DE3519432A1 - N-IMIDAZOLYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

FARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY

N-imidazolyl derivatives, process for their preparation and drugs containing them

The invention relates to new N-imidazolyl derivatives of 3,4-dihydro-2H-1-benzothiopyran, a process for their Manufacture and medicines containing them.

The novel compounds according to the invention have the general formula (I)

(D

where mean:

R., R, R ₃ and R _4, which may be the same or different, each represents hydrogen, hydroxy, halogen, cyano, C ₁ ^ alkyl, C ₁ .- alkoxy, a C.-Acyl or C ₂ _.- acylamino group, -SR ¹ , -NC ^ ₁₁ , -CH ₃ OR ¹ ,

-COOR ¹ , -CON ^! ,, -CH ₂ N ^ ₁ , -PO (OR ¹ ) ₂ ,

Tü «/ where R ¹ and R", which can be the same or different, are each hydrogen or C ₁ , .- alkyl,

as well as pharmaceutically acceptable salts thereof.

The present invention includes all possible isomers, e.g., diastereoisomers and enantiomers of Compounds of formula (I) and mixtures thereof, as well as the metabolites and pharmaceutically acceptable ones Bioprecursors of the compounds of formula (I).

Pharmaceutically acceptable salts of the compounds of formula (I) are acid addition salts with inorganic ones Acids, e.g. with nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, or organic acids, e.g. acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, Malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, fumaric acid, Methanesulfonic acid and salicylic acid. Also included are salts with inorganic substances, e.g. alkali metals, especially sodium or potassium, and with bases or alkaline earth metals, especially calcium

or magnesium, or with organic bases, e.g. alkylamines, preferably triethylamine.

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

Examples of halogen are fluorine, chlorine or bromine, but preferably chlorine or bromine.

A C, _ß- alkyl group is preferably a C _1-4 -alkyl group.

A C .._ ₆ alkoxy group is preferably a C,, alkoxy group and especially a methoxy, ethoxy or isopropoxy group.

The term "acyl" in C _3-4 -ACyI and C ₂ _.- acylamino groups relates to acyl groups which are derived from both saturated and unsaturated carboxylic acids, preferably from alkanoic acids, for example acetyl, propionyl and butyryl.

If one of the radicals R ^, R ₂ , R ₃ and R _{4 is} a halogen, then it is preferably chlorine or bromine.

If one or more of the radicals R ₁ , R ₂ , R ₃ and R ₄ denote a C _1-6 -AlCy! Group, the preferred meaning is methyl, ethyl, isopropyl or t-butyl. 30th

A C_, acyl is an aliphatic carboxylic acid

Acyl group, for example C "_ ₄ alkanoyl.

If one or more of the radicals R., / R ₂ / R ₃ and R C _.- acyl, then it is preferably acetyl or propionyl.

If one or more of the radicals R-, R ₂ , R ₃ and R. denote a C__ ₄ acylamino group, then it is preferably acetylamino or propionylamino.

If one or more of the radicals R ₁ , R ₃ , R ₃ and R. are -SR ¹ , this means, for example, -SH or -S (C _1-4 ) alkyl and in particular methylthio, ethylthio or isopropylthio.

If one or more of the radicals R ₁ , R ₀ , R_ and R. -NC ^ pn are then preferably -NH ₉ , -NHCH ₃ , -NHC ₃ H ₅ , -N (CH ₃ J ₃ or -N (C ₂ H ₅ ) ₂ .

If one or more of the radicals R ₁ , R ₂ , R ₃ and R _{4 is} -CH ₃ OR ¹ , then it is preferably -CH ₂ OH, -CH ₂ OCH ₃ or -CH ₂ OC ₃ H ₅ .

If one or more of the radicals R., R ₂ , R ₃ and R ₄ -COOR ^{1 are} then it is preferably carboxy or C, ₄ -alkoxycarbonyl and in particular methoxycarbonyl or ethoxycarbonyl.

Mean one or more of the radicals R _1, R _0, R_ and R ₄ is -CON ^- C ^ "then it is preferably aminocarbonyl or di (C ₁ _.- alkyl) amino-carbonyl, in particular

around dimethylamino-carbonyl or diethylamino-carbonyl.

If one or more of the radicals R ₁ , R ₀ , R 1 and R. --CH ₂ COOR ¹ , then the meaning is preferably carboxymethyl or C ₁ _ ₂ -alkoxycarbonylmethyl and in particular methoxycarbonylmethyl or ethoxycarbonylmethyl.

One or more of the radicals R ₁ , R ₀ , R ^ and

JJl I * ^J

R ₀ CONC -CH ^ r. ,,, then the importance preferably aminocarbonylmethyl or di (C _1.) Alkyl-aminocarbonylmethyl, particularly dimethylamino or diethylamino carbonylmethyl-carbonylmethyl.

One or more of the radicals R ₁ , R ₀ , R-. and R ₄ -PO (OR ') ₂ , then the meaning is preferably -PO (OH) ₂ or -PO (OCH ₃ ) or -PO (OC ₂ H ₅ J _2. Preferably three of the radicals R ₁ , R _{2 are} , R ₃ and R _{4 are} hydrogen. Preferred compounds of the present invention are compounds of the formula (I) in which one of the radicals R ₁ , R ₀ , R- and R is a substituent which is independently selected from the following groups: C _0th-acyl, CH ₀ OR ^1, -CON ^ !,, -CH ^ ₀ N, ', -COOR', -PO (OR ¹⁾ -, -CH _o C0N <C _D "and -CH ₀ COOR ', where R' and R "are independently hydrogen or C. .. -alkyl and the remaining radicals R ₁ , R ₃ , R ₃ and R _{4 are} hydrogen and the pharmaceutically acceptable salts are included.

Examples of preferred compounds according to the invention are:

(1) 2- (1-imidazolyl) -6-acetyl-3,4-dihydro-2H-1-benzothiopyran,

(2) 2- (1-imidazolyl) -6-carboxy-3,4-dihydro-2H-1-benzothiopyran,

(3) 2- (1-imidazolyl) -7-carboxy-3,4-dihydro-2H-1-benzothiopyran ,

(4) 2- (1-imidazolyl) -6-hydroxymethyl-3,4-dihydro-2H-1-benzothiopyran,

(5) 2- (1-imidazolyl) -e-ethoxycarbonyl-S ^ -dihydro ^ H-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) -obenzothiopyran,

as well as pharmaceutically acceptable salts thereof.

The compounds according to the invention and their salts can be prepared by adding a compound of the general formula (II)
30th

(II)

wherein R-, R ₂ , R- and R. have the meanings given above, reacts with a reactive derivative of an imidazole and, if desired, converts a compound of the formula (I) into another compound of the formula (I) and / or, if desired, a compound of the formula (I) is converted into a salt and / or, if desired, a salt is converted into the free compound and / or, if desired, a mixture of the isomers of the compounds of the formula (I) is separated into the individual isomers.

A reactive derivative of the imidazole is, for example, an N- (trialkyl-silyl) -imidazole, preferably a N- (C, - Trialkyl-silyl) -imidazole and in particular N- (trimethyl-silyl) -imidazole or N- (t-butyl-dimethylsilyl) -imidazole.

The reaction between a compound of the formula (II) and a reactive imidazole derivative is preferably carried out in a temperature range between 120 and 200 ⁰ C and preferably about 150 and 175 ⁰ C and, if necessary, in the presence of a suitable aprotic, organic solvent, preferably of "dimethylacetamide or Dimethylformamide The reaction time is in the range from 2 to about 16 hours and

preferably about 5 to about 10 hours.

Alternatively, the process can also be carried out by mixing a compound of the formula (II) with imidazole and a suitable silylating agent, preferably bis (trimethylsilyl) urea or hexamethyldisilazane with formation of N- (trialkyl-silyl) -imazole treated in situ. The compounds of formula (II) are known compounds or they can be prepared from known compounds by known methods, e.g., by oxidizing the corresponding 3,4-dihydro-2H-1-benzothiopyrans of the formula (III)

! i ί

(HI)

wherein R _1, R ,, R, and R. have the meanings given previously, with a suitable oxidizing agent, preferably by treatment with hydrogen peroxide in acetic acid at a temperature ranging from about -20 to about + 5O ⁰ C or with sodium metaperiodate or with t-butyl hypochlorite in a suitable solvent, for example, a C.. alkyl alcohol, especially methanol or water or mixtures thereof, and preferably a mixture of methanol / water, at a temperature in the range of about -20 to about +50 ⁰ C .
30th

• A compound of the formula (I) can, if desired

converted into another compound of formula (I).

These possible conversions can be carried out in a manner known per se.

For example, one can use a compound of the formula (I) - in which one or more of the radicals R-. , R ₂ / R ₃ and R. are hydrogen, in a compound of the formula

(I) convert, in which one or more of the radicals R-, R ₂ , R ₃ and R. mean a halogen atom, for example chlorine or bromine, by reacting with chlorine or bromine in the presence of a Friedel-Crafts catalyst, preferably AlCl ₃ , and in doing so in a suitable solvent, such as CH ₂ Cl ₃ , works.

A compound of the formula (I) in which one or more of the radicals R ₁ , R ₃ , R ₃ and R _{4 are} hydrogen can be converted into a compound of the formula (I) in which one or more of the radicals R ₁ , R ₀ , R ₀ and R. C _{1 c} -

I Z ο 4 1 — O

Mean alkyl, be converted by carrying out an alkylation by means of a Friedel-Crafts reaction, e.g. repositioning with

(a) a C1-4 alkyl halide, preferably Chloride, bromide or iodide, or

(b) a C, g-aliphatic alcohol in a suitable solvent, for example nitrobenzene or CH ₃ Cl ₂ or CS ₃ .

Both in case (a) and in case (b), the reaction is carried out in the presence of a suitable amount of a Friedel-Crafts catalyst, such as AlCl, ZnCl_ or BF ₀ , and, if a C ₁ - aliphatic alcohol is used, also in the presence a strong mineral acid such as HF, HClO. or, if desired, in concentrated H ₂ SO. or in concentrated H-PO. without additional solvent, the temperature ranging from room temperature to 100 ⁰ C.

Mean a compound of formula (I) in which one or more of the radicals R .., R _2, R, and R. C. _ _ß an alkoxy group, can be converted into a compound of formula (I) in which one or several of the radicals R, R_, R ₃ and R. mean a hydroxyl group, can be converted by using conventional methods of organic chemistry. For example, a treatment with a strong mineral acid, for example with HCl, HBr, HI, preferably HBr, can be carried out at a temperature in the range from 30 ^° C. to the reflux temperature and preferably at the reflux temperature, or a treatment with a Lewis acid, make, for example, AlCl ₃ or BF _3, in a suitable solvent, eg CH ₂ Cl _3, or nitrobenzene, at a temperature between room temperature and 8O ⁰ C. A compound of the formula (I) which contains an esterified carboxy group or an esterified phosphono group can be converted into a compound of the formula (I) which contains a free carboxy group or a free phosphono group by either acidic or alkaline hydrolysis, whereby one in a temperature range between

Room temperature and about 10O ⁰ C works.

A compound of the formula (I) with a free carboxy group or a free phosphono group can be converted into a compound of the formula (I) containing an esterified carboxy group or an esterified phosphono group by carrying out an esterification, for example using the corresponding acid halide , for example chloride, or by reaction with an excess of a suitable C, _g -alkyl alcohol or by direct esterification by means of acid catalysis, for example in the presence of dry HCl or SOCl ₂ or a BF_-etherate.

A compound of the formula (I) containing a carbamoyl group can be converted into a compound of the formula (I) containing a free carboxy group by means of hydrolysis and preferably by means of acid hydrolysis in a suitable solvent such as water, or by means of bouveault Conversion, ie by treatment with NaNO ₂ in an aqueous strong, inorganic acid, for example H ~ SO., ^{Working in a temperature range between room temperature and 100 °} C.

A compound of the formula (I) containing a free or esterified carboxy group can be converted into a compound of the formula (I) containing a -CONd ₁₃₁₁ -GrUpPe,

ti

are converted, in which R ¹ and R "have the meanings given above.

The conversion of the esterified carboxy group into the corresponding amide can be carried out by a direct reaction with Ammonia or a suitable amine in a suitable solvent such as ether or benzene using an excess of the amine as a solvent and using the temperature is between room temperature and reflux temperature.

The conversion of the free carboxy group into a corresponding amide is via an intermediate product resulting reactive derivative, which may or may not be isolated, carried out.

Reactive intermediates can be active esters, e.g. NO ₂ phenyl esters or N-hydroxysuccinimide esters, acid halides, preferably chlorides, mixed anhydrides, e.g. ethoxycarbonyl or t-butylcarbony anhydrides, or the reactive intermediates that can be obtained in situ by reacting the acid with Dicyclohexylcarbodiimide or carbonyldiimidazole.

The reactive intermediates, which have been obtained in a conventional manner, for example by reactions such as those used in the synthesis of peptides, with ammonia or a suitable amine in a suitable solvent or with an excess of the amine itself at a temperature in the range of about -10 to about 5O ⁰ C.

A compound of the formula (I) in which one of the radicals R ₁ , R ₂ , R ₃ and R. is a free or esterified carboxy group, in particular a lower alkoxycarbonyl group,

can be converted into a compound of the formula (I) in which one of the radicals R, R ₂ , R ₃ and R _{4 is} a CH ^ OH group, by carrying out a reduction in the usual way, for example with LiAlH ₄ , in a suitable solvent, for example ethyl ether or THF.

The conversion of a compound of the formula (I) into a salt or the conversion of the salt into the free one The connection or the separation of an isomer mixture into the individual isomers can be carried out in the customary manner.

In the compounds of the formulas (I) and (II), groups are present during the aforementioned reactions must be protected, e.g. amino groups,

Hydroxy groups or carboxyl groups, such groups can be added in the usual way - before the reaction takes place - protect. Examples of protective groups are those commonly used in peptide syntheses deten. For example, acetyl, benzoyl, t-butoxycarbonyl, p-methoxy, benzyloxycarbonyl, o-nitrophenylsulfonyl or dichloroacetyl protecting groups use.'

to protect hydroxyl groups, for example

Acetyl, benzoyl, benzyloxy, tetrahydropyranyl: ß-methoxyethoxymethyl (MEM) - or a trialkylsilyl \ group, eg t-butyldimethylsilyl apply.

To protect the carboxy groups, for example, the t-butyl group, the benzhydry group and the p-methoxy benzyl group suitable.

JNSPECTED

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

The amino, carboxy and hydroxy protective groups are then after the reaction, generally in itself known way, removed. If the amino protective group is, for example, the monochloroacetyl group, then they can be removed by treatment with thiourea, and the formyl and trifluoroacetyl groups can be removed by treating with potassium carbonate in aqueous methanol while removing the trityl group Treating with formic acid or trifluoroacetic acid removed.

The carboxy protective groups can be used, for example, by mild acidic hydrolysis or by catalytic Remove hydrogenation, e.g. with Pd / C at room temperature.

The hydroxy protecting groups can, for example, under mild reaction conditions, for example by a acid hydrolysis, remove.

The compounds according to the invention are selective _{inhibitors of thromboxane A 2} (TxA «) synthetase and therefore increase the ratio between prostacyclin (PGIp) and TxA1 levels. The activity of TxA ^ and PGIp synthetase was examined in vivo. So were

for example rats treated with single oral doses of the compound and killed 2 hours later. Then TxB "and 6-keto-PGF .., concentrations, the stable metabolites of TxA ₂ and PGF", were examined in the serum and in the plasma, respectively.

For example, the compound 2- (1-imidazolyl) 6-acetyl-3,4-dihydro-2H-1-benzothiopyran significantly reduces the serum TxB ₂ concentration and significantly increases the 6-keto-PGF. . -Concentration.

In most tissues, the major products of arachidonic acid metabolism are PGI ₂ and TxA _2, and their ratio plays a paramount role in vascular hemostasis. PGI ₂ has anti-aggregation and vasodilatory activity, while TxA _{2 is} a proaggator (or aggregator) and vasoconstrictor. The enzyme PGI ₂ ~ synthetase is mainly located in the endothelial cells and forms PGI ₂ , whereby the

Adhesion of platelets to the arterial walls and the formation of thrombi can be avoided and it exhibit vasodilatory activity.

The enzyme TxA ^ synthetase, on the other hand, is major Localized in the platelets and forms TxA_, causing blood clots through the formation of platelet aggregates and vasoconstriction are established.

By balancing the opposing activities, vascular hemostasis can be monitored.

Since the compounds according to the invention are able to selectively _{inhibit the formation of TxA 2} , they can be used as vasodilatory and anti-aggregating agents, for example in all cases of thrombosis, peripheral vasculopathies and coronary artery diseases. Indeed, by inhibiting TxA ^ formation, the possibility of thrombus formation and vasoconstriction that result in ischemic disease is decreased and the PGIp production unchanged (or increased), thereby causing vasodilation, blood supply and the Protection of the vessel walls can be improved.

Another application of the compounds according to the invention is to combat migraines. It is known that a migraine has a diffuse vasoconstriction which is induced by an overproduction of platelet TxA_ (J. Clin. Pathol. (1971), 2 ±, 250; J Headache (1977), V7, 101).

An overproduction of platelets of TxA_ and MDA, ie malondialdehyde in diabetes mellitus, is associated with microcirculatory defects (Metabolism (1979), 28, 394; Eu. J. Clin. Invest. (1979), 9_, 223; Thrombosis Haemost. (1979 ), 4J2, 983; J. Lab. Clin. Med. (1981), ST_, 87).

The compounds according to the invention can therefore be used in the treatment of diabetic microangiopatias use. Furthermore, the compounds according to the invention are also anti-inflammatory agents. It is

known that, for example, a fluid obtained from a carrageenin-induced granuloma converts arachidonic acid into TxA ₂ in vitro and that TxA ₂ levels are increased in the synovial fluid of patients suffering from rheumatic arthritis and in the fluid of carraggenin-induced patients Inflammation in rats (Prostaglandins (1977), V3f 17; Scand. J. Theum. (1977), £, 151).

It has recently also been shown that there is an overproduction of TxA ₂ in the pathogenesis of hypertension and that a specific inhibitor of TxA ₂ formation can be used to eliminate this factor in hypertension (Eu. J. Pharmacol. (1981), 7 £, 247).

In fact, the compounds according to the invention can be used use as antihypertensive compounds.

It has also been found that TxA _{2 plays} a role in the pathogenesis of ulcerative disorders in the stomach, specifically in connection with its powerful gastric vasoconstrictive activity, so that a TxA ₂ inhibitor is also useful in this area (Nature (1981), 292 , 472). In fact, the compounds according to the invention can also be used for the treatment of gastric ulcers.

Furthermore, the compounds according to the invention are also anti-tumor agents.

It is known, for example, that the selective inhibition of TxA ₂ synthesis increases the number of lung metastases

decreased and tumor growth slowed down (Natur (1982), ^ 95_, 188).

Due to the connection between TxA ₂ synthesis and calcium transport, some authors have recently shown that specific TxA ₂ synthetase inhibitors, such as the compounds according to the invention, are also suitable for the treatment of osteoporosis, e.g. of postmenopausal osteoporosis (Prostaglandins (1981), 2J_ , 401).

Finally, there are the compounds according to the invention also suitable for the treatment of anginopectoris.

in this connection it is known that high levels of TxB _{2 occur} in patients suffering from Prinzmetal's angina (Prostaglandins and Med. (1979), 2 ^, 243). as well as in patients with repeated angina attacks (6th International Congress on Thrombosis, Monte Carlo, October 1980 Paragraph 140).

The dosage level for oral administration in adult humans is that of the present invention Compounds, e.g. for 2- (1-imidazolyl) -6-carboxy-3,4-dihydro-2H-1-benzothiopyran, about 5 to about 500 mg when administered 1 to 3 times daily and preferably about 20 to about 150 mg incidental to 3 times daily administration, depending on the disease, the Age and weight of each patient.

■ The toxicity of the compounds according to the invention is

negligible and therefore they can be used therapeutically very safely. Mice and rats that 9 hours who had fasted were treated orally with single doses in increasing doses and then continued normally nourished. Orienting acute toxicity

(LD ₅₀ ) was examined 7 days after treatment and found 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 or tablets coated with sugar or a film, as liquid solutions or suspensions, rectally in the form of suppositories, and parenterally, e.g. intermuscularly, or else by intravenous infusions or injections. In an emergency, intravenous injections are preferred. As already mentioned, the exact dose depends on the illness, age, weight and condition of the patient as well as the route of administration. The invention also relates to the pharmaceutical compositions from one of the compounds according to the invention in combination with a pharmaceutically suitable one Carrier or diluent.

The pharmaceutical compositions with the compounds according to the invention are prepared by customary methods, as used in the pharmaceutical industry.

For example, solid, orally administrable forms can be used together with the active compound diluent

contain agents, for example lactose, dextrose, sucrose, cellulose, corn starch or potato starch; or lubricants, for example silicon dioxide _K talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; and binders, for example starch, gum arabic, gelatin, methyl cellulose, carboxyethyl cellulose or polyvinylpyrrolidone; or disintegrants, for example starch, alginic acid, alginates or sodium starch glycolate; or foaming mixtures; Dyes; sweeteners; Humectants such as lecithin, polysorbate, lauryl sulfate; and, in general, non-toxic and pharmacologically inactive substances such as those used in pharmaceutical formulations. These pharmaceutical preparations can be produced in a known manner, for example by mixing, granulating, tabletting, coating with sugar or coating with a film.

Liquid dispersions for oral administration can be, for example, syrups, emulsions or suspensions be. The syrups can, for example, as a carrier sucrose or sucrose with glycerol and / or Contain mannitol and / or sorbitol, in particular a syrup to be administered to diabetics, contains as a carrier only those products that do not metabolize to glucose or only to a very small extent Mass are metabolized, e.g. sorbitol.

The suspensions or emulsions can be used as carriers, for example, natural resins, agar, sodium alginate, pectin, Methyl cellulose, carboxymethyl cellulose or

Contain polyvinyl alcohol. The suspensions or solutions for intramuscular injections can be used together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, Glycols such as propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride .

Solutions for intravenous injections or infusions can, for example, contain sterile water as a carrier and they preferably contain a sterile aqueous, isotonic saline solution.

In addition to the active compound, suppositories can be used as pharmaceutically acceptable carriers, for example cocoa butter, Contain polyethylene glycol, a polyoxyethylene sorbitol fatty acid ester or lecithin.

The NMR spectrum is preferably measured in a solution of dimethyl sulfoxide-dg or CDCl ₃ using a 90 M Hertz Bruker HFX apparatus.

The Rf values are determined by thin layer chromatography determined on finished silica gel plates with a coating thickness of 0.25 mm.

The following examples describe the invention.

example 1

A mixture of 1.1 g (0.0052 mol) 6-carboxy-3,4-dihydro-2H-1-benzothiopyran-S-oxide, F: 190 to 192 ⁰ C (produced by oxidation of the corresponding thiochroman with hydrogen peroxide / acetic acid) and 1.1 ml ■ (0.026 mol) of trimethyl-silyl-imidazole was heated for 8 hours under stirring to 17O ⁰ C.

After the mixture was cooled, it was poured into water, acidified with acetic acid and with ethyl acetate washed.

The aqueous solution was evaporated in vacuo, then absolute ethanol (2 × 50 ml) was added and then was again evaporated to dryness.

The crude product was chromatographed over silica gel (Eluent chloroform: methanol: acetic acid 90: 10: 1), whereby 0.65 g of 2- (1-imidazolyl) -ö-carboxy-S ^ -dihydro-2H-1-benzothiopyran, F: 256-258 ° C.

Elemental analysis for C ₁₃ H ₁₂ N ₂ O ₂ S 25

found : C. 59 , 15 H 4th , 70 N 10 , 65 S. 12th , 15 calculated: 59 , 98 4th , 67 10 , 76 12th , 31

Thin layer chromatography: eluent CHCl ₃ : CH_OH: 30

CH ₃ COOH 90:10: 1; Rf = 0.38

■ NMR (DMSO-d ₆ ) <S ppm: 2.45 (2H, m, CH ₂ -CH ₂ -C

2.87 (2H, m, CH ₀ -CH ₀ -CHN)

6.17 (1H, t, S-CH-N) 6.95-7.80 (6H, m, aromatics + imidazoles).

Similarly, the following compounds were made:

2- (1-imidazolyl) -6-bromo-3,4-dihydro-2H-l-benzothiopyran, F: 131-133 ⁰ C;

Elemental analysis for

found: C 48.84 H 3.78 N 9.35 calcd: 48.82 3.75 9.49

Thin layer chromatography: eluent AcOEt + 2% conc. NH ₄ OH; Rf = 0.56
20th

• NMR (CDCl-.) 6 ppm: 2.38 (2H, m, CH ₀ -CH ₀ -CHN) 2.80 (2H, m, CH ₂ -CH-CHN) 5.71 (1H, m, S. -OH-N) 6.87-7.65 (6H, m, aromatics + imidazoles).

2- (1-imidazolyl) -3,4-dihydro-2H-1-benzothiopyran, F: 78-80 ⁰ C;

Elemental analysis for C _1. , H _{1 0 N_S}

Found: C 66.69 H 5.55 N 12.92 S 14.73 Calculated: 66.63 5.59 12.95 14.82 5

Thin layer chromatography: eluent CHCl ^: CH.J3H 195: 5; Rf = 0.3

NMR (CDCl.) 6 ppm: 2.1-3.0 (4H, m, CH ₀ -CH ₀ )
5.75 (1H, m, S-CH-N)

6.9-7.73 (7H, m, aromatics +
Imidazoles).

MS m / c: 216 (M ⁺ )

-, +

149 (M-N I)

2- (1-imidazolyl) -6-acetyl-3,4-dihydro-2H-1-benzothiopyran, F: 93-95 ⁰ C;

Elemental analysis for C ₁₄ H ₁₄ N ₃ OS

Found: C 64.15 H 5.38 N 10.37 S 12.09 Calculated: 65.09 5.46 10.84 12.41

Thin layer chromatography: eluent AcOEt + 1%
conc. NH ₄ OH; Rf = 0.25
30th

■ NMR (CDCl ₃ ) & ppm: 2.50 (2H, m, CH ₂ -CH ₂ -CH-N)

2.57 (3H, 1, CH ₃ )

. ι.

- 29 -

2.90 (2Η, m, CH ₂ -CH ₂ -CH-N) 5.81 (1Η, dd, S-CH-N) 7.20-7.70 (6H, m, aromatics + imidazoles).

2- (1-imidazolyl) -7-carboxy-3,4-dihydro-2H-1-benzothiopyran; 10

2- (1-imidazolyl) -e-hydroxymethyl-S, 4-dihydro-2H-1-benzothiopyran;

2- (1-imidazolyl) -e-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 . 25th

Example 2

Tablets each weighing 150 mg and • containing 50 mg of the active ingredient manufactured as follows:

Composition ^ (for_10 ^ 000 tablets)

2- (1-imidazolyl) -6-acetyl-3,4-dihydro-

2H-1-benzothipyran 500 g

Lactose 710 g

Corn starch 237.5 g

Talc powder 37.5 g

Magnesia stearate 15 g

2- (1-imidazolyl) -6-acetyl-3,4-dihydro-2H-1-benzothiopyran, Lactose and half of the corn starch were mixed together and then the mixture became passed through a sieve with 0.5 mm openings.

18g of corn starch was suspended in 180 ml of warm water obtained paste was used to granulate the powder. The granules were dried on crushed a sieve a size of 1.4 mm and then the remaining amount of starch, talc and magnesium was added and the whole was mixed carefully and processed into tablets in a tablet press with a diameter of 8 mm.

Example 3

2- (1-imidazolyl) -3,4-dihydro-6-bromo-2H-1-benzothiopyran was treated with the stoichiometric amount of hydrochloric acid, with 2- (1-imidazolyl) -3,4-dihydro-6-bromo-2H-1-benzothiopyran hydrochloride received.

Claims (6)

HOFFMANN · ÖITLE & -PARTNEi =? . \ PATENT AND LAWYERS 3519432 ** PATENTANWÄLTE DIPL.-ING. W. EITLE. DR. RER. NAT. K. HOFFMANN. DIPL.-1NQ. W. LEHN DlPL.-INe. K. FDCHSLE. DR. RER. NAT. B. HANSEN · DR. RER. NAT. HA. BRAUNS DIPL.-ΙΝΘ. K. GDRa DIPL-INe. K. KOHLMANN · LAWYER A. NETTE 41 885 o / wa - 1 - FARMITALIA CARLO ERBA S.p.A., MILAN / ITALY N-imidazolyl derivatives, processes for their preparation and pharmaceuticals containing them PATENT CLAIMS Q- Imidazolyl compound of the general formula (I) (D where mean: R ₁ , R ₉ , R_ and R., which can be the same or different, are each hydrogen, hydroxy, halogen, ARABELLA STREET 4. D-8OOO MUNICH 81 TELEPHONE CO893 811087 TELEX 5-29619 CPATHEJ. TELECOPER 918358 Cyano, C ^ ₆ -alkyl, C,, .- alkoxy, a C ₂ _.- acyl or C -.- acylamino group, -SR ¹ , -NC ,,,, -CH ₂ OR ¹ , -COOR ¹ , -C0N <2n, -CH ₀ N ^ ₁ ', TPO (OR ¹ ) ,, -CH ₀ COOR ¹ , T;,., Where R ¹ and R ", which can be the same or different, are each hydrogen or C,, .- alkyl, as well as pharmaceutically acceptable salts thereof. 2. A compound of the formula (I) according to claim 1, characterized in that one of the substituents R., R ₃ , R ₃ and R _{4 is} a substituent which has been selected from the group C ₂ _ ₄ acyl, CH ₂ OR ¹ , -CONC ^ !, -CH ^^,, -COOR ', -PO (OR ¹ ) ₂ , -CH ₂ CON ^ !, and -CH ₂ COOR ¹ , wherein R ¹ \ and R "independently of one another are hydrogen or C, - alkyl and the remaining radicals R ₁ , R-, R_ and R. mean hydrogen, as well as pharmaceutically acceptable salts thereof. 20th 3rd connection, selected from the group: 2- (1-imidazolyl) -6-acetyl-3,4-dihydro-2H-1-benzothiopyran,
25th 2- (1-imidazolyl) -6-carboxy-3,4-dihydro-2H-1-benzo thiopyran, 2- (1-imidazolyl) -7-carboxy-3,4-dihydro-2H-1-benzo thiopyran, 2- (1-Imidazoly1) -S-hydroxymethyl-3,4-dihydro-2H-1-benzothiopyran , 2- (1-imidazolyl) -e-ethoxycarbonyl-3,4-dihydro-2H-1-benzothiopyran, 2- (1-imidazolyl) -o-carbamoyl-S, 4-dihydro-2H-1-benzothiopyran, 2- (1-imidazolyl) -ö-aminomethyl-S, 4-dihydro-2H-1-benzothiopyran, 2- (1-imidazolyl) -6-phosphono-3,4-dihydro-2H-1- benzothiopyran,
15th as well as pharmaceutically acceptable salts thereof. f 4. Process for producing a compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that a compound of the general formula (II) R. "I Il I (ID wherein R ₁ , R ₂ , R ₃ and R _{4 have} the meanings given in claim 1, with a reactive derivative 35 Ί 9432 of an imidazole and, if desired, a compound of the formula (I) into another compound of the formula (I) and / or, if desired, a compound of the formula (I) into a Salt transferred and / or, if desired, a salt converted into the free compound and / or, if desired, a mixture of the isomers of the compound of the formula (I) is separated into the individual isomers.
10 5. Medicaments containing a compound of the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof together with a suitable carrier and / or diluent. 6. Medicament according to claim 5 for use as a selective inhibitor of thromboxane A2.