EP1087926A2 - Analytic substrates and antioxidative agents - Google Patents

Abstract

The invention relates to novel analytic substrates which, in particular, can be used in biochemical and pharmacological analyses or as medicaments.

Description

 ANALYTICAL SUBSTRATES AND ANTIOXIDATIVE AGENTS

Field of application of the invention The present invention relates to new analytical substrates and antioxidative agents which can be used in particular in biochemical and pharmacological studies. It further relates to the use of therapeutically usable active substances and their derivatives as antioxidant agents. The invention is applicable in the pharmaceutical industry and is used to provide pharmaceutical preparations with, inter alia, an antioxidant effect.

Known Technical Background Organic nitric acid esters such as glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythrityl tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), US Pat. 2370437), isosorbide-5-mononitrate (ISMN) (DE-OS-2221080, DE-OS-2751934, DE-OS-3028873, DE-PS-2903927, DE-OS-3102947, DE-OS-3124410, EP- A1- 045076, EP-A1 -057847, EP-A1 -059664, EP-A1-064194, EP-A1 -067964, EP-A1 -143507, US-PS-3886186, US-PS-4065488, US-PS- 4417065, US-PS-4431829), Isosorbide Dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), Propatyl Nitrate (Medard, Mem. Poudres 35: 113 (1953)), Trolnitrate (FR- PS-984523) or Nicorandil (US-PS-4200640) and similar compounds are vasodilators, some of which have been used for decades for a wide range of therapeutic applications (Nitrangin®, Pentalong®, Monolong®), mainly in the indication of angina pectoris or ischemic heart disease (IHK) , etc.). Likewise, further pentaerythrityl nitrates and their representation have been described (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363; Camp et al., J. Am. Chem. Soc. 77 (1955), 751). Comparable and improved pharmacological activity when used in the above-mentioned indication areas are said to have more recent organic nitrates such as SPM 3672 (N- [3-nitratopivaloyl] -L-cysteine ethyl ester) (US Pat. No. 5284872) and its derivatives. The production of 3-nitryloxy-2,2-bis (nitryloxymethyl) propionic acid and its methyl ester (Nee, Chem. Prum. (1978), 28 (2), 84) and of newer compounds derived from pentaerythrityl tetranitrate ( WO-A1 -98/15521). The galenic processing of the organic nitrates into pharmaceutical preparations for the treatment of angina pectoris or ischemic heart disease are generally known. It is carried out in accordance with the working methods and rules which are generally familiar to the pharmaceutical expert, the choice of the technologies to be used and the pharmaceutical auxiliaries used being based primarily on the active ingredient to be processed. Here are questions of his Chemical-physical properties, in particular the explosive properties known to adhere to the organic nitrates, which requires special safety precautions and special processing technologies to be observed, the chosen form of application, the desired duration of action and the avoidance of drug-auxiliary incompatibilities of particular importance. For medicinal products with the indication angina pectoris or ischemic heart disease, peroral, parenteral, sublingual or transdermal application in the form of tablets, dragees, capsules, solutions, sprays or plasters is described above (DD-A5-293492, DE-AS-2623800 , DE-OS-3325652, DE-OS-3328094, DE-PS-4007705, DE-OS-4038203, JP application 59/10513 (1982)). In addition to the long-known applications of nitrosating substances, their use for the treatment and prevention of diseases is described which are caused by pathologically increased concentrations of sulfur-containing amino acids in body fluids. These disease states, caused by congenital or acquired defects in the metabolism of these amino acids and which are characterized by increased blood and urine concentrations of said amino acids (homocystinuria), are summarized under the term homocysteinemia (WO-A1 -92/18002). The use of certain organic nitric acid esters as endothelial protective agents (DE-A1 -4410997) and as agents for the treatment of erectile dysfunction (WO-A1 -96/32118) have recently been described. On the one hand, the known organic nitrates (nitric acid esters) have a number of therapeutic disadvantages. For example, the so-called nitrate tolerance can be observed, ie the decrease in the nitrate effect at high doses or when long-acting nitrates are applied. Side effects such as headache, dizziness, nausea, weakness, reddening of the skin and the risk of a greater drop in blood pressure with reflex tachycardia are also documented (Mutschier, drug effects, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). On the other hand, PETN has a number of outstanding properties as an active ingredient, which justify the preferred use of this compound as a pharmaceutical over other organic nitrates (series "Pentaerythrityltetranitrat", Dr. Dietrich Steinkopff Verlag, Darmstadt, 1994 to 1997). The fact that despite of the broad therapeutic use of pentaerythrityl tetranitrate mentioned, relatively little is known about the metabolism and the effect of its metabolites (ibid.) In general, the occurrence of the metabolites pentaerythrityltri (PETriN), pentaerythrityldi (PEDN) and pentaerythrityl mononitrate (PEMN) is both free and as free also postulated in conjugated form (Crew et al., Biochem. Pharmacol. 20 (1971), 3077). The metabolism of GTN and other organic nitrates, on the other hand, has been extensively investigated (Taylor et al., Prog. Drug Metab., 10 (1987), 207). It was found, among other things, that organic nitrates have a pronounced oxidative effect on compounds carrying thiol groups (Boschan et al., Chem. Rev. 55, 485 (1955); Taylor et al., Progress in drug metabolism, Vol. 10, 207 ( 1987); Feelisch et al., Methods in Nitric Oxide Research, John Wiley & Sons, Chichester, 1996)). Furthermore, it is generally accepted and scientifically extensively documented that organic nitrates inevitably trigger counter-regulatory processes via the NO mechanism, for example the formation of angiotensin II in the vascular wall, which form large amounts of superoxide radicals by activation of the endothelial enzyme NADH synthase. which themselves have a strong oxidative effect and immediately react with the NO released from organic nitrates

(Münzel et al., The physiology and pathophysiology of the nitric oxide / superoxide System, Vascular Endothelium (GVR Born, CJ Schwartz edt, p. 205-220, Schattauer Verlag, New York (1997); Harrison, J. Clin. Invest , vol. 100, no. 9 (1997), 2153) Oxidative influences on organisms are generally described as triggering a number of pathological processes (Ernster, Chem. Scr. 26 (1986), 525), the same being limited by the administration of antioxidants such as ascorbic acid (vitamin C) or vitamin E can be counteracted.

DISCLOSURE OF THE INVENTION The object of the invention is to provide or to introduce compounds derived from pentaerythritol as substrates for biochemical and pharmacological studies. Furthermore, it is an object of the invention to provide antioxidative agents and pharmaceutical preparations containing them.

The solution to the problem is described below: A) One embodiment of the invention is compounds of the general formula I,

wherein R1, R2 and R3 are identical or different from one another R4, CH -ONO ₂ , CH ₂ -OR5, CH ₂ - X, COOR5, COX, CH -COOR5, or CH -COX, but at least one of the substituents R1 to R3 is the same R4 is, R4 is CHO, R5 is H or a straight-chain or branched C to C ₆ alkyl radical and X is a halogen.

Preferred embodiments are the compounds of the formulas II to VI.

(II)

B) A further embodiment of the invention are compounds of the formula I in which the group CH ₂ -ONO ₂ which is next to R1 to R3 is additionally one of the others for R1 to

R3 may have the meanings indicated, and their use as substrates for biochemical and pharmacological examinations or as medicaments. C) An additional embodiment of the invention is the use of pentaerythrityl tetranitrate, pentaerythrityl nitrate, pentaerythrityl dinitrate, pentaerythrityl mononitrate or their derivatives as antioxidant agents. The object of the invention is further achieved by antioxidative pharmaceutical preparations containing pentaerythrityl tetranitrate, pentaerythritylthnitrate, pentaerythrityl dinitrate, pentaerythrityl mononitrate or their derivatives. They contain the antioxidant component or a pharmacological precursor thereof in an amount of up to 1000 mg, preferably up to 600 mg, up to 300 mg, up to 150 mg, up to 100 mg, up to 50 mg or in an amount which is below the required dose to achieve this hemodynamic effects. In addition to the compounds listed under A) and B), derivatives which include, for example, pentaerythrityl tetranitrate, pentaerythrityltrinitrate, pentaerythrityl dinitrate, pentaerythrityl mononitrate, are accessible as derivatives in the context of this invention, the following being the terms pentaerythritol residue as a synonym for the term pentaneerythritol residue as a synonym for designating derivatives Oxymethyl group (-CH ₂ -O-) and the term oxidized pentaerythritol residue is used as a synonym for the designation of derivatives of pentaerythrityl tetranitrate with at least one oxidized oxymethyl group, for example -CHO, -COO-, -CH ₂ -CHO or -CH ₂ -COO-. D) One embodiment of derivatives are the compounds of the formulas VII to X,

of formulas XI and XII

of formulas XII and XIV,

as well as Formula XV, where n the substituents R can each independently be H or NO ₂ . E) A further embodiment of derivatives are ether or ester conjugates of pentaerythritol or oxidized pentaerythritol residues with carbohydrates, amino carbohydrates, on acids, in particular gulonic acid, uronic acids, in particular glucuronic acid, sugar acids and derivatives derived therefrom, such as esters of carbohydrate residues with organic or inorganic acids or but esters of on acids, uronic acids or sugar acids with alcohols. A special embodiment of these are ether or ester conjugates of pentaerythritol or oxidized pentaerythritol residues with lactones or dehydrolactones, such as ascorbic acid, from

On acids, uronic acids or sugar acids, in particular glucuronolactone, gulonolactone or 2-ketogulonolactone and their isomers.

Possible starting products for the synthesis of the above compounds are: a) the synthesis precursor of pentaerythritol of the formula XVI,

(XVI) b) pentaerythritol or its nitric acid ester namely pentaerythrityl mono- (PEMN),

Pentaerythrityldi- (PEDN), Pentaerythrityltri- (PETriN) and Pentaerythrityltetranitrat (PETN), which in turn in a manner known per se (Simecek, Coll. Czech. Chem. Comm. 27 (1962),

363; Camp et al., J. Am. Chem. Soc. 77 (1955), 751) are synthetically accessible in good yields. Furthermore, carboxylic acid esters of these compounds (Marans et al., J. Am. Chem. Soc. 76 (1954), 1304) and compounds suitable for synthesis as described in WO-A1 -98/15521. The compounds PEMN, PEDN and PETriN are converted by complete or partial oxidation of existing hydroxymethyl groups into the corresponding tri-, di- or monocarboxylic acids, from which the corresponding nitroxy, hydroxyl and carboxy functions are optionally carried out by partial hydrazinolysis of the corresponding nitric acid ester function Derivatives can be obtained. The compounds of the formula I are formed via synthesis methods and processes familiar to the person skilled in the art, for example known aldehyde or ester formation reactions. Oxidations or reductions should be carried out under as mild conditions as possible to maintain the desired aldehyde function. to Synthesis, isolation, purification and characterization of the target compounds can be carried out by a person skilled in the art of specific reaction products of aldehydes or 1,3-diols, such as, for example, hydrates, acetals, half-acetals, mercaptals, half-mercaptals, and all the abovementioned compounds in each case also in cyclic form, such as, for example, lactols, thiolactols as well as 1, 3-dioxanes, 1, 3-dithiolanes, 1, 2-diols, cyanohydrins, bisulfite compounds, aldimines, azomethines, hydrazones, azines, oximes, semicarbazones, etc., which are also within the scope of the present invention. c) The starting compounds for the synthesis are furthermore the compounds of the embodiments A) to E) themselves and d) compounds of the general formula I in which R1, R2, R3 are identical or different from one another CH ₂ -ONO ₂ , CH ₂ -OR6 or CH ₂ -R7, where at least one of the substituents R1 to R3 is CH ₂ -R7, R6 is H or C to C ₃ -alkanoyl, R7 is the C-1 α- or β-configured glycoside residue of a monsaccharide, a monosaccharide, with C _r to C ₃ alkane or mineral acid fully or partially O-acylated, an on acid, a uronic acid, a sugar acid, an on acid, a uronic acid, a sugar acid, with C to C ₃ alkane or mineral acid fully or partially -O-acylated, a C to C ₃ alkyl acid, C to C ₃ alkyluronic acid, Cr to C ₃ alkyl sugar ester or a C to C ₃ alkyl acid, C to C ₃ alkyluronic acid, C _r to C _3- alkyl sugar acid esters fully or partially O-acylated with C to C ₃ -alkane or mineral acid, and compounds gene of the general formula X, wherein R1, R2, R3, R4 have the meaning given above, where at least one of the substituents R1 to R3 is CH ₂ -R7, R7 OR8 and R8 is the carbonyl radical of an onic acid, a uronic acid, a sugar acid or an onic acid, a uronic acid, a sugar acid, fully or partially O-acylated with d- to C ₃ -alkane or mineral acid, obtained by reaction of saccharides or glycosides, formed with suitable alcohols in the presence of catalysts such as acids or Lewis acids, for example salts of silver, cadmium, tin, zinc, titanium, cobalt but also BF ₃ etherate or without a catalyst, for example by the Koenigs-Knorr reaction, in which glycosides are activated in their most general form at C-1 be, the activation for example by halogen, sulfonyl, trichloroacetimidoyl, alkyl / aryl-thio or others

Substituents occur that have good leaving properties per se or after the addition of further activating reagents and enable the formation of a new O-glycoside in the presence of an alcohol, use of the 1,2-didehydrostructure of glycals to activate a saccharide, biosynthetically by catalyzing glycosyl transferases or the inverse action of glycosidases, especially glycosides of uronic acids by chemical, catalytic, electrochemical or enzymatic oxidation of the terminal HOCH ₂ group on the C-6 of glycosides or suitable precursors (Easty, J. Org. Chem. 27 (1962), 2102), glycosides which contain the nitric acid ester grouping in the aglycone, obtainable according to the prior art by methods which can be used Introduction of this nitric acid ester grouping are suitable, with particular advantages in the processes described here being mild and, under the explosives aspect, safe preparation of the nitric acid ester with acetyl nitrate generated in situ, avoiding the formation of the otherwise usual and difficult-to-separate ortho-esters in the Koenigs-Knorr reaction (Garegg et al., Acta Chem. Scand. B 33 (1979), 116), reaction with targeted anomeric yield, mild deacetylation of acylates to intermediate and final stages in the presence of the base-labile nitrate groups by using the system

Alcohol / alcoholate, it is apparent to the person skilled in the art that he can or must use various derivatives in which reactive centers are inactivated by protective groups known to him in order to avoid undesirable side reactions and by-products, these protective groups can be carried out after the respective Reaction or be removed in the respective final stage. The corresponding target derivatives are recognizable to the person skilled in the art on the basis of the structures described above and are generally customary, for example hydroxylation, esterification, hemiacetal or acetal formation, aldol reaction, oxidation, reduction, cyclization etc. or else methods and methods which are customary in carbohydrate chemistry, for example by using suitable ones Protection group technologies, accessible. For example, the ß-propiolactones from corresponding ß-halocarboxylic acids, the γ-butyrolactones from corresponding γ-hydroxycarboxylic acids and the lactides of the formula IX from corresponding ß-hydroxycarboxylic acids are accessible with careful thermal dehydration to avoid decarbonylation. Modified syntheses which refer to known processes for the preparation of ascorbates (Reichstein et al., Helv. Chim. Acta 17, 311 (1934); Ullmann, 3rd edition, vol. 18, 223; Kirk-Othmer , Encycl. Chem. Technol., 2nd ed., Vol. 2, 747), in particular using enzymes (Boudrant, Enzyme Microb. Technol. 12, 322 (1990); Kulbe et al. Ann. NY Akad. Sei 506, 543 (1987) and 613, 820 (1990); Kozhizaka et al., J. Biol. Chem. 263 (4), 1619 (1988); Springer Chem .: Enzyme Handbook, Vol. 10, 825 (1991 ), Class 1.1.1150 - 1.1.99.26 Oxidoreductases). The adducts are thus converted into the desired lactone and dehydrolactone structure in the form of their ester and ether conjugates. Some of the new compounds may exist as optical isomers or racemates, depending on the choice of starting materials and process, or if they contain at least two asymmetric centers, they may exist as a mixture of isomers. The isomer mixtures obtained can be chiral with the aid of chromatography Chromatography, enzymatic methods or fractional crystallization can be separated into the pure isomers. The isomer mixtures obtained can further be separated by methods known per se, such as by recrystallization from an optically active solvent, by using microorganisms, by reaction with optically active agents to form compounds which can be separated, by separation on the basis of the different Solubilities and The active part is preferably isolated. The starting materials are known or, if they are new, can be obtained by methods known per se. The isomer mixtures and optically pure isomers and their salts or addition compounds with optically active agents are also within the scope of the present invention. A particular advantage of a number of the compounds described is that they are present in the form of deuterated analogs, this applies to both the starting and intermediate products and the ultimate target products. Through them and the other described compounds, substances were provided with which, particularly without the use of radioactive labeling, the absorption, distribution, metabolism and excretion of active ingredients derived from pentaerythritol can be investigated bioanalytically, pharmacokinetically, pharmacodynamically and diagnostically. The deuterated starting and intermediate products and their use are therefore also within the scope of the invention. Depending on the process conditions and the starting materials, the respective end product can in some cases also be obtained as the free acid or base, base or acid addition salt, each of which is within the scope of the invention. Acidic, basic, neutral or mixed salts and hydrates can be obtained in this way. On the one hand, the respective salts can be converted into the free acid or base in a manner known per se using appropriate means or by ion exchange. On the other hand, the free acids or bases obtained can form salts with organic or inorganic bases or acids. Bases which form suitable therapeutically acceptable salts are primarily used in the preparation of base addition salts. Such bases are, for example, hydroxides or hydrides of the alkali and alkaline earth metals, ammonia and amines. In the production of acid addition salts, preference is likewise given to using those acids which form suitable therapeutically tolerable salts. Such acids are, for example, hydrogen halide, sulfonic, phosphoric, nitric and perchloric acid, furthermore aliphatic, acyclic, aromatic, heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, amber, glycolic, lactic, apple -, wine, lemon, glucon, sugar, glucuron, aseorbin, maleic, hydroxymalein, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p- Hydroxybenzoic, salicylic, acetylsalicyl, p-aminosalicyl, embon, methanesulfone, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid as well as amino acids such as methionine or methanine, such as methionine, such as methionine, such as methionine Arginine. These and other salts of the new ones can serve as agents for the purification of the free acids or bases obtained. Salts of the acids or bases can be formed and separated from solutions, and then the free acid or base can be recovered from a new salt solution in a purer state. Because of the relationship between the new compounds in their free form and their salts, the salts are within the scope of the invention. At the same time, the use of pharmacologically acceptable derivatives of all the compounds mentioned above is possible. Above all, common addition compounds, salts or enzymatically or hydrolytically cleavable compounds such as esters, amides, hydrazides, for example obtained by N-amination (DD-B1 -230865 and DD-A3-240818) corresponding amino compounds, hydrazinium salts and the like, as far as above not mentioned, possible variations.

The compounds according to the invention are used individually or as part of a pharmaceutical preparation, as a single active ingredient in combination with one another or with known antioxidants, cardiovascular or vascular therapeutics, for example ACE inhibitors, antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, Calcium antagonists, coronary dilators, lipid-lowering agents, peripheral vasodilators, phosphodiesterase inhibitors, in particular - (V) -, or platelet aggregation inhibitors or other substances also used as cardiovascular therapeutics. They can be used in particular in combination with organic nitrates to avoid tolerance or cross-tolerance phenomena. But they are also suitable for use in bioanalytics. In particular in combination with organic nitrates, they can be used for the investigation of biochemical and pharmacological processes, since they represent excellent substrates for the investigation of biochemical and pharmacological processes in in-vitro or in-vivo test systems. They are particularly suitable for the investigation of redox processes, in particular for the investigation of the system cysteine / cystine, the glutathione or the lipoic acid redox system and related systems, and therefore offer improved and considerably expanded analytical possibilities, pathological situations such as e.g. B. to simulate, examine and suppress nitrate and nitrate cross tolerance. Some of the derivatives with an antioxidative effect may themselves be pharmacologically inactive and only from the respectively applied derivative by catalytic formation, in particular under the, in a physiological environment Influence of enzymes that arise or are formed spontaneously, thus acting as a typical prodrug. A special example of this are the nitric acid esters formed from the respective nitric acid esters. The preparation of galenical preparations is carried out according to the procedures and rules generally known to the pharmaceutical expert, the choice of the technologies to be used and the galenic auxiliaries used being based primarily on the active substance to be processed. Questions of its chemical-physical properties, the selected form of application, the desired duration of action, the place of action and the avoidance of drug-auxiliary incompatibilities are of particular importance. It is therefore up to the person skilled in the art to select pharmaceutical form, auxiliary substances and production technology in a trivial manner on the basis of known substance and process parameters. The pharmaceutical form in question should be designed in such a way that it contains the respective active ingredient in order to achieve therapeutic plasma levels in an amount which makes it possible to distribute the daily dose to 1 to 2 in the case of release-controlled systems and to up to 10 individual doses in the case of other dosage forms. Continuous application using long-term infusion is also suitable. In order to achieve endothelial protective effects, long-lasting therapeutic blood levels will generally be desirable. According to the invention, the named compounds can be administered primarily orally, intravenously, parenterally, sublingually or transdermally. The respective pharmaceutical preparation is preferably provided in liquid or solid form. Solutions are suitable for this, in particular for the preparation of drops, injections or aerosol sprays, further suspensions, emulsions, syrups, tablets, film-coated tablets, dragées, capsules, pellets, powders, pastilles, implants, suppositories, creams, gels, ointments, plasters or others transdermal systems. The pharmaceutical preparations contain customary galenically usable, organic or inorganic carriers and auxiliaries which should themselves be chemically indifferent to the respective active ingredients. Chemical derivatization when applied to carrier materials is also included; this applies in particular to the formation of adducts with sugar derivatives such as croscarmeloses or cyclodextrins. Suitable pharmaceutical auxiliaries are, but are not limited to, water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, highly disperse silicon dioxide, paraffin, fatty acid mono- and diglycerides, cellulose derivatives, polyvinylpyrrolidone and the like. The preparation can be sterilized and, if necessary, with auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, humectants, adsorbents or counter-disintegrants, preservatives, stabilizers, emulsifiers, Solubilizers, salts to influence the osmotic pressure, buffer solutions, colorants, fragrances, aromas or sweeteners. The pharmaceutical expert will make a suitable selection based on the respective substance parameters in order to avoid drug-excipient incompatibilities. It has been found that the compounds according to the invention are surprisingly excellent substrates for the investigation of biochemical and pharmacological processes in in-vitro or in-vivo test systems, although such structures were not expected to be metabolically relevant to the person skilled in the art, in particular in humans. It has also been found that they are particularly suitable for the investigation of redox processes, in particular for the investigation of the cysteine / cystine system, the glutathione or lipoic acid redox system, the xanthine, NADH or NADPH redox system and related systems. With the presented invention thus improved and significantly expanded analytical possibilities are opened, pathological situations such. B. to simulate, examine and suppress nitrate and nitrate cross tolerance, which in principle makes the compounds according to the invention also suitable for therapeutic use. In addition, the compounds described with the present invention are helpful starting and intermediate compounds in the production of chemical derivatives which can themselves be used as pharmaceutical active substances. The compounds according to the invention have surprising properties. They are distinguished in part by an optimized NO liberation, e.g. B. by their differentiated content of reductively biotransforming NO precursor groups or by an improved multiphase NO liberation and depending on the application increased lipophilicity or hydrophilicity as well as by pharmacodynamic preload reduction, reduced endothelin increase in plasma, pronounced platelet aggregation inhibition by platelet-active groups and, also in subhemodynamic Dose, characterized by endothelial protective effect. The fact that the properties of the compounds according to the invention strongly counteract the formation of nitrate and nitrate cross tolerances is particularly advantageous. It was particularly surprising that the inventive procedure, on the one hand, triggered the typical strong pharmacodynamic effect known for organic nitrates, but, on the other hand, at the same time an antioxidative effect also occurs in sub-hemodynamic doses, although the antioxidative effect was not to be expected on the basis of the compounds with nitric acid ester structure used. It has also been found that they can be excellently processed into galenic preparations in the form of sprays and injection solutions. The compounds used according to the invention indicate functional tests isolated blood vessels (rabbit aorta) surprisingly high vasodilating properties with improved bioavailability and increased hydrophilicity as well as easier biotransformation to the end metabolite, these end metabolites being generally well tolerated. They are characterized as surprisingly strong nitrate vasodilators, which have a longer half-life with improved bioavailability compared to other nitrates. It was surprising that the compounds according to the invention on the one hand trigger the strong pharmacodynamic effect typical of organic nitrates without its pronounced short-term effect, but on the other hand cause almost no tolerance phenomena, thus combining the advantages of known organic nitrates within the compounds used without their respective pharmacodynamic disadvantages . With the presented invention thus improved and significantly expanded therapeutic possibilities are opened, pathological situations such as heart and vascular diseases, in particular coronary heart disease, vascular stenoses and circulatory disorders of the peripheral arteries, hypertension, micro- and macroangiopathies in the context of diabetes mellitus, atherosclerosis and the associated therefrom resulting diseases, continue to treat erectile dysfunction, increased intraocular pressure, uterine spasms, menopausal symptoms, etc. Some of the compounds described above can be characterized as explosives due to their chemical-physical properties, which could also enable their use as such. To this end, the person skilled in the art is able to select suitable compounds using known test methods. In contrast to this, however, a number of the substances according to the invention do not have these properties, or have them only very weakly, so that these compounds are characterized by the absence of the explosive properties typical of organic nitric acid esters, while at the same time maintaining and improving the pharmacological effects through particularly simple and safe production and handling as well as further processing. In addition, the compounds described with the present invention are helpful starting and intermediate compounds in the production of chemical derivatives which can themselves be used as pharmaceutical active substances.

The following examples are intended to explain the invention in more detail with regard to its nature and its implementation, but without restricting its scope. Embodiments

Example 1 i) Pentaerythrityl nitrate (PETriN) 158 g (0.5 mol) of PETN are dissolved in a mixture of 300 ml of dioxane and 300 ml of ethanol while boiling and in portions with various amounts of aqueous hydrazine hydrate solution (1, 5 - 4 mol) added. The reaction mixture is then heated to boiling under reflux for a further 2.5 hours. The solvents are evaporated off at 15 mm Hg and the residue is shaken out several times with 100 ml portions of water, as required, until the volume of the oil layer no longer decreases when shaken out. The aqueous extracts (A) are collected and the remaining oily layer is dissolved in twice the volume of ethanol. The possibly precipitated white precipitate of PETN is filtered off after 24 hours; F _p = 132 ° C, nitrogen content: 17.35%; _Mp 141 ° C (2x acetone); Nitrogen content: corresponds. Ethanol is evaporated from the filtrate at 15 mm Hg. The viscous, oily residue consists of the raw PETriN; Nitrogen content: corresponds. ii) Pentaerythrityl dinitrate (PEDN) and pentaerythrityl mononitrate (PEMN). The combined aqueous extracts A according to Example 1 are shaken out three times with ether and the ether is evaporated from the ether layer separated from the aqueous layer B after drying over anhydrous Na ₂ SO ₄ . The very viscous, oily evaporation residue consists of raw PEDN. The aqueous portion B, which in addition to the PEMN and pentaerythritol (PE) contains denitration products, mainly hydrazine nitrite, is successively acidified with 2N H ₂ SO ₄ until the evolution of gas (N ₂ , N ₂ O, NO, N ₃ H) has ceased, then concentrated at 20 mm Hg until solid products begin to separate and etherified. The crystalline substance of F _p 62 ° C which remains after the ether has evaporated is crude PEMN. It is then washed with cold chloroform and recrystallized from chloroform. _Mp 79 ° C (HCCI ₃ ); Nitrogen content: corresponds to, iii) pentaerythrityltrinitrate monoacetate (PETriNAc) and pentaerythritol dinitrate diacetate (PEDNDAc) to 135.5 g (0.5 mol) crude PETriN [or 56.5 g (0.25 mol) of PEDN], a mixture of 50 ml of acetic anhydride and 20 ml of acetyl chloride is added in portions with cooling and stirring. The mixture solidified after the reaction is stirred twice with 50 ml of ethanol and suction filtered. Colorless crystals are obtained in both cases. PETriNAc: F _p 89 ° C (2x ethanol); Yield: 77%; Nitrogen content: corresponds. PEDNDAc: F _p 47 ° C (2x ethanol); Yield: 72%; Nitrogen content: corresponds. iv) Pentaerythrityl trinitrate (PETriN) and pentaerythritol dinitrate (PEDN) 104.4 g (0.3 mol) of PETriNAc or 51.7 g (0.15 mol) of PEDNDAc are dissolved in 400 ml of hot ethanol, a solution of 1.5 g of NaOH added in 50 ml of ethanol and the azeotropic mixture of ethanol and ethyl acetate (K _p76 o 71, 8 ° C) distilled off. After the ethyl acetate formation has ended, a further 1.5 g of NaOH in 50 ml of ethanol are added and fractionation is continued until further ethyl acetate no longer passes over. Then the ethanol is evaporated off at 15 mm Hg and the residue is shaken three times with 20 ml water in the case of PETriN and stirred with 100 ml water in the case of PEDN and etherified three times. After drying in vacuo or removing the ether, the pure substances PETriN or PEDN remain as colorless viscous liquids which are dried in vacuo over P ₂ O ₅ . PETriN: nitrogen content: corresponds. PEDN: nitrogen content: corresponds. v) Pentaerythrityltrinitrate V ₃ H ₂ O (PETriN V ₃ H ₂ O) PETriN obtained according to Example 4 is washed with water and then stirred with 100 ml of water and then left at the temperature not higher than 20 ° C. until the next day. After suction and drying, stable, colorless crystals are obtained in air. F _p 32 ° C; Water content: (Karl Fischer method) corresponds to, after vacuum drying at 60 ° C. vi) pentaerythrityl _{^1/3 of} H ₂ O (PETriN _{^1/3 of} H ₂ O) PETriN is represented by the nitration of pentaerythritol with _HNO3 (95%) in the presence of urea. vii) Pentaerythrityl trinitrate (PETriN) and pentaerythritol dinitrate (PEDN) PEDN and PEMN are prepared from PETriN by hydrazinolysis (4 mol NH ₂ NH ₂ (50%)) with subsequent column chromatography separation of the 1: 1 mixture. viii) heptadeuteropentaerythritol (D ₇ -PE)

1.96 g of calcium oxide are initially charged with 42.28 g of D ₂ -formalin (18.5% by weight in deuterium oxide) in a 100 ml three-necked flask with a reflux condenser. A solution of 2.92 ml of acetaldehyde (freshly distilled) in 20 ml of deuterium oxide is added dropwise so that the temperature remains below 15 ° C. The solution is slowly warmed to 50 ° C. and the mixture is stirred at this temperature for 3 hours. The color changes to yellow after 90 minutes. The solution is brought to room temperature, filtered, the filtrate is concentrated with. Hydrochloric acid brought to pH 6, mixed with 0.5 g of activated carbon and stirred for 5 minutes. The solution is concentrated on a Rotavapor at 40 ° C until the first crystals precipitate. These are filtered hot over a glass frit and the solution is left to stand at 0 ° C. for 2 h. The crystals are suctioned off again and the solution is further concentrated. The filtrate is left overnight at 0 ° C, and also suctioned off. A total of 5.19 g (69 % of theory) colorless crystalline product of mp 215 ° C, (decomp.), soluble in water and

Methanol, insoluble in chloroform. DC, Table 5. ix) Pentaerythrityl monoacetate (PEMAc)

5.0 g of powdered pentaerythritol is slurried in 90 ml of N, N-dimethylformamide and 3.5 ml of acetic anhydride are added with stirring. The mixture is boiled under reflux (150 ° C.) for 5 hours, giving a clear brownish solution. The mixture is then evaporated to dryness on a Rotavapor at a bath temperature of approx. 70 ° C and approx. 1 torr. The oily residue (6.6 g = 100.9% of theory) is dissolved in 66 ml of acetone and the insoluble constituents are filtered off with suction (1.6 g). The acetone solution is again concentrated to dryness on a Rotavapor. The oily residue is again in 50 ml

Dissolved acetone and suctioned off the insoluble constituents (0.2 g). After clarification with 1.0 g of powdered activated carbon and filtration on a Rotavapor, the acetone solution is evaporated to dryness. The oily residue is dissolved in 25 ml of ethyl acetate and the filtered solution, after inoculation with pentaerythrityl monoacetate crystals, is placed in the refrigerator at approx. -30 ° C. After standing overnight in the refrigerator, the crystals are filtered off, washed with diethyl ether and then dried to constant weight in a vacuum drying cabinet at room temperature and about 1 Torr. The obtained (1.45 g) pentaerythrityl monoacetate is recrystallized from 12 ml of ethyl acetate as before and dried. Yield 1.0 g (15.3%) pentaerythrityl monoacetate (purity> 95% / TLC / NMR), TLC and mp, Table 5.x) D ₇ -pentaerythrityl monoacetate (D ₇ -PEMAc)

2.5 g of pulverized D ₇ pentaerythritol is suspended in 75 ml of N, N-dimethylformamide and heated to approx. 70 ° C. 1.73 ml of acetic anhydride are added dropwise to this slurry with stirring. After stirring for 70 hours at 60 ° C. and cooling to room temperature, the insoluble constituents (1.14 g) are filtered off with suction and the clear solution is evaporated to dryness on a rotavapor at a bath temperature of approx. 75 ° C. and approx. 0.1 Torr . The oily residue is dissolved in acetone, filtered again and concentrated. The colorless oil obtained (1.09 g, 33.6% of theory) is dissolved in a mixture of 3.2 ml of methanol and 4.8 ml of water and purified by column chromatography on an RP ₁₈ column. The second fraction is evaporated to dryness on a Rotavapor and recrystallized twice from ethanol / water; Yield: 0.265 g (8.2%), colorless crystals of D ₇ - pentaerythrityl monoacetate, purity> 95% (TLC / NMR). DC and Fp, Table 5. xi) Pentaerythrityltrinitrate acetate (PETriNAc)

3.6 g of pentaerythrityl monoacetate are dissolved in 50 ml of CH ₂ Cl ₂ and 10 ml of acetic acid at room temperature. The slightly cloudy solution is filtered, the filtrate diluted with 50 ml CH ₂ CI ₂ and cooled to approx. 3 ° C. For this purpose, 4.3 ml. With stirring and ice bath cooling HNO ₃ 100% added dropwise so that the temperature does not exceed 5 ° C. Then 9.1 ml of acetic anhydride (100%) are also added dropwise so that the temperature remains below 5 ° C. After stirring overnight at room temperature, the reaction solution is poured into 50 ml of ice water and stirred. The CH ₂ CI ₂ phase is separated off and washed three times in succession with 20 ml of 5% aqueous NaHCO ₃ solution and 20 ml of H ₂ O. The CH ₂ CI ₂ extract, dried over anhydrous MgSO 4, is concentrated to a volume of 60 ml. From this, an aliquot for determining the yield on the Rotavapor is concentrated to constant weight. Weighing out and DC and NMR quantification give a total yield of 6.32 g (99% of theory), purity> 98%. When the dichloromethane solution is cooled, colorless crystalline PETriNAc is obtained. Fp and DC, Table 5. xii) D ₇ -pentaerythrityltrinitrate acetate (D ₇ -PETriNAc)

265.0 mg of D ₇ pentaerythrityl monoacetate are converted to D ₇ - PETriNAc as described above for PETriNAc, yield 450.9 mg (98% of theory), colorless crystals, purity (DC)> 95%, Table 5. xiii ) Pentaerythrityl trinitrate (PETriN)

50 ml of methanol are added to a solution of 6.0 g of pentaerythrityltrinitrate acetate in 60 ml of tetrahydrofuran and the mixture is cooled to about 5 ° C. For this purpose, 4.2 g of a freshly prepared sodium methylate solution (prepared by dissolving 2.3 g of sodium metal in 107.3 g of absolute methanol) are added with stirring. After one day, 4.2 g of a freshly prepared sodium methylate solution are added. After a further hour of reaction time at room temperature, no more educt can be detected in the TLC. The reaction solution neutralized with 0.7 ml 37% HCI is carefully concentrated on a Rotavapor to a volume of 10 ml. This solution is mixed with 100 ml of ethyl acetate and again as before on a Rotavapor at max. 40 ° C bath temperature and a vacuum of approx. 120 mbar to a volume of approx. 10 ml. This solution is diluted with 100 ml of ethyl acetate and washed successively once with 30 ml of 1N HCl, 30 ml of 5% NaHCO ₃ solution and twice with 30 ml of 20% NaCl solution. The ethyl acetate extract dried over anhydrous MgSO 4 is concentrated to a volume of 44 ml. From this, an aliquot for determining the yield on the Rotavapor is concentrated to constant weight.

Raw yield extrapolated to total batch (DC / NMR): 4.95 g PETriN = 95.3% of theory An analytical sample was obtained in pure yield in 66% yield by column chromatography on silica gel, colorless oil, purity (TLC / NMR)> 95% Table 5.xiv) Dy-pentaerythrityltrinitrate (D ₇ -PETriN) D ₇ -pentaerythrityltrinitrate-acetate (450 mg ) is deacetylated with methanol / sodium methoxide as in the example described above and worked up. There are 0.33 g of D ₇ -PETriN (84% raw yield, purity 90%). Column chromatographic purification, as described above, gives 303.7 mg (77% of theory) of a colorless oily product

purity

> 99%, Table 5.xv) Pentaerythrityltrinitrate-glucuronide methyl ester triacetate (PETriN-G-Me-TriAc)

A solution of pentaeryttrinitrate (11.7 mmol) in ethyl acetate is mixed with 100 ml of toluene and the Rotavapor at max. 40 ° C bath temperature concentrated to a volume of about 40 ml. This solution is mixed with 100 ml of toluene and again concentrated as described above to a volume of about 20 ml. (gives 18.3 g of solution). 5.80 g of methyl 2,3,4-tri-O-acetyl-1-bromo-D-glucuronate are dissolved in 63 ml of toluene and cooled to -30 ° C. For this, the pentaeryttrinitrate solution and 50 ml CH ₂ CI _{2 are} added. A solution of 3.75 g of silver trifluoromethanesulfonate in 40 ml of toluene is added dropwise at -30 ° C. in 20 minutes while stirring with N ₂ gassing and ethanol dry ice cooling. A white precipitate falls out. The mixture is left to react for a further 40 minutes with stirring at -25 ° C. 1.22 ml of pyridine (15.0 mmol), dissolved in 10 ml of ethyl acetate, are then added dropwise, and 400 ml of ethyl acetate are added to the mixture. The insoluble constituents are filtered off and the clear solution is washed in succession once with 80 ml of 5% Na ₂ S ₂ O ₃ solution, 80 ml of 5% NaHCÖ ₃ solution and twice with 80 ml of 20% NaCl solution . After drying (sodium sulfate), the mixture is filtered, concentrated and purified by column chromatography on silica gel (eluent n-hexane / ethyl acetate, 70/30). 2.14 g (31.1% of theory) of crude product are obtained which, after recrystallization from ethyl acetate / hexane, 1.0 g (14.5% of theory) of colorless crystalline PETriN-G-Me-TriAc in a purity (DC / NMR)> 95%. MP and TLC, table 5. xvi) D ₇ -pentaerythrityltrinitrate-glucuronide methyl ester triacetate (D ₇ -PETriN-G-Me-TriAc) In the manner described above, 1.09 mmol of D ₇ -PETriN are reacted, worked up and by column chromatography and Recrystallization purified, finally 80.1 mg (12.4% of theory) of colorless crystals (purity> 98%) are obtained; MP and TLC, table 5. xvii) Pentaerythrityltrinitrate-glucuronide sodium salt (PETriN-G-Na salt) To a solution of 653.5 mg of pentaerythrityltrinitrate-glucuronide methyl ester triacetate in 8.0 ml chloroform and 8.0 ml methanol 2930 mg of sodium methylate solution (prepared from 351.6 mg of sodium metal in 13.45 g of absolute methanol) are added dropwise with stirring and gassing with nitrogen at about 10 ° C., the solution turning light yellow. After DC, no more educt can be detected after 30 minutes (splitting off of the acetate groups). After 30 minutes at room temperature, the mixture is evaporated to dryness and the remaining residue is dissolved in 8.0 ml of methanol and 8.0 ml of water. After DC is only after 30 minutes another trace of educt can be detected (saponification of the methyl ester, formation of the sodium salt). The reaction solution is then separated directly on an RP ₁₈ ODS column with an eluent of 50% methanol and 50% water. After concentration on the Rotavapor, the combined fractions of the second UV and RI peak give 504.4 mg (96.6% of theory) of solid white substance in a purity (NMR)> 60%. An analytical sample (> 94% purity) is obtained by recrystallization from methanol / isopropyl alcohol. TLC and MP, Table 5. xviii) D ₇ -pentaerythrityltrinitrate-glucuronide sodium salt (D ₇ -PETriN-G-Na salt) In the manner described above, 80 mg of D ₇ -PETriN-G-Me-TriAc are added 33.3 mg D ₇ -pentaerythrityltrinitrate-glucuronide sodium salt in 52% yield d. Th. Which, after recrystallization as described, gave> 98% pure (DC) D ₇ -PETri-G-Na salt. TLC and mp, Table 5. xix) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid (Tri-PS) A solution of 0.0037 mol pentaerythrityl trinitrate (PETriN), 5.5 ml benzene, 9 ml water and 0.15 ml Aliquat ^® 336 is mixed in portions with vigorous stirring with 0.0074 mol KMnO. After the addition has ended, the temperature is kept at 15 ° C. for 2 hours. Then aqueous hydrogen sulfite solution is added, acidified with H ₂ SO ₄ and the benzene layer is separated off. After removal of the solvent, 3-nitryloxy-2,2-bis (nitryloxymethyl) propionic acid (Tri-PS) is obtained as a solid residue which is recrystallized several times from methylene chloride (yield: 72%). xx) 2,2-bis (nitryloxymethyl) malonic acid (bis-MS)

1.0 g (0.0061 mol) of 2,2-bis (hydroxymethyl) is added to a mixture of 2.5 g of 95% HNO ₃ , a spatula tip of urea and 10 ml of water, cooled to 0 ° C., while stirring and cooling with ice. -malonic acid. After 10 minutes, 2.5 g of 94% H ₂ SO _{4 are added} dropwise with stirring and the mixture is stirred at 0 ° C. for a further hour. The organic layer is separated and evaporated. The residue obtained is 2,2-bis (nitryloxymethyl) malonic acid as a viscous oil, which is purified by column chromatography. Yield: 45%. Elemental analysis: (C: corresponds, H: corresponds, N: corresponds), xxi) 2-carboxy-2-nitryloxymethyl-malonic acid (CN-MS) to a mixture of 2.5 g 95% HNO ₃ cooled to 0 ° C , a spatula tip of urea and 10 ml of water are added with stirring and ice cooling 1.0 g (0.004 mol) of carboxy-2-hydroxymethylmalonic acid. After 10 minutes, 2.5 g of 94% H ₂ SO _{4 are added} dropwise with stirring and the mixture is stirred at 0 ° C. for a further hour. The organic layer is separated and evaporated. The residue obtained is 2-carboxy-2-nitryloxymethyimalonic acid as a viscous oil, which is purified by column chromatography. Yield: 30%. Elemental analysis: (C: corresponds, H: corresponds, N: corresponds). xxii) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid chloride (Tri-PSCI), of 2,2-bis (nitryloxymethyl) malonic acid dichloride (Bis-MSCI) and 2-chlorocarbonyl-2-nitryloxymethylmalonic acid dichloride (CN-MSCI ) 1 g (3.5 mmol) of Tri-PS is refluxed with 5.3 mmol of thionyl chloride for 1.5 hours: the excess of thionyl chloride is distilled off first on a water bath and then in vacuo. The residue is taken up in diethyl ether and washed quickly with a little ice water. The organic phase is separated off, dried over sodium sulfate and the solvent is evaporated in vacuo. The resulting oily 3-nitryloxy-2,2- bis (nitryloxymethyl) propionic acid chloride (Tri-PSCI) is pure enough for further reactions. Yield: 75%. The acid chlorides of the compounds 2,2-bis (nitryloxymethyl) malonic acid (Bis-MS) and 2-carboxy-2-nitryloxymethylmalonic acid (CN-MS) are obtained analogously. To prepare 2,2-bis (nitryloxymethyl) malonic acid dichloride (Bis-MSCI), double the amount of thionyl chloride and 2-chlorocarbonyl-2-nitryloxymethyl-malonic acid dichloride (CN-MSCI), three times the amount of thionyl chloride. Yield: 70 or 45%. xxiii) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid methyl ester

7 mmol of Tri-PS are mixed with 1 ml of thionyl chloride and 1 drop of dry DMF and stirred for 20 minutes at room temperature with exclusion of moisture. Excess thionyl chloride is then distilled off and 10 ml of dry methanol are added to the reaction mixture which is cooled to 0.degree. After 30 min, the mixture is diluted with 30 ml of water and extracted five times with diethyl ether. Column chromatographic purification (hexane: ethyl acetate = 2: 1) of the crude product obtained after the solvent has evaporated gives methyl 3-nitryloxy-2,2-bis (nitryloxymethyl) propionate as colorless crystals. Yield: 44%. CeHgNsön, M = 299.14; Mp = 66 ° C; R _f = 0.65 (silica gel, hexane: ethyl acetate = 1: 1). xxiv) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid ethyl ester

1 g (3.5 mmol) of Tri-PS is mixed with 10.5 mmol of ethanol, 20 mg of toluenesulfonic acid and 30 ml of chloroform and heated under reflux for 12 hours on a water separator. The chloroform phase is washed with aqueous bicarbonate solution and with water, the solvent is evaporated in vacuo and the residue is purified by column chromatography. 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid ethyl ester is obtained as a colorless oil. Yield: 85%. xxv) butyl 3-nitryloxy-2,2-bis (nitryloxymethyl) propionate

1 ml of n-butanol is dissolved in 5 ml of pyridine and 0.5 g (1.7 mmol) of tri-PSCI dissolved in 5 ml of tetrahydrofuran are added with ice cooling. It is heated on the water bath for 1 hour. Then poured into 50 ml of ice water and carefully neutralized with hydrochloric acid. The oily ester is taken up in diethyl ether, with aqueous Washed sodium carbonate solution and water, the organic phase dried over sodium sulfate and the solvent evaporated in vacuo. The column-chromatographic purification of the 3-nitryloxy-2,2-bis (nitryloxymethyl) propionic acid butyl ester as a colorless oil. Yield: 69%. The esters of the carboxylic acid Bis-MS and CN-MS are obtained analogously, correspondingly multiplying the added reagents, xxvi) 2,2-bis (nitryloxymethyl) malonic acid diethyl ester

0.015 mol of 2,2-bis (hydroxymethyl) malonic acid diethyl ester is slowly added to a solution of 90 g of degassed 100% nitric acid at -5 ° C. under a stream of air. The reaction mixture is gasified for a further 120 min at -5 ° C. and then poured into ice water. The aqueous phase is etherified twice, the organic phase washed with 10% hydrogen carbonate solution and with water, dried over sodium sulfate and the solvent evaporated in vacuo. The residue (2,2-bis (nitryloxymethyl) malonic acid diethyl ester) is separated by column chromatography. Yield: 94%. R _f = 0.52 (silica gel, hexane: ethyl acetate = 2: 1); ¹ H-NMR (300 MHz, CDCI ₃ ): corresponds to; ¹³ C-NMR (75 MHz, CDCI ₃ ): corresponds. xxvii) 2,2-bis (nitryloxymethyl) -3-nitryloxypropanoic acid amide

1 g (3.4 mmol) of tri-PSCI is dissolved in 25 ml of dioxane and excess concentrated ammonia solution is added. After 30 minutes, pour into 100 ml of ice water and weakly acidify with dilute hydrochloric acid. The oily separated 2,2-bis (nitryloxymethyl) -3-nitryloxypropanoic acid amide is purified by column chromatography. Yield: 65%. xxviii) 2,2-bis (nitryloxymethyl) -3-nitryloxypropanoic acid amide

7 mmol of Tri-PS are mixed with 1 ml of thionyl chloride and 1 drop of dry DMF and heated under reflux for 1.5 hours with exclusion of moisture. Then 3 ml of cold concentrated NH ₃ solution are added to the reaction mixture and the solution is allowed to cool to room temperature. After extracting the aqueous phase five times with

Diethyl ether and removal of the solvent give an oily crude product from which 3-nitryloxy-2,2- bis (nitryloxymethyl) propionic acid amide is isolated as colorless crystals by means of column chromatography (hexane: ethyl acetate = 1: 1). Yield: 32%; C ₅ H ₈ N ₄ O ₁₀ , M = 284.13; R _f = 0.52 (silica gel, hexane ethyl acetate = 1: 1). F _p = 71-72 ° C (CHCI ₃ ). xxix) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid N-benzylamide 1 g (3.5 mmol) of 3-nitryloxy-2,2-bis (nitryloxymethyl) propionic acid methyl ester is mixed with 3 ml benzylamine and 100 mg ammonium chloride 3 Heated to 130 ° C, cooled, taken up in 50 ml of chloroform and washed successively with water, dilute hydrochloric acid, aqueous bicarbonate solution and again with water. The crude product obtained after evaporation of the solvent is purified by column chromatography. You get

21

REPLACEMENT BLADE (RULE 26) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid-N-benzylamide as a colorless oil. Yield:

73%. xxx) 3-Nitryloxy-2,2-bis (nitryloxymethyl) propionic acid hydrazide

1 g (3.5 mmol) of 2,2-bis (nitryloxymethyl) -3-nitryloxypropanoic acid methyl ester is heated with excess aqueous hydrazine hydrochloride solution for 5 hours on a water bath. It is poured onto ice and weakly acidified with hydrochloric acid. After separation of the separated oil by column chromatography, 3-nitryloxy-2,2- bis (nitryloxymethyl) propionic acid hydrazide is obtained as a colorless oil. Yield: 63%. The amides or hydrazides of the carboxylic acids Bis-MS and CN-MS are prepared analogously by multiplying the reagents accordingly. xxxi) 3-hydroxy-2,2-bis (nitryloxymethyl) propionic acid and 3-hydroxy-2-hydroxymethyl-2-nitryloxymethyl propionic acid

The compounds Tri-PS are converted to 3-hydroxy-2,2-bis (nitryloxymethyl) propionic acid and 3-hydroxy-2 by hydrazinolysis (4 mol NH ₂ NH ₂ (50%)) followed by column chromatography of the mixture -hydroxymethyl-2-nitryloxymethyl-propionic acid shown. xxxii) [3-Nitryloxy-2,2-bis (nitryloxymethyl) propyl] phosphorylcholine To a stirred solution of 3.5 ml (26 mmol) triethylamine and 0.81 g (5.25 mmol phosphoryl chloride in 30 ml chloroform are within 30 min under argon 1.35 g of PETriN (5.0 mmol) dissolved in 25 ml of chloroform are added dropwise at 0 ° C. After the cooling has been removed, the mixture is stirred for 1 h and then cooled again to 0 ° C. and a solution of 2. 06 g (7.5 mmol) of choline tosylate in 60 ml of pyridine were added dropwise, the mixture was then stirred at room temperature for 15 h After the addition of 3.5 g of NaHCO ₃ , dissolved in water (saturated), the mixture was evaporated in vacuo, the residue was taken up in methylene chloride and The crude product obtained after evaporation of the solvent in vacuo is purified by column chromatography on silica gel (hexane / ethyl acetate / methanol = 1: 1: 1), giving 830 mg of [3-nitryloxy-2,2-bis (nitryloxymethyl) propyl] phosphorylcholine as a colorless oil. Yield: 37%; elemental analysis: (C: corresponds to, H: corre direction, N: corresponds, P: corresponds).

The compounds described above under i) to xxxii) serve as starting and intermediate compounds for further reactions.

Example 2 The compound Tri-PSCI is subjected to a Rosenmund reduction in the presence of a strongly deactivated Pd catalyst. The reaction product (3-nitryloxy-2,2-bis- nityloxymethyl-propanal) is isolated in the form of its bisulfite compound, purified and released from it. Yield: 43%. ¹ H-NMR (300 MHz, CDCI ₃ ): corresponds to; ¹³ C-NMR (75 MHz, CDCI ₃ ): corresponds.

Example 3

The compound Bis-MSCI is implemented analogously to Example 2. The reaction product (2,2-bis-nitryloxymethyl-propanedial) is obtained in a yield of 35%. ¹ H-NMR (300 MHz, CDCI ₃ ): corresponds to; ¹³ C-NMR (75 MHz, CDCI ₃ ): corresponds.

Example 4

The compound CN-MSCI is implemented analogously to Example 2. Yield: 27%. ¹ H-NMR (300 MHz, CDCI ₃ ): corresponds to; ¹³ C-NMR (75 MHz, CDCI ₃ ): corresponds.

Example 5 Investigation of the Biochemical Activity of the Compounds: i) The investigation is carried out using the compounds according to Examples 2 to 4 in vitro on the system cysteine / cystine. The redox processes taking place are monitored using IR and UV spectroscopic data. ii) The test is carried out using the compounds according to Examples 2 to 4 in vitro on the cysteine / cystine system. The redox processes taking place are tracked using cyclovoltametric data.

Example 6

The investigation is carried out using the compounds according to Examples 2 to 4 in vitro on the glutathione redox system. The redox processes taking place are followed analogously to Example 5.

Example 7

Investigation of the pharmacological activity of the compounds: i) The investigation is carried out on cultured cells (RFL-6 fibroplasts, LLC-PK1 epithelial cells), which are known as a model for characterizing the activity and toxicity profiles of NO donors (Bennett et al ., J. Pharmacol. Ther. 250 (1989), 316; Schröder et al., J. Appl. Cardiol. 2 (1987), 301; J. Pharmacol. Exp. Ther. 245 (1988), 413; Naunyn Schmiedeberg's Arch. Pharmacol. 342 (1990), 616; J. Pharmacol. Exp. Ther. 262 (1992), 298; Adv. Drug Res., 28 (1996), 253). The intracellular accumulation of cGMP as Parameters of nitrate activity and bioactivation are measured using a radioimmunoassay. ii) The antiplatelet and antiplatelet effects of

Compounds are determined by the method of Rehse et al. (Arch. Pharm. 324, 301-305 (1991); Arch. Pharm. Pharm. Med. Chem. 329, 535 (1996)), which is established as a model for describing anticoagulant and antithrombotic properties. iii) The endothelium-protective effect of the compounds is determined by the method of Noack and Kojda (DE-A1-4410997). iv) The vasodilating properties were investigated in experiments on isolated aortic rings of the rabbit (Hüsgen, Noack, Kojda: Int Confer. "Mediators in the cardiovascular System", p. 9, Malta 2nd-5th June 1994) by hanging them in organ baths and stimulated by vasoconstrictors such as phenylephrine. After establishing a stable smooth muscle tone, the influence of the tone on cumulative concentration-activity curves is determined by adding the above vasodilators. For this purpose, the organ bath buffer is mixed with increasing concentrations between 1 nM and 10 μM of the vasodilator, The aeration of the aortic rings resulted in a gradual abolition of the contraction in the presence of the vasoconstrictor. The extent of relaxation is expressed as a percentage of the contraction remaining at the respective active ingredient concentration (residual contraction) maximum effective concentration EC50 reflects the potency and can be recorded as pD2 value (concentration in logM). v) The studies of the effectiveness with nitrate tolerance is carried out according to the method of Fink et al. (J. Cardiovasc. Pharmacol. 30,6 (1997), 831). Dogs with a body weight between 25 and 30 kg were given 25 mg / kg

Pentobarbital body weight anesthetized. The circumflex coronary artery was instrumented with a perivascular piezoelectric element for the purpose of continuously determining the vessel diameter. 1.5 μg / kg / min of glycerol trinitrate (GTN) was infused continuously via a pulmonary catheter for 96 hours, ie for the period within which, according to preliminary studies, a nitrate tolerance is certain to occur. Subsequently, with continuous GTN infusion, the test compounds were co-infused for up to 3 hours and the subsequent relaxation of the coronary artery was registered. Example 8

One tablet has the composition:

Active ingredient / e x mg

Lactose DAB 10 137 mg

Potato starch DAB 10 80 mg

Gelatin DAB 10 3 mg

Talc DAB 10 22 mg

Magnesium stearate DAB 10 5 mg

Silicon dioxide, highly dispersed DAB 10 6 mg

Active ingredient (s): i) compound according to example 2 20 mg ii) compound according to example 2 50 mg iii) compound according to example 2 80 mg iv) compound according to example 3 50 mg v) compound according to example 4 50 mg vi) compound according to example 2 50 mg

Pentaerythrityl tetranitrate 10 mg vii) Compound according to Example 2 50 mg

Glycerol trinitrate 0.3 mg

Example 9 i) In a suitable mixer, 160 g of pentaerythrityl tetranitrate (PETN), 300 g of lactose, 80 g of microcrystalline cellulose, 76 g of corn starch, 20 g of talc, 20 g of silicon dioxide and 4 g of magnesium stearate are mixed homogeneously. The mix is pressed into tablets with a nominal mass of 600 mg at a pressure of 10 - 30 kN. ii) 350 g of PETN, 1000 g of lactose, 323 g of microcrystalline cellulose and 273 g of potato starch are mixed in a fluidized bed granulator, granulated with 1050 ml of a 4% strength aqueous starch solution, then dried, sieved and mixed with 60 g of talc, 20 g of magnesium stearate and 32 g of homogeneously mixed silicon dioxide. The granules are pressed on a rotary tablet press with a compressive force of 10 - 30 kN to tablets with a nominal weight of 1050 mg. iii) 900 g lactose, 300 g corn starch, 30 g silicon dioxide and 300 g PETN are mixed in a suitable mixer until homogeneous. The mixture is filled into sachets with a filling weight of 1530 mg. iv) 450 g of PETN, 1350 g of lactose, 300 g of microcrystalline cellulose and 400 g of potato starch are mixed in a fluidized bed granulator. 36 g gelatin and 18 g

25

REPLACEMENT SHEET (RULE 26 Sorbitol, dissolved in 350 g of water, is sprayed onto the mixture. The resulting granulate is dried and sieved. 80 g talc, 25 g magnesium stearate and 41 g silicon dioxide are added to the raw granulate and mixed until homogeneous. Compresses with a nominal mass of 900 mg are produced on a rotary tablet press with a compression force of 10 - 30 kN. v) PETN and galenic auxiliaries are mixed homogeneously in defined amounts in a mixer. The mix is processed into tablets on a tablet press (Table 1). The substances PETN and galenic auxiliaries in defined quantities are mixed in a mixer until homogeneous and then (A) filled in sachets and (B) in capsules (Table 2). vi) PETN and a defined amount of galenic excipients are mixed in a mixer. Then compacting takes place. The compressed products are homogenized with a sieving machine to a uniform particle size. The screenings are filled (A) in sachets and (B) in capsules (Table 3). vii) In a fluidized bed granulator, PETN and defined amounts of galenic excipients are mixed and then granulated with an aqueous binder solution. The dried granulate is sieved and mixed with galenic flow regulators, lubricants and lubricants. Compresses are made on a tablet press (A). The compressed products thus obtained are (B) filmed in a coating system (Table 4). viii) 50 g of pentaerythrityl tetranitrate (PETN), 100 g of lactose,

30 g microcrystalline cellulose, 25 g corn starch, 5 g talc, 5 g silicon dioxide and 2 g magnesium stearate mixed homogeneously. The mix is pressed into tablets with a nominal weight of 217 mg at a pressure of 10 - 30 kN. ix) 10 g of pentaerythrityl tetranitrate (PETN), 100 g of lactose, 30 g of microcrystalline cellulose, 25 g of corn starch, 5 g of talc, 5 g of silicon dioxide and 2 g of magnesium stearate are mixed homogeneously in a suitable mixer. The mix is pressed into tablets with a nominal weight of 177 mg at a pressure of 10 - 30 kN.

Table 1 :

Table 2:

Table 3:

Table 4:

Table 5: Identification of the connections

za

DO

PO

ZO 10

CD rπ

¹⁾ eluent: methanol / water (70:30, v / v); Stationary phase: RP-18 F254, ODS silica gel (E. Merck) Detection: H ₂ SO _4/140 ° C; KMn0 ₄ solution; Nitrate reagent

claims

1. Compounds of the general formula I

wherein

R1, R2 and R3 are the same or different

R4, CH ₂ -ON0 ₂ , CH ₂ -OR5, CH ₂ -X, COOR5, COX, CH ₂ -COOR5, or CH ₂ -

COX, but at least one of the substituents R1 to R3 is R4, R4 CHO,

R5 is H or a linear or branched d- to C ₆ alkyl and

X is a halogen, except 3-hydroxy-2,2-bis (nitryloxymethyl) propanal and 2,2-bis (nitryloxymethyl) propandial.

2. Compounds of the formula I in which the group CH ₂ -ON0 ₂ next to R1 to R3 can additionally have one of the other meanings given for R1 to R3, and

3-Hydroxy-2,2-bis (nitryloxymethyl) propanal and 2,2-bis (nitryloxymethyl) propandial as a) substrates for biochemical and pharmacological examinations or b) medicinal products, provided they are not an acid halide.

3. Use of the compounds according to claim 1 or the biochemical and pharmacological substrates according to claim 2 for the investigation of biochemical and pharmacological processes, in particular for the investigation of a) enzyme-catalyzed biochemical and pharmacological processes, mainly i) biochemical and pharmacological redox processes, especially in the presence of oxidoreductases, such as xanthine, NADH or NADPH oxidase (oxidoreductase), ii) enzyme-catalyzed biochemical and pharmacological redox processes of sulfur-containing compounds, iii) the cysteine / cystine system, iv) the glutathione redox system, v) the lipoic acid redox system or b) nitrate or nitrate cross-tolerance phenomena.

4. Use of the compound of formula XVI

(XVI) for the production of a) the compounds according to claim 1 and b) the biochemical and pharmacological substrates or medicaments according to claim 2.

5. Pharmaceutical preparations containing compounds according to claim 1 or medicaments according to claim 2 a) as a single active ingredient, b) in combination with one another or c) in combination with other active ingredients used for the treatment of cardiovascular or vascular diseases, in particular with those from the

Indicator groups of ACE inhibitors, antiatherosclerotics, antihypertensives, beta blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilators, lipid-lowering agents, peripheral vasodilators, phosphodiesterase or platelet aggregation inhibitors.

6. Use of the compounds according to claim 1 or the medicament according to claim 2 for the production of pharmaceutical preparations according to claim 5.

7. Use of pentaerythrityl tetranitrate, pentaerythrityl trinitrate,

Pentaerythrityl dinitrate, pentaerythrityl mononitrate or their derivatives a) as an antioxidant or b) for the production of pharmaceutical preparations with an antioxidant effect.

Claims

8. Antioxidative pharmaceutical preparations containing pentaerythrityl tetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate, pentaerythrityl mononitrate or their derivatives a) as a single active ingredient, b) in combination with one another or c) in combination with others for the treatment of cardiovascular or

Active substances used in vascular diseases, especially those from the indication groups of ACE inhibitors, antiatherosclerotics, antihypertensives, beta blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilators, lipid-lowering agents, peripheral vasodilators, phosphodiesterase or antiplatelet agents.

9. Antioxidative pharmaceutical preparations according to claim 8, characterized in that they contain the active agent in an amount a) to 1000 mg, to 600 mg, to 300 mg, to 150 mg, to 100 mg, to 50 mg or b) below the Dose required to achieve hemodynamic effects.

10. Antioxidative pharmaceutical preparations according to claim 8 to 10, characterized in that they contain effective agents in a unit dose.

32

HE