IE911619A1 - Substituted 3-aminosydnone imines, processes for their¹preparation and their use - Google Patents

Abstract

Substituted 3-aminosydnone imines of the formula I and their pharmacologically acceptable acid addition salts, in which A denotes the -SO- radical, R<1> denotes the -COR<2> radical or hydrogen, R<2>, for example, denotes (C1 to C4)alkyl, have useful pharmacological properties and can be prepared by reacting a compound of the formula I in which A denotes -S- with an oxygen-donating substance.

Description

-Substituted 3-aminosvdnone imines, processes for their preparation and their use The invention relates to pharmacologically active substituted 3-aminosydnone imines of the general formula I CH / A \ CH 2 \ N/ 2-CH2 N-CH I * I ^C=N-R (I) and their pharmacologically acceptable acid addition salts, in which A denotes the radical -SO-, R1 denotes the radical -CO-R2 or hydrogen, R2 denotes (Ci to C4)alkyl, (Cx to C,,)alkoxy-(Cx to C4)alkyl, (Cx to C4)alkoxy, (C5 to C7)cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.

The invention furthermore relates to processes for the preparation of the compounds according to the invention and to their use.

Alkyl radicals, alkoxyalkyl radicals and alkoxy radicals may be straight-chain or branched. This also applies if they occur as substituents of phenyl.

(Cx to C4)alkyl radicals may be: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl and sec.-butyl. Examples of (Cx to C4)alkoxy radicals may be: methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec.-butoxy and tert.-butoxy.

(Cx to C4) alkoxy-(Cx to C4) alkyl radicals may be, for examples methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, i-butoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 430 methoxybutyl, 2-ethoxyethyl, 3-propoxypropyl, 4-propoxybutyl, 2butoxyethyl, 3-butoxypropyl, 4-butoxybutyl, 3-i-propoxypropyl, . XA *-i-propoxybutyl, 2-ethoxyethyl, 2-propoxyethyl, 2-i-propoxyethyl, 2-butoxyethyl, 2-i-butoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 2propoxypropyl, 2-i-propoxypropyl, 3-methoxybutyl, 3-ethoxybutyl, 3-propoxybutyl, 3-i-propoxybutyl, 3-butoxybutyl, 3-i-butoxybutyl, 3-tert.-butoxybutyl, 2-methoxybutyl, 2-ethoxybutyl, 2-propoxybutyl, 2-i-propoxybutyl, 2-butoxybutyl and 2-i-butoxybutyl.

Of the (C5 to C7)cycloalkyl radicals, cyclopentyl and cyclohexyl are preferred.

Possible halogen atoms for the substituted phenyl radical are fluorine, chlorine, bromine and/or iodine, of which bromine and chlorine are preferred.

R2 preferably denotes (Cx to C4)alkyl, (Cx to C4)alkoxy, phenyl, or phenyl which is monosubstituted by chlorine, methyl or methoxy, monosubstituted phenyl preferably being substituted in the 4- or 2-position.

Hydrogen is preferred for R1. Preferred compounds are: Np-anisoyl-3-(3,3-dimethylperhydro-1-oxo-1,4-thiazin-4-yl)sydnone imine, N-ethoxycarbonyl-3-(3,3-dimethylperhydro-l-oxo20 1,4-thiazin-4-yl)sydnone imine and N-pivaloyl-3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin-4-yl)sydnone imine and the pharmacologically acceptable acid addition salts of the abovementioned compounds, in particular their hydrochlorides, and the pharmacologically acceptable acid addition salts, in particular the hydrochloride, of the compound: 3-(3,3-dimethylperhydro1-oxo-l,4-thiazin-4-yl)sydnone imine.

A compound of the general formula I can be prepared by cyclising a compound of the general formula II CH.

CH CH\3/ 3 -C \ N/ -CH-N-CH--CN I 2 NO (II) in which A has the meaning already mentioned, to give a compound of the general formula la CH / A \ CH CH CH., \3/ 3 -C \ N/ —CH2 (la) N-CH I * I N C=NH \ / and isolating the compound obtained as the acid addition salt, or in the case in which it is intended to prepare a compound of the formula I where R1 = -COR2, acylating the compound la or an acid addition salt thereof with an acylating agent which introduces the radical -COR2, and isolating the compound thus obtained or, if desired, converting it into a pharmacologically acceptable acid addition salt, and isolating this.

The cyclisation of the compounds II to give the compounds 10 la can be carried out in a suitable organic or inorganic solvent, dispersant or diluent with the addition of a cyclising agent, normally at temperatures from -10 to 40°C, in particular 0 to 40°C, preferably at 0 to 20°C.

Suitable cyclising agents are those which establish a pH 15 below 3 in aqueous solution, that is to say, for example, mineral acids, such as sulphuric, nitric or phosphoric acid, preferably hydrogen chloride, but also strong organic acids, such as trifluoroacetic acid. The cyclisation is normally carried out with ice-cooling. 0.1 to 10 mol, preferably 1 to 5 mol, of the cyclising agents are used, for example, relative to 1 mol of the compound of the formula II. The cyclising agent is normally employed in excess. The use of hydrogen chloride as a cyclising agent is particularly convenient, and it is normally passed into the reaction mixture until it is saturated. The corresponding acid addition salt of the compound la is normally obtained in the cyclisation.

Suitable solvents, dispersants or diluents are, for example: alcohols, for example those having 1 to 8 C atoms, in particular those having 1 to 6 C atoms, preferably those having 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and npropanol, i-, sec- and tert-butanol, η-, i-, sec- and inol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture) and benzyl alcohol; ethers, in particular those having 2 to 8 C atoms in the molecule, such as, for example, diethyl ether, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether, methyl tert-butyl ether, ethyl propyl ether, di-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and bis-^-methoxyethyl ether; oligoethylene glycol dimethyl ethers, such as, for example, tetraglyme or pentaglyme; alkyl carboxylates, in particular those having 2 to 10 C atoms in the molecule, such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate or methyl, ethyl or butyl propionate; ketones, in parti15 cular those having 3 to 10 C atoms in the molecule, such as, for example, acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl ketone, 2-hexanone, 3-hexanone, di-n-propyl ketone, diiso-propyl ketone, di-iso-butyl ketone, cyclopentanone, cyclohexanone, methylcyclohexanone, dimethylcyclohexanone, benzophen20 one and acetophenone; aliphatic hydrocarbons, such as, for example, hexane and heptane, low- and high-boiling petroleum ethers, petroleum spirits and white spirit; cycloaliphatic hydrocarbons, such as, for example, cyclopentane, cyclohexane, methylcyclohexane, tetralin and decalin; aromatic hydrocarbons, such as, for example, benzene, toluene, ο-, m- and p-xylene, and ethylbenzene; halogenated aliphatic or aromatic hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; hexamethylphosphoramide; sulphoxides, such as, for example, dimethyl sulphoxide; tetramethylene sulphone; and water. Mixtures of different solvents or dispersants may also be used, for example water-methanol or, preferably, ethyl acetatemethanol .

The acylation of the compound of the formula la, which may also be present in the form of an acid addition salt, in order to introduce the radical R1 = -COR2 can be carried out in a manner known per se using a suitable acylating agent of the (III) formula τιι in which X represents a radical which can be removed nucleophilically.

In the formula III, X, for example, in particular denotes halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular having 1 to 5 C atoms; -O-aryl, the aryl radical in particular being a phenyl radical which may also be mono- or polysubstituted by alkyl, in particular methyl, and/or nitro, and is, for ex10 ample, a tolyl, dinitrophenyl or nitrophenyl radical; -O-CO-R2; -O-CO-O-alkyl, in particular having 1 to 5 C atoms in the alkyl radical, or the radical of an azole or benzazole which has at least 2 N atoms in the quasi-aromatic 5-membered ring and is bonded via an N atom.

The acylation is expediently carried out in a liquid or liquid disperse phase in the presence of an inert solvent, dispersant or diluent or in an excess of the acylating agent, expediently with stirring.

In the acylation, the molar ratio between the compound of the formula la and the acylating agent of the formula III is theoretically 1:1. However, the acylating agent can also be employed in excess or in a sub-equivalent amount. The acylating agent of the formula III is expediently employed in excess. Excesses of up to 30 mol% are usually sufficient, i.e. the molar ratio between the compound of the formula la and the acylating agent of the formula III is normally 1 : (1 to 1.3), preferably 1 : (1 co 1.2). If an acid is eliminated in the acylation reaction, the addition of an acid scavenger, such as, for example, an alkali metal hydroxide, such as, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide, a tertiary organic amine, such as, for example, pyridine or triethylamine, an alkali metal carbonate or alkali metal bicarbonate, such as, for example, sodium carbonate or sodium bicarbonate, or an alkali metal salt of a weak organic acid, such as, for example, sodium acetate, is expedient. Suitable catalysts, such as, for example, IE 911619 tninopyridine, may also be added during the acylation xcau LlUIl.

The acylation may in principle be carried out at temperatures between -10°C and the boiling point of the solvent, dispersant or diluent used. In many cases, the reaction is carried out at 0 to 50°C, in particular at 0 to 30"C and preferably at room temperature.

The compounds of the formula III are acylating agents and thus represent, for example: for X = halogen: acid halides or haloformic acid esters, of which acid chlorides and chloroformic acid esters are preferred; for -OH: carboxylic acids; for -O-alkyl and -0-aryl: esters, of which the tolyl, 2,4-dinitro- or 4-nitrophenyl esters are preferred; for -O-CO-R: anhydrides; for -O-CO-O-alkyl; mixed carboxylic acid/carbonic acid anhydrides; or heterocyclic amides or azolides, in particular of N,N'-carbonyldiazoles, such as, for example, Ν,Ν'-carbonyldiimidazole, 2,2'carbonyl-1,2,3-ditriazole, 1,1'-carbonyl-1,2,4-ditriazole, N,N'carbonyldipyrazole and 2,2'-carbonylditriazole (compare, for example, H.A. Staab, M. Lucking and F.H. Durr, Chem. Ber. 95, (1962), 1275 et seq., H.A. Staab and A. Mannschreck, Chem. Ber. 95, (1962), 1284 et seq.; H.A. Staab and W. Rohr, Synthesen mit heterocyclischen Amiden (Azoliden) [Syntheses with heterocyclic amides (azolides)] in Neuere Methoden der Praparativen Organischen Chemie [Newer methods of preparative organic chemistry], volume V, Verlag Chemie, 1967, p. 53 et seq., in particular pp. 65 to 69). The acylating agents of the formula III can be prepared by processes which are known per se.

When using a carboxylic acid as the acylating agent, the addition of an activating agent which has the object of increas30 ing or of activating the acylating potential of the carboxylic acid or of converting the carboxylic acid into a reactive carboxylic acid derivative of the formula III in situ or preferably shortly before the reaction with the compound of the formula Ia is expedient. Suitable activating agents of this type are, for example: N,N'-disubstituted carbodiimides, in particular if they contain at least one secondary or tertiary alkyl radical, such as, for example, diisopropyl, dicyclohexyl or N-methyl-N'-tert.6 t-jr x No. 43, 4943-4946), if desired in the presence of suitable catalysts, such as, for example, 4-dimethylaminopyridine. In addition, Ν,Ν'-carbonyldiazoles, such as, for example, N,N'carbonyldiimidazole, 2,2'-carbonyl-1,2,3-ditriazole, 1,1'-car15 bonyl-l,2,4-ditriazole, N,N'-carbonyldipyrazole, 2,2'-carbonylditetrazole, N,N'-carbonylbenzimidazole or N,N'-carbonylbenzotriazole are suitable as activating agents (compare, for example, ' H.A. Staab, M. Lucking and F.H. Durr, loc. cit; H.A. Staab and A. Mannschreck loc. cit.; H.A. Staab and W. Rohr loc. cit). The Ν,Ν'-carbonyldiazole used is frequently the commercially available N,N'-carbonyldiimidazole. However, the other N,N'-carbonylazoles are also easily accessible from the respective azole and phosgene.

In addition, suitable activating agents for carboxylic acids are: derivatives of oxalic acid, such as, for example, oxalyl chloride (compare, for example, GB Patent Specification 2,139,225) or Ν,Ν'-oxalyldiazoles, such as, for example, 1,1'oxalyldiimidazole, 1,1'-oxalyldi-1,2,4-triazole and 1,1'-oxalyldi-1,2,3,4-tetrazole (compare, for example, Shizuaka Murata, Bull. Chem. Soc. Jap. 57, 3597-3598 (1984)); methylethylphosphinic anhydride (compare, for example, German Offenlegungsschrift 3,101,427); diphosphorus tetraiodide (Chem. Lett. 1983. 449); dialkyl disulphite (Indian J. Chem. 21. 259 (1982)); or other reactive agents.

Suitable solvents, dispersants or diluents are, for example, those which have been mentioned for carrying out the cyclisation, and moreover also, for example, pyridine and amides, -----rur example, dimethylformamide. In addition to water, polar organic solvents, such as dimethylformamide, dimethyl sulphoxide or pyridine, are preferred for the acylation. Solvent mixtures, such as, for example, a mixture of water and methylene chloride, are also suitable.

The substituted 3-aminosydnone imines of the general formula I can form acid addition salts with inorganic or organic acids. Inorganic or organic acids are suitable for the formation of acid addition salts of this type. For the formation of pharmacologically acceptable acid addition salts, suitable acids are, for example: hydrogen chloride, hydrogen bromide, naphthalenedisulphonic acids, in particular 1,5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. The acid' addition salts may be prepared in a customary manner by combining the components, expediently in a suitable solvent or diluent.

The compounds of the formula la are unstable in the free form, but are isolated in the form of their acid addition salts. In the synthesis of the compounds of the formula la, the acid addition salts are normally obtained.

The starting compounds of the general formula II required may be prepared in a manner known per se by Strecker's aminonitrile synthesis from compounds of the general formula IV or their acid addition salts N—NH (IV) in which A has the meaning already mentioned, by reaction with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent or dispersant or solvent or dispersant mixture, for example in water, a compound of the general formula V CH / A \ CH CH CH. \3/ 3 2 \ N-NH / 2-CH2 CH2-CN (V) first being formed, which is converted by nitrosylation into the compound II. The nitrosylation is carried out in a known manner in a suitable solvent or dispersant or solvent or dispersant mix5 ture, for example in water, for example at temperatures of -10 to 10°C. The nitrous acid is in this case normally generated from an alkali metal nitrite, for example sodium nitrite, and hydrochloric acid. It is expedient to adjust the aqueous solution of the compound V to a pH of 1 to 3 with hydrochloric acid and to add the alkali metal nitrite dropwise in the form of an aqueous solution to the stirred and cooled solution. The solution of the compound II obtained here can be subjected directly to the cyclisation reaction. However, normally it is appropriate to take up the nitroso compound II in a suitable organic solvent first and to carry out the cyclisation to give the compound of the formula la in it, if desired after addition of a further solvent.

The compounds of the general formula IV can be prepared, starting from compounds of the general formula VI CH / A \ CH CH CH. \3/ 3 -C \ N—H / -CH„ (VI), by either a) nitrosylating a compound of the formula VI to give the Nnitroso compound VII and then reducing, expediently with lithium aluminium hydride: (vi) CH / A \ CH C\ N-NO / -CH2 CH, CH, \3/ 3 CH,-C / 2 \ (VII) CH 2 ( IV ) N—NH / 2 CH. or, in a manner known per se b) converting a compound of the formula VI into the urea derivative VIII with potassium cyanate in acidic medium, and then converting by means of oxidation with sodium hypochlorite by the Hoffmann degradation into the compound IV: C<3/CH3 zch2 C^ A N-H \ / CH2—CH2 KNCO CH 2C\3/CH3 CH2-CH2 \ N-CO-NH / 2 ( VI ) (VIII ) CH -c / 2 \ A N-CO-NH^ \ / 2 ch2-ch2 NaOCl 2 W3 CH-C / \ \ /" NH2 CH2-CH2 VI I I ) ( IV ) Compounds of the formula I according to the invention can also be prepared by reacting a compound of the formula I where A = —S— or an acid addition salt of such a compound, with an oxygen-donating substance and converting the compound obtained, if desired, into an acid addition salt and isolating it, or in the case in which a compound of the formula la has been obtained and it is intended to prepare a compound of the formula I where A = -SO- and R2 = -COR2, acylating the compound la or an acid addition salt thereof with an acylating agent which introduces the radical -COR2 and isolating the compound thus obtained or, if IE 911619 averting it into a pharmacologically acceptable acid addition salt and isolating this.

Examples of suitable oxygen-donating substances which may be mentioned are: hydrogen peroxide, peroxo acids, such as, for example, performic, peracetic, perbenzoic, m-chloroperbenzoic and perphthalic acid, and also diacyl peroxides. Mixtures of various oxygen-donating substances may also be used. The oxygen-donating substance is normally employed in the stoichiometrically necessary amount or in a slight excess to this stoichiometrically necessary amount. Larger excesses are avoided as otherwise the sulphone, i.e. a compond of the formula I where A = -SO2-, is formed. The reaction may expediently be carried out in a suitable solvent or dispersant or solvent or dispersant mixture, for example, at temperatures from 0°C, preferably from room temperature, up to the boiling point of the solvent or dispersant or solvent or dispersant mixture. Suitable solvents or dispersants are, for example, the ethers already mentioned, aliphatic, cycloaliphatic and aromatic hydrocarbons, halogenated aliphatic and aromatic hydrocarbons, water, but in particular lower carboxylic acids, such as formic or acetic acid.

An acylation with an acylating agent introducing the radical -COR2 to be carried out, if desired, after the reaction with the oxygen-donating agent is carried out in the manner already mentioned using an acylating agent of the formula III.

The conversion to be carried out, if desired, into the acid addition salt is carried out, as already mentioned above, in a manner known per se.

The compounds of the formula I where A = -S- can be prepared analogously to the compounds of the formula I where A = -SO- from compounds of the formula II where A = -S-.

The compounds of the general formula I according to the invention and their pharmacologically acceptable acid addition salts have useful pharmacological properties, for example haemodynamic, thrombocyte function-inhibiting and antithrombotic, in particular coronary antithrombotic, properties. Their action on the cardiovascular system is particularly pronounced. Compared with known sydnone imine compounds, for example those of French .fication 1,496,056 and the compounds described in the German Offenlegungsschrift 3,820,210, they unexpectedly have a surprisingly longer duration of action. For example, they lower the blood pressure as well as the pulmonary artery pressure and the left ventricular end-diastolic pressure and thus contribute to a relief of the load on the heart in the sense of an antianginal action, without provoking reflex tachycardia at the same time.

The compounds of the formula I according to the invention and their pharmacologically acceptable acid addition salts can therefore be administered to humans as medicaments by themselves, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral use and which contain as the active component an effective dose of at least one compound of the formula I according to the invention or an acid addition salt thereof, in addition to one or more customary pharmaceutically acceptable excipients or diluents and, if desired, one or more additives.

The medicaments can be administered orally, for example in the form of tablets, film tablets, coated tablets, hard and soft gelatin capsules, microcapsules, granules, powders, pellets, solutions, syrups, emulsions, suspensions, aerosols, foams, pills or pastilles. Administration may, however, also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions, or percutaneously, for example in the form of ointments, creams, gels, pastes, aerosols, foams, powders, tinctures, liniments or socalled transdermal therapeutic systems (TTS).

The pharmaceutical preparations can be prepared in a manner known per se using pharmaceutically inert inorganic or organic auxiliaries, excipients, fillers or diluents. For the preparation of pills, tablets, film tablets, coated tablets and the pellet or granule fillings of hard gelatin capsules, for example calcium phosphate, lactose, sorbitol, mannitol, starches, prepared starches, chemically modified starches, starch hydrolysates, cellulose, cellulose derivatives, synthetic polymers, talc etc., can be used. Excipients or diluents for soft gelatin IE 911619 I suppositories are, for example, fats, waxes, semisonci and liquid polyols, natural or hardened oils etc. Suitable excipients or diluents for the preparation of solutions and syrups are, for example, water, polyols, solutions of sucrose, dextrose, glucose etc. Suitable excipients for the preparation of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils. Suitable excipients or diluents for ointments, creams and pastes are, for example, natural petroleum jelly, synthetic petroleum jelly, viscous and mobile paraffins, fats, natural or hardened vegetable and animal oils, neutral oils, waxes, wax alcohols, polyethylene glycols, polyacrylic acid, silicone gels etc.

The pharmaceutical preparations may also contain, in a manner known per se, in addition to the active compounds and diluents, fillers or excipients, one or more additives or auxiliaries, such as, for example, disintegrants, binders, glidants, lubricants, mould release agents, wetting agents, stabilisers, * emulsifiers, preservatives, sweeteners, colourings, flavourings, aromatisers, buffer substances, and in addition solvents or solubilisers, solution accelerators, antifoams, salt-forming agents, gelling agents, thickeners, flow regulators, absorbents, agents for achieving a depot effect or agents, in particular salts, for changing the osmotic pressure, coating agents or antioxidants, etc. They may also contain two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and also one or more other therapeutically active substances .

Examples of other therapeutically active substances of this type may be: ^-receptor blockers, such as, for example, propranolol, pindolol, metoprolol; vasodilators, such as, for example, carbochromen; tranquilisers, such as, for example, barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; diuretics, such as, for example, chlorothiazide; cardiotonic agents, such as, for example, digitalis preparations; hypotensive agents, such as, for example, hydralazine, dihydralazine, prazosine, clonidine, Rauwolfia alkaloids; agents which lower the fatty acid level in the blood, such as, for example, bezafibrate, IE 911619 and agents for thrombosis prophylaxis, such as, for example, phenprocoumon.

The content of the active compound or the active compounds of the formula I in the pharmaceutical preparations can vary within wide limits and is, for example, 0.05 to 50% by weight, preferably 0.05 to 20% by weight. In solid administration forms, such as coated tablets, tablets etc., the content of one or more active compounds of the formula I is in many cases 2 to 20% by weight. Liquid administration forms, such as drops, emulsions and injection solutions frequently contain 0.05 to 2% by weight, preferably 0.05 to 1% by weight, of one or more active compounds of the formula I. The content of one or more active compounds of the formula I in the pharmaceutical preparations may be partially replaced, if desired, for example up to 50% by weight, preferably up to 5 to 40% by weight, by one or more other therapeutically active substances.

The compounds of the formula I according to the inven- tion, their pharmacologically acceptable acid addition salts and pharmaceutical preparations which contain the compounds of the formula I according to the invention or their pharmacologically acceptable acid addition salts as active compounds can be used in humans for combating or preventing disorders of the cardiovascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, and in combating or prevention of angina pectoris etc. The dosage may vary within wide limits and is to be suited to the individual requirements in each individual case. In general, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is suitable for oral administration. For other administration forms, the daily dose, owing to the good absorption of the active compounds, is in similar amount ranges, i.e. in general also 0.5 to 100 mg/ human. The daily dose is normally divided into several, for example 2 to 4, part administrations.

The pharmacological action of the compounds of the formula I according to the invention was determined by a modified method of Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and of Schuman et al.

IE 911619 timiedeberg's Arch. Pharmacol. 289. 409 to 418, 1975).

In this connection, spiral strips of the pulmonary artery of the guinea-pig are depolarised with 40 mmol/1 of potassium after equilibration in calcium-free Tyrode solution. An addition of 0.5 mmol/1 of CaCl2 then induces a contraction.

The relaxing action of the test substance is determined by cumulative addition in 1/2 log 10 stepped concentrations. From the concentration-effect curve (abscissa: -log mol/1 of test substance, ordinate: % inhibition of the maximum contraction, average value of 4 to 6 vessel strips), the concentration of the test substance is determined which inhibits the contraction by 50% (= IC50, mol/1). The duration of action of the test substance is shown by the time which is needed after the addition of the test substance until the starting value is obtained again. The values thus obtained are indicated in the following table.

IC50 values and duration of action of sydnone imines of the formula /2 A \ cn2- R R \ / -C \ N— / —ch2 -N-CH I I 1 /C=NH 0 ' HCl Compound A R ic50 Duration of action No. in mol/1 in min 1 °S\ ch3 3 X 10'6 270 2 H 1 X 10'8 80 3 << CH, 1 X 108 120 Compound No. 1 of the table is the compound according to 25 the invention 3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin-4-yl)sydnone imine hydrochloride.

Compound No. 2 of the table is the compound 3-morpholinosydnone imine hydrochloride known from Example 2 of French Patent IE 911619 on 1,406,056.

Compound No. 3 of the table is the compound 3-(3,3-dimethylmorpholin-4-yl)sydnone imine hydrochloride of Example No. 1 of German Offenlegungsschrift 3,820,210.

As can be seen from the above table, the compounds according to the invention have a substantially longer duration of action at a comparable IC50 value than the two comparison compounds.

If not indicated otherwise in the examples which follow, 10 percentage data are percentages by weight.

Example 1 3-(3,3-Dimethvlperhvdro-l-oxo-l,4-thiazin-4-vl)sydnone imine hydrochloride a) 2,2-Dimethvlaziridine 100 g of 2-amino-2-methylpropan-l-ol are dissolved in 200 ml of water. A cold solution of 110 g of cone, sulphuric acid in 200 ml of water is then added dropwise with stirring and the' water is then distilled off at normal pressure until an internal temperature of 115°C is attained. Distillation is continued in a water-jet vacuum up to a bath temperature of 180°C and the flask contents are kept under these conditions until they are solid.

The mixture is then additionally heated in a water-jet vacuum and at 180°C for 1 hour more.

The product is treated with a solution of 100 g of NaOH in 200 ml of water, pulverised and allowed to stand overnight.

Water is distilled off from the suspension under normal pressure. 50 g of KOH are added to the residue with stirring and the mixture is stirred for 3 hours. After allowing to stand, the upper layer is separated off, treated with 20 g of KOH and allowed to stand overnight. The oil is poured off, treated with 10 g of KOH and distilled under normal pressure.

Yields 60.3 g b) 2-Hydroxvethvl 2-amino-2-methvlpropyl sulphide 234 g of 2-mercaptoethanol are dissolved in 90 ml of dimethoxyethane. 63.3 g of 2,2-dimethylaziridine are added dropwise to this solution and it is stirred at 70°C for 4 hours, concentrated and distilled in a water-jet vacuum.

IE 911619 2°C (at 20 mbar) ci j,j-urmethvlperhydro-l,4-thiazine Hydrogen chloride is introduced with stirring into a solution of 14.9 g of 2-hydroxyethyl 2-amino-2-methylpropyl sulphide (step b) in 100 ml of dimethoxyethane until it is saturated and then 17.9 g of thionyl chloride are added dropwise and the mixture is subsequently stirred at room temperature for 1 hour and then heated to reflux for 1 hour. The solution is then concentrated in a water-jet vacuum. The residue of 2-chloroethyl 2-amino-2-methylpropyl sulphide hydrochloride crystallises out.

The hydrochloride obtained is dissolved in water, the solution is rendered strongly alkaline using potassium carbonate, the free base is taken up in 100 ml of toluene and the aqueous phase is extracted again by shaking with 2 x 30 ml of toluene.

The organic phases are combined, dried over potassium carbonate, concentrated and distilled in a water-jet vacuum.

Yield: 8.1 g B.p.: 73-75’C (at 20 mbar) d) 4-Nltroso-3.3-dimethylperhydro-l,4-thiazine A mixture of 15.7 g of 3,3-dimethylperhydro-l,4-thiazine (step c) and 60 ml of ice-water are treated with cooling with 12 ml of 10 N HC1. A solution of 12.4 g of sodium nitrite in 40 ml of water is then added dropwise at 4 to 6eC. The mixture is subsequently stirred at room temperature for 4 hours, rendered alkaline with potassium carbonate and extracted by shaking with ethyl acetate. The organic phase is dried and concentrated in a water-jet vacuum.

Yield: 17.5 g M.p.: Yellow oil e) 4-Amino-3.3-dimethvlperhvdro-l,4-thiazine hydrochloride A solution of 17.2 g of 4-nitroso-3,3-dimethylperhydro1,4-thiazine (step d) in 150 ml of tetrahydrofuran is treated with 4.4 g of lithium aluminium hydride in portions at 60-65°C and the mixture is then heated to reflux for 2 hours. The suspension is cooled and a solution of 5 ml of water in 50 ml of tetrahydrofuran is added dropwise. After 20 minutes, 10 ml of 27% strength by weight sodium hydroxide solution are added dropwise and the mixture is allowed to stand for a few hours. The precipitate is then filtered off and the hydrochloride is precipitated M.p.: 49-51"C cooled filtrate.

Yield: 12.2 g f) 4-(2-Cyanoethyl-amino)-3,3-dimethvlperhydro-l,4-thiazine A solution of 6.1 g of KCN in 30 ml of water is added 5 dropwise to a solution, cooled to -3 to -5eC, of 12.1 g of 4-amino-3,3-dimethylperhydro-l,4-thiazine hydrochloride (step e). The pH of the solution is then adjusted to 7.2 with hydrochloric acid and 16.3 g of 39% strength by weight aqueous formaldehyde are then added, the pH being kept at 6 to 7. The mixture is sub10 sequently stirred overnight at a temperature rising to room temperature. The suspension is extracted by shaking with ethyl acetate and the organic phase is dried and concentrated.

Yield: 9.4 g M.p.: oil q) 3-(3,3-Dimethvlperhvdro-l,4-thiazin-4-vl)sydnone imine hydrochloride 9.4 g of 4-(2-cyanoethylamino)-3,3-dimethylperhydro1,4-thiazine (step f), 40 ml of ethyl acetate, 40 g of ice-water and 5 ml of 10 N hydrochloric acid are cooled to -5°C. 5.3 g of sodium nitrite are introduced into this mixture and it is subse20 quently stirred at room temperature for 3 hours. The organic phase is separated off and dried, the solid is filtered off and 20 ml of a saturated solution of HC1 in isopropanol are added dropwise with cooling. The mixture is subsequently stirred overnight at room temperature. The precipitate is separated off and recrystallised from isopropanol.

Yield: 5.9 g M.p.: 172°C (decomposition) h) 3-(3.3-Dimethvlperhvdro-l-ox6-l,4-thiazin-4-vl)svdnone imine hydrochloride The solution obtained from 3 g of 3-(3,3-dimethyl30 perhydro-l,4-thiazin-4-yl)sydnone imine hydrochloride (step g) is treated at room temperature with stirring with 1.2 g of a 35% strength aqueous hydrogen peroxide solution, the temperature rising somewhat. The mixture is stirred for 2 hours and then concentrated in a water-jet vacuum, and the residue is recrystal35 Used from ethyl acetate.

Yield: 2.5 g M.p. 192eC (dec.) N-p-Anisovl-3-(3.3-dimethvlperhvdro-l-oxo-l,4-thiazin-4-vl) sydnone imine g of 3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin-4-yl)sydnone imine hydrochloride (Example 1 h) are dissolved in 20 ml of ice-water and 2 g of NaHC03 are added. 2.1 g of p-anisoyl chloride, dissolved in 30 ml of ethyl acetate, are added dropwise. The mixture is subsequently stirred for 3 hours, the temperature rising to room temperature. The phases are then separated, the aqueous phase is extracted by shaking with ethyl acetate, and the organic phases are combined, dried and concentrated. The crystalline product obtained is recrystallised from isopropanol.

Yield: 1.8 g M.p. 183 to 185°C (decomposition) Example 3 N-Ethoxycarbonyl-3-f 3,3-dimethylperhvdro-l-oxo-l,4-thiazin4-yl)sydnone imine The compound is obtained analogously to Example 2 using ethyl chloroformate (1.8 g) instead of p-anisoyl chloride and is recrystallised from isopropyl acetate.

Yield: 1.4 g M.p. 138eC (decomposition) Example 4 N-Pivaloyl-3-(3,3-dimethvlperhvdro-l-oxo-l,4-thiazin-4-vl)sydnone imine The compound is obtained analogously to Example 2 using 2.1 g of pivaloyl chloride instead of p-anisoyl chloride and is recrystallised from diisopropyl ether.

Yield: 1.3 g M.p.: 110°C (decomposition) Pharmaceutical preparations are described in the following examples A to H.

Example A Soft gelatin capsules, containing 5 mg of active compound per capsule: per capsule Active compound 5 mg Triglyceride mixture fractionated from coconut oil 150 mg - 19 IE 911619 >nts 155 mg Example B Injection solution, containing 1 mg of active compound per ml: per ml Active compound 1.0 mg Polyethylene glycol 400 0.3 ml Sodium chloride 2.7 mg Water for injection purposes to 1 ml Example C Emulsion, containing 3 mg of active compound per 5 ml per 100 ml of emulsion Active compound Neutral oil Sodium carboxymethylcellulose Polyoxyethylene stearate Glycerol, pure Flavouring Water (demineralised or distilled) to Example D Rectal medicament form, containing 4 mg suppository 0.06 g g. s. 0.6 g q. s. 0.2 to 2.0 g q. s . 100 ml of active compound per Active compound Suppository base Example E Tablets, containing 2 mg of Active compound Lactose Cornflour Soluble starch Magnesium stearate per suppository mg to 2 g active compound per tablet per tablet mg 60 mg 30 mg mg mq 100 mg Example F Coated tablets, containing 1 mg of active compound per coated tablet per coated tablet Active compound 1 mg Cornflour 100 mg Lactose 60 mg sec Calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silicic acid 4 mq 200 mg Example G The following recipes are suitable for the preparation of contents of hard gelatin capsules: a) Active compound 10 mg Cornflour 190 mq 200 mg b) Active compound 40 mg Lactose 80 mg Cornflour 80 mg 200 mg Example H Drops can be prepared according to the following recipe (: active compound in 1 ml = 20 drops) • • Active compound 2 .00 g Methyl benzoate 0 .07 g Ethyl benzoate 0 .03 g Ethanol, 96% strength 4 ml Demineralised water to 100 ml

Claims (16)

1. Substituted 3-aminosydnone imines of the general formula A N-CH N C=N-R \ / (I) and their pharmacologically acceptable acid addition salts, in which A denotes the radical -SO-, R 1 denotes the radical -CO-R 2 or hydrogen, R 2 denotes (C x to C 4 )alkyl, (C x to C 4 )alkoxy-(0 χ to C 4 )alkyl, (C x . to C 4 )alkoxy, (C 5 to C 7 )cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms.

2. Substituted 3-aminosydnone imines according to Claim 1, characterised in that R 2 denotes (C x to C 4 )alkyl, (Ci to C 4 )alkoxy, phenyl, or phenyl monosubstituted by chlorine, methyl or methoxy.

3. The pharmacologically acceptable acid addition salts, in particular the hydrochloride of the compound 3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin-4-yl)sydnone imine.

4. N-p-Anisoyl-3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin4-yl)sydnone imine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

5. N-Ethoxycarbonyl-3-(3,3-dimethylperhydro-l-oxo1,4-thiazin-4-yl)sydnone imine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

6. N-Pivaloyl-3-(3,3-dimethylperhydro-l-oxo-l,4-thiazin4-yl)sydnone imine and its pharmacologically acceptable acid addition salts, in particular its hydrochloride.

7. Process for the preparation of the compounds of the formula I indicated in Claim 1 and/or 2 and/or the compounds indicated in one or more of Claims 3 to 6, characterised in that - 23 a compound of the general formula II ·„ c 3 / c 3 / 2 —\ CH. -N-CH 2 -CN CH_ NO (II) in which A denotes the radical -SO-, is cyclised to give a compound of the formula la CH 3 CH 3 \ / CH„-C CH, \ N/ -CH„ -NI N CH I C=NH (la) and the compound obtained is isolated as the acid addition salt, and in that in the case in which it is intended to prepare a compound of the formula I where R 1 = -COR 2 , the compound la or an acid addition salt thereof is acylated with an acylating agent which introduces the radical -COR 2 and the compound thus obtained is isolated or, if desired, converted into a pharmacologically acceptable acid addition salt, and this is isolated.

8. Process according to Claim 7, characterised in that the cyclisation is carried out in a solvent, dispersant or diluent at temperatures of -10 to 40°C, preferably 0 to 20°C, with the aid of a cyclising agent which establishes a pH below 3 in aqueous solution.

9. Process for the preparation of the compounds of the formula I indicated in Claim 1 and/or 2 and/or of the compounds indicated in one or more of Claims 3 to 6, characterised in that a compound of the general formula lb C \V CH 3 CH,-C / 2 \ NCH, / -CH. -N-CH • I I l N^ C=N-R (lb) in which A denotes the radical -S- and - 24 R 1 denotes hydrogen or the radical -COR 2 , R 2 denotes (C x to C 4 )alkyl, (C x to C 4 ) alkoxy-(C x to C 4 )alkyl, (C x to CJalkoxy, (C 5 to C 7 ) cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms, or an acid addition salt thereof is reacted with an oxygen-donating compound and the compound obtained is converted, if desired, into an acid addition salt and isolated, or in that in the case in which a compound of the formula I where A = -SO- and R 1 = H has been obtained and it is intended to prepare a compound of the formula I where A = -SO- and R 2 = -COR 2 , the compound obtained or an acid addition salt thereof is acylated with an acylating agent which introduces the radical -COR 2 , and the compound thus obtained is isolated or, if desired, converted into a pharmacologically acceptable acid addition salt and this is isolated.

10. Process for the preparation of substituted 3-aminosydnone imines of the general formula I CH / A \ CH C <3/ CH 3 2 \ N/ 2- CH 2 NI N; -CH = N-R (I) and their pharmacologically acceptable acid addition salts, in which A denotes the radical -SO-, R 1 denotes the radical -CO-R 2 , R 2 denotes (C x to CJalkyl, (C x to C 4 )alkoxy-(C x to CJalkyl, (C x to C A )alkoxy, (C 5 to C 7 )cycloalkyl, phenyl, or a phenyl radical which is mono-, di- or trisubstituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals having 1 to 4 C atoms and/or 1 to 3 alkoxy radicals having 1 to 4 C atoms, characterised in that a compound of the formula I in which R 1 denotes hydrogen or an acid addition salt thereof, is acylated with an acylating agent which introduces the radical -COR 2 and the compound thus obtained is isolated or, if desired, converted into a - 25 pharmacologically acceptable acid addition salt and this is isolated.

11. 3-Aminosydnone imines and their pharmacologically accept able acid addition salts of one or more of Claims 1 to 5 as pharmacological active compounds for use in the combating and prevention of cardiovascular disorders or as pharmaceutical active compounds for the production of pharmaceutical preparations .

12. Pharmaceutical preparation, characterised in that it contains a compound of one of Claims 1 to 6 or an acid addition salt thereof as the active compound together with pharmaceutically acceptable excipients and additives and, if desired, also one or more other pharmacological active compounds.

13. A substituted 3-aminosydnone imine of the general formula (I) given and defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described and exemplified.

14. A process for the preparation of a substituted 3aminosydnone imine of the general formula (I) given and defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described and exemplified.

15. A substituted 3-aminosydnone imine of the general formula (I) given and defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process claimed in a preceding claim.

16. A pharmaceutical preparation according to Claim 12, substantially as hereinbefore described and exemplified.