JPH09510979A - Pharmaceutical formulations and drugs for the prevention and treatment of endothelial dysfunction - Google Patents

Abstract

  (57) [Summary] The present invention provides compounds that release or transfer nitric oxide, endogenous monoxide, for the prevention, treatment and elimination of endothelial dysfunction, and diseases caused by or associated with endothelial dysfunction. Disclosed is the use of a nitrogen-forming stimulant, as well as a guanylate cyclase stimulant, and the use of the above compounds in the manufacture of a pharmaceutical formulation for the above indications.

Description

Detailed Description of the Invention           Pharmaceutical formulations and drugs for the prevention and treatment of endothelial dysfunction                               Field of the invention   The present invention is caused by endothelial dysfunction, as well as endothelial dysfunction, Or nitric oxide for the prevention, treatment and elimination of associated diseases Compounds that release or translocate, stimulants of endogenous nitric oxide formation, and Relates to the use of guanylate cyclase stimulants. At the same time according to the invention, Provide a pharmaceutical formulation for an indication.                               Background technology   Glycerin trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), tetranitric acid Pentaerythrityl (PETN) (Reisemann et al., Circulation, Vol. XVII, 22 (1 958), US-PS 2370437), 5-nitrate-5-isosorbitol mononitrate (ISM). N) (DE-OS 222210, DE-OS 2751934, DE-OS   3028873, DE-PS 2903927, DE-OS 3102947 , DE-OS 3124410, EP-PS 45076, EP-PS 578. 47, EP-PS 59664, EP-PS 64194, EP-PS 679. 64, EP-PS 143507, US-PS 3886186, US-PS. 4065488, US-PS 4417065, US-PS 4431829). , Isosorbitol dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand , 15, 173 (1948)), Propatylnitrat (Medard, Mem. Poudres 35 : 113 (1953)), Trolnitrat (FR-PS 984523) or Nicorandil (Ni corandil) (US-PS 4200460) and the like. Compounds have been focused on angina or ischemia for decades. Widely used in the treatment of heart disease (IHK) indications (Nitrangin^R, Pentalon g^R, Monolong^R, Isoket^R, Elanta^R,etc). When used in the above indication fields Equivalent and improved efficacy of the drug is found, for example, in SPM 3672 (N- [3-Nitray). Topivaloyl] -L-cysteine-ethyl ester) (US-PS 52848) 72) as well as new classes of organic nitrates such as their derivatives. Also, organic nitrites such as isoamyl nitrite have long been used as coronary vasodilators. (Brunton, Lancet: 97 (1867)). Releases other nitric oxide, Or compounds to be transferred, such as thionitrite, thionitrate, S-ni Trosothiol or nitrosoprotein (Harrison et al., Circulation 87: 1461- 1467 (1993)) and substituted furoxane (1,2,5-oxadiazole-2-o) Xide, furazane-N-oxide) (Feelisch et al., Biochem. Pharmacol. 44: 114. 9-1157 (1992) or substituted sydnonimines, especially molsidomine (DE-AS 169). 5897, DE-AS 2532124, DD-PS 244980) as well. It is described as a potent coronary vasodilator. All these substances are themselves , Or a pharmaceutically active metabolite, eg molsidomine-metabolite “SIN 1 "And" SIN-1A "(Noack, Nitroglycerin VII, Walter de Gruyter &  Co., Berlin 1991, 23-28) and their derivatives and structural analogues (Noack and And Feelisch, Molecular Mechanism of Nitrovascular Bioactivation, “Endothelial Mechanism of Vasomotor Regulation” (Molecular mechanism of nitrovascular bioactivation, in “Endothelial Mec hanisms of Vasomotor Control ”) (Hrsgb. Drexler et al.), pp. 37-50, Steinkopf f Verlag, Darmstadt, F.R.G. (1991)), releasing nitric oxide in vivo, Or it can be moved.   No organic nitrates in pharmaceutical formulations for treating angina or ischemic heart disease Nitrite and other nitric oxide releasing or migrating compounds It is generally known to formulate Prescriptions are commonly known to pharmacists The work method and work standard are The choice of surgery and the formulation aids used depends primarily on the active ingredient to be treated. You. In this regard, the chemical-physical properties of the active ingredient, the selected dosage form, the desired The issue of duration of action as well as incompatibility between the drug and the auxiliaries is of particular importance. Angina The drugs used for ischemic heart disease include, among others, tablets, dragees, capsules, Oral, parenteral, sublingual or transdermal administration in the form of solutions, sprays or salves Are described (DD-PS 293492, DE-AS 2623800, DE-OS 3325652, DE-OS 3328094, DE-PS 40 07705, DE-OS 4038203, JP-application 59/10513 (19). 82)). In addition to the use of previously known nitrating substances, the addition of these substances in body fluids For the treatment and prevention of diseases caused by pathologically high concentrations of sulfur-containing amino acids in The use is described. Innate or acquired in the metabolism of these amino acids High blood and urine concentrations of the amino acid (homology These conditions are characterized by the concept of homocystinosis (WO92 / 18002).   The anti-ischemic effects of organic nitrates and the above-mentioned substance groups are In addition, it saves oxygen consumption in the heart, or O generated during IHK.₂Lack of supply and demand Explained by the effect of compensating for balance, reducing the burden on the heart. The reason is venous blood Preferential dilation of vessel volume (venous pooling) or preload relief and especially coronary vessels Direct coronary vasodilatory effect in the area of stenosis. As a result, organic nitric acid Stells are particularly relevant in areas of atherosclerosis, especially in the area of coronary stenosis. Acts significantly more potent than in loose vascular areas (Kojda et al. Endotheliu m 1 (Suppl,): Abstr. 299, p.s76 (1993)), which is probably beneficial for the lack of perfusion after stenosis. It will have an effect (a favorable steel effect). This pure hemodynamic effect The fruits are all nitrovasodilators, despite having very different chemical structures. It is mediated by the free radical nitric oxide, NO, which equally arises from tonicity agents. I Nonetheless, it will eventually supply NO to the vascular endothelial cells and smooth muscle cells. Product activation modes are very diverse (Noack and Feelisch, Nitrovascular bioactivity Molecular mechanism of vascularization, `` Molecular mechanism of nitrovas '' cular bioactivation, in “Endothelial Mechanisms of Vasomotor Control”) ( Hrsgb. Drexler et al.), Pp. 37-50, Steinkopff Verlag, Darmstadt, F.R.G. (1991) )). This has recently been elucidated by directly measuring NO using various techniques. (Methode Noack et al., Neuroprotocols 1: 133-139 (1992)). NO acts as a vasodilator by activating soluble guanylyl cyclase. You. This stimulates the formation of cGMP from GTP. cGMP itself , Various phosphorylation reactions that promote intracellular Ca storage (eg protein kinases) (Z. Kardiol. 79 (Suppl. 1): 212 (1990). )). Free Ca in cells²⁺When the level drops, relaxation occurs. Since 1987 Skin-derived relaxation factor (EDRF) is identical to NO or NO-containing substances Ri (Palmer et al., Nature, 327: 524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sc. i. 84: 9265-9269 (1987)), and is known to have important implications for local circulation. You.   Endothelial cells form a tight monolayer in the inner wall area of blood vessels. By this, About 800 m, which has a weight equivalent to 1.5 to 2 kg of human liver.² The total area of The functions that endothelial cells perform today are mechanical and functional. There are probably two. On the other hand, endothelial cells have low density lipoprotein (LDL) To prevent blood components such as from entering the blood vessel wall (arterial intima) near the lumen, Acts as a barrier of some kind. On the other hand, endothelial cells have an endocrine function. various Stimulating EDRF / NO and prostaglandin-I₂(PGI₂) Like The synthesis of various bioactive substances is increased, which causes the cellular functions (Pohl and Bu) to flow. sse, Eur. Heart J .: 11 (Suppl. B) 35-42 (1990)), local hemodynamics (Furchgo tt, Circ. Res. 53: 557-573 (1983)) and the tissue structure of the blood vessel wall (Di Corleto, Exp. Cell Res. 153: 167-172 (1984)) is fundamentally affected. By this, at the same time Whenever the skin is damaged, (endothelial damage due to hypercholesterolemia (TJ Verb euren et al., Circ. Res. 58: 552-564 (1986), Endothelial injury (M.R.Si. Greid et al., Circ. 86 (Suppl. 1): 21 (1992)) Pathological effects of endothelial function occur, and It is easy to see that various results occur. This includes atherogenesis Local vasoconstriction or vasospasm and vascular wall, considered to be in the early stages of The process of remodeling and growth will occur.   Endothelial dysfunction is a limitation or loss of endothelium-mediated physiological vasodilation. It is characterized by being told. At the same time, NO-mediated vasorelaxation, NO-mediated Process in media and media of arterial intima and NO suppressed by vascular protection Has been observed to decrease or stop. Endothelial dysfunction further increases mitotic reproduction. Proliferation process in blood vessel wall by addition, endothelial adhesion of leukocytes and macrophages and And migration, and increased oxidation of low-density lipoprotein (LDL), which is harmful to endothelium Characterized by addition. This dysfunction is associated with atherosclerosis, high blood pressure, and high cholesterol. Must be observed in pathophysiological conditions within the framework of terolemia, diabetes and heart failure (Creager et al., J. Cli. Invest. 86: 228-234 (1990); Linder et al., Circulatio. n 81: 1762-1769 (1990); Zeiher et al., Circulation 83: 391-401 (1991)). Similarly, Hypoxia and low shear upon release are also compatible with endothelial dysfunction. Endothelial dysfunction Harm is, inter alia, like acetylcholine or serotonin, which usually lowers blood pressure. Because of their direct vasoconstrictor effect, vasoactive substances cause blood flow in smooth vascular muscles. It causes the tubes to contract, which adversely affects the disease. (Golino et al., N. Engl. J. Me. d, 324: 641-648 (1991)). Therefore, physiological vasomotor control is impaired in endothelial function. In harm, not only is it disturbed, but the opposite. Even more striking is the blood vessels Changes in the atherosclerotic remodeling of the inner wall (Ludmer et al., N. Engl. J. Med. 315: 1046-1051 (1986)).   Endothelium has its autokrin and Instead of having parakrin activity, form EDRF / NO by yourself It also influences exogenous NO-releasing action like PETN or GTN. You. For example, mechanical removal of endothelium from the arterial wall (in invasive catheter diagnostics , Or against isolated vascular fragments outside the body) or with a special inhibitor. Suppressing NO formation in the skin, blood of nitro vasodilators such as GTN or PETN Vascular dilation is enhanced (Busse et al., Cardiovasc. Pharmacol. 14 (Suppl. 11): S81. -S85 (1989); Kojda et al. Vasc. Res. 29: 151 (1992A)). Pharmacological NO synthesis of endothelium Biological inhibition has the same effect on the coronary veins (Kojda et al., Naunyn-Schmiedeberg. Arch. Pharmacol. 346: R35 (1992B)). Calcium antagonists, especially 1,4-dihydride The effects of lopyridine type (DHP) are known to weaken after removal of endothelium (Kojda et al. Bas. Res. Cardiol. 86: 254-256 (1991)). Subsequent research has shown that These substances were found to be probably stimulators of endothelial NO formation and release (Guenther et al., Basic Res. Cardiol. 87: 452-460 (1992)). Similarly, Bradykini Quinines, such as amino acids, are also biologically involved in the increased endothelialization and release of EDRF / NO. Briner et al., Am. J. Physiol. 264: F322-F327 (1993);  Kelm et al., Biochem. Res. Commun. 154: 236-244 (1988)).                               Disclosure of the invention   Endothelial dysfunction frequently causes cardiac and circulatory disorders such as atherosclerosis. It is considered to be a pathophysiologically important trigger that causes That These functional disorders and appear with or caused by it Prevention, treatment and elimination of the diseases being treated are important therapeutic requirements.   Here, endothelial dysfunction, and manifestations with this dysfunction, and / or To prevent, treat and eliminate the diseases it causes, nitric oxide Compounds that release and / or give, stimulants of endogenous nitric oxide formation and And guanylate cyclase stimulants, especially soluble guanylate cyclase stimulants It has been found to be effective to use. These endothelial dysfunctions and diseases , Especially endothelium damage due to hypercholesterolemia, endothelium damage due to hypoxia, Endothelial damage due to mechanical and chemical pathogenesis, especially by drugs on narrowed blood vessels, and During mechanical reopening and thereafter, for example, percutaneous transluminar angioplasty. Endothelial damage after shadow (PTA) and percutaneous transluminal coronary angiography (PTCA), after infarction Stage endothelial damage (endothelial dysfunction during reperfusion), mediating endothelium after bypass surgery -Mediated reclosure, peripheral arterial circulation disorders and atherosclerotic hearts And cardiovascular disease, hypertension including pulmonary and portal hypertension, hypertensive heart disease, diabetes Pathological capillary and arteriosclerotic lesions, coronary heart disease, heart failure, or endothelial function It is another disease caused by the disorder.   Compounds that release and / or transfer nitric oxide within the meaning of the invention , Stimulants of endothelial nitric oxide formation and guanylate cyclase In particular, a compound that acts directly or indirectly on guanylate cyclase In that case, as an indirect stimulant of guanylyl cyclase, guanylyl cycla Can release stimulants of enzyme, or the enzymatic efficacy of guanylyl cyclase The concentration is otherwise increased and / or the inhibitor of guanylate cyclase is And act to antagonize, or reduce the effective enzyme concentration of the inhibitor by other means. Compound. As an indirect stimulant of guanylyl cyclase, To increase the formation or release of endogenous NO, such as calcium antagonists Suitable compounds, especially compounds of the 1,4-dihydropyridine type, eg nifedipine , Felodipine, nimodipine, amlodipine, etc. are used. Similarly, for endothelium It is also advantageous to use compounds which can have a high quinine content. Especially this Kinin receptor stimulators, such as kinins or similar acting substances, endothelial kinins Formation And quinine degradation inhibitors, especially vascular pressure-converting-enzyme inhibitors (A CE-inhibitors), for example captopril, enalapril, moexipril, ramip Lil, and similar substances. Generally, endogenous or exogenous nitric oxide release The use of a compound that exerts its effect upon exit and / or migration is It is a particularly preferred embodiment of the invention. Substances and compounds of particular interest are organic Nitrate, especially glyceryl trinitrate, pentaerythrityl tetranitrate, mononitrate-5 -Isosorbitol, isosorbitol dinitrate, mannitol hexanitrate, hexanitrate a New products like Nositol, Propatyl Nitrate, Troll Nitrate, Nicorandil, SPM 3672 New nitrates and their physiologically compatible derivatives, isonitrite Amyl-like organic nitrites, thionitrites, thionitrites, S S-nitrosothiols such as -nitroso-N-acetyl-D, L-penicillamine , Nitrosoprotein, nitric oxide-releasing furoxan derivative, nitric oxide-releasing Cidononimine derivatives, especially molsidomine, mesocarb and its analogues, nit Rosyl complex compounds, especially iron-nitrosylation such as nitroprusside-sodium Compound, as well as nitric oxide itself. Where the release of nitric oxide and / or Migration can occur in vivo via pharmacologically active metabolites. Because of the large number, it is basically preferred in the present invention to utilize these metabolites as well. Yes. At the same time, use physiologically compatible derivatives of all the above compounds. It is also possible. In particular, commonly used addition compounds, salts or Enzymatic or hydrolytically dissociable compounds such as esters, amides, etc. are also used it can.   The selection of each active ingredient will depend on the general pharmacological principles and cures familiar to those skilled in the art. Perform according to medical requirements. In addition to the desired pharmacological effects, health Condition, illness investigation, physical condition, known effects and side effects, justification, treatment Consider frequency, duration of use, drug interactions, and parallel drug use.   Administration is a therapeutic administration in which each active ingredient is already used for a known indication. Do in quantity. The total daily dose may be up to 500 mg, depending on the active ingredient. General In general, a daily dose of up to 350 mg is sufficient. Administration and administration interval are possible It should be chosen so that only a constant therapeutic plasma level is obtained. In the present invention A more used compound is a single active ingredient, either as such or as part of a pharmaceutical formulation. Or as a reciprocal or known cardio / circulatory system therapeutic agent, eg ACE inhibition Agents, anti-atherosclerotic agents, antihypertensive agents, beta blockers, cholesterol Hypoleptics, diuretics, calcium channel blockers, coronary vasodilators, lipid lowering agents, peripheral blood Used as vasodilators, platelet aggregation inhibitors, or other cardiac / circulatory therapeutics It can be supplied in combination with the substances used.   Manufacture of pharmaceutical formulations involves the use of operating methods and operating standards generally known to those skilled in the art. The technique to be used and the selection of formulation aids to be used should be followed. The choice depends primarily on the active ingredient to be treated. At that time, the chemical of the active ingredient -Physical properties, selected dosage form, desired duration of action, site of action and medication The problem of product-auxiliary incompatibility becomes particularly important. Therefore, experts are familiar with known substances And the parameters of the manufacturing method, and as such, the medicinal And manufacturing technology must be selected. At that time, the medicinal product form in question has a fixed cure. Adjust the release of each active ingredient to achieve therapeutic plasma levels The daily dose may be divided into 1 to 2 individual doses and up to 10 individual doses in other pharmaceutical forms. It should be included in an amount that can be divided.   According to the present invention, the above-mentioned compounds are especially oral, intravenous, parenteral, sublingual or transdermal. Can be administered locally. Each pharmaceutical formulation is preferably liquid or solid Prepared in the form of. This includes solutions, especially drip, injection or aerosol sprays. , As well as suspensions, emulsions, syrups, tablets, film tablets, dragees , Capsules, pellets, powders, pastilles, implants, suppositories, creams, gels, ointments, salves medicine, Or other transdermal methods are suitable.   The pharmaceutical preparations can be used in the usual preparations and as such are compatible with the individual active ingredients. It contains active, organic or inorganic carriers and auxiliaries. Suitable substances for this include water, salt Solution, alcohol, vegetable oil, polyethylene glycol, gelatin, lactose, Amylose, magnesium stearate, talc, highly dispersible silicon dioxide, para Fins, fatty acid mono- and diglycerides, cellulose derivatives, polyvinyl pyro Redon, etc., but are not limited to these. The formulation should be sterilized and Fillers, binders, lubricants, release agents, lubricants, disintegrants, moisturizers, adsorbents or Affects rupture inhibitors, preservatives, stabilizers, emulsifiers, solubilizers, osmotic pressure Salts, buffers, colorants, flavors, fragrances, or sweeteners can be added. Made Pharmaceutical experts use known substance parameters to avoid incompatibilities between drugs and auxiliaries. An appropriate choice can be made to   According to the present invention, hypoxia, high serum cholesterol concentration, high blood pressure, diabetes, For example, reperfusion after stenosis during myocardial infarction, mechanical and chemical pathogenesis, etc. Prevents the pharmacological condition that promotes cutaneous dysfunction or prevents the development of endothelial dysfunction It opens up new therapeutic possibilities that completely block it. Therefore, the appropriate compound When used therapeutically, any formulation will contribute to this etiology, as explained above. Due to heart and vascular diseases, such as atherosclerosis and its consequent It is only possible to prevent and actually treat the disease. This is the coronary heart Disease, vascular stenosis, and peripheral arterial blood flow disorders, and capillary disease in the framework of diabetes. And atherosclerotic lesions. Surprisingly, the above compounds are known to date , Especially pure hemodynamic and anti-ischemic properties, eg in hypercytosis It exhibits a voluntary endothelium-protecting effect independent of organic nitrates or their potency. So Stop these pharmacological situations because of using these compounds Or even revert to the original state unless those circumstances are irreversible Yes Noh. At that time, it is not expected in this form, which has not been disclosed so far. The only new active ingredients are problems.   The following examples explain the invention in more detail with regard to its nature and practice. However, these examples do not limit the scope of the invention.                                 Example                                   Example 1           Pharmacological in vivo model (New Zealand rabbit)   In animal studies, it is possible to test and quantify the effects of pharmaceuticals over a period of weeks to a few doses. Cholesterol rearing is appropriate for creating possible endothelial dysfunction (Jayakod y et al., Can. J. Physiol. Pharmacol. 63: 1206-1209 (1985), Verbeurey et al., Circ . Res. 58: 552-564 (1986), Freiman et al., Circ. Res. 58: 783-789 (1986)). Nine female New Zealand rabbits each were treated with standard diet or cholesterin concentrate. The diet (40 g / kg / day) with a high degree (0.75%) was bred for 15 weeks. this Plasma levels increased from 69.8 ± 10.4 to 907.1 ± due to cholesterin rearing Increased to 85.5 mg / dl, and the area of the aorta showed atherosclerotic lesions. It was dyed with Sudan IV and then computer-assisted laser scanning technique was applied. It was quantified using surgery. Aortic changes were 73.3 ± 1.9% in the aortic arch, chest Includes an area of 46.3 ± 2.5% in the aorta and 49.6 ± 3.5% in the inferior abdominal aorta (Fig. 2, comparison).                                   Example 2 Vessels damaged by atherosclerosis are treated with phenylephrine Although contractile, vascular relaxation mediated by endothelium After feeding, in its function compared to the comparison sample (standard diet), the endothelial function was sufficiently It had changed to the extent that it could be described as an obstacle. Breast size of cholesterol-fed animals (+) The arterial segment is significantly weaker than acetylcholine than the aortic segment of the control animal Feeling It showed acceptability (Fig. 1). The degree of endothelial dysfunction measured is atherosclerosis Directly correlated with each severity of symptomatic disorder (r = 0.67, p <0.00 01) (Fig. 3). These data show that endothelial function is dependent on samples containing cholesterol. Indicates that the fault has evolved.                                   Example 3   Two other groups of 9 White New Zealand rabbits each with an additional penitrate pen Taeritrityl (PETN) (6 mg / kg / day) was given, with the addition of fal to the compressed feed. I put Mon. At the same time, animals treated with PETN show atherosclerotic lesions Was significantly reduced. The degree of this damage was measured as in Example 1. All of the aorta It was found that the proportion of atherosclerotic disorders was significantly reduced in some areas Aortic arch 58.6 ± 2.1%, thoracic aorta 34.7 ± 2.0%, and inferior abdominal Arteries 39.3 ± 3.1%) (Fig. 2).                                   Example 4   Similarly, after breeding PETN, animals not fed cholesterol (endothelial dysfunction) Maximal (1 μM acetylcholine) endothelium-mediated relaxation compared to No significant differences were observed with the nitrovascular vasodilator PET. It shows a marked protective effect of N, which is an endothelial dysfunction within the meaning of the present invention. Prevents harm (Figures 3 and 4, Table 1).   Comparing FIGS. 3 and 4 shows that PETN was associated with atherosclerotic lesions. It can be seen that the degree of harm can be reduced and endothelial dysfunction can be improved. For PETN group The poor correlation coefficient between PETN and PET is that atherosclerotic lesions and endothelium It shows that it also breaks the close relationships between functions.   Table 1 shows cholesterol in the thoracic aorta of white New Zealand rabbits. Of endothelium dysfunction induced by breeding diet (0.75%, 15 weeks) 2 shows the effect of PETN (6 mg / kg / day) on the. Endothelium-dependent vasodilator ASE The potency of tilcholine is displayed as the concentration (log M, pD²Value) is this strength The degree of antagonism was half that of the vasoconstrictor phenylephrine in cumulative administration ( The higher this value, the stronger the effect of acetylcholine). Maximum dilation efficacy is vasoconstrictor Expressed as a percentage of the efficacy of phenylephrine, phenylephrine does not It was antagonized with the maximum effective concentration of phosphorus (1 μM). Cholesterol feeding alone (comparison) Induced endothelial dysfunction has markedly reduced potency and maximal potency of acetylcholine You can see that^*, P <0.05). If PETN is given at the same time, , The difference can no longer be confirmed. Moreover, PETN is acetylcholine and it Therefore, the potency of endothelial function after cholesterol rearing is significantly improved (#, p <0. On the other hand, after the standard breeding, the endothelial function is significantly deteriorated. The entire This in turn implicates endothelial function in experimentally induced atherosclerosis The positive effect of PETN on the other hand is shown. Absorption of PETN into plasma And Anfluten were metabolized in plasma 24 hours after the animals were last fed. Proof by measuring the concentration of pentaerythrityl mononitrate (PEMN) (FIG. 5).                                   Example 5   A typical tablet has the following composition                                   Example 6   A tablet containing 20 mg of pentaerythrityl trinitrate (PETriN) has the following composition. Have                                   Example 7   Tablets containing 20 mg pentaerythrityl dinitrate (PEDN) have the following composition: Do                                   Example 8   Tablets containing 20 mg of erythrityl tetranitrate (ETN) have the following composition                                   Example 9   Tablets containing 20 mg of isosorbitol mononitrate (ISMN) have the following composition To                                   Example 10   Tablets containing 20 mg of isosorbitol dinitrate (ISDN) have the following composition To                                   Example 11   40 mg of pentaerythrityl tetranitrate (PETN) and propranolol hydrochloride

[Procedure of Amendment] Article 184-8 of the Patent Act [Submission date] April 2, 1996 [Correction contents] And quinine degradation inhibitors, especially vascular pressure-converting-enzyme inhibitors (A CE-inhibitors), for example captopril, enalapril, moexipril, ramip Lil, and similar substances. Generally, endogenous or exogenous nitric oxide release The use of a compound that exerts its effect upon exit and / or migration is It is a particularly preferred embodiment of the invention. Substances and compounds of particular interest are organic Nitrate, especially glyceryl trinitrate, pentaerythrityl tetranitrate, mononitrate-5 -Isosorbitol, isosorbitol dinitrate, mannitol hexanitrate, hexanitrate a New products like Nositol, Propatyl Nitrate, Troll Nitrate, Nicorandil, SPM 3672 New nitrates and their pharmacologically compatible derivatives, isonitrite Amyl-like organic nitrites, thionitrites, thionitrites, S S-nitrosothiols such as -nitroso-N-acetyl-D, L-penicillamine , Nitrosoprotein, nitric oxide-releasing furoxan derivative, nitric oxide-releasing Cidononimine derivatives, especially molsidomine, mesocarb and its analogues, nit Rosyl complex compounds, especially iron-nitrosylation such as nitroprusside-sodium Compound, as well as nitric oxide itself. Where the release of nitric oxide and / or Migration can occur in vivo via pharmacologically active metabolites. Because of the large number, it is basically preferred in the present invention to utilize these metabolites as well. Yes. At the same time, use pharmacologically compatible derivatives of all the above compounds. It is also possible. In particular, commonly used addition compounds, salts or Enzymatic or hydrolytically dissociable compounds such as esters, amides, etc. are also used it can.   The selection of each active ingredient will depend on the general pharmacological principles and cures familiar to those skilled in the art. Perform according to medical requirements. In addition to the desired pharmacological effects, health Condition, illness investigation, physical condition, known effects and side effects, justification, treatment Consider frequency, duration of use, drug interactions, and parallel drug use. Or other transdermal methods are suitable.   The pharmaceutical preparations can be used in the usual preparations and as such are compatible with the individual active ingredients. It contains active, organic or inorganic carriers and auxiliaries. Suitable substances for this include water, salt Solution, alcohol, vegetable oil, polyethylene glycol, gelatin, lactose, Amylose, magnesium stearate, talc, highly dispersible silicon dioxide, para Fins, fatty acid mono- and diglycerides, cellulose derivatives, polyvinyl pyro Redon, etc., but are not limited to these. The formulation should be sterilized and Fillers, binders, lubricants, release agents, lubricants, disintegrants, moisturizers, adsorbents or Affects rupture inhibitors, preservatives, stabilizers, emulsifiers, solubilizers, osmotic pressure Salts, buffers, colorants, flavors, fragrances, or sweeteners can be added. Made Pharmaceutical experts use known substance parameters to avoid incompatibilities between drugs and auxiliaries. An appropriate choice can be made to   According to the present invention, hypoxia, high serum cholesterol concentration, high blood pressure, diabetes, For example, reperfusion after stenosis during myocardial infarction, mechanical and chemical pathogenesis, etc. Prevents the pharmacological condition that promotes cutaneous dysfunction or prevents the development of endothelial dysfunction It opens up new therapeutic possibilities that completely block it. Therefore, the appropriate compound When used therapeutically, any formulation will contribute to this etiology, as explained above. Due to heart and vascular diseases, such as atherosclerosis and its consequent It is only possible to prevent and actually treat the disease. This is the coronary heart Disease, vascular stenosis, and peripheral arterial blood flow disorders, and capillary disease in the framework of diabetes. And atherosclerotic lesions. Surprisingly, the above compounds are known to date , Especially pure hemodynamic and anti-ischemic properties, eg in homocysteine It exhibits a voluntary endothelium-protecting action independent of organic nitrates or their potency. Therefore, the use of these compounds will stop these pharmacological situations. Stop or revert to their original state unless the situation is irreversible. Yes yes [Procedure of Amendment] Article 184-8 of the Patent Act [Submission date] June 25, 1996 [Correction contents]                               The scope of the claims   1. Endothelial dysfunction, and associated with and / or Or caused by endothelial dysfunction, a) Endothelial damage due to hypercholesterolemia, b) Endothelial damage due to hypoxia, c) The endothelium damage caused by mechanical and chemical pathogens, especially narrowed blood vessels, is And during mechanical reopening and thereafter, for example, percutaneous transluminar blood Endothelial injury after angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), d) Endothelial damage at post-infarction stage (endothelial dysfunction during reperfusion), e) endothelium-mediated reokklusion after bypass surgery, f) Peripheral arterial blood flow disorder due to atherosclerotic vascular wall change and General atherosclerosis, g) hypertension, including pulmonary and portal hypertension, h) hypertensive heart disease, i) diabetic capillary and arteriosclerotic lesions, and j) heart failure Diseases selected from (but triggered by genetic defects in enzyme defects, Or caused by homocysteinemosis and homocysteinemosis Release nitric oxide for the prevention, treatment and elimination of And / or the use of migrating compounds.   2. The compound that releases and / or transfers nitric oxide is a) Organic nitrates, especially Glycerin trinitrate (GTN), pentaerythrityl tetranitrate (PETN), mononitric acid -5-isosorbitol (ISMN), isosorbitol dinitrate (ISDN), Mannitol hexanitrate, inositol hexanitrate, propatil nitrate, troll nitrate, nitric acid Corandil or SPM 3672 and their pharmacologically compatible derivatives, b) an organic nitrite such as isoamyl nitrite, c) thionitrite, d) thionitrate, e) S such as S-nitroso-N-acetyl-D, L-penicillamine (SNAP). -Nitrosothiol, f) nitrosoprotein, nitric oxide-releasing furoxan derivative, g) Nitric oxide-releasing sydnonimine derivatives, especially mesocarb, molsidomine or Is their pharmacologically effective metabolite, h) Nitro such as iron-nitrosyl compounds, especially nitroprusside-sodium A sil complex compound, and i) Nitric oxide (NO) itself Releasing nitric oxide according to claim 1 and / or Is the use of a transfer compound.   3. A compound for releasing and / or migrating nitric oxide according to claim 1. Described endothelial dysfunction, and appearing with endothelial dysfunction, and / or For the prevention, treatment and elimination of diseases caused by endothelial dysfunction Use in the manufacture of pharmaceutical formulations.   4. A compound according to claim 3, characterized in that the compound according to claim 2 is used. Use of a compound that releases and / or transfers nitric oxide.   5. The compound may be combined with other active ingredients used in the treatment of heart / circulatory disorders. ACE inhibitors, anti-atherosclerotic agents, antihypertensive agents, beta blockers , Cholesterol lowering agents, diuretics, calcium channel blockers, coronary vasodilators, lipid lowering agents An active ingredient selected from the group consisting of laxatives, peripheral vasodilators, and platelet aggregation inhibitors Minute Releasing nitric oxide according to claim 3 or 4, characterized in that And / or the use of migrating compounds.   6. Endothelial dysfunction, and associated with and / or Or caused by endothelial dysfunction, a) Endothelial damage due to hypercholesterolemia, b) Endothelial damage due to hypoxia, c) The endothelium damage caused by mechanical and chemical pathogens, especially narrowed blood vessels, is And during mechanical reopening and thereafter, for example, percutaneous transluminar blood Endothelial injury after angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), d ) Endothelial injury at post-infarction stage (endothelial dysfunction during reperfusion), e) endothelium-mediated reokkulusion after bypass surgery, f) Peripheral arterial blood flow disorder due to atherosclerotic vascular wall change and General atherosclerosis, g) hypertension, including pulmonary and portal hypertension, h) hypertensive heart disease, i) diabetic capillary and arteriosclerotic lesions, and j) heart failure Diseases selected from (but triggered by genetic defects in enzyme defects, Or caused by homocysteinemosis and homocysteinemosis (Excluding diseases) to prevent, treat and eliminate nitric oxide. A method characterized by using a compound that emits and / or transfers.   7. 7. The compound according to claim 6, characterized in that the compound according to claim 2 is used. How to list.   8. The compound may be combined with other active ingredients used in the treatment of heart / circulatory disorders. ACE inhibitors, anti-atherosclerotic agents, antihypertensive agents, beta blockers , Cholesterol lowering agents, diuretics, calcium channel blockers, coronary vasodilators, lipid lowering Active ingredient selected from the group consisting of agents, peripheral vasodilators, and platelet aggregation inhibitors Method according to claim 6 or 7, characterized in that it is combined with

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI A61K 38/00 ADS 9051-4C A61K 37/02 ADS (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), AM, AU, BG, BR, BY, CA, CN, CZ, DE, EE, FI, GE , HU, IS, JP, KP, KR, KZ, LT, LV, MD, MX, NO, NZ, PL, RO, RU, SI, SK, TJ, UA, US, UZ, VN

Claims (1)

[Claims]   1. Endothelial dysfunction, and associated with and / or Or to prevent, treat and eliminate diseases caused by endothelial dysfunction , A compound that releases and / or transfers nitric oxide, endogenous nitric oxide Use of formation stimulants or guanylyl cyclase stimulants.   2. Endothelial dysfunction, and associated with and / or Or diseases caused by endothelial dysfunction, Endothelial damage due to hypercholesterolemia, endothelial damage due to hypoxia, mechanical and Endothelial damage due to chemical pathogens, especially narrowed blood vessels, by means of drugs and mechanically During and after opening, eg percutaneous transluminar angiography (PTA) And endothelial injury after percutaneous transluminal coronary angiography (PTCA), in post-infarction stage Endothelial injury (endothelial dysfunction during reperfusion), endothelium-mediated reclosure after bypass surgery, peripheral Cardiovascular and circulatory disorders such as arterial circulation disorders and atherosclerosis, Hypertension, including pulmonary and portal hypertension, hypertensive heart disease, diabetic capillarity And atherosclerotic lesions, coronary heart disease, heart failure. A compound that releases and / or transfers nitric oxide, endogenous monoxide Use of nitrogen formation stimulants or guanylate cyclase stimulants.   3. Claim, characterized in that it stimulates soluble guanylyl cyclase. The compound which releases and / or transfers nitric oxide according to Item 1 or 2. , The use of endogenous nitric oxide formation stimulants, or guanylate cyclase stimulants.   4. Direct and / or indirect stimulation of soluble guanylyl cyclase Discharge nitric oxide according to any one of claims 1 to 3, characterized in that A compound that emits and / or transfers, an endogenous nitric oxide formation stimulant, or Use of guanylate cyclase stimulants.   5. Indirect guanylate cyclase stimulator stimulates guanylate cyclase Agents can be released, or other effective enzyme concentrations of guanylyl cyclase Method and / or antagonize inhibitors of guanylyl cyclase A compound that acts like an activator or otherwise reduces the effective enzyme concentration of the inhibitor. Release of nitric oxide according to any one of claims 1 to 4, characterized in that Compounds that induce and / or translocate, endogenous nitric oxide formation stimulants, or Use of anilic acid cyclase stimulants.   6. As an indirect stimulant of guanylate cyclase, a calcium antagonist, In particular, it is characterized by using a 1,4-dihydropyridine type calcium antagonist Release nitric oxide according to any one of claims 1 to 5 and / or Is a migrating compound, an endogenous nitric oxide formation stimulant, or a guanylate cycler Use of ze stimulants.   7. Using a compound that releases and / or transfers nitric oxide Releasing nitric oxide according to any one of claims 1 to 5, And / or migrating compounds, endogenous nitric oxide formation stimulants, or guanylic acid Use of cyclase stimulants.   8. Compounds that release and / or transfer nitric oxide are organic nitrates. Tell, especially glyceryl trinitrate (GTN), pentaerythrityl tetranitrate (PETN) ), Mononitrate-5-isosorbitol (ISMN), isosorbitol dinitrate (I SDN), mannitol hexanitrate, inositol hexanitrate, propatil nitrate, nitrate Rolls, Nicorandil or SPM 3672 and their physiologically compatible Derivatives, organic nitrites such as isoamyl nitrite, thionitrites, O Nitrate ester, S-nitroso-N-acetyl-D, L-penicillamine (SNA P-like S-nitrosothiols, nitrosoproteins, nitric oxide-releasing flora Xanthane derivatives, nitric oxide-releasing sydnonimine derivatives, especially mesocarb, molcy Dormi Or their pharmacologically effective metabolites, iron-nitrosyl compounds, especially nit Nitrosyl complex compounds such as Roprusid-sodium, and nitric oxide ( NO) itself, as described in any one of claims 1 to 5 and 7. Compounds that release and / or transfer nitric oxide, endogenous nitric oxide Use of formation stimulants or guanylyl cyclase stimulants.   9. As an indirect stimulant of guanylyl cyclase, the quinine content of the endothelium 6. Any one of claims 1 to 5, characterized in that an increasing compound is used. Compounds that release and / or transfer nitric oxide, endogenous nitric oxide Use of priming stimulants or guanylyl cyclase stimulants.   10. Compounds that increase the kinin content of the endothelium act as kinins or similar Of kinin receptors such as stimulating substances, stimulators of endothelial kinin formation or vascular pressure -Conversion-characterized in that it is an inhibitor of quinine degradation, such as an enzyme inhibitor. Item 9. A compound which releases and / or transfers nitric oxide, endogenous one Use of nitric oxide formation stimulants or guanylate cyclase stimulants.   11. Compounds that release and / or transfer nitric oxide, endogenous ones Endothelial dysfunction of nitric oxide formation stimulant or guanylate cyclase stimulant , And with and / or due to endothelial dysfunction Use in the manufacture of pharmaceutical formulations for the prevention, treatment and elimination of disease-causing diseases. for.   12. These compounds can be used for other effective uses in the treatment of heart / circulatory system disorders. Ingredients and especially ACE inhibitors, anti-atherosclerotic agents, anti-hypertensive agents, beta Blockers, cholesterol lowering agents, diuretics, calcium channel blockers, coronary vasodilation From the group of indications consisting of drugs, lipid lowering agents, peripheral vasodilators or platelet aggregation inhibitors Use according to claim 11, characterized in that it is combined with selected active ingredients.