DE19641667A1 - New pentaerythritol nitrate ester derivatives - Google Patents

Abstract

Nitrate esters of formula (I)-(III), their salts and compounds of formula (IV) are new. In (I), R1-R3 = H, OR6, ONO2, OR4 or R5; R4 = COR6 or R10; R5 = PO4R7, PO4R9, SO3R9 or COOR6; R6 = H or 1-6C alkyl; R7 = 1-6C alkylene-R8; R8 = N(R6)2, N<+>(R6)3 or N<+>(R6)3 X<->; R9 = R6, aryl or N(R6)2; R10 = a 3- or 5-carbonyl residue of a 2,4 and/or 6-optionally substituted 1,4-dihydropyridine-3,5-dicarboxylic acid; 1-substituted pyrrolidine-2-carbonyl group; an N-carbonyl residue of a substituted sydnoneimine; CO-CH(NHCOR6)-C(R6)2-S-NO; CO-CH(NH2)-C(R6)2-S-NO or NH-CH(COOR6)-C(R6)2-S-NO; X = halogen or an anion-forming group. The following combinations ar excluded: R1-R3 = ONO2; R1 = OH and R2, R3 = ONO2; R1 = R2 = OH and R3 = ONO2; and R1-R3 = OH. In (II), R11 = NO2 acyl, alkyl or alkenyl. In (III), R12 = NO2 or as for R4-R10; n = 0-10. In (IV), each Q is the same and is OH or ONO2.

Description

Field of application of the invention

The invention presented here relates to new esters of nitric acid and their preparation and Use, especially as pharmaceuticals.

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. No. 2,370,437) , Isosorbide-5-mononitrate (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-PS 045 076, EP-PS 057 847, EP-PS 059 664, EP-PS 064 194, EP-PS 067 964, EP-PS 143 507, US-PS 3 886 186, US-PS 4065 488 , US-PS 4417065, US-PS 4431 829), isosorbide dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (Medard, Mem. Poudres 35: 113 (1953)), Trolnitrate (FR-PS 984 523) or Nicorandil (US Pat. No. 4,200,640) and similar compounds are vasodilators, some of which have been used for decades in the broadest therapeutic application (Nitrangin ^® , Pentalong ^® , Monolong ^® , Isoket ^® , Elantan ^® and others). Other pentaerythrityl nitrates have also been described (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363). Comparable and improved pharmacological efficacy when used in the indication areas mentioned above have organic nitrates of a newer type, such as, for example, SPM 3672 (N- [3-nitratopivaloyl] -L-cysteine ethyl ester) (US Pat. No. 5,284,872) and its derivatives.

The pharmaceutical processing of organic nitrates into pharmaceutical preparations for Treatment of angina pectoris or ischemic heart disease is generally known. It is carried out in accordance with the working methods and which are generally familiar to the pharmaceutical expert - rules, whereby the selection of the technologies to be used and the galenic used Auxiliaries primarily based on the active ingredient to be processed. Here are questions  its chemical-physical properties, the chosen form of application, the desired Duration of action and the avoidance of drug-excipient incompatibilities of special meaning. For medicinal products with the indication angina pectoris or ischemic Heart disease is primarily peroral, parenteral, sublingual or transdermal application described in the form of tablets, coated tablets, capsules, solutions, sprays or plasters (DD-PS 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 application 59/10513 (1982)).

In addition to the long-known applications of nitrosating substances, there is their Use for the treatment and prevention of diseases described their Cause in pathologically increased concentrations of sulfur-containing amino acids in Have body fluids. These disease states, caused by congenital or acquired defects in the metabolism of these amino acids and those caused by increased blood and Urine concentrations of said amino acids (homocystinuria) are characterized below summarized the term homocysteinemia (WO-A1-92118002).

The use of the above substances as endothelial protective agents has been recently described (DE-A1-44 10 997).

A number of the organic nitrates (nitric acid esters) known up to now adhere therapeutic disadvantages. So z. B. to observe the so-called nitrate tolerance, d. H. 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 severe drop in blood pressure with reflex tachycardia documented (Mutschler, drug effects, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991).

Statement of the invention

The object of the invention presented here is new pharmacologically acceptable Nitric acid ester derivatives with improved effectiveness and reduced  To provide a spectrum of side effects, which at the same time with good yields should be accessible and suitable for processing into pharmaceutical preparations.

This object has been achieved by providing compounds of the formulas I to V, such as they are defined in the claims. Regarding the individual substituents is in following referred simultaneously to the claims.

Preferred embodiments of the invention are compounds with hydrophilic groups such as Phosphoric acid, sulfonic acid, ester, carboxyl groups and polyethers with 2 and more Hydroxy functions or compounds with quaternary ammonium functions.

Particularly preferred embodiments of the invention are dipentaerythritol nitrates, mixed esters of pentaerythritol nitrates, pentaerythritol nitrate ethers and phosphatidylcholine-derivatized pentaerythritol nitrates, in particular the compounds of the formula II in which R ^{11 is} NO ₂ , the compounds of the formula III in which R ^{12 is} H or NO ₂ , and especially the compounds of formulas IV and V.

At the same time, the use of pharmacologically acceptable derivatives is all of the above named connections possible. Above all, common addition compounds, salts or make enzymatically or hydrolytically cleavable compounds such as esters, amides and the like possible variations.

The readily available nitrates of pentaerythritol serve as starting compounds, where with regard to their representation expressly on the process of partial denitrification of the Pentaerythrityl tetranitrate using hydrazine (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363) is referred to. Another method is the nitration of pentaerythritol to the trinitrate, followed by its hydrazinolysis to pentaerythrityl di- and mono-nitrate and chromatographic separation of the resulting mixture.

The further processing of the individual target connections is carried out by the person skilled in the art common reactions and methods.  

For example, by reacting the partially nitrated pentaerythritol derivatives with organic acids or acid chlorides or through the use of esters by transesterification the corresponding esters are obtained in good yields. The following are particularly suitable Alkane carboxylic acids, derivatized phosphoric or sulfonic acids, but also substituted 1,4-dihydropyridine-3,5-dicarboxylic acids, as known from the class of calcium channel blockers are, or 1-substituted pyrrolidine-2-carboxylic acids from the class of ACE inhibitors. As well carboxyl derivatives of NO-liberating compounds such as SNAP or Sydnonimines. In all of the above cases, they are also suitable for ester formation qualified functional derivatives.

Dipentaerythritol nitrates and pentaerythritol nitrate ethers are proton-catalyzed via the corresponding alcohols accessible. The alkyl ether nitrates of pentaerythrityl tri, di or -mononitrate can by acylation and replacement of the carboxyl group by an alcohol be preserved.

Phosphatidylcholine-derivatized pentaerythritol nitrates are derived from the lower nitrates of Pentaerythritol through the steps of acylation, exchange of the resulting carboxyl function an alcohol, if necessary secondary acylation, esterification of remaining OH groups with phosphoric acid and transfer of the phosphocholine residue accessible.

The choice of the respective substance as a pharmaceutical depends on general pharmacological principles and the therapeutic requirements, which the expert are common. In addition to the desired pharmacological effect, the Health status, the stage of the disease, the physical condition, the known effects and side effects, contraindications, the frequency of treatment, the duration of use, Consider drug interactions and parallel drug applications.

The dosage is in each case therapeutic doses, which are based on those in which the respective active ingredients are already used for known indications. The daily Depending on the active ingredient, the total dose can be up to 500 mg. Generally will  Daily doses up to 350 mg are sufficient. Dosage and dosing interval are so too choose that effective or as constant as possible therapeutic plasma levels are built up.

The compounds used according to the invention can be used themselves or as part of a pharmaceutical Preparation, as a single active ingredient or in combination with one another or with known cardiovascular therapeutics, for example ACE inhibitors, antiatherosclerotics, antihypertensives, Beta-blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilators, Lipid-lowering agents, peripheral vasodilators, platelet aggregation inhibitors or others, substances also used as cardiovascular drugs, combined, their Use can be supplied. The preparation of galenical preparations takes place according to the working methods and rules generally familiar to the pharmaceutical expert, whereby the selection of the technologies to be used and the galenic used Auxiliaries primarily based on the active ingredient to be processed. Here are questions its chemical-physical properties, the chosen form of application, the desired Duration of action, the place of action and the avoidance of drug-auxiliary incompatibilities really important. It is therefore up to the expert, based on Known substance and process parameters in a trivial manner pharmaceutical form, excipients and Select manufacturing technology. The pharmaceutical form in question should be designed so that they to achieve constant therapeutic plasma levels, the respective active ingredient in a Contains amount that makes it possible to reduce the daily dose to 1 in release-controlled systems to distribute up to 2 and for other dosage forms up to 10 single doses. Is also suitable continuous application using long-term infusion. According to the named compounds especially oral, intravenous, parenteral, sublingual or transdermal be applied. The particular pharmaceutical preparation is preferably in liquid or solid form provided. Solutions are particularly suitable here, especially for preparing drops, Injections or aerosol sprays, furthermore suspensions, emulsions, syrups, tablets, Film-coated tablets, coated tablets, capsules, pellets, powders, lozenges, implants, suppositories, creams, Gels, ointments, plasters or other transdermal systems. The pharmaceutical preparations contain common galenically usable, organic or inorganic carriers and auxiliaries, which are themselves chemically indifferent to the respective active ingredients. Suitable for this 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 similar. The preparation can be sterilized and if necessary with auxiliaries such as Fillers, binders, lubricants, mold separators, lubricants, disintegrants, moisturizers, adsorbents or Anti-explosives, preservatives, stabilizers, emulsifiers, Solubilizers, salts to influence the osmotic pressure, buffer solutions, color, Fragrance, aroma or sweeteners can be added. The pharmaceutical professional will use Known substance parameters a suitable selection to avoid drug-excipient incompatibilities to meet.

It has also been found that the compounds according to the invention are surprisingly have the desired properties. In addition, they excel. T. by a optimized NO liberation due to its content of reductively and oxidatively biotransforming NO precursor groups or through an improved multi-phase NO liberation and depending Application purpose increased lipophilicity or hydrophilicity as well as pharmacodynamic Reduced preload, decreased endothelin increase in plasma, pronounced Inhibition of platelet aggregation by platelet-active groups and endothelial protection Effect.

With the invention set forth thus improved and significantly expanded therapeutic Opens up opportunities, pathological situations such as heart and vascular diseases, especially the coronary heart disease, vascular stenosis and circulatory disorders of the peripheral arteries, micro- and macroangiopathies in the context of diabetes mellitus, Treat atherosclerosis and the resulting complications, etc.

The following examples are intended to illustrate the nature of the invention and its implementation explain in more detail, but without restricting their scope.

Embodiments example 1

158 g (0.5 mol) of pentaerythrityl tetranitrate (PETN) were mixed in a mixture of 300 ml of dioxane and 300 ml of ethanol dissolved in boiling and portioned with various for 1 hour Amounts of aqueous hydrazine hydrate solution (1.5-4 mol) were added. Then that became 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 at 15 mm Hg Solvent evaporated and the residue, as required, several times with 100 ml portions Water shaken out until the volume of the oil layer no longer shook out decreased. The aqueous extracts (A) were collected and the remaining oily layer in the dissolved twice the volume of ethanol. The possibly precipitated white precipitation of PETN was filtered after 24 hours; it showed the mp. 132 ° C, and its content of nitrate nitrogen was 17.35%. After recrystallization from acetone twice, its mp. Was at 141 ° C and the Nitrogen content increased to 17.70%; theoretical nitrogen content 17.72% of mp. 141 ° C. Ethanol was evaporated from the filtrate at 15 mm Hg. The viscous, oily residue persisted from the crude pentaerythrityl trinitrate (PETriN) (approx. 14.7% nitrogen content; theory 15.48%).

Example 2

The combined aqueous extracts A were shaken out three times with ether and the ether was 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 was identified as crude pentaerythrityl dinitrate (PEDN). The aqueous portion B, which contains pentaerythritol mononitrate (PEMN) and pentaerythritol denitration products, mainly hydrazine nitrite, was acidified successively with 2N-H ₂ SO ₄ until gas evolution ceased (N2, N ₂ O, NO, N ₃ H), then concentrated at 20 mm Hg until solid products begin to precipitate and is extracted. The crystalline substance which remained after the ether had evaporated and had a melting point of 62 ° C. was identified as crude PEMN. After washing with cold chloroform and recrystallization from chloroform, the leaves obtained had a melting point of 79 ° C .; Nitrogen content 7.74 ± 0.03%; calculated for the pure substance 7.76% N. The extraction residue was evaporated to dryness at 10 mm Hg and the residue was stirred with a small amount of water. The filtered off white crystals, which had a melting point of 260 ° C. after recrystallization from the same amount of water, were identified as pure pentaerythritol.

Example 3

For the purification of the raw substances PETriN and PEDN, these were put into the relevant Acetates transferred and alcoholized after recrystallization from ethanol to the pure products. To 135.5 g (0.5 mol) of crude PETriN [or 56.5 g (0.25 mol) of PEDN] was cooled and Stirring a mixture of 50 ml acetic anhydride and 20 ml acetyl chloride was added in portions. The after the reaction solidified mixture was stirred twice with 50 ml of ethanol and suction filtered. The colorless crystals of pentaerythritol trinitrate acetate (PETriNAc) with a melting point of 85-86 ° C. showed after two recrystallizations from ethanol the mp. 89 ° C, nitrogen content 13.42 ± 0 03% N (calculated: 13.43% N). Yield of pure product 121 g (77%). Pentaerythritol dinitrate diacetate (PEDNAc) also forms colorless crystals, the mp. 42-43 ° C after two Recrystallization from ethanol rose to 47 ° C; Nitrogen content 8.98 ± 0.03% N (calculated: 9.04% N). Yield of pure product 56 g (72%).

104.4 g (0.3 mol) of PETriNAc or 51.7 g (0.15 mol) of PEDNAc were dissolved hot in 400 ml of ethanol, a solution of 1.5 g of NaOH in 50 ml of ethanol was added and the azeotropic mixture of ethanol- Ethyl acetate (bp 71.8 ° C / 760 mm) distilled off. After the ethyl acetate formation had ended, a further 1.5 g of NaOH in 50 ml of ethanol were added and fractionation was continued until further ethyl acetate no longer passed over. Then the ethanol was evaporated at 15 mm Hg and the residue in the case of the substance PETriN was shaken three times with 20 ml of water and in the case of the substance PEDN stirred with 100 ml of water and extracted three times. After drying in vacuo or removing the ether, the pure substances PETriN or PEDN remain as colorless viscous liquids which have been dried for analysis in vacuo over P ₂ O ₅ . Calculated for C ₅ H ₉ O ₁₀ N ₃ (271.1): 15.49% N; found: 15.43% ± 0.03% N. Calculated for C ₅ H ₁₀ O ₈ N ₂ (226.1): 12.39% N; found: 12.37 ± 0.03% N.

Example 4

The PETriN 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 mp 32 ° C in the air, in which 2.14 ± 0.05% water were found with Karl Fischer reagent and 2.15% water by vacuum drying at 60 ° C, corresponding to a hydrate of composition C ₅ H ₉ O ₁₀ N ₃ 1 / 3H ₂ O.

Example 5

PETriN is represented by urea-catalyzed nitration of pentaerythritol with HNO ₃ (95%).

Example 6

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.

Example 7

A typical tablet has the following composition:

Claims (11)

1. Compounds of the general formula I,
wherein
R ¹ , R ² and R ^{3 are} identical or different from one another H, OR ⁶ , ONO ₂ , OR ⁴ or R ⁵ ,
R ⁴ COR ⁶ or R ¹⁰
R ⁵ PO ₄ R ⁷ , PO ₄ R ⁹ , SO ₃ R ⁹ or COOR ⁶ ,
R ⁶ H or a straight-chain or branched C ₁ - to C ₆ -alkyl radical,
R ⁷ straight-chain or branched C ₁ -C ₆ -alkylene-R ⁸ ,
R ⁸ NR ⁶ ₂ , N⁺R ⁶ ₃ or N⁺R ⁶ ₃ X⁻,
R ⁹ R ⁶ , aryl or NR ⁶ ₂ ,
R ^{10 is} a 3- or 5-carbonyl radical of a 1,4-dihydropyridine-3,5-dicarboxylic acid which is optionally substituted in the 2, 4 and / or 6-position,
a 1-substituted pyrrolidine-2-carbonyl radical,
an N-carbonyl radical of a substituted sydnonimine,
a radical -CO-CH (NHCOR ⁶ ) -CR ⁶ ₂ -S-NO,
a radical -CO-CH (NH ₂ ) -CR ⁶ ₂ -S-NO or
a residue -NH-CH (COOR ⁶ ) -CR ⁶ ₂ -S-NO and
X represents a halogen or a group capable of forming anions, and their pharmacologically acceptable salts,
being the combinations
R ¹ = R ² = R ³ = ONO ₂ ,
R ¹ = OH, R ² = R ³ = ONO ₂ ,
R ¹ = R ² = OH, R ³ = ONO ₂ and
R ¹ = R ² = R ³ = OH
with exception of. 2. Compounds of the general formula II,
wherein
R ¹¹ NO ₂ , acyl, alkyl or alkenyl
means, and their pharmacologically acceptable salts. 3. Compounds of the general formula III,
wherein
R ¹² independently of one another NO ₂ or R ⁴ to R ¹⁰ , each with the meaning defined in claim 1, and
n is an integer from 0 to 10
are, as well as their pharmacologically acceptable salts. 4. Compound of formula IV
5. Compound of formula V
6. Compounds according to claim 1 to 5 as a medicament. 7. Compounds according to claim 1 to 5 as explosives. 8. Pharmaceutical preparations, characterized in that they contain at least one of the Contain compounds according to claim 1 to 5. 9. Pharmaceutical preparations according to claim 8, characterized in that they Compounds according to claims 1 to 5 combined with others for the treatment of cardiovascular diseases applied active ingredients, especially those from Indication groups of ACE inhibitors, antiatherosclerotics, antihypertensives, Beta blockers, cholesterol-lowering agents, diuretics, calcium channel blockers, coronary dilators, Lipid-lowering agents, peripheral vasodilators or platelet aggregation inhibitors, contain. 10. explosive mixtures, characterized in that they contain at least one of the compounds according to claim 1 to 5 included.