CA2060030A1

CA2060030A1 - Substituted 3-aminosydnone imines, process for the preparation therefore and the use thereof

Info

Publication number: CA2060030A1
Application number: CA002060030A
Authority: CA
Inventors: Karl Schoenafinger; Rudolf Binder; Helmut Bohn; Melitta Just
Original assignee: Individual
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1991-01-26
Filing date: 1992-01-24
Publication date: 1992-07-27
Also published as: HU9200230D0; PL293281A1; JPH04312581A; HUT62275A; ZA92505B; EP0497122A1; KR920014789A; DE4102282A1; IE920223A1

Abstract

ABSTRACT
Novel 3-aminosydnone imines of the general formula

Description

2~Q~ Ref 3471 Substituted 3-aminosydnone imines, Pro~ess for the preparation therefore and the use thereof The present invention relates to pharmacologically active substituted 3-aminosydnone imines, process for the preparation thereof and the use thereof.

3-Aminosydnone imines have already been disclosed in a number of publications. Structurally related to the compounds according to the invention are those disclosed in EP-A 59356 and especially in EP-A 346684.
The invention relates to 3-aminosydnone imines of the general formula I

H C--C--C H
R --N N CH ( I ) I =N--R 2 o and the pharmacologically acceptable acid addition salts thereof, in which R1 denotes alkyl with 1 to 6 C atoms;
R2 denotes hydrogen or the radical -CoR3; and R3 denotes an aliphatic radical with 1 to 4 C atome, which can also be substituted by alkoxy with 1 to 3 C atoms; a cyclo-aliphatic radical with 5 to 7 C atoms; a bicycloaliphatic radicalwith 7 to 14 C atoms; a tricycloaliphatic radical with 7 to 16 C
atoms; an alkoxy radical with 1 to 6 C atome; an aryloxy radical with 6 to 10 C atoms; an alkoxycarbonyl radical with a total of 2 to 7 C atoms; an aryl radical with 6 to 10 C atoms; an aryl radical which has 6 to 10 C atoms and i~ mono-, di- or trisub-stituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals with 1 to 3 C atoms and/or l to 3 alkoxy radical~ with 1 to 3 C
atoms and/or l or 2 nitro groups; or a five- or ~ix-membered heterocycle which can have 1 to 3 nitrogen, oxygen ~nd/or sulphur atoms as ring members and can also be benzo-fused.
Aliphatic radicals, alkyl radicals and alkoxy radicals can be straight-chain or branched. This also applies when they occur as ~ubstituents of other radicals, for example as Q~
substituents for aryl radicals, or in conjunction with other radicals, for example as alkoxycarbonyl.
Rl pref erably represents alkyl with 1 to 4 C atoms and particularly pref erably denotes methyl, ethyl, n-propyl or 5 n-butyl.
Particularly suitable aliphatic radicals representing R3 are alkyl radicals. Particular mention should be made of the methoxymethyl radical as aliphatic radical~ which represent R3 and are substituted by alkoxy with 1 to 3 C atoms. Particularly 10 ~uitable cycloaliphatic radicals representing R3 are cycloalkyl radicals with 5 to 7 C atoms, especially cyclopentyl and prefer-ably cyclohexyl. Particularly suitable as bicycloaliphatic radi-cal repre~enting R3 i~ 2, 6, 6-trimethylbicyclo [ 3 . 1. 1 ] heptan-3-yl ( - 3-pinanyl ) .
Particularly suitable tricycloaliphatic radical repre-senting R3 is tricyclo[3.3.1.13 ']decan-l-yl (= adamantanyl) .
Particularly ~uitable alkoxy radicals representing R3 are those with 1 to 4 C atoms.
Particularly suitable alkoxycarbonyl radical~ repre~ent-2~ ing R3 are tho~e with a total of 2 to 4 C atom~, e~pecially theethoxycarbonyl radical. Examples of aryl radical~ representing R3 which should be mentioned are ~- or ~-naphthyl radicals and the phenyl radical. Examples of aryloxy radicals repre~enting R3 which ~hould be mentioned are ~- or ,~-naphthoxy radicals and the phen-25 oxy radical. The aryl radical~ repre~enting R3 can be mono-, di-or trisubstituted, but only a maximum of 2 nitro group~ can be present even in the case of tri~ub~titution, ~uch as, for example, 2-methyl-4, 6-dinitrophenyl and 2-chlox:o-6-methyl-4-nitrophenyl . Example~ of suitable halogen ~ub~tituent~ f or the 30 aryl radical~ are chlorine and bromine atom~. Sub~tituted aryl radical~ repre~enting R3 which should be particularly mentioned are : methylphenyl ( - tolyl ), methoxyphenyl , nitrophenyl and chlorophenyl. Five- or ~ix-membered heterocycle~ which c:an repre-~ent R3 are, f or example, thiophene, di- or tetrahydrothiophene, 35 pyrrole, pyrroline, pyrrolidine, pyridine, dihydropyridine, piperidine, pyran, perhydropyran, imidazole, imidazoline, imid-azolidine, oxazole, oxazoline, oxazolidine, thiazole, thiazoline, thiazolidine, pyrimidine, pyridazine, pyrazine, piperazine, morpholine and thiomorpholine. A benzo-fused heterocycle i~, in 2~S~n9 particular, indole.
Preferred radicals R3 are alkyl with 1 to 4 C atoms;
alkoxy with 1 to 4 C atoms; phenyl; phenyl and pyridyl which are substituted by halogen and/or nitro or alkoxy with 1 to 3 C
atoms.
Particularly preferred radicals R3 are methyl, ethyl, n-propyl, isopropyl, tert.-butyl, methoxy, ethoxy, phenyl, 2-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-ethoxyphenyl a~d 3-pyridyl.
A compound of the general formula I can be prepared by cyclising a compound of the general formula II
l~3 H C--C--C H
R --N N CH2--CN ( I J ) NO
in which R1 has the abovementioned meaning, to give a compound of the general formula Ia f H 3 H C--(;--C H
R --N N CH ~ l a ) N - C=NH

and acylating the latter or an acid addition salt thereof in the ca~e where a compound of the formula I with R2 z -co~3 iB to be prepared, with an acylating agent which introduces the radical -CoR3, and converting the compound obtained in this way where appropriate into a pharmacologically acceptable acid addition salt.
The cyclisation of the compound~ II to give the compounds Ia iB carried out in a suitable organic or inorganic solvent, dispersant and/or diluent with the addition of a cyclising agent, normally at temperatures from -lO to 40C, in particular 0 to 40C, preferably at 0 to 20C.
Suitable cyclising agents are those which set up a pH
below 3 in aqueous colution, that is to say, for example, strong acids such as mineral acids, such a~ sulphuric, nitric or QQqr3 phosphoric acid, preferably hydrogen chloride, but also strong organic acids such as trifluoroacetic acid. The cyclisation is normally carried out while cooling in ice. From 0.1 to 10 mol, preferably 1 to 5 mol, of the cyclisation agent is used, for example, based on 1 mol of the compound of the formula II. The cyclisation agent is normally employed in exces~. It is parti-cularly convenient to use hydrogen chloride as cyclising agent, which is normally passed in until the reaction mixture is satur-ated. The cyclisation normally re~ults in the corresponding acid addition salt of the compound Ia.
Examples of suitable solvents t dispersants or diluents are: alcohols, for example those with 1 to 8 C atoms, especially those with 1 to 6 C atoms, preferably those with 1 to 4 C atoms, such as, for example, methanol, ethanol, i- and n-propanol, i-, sec- and tert-butanol, n-, i-, sec-, tert-pentanol, n-hexanol, 2-ethylbutanol, 2-ethylhexanol, isooctyl alcohol, cyclopentanol, cyclohexanol, methylcyclohexanol (mixture), benzyl alcohol;
ethers, especially those with 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, tetrahydro-furan, 1,4-dioxane, 1,2-dimethoxyethane, bi~-~-methoxyethyl ether; oligoethylene glycol dimethyl ether~ such as, for example, tetraglyme or pentaglyme; alkyl carboxylate~, especially those with 2 to 10 C atoms in the molecule, such as, for example, methyl, ethyl, butyl or isobutyl formate, methyl, ethyl, propyl, i~opropyl, butyl, isobutyl or sec-butyl, amyl, isoamyl, hexyl, cyclohexyl or benzyl acetate, methyl, ethyl or butyl propionate, ketones, e~pecially tho~e with 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, di-iso-propyl ketone, di-i~o-butyl ketone, cyclo-pentanone, cyclohexanone, methylcyclohexanone, dimethylcyclo-hexanone, benzophenone, acetophenone; aliphatic hydrocarbons such as, for example, hexane, heptane, low- and high-boiling petroleum ethers, special petroleum spirit~ and white spirit; cycloali-phatic hydrocarbons such as, for example, cyclopentane, cyclo-hexane, methylcyclohexane, tetralin, decalin; aromatic hydrocar-bon3 such as, for example, benzene, toluene, o-, m- and p-xylene, ;~c~
ethylbenzene; halogenated aliphatic or aromatic hydrocarbons such as, for example, methylene chloride, chloroform, tetrachloro-methane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene;
hexamethylphosphoric triamide; sulphoxides such as, for example, dimethyl sulphoxide; tetramethylene sulphone; water. It is also possible to use mixtures of various solvents or dispersants, for example water/methanol or, preferably, ethyl acetate/methanol.
The compounds of the formula Ia represent compounds of the general formula I according to the invention in the case where RZ i~ hydrogen.
The acylation of the compound of the formula Ia, which can also be in the form of an acid addition salt, to introduce the radical R2 = -CoR3 can be carried out in a manner known per se using a suitable acylating agent of the formula III

X-C-R ( II I ) in which X is a radical which can be eliminated nucleophilically.
X in the formula III denotes, for example, in particular halogen, preferably -Cl or -Br; -OH; -O-alkyl, in particular with 1 to 5 C atoms; -O-aryl, where the aryl radical i~, in parti-cular, a phenyl radical which can also be substituted one or more times by alkyl, in particular methyl, and/or nitro, and i~, for example, a tolyl, dinitrophenyl or nitrophenyl radical; -o-co-R3;
-O-CO-O-alkyl, in particular with 1 to 5 C atom~ in the alkyl radical, or the radical, which iB bonded via an N atom, of an azole or benzazole with at least 2 N atom~ in the qua~i-aromatic ~5 five-membered ring.
The acylation i~ expediently carried out in liquid phase in the presence of an inert ~olvent, di~perQant or diluent or in an exces~ of the acylating agent, expediently with stirring.
The molar ratio between the compound of the formula Ia and the acylating agent of the formula III in the acylation iB
1:1. The acylating agent of the formua III i8 expediently employed in a small molar exce~s. Exces~es of up to 30 mol% are usually sufficient, that is to ~ay the molar ratio between the compound of the formula Ia and the acylating agent of the formu}a III is normally 1:(1 to 1.3~, preferably 1:(1 to 1.2). If an acid 2~ ql~
is eliminated in the acylation reaction, it is expedient to add an acid acceptor such as, for example, an alkali metal hydroxide such as, for example, sodium, potassium or lithium hydroxide, a tertiary organic amine such as, for example, pyridine or tri-ethylamine, 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. It is also possible to add suitable catalysts to the acylation reaction, such as, for example, 4-dimethylaminopyridine.
The acylation can in principle be carried out at tempera-tures between -10C and the boiling point of the solvent, disper-sant or diluent used. In many cases, the reaction is carried out at 0 to 50C, in particular at 0 to 30C 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 esters, of which acid chlorides and chloroformic esters are preferred; for -OH carboxylic acids; for -O-alkyl and -O-aryl ester~, of which the tolyl, 2,4-dinitro or 4-nitro-phenyl ester~ are preferred; for -O-CO-R1 anhydrides; for -O-CO-O-alkyl mixed carboxylic acid/carbonic anhydrides; or heterocyclic amides or azolides, especially of N,N'-carbonyl-diazoles such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyl-di-1,2,3-triazole, 1,1'-carbonyldi-1,2,4-triazole, N,N'-carbonyldipyrazole, 2,2'-carbonylditetrazole (compare, for example, H.A. Staab, M. L~cking and F.H. D~rr, Chem. Ber. 95, (1962), 1275 et ~eq., H.A. Staab and A. Mann~chreck, Chem. Ber.
95, (1962), 1284 et ~eq.; H.A. Staab and W. Rohr, "Synthesen mit heterocyclischen Amiden (Azoliden)" (Syntheqe~ with Heterocyclic Amides (Azolides)) in "Neuere Methoden der Praparativen Organischen Chemie" (Newer Methods of Preparative Organic Chemistry), volume V, Verlag Chemie, 1967, page 53 et seq., especially pages 65 to 69). The acylating agent~ of the formula III can be prepared by proces~es known per ~e.
When a carboxylic acid i~ used a~ acylating agent, it is expedient to add an activating agent which ha~ the ta~k of activ-ating or increasing the acylating potential of the carboxylic acid, or converting the carboxylic acid in situ or, preferably, 2~
shortly before the reaction with the compound of the formula Ia into a reactive carboxylic acid derivative of the formula III.
Examples of suitable activating agents of this type are: N,N'-disubstituted carbodiimides, especially when they contain at least one secondary or tertiary alkyl radical, such as, for example, diisopropyl-, dicyclohexyl or N-methyl-N'-tert.-butyl-carbodiimide (compare Methodicum Chimicum, Verlag G. Thieme, Stuttgart, Vol. 6, (1974), pages 682/683, and Houben-Weyl, Methoden der Org. Chemie (Methods of Org. Chemistry), Vol. 8, (1952), page~ 521/522); carbonic acid derivatives such as, for example, phosgene, chloroformic esters, especially with 1 to 5 C
atoms in the alkyl radical (compare, for example, Tetrahedron Letters 24 (1983), 3365 to 3368); carbonic esters such as, for example, N,N'-disuccinimidyl carbonate, diphthalimidyl carbonate, l,l'-(carbonyldioxy)dibenzotriazole or di-2-pyridyl carbonate (compare, for example, Tetrahedron Letters, Vol. 25, No. 43, 4943-4946) where appropriate in the presence of ~uitable cata-lysts ~uch as, for example, 4-dimethylaminopyridine. Also suitable as activating agents are N,N'-carbonyldiazole~ such as, for example, N,N'-carbonyldiimidazole, 2,2'-carbonyldi-1,2,3-triazole, l,l'-carbonyldi-1,2,4-triazole, N,N'-carbonyldi-pyrazole, 2,2'-carbonylditetrazole, N,N'-carbonylbis~enzimidazole or N,N'-carbonylbisbenzotriazole (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.).
N,N-Carbonyldiimidazole, which can be bought, is often used as N,N'-carbonyldiazole. The other N,N'-carbonyldiazoles can, how-ever, likewise easily be obtained from the rel2vant azole and phosgene .
Further activating agents suitable for carboxylic acids are: derivatives of oxalic acid such as, for example, oxalyl chloride (compare, for example, GB Patent 2 139 225) or N,N'-oxazolyldiazoles such as, for example, l,l'-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 31 01 427); disphosphorus tetraiodide (Chem. Lett. 1983, 449); dialkyl disulphite (Indian J. Chem. 21, 259 (1982)); or other reactive agents.

2~
Examples of suitable solvents, dispersants or diluents are those which have been indicated for carrying out the cyclis-ation, in addition, for example, pyridine and amides such as, for example, dimethylformamide. Besides water, preferred for the acylation are polar organic solvents such as dimethylformamide, dimethyl sulphoxide or pyridine. 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 f orm acid addition salts with inorganic or organic acids. Inoxganic or organic acids are suitable for forming acid addition salts of these types. Examples of suitable acids are hydrogen chloride, hydrogen bromide, naphthalenedisulphonic acids, especially 1,5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, f ormic r propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenyl-propionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluenesulphonic, citric or adipic acid. Pharmacologically acceptable acid addition salts are preferred. The acid addition salts can be prepared as usual by combining the components, expediently in a suitable solvent or diluent.
The synthesis of the compounds of the formula Ia normally results in the acid addition salts. The free compounds of the general formula I or Ia can, if required, be obtained from the acid addition salts in a known manner, that is to ~ay by dis~olv-ing or su~pending in water and making alkalinet for example with sodium hydroxide ~olution, and subsequently is~lating.
The required starting compounds of the general formula II
can be prepared in a manner known per se by Strecker' 8 amino nitrile synthesis from compounds of the general formula IV

CH

3 f 3 ( I V ) 1? 1 _N--N H 2 in which R1 has the abovementioned meaning, by reacti~n with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, the initial product being a compound of the general formula V

3 F 3 ( V ) which is converted into the compound II by nitrosation. The nitrosation is carried out in a known manner in a suitable sol-vent, preferably in water, for example at temperatures from 0 to 10C. The nitrous acid is in this case normally produced from an alkali metal nitrite, for example sodium nitrite, and hydro-chloric 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 in the form of an aqueous solution dropwise to the stirred and cooled solution of the compound.
The solution of the compound II which is obtained thereby can be subjected directly to the cyclisation reaction. However, it is normally appropriate first to take up the nitroso compound II in a suitable organic solvent and to carry out the cyclisation to give the compound of the formula Ia therein, where appropriate after addition of another solvent.
The compounds of the general formula IV are in some cases known and can be prepared, starting from compound~ of the general formula VI
f H 3 H3C--IC--CH3 IVI ) R 1_N--H

by either ~0 a) nitrosating a compound of the formula VI to give the N-nitroso compound VII and subsequently reducing, expediently with lithium aluminium hydride:

fH3 ICH3 3 f 3 H C--C--C H
(VI ) ~ R1--N--NO ~ R --N--NH2 (VIi ) I IV) or in a known manner 2~
b) converting a compo~nd of the formula VI with potassium cyanate in acidic medium into the urea derivative VIII, which is then converted by oxidation with sodium hypochlorite by the ~offmann degradation into the compound IV.

l H3 ~H3 f 3 K N C O H C--f--C H
R --N--H ) ~ --CO-~H2 ( V I ) ( VI I I ) FH3 f H3 H C--C--CH H C--f--CH
31 1 3 NaOCl 31 1 3 R --N--CO-NH2 > R --N--NH2 ( V I I I ) ( i V ) The preparation of the starting compounds of the formulae IV and VI is known or can be carried out by processes known per se.
The compounds of the general formula I and their pharma-cologically acceptable acid addition salts have valuable pharma-cological properties. They have a particularly pronounced action on the cardiovascular system. Compared with known sydnone imine compounds substituted in position 3, for example those in EP-A 59356 or EP-A 346684, a~ well as the compound molsidomine which i~ of similar structure and is commercially available, they ~urprisingly have a considerably longer duration of action. For example, they lower the blood pressure as well as the pulmonary artery pressure and the left ventricular end-diastolic pres~ure and thus contribute to relieving the action of the heart in the sense of an antianginal effect without also provoking reflex tachycardia.
The compounds may also display antithrombotic effects owing to inhibition of platelet aggregation.
The compounds of the formula I and their pharmaco-logically acceptable acid addition ~alts can therefore be admin-i~tered to humans as medicines on their own, in mixtures with one another or in the form of pharmaceutical compositions which 2~ Q~
permit enteral or parenteral use and which contain as active -omponent an effective dose of at least one compound of the formula I or of an acid addition salt thereof, in addition to customary pharmaceutically acceptable vehicles and additives.
The medicines can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. ~lowever, adminis-tration can also take place rectally, for example in the form of suppo~itories, or parenterally, for example in the form of injec-tion solutions, or percutaneously, for example in the form of ointments or tinctures.
The pharmaceutical products can be prepared using pharma-ceutically inert inorganic or organic vehicles. To prepare pills, tablets, sugar-coated tablets and hard gelatin capsules it is possible for example, to use lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof etc. Examples of vehicles for ~oft gelatin capsules and suppositories are fats, waxes, semisolid and liquid polyols, natural or hardened oils etc. Examples of suitable vehicles for preparing solutions and syrups are water, sucrose, invert ~ugar, glucose, polyols etc.
Examples of suitable vehicles for preparing injection solutions are water, alcohols, glycerol, polyols or vegetable oils.
The pharmaceutical products can, besi~es the active substances and vehicles, also contain additives such as, for example, fillers, extenders, disintegrants, binders, lubricants, wetting agents, etabilisers, emulsifiers, preservatives, sweet-eners, colorants, flavouring or aromatising agents, buffer sub-stances as well as solvents or solubilisers or agents to achieve a depot effect, plus salts to alter the osmotic pressure, coating agents or antioxidants. They can also contain two or more com-pounds of the formula I or the pharmacologically acceptable acid addition salts thereof and, in addition, other therapeutically active substance~.
Examples of other therapeutically active substances of these types are: ~-receptor blockers such as, for example, pro-pranolol, pindolol, metoprolol; vasodilators such as, for example, carbochromen; sedatives, such as, for example, barbi-turic acid derivatives, 1,4-benzodiazepines and meprobamate;

diuretics such as, for example, chlorothiazide; heart tonics such as, for example, digitalis products; agents to lower the blood pressure, such as, for example, hydralazine, dihydralazine, ramipril, prazosin, clonidine, rauwolfia alkaloids; agents which lower the level of fatty acids in the blood, sllch as, for example, bezafibrate, fenofibrate; agents for thrombosis prophy-laxis such as, for example, phenprocoumon.
The compounds of the formula I, the pharmacologically acceptable acid addition salts thereof and pharmaceutical pro-ducts which contain the compounds o~ the formula I or the pharmacologically acceptable acid addition salts thereof as active substances can be used in humans for controlling or pre-venting diseases of the cardiovascular syRtem, for example as antihypertensive medicines for the various forms of high blood pressure, for controlling or preventing angina pectoris etc. The dosage can vary within wide limits and should be adjusted in each individual case to suit individual circumstances. An appropriate daily dose on oral administration is, in general, from about 0.5 to 100 mg, preferably 1 to 20 mg, per individual person. The daily dose with other administration forms is, because of the good absorption of the active substances, also in similar ranges of quantity, that is to say in general likewise 0.5 to 100 mg/-person. The daily dose is normally divided into several, for example 2 to 4, part administrations.
The pharmacological action of the compounds of the for-mula I has been determined by a modification of the method of Godfraind and Kaba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972) and of Schuman et al (Naunyn-Schmiedeberg's Arch.
Pharmaaol. 289, 409 to 418, 1975). This entail~ spiral strips of the guinea pig pulmonary artery being equilibrated in calcium-free Tyrode's solution and then depolarised with 40 mmol/1 potas-sium. Addition of 0.5 mmol/l CaCl2 then elicits a contraction. The relaxant effect of the test substance is determined by cumulative addition in 1/2 log lO concentration steps. The concentration of the test substance which inhibits contraction by 50 ~ (IC50, mol/l) is determined from the concentration-effect plot (ab~ci-ssa: -log mol/l test substance, ordinate: % inhibition of maximum contraction, mean of 4 to 6 vessel strips). IC50 values obtained in this way are shown in the table which follows. As is evident from comparison with the IC50 for known compounds from the state ~f the art, the compounds according to the invention are more effective.

Compound IC50 Example 1 3.0 x 10-6 Example 6 3.0 x 10 6 N-Ethoxycarbonyl-3-morpholino-sydnone imine (molsidomine) 3.0 x :Lo-4 3-~tert.-Butyl-(2-diisopropylamino-ethyl)amino)sydnone imine dihydro-chloride (Example 6 from EP-A 3466843 4.0 x 10-6 ~ 3 ~V

Example 1 3-(N-tert.-Butyl-N-methylamino)sydnone imine hydrochloride a) A solution of 4.5 g of sodium nitrite in 20 ml of water is added dropwise to a mixture of 6.1 g of N-tert.-butyl-N-methylhydrazinoacetonitrile, 25 ml of water, 25 ml of ethyl acetate and 4 ml of 10 N hydrochloric acid. After stirring at room temperature for 4 hours, the organic phase is separated off, and the aqueous phase i6 extracted twice more by ~haking with a little ethyl acetate. 20 ml of a solution of hydrochloric acid in isopropanol are added to the combined organic phases, which are then stirred at room temperature for 15 hours and concentrated under waterpump vacuum. The residue is chromatographed on a silica gel column with a 9:1 mixture of methylene chloride and methanol, and the residue which remains after concentration of ~5 the fraction which contains the required compound is again boiled with ethyl acetate, filtered off with suction and dried.
Yield: 0.50 g Melting point: 14B (decomp.) b) The ~tarting material N-tert.-butyl-N-methylhydrazino-acetonitrile required under a) is prepared in the following way:
a solution of 1'.8 g of potassium cyanide in 50 ml of water is added dropwise to an ice-cooled mixture of 22.6 g of N-tert.-butyl-N-methylhydrazine, 22.2 ml of 10 N hydrochloric acid and 120 ml of water, and the pH is adju~ted to 7 with hydrochloric acid. Then 17.0 g of a 39 % strength formaldehyde solution are added, the fall in pH is compen~ated by adding a sodium carbonate solution, and the reaction mixture i~ ~tirred at 0C for 2 hours and at room temperature for a further 3 hour~. The product i~
extracted with ethyl acetate, and the organic phase is washed with dilute glacial acetic acid and dried over sodium sulphate.
Remaining after concentration is an oily residue ~13.0 g) which is further processed as in a) without further purification.
Example 2 3-(N-tert.-Butyl-N-propylamino)~ydnone imine hydrochloride a) A solution of 11.9 g of sodium nitrite in 40 ml of water is added dropwise to a mixture of 19.5 g of N-tert.-butyl-N-propylhydrazinoacetonitrile, 60 ml of water, 60 ml of ethyl acetate and 12 ml of 10 N hydrochloric acid. After ~tirring at room temperature for 4 hours, the organic phase is separated off, and the aqueous phase is extracted twice more by shaking with a little ethyl acetate. 42 ml of a solution of hydrochloric acid in isopropanol are added to the combined organic phase~, which are then stirred at room temperature for 40 hours and concentrated under waterpump vacuum. The residue is boiled with ethyl acetate, filtered off with suction and dried.
Yield: 5.40 g Melting point 143 (decomp.) b) The starting material N-tert.-butyl-N-propylhydrazino-acetonitrile required under a) is prepared in the following way:
a solution of 20.0 g of potassium cyanide in 70 ml of water is added dropwise to an ice-cooled mixture of 36.3 g of N-tert.-butyl-N-propylhydrazine, 28.0 ml of 10 N hydrochloric acid and 170 ml of water, and the pH is adjusted to 7 with hydrochloric acid. ~hen 21.5 g of a 39 % strength formaldehyde solution are added, the fall in pH is concentrated by adding a sodium car-bonate solution, and the reaction mixture is stirred at 0C for 2 hours and at room temperature for a further 20 hours. The pro-duct is extracted with ethyl acetate, and the organic phase iswashed with dilute glacial acetic acid and dried over sodium sulphate. Remaining after concentration is an oily residue (39.2 g) which is further processed as in a) without further purification.
Example 3 3-(N-tert.-Butyl-N-propylamino)-N-(2,2-dimethylpropionyl)sydnone imine 2.8 g of 3-(N-tert.-butyl-N-propylamino)sydnone imine hydrochloride prepared as in Example 2a) are dissolved in 40 g of water and, at 0, 2.5 g of sodium bicarbonate and, after stirring for 5 minutes, a solution of 1.6 g of pivaloyl chloride in 40 ml of ethyl acetate are added. The reaction mixture i8 stirred at room temperature for 5 hours, and then the phases are ~eparated, the aqueous phase is extracted once more by shaking with ethyl acetate, and the combined organic phases are dried, and the volatile components are stripped off in vacuo. The residue is recrystallised from petroleum spirit.
Yield: 0.95 g Melting point: 96-98 (decomp.) z~
Example 4 3-(N-tert.-Butyl-N-propylamino)-N-(nicotinoyl)sydnone imine 2.8 g of 3-(N-tert.-butyl-N-propylamino)sydnone imine hydrochloride prepared as in Example 2a) are introduced into a stirred solution of 3.4 g of nicotinoyl chloride in 30 ml of pyridine with external cooling. After stirring at room tempera-ture for 16 hours, the volatile components are ctripped off in vacuo, the residue i taken up in water and methylene chloride, the aqueous phase is extracted by shaking twice with methylene chloride, and the combined organic phases are dried and then concentrated in vacuo. The residue is recrystallised from petroleum spirit.
Yield: 1.30 g Melting point: 93-95 lS Example 5 3-(N-tert.-Butyl-N-propylamino)-N-(4-methoxybenzoyl)sydnone imine 2.8 g of 3-(N-tert.-butyl-N-propylamino)sydnone imine hydrochloride prepared as in Example 2a) are dissolved in 40 g of water and, at 0, 2.5 g of ~odium bicarbonate and, after stirring for 5 minutes, a solution of 2.25 g of anisoyl chloride in 40 ml of ethyl acetate are added. The reaction mixture is stirred at room temperature for 5 hours and then the phases are separated, the aqueous phase iæ extracted once more by shaking with ethyl acetate, and the combined organic phases are dried and the volat-ile components are stripped off in vacuo. The residue crystal-li~es on ~tirring with diethyl ether, and it is filtered off with suction, washed with ether and dried.
Yield: 1.80 g Melting point: 90-92 Exam~le 6 3-(N-tert.-Butyl-N-butylamino)sydnone imine hydrochloride a) 27.62 g of sodium nitrite are added to a solution of 66.7 g of N-tert.-butyl-N-n-butylhydrazinoacetonitrile in 75 ml of water and 33 ml of concentrated hydrochloric acid at 0-5C.
The reaction mixture i8 stirred at room temperature for 2 hours and then extracted with methylene chloride, and the methylene chloride is dried and eolvent is removed in vacuo. The oily re~idue (about 60 g) is cooled in ice and 140 ml of an approxi-mately 10 % strength solution of hydrogen chloride in ethyl ~ n~
P~ v ~
acetate is added and the mixture is left to stand at 0 to 5C for 20 hours. The resulting precipitate is filtered off with suction, chromatographed on a silica gel column with a 95:5-90:10 mixture of methylene chloride and methanol, and the fraction which con-tains the required compound is concentrated.
Yield: 12. 41 g Melting point: 129-133 (decomp.) b) The starting material N-tert.-butyl-N-n-butylhydrazino-acetonitrile required for a) is prepared in the following way:
10 21. 6 g of sodium cyanide are added to an ice-cooled mixture of 53.0 g of N-tert.-butyl-N-n-butylhydrazine, 32.0 ml of concen-trated hydrochloric acid and 100 ml of water, and the pH is adjusted to 7.5 with hydrochloric acid. Then 33 . 9 g of a 39 %
strength formaldehyde solution are added dropwise, the pH is readjusted to about 7.5 with a 15 ~ strength sodium carbonate solution, and the reaction mixture is stirred for 24 hours. Then a further 4 . 32 g of sodium cyanide and 6.78 g of formaldehyde solution are added, and the mixture is again stirred at room temperature for 8 hours. The solution is extracted with methylene chloride, the methylene chloride phase is dried and the solvent is removed in vacuo. Remaining after concentration is an oily residue (67.2 g) which is further processed as in a) without further purification.
Examl~le 7 2 5 3- ( N-tert.-Butyl-N-n-butylamino)-N-(ethoxycarbonyl)sydnone imine 3.0 g of 3-(N-tert.-butyl-N-n-butylamino)sydnone imine hydrochloride are dissolved in 30 ml of water, and 2 . 77 g of sodium bicarbonate are added. A solution of 1. ~3 g of ethyl chloroformate in 30 ml of methylene chloride is added dropwi~e to this solution. After ~tirring at room temperature for 1 1/2 hour8~ the organic phase is separated off, the aqueous phase is extracted several times with methylene chloride, the combined organic phases are dried and solvent i~ removed under waterpump vacuum. The residue is chromatographed on a silica gel column with a 98:2 mixture of methylene chloride and methanol, and the fraction which contains the required compound is concen-trated.
Yield: 3. 60 g Melting point: - (oil~

2~
Example 8 3-(N-tert.-Butyl-N-methylamino)-N-(benzoyl)sydnone imine as described in Example 7 using 2.12 g of benzoyl chloride in place of ethyl chloroformate.
Yield: 1.50 g Melting point: - (oil) Pharmaceutical products are described .in Examples A to F
which follow.
Example A
10 Soft qelatin capsules containing 5 mg of active substance per capsule:
per capsule Active substance 5 mg Triglyceride mixture fractionated from coconut fat 150 mg Capsule contents 155 mg Example B
Injection solution containing 1 mg of active substance per ml:
per ml Active substance 1.0 mg Polyethylene glycol 400 0.3 ml Sodium chloride 2.7 mg Water for injections ad 1 ml Example C
Em~lsion containing 3 mg of active ~ubstance per 5 ml:
E~- 100 ml of emulsion Active substance 0.06 g Neutral oil q.s.
Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.~.
Glycerol, pure 0.2 to 2.0 g Flavouring q.s.
Water (deionised or distilled~ ad100 ml Example D
Rectal drug form containing 4 mg of active substance per suppository per suppository Active substance 4 mg Suppository base ~ ad 2 g Example E
Tablets containing 2 mg of active substance per tablet per tablet Active substance 2 mg Lactose 60 mg Maize starch 3Q mg Soluble starch 4 mg Magnesium stearate 4 mg 100 mg Example F
Sugar-coated tablets containing 1 mg of active substance per tablet Per tablet Active substance 1 mg Maize starch 100 mg Lactose 60 mg sec calcium phosphate 30 mg Soluble starch 3 mg Magnesium stearate 2 mg Colloidal silica 4 mg 200 mg

Claims

1. A 3-aminosydnone imine of the general formula I

(I) and a pharmacologically acceptable acid addition salt thereof, in which R1 denotes alkyl with 1 to 6 C atoms;
R2 denotes hydrogen or the radical -COR3; and R3 denotes an aliphatic radical with 1 to 4 C atoms, which may be substituted by alkoxy with 1 to 3 C atoms; a cyclo-aliphatic radical with 5 to 7 C atoms; a bicycloaliphatic radical with 7 to 14 C atoms; a tricycloaliphatic radical with 7 to 16 C
atoms; an alkoxy radical with 1 to 6 C atoms; an aryloxy radical with 6 to 10 C atoms; an alkoxycarbonyl radical with a total of

2 to 7 C atoms; an aryl radical with 6 to 10 C atoms; an aryl radical which has 6 to 10 C atoms and is mono-, di- or trisub-stituted by 1 to 3 halogen atoms and/or 1 to 3 alkyl radicals with 1 to 3 C atoms and/or 1 to 3 alkoxy radicals with 1 to 3 C atoms and/or 1 or 2 nitro groups; or a five- or six-membered heterocycle which can have 1 to 3 nitrogen, oxygen and/or sulphur atoms as ring members and can also be benzo-fused.

2. A 3-aminosydnone imine according to Claim 1, wherein R1 denotes methyl, ethyl, n-propyl or n-butyl.

3. A 3-aminosydnone imine according to Claim 1 or 2, wherein R3 denotes alkyl with 1 to 4 C atoms; alkoxy with 1 to 4 C atoms; phenyl; phenyl or pyridyl which is substituted by halogen and/or nitro or alkoxy with 1 to 3 C atoms.

4. A 3-aminosydnone imine according to Claim 1 or 2, wherein R3 denotes methyl, ethyl, n-propyl, isopropyl, tert.-butyl, methoxy, ethoxy, phenyl, 2-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-ethoxyphenyl or 3-pyridyl.

5. A process for the preparation of the compounds of the general formula I according to Claim 1 or 2, which comprises cyclising a compound of the general formula II

(II) in which R1 has the meanings indicated in Claim 1 or 2, to give a compound of the formula Ia (Ia) or an acid addition salt thereof, and, if required, isolating the free compound from the acid addition salt, and, in the case where a compound of the formula I with R1 = -COR3 is prepared, acylating the compound of the formula Ia or an acid addition salt thereof with an acylating agent which introduces the radical -COR3, and, if required, converting the resulting compound into an acid addition salt.

6. A process according to Claim 5, wherein the cyclisation is carried out in a solvent, dispersant or diluent, at a temperature of from about -10 to about 40°C, with the aid of a cyclising agent which sets up a pH below 3 in aqueous solution.

7. A process according to Claim 6, wherein the cyclisation is carried out at a temperature of from about 0°C to about 20°C.

8. Use of a 3-aminosydnone imine of the general formula I according to Claim 1 or 2 or a pharmacologically acceptable acid addition salt thereof for controlling and preventing cardiovascular diseases.

9. A pharmaceutical composition comprising an effective amount of a 3-aminosydnone imine of the general formula I according to Claim 1 or 2 or a pharmacologically acceptable acid addition salt thereof in admixture with pharmaceutically acceptable diluent or carrier.

10. A commercial package containing as an active pharma-ceutical ingredient a 3-aminosydnone imine of the general formula I according to Claim 1 or 2 or a pharmacologically acceptable acid addition salt thereof, together with instructions for the use thereof for controlling and preventing cardiovascular diseases.