GB2161801A - N-Imidazolyl derivatives and process for their preparation - Google Patents

Abstract

N-Imidazolyl derivatives of 3,4-dihydro-2H-1-benzothiopyran and having the formula (I> <IMAGE> wherein each of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C1-C6 alkyl; C1-C6 alkoxy; a C2-C4 acyl or C2-C4 acylamino group; <IMAGE> in which each of R' and R'', being the same or different, is hydrogen or C1-C6 alkyl, and the pharmaceutically acceptable salts thereof, are selective inhibitors of thromboxane A2.

Description

SPECIFICATION "N-lmidazolyl derivatives and process for their preparation" The present invention relates to new N-imidazolyl derivatives of 3,4-dihydro-2H-1-benzothiopyran, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds having the following general formula (1)

wherein each of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C1-C6 alkyl; C1-C6 alkoxy; a C2-C4 acyl or C2-C4 acylamino group;

in which each of R' and R", being the same or different, is hydrogen or C1-C6 alkyl, and the pharmaceutically acceptable salts thereof. The present invention includes all the possible isomers, e.g. diastereoisomers and enantiomers, of the compounds of formula (I) and their mixtures, and the metabolites and pharmaceutically acceptable bioprecursors of the compounds of formula (I).

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids, or organic, e.g.

acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, fumaric, methanesulfonic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases, or with organic bases, e.g. alkylamines, preferablytriethylamine.

The alkyl, alkoxy and alkylthio groups may be branched or straight chain groups.

A halogen atom is, for example, fluorine, chlorine or bromine, preferably chlorine or bromine.

A C1-C6 alkyl group is preferably a C1-C4 alkyl group.

A C1-C6 alkoxy group is preferably a C1-C4 alkoxy group, in particular methoxy, ethoxy or isopropoxy.

The term acyl in C2-C4 acyl and C2-C4 acylamino groups refers to acyl groups deriving fom both saturated and unsaturated carboxylic acids, preferably alkanoic acids, e.g. acetyl, propionyl and butyryl.

When one or more of R1, R2, R3 and R4 is halogen, it is preferably chlorine or bromine. When one or more of R1, R2, R2 and R4 is Ci-Ce alkyl, it is preferably methyl, ethyl, isopropyl ortert.butyl.

A C2-C4 acyl is an aliphatic carboxylic acyl group, e.g. C2-C4 alkanoyl. When one or more of R1, R2, R3 and R4 is C2-C4 acyl, it is preferably acetyl or propionyl.

When one or more of R1, R2, R3 and R4 is C2-C4 acylamino, it is preferably acetylamino or propionylamino.

When one or more of R1, R2, R2 and R4 is -SR', it is, e.g. -SH or -S(C1-C4) alkyl, in particular methylthio, ethylthio or isopropylthio.

When one or more of Ri, R2, R3 and R4 is

it is preferably -NH2, -NHCH5 -NHC2H5, -N(CH3)2 or -N(C2H5)2.

When one or more of Ri, R2, R3 and R4 is -CH20R', it is preferably -CH20H, -CH20CH3 or -CH20C2H5.

When one or more of R1, R2, R3 and R4 is -COOR', it is preferably carboxy or C1-C4 alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl.

When one or more of R1, R2, R3 and R4 is

it is preferably amino-carbonyl or di (C1-C4 alkyl) amino-carbonyl, in particular dimethylamino-carbonyl or diethylamino-carbonyl.

When one or more of R1, R2 R3 and R4 is -CH2COOR', it is preferably carboxymethyl or C-C2 alkoxy-carbonyl-methyl, in particular methoxy-carbonylmethyl or ethoxy-carbonyl-methyl.

When one or more of R1, R2, R3 and R4 is

it is preferably aminocarbonylmethyl or di(C1-C4)alkyl-aminocarbonylmethyl, in particular dimethylamino-carbonylmethyl or diethylamino-carbonylmethyl.

When one or more of R1, R2, R3 and R4 is -PO(OR')2 , it is preferably -PO(OH)2 or -PO(OCH3)2 or -PO(OC2H5)2. Preferably three of R1, R2, R3 and R4 are hydrogen. Preferred compounds of the invention are the compounds of formula (I) wherein: one of R1, R2, R3 and R4 is a substituent chosen, independently, from the group consisting of C2-C4 acyl, CH2OR',

and -CH2COOR', wherein R' and R" are independently hydrogen or C1-C4 alkyl, and the remaining of R1, R2, R3 and R4 are hydrogen, and the pharmaceutically acceptable salts thereof.

Examples of preferred compounds of the invention are: 1 ) 2-(1 -imidazolyl )-6-acetyl-3,4-dihydro-2H-1 -benzothiopyran; 2) 2-(1 imidazolyl)-6-carboxy-3,4-dihydrn-2H-1 -benzothiopyran; 3) 2-(1 -imidazolyl)-7-ca rboxy-3,4-dihydro-2H-1 -benzothiopyran; 4) 2-( 1 -imidazolyl )-6-hydroxymethyl-3,4-dihydro-2H-1 -benzothiopyran; 5) 2-(1 -imidazolyl)-6-ethoxycarbonyl-3,4-dihydro-2H-1 -benzothiopyran; 6) 2-(1 -imidazolyl)-6-carbamoyl -3,4-dihydro-2H-1 -benzothiopyran; 7) 2-(1 -imidazolyl)-6-aminomethyl-3,4-dihydro-2H-1 -benzothiopyran; 8) 2-(1 -imidazolyl)-6-phosphono-3,4-dihydro-2H-1 -benzothiopyran, and the pharmaceutically acceptable salts thereof.

The compounds of the invention, and the salts thereof, can be prepared by a process comprising reacting a compound of formula (II)

wherein R1, R2, R3 and R4 are as defined above, with a reactive derivative of imidazole, and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desidered, converting a salt into a free compound, and/or, if desired, resolving a mixture of isomers of compounds of formula (I) into the single isomers.

A reactive derivative of imidazole is for example a N-(trialkyl-silyl)-imidazole, preferably a N-(C1-C6-trialkylsilyl)-imidazole, more preferably N-(trimethyl-silyl)-imidazole or N-(tert.butyl-dimethyl-silyl)-imidazole.

The reaction between a compound of formula (II) and a reactive derivative of imidazole as mentioned above is preferably carried out at a temperature ranging from about 12000to about 200"C, more preferably from about 1 50"0 two 175"C, and, if necessary in the presence of a suitable aprotic organic' solvent, preferably dimethylacetamide or dimethylformamide. The reaction time may range from about 2 to about 16 hours; preferably form about 5 to about 10 hours.

Alternatively the process may be also carried out by treating a compound of formula (II), as defined above, with imidazole and a suitable silylating agent, preferably bis-(trimethyl-silyl)-urea or hexamethyldisilazane, so as to form the N-(trialkyl-silyl)-imidazole in situ.The compounds of formula (II) are known compounds, or they may be prepared by known methods from known compounds, e.g. by oxidizing the corresponding 3,4-dihydro-2H-1 -benzothiopyrans of formula (III)

wherein R1, R2, R3 and R4 are as defined above, with a suitable oxidizing agent, preferably by treating with hydrogen peroxide in acetic acid at a temperature ranging from about -20 Cto about + 50"C, or with sodium metaperiodate or with tert. butyl hypochlorite, in a suitable solvent, e.g., a C1-C4 alkyl alcohol, in particular methanol, or water or mixtures thereof, preferably methanol/water, at a temperature ranging from about -20 C to about + 50"C.

A compound of formula (I) may be converted, if desired, into another compound of formula (I).

These optional conversions may be carried out by methods known in themselves.

Thus, for example, a compound of formula (I) wherein one or more of Rn, R2, R3 and R4 is hydrogen may be converted into a compound of formula (I) wherein one or more of R1, R2, R3 and R4 is a halogen atom, e.g.

chlorine or bromine, by reaction with chlorine or bromine in the presence of a Friedel-Crafts catalyst, preferably AICI3, operating in a suitable solvent, e.g. CH2C12.

A compound of formula (I), wherein one or more of Rt, R2, R3 and R4 is hydrogen may be converted into a compound of formula (I), where one or more of R1, R2, R3 and R4 is C-C6 alkyl, by alkylation through a Friedel-Crafts reaction, e.g. by reaction with a) a C1-Cs alkylhalide, preferably chloride, bromide or iodide; or with b) a C-C6 aliphatic alcohol in a suitable solvent, e.g. nitrobenzene or CH2CI2, or CS2.

In both the cases (a) and b), the reaction is performed in the presence of appropriate amounts of a Friedel-Crafts catalyst, such as AIC13, ZnCI2, or BF3; and when a C1-C6-aliphatic alcohol is used, also in the presence of a strong mineral acid as HF, HC104 or , if desired, in concentrated H2SO4 or in concentrated H3PO4 without additional solvent, at temperatures ranging from the room temperature to 10000.

A compound of formula (I) wherein one or more of R1, R2, R3 and R4 is a C1-C6 alkoxy group may be converted into a compound of formula (I) wherein one or more of R1, R2, R3 and R4 is a hydroxy group by following conventional procedures well known in organic chemistry. For example by treatment with a strong mineral acid, i.e. HCI, HBr, HI, preferbly HBr, at temperature ranging from 30"C to the reflux tempertaure, preferably at reflux temperature, or by treatment with a Lewis acid, for example AICI3 or BF3, in a suitable solvent, i.e. CH2C12 or nitrobenzene, at temperatures ranging from the room temperature to 80"C.

A compound of formula (I) containing an esterified carboxy group or an esterified phosphono group, may be converted into a compound of formula (I) containing a free carboxy group or a free phosphono group, respectively, by acidic or alkaline hydrolysis, operating at temperature ranging from the room temperature to about 10000.

A compound of formula (I) containing a free carboxy group or a free phosphono group, may be converted into a compound of formula (I) containing an esterified carboxy group or an esterified phosphono group, respectively, by esterification, e.g. via the corresponding acid halide, e.g. chloride, reacting with an excess of a suitable C1-C6 alkyl alcohol, or by direct esterification by means of acidic catalysis i.e. in the presence of dry HCI or SOCI2 or BF3-etherate.

A compound of formula (i) containing a carbamoyl group may be converted into a compound of formula (I) containing a free carboxy group by hydrolysis, preferably by acid hydrolysis, in a suitable solvent, such as water, or by the Bouveault procedure, that is by treatment with NaN02 and an aqueous strong inorganic acid, i.e. H2SO4, operating at temperature ranging between the room temperature and 10000.

A compound of formula (I) containing a free or esterified carboxy group may be converted in a compound of formula (I) containing a

wherein R' and R" are as defined above.

Accordingly, the conversion of an esterified carboxy group into the corresponding amide may be performed by direct reaction with ammonia or an appropriate amine in a suitable solvent, e.g., ether or benzene or using an excess of the amine as solvent, at temperatures ranging from room temperature to reflux.

The conversion of free carboxy group into the corresponding amides may be carried out via an intermediate reactive derivative which may be isolated or not.

Intermediate reactive derivatives may be active esters e.g. NO2-phenyl esters, or N-hydroxysuccinimide esters, acid halides, preferably chloride, mixed anhydrides e.g. ethoxycarbonyl ortert-butylcarbonyl anhydrides, or the reactive intermediates obtained in situ by reaction of the acid with dicyclohexylcarbodiimide or carbonyldiimidazole. The reactive intermediates obtained following conventional ways, as those usually employed in the synthesis of peptides, are reacted with amonia or an appropriate amine in a suitable solvent or with an excess of the amine itself at temperatures ranging from about 0 C to about 50"C.

A compound of formula (I) wherein one of R1, R2, R3 and R4 is a free or esterified carboxy group, in particular a lower alkoxycarbonyl group, may be converted into a compound of formula (I) wherein one or R1, R2, R3 and R4 is a 0H2OH group by reduction in conventional ways, preferably with LiAIH4 in a suitable solvent, e.g. ethylether orTHF.

The optional saiification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

When in the compounds having the formulae (I) and (11) groups are present which need to be protected during the reactions reported above, e.g. amino, hydroxy, further carboxy groups, etc., such groups can be protected in a conventional way before the reaction take place.

Examples of protecting groups are those usually employed in the synthesis of peptides, for example, to protect amino groups, acetyl, benzoyl, tert-butoxy-carbonyl, p-methoxy-benzyloxy-carbonyl, o-nitrophenylsulphonyl, dichioroacetyl protective groups, may be employed.

To protect hydroxy groups acetyl, benzoyl, benzyloxy, tetrahydropyranyl, -methoxyethoxymethyl (MEM) or a trialkylsilyl as tert-butyldimethylsilyl groups may be, for instance, employed. To protect the carboxy groups, tert-butyl, benzhydryl and p-methoxy-benzyl groups may be employed.

The protecting groups are then removed, at the end of the reaction, in a known manner, e.g. by mild acid hydrolysis or by mild catalytic reduction, for example with Pd/C as catalyst at atmospheric pressure.

The amino, carboxyand hydroxy protecting groups are then removed atthe end of the reaction, usually in a known manner. For example, when the amino protecting group is the monochloroacetyl group, it may be removed by treatment with thiourea; the formyl and the trifluoroacetyl groups may be removed by treatment with potassium carbonate in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid.

The carboxy protecting groups, for example, may be removed by mild acid hydrolysis or by catalytic hydrogenation, e.g. with Pd/C at room pressure.

The hydroxy protecting groups, for instance, may be removed by mild reaction conditions, e.g. acid hydrolysis. The compounds of this invention are selective inhibitors of Thromboxane A2 (TxA2) synthetase and therefore increase the ratio between Prostacyclin (PGl2) and TxA2 levels.

The activity on TxA2 and PGl2 synthetase has been evaluated in vivo. For example, rats were treated with a single oral dose of compound and killed 2 hours later. TxB2 and 6-keto-PGF1a concentrations, the stable metabolites of TxA2 and PGF2 respectively, were determined on serum and plasma respectively.

For example, the compound 2-(1-imidazolyl)-6-acetyl-3,4-dihydro-2H-1 -benzothiopyran reduces significatively serumTxB2 concentration, and raises significantly 6-keto-PGF1 concentration.

In most tissues the main products of arachidonic acid metabolism are Pig12 and TxA2 and their ratio plays a paramount role in vascular haemostasis. PGl2 has antiaggregatory and vasodilatory activity while TxA2 is a proaggregatory (or aggregatory) and vasoconstrictory compound. The enzyme PGl2 synthetase is located mainly in the endothelial cell and produces PGl2, which avoid adhesion of platelets to the arterial wall with production ofthrombi and has a vasodilatory activity. The enzyme TxA2 synthetase in turn is mainly located in platelets and produces TxA2 which blocks haemorrhage via the formation of platelet aggregates and vasoconstriction.

Balancing the opposite activities, vascular haemostasis is regulated.

The compounds of the invention, being able to inhibit selectively the formation of TxA2, can be used as vasodilatory and antiaggregant agents, for example in all the casesofthrombosis, perifieral vasculopaties and coronary artery diseases. In fact inhibition of TxA2 production reduces the probability of thrombi formation and of vasoconstriction with consequent ischemic everits and, leaving unaltered (or increasing) PGI2 production, improves vasodilation, tissue blood supplies and protects the vessel wall.

Another use of the compounds of the inventions is for the treatment of migraine. As is known, for example, in the case of migraine it has been demonstrated a diffused vasoconstriction induced by platelet TxA2 overproduction [J. Clin. Pathol. (1971),24, 250; J Headache (1977), 17, 101].

A platelet overproduction of TxA2 and MDA, i.e. malondialdehyde, in diabetes mellitus has been demonstrated and correlated with microcirculatory defects in the illness [Metabolism (1979), 28,394; Eu. J.

Clin. Invest. (1979), 9,223; Thrombosis Haemost. (1979), 42,983; J. Lab. Clin. Med. (1981),97,87].

Therefore the compounds of the invention can be used, e.g., in the treatment of diabetic microangiopathy.

Moreover, the compounds of the invention can be used as anti-inflammatory agents. As is known, for example, fluid obtained from carrageenin-induced granuloma converts arachidonic acid into TxA2 in vitro and TxA2 levels are increased in the synovial fluid of rheumatoid arthritis patients and in the fluid of carrageenin-induced inflammation in rats [Prostaglandins (1977), 13, 17; Scand. J. Theum. (1977), 6, 151].

Recently it has been also demonstrated that an overproduction of TxA2 is involved in the pathogenesis of hypertension and that a specific inhibitor of TxA2 production may be employed in the elimination of such a factor in hypertension [Eu. J. Pharmacol. (1981), 70, 247]. In fact the compounds of the invention con be used as hypotensive agents.

Furthermore it has been shown a role of TxA2 in the phatogenesis of ulcerative disorders of the stomach in accordance with its powerful gastric vasoconstrictory activity, so that also in this field a TxA2 inhibitor is useful [Nature (1981), 292,472]. In fact the compounds of the invention are indicated for the treatment of peptic ulcers.

The compounds of the invention can be also antitumoral agents.

It is known, for example, that a selective inhibition of TxA2 synthesis has been demonstrated to reduce the number of lung methastases and to slow down tumor growth [Nature (1982), 295, 188].

In view of the correlation between TxA2 synthesis and calcium transport, recently showed by some authors, specific TxA2 synthetase inhibitors, such as the compounds of the invention, can also find use in the treatment of osteoporosis, e.g. postmenopausal osteoporosis [Prostaglandins (1981), 21,401].

Moreover the compounds of the invention are indicated for the treatment of angina pectoris. In this respect, it is known, for example, that high levels of TxB2 have been found in patients with Prinzmetal's angina [Prostaglandins and Med. (1979),2,243] and in patients with recurrent angina attacks (Sixth Intern.

Congress on Thrombosis, Monte Carlo - October 1980 Abs No. 140].

The dosage level suitable for oral administration to adult humans of the compounds of the invention, e.g., 2-(i-imidazolyl)-6-carboxy-3,4-dihydro-2H-1-benzothiopyran may range from about 5 mg to about 500 mg per dose 1 to 3 times a day, preferably from about 20 mg to about 150 mg per dose 1 to 3 times a day depending on the disease, age and weight of the patients involved.

The toxicity of the compounds of the invention is negligible, therefore they can be safely used in therapy.

Nine hours food deprived mice and rats were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD50) was assessed on the seventh day after the treatment and resulted to be negligible.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions, rectally, in the form of suppositories, parenterally, e.g. intramuscularly, or by intravenous injection of infusion. In emergency situations the preferred one is intravenous. As stated above, the exact dosage depends on the disease, age, weight, conditions of the patient and administration route.

The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose dextrose, sacharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxylethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures, dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for eaxmple, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carrier only products which cannot be metabolized to glucose, or metabolized only in very small amount, for example sorbitol.

The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The N.M.R. spectrum was measured preferably in solution of dimethyl sulphoxide-d6 or of CDCI3, using a 90 M-hertz Bruker HFX apparatus.

The Rf values were determined by thin layer chromatography on ready-to-use silica gel plates of 0.25 mm coating, thickness.

The following examples illustrate but do not limit the invention.

Example 1 A mixture of 1.1 g (0.0052 mol) of 6-carboxy-3,4-dihydro-2H-1-benzothiopyran-S-oxide, m.p. 190-192"C, (prepared by oxidation with hydrogen peroxide/acetic acid of the corresponding thiochroman) and 1.1 ml (0.026 mol) of trimethyl-silyl-imidazole was heated at 1700C for 8 hours with stirring.

After cooling the mixture was poured in water, acidified with acetic acid and washed with ethyl acetate.

The aqueous solution was evaporated under vacuum, absolute ethanol (2 x 50 ml) was added and evaporated again to dryness.

The crude product was chromatographed on silica gel (eluant chloroform/methanol/acetic acid 90/10/1) giving 0.65 g of 2-(1 -imidazolyl)-6-carboxy-3,4-dihydro-2H-1-benzothiopyran, m.p. 256-258"C.

Elemental analysis: Found: C59.15; H 4.70; N10.65; S12.15 Calculated for C13H12N202S: C 59.98 H 4.67; N 10.76; S 12.31 T.L.C. : eluant CHCI3: CH3OH : CH3COOH :90/10/1 Rf = 0.38 N.M.R. (DMSO d6) # p.p.m.:

6.17 (1H, t, S-CH-N) 6.95 - 7.80 (6H, m, aromatics + imidazole) In a similar way the following compounds were prepared: 2-(1-imidazolyl)-6-bromo-3,4-dihydro-2H-1-benzothiopyran, m.p. 131-133 C Elemental analysis: Found: C 48.84; H 3.78: N 9.35 Calculated for C12H11BrN2S : C 48.82; H 3.75; N 9.49 T.L.C. : eluant AcOEt + 2% NH40H conc. Rf = 0.56 N.M.R. (CDCl3) # p.p.m.

6.87 - 7.65 (6H, m, aromatics + imidazole) 2-(1-imidazolyl)-3,4-dihydro-2H-1-benzothiopyran m.p. 7880O0 Elemental analysis: Found: C66.69; H 5.55; N 12.92; S 14.73 Calculated for C12H12N2S: C66.63; H 5.59; N 12.95; S14.82 T.L.C.: eluant CHCl3: CH3OH (195: 5) Rf = 0.3 N.M.R. (CDCl3) # p.p.m.

2.1 - 3.0 (4H, m CH2-CH2)

6.9 - 7.73 (7H, m, aromatics + imidazole) M.S. mlc 216 (M+)

2-(1-imidazolyl)-6-acetyl-3,4-dihydro-2H-1-benzothiopyran, m.p. 93 - 95 C Elemental analysis: Found C64.15; H 5.38; N10.37; S12.09 Galculatedfor C14H14N2OS:C65.09; H 5.46; N 10.84; S 12.41 T.L.C. : eluant AcOEt + 1% NH40H conc.Rf = 0.25 N.M.R. (CDCI3) 8 p.p.m.

2.57 (3H,1,0H3)

5.81 (1H,dd,S-CH-N) 7.20 - 7.70 (6H, m, aromatics + imidazole) 2-(1 -imidazolyl )-7-carboxy-3,4-di hyd ro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-hydroxymethyl-3,4-dihydro-2H-1-benzothiopyran; 2-(1 -imidazolyl)-6-ethoxycarbonyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-carbamoyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-aminomethyl-3,4-dihydro-2H-1 -benzothiopyran; and 2-(1 -imidazolyl)-6-phosphono-3,4-dihydro-2H-1 -benzothiopyran.

Example 2 Tablets, each weighing 150 mg and containing 50 mg of the active substance were manufactured as follows: Composition (for 10,000 tablets) 2-(1 -imidazolyl)-6-acetyl-3,4-di hydro-2H-1 -benzothiopyran 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-(1 -imidazolyl)-6-acetyl-3,4-dihydro-2H-1 -benzothiopyran, lactose and a half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm openings.

Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, taic and magnesium was added, carefully mixed, and processed into tablets using punches of 8 mm diameter.

Example 3 2-(1 -imidazolyl )-3,4-dihydro-6-bromo-2H-1 -benzothiopyran was treated with the stoichiometric amount of hydrogen chloride, to give 2-(1 -imidazolyl)3,4-dihydro-6-bromo-2H-l -benzothiopyran hydrochloride.

Claims (11)

1. Acompound havingthefollowing general formula (I)

wherein each of R1, R2, R3 and R4, which may be the same or different, is hydrogen; hydroxy; halogen; cyano; C-C6 alkyl; C,-Cg alkoxy; a C2-C4 acyl orC2-C4acylamino group;

in which each of R' and R", being the same or different, is hydrogen or Ca-C6 alkyl, and the pharmaceutically acceptable salts thereof.

2. A compound of formula (I) according to claim 1 wherein one of Ri, R2, R3 and R4 is a substituent chosen, independently, from the group consisting of C2-C4 acyl, CH2OR',

and -CH2COOR', wherein R' and R" are independently hydrogen or C-C4 alkyl, and the remaining of R1, R2, R3 and R4 are hydrogen, and the pharmaceutically acceptable salts thereof.

3. A compound selected from the group consisting of: 2-(1 -imidazolyl)-6-acetyl-3,4-dihydro-2H-1 -benzothiopyra n; 2-(1 -imidazolyl)-6-carboxy-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyi)-7-carboxy-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-hydroxymethyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-ethoxycarbonyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-carbamoyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1 -imidazolyl)-6-aminomethyl-3,4-dihydro-2H-1 -benzothiopyran; 2-(1-imidazolyl)-6-phosphono-3,4-dihydro-2H-1-benzothiopyran, and the pharmaceuticaliy acceptable salts thereof.

4. A process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (Il)

wherein Ri, R2, R3 and R4 are as defined in claim 1, with a reactive derivative of imidazole, and, if desired, converting a compound of formula (i) into another compound of formula (I), and/or, if desired, converting a compound of formula (I) into a salt thereof, and/or, if desired, converting a salt into a free compound, and/or, if desired, resolving a mixture of isomers of compounds of formula (i) into the single isomers.

5. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

6. A compound of formula (I) as defined in claim 1 hereinbefore specified other than a compound claimed in claim 3.

7. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

8. A compound of formula (i) or salt thereof according to claim 7 for use as a selective inhibitor of Thromboxane A2.

9. A process for the preparation of a compound of formula (i) as defined in claim 1, said process being substantially as herinbefore described in Example 1.

10. A process for the preparation of a pharmaceutically acceptable salt of a compound of formula (i) as defined in claim 1, said process being substantially as hereinbefore described in Example 3.

11. A pharmaceutical composition substantially as hereinbefore described in Example 2.