EP0988282A2 - Novel pentaerythrite derivatives, the production and use thereof and intermediate products for the synthesis of the same - Google Patents

Abstract

The invention relates to novel compounds derived from pentaerythrite as defined in the patent claims, i.e. compounds of formula (XII) and (XVI), which can be used as pharmaceutically active substances, specially in the treatment of cardiac and circulatory diseases.

Description

 New pentaerythritol derivatives, their production and use and intermediates for the synthesis thereof

Field of application of the invention

The invention presented here relates to new pentaerythritol derivatives, their preparation and use and intermediates for the synthesis thereof, which can be used in particular as pharmaceuticals

Known technical background

Organic nitric acid esters such as glycerol nitrate (GTN) (Murrel, Lancet 80, 1 13, 151 (1879)), pentaerythritol tetranitrate (PETN) (Risemann et al, Circulation, Vol XVII, 22 (1958), US Pat. No. 2,370,437), Isosorbid-5-monontrate (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934, DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947 DE- OS-31 24 410, EP-A1-045 076 EP-A1-057 847, EP-A1-059 664, EP-A1-064 194, EP-A1-067 964, EP-A1-143 507, US-PS -3 886 186, U.S. Patent 4,065,488, U.S. 4,417,065, U.S. 4,431,829), Isosorbide Diitrate (ISDN) (L. Goldberg, Acta Physiolog Scand 15, 173 (1948)), Propatyl nitrate (Mέdard, Mem Poudres 35 113 (1953)), trolnitrate (FR-PS-984 523) or Nicorandil (US-PS-4 200 640) and similar compounds are vasodilators, some of which have for decades been the focus of angina pectoπs or ischemic heart disease (IHK) find the widest therapeutic use (Nitraπgin ^® , Pentalong ^® , Monolong ^® , etc.) Likewise, other pentaerythritol nitrates are like this as their description is described (Simecek, Coll Czech Chem Comm 27 (1962), 363, Camp et al, J Am Chem Soc 77 (1955), 751) Comparable and improved pharmacological effectiveness when used in the above-mentioned indication areas are said to be more recent organic nitrates such as SPM 3672 (N- [3-Nιtratopιvaloyl] -L- system ethyl ester) (US Pat. No. 5,284,872) and its derivatives. The preparation of 3-Nιtryloxy-2,2-bιs- (nιtryloxymethyl ) -propιonsaure and its methyl ester (Nee, Chem Prum (1978), 28 (2), 84) The galenic processing of the organic nitrates into pharmaceutical preparations for the treatment of angina pectoπs or ischemic heart disease are generally known. They are carried out according to the pharmaceutical expert generally familiar working methods and rules, whereby the selection of the technologies to be used and the galenic auxiliaries used primarily depend on the active ingredient to be processed H Questions regarding its chemical-physical properties, in particular the explosive properties known to adhere to the organic nitrates, which require special safety precautions and special processing technologies, the chosen form of application, the desired duration of action and the avoidance of drug-auxiliary incompatibilities are of particular importance for medicinal products with The indication angina pectoπs or ischemic heart disease is primarily peroral, parenteral, subimgual or transdermal application in the form of tablets, coated tablets, solutions, Cover sprays or plasters (DD-A5-293 492. DE-AS-26 23 800, DE-OS-33 25 652, DE-OS-33 28 094, DE-PS-40 07 705, DE-OS-40 38 203, JP-Anmeidung 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 conditions, 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 (homocystmuπe) are summarized under the term homocysteinemia (WO-A1 -92/18002). The use of certain organic nitric acid esters as endothelium-protective agents (DE-A1 - 44 10 997) and as a means of treating erectile

Dysfunction (WO-A1 -96 / 321-18) have recently been described. Furthermore, it is known that 3-amino-1,2,4-oxadiazol-5-ones are suitable as prodrugs for hydroxyguanidines (Rehse et al, Arch Pharm Pharm Med Chem 329, 535 (1996)) On the one hand, the previously 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 , Dizziness, nausea, weakness of skin reddening and the risk of a greater drop in blood pressure with reflex tachycardia (Mutschier drug effects, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). On the other hand, PETN as an active ingredient has a number of outstanding properties, which make it a preferred use of this compound as a pharmaceutical over other organic drugs Justify nitrates, each A limited bioavailability of this active ingredient can also be observed (publication series "Pentaerythπtyltetranitrat", Dr Dietrich Steinkopff Verlag, Darmstadt, 1994 to 1995) Lipophilic organic nitrates are, as a result of a faster metabolic breakdown to less effective or ineffective biotransformation products, generally only effective for a short time (Bonn, "Pharmacokinetics of Organic Nitrates" in "Pentaerythyltetranitrate", Dr Dietrich Steinkopff Verlag, Darmstadt, 1995)

Statement of the invention

The object of the invention is to provide new compounds derived from pentaerythritol with pharmacologically advantageous effects.

The object of the invention is achieved by the new compounds of the formulas (I) and (III), (O ₂ NOCH ₂ ) _m C (CH ₂ OH) _n (CH ₂ C0R ¹ ) ₀ (C0R ¹ ) _p , (I) (θ2NOCH ₂ ) _m C (CH ₂ OH) _n (CH ₂ COR) o (COR ³ ) p (III) woπn R 'is a group of the formula (II), or R ^{3 is} a group of the formula (IV),

R ² C bιs C ₂₀ alkyl, especially methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl, cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl,

3-phenylpropyl, 3-cyclohexylpropyl, 3-phthalιmιdylpropyl, 1-naphthylmethyl, cmnamyl,

5-ethoxycarbonylbutyl, 3-aminopropyl, - (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOH,

- (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOCH ₃ , or 1 6-hexane-bιs- and m to p are integers, for which m + n + o + p = 4, m ≥ 1 and o and / or p _ 1 Preferred are the compounds in which R ^{2 is} n-butyl, n-pentyl, n-hexyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-phthalιmιdylpropyl or 5-ethoxycarbonyibutyl

The starting products for the synthesis of the compounds of the formulas (I) and (III) are pentaerythritol or its nitric acid ester, namely pentaerythritol mono- (PEMN), pentaerythritol ti- di (PEDN), pentaerythryl tri- (PETnN) and pentaerythryl tetranitrate (PETN), which in turn are 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. The compounds PEMN, PEDN and PETnN are obtained by complete or partial oxidation of existing hydroxymethyl groups converted into the corresponding Tn-, di- or monocarboxylic acids, from which the corresponding derivatives carrying both nitroxy, hydroxyl and carboxy functions are optionally obtained by partial hydrazolysis of the corresponding nitrate function

Compounds of the formulas (I) and (III) are made via synthesis methods and processes familiar to the person skilled in the art, for example known ester or amide formation reactions. The compounds of the formula (IV 1), (FIG. 1), the synthesis of which is described in, are used as further starting materials Rehse et al, Arc Pharm Pharm Med Chem 329, 535 (1996), reference being made to the disclosure content of this publication, and in which one or two hydrogen atoms of the amino group can also be replaced by a suitable leaving group, and the compounds of the formula ( V),

wherein R ^{2 has} the meaning given in the formula (I) and R ^{4 represents} H or a suitable leaving group which can be obtained in good yields from the compounds of the formula (IV 1) according to the reaction scheme given in FIG. 1

Fig 1

The compounds of formula (V)

where R ^{2 has} the meaning already given in formula (I) and R ^{4 is} H, C to C ₆ -alkanoyl, salicyloyl or acetylsalicyloyl, are an independent embodiment of the invention. The compounds in which R ^{2 is} n-butyl, n-Pentyl, n-hexyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-phthalιmιdylpropyl or 5-ethoxycarbonylbutyl is further preferred are compounds in which R ^{4 is} salicyloyl or acetylsalicyloyl and compounds in which R ^{2 is} n-butyl, n-pentyl , n-hexyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-phthalιmιdylpropyl or 5-ethoxycarbonylbutyl and R ^{4 are} salicyloyl or acetylsalicyloyl

The compounds of the formula (V!) wherein R ^{5 is} (2-carboxyphenyl) oxy or (2-alkoxycarbonylpheπyl) oxy, and m to p are integers for which m + n + o + p = 4, m> 1 and o and / or p> 1 furthermore the compounds of the formula (VII),

(HOCH ₂ ) _q (0 ₂ NOCH ₂ ) _r C (CH ₂ OR ⁶ ) _s , (VII) where R ^{6 is} salicyloyl or acetylsalicyloyl, and q to s are integers, for which q + r + s = 4 and r and s> 1, furthermore the compounds of the formula (VIII), (0 ₂ NOCH ₂ ) _m C (CH ₂ OH) _n (CH ₂ COR ⁷ ) ₀ (COR ⁷ ) p, (VIII) where R ^{7 is} a group of the formula (IX),

_n . R ^a (IX)

R ⁸ and R ⁹ independently of one another Ci to C ₆ alkyl or together C to C ₆ alkylene, R '° OH, NHR ⁸ R ⁹ , d to C ₆ alkoxy, (2-carboxyphenyi) oxy, (2 -Alkoxycarbonylphenyl) oxy, (1-carboxymethyl-2-dialkylamino) ethoxy, (1-carboxymethyl-2-trialkylammonium) ethoxy, (1-alkoxycarbonylmethyl-2-dialkylamino) ethoxy, (1-alkoxycarbonylmethyl-2-trialkylammonium) ethoxy, and m to p are integers for which the following applies: m + n + o + p = 4, m> 1 and o and / or p> 1.

A particular embodiment of the present invention are the compounds of the formula (X)

wherein R ⁸ to R ^{10 have} the meaning given in the formula (IX) and R ^{11 is} N0 ₂ , and the compounds of the formula (XI) derived therefrom,

wherein R ^{12 is} additionally a C to C ₆ alkyl, in particular methyl, ethyl or n-propyl, and X represents a group capable of forming anions which need not be present if the function COR ^{10 has} the ability to form internal salts. The compounds of the formula (XII) are particularly preferred

of the formula (XIII),

and the formula (XIV),

woπn R> 13 H or d- to C ₆ alkyl

To achieve the object of the invention, in particular, compounds of the formula (XV),

(HOCH ₂ ) _q (0 ₂ NOCH ₂ ) _r C (CH ₂ OR ^{, 4} ) _s , (XV) where R ^{14 is} the acyl radical of a compound of the formulas (X) to (XIV), where R is additionally H, C- * - to C ₆ -alkanoyl, salicyloyl or acetylsalicyloyl or -CO-CH ₂ -CH (OH) -CH ₂ -NR ⁸ R ⁹ , and q to s are integers for which q + r + s ^• = 4 and r and s> 1, especially the compounds of the formula (XVI),

and that of formula (XVII),

Depending on the process conditions and the starting materials, the end product is obtained either as free acid or base, base or acid addition salt or betaine, each of which is within the scope of the invention. Acidic, basic, neutral or mixed salts and hydrates can be obtained 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 such as these are mainly used in the preparation of base addition salts which form suitable therapeutically compatible salts. Such bases are, for example, hydroxides or hydrides of the alkali and alkaline earth metals, ammonia and ames. In the preparation of acid addition salts, preference is likewise given to using those acids which are suitable therapeutically contractual salts Such acids are, for example, hydrogen halide, sulfonic, phosphoric, nitric and perchloric acid, furthermore aliphatic, acyclic, aromatic, heterocyclic carbonic or sulfonic acids such as formic, acetic, propionic, amber, glycolic, lactic, Apple, who, lemon, glucon, sugar, glucuron, ascorbic, maleic, hydroxymalein, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybezoic, salicyl -, Acetylsa cyl- p-aminosa cyl, embon, methanesulfone, ethanesulfone, hydroxyethanesulfone, ethylenesulfone, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid as well as amino acids such as methionine, tryptophan, these and lysine or lysine other salts of the new ones can serve as means for purifying 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 obtained 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. Some of the new compounds may be present as optical isomers or racemates (or at least, depending on the choice of starting materials and process) contain two asymmetric carbon atoms, they can exist as a mixture of isomers (racemate mixture). The isomer mixtures (racemate mixtures) obtained can be separated into two stereoisomeric (diastereomeric) pure racemates with the aid of chromatography or fractional crystallization. The racemates obtained can be separated by methods known per se as by re-installation 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 αer diastereoisomers Suitable optically active agents are the L and D forms of Wem, Dι-o-tolylweιn, apple, almond, gluconic, sugar, glucuronic, camphorsuifoπ, quinine or binaphthyl phosphoric acid more active part of the two antipodes isolated. The starting materials are known or, if they are new, can be obtained by methods known per se. 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-B1-230 865 and DD-A3-240 818) correspondingly

Amino compounds, hydrazmium salts and the like, if not mentioned above, represent possible variations

The compounds according to the invention can be used themselves or as part of a pharmaceutical preparation, as a single active ingredient in combination with one another or with known cardiovascular or vascular therapeutics, for example ACE inhibitors, antiatherosclerotic agents, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilatants, coronary dilatants Vasodilators, phosphodiesterase inhibitors, in particular - (V) -, or platelet aggregation inhibitors or other substances, also used as cardiovascular therapeutics, combined, can be used for their clinical use The provision of galenical preparations is carried out according to the procedures and regulations generally familiar 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 are regarding its chemical-physical properties and the chosen form of application , the desired duration of action, the

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, based on known substance and process parameters, to select medicinal form, auxiliary substances and production technology in a trivial manner per se. The pharmaceutical form in question is to be designed such that it is therapeutic in order to achieve it Plasma level contains the respective active ingredient in an amount that makes it possible

Distribution of the daily dose to 1 to 2 in the case of release-controlled systems and to up to 10 single doses in the case of other dosage forms. Continuous administration by means of long-term infusion is also suitable. To achieve endothelium-protective effects, long-term therapeutic blood level values are generally desirable , parenterally, sublmgual 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, furthermore suspensions, emulsions, syrups, tablets, film tablets, dragees, capsules, Pellets, powders, lozenges, implants, suppositoπen, creams, gels, ointments, plasters or other transdermal systems The pharmaceutical preparations contain customary galenically usable, organic or inorganic carriers d Auxiliary substances, which should themselves be chemically indifferent to the respective active substances. The chemical devatization during application to carrier materials is also included, this relates in particular to the formation of adducts with sugar derivatives such as croscarmeloses or cyclodextiles. Suitable pharmaceutical auxiliary substances are, without being restricted to this, water , Salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, highly disperse silicon dioxide, paraffin, fatty acid mono- and diglycides, cellulose derivatives, polyvinylpyrrolidone and the like. The preparation can be sterilized and, if necessary, with auxiliary agents such as lubricants, fillers, fillers -, mold release agents, lubricants, disintegrants, moisturizers, adsorbents or counter-explosives, preservatives, stabilizers, emulsifiers, solubilizers, salts for influencing the osmotic pressure, buffer solutions, coloring, fragrance, aroma or sweet 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 surprisingly have the desired properties. In addition, they are distinguished, in part, by an optimized NO transfer, for example by their differentiated content of reductively biotransforming NO precursor groups or by an improved multiphase NO liberation and depending on the intended use increased lipophysis or hydrophilicity as well as by pharmacodynamic Reduction in preload, reduced increase in endothelin in plasma, pronounced inhibition of platelet aggregation by platelet-active groups and, even in a subhemodynamic dose, by endothelium-protective action. The fact that the compounds according to the invention are notable for good penetration of physiological membranes is particularly advantageous. It has also been found that, above all the compounds derived from carboxyl compounds and their salts or quaternary ammonium compounds can be processed excellently into galenical preparations in the form of sprays and injection solutions. The compounds used according to the invention show surprisingly high vasodilating properties with improved bioavailability and increased hydrophilicity as well as easier biotransformation in functional tests on isolated blood vessels (rabbit aorta) to end metabolism, these end metabolites generally well tolerated or ubiquitous Pure body-own compounds They are characterized as surprisingly strong hydrophilic nitrate vasodilators, which have a longer half-life and improved bioavailability compared to lipophilic nitrates. It was surprising that the compounds according to the invention on the one hand trigger the strong pharmacodynamic effect typical of lipophilic organic nitrates without its pronounced short-term effect , on the other hand, have the long-term effect which is characteristic of more hydrophilic organic nitrates, thus the advantages of lipophilic and hydrophilic organic nitrates within the compounds used, without their respective pharmacodynamic disadvantages, are combined with one another With the invention described, improved and considerably expanded therapeutic possibilities are opened up, pathological situations such as Heart and vascular diseases, especially coronary heart disease, vascular stenosis and circulatory disorders of the peπ to treat peripheral arteries, hypertension, micro- and macroangiopathies in the context of diabetes mellitus, atherosclerosis and the resulting complications, erectile dysfunction, increased intraocular pressure, uterine spasms, climatic symptoms, etc. Some of the compounds described above can be classified as due to their chemical-physical properties Characterize explosives, which may also enable their use as such. To this end, the person skilled in the art is able to select suitable compounds on the basis of known test methods. In contrast, 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 due to 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, handling and range Distinguishing 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 active pharmaceutical ingredients. The examples below are intended to explain the invention in more detail in terms of its nature and design, but without it to limit their scope Practical examples

example 1

158 g (0.5 mol) of pentaerythryl tetranitrate (PETN) were dissolved in a mixture of 300 ml of dioxane and 300 ml of ethanol with boiling and portioned with various solutions for 1 hour

Amounts of aqueous hydrazine hydrate solution (1.5-4 mol) were then added. The reaction mixture was heated to boiling under reflux for a further 2.5 hours. During the reaction, nitrogen, ammonia and nitrogen oxides escape. After the reaction, the solvents were evaporated at 15 mm Hg and the Residue, shaken out several times with 100 ml portions of water as required until the volume of the oil layer no longer diminished when shaken out. The aqueous extracts (A) were collected and the remaining oily layer was dissolved in twice the volume of ethanol. The possibly precipitated white precipitate of PETN became after 24 hours filtered, it showed the F _p 132 ° C. After two re-installations from acetone, her F _{p had} risen to 11 ° C. The filtrate was evaporated at 15 mm Hg ethanol. The viscous, oily residue consisted of the crude pentaerythrityl nitrate (PETnN )

Example 2

The combined aqueous extracts A were extracted three times with ether, and from the separated from the aqueous layer B ether layer after drying flashed over anhydrous Na ₂ S0 _4, the ether The very viscous, oily Eindampfruckstand was as crude Pentaerythπtyldinitrat (PEDN) identifies The wäßnge portion B, which, in addition to the pentaerythritol mononitrate (PEMN) and pentaerythritol denitration products, mainly hydrazine nitrate, was acidified with 2N-H ₂ SO "until the gas evolution ceased (N ₂ , N ₂ O _t NO N ₃ H), then at 20 mm Hg to incipient separation of solid products concentrated and extracted with ether, the remaining after evaporation of the ether crystalline substance from F _p 62 ° C was used as crude PEMN identified after washing with cold chloroform and Umkπstallisation from chloroform showed the leaflets received the F _p 79 ° C the extraction residue was evaporated to dryness at 10 mm Hg and the residue with a small n Amount of water stirred The filtered white crystals, which after conversion from the same weight of water had an F _{p of} 260 ° C., were identified as pure pentaerythnite

Example 3

For the purification of the raw substances PETnN and PEDN, these were transferred to the acetates concerned and, after conversion from ethanol to alcohol to the pure products, alcoholized to 135.5 g (0.5 mol) of crude PETnN [or 56.5 g (0.25 mol) of PEDN ] was inflicted aπteilsweise the solidified after the reaction mixture was stirred twice with 50 ml of ethanol and filtered off with suction under hollows and stirring a mixture of 50 ml and 20 ml Acetanhydπd Acetylchlond the colorless crystals of Pentaerythπttπnitratacetats (PETnNAc) from F _p 85-86 ° C showed after two re-installations from ethanol, the F _p 89 ° C yield of pure product 121 g (77%) pentaerytthin dinitrate diacetate (PEDNAc) also forms colorless crystals, the F _{p of} 42-43 ° C after two re-installations from ethanol to 47 ° C yield of pure product 56 g (72%) 104 4 g (0.3 mol) PETπNAc or 51.7 g (0.15 mol) PEDNAc were dissolved hot in 400 ml ethanol, a solution of 1.5 g NaOH in 50 ml ethanol was added and the azeotropic mixture ethanol-ethyl acetate (K _p 71.8 ° C / 760 mm). After completion of the ethyl acetate formation, a further 1.5 g of NaOH in 50 ml of ethanol were added and fractionated again until further ethyl acetate no longer passed over. Then the ethanol was removed at 15 mm Hg evaporated and the residue in the case of the substance PETnN shaken three times with 20 ml of water and stirred in the case of the substance PEDN with 100 ml of water and three times etherified After drying in vacuo or removing the ether, the pure substances PETnN or PEDN remain as colorless viscous liquids which were dried over P ₂ 0 ₅ for analysis in vacuo

Example 4

The PETnN was also processed in such a way that after washing with water it was stirred with 100 ml of water and then left at a temperature not higher than 20 ° C. until the next day. It gave stable, colorless crystals of F p 32 ° in air C, where 2.15% water was determined with Karl-Fischer reagent 2.14 + 0.05% of water and by vacuum drying at 60 ° C, corresponding to a hydrate of composition C 5 H 9 O 3 N 10 1/3 of H 2 0

Example 5

PETnN is represented by nitration of pentaerythritol with HN0 ₃ (95% ιg) in the presence of urea.

Example 6

PEDN and PEMN are prepared from PETnN by hydrazinolysis (4 mol NH ₂ NH ₂ (50% ιg)) with subsequent column chromatography separation of the 1 1 mixture

Example 7

A solution of 0.0037 mol Pentaerythntyltπnitrrat (PETnN), 5.5 ml of benzene, 9 ml of water and 0.15 ml of Aliquat ¹ 336 is mixed in portions with vigorous stirring with 0.0074 mol of KMn0 _4. After the addition has ended, the temperature for 2 Hours at 15 ° C. Then aqueous hydrogen sulfite solution is added, the mixture is acidified with H ₂ SO ₄ and the benzene layer is separated off. After removal of the solvent, 3-nιtryloxy-2,2-bιs (nιtryloxymethyl) propionic acid (Tπ-PS) is obtained as a solid Residue that is re-installed from methylene chloride several times (yield 72%)

Example 8

To a mixture of 2.5 g of 95 g HN0 ₃ cooled to 0 ° C., a spatula of urea and 10 ml of water, 1.0 g (0.0061 mol) of 2,2-bis (hydroxy- After 10 minutes, 2.5 g of 94% H ₂ SO _{4 are added} dropwise with stirring and the mixture is stirred for a further hour at 0 ° C. The organic layer is separated and evaporated. The residue obtained is 2,2-bis (nitryloxymethyl ) Maionic acid as a viscous oil, the is purified by column chromatography

Yield 45% elemental analysis (C corresponds to H corresponds to N corresponds to)

Example 9 2-Carboxy-2-nιtryloxymethylmalonic acid

1.0 g (0.004 mol) of carboxy-2-hydroxymethylmalonic acid is added after 10 minutes to a mixture of 2.5 g of 95 g HN0 ₃ , a spatula tip of urea and 10 ml of water, cooled to 0 ° C., with stirring and ice cooling with stirring 2.5 g of 94% H 2 SO ₄ and stirred for a further hour at 0 ° C. The organic layer is separated off and evaporated. The residue obtained is 2-carboxy-2-netryloxymethylmalonic acid as a viscous oil which is purified by column chromatography. Yield 30% elemental analysis (C corresponds to H corresponds to N corresponds to)

Example 10 0 001 mol of bis-MS is esterified azeotropically with 0.0011 mol of 4-butyl-3-hydroxy-1, 2,4-oxadιazol-5-one in the presence of benzene and catalytic amounts of H ₂ S0 (yield 60%)

Example 11

0 001 mol of bis-MS is esterified azeotropically with 0.0011 mol of 4- (2-phenylethyl) -3-hydroxy-1, 2,4-oxadιazol-5-one in the presence of benzene and catalytic amounts of H ₂ SO ₄ (yield 53%)

Example 12

0 001 mol CN-MS with 0.0022 mol 4-butyl-3-hydroxy-1, 2,4-oxadιazol-5-one in the presence of

Benzene and catalytic amounts of H ₂ S0 ₄ esterified azeotropically (yield 45%)

Example 13

0.01 mol of 4-chloro-3-hydroxybutanoic acid is converted into 4-chloro-3-nitroxybutanoic acid with three times the amount of HN0 ₃ / H ₂ S0 (nitric acid) (yield 76%)

Example 14

0.005 mol of 4-chloro-3-nitroxy-butanoic acid is mixed in a closable vessel with aqueous tπmethyiamine solution, the vessel is closed and the resulting mixture is heated to 80 ° C. for 1 hour. After cooling, the solution is concentrated, cooled and cooled for installation left 3-Nιtryloxy-4-tπmethylammonιum-buttersaure-chloπd (salt) is obtained (yield 71%)

Example 15

0.001 mol of the compound according to Example 14 are mixed with 0.001 1 mol of PETnN in the presence of

Benzene and catalytic amounts of H ₂ S0 ₄ esterified azeotropically (yield 37%) Example 16 a) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιonsaurechloπd

1 g (3.5 mmol) of Tπ-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-nιtryloxy-2,2-bιs (nιtryloxymethyl) propionic acid chloride (Tπ-PSCI) is pure enough for further reactions. Yield 75%

b) 2,2-Bιs (nιtryloxymethyl) malonic acid chloride and 2-chlorocarbonyl-2-nιtryloxymethyl-malonic acid dichloride

The acid chlorides of the compounds 2,2-bιs (nιtryloxymethyl) malonic acid (bis-MS) and 2-carboxy-2-nιtryloxymethylmalonic acid (CN-MS) are obtained analogously to the representation of 2,2-bιs (nιtryloxymethyl) malonic acid idchloride (bis-MSCl ) is twice the amount of thionyl chloride and 3-times of 2-chlorocarbonyl-2-nιtryloxymethyl-malonsäuredιchloπd (CN-MSCI)

Amount of thionyl chloride uses 70% or 45% yield

c) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propionic acid methyl ester

7 mmol of Tπ-PS are mixed with 1 ml of thionyl chloride and 1 drop of dry DMF and stirred under exclusion of moisture for 20 mm at room temperature. Then excess thionyl chloride is distilled off and 10 ml of dry methanol are added to the reaction mixture cooled to 0 ° C. After 30 mm, add 30 Diluted ml of water and extracted five times with diethyl ether Purification by column chromatography (hexane, ethyl acetate = 2 l) of the crude product obtained after evaporation of the solvent gives 3-nιtryloxy-2,2-bιs (nιtryl-oxymethyl) propionic acid methyl ester as colorless crystals Yield 44%

CeHgNaOn, M = 299.14, mp = 66 "C R, = 0.65 (silica gel, hexane ethyl acetate = 1 1)

d) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιonic acid ethyl ester

1 g (3.5 mmol) of Tπ-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 off in vacuo and the residue is purified by column chromatography. 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propionic acid ethyl ester is obtained as a colorless oil, yield 85%.

e) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιonsaurebutylester

1 ml of n-butanol is dissolved in 5 ml of Pyndm and 0.5 g (1.7 mmol) of Tπ-PSCI dissolved in 5 ml of tetrahydrofuran are added with ice cooling. The mixture is warmed for 1 hour on a water bath and then poured into 50 ml of ice water and carefully neutralized with hydrochloric acid. The oily ester is taken up in diethyl ether, washed with aqueous sodium carbonate and water, the organic phase is dried over sodium sulfate and the Evaporated solvent in vacuo. Purification of the residue by column chromatography 3-nιtryloxy-2 2-bιs (nιtryloxymethyl) propyl butyl ester as colorless oil Yield 69%

The esters of the carboxylic acid Bis-MS and CN-MS are obtained analogously by doubling (in the case of Bis-MS) or tripling (in the case of CN-MS) the added reagents

g) 2,2-Bιs (nιtryloxymethyl) malonic acid methyl ester

To a solution of 90 g degassed 100% nitric acid, 0.015 mol of 2,2-bis (hydroxymethyl) malonic acid methyl ester are slowly added at -5 ° C. under a stream of air

The reaction mixture is gasified for a further 120 mm at -5 ° C. and then poured into ice water. The aqueous phase is etherified twice, the organic phase is washed with 10% hydrogen carbonate solution and with water, dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is separated by column chromatography Yield 94% R _f = 0.52 (silica gel, hexane ethyl acetate = 2 1), Η-NMR (300 MHz,

Corresponds to CDCI ₃ ), corresponds to ¹³ C-NMR (75 MHz, CDCI ₃ )

h) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιonsäureamιd

1 g (3.4 mmol) of Tπ-PSCI is dissolved in 25 ml of dioxane and excess concentrated ammonia solution is added. After 30 mm, the mixture is poured into 100 ml of ice water and weakly acidified with dilute hydrochloric acid. The oily, separated 2,2-Bιs (nιtryloxymethyl) -3-nιtryloxy- propanoic acid amide is purified by column chromatography Yield 65%

i) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιonsäureamιd 7 mmol Tn-PS are mixed with 1 ml of thionyl chloride and 1 drop of dry DMF and stirred with exclusion of moisture for 20 min at room temperature. Then 3 ml of cold concentrated NH are added to the reaction mixture ₃ solution and let the solution cool to room temperature After five times extraction of the aqueous phase with diethyl ether and removal of the solvent, an oily crude product is obtained, from which 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) is obtained by means of column chromatography (hexane ethyl acetate = 1 1) ) - Propionic acid amide are isolated as colorless crystals. Yield 32%, C ₅ H ₈ N ₄ O ₁₀ , M = 284.13, R _r = 0.52 (silica gel, hexane ethyl acetate = 1 1) F _p = 71 -72 ° C (CHCI ₃ )

j) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propιoπsaure-N-benzylamιd 1 g (3.5 mmol) 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) propionic acid methyl ester with 3 ml

Benzylamine and 100 mg of ammonium chloride heated to 130 ° C. for 3 hours, 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. 3- Nιtryloxy- 2,2-bιs (nιtryloxymethyl) propιonsaure-N-benzylamιd as colorless oil yield 73% k) 3-Nιtryloxy-2,2-bιs (πιtryloxymethyl) ρropιonsäurehydrazιd

1 g (3.5 mmol) of 2,2-bis (netryloxymethyl) -3-netryloxypropanoic acid methyl ester was warmed with excess aqueous hydrazole hydrochloride solution for 5 hours on a water bath. Poured onto ice and acidified weakly with hydrochloric acid. After separation of the separated oil by column chromatography 3-Nιtryloxy-2,2-bιs (nιtryloxymethyl) - propioπsäurehydrazid as a colorless oil yield 63%

I) The amides or hydrazides of the carboxylic acids Bis-MS and CN-MS are prepared analogously by doubling or tripling the reagents

The compounds described above under a) to I) serve as starting and intermediate compounds for further reactions

Example 17 3.4 mmol of L-carnitine hydrochloride are esterified with 1 g (3.4 mmol) of Tπ-PSCI dissolved in 25 ml of dioxane. After 30 mm, the mixture is poured into 100 ml of ice water and weakly acidified with dilute hydrochloric acid. The oily product is subjected to column chromatography purified yield 40%

Example 18

3-Tπmethylammonιum-2-nιtryloxy propane carboxylate

1 g of carnite hydrochloride is added to 8 ml of 70% nitric acid cooled to 0 ° C. After adding 5.5 ml of 96% sulfuric acid at 0 ° C., the mixture is stirred for 1 hour at room temperature and poured onto 50 ml of ice water. After neutralization (pH 7.0) with 10% sodium hydroxide solution is evaporated to dryness in vacuo, the residue is extracted twice with ethanol, the alcohol is evaporated and the crude product obtained is purified by column chromatography (silica gel, methanol) (yellowish oil) yield 56%

Example 19 Investigation of the pharmacological activity of the compounds

a) 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 tolerance 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 a parameter of nitrate activity and bioactivation is measured using a radioimmunoassay

b) The antiplatelet and antiplatelet activity of the compounds is 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.

c) The eπdothelprotective effect of the compounds is determined by the known method of Noack and Kojda (DE-A1-44 10 997).

d) The vasodilating properties were investigated in experiments on isolated aortic rings of the rabbit (Hüsgen, Noack, Kojda: Int Coπfer. "Mediators in the cardiovascular System", p. 9, Malta 2.-5.6J 994) by hanging them in organ baths and stimulated by vasoconstrictors such as phenylephrine. After establishing a stable smooth muscular tone, the influence of the tone on cumulative concentration-effect curves is determined by adding the above vasodilators. For this purpose, the organ bath buffer is mixed with increasing concentrations between 1nM and 10 μM of the vasodilator, whereby between the different fractions is not washed out. The substance administration led to a gradual abolition of the contraction in the presence of the vasoconstrictor in all aortic rings. The extent of relaxation is expressed as a percentage of the contraction remaining at the respective active substance concentration (residual contraction) bMaximum effective concentration EC50 reflects the potency and can be recorded as a pD2 value (concentration in logM).

Example 20

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 substance / s: a) compound according to example 10 20 mg b) compound according to example 10 50 mg c) compound according to example 10 80 mg d) compound according to example 11 20 mg e) compound according to example 11 50 mg f) compound according to example 11 80 mg g) compound according to Example 12 20 mg h) compound according to Example 12 50 mg i) compound according to Example 12 80 mg j) compound according to Example 14 20 mg k) compound according to Example 14 50 mg I) compound according to Example 14 80 mg m) compound according to Example 15 20 mg n) compound according to Example 15 50 mg o) compound according to Example 15 80 mg p) compound according to Example 17 50 mg q) Compound according to Example 7 30 mg

Compound according to Example 14 50 mg r) Compound according to Example 7 30 mg Compound according to Example 15 50 mg s) Compound according to Example 14 30 mg

Pentaerythrityl tetranitrate 50 mg t) Compound according to Example 15 30 mg

Pentaerythrityl tetranitrate 50 mg u) Compound according to Example 10 50 mg

Acetylsalicylic acid 50 mg v) Compound according to Example 12 50 mg

Acetylsalicylic acid 50 mg w) compound according to Example 14 50 mg acetylsalicylic acid 50 mg x) compound according to Example 15 50 mg

Acetylsalicylic acid 50 mg y) compound according to Example 14 50 mg

Captopril 25 mg z) compound according to Example 15 50 mg

Captopril 25 mg

Claims

claims

1. Compounds of formula (I)

(0 ₂ NOCH ₂ ) mC (CH2θH) n (CH ₂ COR ¹ ) o (COR ¹ ) p ₁ (I) where

R 'is a group of the formula (II),

C _{t to} C ₂₀ alkyl, in particular

Methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl, cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyi, 3- Cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthylmethyl, cinnamyl, 5-ethoxycarbonylbutyl, 3-aminopropyl, - (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOH, - (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOCH ₃ , or 1, 6-Hexane-bis- and m to p are integers for which the following applies: m + n + o + p = 4, m ≥ 1, o and / or p ≥ 1, and their therapeutically tolerable salts.

Compounds of the formula (III), woπn o3 is a group of the formula (IV),

R 'Ci to C ₂ o-alkyl, in particular

Methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl, cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyl, 3- Cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthyimethyl, cinnamyl, 5-ethoxycarbonylbutyl, 3-aminopropyl, - (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOH, - (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOCH ₃ , or 1, 6-hexane-bis- and m to p are integers for which the following applies: m + n + o + p = 4, m> 1, o and / or p> 1, and their therapeutically tolerable salts.

3. Compounds of the formula (V),

woπn

R ² d-bis-alkyl, in particular

Methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl, cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyl, 3- Cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthylmethyl, cinnamyl, 5-ethoxycarbonylbutyl, 3-aminopropyl, - (CH2) ₃ CH (NHCOCH ₃ ) COOH,

- (CH ₂ ) ₃ CH (NHCOCH ₃ ) COOCH ₃ , or 1, 6-hexane-bis and R ⁴ H, C to C ₆ -alkanoyl, salicyloyl or acetylsalicyloyl, and their therapeutically acceptable salts.

4. Compounds of the formula (VI),

(0 ₂ NOCH ₂ ) _m C (CH ₂ OH) n (CH2COR ⁵ ) ₀ (COR ⁵ ) _pι (VI) where

R ^{5 is} (2-carboxyphenyl) oxy or (2-alkoxycarbonylphenyl) oxy, and m to p are integers for which the following applies: m + n + o + p = 4, m ≥ 1, o and / or p> 1 , and their therapeutically acceptable salts.

5. Compounds of the formula (VII),

(HIGH ₂ ) _q (0 ₂ NOCH ₂ ) _r C (CH2θR ⁶ ) _s , (VII) wherein

R ^{6 is} salicyloyl or acetylsalicyloyl, and q to s are integers for which: q + r + s = 4, r and s> 1, and their therapeutically acceptable salts.

6. Compounds of the formula (VIII), (O ₂ NOCH ₂ ) _m C (CH ₂ OH) _n (CH ₂ COR ⁷ ) ₀ (COR ⁷ ) _p , (VIII) where 7 is a group of the formula (IX), _.

^R (IX)

R ⁸ and R ⁹ independently of one another d- to Ce-alkyl or together d- to C ₆ -alkylene, R ¹⁰ OH, NHR ⁸ R ⁹ , C, - to Cg-alkoxy, (2-carboxyphenyl) oxy, (2- Alkoxycarbonylphenyl) oxy, (1-carboxymethyl-2-diaikylamino) ethoxy,

(1-carboxymethyl-2-trialkylammonium) ethoxy, (1-alkoxycarbonylmethyl-2-dialkylamino) ethoxy, (1-alkoxycarbonylmethyl-2-trialkylammonium) ethoxy, and m to p are integers for which: m + n + o + p = 4, m> 1, o and / or p> 1, and their therapeutically acceptable salts, quaternary salts or betaines.

7. Compounds of the formula (X),

woπn

R ⁸ to R ^{10 have} the meaning given in claim 6 and

R ^{11 is} N0 ₂ , and their therapeutically acceptable salts.

Compounds of the formula (XI),

woπn

R ι3 bi „s R have the meanings given in claims 6 and 7, R ^{12 is} a d- - bbiiss CCβ-r-AAllkkyyll ,, iinnssbbeessoonnddeerree methyl, ethyl or n-propyl, and

X represents a group capable of forming anions,

2ö 10 which need not be present if the -COR function has the ability to form internal salts.

9. A compound according to claim 8 of formula (XII).

10. A compound according to claim 8 of the formula (XIII).

11. Compounds according to claim 8 of the formula (XIV),

woπn

_R 13 H or d- to d-alky! is.

12. Compounds of the formula (XV),

(HIGH ₂ ) _q (0 ₂ NOCH ₂ ) _r C (CH ₂ OR ⁴ ) _s (XV) woπn

D14 is the acyl radical of a compound according to claims 7 to 11, wherein additionally H, d- to C < ₅ -alkanoyl, salicyloyl or acetylsalicyloyl or -CO-CH ₂ -CH (OH) -CH ₂ -NR ⁸ R ⁹ can be, and q to s are integers for which the following applies: q + r + s = 4, r and s> 1, and their therapeutically tolerable salts.

13. A compound according to claim 12 of formula (XVI).

14. A compound according to claim 12 of the formula (XVII).

15. Compounds according to claims 1 to 14 as medicaments, in particular as vasodilating, endothelium-protecting or antiplatelet agents.

16. Pharmaceutical compositions containing one or more of the compounds according to claims 1 to 14.

17. Pharmaceutical compositions according to claim 16, characterized in that they apply one or more of the compounds according to claims 1 to 14 in combination with others for the treatment of cardiovascular or vascular diseases

Active ingredients, especially those from the indication groups of ACE inhibitors, antiatherosclerotics, anti-hypertensives, beta blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilators, lipid-lowering agents, peripheral vasodilators, phosphodiesterase or platelet aggregation inhibitors.

18. Use of compounds according to claim 1 to 14 for the preparation of pharmaceutical compositions.