R 1 CH 2 OH SOCl 2 / C 3 N (GL -

PBr * (α = flH on ωMe, SO Cl / Et, NP1 - 3

“CH, 6L (oso ^ Ma) • x 235050

Alternatively, when Q is chloro, CH 2 Cl 2 may be introduced by chloromethylation:

a.lk q, C

a-tk OC »

HCl

ZnCL · -Q> Ε * = ° α]

If CH2Q = CH2Br, a group may be used. This procedure illustrates the following bromination of the starting methyl derivative. In this reaction scheme: preferably R 1 is not alkyl N-bromosuccinine

alk OC is full λ '. azobisisobutyrometril or benzoylperoxideR1 [x = O, S, -CW = CW-]

Certain intermediate 3-chloro-2-hydroxylating reactions: methylbenzo [b] thiophenes can be prepared as follows:

- ”Br40UC- ° H atJ ..

This cyclization reaction is described in J.Het. Chem., 8, 711 (1071) and J. Org. Chem., 41, 3399 (1976).

In the above reaction schemes, the following symbols and abbreviations have the following meanings:

Me = methyl

Et = ethyl

Bu = butyl

Ph = phenyl THF = tetrahydrofuran.

The remaining general symbols then have the meanings given.

The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by conventional procedures, for example by reacting the corresponding compound in an organic solvent with a solution of the appropriate acid in an organic solvent to form acid addition salts which can be isolated by precipitation or evaporation of the reaction solution. When the ester of the starting material is used, the acid is often hydrolyzed to the free acid (except salt formation).

It has been found that the compounds of general formula I and their pharmaceutically acceptable salts selectively inhibit the action of enzymuthromboxane synthetase without significantly affecting the effects of prostacyclin synthetase or cyclooxygenase enzymes. Thus, these compounds can be used to treat various clinical conditions characterized by an imbalance between prostacyclin and thromboxane A2. For the reasons given below, these conditions may include thrombosis, ischemic heart disease, stroke, transient ischemia, migraine, peripheral vascular disease, cancer, vascular complications, and endotoxin shock. Research has confirmed that in most tissues, arachidonic acid metabolite is predominant in some of 235050 two volatile substances, thromboxane A2 (TxAa) or prostacyclin (PGI2) (Proc. Nat.Acad. Sci. USA, 1975, 72, 2994, Nature, 1976,263, 663, Prostaglandins, 1976, 12, 897).

In most cases, in this biosynthetic pathway, the prostaglandins E2, F2 ' and D2 are by-products of smaller amounts. The discovery of thromboxane A2 and prostacyclin has greatly enhanced our knowledge of vascular homeostasis. For example, prostacyclin is a potent vasodilator and a platelet aggregation inhibitor, with the latter being the most effective endogenous agent to date.

The prostacyclin synthetase enzyme is found in the endothelial blood vessel layer and can convert endoperoxides released by the blood platelets coming into contact with the vessel wall. The prostacyclin thus produced is important for preventing deposition of blood platelets on vessel walls (Prostaglandins, 1976, 12, 685, Science, 1976, 17, Nature, 1978,273, 765).

Thromboxane A2 is synthesized by enzyme thromboxane synthetase found for example in platelets. Thromboxane A2 is a very potent vasoconstrictor and blood platelet aggregation agent. Thus, in this respect, its effect is in direct opposition to the effect of propacyclin. If, for any reason, the formation of prostacyclin by the vessels is impaired, the endoperoxides produced by the platelets come into contact with the vessel wall and are converted to thromboxane but are not effectively converted to prostacyclin (Lancet, 1977, 18, Prostaglandins, 1978, 13,3). A change in the balance between prostacyclinema thromboxane in favor of the latter may result in clustering of blood platelets, vasospasm (Lancet, 1977, 479, Science, 1976, 1135, Amer. J. Carolology, 1978, 41, 787) and increased susceptibility It is also known that prostatic cyclin formation is reduced in experimental atherosclerosis and thromboxane A 2 production is increased (Prostaglandins, 1977, 14, 1025 and 1035).

Thus, thromboxane A2 was considered to cause various types of angina pectoris, myocardial infarction, sudden cardiac death and thrombosis (Thromb. Haemostasis, 1977, 38, 132). Studies in rabbits have shown that changes in the ECG typical of these conditions occur when freshly prepared thromboxane A2 is injected directly into the heart of the animal (Biochem. Aspects of Progestaglandins and Thromboxanes, Ed. N. Kha-rasch and J. Fried, Academic Press 1977, pp. 189).

This technique is considered to be a representative and unique animal model for heart attacks in patients with coronary disease and is also used to demonstrate that application of the thromboxane A2 antagonist compound protects rabbits from the adverse consequences of injectromboxane A2 ,

Migraine is another area in which the interrostacycline and thromboxane A2 imbalance is a factor contributing to the onset and worse course of disease.

Migraine headaches are associated with blurring in intra- and extracerebral blood flow, specifically in reducing cerebral blood flow in the pre-headache phase following dilatation in both vascular areas during the painful phase. Before the onset of pain, there is an increase in the level of 5-hydroxytryptamine in the blood, indicating the occurrence of in vivo aggregation and release of the amine from the platelets. It is known that platelets of patients suffering from migraine tend to be more agglomerated than blood platelets of normal individuals (J. Clin. Pathol., 1971, 24, 250, J. Headache, 1977, 17, 101). it is not only a major factor in migraine seizure pathogeneis, but is in fact their primary cause [Lancet (ij, 1978, 501], a drug that selectively modifies platelet function in particular by inhibiting thromboxane A2 formation would then be of considerable benefit to migraine treatment.

Abnormalities in platelet behavior have been reported in patients with diabetes [Me-tabolism. 1979, 28, 394, Lancet, 1978 (i) 235]. Diabetic patients are known to be particularly susceptible to microvascular complications, Batherosclerosis and thrombosis, with the result that such angiopathy is considered to be hyperreactive and platelets.

Diabetic plates produce increased levels of thromboxane B2 and malondialdehyde (Symposium "Diabetes and Thrombosis" Implications for Therapy, Leeds, Great Britain, April 1979). It has also been shown that in rats with experimental diabetes vascular formation of prostacyclin and increased thromboxane A2 synthesis from platelets (IV International Pirostaglandin Conferencing, Washington, DC, May 1979) was reduced. It is believed that the imbalance between prostacyclin and thromboxane A2 is responsible for the zamicrovascular complication of diabetes. Thromboxane A 2-synthetase inhibitor could therefore be clinically useful in the prevention of these vascular complications.

Aspirin and most other non-steroidal anti-inflammatory drugs inhibit the cyyclooxygemase enzyme. The effect of this action is to suppress the production of prostaglandin G 2 / H 2 -endoperoxides and thereby reduce both the prostacyclin and thromboxane A 2 levels. Aspirin and aspirin-type drugs have been clinically evaluated for efficacy in stroke prevention and heart attacks (New England and J. Med. 1978, 299, 53, BMJ, 1978, 1188, Stroke, 1977, 8, 301). Although some encouraging results have been obtained with these drugs, a compound that specifically inhibits the formation of buthromboxane A 2 would be more valuable in these conditions, without being involved in prostacyclin synthesis [Lancet (ii), 1978,780],

The ability of primary metastatic tumors is the underlying cause of the failure to treat malignant tumors in human medicine. It is claimed that nietastatic tumor cells can alter the critical equilibrium prosta-cyclin / thromboxane A 2 in favor of thrombosis (Science, 1981, 212, 1270). . Recently, prostacyclin has been shown to be an effective antimetastatic agent due to its antiplatelet activity. These results indicate that Az synthetase inhibitor thromboxane may act as an antimetastatic agent (J. Cell Biol. 1980, 87, 64). The shock caused by bacterial endotoxin is related to thrombocytopenia, disseminated intra-vascular coagulation, lysosomal labillation and pulmonary and mesenteric vasoconstriction. In addition, a significant increase in plasma levels of thiromboxane was observed. The application of the imidazole inhibitor thromboxane As synthetase to experimental animals before the endo-toxin results in a decrease in symptoms and a marked increase in survival ratio [Prostaglandins and Medicine, 4, 215 (1980) Circulation Res. 46: 854 (1980)]. The effect of the compounds of the formula I on the thromboxane synthetase enzyme and on the enzyme enzymatic prostacycline synthetase and cyclooxygenase was determined by the following in vitro tests. Cyclooxygenase

Rat seminal vesicle microsomes (Bio-Chemistry, 1971, 10, 2372) are incubated with arachidic acid (100, 1 mol, 1 min. 22 degrees C) to produce prostaglandin H 2 and the aliquots of the reaction mixture are injected into the Krebs solution with hydrogen carbonate, washing the spiral-cut strip of the rabbit aorta (Nature, 1969, 223, 29). The wash solution has a temperature of 37 degrees C and contains a mixture of antagonists (Nat., 1978, 218, 1135) and indomethacin (Brit. J. Pharmacol., 1972, 45, 451).

The ability of the test compound to inhibit the enzyme is measured by comparing the prostaglandin-induced isomeric stress increase in the absence of the test compound and 5 minutes prior incubation with the test substance (Agents and Actions, 1981, 11, 274). 2. Prostacyclin synthetase

Porcine aortic microsomes (Nature, 1976, 263, 663) were incubated with prostaglandin IIa produced at 22 ° C for 30 seconds, then quenched with 5 volumes of ethanol. The production of prostacyclin (prostaglandin Is) is determined by measuring its stable degradation product, 6-ketoprostaglandin F 1, using a specific radiological assay.

The production of prostaglandin I2 can be completely inhibited by pre-incubating the enzyme with a selective prostaglandin I2-synthetase inhibitor, i.e., 15-hydroperoxyarachidic acid (Prostaglandins, 1976, 12,715). The test compound is incubated with the enzyme for 5 minutes and its ability to inhibit the production of prostaglandin I2 (6-ketoprostaglandin F1) is measured. 3. Thromboxane A21 - synthetase

Human platelet microsomes pre-treated with indomethacin (Sci., 1976, 193, 163) are incubated for 2 minutes at room temperature with 0 ° C with prostaglandin H 2 produced as test 1. The reaction is terminated by the addition of 5 volumes of ethanol. The production of thromboxane A2 is determined by measuring its stable metabolite, jethromboxane B2, using a specific radio-immunoassay.

The test compound is incubated with the enzyme for 5 minutes and its ability to inhibit the thromboxane synthetase enzyme as a reduction in thromboxane A2 (thromboxane B2) production is measured.

It has been found that the compounds of general formula I tested in this manner are capable of selectively inhibiting the thromo-boxan synthase enzyme.

In addition to the above assays, an in vitro assay to measure human platelet aggregation inhibition, from which clinical antithrombotic efficacy can be inferred [Lancet (ii), 1974, 1223, J. Exp. Med., 1967, 126, 171], has been described. Both clinically active agents, aspirin and sulfinpyrazone, exhibit in vitro inhibitory activity in a variety of different platelet aggregation agents.

A series of in vivo test animals have also been described for animal testing to evaluate potential antithrombotic drugs.

The method described by Patrono et al. Is adapted to study the formation of thromboxane B2 in whole blood samples taken from animals before and after drug application. Blood samples are taken into glass tubes and allowed to clot at 37 ° C. . The serum is separated by centrifugation and the samples are stored at -40 ° C until thromboxane B2 is assayed by RIA for appropriately diluted ethanolic solutions. This technique is used in experiments to test the compounds to be assayed. their efficacy in intravenous administration to anesthetized rabbits. 235030 13 14

Anesthetized rabbit

Male New Zealand white rabbits (2.6-5.6 kg) were anesthetized by intravenous administration of 30 mg / kg sodium pentobarbone followed by intraperitoneal administration of 500 mg / kg urethane. After the cannula, the carotid artery is catheterized to collect blood samples. The catheter patency is maintained by slow infusion (0.2 ml / mim) of sterile saline. 30 and 5 minutes before application of the test compound or vehicle [0.9% solution (w / v / v) of sodium chloride, 0.2 ml / kg] to the peripheral ear vein, blood samples from the neck are collected. Three groups of rabbits are used for the test. The first group is given 0.03 mg / kg of the test compound and 0.1 mg / kg after 1 hour. The third group is given only carrier medium and after one hour another dose of vehicle is applied. Blood samples from the blood vessel are taken at 15 and 45 minutes after each application. At each of these collections, 1 ml of blood is drawn into a glass tube containing no anticoagulant to determine thromboxane B 2. For this purpose, the blood samples are allowed to clot during a 2 hour incubation at a temperature of 37 ° C (according to preliminary experiments, it was found that the most thromboxane Bz is formed in this case) and the serum is separated by centrifugation. After deproteinization with ethanol and dilution with tris buffer (Isogel), the thromboxane B2 content was determined in the sample serum by RIA.

Intravenous injection of arachidonic acid kills rabbits because it induces platelet aggregation and pulmonary embolism. Again, both clinically effective drugs, aspirin (Agents and Actions, 1977, 1, 481) and sulfinpyrazone (Pharmacology, 1976, 14, 522) protect the rabbit from the lethal effect of this injection. It has also been shown that sulfin pyrazone prevents platelet aggregation in the extrinsic loop of the abdominal aorta of the rat in vivo (Thromb. Diathes. Haem. 1973, 30, 138). The following table shows the results of thromboxane Bz production inhibition tests.

Compound Dose Inhibition of thromboxane Ba production in%, measured at the following time after application of mg / kg intestinal 2 min 15 min 30 min 45 min 75 min 00

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235050 15

The compounds described herein can be applied in the form of tablets or capsules containing a unit dose of the active ingredient together with excipients such as corn starch, calcium carbonate, calcium monohydrogen phosphate, alginic acid, lactose, magnesium stearate or talc. Typically, these tablets are prepared by granulating the above ingredients and then compressing the desired size tablets from the granules. Generally, the capsules are prepared by granulating the mixture of the above ingredients and filling the hard gelatin capsules with the granulate so that the desired dosage is obtained.

The compounds of the invention may also be administered parenterally, for example by intramuscular, intravenous or subcutaneous injection. For parenteral administration, the capsules are preferably used in the form of a sterile aqueous solution which may contain other soluble ingredients for, for example, isotonization or pH adjustment.

The compounds of the invention may be incorporated into the distilled water and the pH of the solution by means of an acid such as citric acid, lactic acid or hydrochloric acid to a value of 3 to 6. Appropriate amounts of other soluble additives such as dextrose or sodium chloride may then be added to the solution to isotonize. The resulting solution is sterilized and filled with sterile glass bottles of a size such that the desired volume of solution is obtained. The compounds of the invention can also be administered by infusing the parenteral preparation described above. It is expected that when administered orally in human medicine, the daily dose of a compound of formula I for a typical adult patient (70 kg) will range from 0.1 to 20 mg / kg. In the case of parenteral administration, the daily dose of general formula I compound for a typical adult patient will be 0.01 to 0.5 mg / kg. Thus, tablets or capsules will contain 5 to 150 mg of the active ingredient and will be administered orally up to three times per week. Dosage units for parenteral administration will contain 0.5 to 35 mg active ingredients. A typical ampoule preparation is a 10 ml ampoule containing 5 mg of active ingredient in 6-10 ml of solution.

It will be understood that, in any event, the most appropriate dosage for the patient to be treated by the attending physician will vary depending upon the patient's age, weight, and response to the administered dose.

The above dosages are merely exemplary doses for the average patient, and, of course, there may be individual cases where higher or lower doses will be required. The following examples illustrate the preparation of the novel compounds of formula X, but are not limited thereto. Example 1

2- (1-Imidazolylmethyl-3-ethyl-benzo [b] thiophene-5-carboxylic acid ethyl ester (ij 2-Chloromethyl-3-methyl-benzo [b] thiophene-5-carboxylic acid ethyl ester)

Hydrogen chloride gas was introduced into a mixture of 5.50 g of 3-methylbenzo [b] thiophine-5-carboxylic acid ethyl ester, 1.25 g of anhydrous zinc chloride and 1.50 g of paraformaldehyde in 50 ml of chloroform for 30 minutes. then the chloroform solution is decanted off from the resin precipitate, thoroughly washed and dried over sodium sulfate. Evaporation of the solvent gave crude ethyl 2-chloromethyl-3-methylbenzo [b] thiophene-5-carboxylic acid, which was used directly in the next step. (iij 2- (1-Imidazolylmethyl-3-methylbenzo [b] thiophene-5-carboxylic acid ethyl ester

To a solution of 0.68 g of imidazole in 30 ml of dry Ν-dimethylformamide, 0.5 g of a 50% strength trihydric anhydride dispersion in mineral oil is added in portions and the mixture is stirred at room temperature for 30 minutes. A solution of 2.70 g of 2-chloromethyl-3-methylbenzo [b] thiophene-5-carboxylic acid ethyl ester in 5 ml of dry N, N-dimethylformamide was added thereto, followed by stirring for 2 hours. The residue was dissolved in ethyl acetate, washed thoroughly with water and dried over sodium sulfate. After evaporation of the solvent, the oily residue was chromatographed on silica gel.

Elution of the column with a 3: 1 mixture of chloroform and petroleum ether (b.p. 40 DEG-60 DEG C.) first eluted some impurities and then the pure product. Evaporation of the product-containing fractions gave a solid material which, after crystallization from ethyl acetate / petroleum ether (b.p. 60 DEG -80 DEG C., gave 1.40 g of 2- (1-imidazolylmethyl) -3-methylbenzoate [ b] thiophene-5-carboxylic acid, m.p. 126-127 ° C 235050 17

H, 5.37; N, 9.33; Found: C, 64.39; H, 5.07; H, 9.46;

2- (1-Imidazolylmethyl) -3-methylbenzo [b] thiophene-5-carboxylic acid hydride

A mixture of 1.0 g of 2- (1-imidazolyl-methyl) -3-methyl-benzo [b] thiophene-5-carboxylic acid ethyl ester and 80 ml of hydrochloric acid was heated to a boil bath for 5 hours then cooled. The solid material was filtered off, dried and crystallized from ethanol / ether. 0.72 g of 2- (1-imidazolylmethyl) -3-methylbenzo [b] thiophene-5-carboxylic acid hydrochloride having a melting point of 298 DEG-299 DEG C. is obtained.

Analysis for C 14 H 12 N 2 O 2 S. HCl calculated: 54.45% C, 4.24% H, 9.07% N, found: 54.61% C, 4.19% H, 9.21% N. Example 3

2- (1-Imidazolylmethyl) benzo [b] thiophene-5-carboxylic acid methyl ester (i) 2-methylbenzo [h] thiophene-5-carboxylic acid

By converting 5-bromo-2-methylbenzo [b] thiophene to the Grignard reagent and subsequently reacting with carbon dioxide according to the

Xas

13 of Example 3 (i) of the published European Patent Publication No. 0073663 gives 2-methylbenzo [b] thiophene-5-carboxylic acid, m.p. 220-222 ° C.

H, 4.19; H, 4.14; found: 62.06% C, 4.07% H. (ii) 2-Methylbenzo [h] thiophene-5-carboxylic acid methyl ester

A solution of 17.4 g of 2-methylbenzo [b] thiophene-5-carboxylic acid in 250 ml of methanol was saturated with hydrogen chloride and then heated at reflux for 30 minutes. The solid product which crystallizes upon cooling of the reaction mixture is filtered off and dried. 16.7 g of methyl 2-methylbenzo [b] thiophene-5-carboxylic acid are obtained, m.p. 97-98 ° C.

H, 4.89; Found: C, 64.05; found: 64.39% C, 4.94% H (iii) 2-Bromomethyl-benzo [b-thiophene-5-carboxylic acid methyl ester

Reaction of 2-methylbenzo [b-thiophene-5-carboxylic acid methyl ester with N-bromosuccinimide and azobisisobutyronitrile in tetrachloromethane by the procedure of Example 3 (iii) of the above-cited European Patent Application discloses 2-bromomethylbenzo [b] thiophene-5-carboxylic acid methyl ester 106 DEG-107 DEG C. Analysis: for C11H8BrCl3S: calculated: 46.33% C, 3.18% H; found: 45.89% C, 3.11% H. (iv) 2- (1-Imidazolylmethyl) -benzo [b] thiophene-5-carboxylic acid methyl ester N-i + o

N

Ns.HCO3

235050 19 20

A mixture of 1.71 g of 2-bromomethyl-beuzo [b] thiophene-5-carboxylic acid methyl ester,

4.08 g of imidazole and 0.55 g of sodium bicarbonate in 50 ml of acetone were heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with water, dried over sodium sulfate, and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform yielded a small amount of starting material followed by the product. From the fractions containing the desired product, a solid was obtained after evaporation, which after crystallization from a mixture of ethyl acetate and petroleum ether (b.p. 60 DEG-80 DEG C.) gave 0.81 g of methyl 2- [1-imidazolylmethyl) benzo [b] thiophene. 127 DEG-128 DEG C. Analysis: for C14H12N2O2S calculated: 61.75 10/0 C, 4.44% H, 10.29% N, found: 61.49% C, 4.52% H, 10.40% N. Example 4

3-Chloro-2- (1-imidazolylmethyl) -benzo [b] thiophene-5-carboxylic acid methyl ester (ij 3-Chloro-2-methyl-benzo [b] -thiophene-5-carboxylic acid methyl ester To a solution of 5.15 g of methyl ester 2 3.38 g of sulfuryl chloride are added dropwise with stirring in 50 ml of chloroform, the solution is refluxed for 2 hours, then cooled, washed with water and evaporated to dryness with sodium sulfate. The residue is crystallized from methanol / water to give 3.00 g of 3-chloro-2-methylbenzo [b] thiophene-5-carboxylic acid methyl ester, m.p.

Analysis calculated for C 11 H 9 ClO 2 S: C, 54.09; H, 3.77; found: 55.06% C, 3.64% H. (2-Bromomethyl-3-chloro-benzo [b] thiophene-5-carboxylic acid methyl ester)

Reaction of 3-chloro-2-methylbenzene [b] thiophene-5-carboxylic acid methyl ester with N-bromosuccinimide and azobisisobutyronitrile in carbon tetrachloride by the procedure of Example 3 above gives the methyl ester of 2-bromomethyl- 3-chlorobenzo [b] thiophene-5-carboxylic acid melting at 144-145 ° C.

Analysis: for C 11 H 8 BrClO 2 S: C, 41.33; H, 2.52; found: 41.53% C, 2.56% H. (iiij. 3-Chloro-2- (1-imidazolyl-methyl-benzo [b] thiophene-5-carboxylic acid methyl ester

CW

N4HCO3

Reaction of 2-bromomethyl-3-chloro-benzo [b] thiophene-5-carboxylic acid methyl ester with simidazole and sodium bicarbonate as described in Example 3 (iv) affords 3-chloro-2- (1-imidazolylmethyl) benzo [b] methyl ester. thiophene-5-carboxylic acid, after crystallization from ethyl acetate / ether (b.p. 60-80 ° C at 138-139 ° C).

Analysis calculated for C14H11ClN2O2S: 4.81% C, 5.61 UH, 9.15% N, found: 54.74% C, 3.38% H, 9.39% N. Example 5

3-Bromo-2- (1-imidazolylmethyl) -benzo (b) thiophene-5-carboxylic acid methyl ester (ij 3-Bromo-2-methyl-benzo [b] -thiophene-5-carboxylic acid methyl ester To a mixture of 2.40 g of methyl ester 2 2.08 gbromone was added dropwise with stirring, and the reaction mixture was stirred at room temperature for 2 hours, then washed with water and sodium bicarbonate solution. - 21

dried with sodium sulfate and chloroform evaporated. The solid residue, after crystallization of aqueous methanol, yields 2.00 g of 3-bromo-2-methylbenzo [b] thiophene-5-carboxylic acid methyl ester, m.p. 84-85 ° C. H, 3.19; found: 46.22% C, 3.01% H. (li] 3-Bromo-2-bromomethyl-benzoyl] -thiophene-5-carboxylic acid methyl ester

Using the procedure described in Example 3 (111) of the above-cited European Patent Application, the reaction of methyl ester 22 of 3-bromo-2-methylbenzo [b] thiophene-5-carboxylic acid with N-bromosuccinimide and azo-bisisobutyronitrile in carbon tetrachloride methyl ester 3 -bromo-2-bromomethyl-benzo [b] thiophene-5-carboxylic acid, m.p. from a mixture of ethyl acetate and ether (b.p. 60-80 ° C at 173-174 ° C).

Analysis: for C 11 H 6 Br 2 O 2 S: C, 36.29; H, 2.21; found: 36.22% C, 2.24% H. (III) 3-Bromo-2- (1-imidazolyl-methyl) benzo [b] thiophene-5-carboxylic acid methyl ester

Reaction of 3-bromo-2-bromomethyl-benzoyl-thiophene-5-carboxylic acid methyl ester with imidazole and sodium bicarbonate according to Example 3 (iv) to give 3-bromo-2- (1-imidazolylmethyl) -benzo (b) thiophene-5 ethyl ester carboxylic acid, after crystallization from a mixture of ethyl acetate and ethyl ether (b.p. 60-80 ° C at 146-147 ° C).

H, 3.14; N, 7.98; Found: C, 48.01; H, 2.98; H, 8.07;

2- (1-Imidazolylmethyl) -3-methylthiobenzopb] thiophene-5-carboxylic acid methyl ester (ij 5-bromo-3-methylthiobenzo [b] thiophene To a solution of 14.6 g of 3,5-dibromobenzo [b] thiophene in 600 mL of dry ether was added 35 mL of a 1.55 M solution of n-butyllithium in hexane while stirring under dry nitrogen at -70 ° C and the reaction mixture was stirred at -70 ° C for 30 min. with stirring, a solution of 4.90 g of dimethyl sulfide in 10 ml of dry ether was added over 5 minutes and the resulting mixture was stirred at -70 DEG C. for 4 hours, then allowed to warm to room temperature. The organic layer was separated, washed with water and dried over sodium sulfate, and the oily residue after evaporation of the ether was chromatographed on silica gel, eluting with petroleum ether (b.p. 40 DEG -60 DEG C.) to give a small amount of impurities followed by a pure product. .

The product-containing fractions were combined, evaporated and the residue was distilled. 10.36 g of 5-bromo-3-methylthiobenzo [b] thiophene are obtained boiling at 140 to 144 ° C / 80 Pa, m.p. 56-57 ° C.

Calcd for C9H7BrS2: C, 41.70; H, 2.72; found: 41.87% C, 2.62% by weight H. (ii) 3-methylthiobenzo [b] thiophene-5-carboxylic acid To a mixture of 1.50 g of magnesium and 10 ml of dry ether was stirred with stirring. at such a rate to maintain a gentle reflux, 2.60 g of 5-bromo-3-methylthiophenyl] thiophene and 4.80 g of methyl iodide in 50 ml of dry ether are added. The reaction mixture was heated to reflux for 30 minutes, then cooled and poured into a mixture of crushed carbon dioxide and ether. After evaporation of the carbon dioxide, the mixture is shaken with 2N hydrochloric acid, the layers are separated, the ether layer is extracted several times with 2N sodium hydroxide solution and the combined extracts are acidified with acetic acid. The solid product was filtered off, washed with water and crystallized from aqueous ethanol. 1.24 g of 3-methylthiobenzo [b] thiophene-5-carboxylic acid of melting point 205-207 ° C are obtained.

Analysis: for C 10 H 8 O 2 S 2 calculated: 53.55% C, 3.60% H; found: 53.23% C, 3.53% H. (iii) 3-Methylthiobenzo [b] thiophene-5-carboxylic acid ethyl ester

A mixture of 5.62 g of 3-methylthiobenzo [b] thiophene-5-carboxylic acid and 2 ml of oxychloride phosphorous in 200 ml of ethanol was heated to reflux for 18 hours and evaporated. The residue was dissolved in ether, washed with sodium bicarbonate solution and water, dried over sodium sulfate, and the solvent was evaporated. The solid product obtained after crystallization from ethanol gave 5.84 g of 3-methylthiobenzo [b] thiophene-5-carboxylic acid ethyl ester, m.p. 67-69 ° C. found: 57.25% C, 4.76% H. (iv) 2-Chloromethyl-3-methyl-thiobenzo [b] thiophene-5-carboxylic acid ethyl ester

To a mixture of 1.0 g of 3-methylthio-benzo [b] thiophene-5-carboxylic acid ethyl ester, 0.24 g of iparaformaldehyde and 0.2 g of anhydrous zinc chloride in 30 ml of chloroform under stirring at 0 ° C for 2 hours -din lists hydrogen chloride. The resulting mixture was stirred at room temperature for 18 hours, then washed with water, the organic layer was separated, dried over sodium sulfate and evaporated to an oil which was chromatographed on silica gel.

Elution with toluene gave a solid which after crystallization from petroleum ether (b.p. 60-80 ° C) gave 0.42 g of 2-chloro-methyl-3-methylthiobenzo [b] thiophene-5-carboxylic acid ethyl ester by temperature of 95 to 96 ° C.

Analysis calculated for C13H13ClO2S2: C, 51.90; H, 4.35; Found: C, 51.95; H, 4.31;

&Amp; HCO &

Using the procedure described in Example 3 (iv), the reaction of ethyl 2-chloromethyl-3-methylthiobenzoylthiophene-5-carboxylic acid with imidazole and sodium bicarbonate yields ethyl 2- (1-imidazolylmethyl) -3-methylthiobenzoate. [b] thiophene-5-carboxylic acid, melting point after crystallization with ethyl acetate / petroleum ether (b.p. 60-80 ° C) at 105-107 ° C. Analysis: for C 16 H 16 N 2 O 2 S: C, 57.80; % H, 8.43% N, found: 57.73% C, 4.82% O / r, 8.55% N. Example 7

3-Methyl-2- (1-imidazolylmethyl) -benzofuran-5-carboxylic acid methyl ester (ij 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid To a solution of 12.90 ml of 1.55 M hexane solution) n-butyllithium in 50 ml of dry ether under a dry nitrogen atmosphere at 0 ° C with a solution dropwise added to a solution of 1.93 g of 5-bromo-2-hydroxymethyl-3-methylbenzofuran (Annalen, 1112, 1973) in 50 ml of dry ether The mixture was stirred at 0 ° C for 2 hours and then poured into a mixture of crushed solid carbon dioxide and ether, after evaporation of 23 2 3 5 O 3 (1 26 of all carbon dioxide, the reaction mixture was shaken with water, the aqueous layer The solid product was collected by filtration, washed with water and crystallized from isopropanol / petroleum ether (boiling point 80 to 100 ° C) to give 0.50 g of 2-ol. hydroxymethyl-3-methylbenzofuran-5-carboxylic acid, m.p. 220-222 ° C.

H, 4.89; Found: C, 64.08; found: 64.31% C, 4.96% H. (ii) 2-Hydroxymethyl-3-methyl-benzofuran-5-carboxylic acid methyl ester To a solution of 0.69 g of 2-hydroxymethyl-3-methyl-benzofuran-5- of carboxylic acid in 250 ml of methanol is added an excess of ethereal solution of diazomethane. The reaction solution was allowed to stand at 0 DEG C. for 1.5 hours and then the excess diazomethane was quenched by dropwise addition of acetic acid until the foaming was complete. The resulting solution was evaporated, the residue was dissolved in ether, the ethereal solution was washed with sodium bicarbonate, dried over sodium sulfate and evaporated. In quantitative yield, 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester, melting after crystallization from ethyl acetate / petroleum ether at 96-98 ° C, was obtained.

H, 5.49; H, 5.49; found: 65.28% C, 5.49% H. (iii) 2-Chloromethyl-3-methyl-beuzofuran-5-carboxylic acid methyl ester To a solution of 0.20 g of 2-hydroxymethyl-3-methylbenzofuran-5 methyl ester 0.25 ml of thionyl chloride are added dropwise with stirring to the 2-carboxylic acid and 2 drops of pyridine in 5 ml of chloroform. The solution was stirred at room temperature for 30 minutes and then washed with water, sodium bicarbonate solution, dried over sodium sulfate and the solvent was evaporated. 0.18 g of crude 2-chloromethyl-3-methylbenzofuran-5-carboxylic acid methyl ester of melting point 114 DEG-115 DEG C. is obtained, which is used directly in the next step. (ivj 2- (1-Imidazolylmethyl) -3-methylbenzofuran-5-carboxylic acid methyl ester

Using the procedure of Example 3 (reaction of 2-chloromethyl-3-methylbenzofuran-5-carboxylic acid methyl ester with i-imidazole and sodium bicarbonate sodium 2- (1-imidazolylmethyl-3-methyl-benzofuran-5-carboxylic acid methyl ester, m.p. 135 DEG-136 DEG C. The product was not further characterized Example 8

3- (1-Imidazolylmethyl) -2-methylbenzo [b] thiophene-7-carboxylic acid methyl ester (ij 2-Methylbenzo [b] thiophene-7-carboxylic acid methyl ester)

A solution of 5.1 g of 2-methylbenzo [b] thiophene-7-carboxylic acid in 100 ml of methanol is saturated with hydrogen chloride and then refluxed for 18 hours. The resulting solution was evaporated, the residue was dissolved in ether, the ethereal solution was washed with sodium carbonate solution and dried over sodium sulphate. Evaporation of ether gave 4.7 g of 2-methylbenzo [b] thiophene-7-carboxylic acid methyl ester, m.p. (iij 3-Chloromethyl-2-methyl-benzo [b] thiophene-7-carboxylic acid methyl ester

To a mixture of 4.50 g of 2-methyl-benzo [b] thiophene-7-carboxylic acid methyl ester, 1.23 g of paraformaldehyde and 1.03 g of anhydrous zinc chloride in 50 ml of chloroform, with stirring for 30 hours. minutes of hydrogen chloride gas. The reaction mixture was stirred at room temperature for 5 hours, stirred for 18 hours, washed several times, the organic layer was dried over sodium sulfate and evaporated. The residue is recrystallized from chloroform / petroleum ether (b.p. 60-80 ° C) to give 4.10 g of 3-chloromethyl-2-methyl-benzo [b] thiophene-7-carboxylic acid methyl ester of 125-126 ° C. (iii) 3- (1-Imidazolylmethyl) -2-methylbenzo [b] thiophene-7-carboxylic acid methyl ester

number

Using the procedure described in Example 1 (ii), by sequentially reacting imidazole with na-trihydride and 3-chloromethyl-2-methylbenzo [b] thiophene-7-carboxylic acid methyl ester in Ν, Ν-dimethylformamide, 3- (1-imidazolylmethyl) methyl ester is obtained -2-methylbenzo [b] thiophene-7-carboxylic acid, m.p. 148-149 ° C.

Analysis calculated for: C15H14N2O2S: C, 62.91; H, 4.93; N, 9.79 Found: C, 62.60; H, 4.90; N, 9.72. the table shows carboxylic acids prepared by hydrolysis of the corresponding esters with potassium hydroxide in aqueous methanol at reflux, using the procedure of Example 3 (European Patent Application Publication, cited above).

Temperature Melting Analysis (° C) 10 11

Br

for C13H10N2O2S0-282: C, 60.45; H, 3.90; N, 10.85. found · 60.25% C, 3.83% H, 10.88 Ό / ο N. for C13H9CIN21O2SΓ ~ - | H, 3.10; N, 9.51. Found: C, 52.96; H, 3.05; N, 9.55. Found: C, 46.31; H, 2.69; N, 8.31. found: 46.19% C, 2.70% H, 8.18 0/0 N. 12 13

£ 14

for C14H12N2O2S2256-258: C, 55.24; H, 3.98; N, 9.21. Found: 54.97. N, 9.26%. Found: C, 61.74; H, 4.44; N, 10.29. Found: C, 61.56; N, 10.29%. For C14H12N2O3237-239, calculated: 65.62% C, 4.72% H, 10.93% N; % H, 10.92%.

Claims (2)

EXAMPLE 15 2- (1-Imidazolylmethyl] naphthalene-6-carboxylic acid (i) 2-Bronimethylnaphthalene-6-carboxylic acid methyl ester Using the procedure described in Example 3 (iii) of the above-cited European Patent Application, Methylnaphthalene-6-carboxylic acid with N-bromosuccinimide and azobis-isobutyronitrile in carbon tetrachloride yields 2-bromomethyl-naphthalene-6-carboxylic acid methyl ester, m.p. 103-106 ° C: Calculated: C, 55.93; H, 3.97%, found: 55.45 ° C, 4.02% H. (ii) 2- (1-Imidazolylmethyl) -naphthalene-6-carboxylic acid methyl ester Using the procedure described in Example II. ) by sequentially reacting imidazole with na-trihydride and 2-bromomethyl-naphthalene-6-carboxylic acid methyl ester in N, N-dimethylformamide to give 2- (1-imidazolylmethyl-naphthalene-6-carboxylic acid methyl ester, m.p. 148-149 ° C). Analysis: for C 16 H 14 N 2 O 2 calculated: 72.16% C H, 10.52% N, found: 71.79% C, 5.31% H, 10.50% N. (iii j 2- (1-Imidazolylmethyl) -naphthalene-6 - Carboxylic acid Analysis: for C 15 H 12 N 2 O 2 Using the procedure described in Example 3 (v) of the above-cited European Patent Application, 2- (1-imidazolylmethyl) naphthalene-6-carboxylic acid methyl ester was hydrolyzed with sodium hydroxide in aqueous methanol under reflux to give 2- (1-imidazolylmethyl-naphthalene-6-carboxylic acid 0 ° 275-278 ° C). H, 4.79; N, 11.10. Found: C, 71.36; H, 4.84; N, 10.84. N. PREDMET invent A process for the preparation of naphthalene and benzo-heterocyclic thromboxane-synthetase inhibitors of the general formula ILL = J (I) wherein alk is an alkyl group having 1 to 4 carbon atoms, or is a group -CH = CH-and R 1 is attached to one of the carbon atoms the ring B is a hydrogen atom, an atom of halogen, an alkyl group having 1 to 4 carbon atoms, or an alkylthio group having 1 to 4 carbon atoms, wherein the 1-imidazolylmethyl group is bonded to one of the carbon atoms of the ring B, and pharmaceutically acceptable salts thereof characterized in that the compound of the formula wherein Y is bonded to ring A and represents a carbonyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety, or an Icarbamoyl group, X is an oxygen atom, a sulfur group, an N-alk group in which alk, R 1 and X have the above said meaning and Q represents a readily cleavable moiety, wherein the midazole salt group 31 235050 32 is an alkali metal salt and as is sodium bicarbonate. 3. Process according to claim 2, characterized in that the product obtained is subjected to hydrolysis according to step 1, to produce a compound of formula O alk-O-C-HO1C. CHL is attached to one of the carbon atoms of A and the group - CH2Q is bonded to one of the carbon atoms of ring B, not reacting with either imidazole in the presence of a base or with a metal salt of imidazole to form a compound of formula I in which Y is a COO-alk group, where alk is as defined above, whereupon the product obtained by acidic or alkali hydrolysis is converted to the corresponding compound of formula I wherein Y is a carboxyl group and / or the product obtained is converted to the corresponding compound by reaction with ammonia of formula (I) wherein Y is a carbamoyl group and / or the obtained compound of formula (I) is converted into a pharmaceutically acceptable salt thereof. 2. A process as claimed in claim 1, wherein the starting material of the general formula described in 1, wherein Q is chlorine or bromine, is used as the metal salt of i-1. HOOC WITH CH ^ N - ^ N SCH, CHg · N hcbo HOOC