DE4209462A1 - Treatment of impotence - Google Patents

Abstract

Treatment of erectile dysfunction comprises admin. of sydnonime of formula (I) or salt. In (I), R1 is -NR4R5; 2-R6-1-piperidinyl; N-R6-N-(1,1-dioxo-tetrahydrothiophen-3-yl)-amino; or a gp. of the formula (a) or (b); A is H; COOH; or 2,2-dialkyl, 2,6-dialkyl or 2,2,6,6-tetraalkyl substitution; R2 is H; hal; alkyl opt. substd. by Ar, ArO, ArS, alkoxy, alkylthio or alkenylthio; or cycloalkyl; R3 is H; -NO; -SO2R8; or -COR7; R4 is alkyl; alkenyl; cycloalkyl; bi- or tricycloalkyl; alkyl-X-alkyl; aralkyl opt. substd. by alkyl or hal; 1,1-dioxo-tetrahydrothiophen-3-yl; or a heterocyclic gp. bonded via an alkylene chain; R5 is H or R4; R6 is alkyl; R7 is Ar opt. mono-, di- or tri-substd. by hal, alkyl and/or alkoxy and/or opt. mono- or di-substd. by NO2; arylalkenyl; tricycloalkyl; bi- or tricycloalkoxy; ArO; alkoxycarbonyl; pyridyl; pyrrolyl; imidazolyl; pyrazolyl; pyrazinyl; pyrimidinyl; pyridazinyl; OR2; or R2; R8 is alkyl; Ar opt. substd. by alkyl or hal; or dialkylamino; X is NR4; NSO2R8; NCO2alkyl; S(O)n; O; (CH2)m; or a single bond; n is 0-2; and m is 1-3; cpds. (I) where X is O and R2 and R3 are H are excluded.

Description

The present invention relates to the use of Sydnonimines and pharmacologically acceptable salts of which for the treatment of erectile dysfunctions.

About 5% of men in their 40s and 20% in their 60s Years of age suffer from erectile dysfunction. These Disorders require medical treatment because especially patients with chronic erectile dys function in their sexuality and personality secure and are to be regarded as sick.

For the treatment of predominantly until the 1970s potency disorders attributed to psychological causes in addition to psychotherapeutic measures were testosterone or aphrodisiacs of controversial value. First by researching the physiology of erectile dysfunction It was found that more than 60% of the Pa organic causes that cause erectile dysfunction ken, with autonomous efferences from the parasympathetic Proportion of the sacral marrow, neurotransmitter, dilation of the Penile arteries, relaxation of the cavernous spaces and con stricture of the veins play a role. In over 70% of the Cases such as vascular factors are involved pathological arterial blood supply or abnormal increased venous outflow from the cavernous spaces. About 20% of neurogenic disorders are involved.

Oral therapy for this organic dysfunction with vasoactive substances such as yohimbine, phenoxy benzamine, terbutaline, Bethanechol, Levodopa, Verapamil or theophylline was unsuccessful. In addition to the Use of prosthetic implants or revasculari surgery proved to be an intracavernous In  injection of papaverine (Virag, Lancet, 2, 938, 1982), the α-receptor blockers phenoxybenzamine (Brindley, Br. j. Psychiatr., 143, 332, 1983) and a combination of Papaverin and the α-receptor blocker phentolamine (Stief, Urologe A, 25, 63, 1986) as successful. The latter therapy method can be used by the patient himself perform constantly and is also used as a erectile tissue Auto Injection Therapy (SKAT).

However, a partially unsuccessful disadvantage wishes prolonged erection with the risk of priapis mus when using papaverine, undesirable Painful when using phenoxybenzamine as well as a possible carcinogenicity of this compound.

In animal experiments (cynomolgus), 1-2 Intra-cavernous injections of papaverine weekly over 12 Fibroizations of large parts of the Erectile tissue found, which in humans too extreme would lead to negative long-term results, since one Fibroization of the cavernous body no longer an erection can be done.

The use of acetylcholine is associated with strong systemic side effects in the case of a short-term erection and the injection of prostaglandin E ₁ is rejected by the patient because of excessive pain.

The object of the invention was therefore the development and manufacture Provision of drugs for the treatment of neurogenic, arterial, neurotransmitter-related, myopathic, venous or psychogenic erectile dysfunction without the mentioned side effects.

Surprisingly, it has now been found that this task can be solved by Sydnonimine.  

Sydnonimines are compounds whose pharmacology does has long been known (chemistry in our time, 13th year, Page 51 (1984)), whereby in addition to the vasodilating ins also described the antithrombotic effects ben (J. Cardiovasc. Pharmacol. 1989, 14 (Suppl. 11), Page 129). Sydnonimine can be used as a preventative and treatment of diseases of the cardiovascular system tems are used and are commercially available as such.

The present invention thus relates to the use of sydnonimines of the general formula I

or a pharmacologically acceptable salt thereof, wherein
R ^{1 is} an amino group of the formula

means;
R ^{2 represents} hydrogen, alkyl, cycloalkyl, arylalkyl, aryl-O-alkyl, aryl-S-alkyl, alkoxyalkyl, alkylthioalkyl or alkenylthioalkyl;
R ^{3 represents} hydrogen or the group -COR ⁷ ;
R ^{4 represents} alkyl, cycloalkyl, alkyl-X-alkyl, arylalkyl or hydroxyalkyl;
R ^{5 represents} hydrogen or has one of the meanings of R ⁴ ;
R ^{6 represents} alkyl;
R ^{7 is} aryl, by 1 to 3 halogen atoms and / or 1 to 3 alkyl radicals and / or 1 to 3 alkoxy radicals and / or 1 or 2 nitro groups, mono-, di- or tri-substituted aryl radical or OR ² or one of the meanings of R Has ² ;
X represents NR ⁴ , NSO ₂ R ⁸ , NCO ₂ alkyl, S (O) _n O, CH ₂ or a single bond;
Y is NR ⁴ , NSO ₂ R ⁸ , NCO ₂ alkyl, S (O) _n , CH ₂ or a single bond;
n is 0, 1 or 2 and
R ⁸ denotes alkyl, aryl, alkylaryl or dialkylamino,
to treat erectile dysfunction.

Alkyl residues and alkenyl residues can be straight-chain or ver be branched and preferably have 1 to 6 carbon atoms, esp but preferably 1-4 carbon atoms. This also applies if they are in Connect with other groups, e.g. B. as alkoxy, arylal kyl etc. are available.

Examples of alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. Cycloalkyl preferably has 5 to 7 carbon atoms and is particularly preferably cyclopentyl and cyclohexyl. Aryl preferably has 6 to 10 carbon atoms and is particularly preferably α- or β-naphthyl or phenyl. Arylalkyl is preferably benzyl and phenylethyl. Aryl-O-alkyl is preferably phenoxymethyl and phenoxy ethyl. The same applies to aryl-S-alkyl. The aryl radicals representing R ⁷ can be mono-, di- or trisubstituted, although only a maximum of 2 nitro groups can be present even when trisubstituted, such as 2-methyl-4, 6-dinitrophenyl and 2-chloro-6- methyl-4-nitrophenyl. As halogen substituents for the aryl radicals come, for. B. chlorine and bromine atoms in Be. Aryl radicals which stand for R ⁷ are to be mentioned in particular: methylphenyl (= tolyl), nitrophenyl and chlorophenyl, in particular 4-nitrophenyl and 4-chlorophenyl.

Preferred radicals R ₁ are piperidino, pyrrolidino, dimethylamino, diethylamino, diisopropylamino, tert-butyl methylamino, tert-butyl-ethylamino, tert-butyl-propyl amino, tert-butyl-butylamino, tert-butyl-hydroxyethyl amino, dibenzylamino, 2-carboxy -pyrrolidino, 2-carboxy piperidino 4-carboxypiperidino, dicyclohexylamino, N-methylpiperazino, 2, 2-dimethylpiperidino, 3.3-dimethyl morpholino, 3.3-dimethylthiomorpholino, 3.3-dimethyl-1. 1-dioxothiomorpholino, 3. 3-dimethyl- 1-oxo-thiomorpholino, cis-2,6-dimethylpiperidino, 2.2.6.6-tetramethyl piperidino, 2.2-dimethyl-N-methylsulfonyl-piperazino, 2. 2-dimethyl-N-tosyl-piperazino, 2.2-dimethyl-pyrrolidino no, 2.2 -Dimethyl-N-dimethylaminosulfonyl-piperazino, ethylamino, (2-hydroxyethyl) -amino and cyclohexylamino. Preferred radicals R ₂ are hydrogen, methyl, ethyl, propyl, isopropyl and butyl, with hydrogen being particularly preferred.

Preferred radicals R ₃ are hydrogen, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, aniso yl, hydrogen is particularly preferred.

Pharmacologically acceptable salts of the Sydnonimine der general formula I are in particular acid additions salts with inorganic or organic acids. Appropriate Nete acids are, for example, hydrogen chloride, bromine hydrogen, naphthalene disulfonic acids, in particular Naphthalene disulfonic acid (1.5), phosphoric, nitric, Sulfur, oxal, milk, wine, vinegar, salicyl, ben zoe, ants, propion, pivaline, diethyl vinegar, malon, Amber, pimeline, fumar, malein, apple,  Sulfamine, phenylpropion, glucon, ascorbin, isonico tin, methanesulfone, p-toluenesulfone, lemon or Adipic acid. The hydrochlorides are particularly preferred.

The production of the sophisticated Sydnonimine as well their pharmacologically acceptable salts are known and for example in DE-OS-16 20 501; DE-OS-16 70 127; DE-OS-16 95 897; EP-A-23343; EP-A-59356; EP-A-76952; EP-A-210474; EP-A-276710; EP-A-312773; EP-A-324408; EP-A-346684; EP-A-346694; EP-A-367036; EP-A-406659 and EP-A-406661.

It is usually convenient to do the demanding ones Sydnonimine in a pharmaceutical preparation too administer. Parenteral and topical forms of application such as lotions, Creams, solutions, gels, sprays, elastic liquid plas ter, transdermal systems or coatings for condoms in question.

Parenteral administration is preferred since it is the The safest form is a targeted amount of active ingredient targeted without further adulteration by other factors to use.

Preparations for parenteral administration contain 0.1 to 5 mg, preferably 0.1 to 2 mg of sydnonimine in general NEN Formula I per dose unit and can be in separate Dosage unit forms such as B. ampoules or vials Solutions of the active ingredient are preferably used det, preferably aqueous solutions and especially isotoni solutions, but also suspensions. This injection molds can be provided as a finished product or by mixing just before use the active compound, e.g. B. of the lyophilisate if necessary with other solid carriers, with the ge  desired solvent or suspending agent the. For topical application forms is a matter of course Lich a higher active ingredient concentration than that for called parenteral preparations.

Parenteral and topical forms can be sterilized and / or optionally auxiliaries such as preservatives agents, stabilizers, wetting agents, penetrants, Emulsifiers, spreading agents, solubilizers, salts for Regulation of osmotic pressure or for buffering and / or contain viscosity regulators.

Such additives are e.g. B. tartrate and citrate buffers, Ethanol, complexing agent (such as tetraacetic ethylenediamine acid and its non-toxic salts). To regulate the Viscosity, high molecular weight polymers come into question as for example liquid polyethylene oxide, carboxymethyl cellulosic, polyvinylpyrrolidones, dextrans or gelatin. Solid carriers are e.g. B. starch, lactose, mannitol, Methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, Agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers such as Polyethylene glycol.

Oily suspensions for parenteral or topical applications dung can be vegetable synthetic or semi synthetic table oils such as liquid fatty acid esters each 8 to 22 carbon atoms in the fatty acid chains, e.g. B. Palmitin, laurin, tridecyl, margarine, stearin, Arachine, myristic, behen, pentadecyl, linoleic, Elaidinic acid, brasidinic acid, erucic acid or oleic acid to trihydric alcohols with 1 to 6 carbon atoms as in for example methanol, ethanol, propanol, butanol, penta nol or their isomers, glycol or glycerol esterified be. Such fatty acid esters are, for example, han  standard Miglyole, Isopropylmyristat, Isopropylpalmi tat, isopropyl stearate, PEG 6-capric acid, cypryl / caprin acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters like artificial duckling glandular fat, coconut fatty acid isopropyl ester, oleic acid oleyl ester, oleic acid decyl ester, Lactic acid ethyl ester, dibuthyl phthalate, adipic acid diiso propyl ester, polol fatty acid ester and the like. a. Also suitable are silicone oils of different viscosities or fatty alcohols get like isotridexyl alcohol, 2-octyldodecanol, cetyl stearyl alcohol or oleyl alcohol, fatty acids as in for example oleic acid. Vegetable oils such as Castor oil, almond oil, olive oil, sesame oil, cottonseed oil, Use peanut oil or soybean oil. The ge mentioned substances also have the properties of a Spreading agent, d. H. there is a particularly good ver division on the skin.

Com as a solvent, gelling agent and solubilizer men in question water or water-miscible solvents tel. Are suitable for. B. alcohols such as Ethanol or isopropyl alcohol, benzyl alcohol, 2-octyl dodecanol, polyethylene glycols, phthalates, adipates, pro pylene glycol, glycerin, di- or tripropylene glycol, Waxes, methyl cellosolve, cellosolve, esters, morpholines, Dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydro furan, cyclohexanone etc.

Cellulose ethers can be used as film formers, which are found in both water and organic solvents can dissolve or swell solvents and after Drying form a kind of film, such as Hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or soluble starches.  

Mixed forms between gel and film formers are quite also possible. Ionic macros come primarily here molecules for use, such as sodium car boxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, algin acidic or propylene glycol alginate as sodium salt, rubber arabicum, xanthan gum, guar gum or carrageenan.

Can be used as additional formulation aids are: glycerin, paraffin of different viscosity, Triethanolamine, collagen, allantoin, novantisol acid, Perfume oils.

The use of surfactants, emulsifiers or wetting means may be necessary for the formulation, such as. B. of Na lauryl sulfate, fatty alcohol ether sulfates, di-Na-N- lauryl-β-iminodipropionate, polyoxyethylated Rizi nut oil or sorbitan monooleate, sorbitan monostearate, Cetyl alcohol, lecithin, glycerol monostearate, polyoxy ethylene stearate, alkylphenol polyglycol ether, cetyltri methyl ammonium chloride or mono- / dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts.

Stabilizers such as montmorillonite or colloidal kie acids for stabilizing emulsions or for ver preventing the breakdown of active substances such as antioxidants dantien, for example tocopherols or butylhydroxy anisole, or preservatives such as p-hydroxybenzoe acid esters can also be used to prepare the ge desired formulations may be required be.

To promote penetration contain transdermal Formulations preferably organic, well tolerated by the skin Liche solvents such as ethanol, methylpyrrolidone, poly ethylene glycol, oleyl alcohol, octanol, linoleic acid, tri  acetin, propylene glycol, glycerin, solketal or dimethyl sulfoxide.

Due to the light sensitivity of the Sydnonimine the general formula I it is appropriate to the presentation form photostabilizers or add them in ent to provide appropriately light-protecting packaging, such as in opaque, disposable products inject.

Compounds such as can be used as photostabilizers Quinolines, e.g. B. 8-hydroxyquinoline or quinoline yellow; suitable food colors; Flavanoids such as B. Hesperidin, hesperidin-methylchalcon, hesperidin phosphate, Hesperitin, quercetin, quercitrin, rutin, rutin sulfate, Naringenin, fighter oil, fighter oil 7,4′-dimethyl ether, Morin, Apigetrin, Luteolin and its 7-glycoside, or Troxerutin. They are in the quantitative ratio of 0.001: 1 to 50: 1, preferably 0.1: 1 to 20: 1 added.

The production, filling and sealing of the pre parate takes place under the usual antimicrobial and aseptic conditions. Also for topical relationships wise transdermal use, packaging is possible if possible in separate dose units to facilitate the Handling, also here as with parenteral forms otherwise, for stability reasons, by separate packaging of the active ingredients or their combinations as Lyophilisate, optionally with solid carriers, and the necessary solvents etc.

In a particular embodiment of the invention, the sydnonimines of the general formula I are used in combination with one or more synergistic substances. Such synergistic substances are, for example, adenosine, vitamins, e.g. B. Vitamin A or H, prostaglandins, e.g. B. E ₁ , peptides such. B. Calcitonine gene related peptides (CGRP), calcium antagonists such as nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine, prenylamine, fendiline, terodiline, nisaldipine, nitrendipine or perhexiline, α-receptor blocker methane, for example or Minoxidil, relaxants of smooth muscles such as papaverine, trinitroglycerin, sodium nitroprusside or S-nitroso-N-acetylpenicillamine.

Particularly advantageous and also subject matter the invention includes a disposable medicament pack tends to be a single-use syringe with a parenteral preparation of a sydnonimine of general NEN Formula I, optionally in combination with a synergistic substance; with disinfectant provided sterile swabs and usage information nen.

The disposable syringes mentioned are preferably from Type ultra-fine, such as that found in insulin therapy. Syringes are also preferred in the way of auto injectors that are even easier in are their handling. The pre-filled syringes are preferred executed in an opaque form because the addition of photostabilizers to the parenteral ones Preparations are unnecessary. However, you can also do so forms that active ingredient and associated injection Solvent mixed just before injection will. This can e.g. B. in two-container ampoules or Injections happen. This may result in a required photostabilizer additive also unnecessary gene.  

The sterile swabs for disinfection contain the usual Chen agents for skin disinfection such as Ethanol. However, you can also do additional erection-promoting agents in a topically applicable Contain form to increase or prolong the effect ten.

example 1

To prepare a solution for injection, 500 mg 3- (3,3-Dimethyl-thiomorpholino) -sydnonimine hydrochloride and 750 mg NaCl dissolved in distilled water, with 1N Hydrochloric acid adjusted to pH 4.0 with distilled Water made up to 100 ml and in 0.5 ml ampoules packed.

In the same way, white can be produced the following Sydnonimine ver turn:

• 2. 300 mg of 3-dibenzylamino-sydnonimine hydrochloride
• 3. 400 mg of 3- (cis-2,5-dimethyl-pyrrolidino) -sydnonimine hydrochloride
• 4. 600 mg of 3- (3,3-dimethyl-1,1-dioxothiomorpholino) sydnonimine hydrochloride
• 5. 500 mg of 3- (2,2-dimethylpiperidino) sydnonimine hydrochloride
• 6. 400 mg of 3- (3,3-dimethyl-morpholino) -sydnonimine hydrochloride
• 7. 500 mg of 3- (tert-butyl-methylamino) -sydnonimine hydrochloride
• 8. 300 mg of 3- (dicyclohexylamino) -sydnonimine hydrochloride
• 9. 400 mg of 3-diisopropylamino-sydnonimine hydrochloride
• 10. 500 mg of 3- (tert-butyl-ethyl-amino) -sydnonimine hydrochloride
• 11. 550 mg of 3- (tert-butyl-propyl-amino) -sydnonimine hydrochloride  
• 12. 550 mg of 3- (tert-butyl-butyl-amino) -sydnonimine hydrochloride
• 13. 300 mg of 3- (tert-butyl-hydroxyethyl-amino) -sydnonimine hydrochloride
• 14. 750 mg of 3- (cis-2,6-dimethyl-piperidino) sydnonimine hydrochloride
• 15. 750 mg of 3- (2.2.6.6-tetramethyl-piperidino) -sydnonimine hydrochloride
• 16. 400 mg of 3- (N-methyl-piperazino) -sydnonimine hydrochloride
• 17. 700 mg of 3- (2-carboxypyrrolidinone) sydnonimine hydrochloride
• 18. 700 mg of 3- (2-carboxypiperidino) sydnonimine hydrochloride
• 19. 400 mg of 3- (1,1-dioxothiomorpholino) sydnonimine hydrochloride
• 20. 400 mg of 3- (2,2-dimethyl-4-methylsulfonyl-piperazino) sydnonimine hydrochloride
• 21. 500 mg of 3- (2,2-dimethyl-4-tosyl-piperazino) sydnonimine hydrochloride
• 22. 250 mg of 3-ethylamino-sydnonimine hydrochloride
• 23. 500 mg of 3- (2-hydroxyethylamino) sydnonimine hydrochloride
• 24. 250 mg of 3-methylamino-sydnonimine hydrochloride
• 25. 350 mg of 3-cyclohexylamino-sydnonimine hydrochloride
• 26. 400 mg of 3-piperidino-4-methyl-sydnonimine hydrochloride
• 27. 500 mg of 3-dimethylamino-4-ethyl-sydnonimine hydrochlori d
• 28. 500 mg of 3-diisopropylamino-4-isopropyl-sydnonimine hydrochloride
• 29. 600 mg of N-formyl-3- (2,2-dimethyl-thiomorpholino) sydnonimin
• 30. 750 mg of N-acetyl-3-diethylamino-sydnonimine
• 31. 800 mg of N-propionyl-3- (3,3-dimethyl-thiomorpholino) sydnonimin
• 32.950 mg of N-ethoxycarbonyl-3- (2,2-dimethyl-4-isopropyl  piperazino) -sydnonimine
• 33. 1.5 g of N-p-anisoyl-3- (cis-2,6-dimethyl-piperidino) sydnonimin
• 34. 1.0 g of N-pivaloyl-3- (2,2-dimethyl-1-oxothio morpholino) -sydnonimine
• 35. 350 mg of 3- (4-ethoxycarbonyl-piperazino) sydnonimine hydrochloride.

Claims (7)

1. Use of sydnonimines of the general formula I or a pharmacologically acceptable salt thereof, wherein:
R ^{1 is} an amino group of the formula means;
R ^{2 represents} hydrogen, alkyl, cycloalkyl, arylalkyl, aryl-O-alkyl, aryl-S-alkyl, alkoxyalkyl, alkylthioalkyl or alkenylthioalkyl;
R ^{3 represents} hydrogen or the group -COR ⁷ ;
R ^{4 represents} alkyl, cycloalkyl, alkyl-X-alkyl, arylalkyl or hydroxyalkyl;
R ^{5 represents} hydrogen or has one of the meanings of R ⁴ ;
R ^{6 represents} alkyl;
R ^{7 is} aryl, by 1 to 3 halogen atoms and / or 1 to 3 alkyl radicals and / or 1 to 3 alkoxy radicals and / or 1 or 2 nitro groups, mono-, di- or tri-substituted aryl radical or OR ² or one of the meanings of R Has ² ;
X represents NR ⁴ , NSO ₂ R ⁸ , NCO ₂ alkyl, S (O) _n , O, (CH ₂ or a single bond;
Y is NR ⁴ , NSO ₂ R ⁸ , NCO ₂ alkyl, S (O) _n , CH ₂ or a single bond;
n is 0, 1 or 2 and
R ⁸ denotes alkyl, aryl, alkylaryl or dialkylamino, for the treatment of erectile dysfunctions. 2. Use according to claim 1, characterized in that R ¹ piperidino, pyrrolidino, dimethylamino, diethyl amino, diisopropylamino, tert-butyl-methylamino, tert-butyl-ethylamino, tert-butyl-propylamino, tert-butyl-butylamino, tert-butyl- hydroxyethylamino, di benzylamino, 2-carboxy-pyrrolidino, 2-carboxypiperidino, 4-carboxypiperidino, dicyclohexylamino, N-methylpiperazino, 2,2-dimethylpiperidino, 3,3-dimethylmorpholino, 3,3-dimethylthiomorpholino, 3,3-dimethyl-1.1-dioxo thio morpholino, 3,3-dimethyl-1-oxo-thiomorpholino, cis-2,6-dimethylpiperidino, 2.2.6. 6-tetramethylpiperidino, 2,2-dimethyl-N-methylsulfonyl-piperazino, 2,2-dimethyl-N-tosyl-piperazino, 2,2-dimethyl-pyrrolidino, 2,2-dimethyl-N-dimethylaminosulfonyl-piperazino, ethylamino, (2-hydroxyethyl) amino or Cyclohexylamino means. 3. Use according to claim 1 and / or 2, characterized in that R ^{2 is} hydrogen. 4. Use according to one or more of claims 1 to 3, characterized in that R ^{3 means} hydrogen. 5. Use according to one or more of claims 1 to 4, characterized in that the Sydnonimin der general formula I in combination with an or  used several synergistic substances becomes. 6. Use according to claim 5, characterized in that that the synergistic substance is an adenosine, Vitamin, peptide, calcium antagonist, α-receptors smooth muscle blocker or relaxant. 7. Disposable medicament pack containing in sterile packaging

• a single-use syringe with a parenteral preparation of a sydnonimine of the general formula I according to one or more of claims 1 to 4, if appropriate in combination with a synergistically active substance according to claim 5 and / or 6;
• - sterile swabs provided with disinfectants and
• - usage information.