Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/55—Protease inhibitors
  • A61K38/556—Angiotensin converting enzyme inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention presented here relates to the use of nitrogen monoxide releasing and / or transmitting compounds, stimulators of endogenous nitrogen monoxide formation and stimulators of guanylate cyclase for the prevention, treatment and elimination of endothelial dysfunctions as well as diseases which are caused by or associated with endothelial dysfunctions. According to the invention, the provision of pharmaceutical preparations for the named indications is made possible at the same time.
• GTN glycerol trinitrate
• PETN pentaerythrityl tetranitrate
• ISMN Isosorbide-5-mononitrate
• trolnitrate FR-PS 984 523
• Nicorandil US-PS 4,200,640
• Vasodilators some of which have had the broadest therapeutic use for decades in the indication of angina pectoris or ischemic heart disease (IHK) (Nitrangin®, Pentalong®, Monolong®, Isoket®, Elantan® and others).
• IHK ischemic heart disease
• Comparable and improved pharmacological activity when used in the above-mentioned indication areas have organic nitrates of a newer type such as SPM 3672 (N- [3-nitrato ⁇ ivaloyl] -L-cysteine-ethyl ester) (US Pat. No.
• the pharmaceutical processing of the organic nitrates or nitrites and other nitrogen monoxide liberating or transferring compounds into pharmaceutical preparations for the treatment of angina pectoris or ischemic heart disease is generally known. It is carried out in accordance with the working methods and rules which are generally familiar to the pharmaceutical expert, the choice of the technologies to be used and the pharmaceutical auxiliaries used being based primarily on the active ingredient to be processed. Questions of its chemical-physical properties, the chosen form of application, the desired duration of action and the avoidance of drug-excipient incompatibilities are of particular importance.
• the anti-ischemic effectiveness of the organic nitrates and the other substance classes mentioned above is explained by hemodynamic effects, in particular a heart-relieving effect, which leads to a saving in heart oxygen consumption or corrects the mismatch between the O 2 supply and demand at the Chamber of Industry and Commerce .
• the cause is a preferred expansion of the venous capacity vessels (venous pooling) or reduction in preload and a direct coronary dilatation effect, particularly in the area of coronary stenoses.
• the endothelial cells form a complete monolayer in the area of the inner wall of the blood vessels. This results in a total surface area of approximately 800 m 2 for the adult human being with a weight that corresponds to that of the human liver with 1.5 to 2 kg.
• the functions performed by endothelial cells relate to two things: a mechanical and a functional one. On the one hand, they exercise a kind of barrier function with the aim of preventing blood components such as low-density lipoproteins (LDL) from penetrating into the lumen-like vessel wall (intima). On the other hand, they have an endocrine function.
• LDL low-density lipoproteins
• Endothelial dysfunction is generally characterized by a restriction or loss of endothelium-mediated physiological vasodilation. At the same time, a reduction or abolition of the NO-mediated vessel relaxation, the NO-mediated vascular protection and the growth processes suppressed by NO in the intima and media can be observed. Endothelial dysfunction is also characterized by proliferative processes in the vascular wall due to increased mitogenesis, increased endothelial adhesion and migration of leukocytes and macrophages, and increased oxidation of low-density lipoproteins (LDL), which are endothelial-damaging.
• LDL low-density lipoproteins
• vasoactive substances such as acetylcholine or serotonin, which normally cause vasorelaxation, cause vasoconstriction due to their direct vasoconstrictive effects on the smooth vascular muscles, which negatively influence the clinical picture (Golino et al., N. Engl. J. Med. 324: 641-648 (1991)).
• the physiological vasomotor regulation is therefore not only disturbed in the case of endothelial dysfunction, but also the opposite. These changes are even more pronounced with atherosclerotic remodeling of the inner wall of the vessel (Ludmer et al., N. Engl. J. Med. 315: 1046-1051 (1986)).
• the endothelium not only contributes with its autocrine and paracrine activity
• the wall of the blood vessel healthy, but also influences the action of exogenous NO-Liberators such as PETN or GTN in that it itself forms EDRF / NO. If, for example, the endothelium is removed from the arterial wall mechanically (in the case of invasive catheter diagnosis or extracorporeally on isolated vascular segments) or if the endothelial NO formation is suppressed by specific inhibitors, the vasodilatory effect of nitrovasodilators such as GTN or PETN is enhanced (Busse et al. , Cardiovasc. Pharmacol. 14 (Suppl. 11): S81-S85 (1989); Kojda et al., J. Vase. Res. 29: 151 (1992A)).
• Endothelial dysfunctions are now seen as triggers of common and pathophysiologically significant cardiovascular diseases such as atherosclerosis. Prevention, treatment and elimination of these dysfunctions and the diseases associated with or caused by them are therefore important therapeutic necessities.
• endothelial damage in the postinfarct phase endothelial dysfunction at reperfusion
• endothelial-mediated reocclusion after bypass surgery blood supply disturbances in peripheral arteries, as well as cardiovascular diseases such as atherosclerosis, hypertension, including pulmonary and portal hypertension, hypertensive heart disease, diabetic micro- and macroangiopathy, coronary heart disease, heart failure or other diseases that are causally based on endothelial dysfunction.
• Nitric oxide releasing and / or transmitting compounds stimulators of endogenous nitric oxide formation as well as stimulators of guanylate cyclase in the sense
• This invention includes, inter alia, compounds which act directly or indirectly on the guanylate cyclase, compounds which can be released as indirect stimulators of the guanylate cyclase being those which can release guanylate cyclase stimulants or otherwise increase their enzyme-effective concentration and / or have an antagonistic effect against inhibitors of guanylate cyclase or their enzyme-effective concentration humiliate.
• indirect stimulators of the guanylate class compounds are used which are suitable for increasing endogenous NO formation or release, such as calcium channel blockers, in particular those of the 1,4-dihydropyridine type, for example nifedipine, felodipine, nimodipine, amlodipine and others.
• compounds which are capable of increasing the endothelial kinine content is also suitable.
• ACE inhibitors angiotensin converting enzyme
• Substance classes and compounds that are particularly suitable here are organic nitrates, in particular glycerol trinitrate, pentaerythrityl tetranitrate, isosorbide-5-mononitrate, isosorbide dinitrate, mannitol hexanitrate, inositol hexanitrate, propatyl nitrate, trol nitrate,
• Nitrosyl compounds such as nitroprusside sodium and nitrogen monoxide itself. Since the nitrogen monoxide release and / or transfer often takes place in vivo via pharmacologically active metabolites, these are in principle also suitable for use in the sense of the present invention. At the same time, the use of physiologically compatible 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 and the like are possible variations. The selection of the respective active ingredient is based on general pharmacological principles and the therapeutic requirements which are known to the person skilled in the art.
• the dosage is in each case in therapeutic doses, which are based on those in which the respective active ingredients are already used for known indications.
• the daily total dose can be up to 500 mg depending on the active ingredient. In general, daily doses up to 350 mg will be sufficient. Dosage and dosing interval should be chosen so that therapeutic plasma levels that are as constant as possible are built up.
• the compounds used according to the invention can themselves or as part of a galenical 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-antagonists, coronary dilators, lipid-lowering agents, peripheral Vasodilators, platelet aggregation inhibitors or other substances, also used as cardiovascular therapeutics, combined, can be used.
• cardiovascular therapeutics for example ACE inhibitors, antiatherosclerotics, antihypertensives, beta-blockers, cholesterol-lowering agents, diuretics, calcium-antagonists, coronary dilators, lipid-lowering agents, peripheral Vasodilators, platelet aggregation inhibitors or other substances, also used as cardiovascular therapeutics, combined, can be used.
• the preparation of galenical preparations is carried out according to the working methods and rules generally familiar to the pharmaceutical expert, the choice of the technologies to be
• the named compounds can be administered primarily orally, intravenously, parenterally, sublingually or transdermally.
• the respective pharmaceutical preparation is preferably provided in liquid or solid form. Solutions are suitable for this, in particular for the preparation of drops, injections or aerosol sprays, furthermore suspensions, emulsions, syrups, tablets, film-coated tablets, dragées, capsules, pellets, powders, pastilles, implants, suppositories, creams, gels, ointments, plasters or other transdermal Systems.
• the pharmaceutical preparations contain customary 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, 95/26725
• the preparation can be sterilized and, if necessary, with auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, humectants, adsorbents or counter-disintegrants, preservatives, stabilizers, emulsifiers, solubilizers, salts for influencing the osmotic pressure , Buffer solutions, coloring, fragrance, aroma or sweeteners may be added.
• auxiliary substances such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, humectants, adsorbents or counter-disintegrants, preservatives, stabilizers, emulsifiers, solubilizers, salts for influencing the o
• the compounds identified above show an independent endothelial protective effect, which is independent of the previously known, especially the purely hemodynamic and anti-ischemic properties, e.g. the organic nitrates or their effectiveness in hypercysteinemia. Their use can therefore bring these pathological processes to a standstill or even reverse them as long as they are not yet irreversible. It is therefore an unexpected, novel effect component that has not been described so far and was not expected in this form.
• cholesterol feeding is suitable for producing endothelial dysfunction within weeks to months, which allows the effects of pharmaceuticals to be investigated and quantified (Jayakody et al., Can. J. Physiol. Pharmacol. 63: 1206-1209 (1985 ); Verbeuren et al., Circ. Res. 58: 552-564 (1986); Freiman et al, Circ. Res. 58: 783-789 (1986)).
• the atherosclerotic vessels showed no change in the willingness to contract to phenylephrine, but the function of the endothelium-mediated vasorelaxation after administration of 1 ⁇ M acetylcholine was changed in comparison to the controls (standard diet) in a manner that can best be described as endothelial dysfunction.
• the segments of the thoracic aorta of the cholesterol-fed animals (+) show a significantly weaker sensitivity to acetylcholine than the aortic segments of the control animals (Fig. 1).
• PETN can reduce the extent of atherosclerotic lesions and improve endothelial function.
• the poorer correlation coefficient in the PETN group indicates that PETN also leads to a dissociation of the close relationship between atherosclerotic lesions and endothelial function.
• Table 1 shows the influence of PETN (6 mg / kg / day) on the development of endothelial dysfunction in the thoracic aorta of New Zealand white rabbits, which was induced by feeding on a cholesterol diet (0.75%; 15 weeks).
• the potency of the endothelium-dependent vasodilator acetylcholine is expressed as the concentration (in - logM; pD2 value) that, when administered cumulatively, antagonized half the action of the vasoconstrictor phenylephrine (the higher this value, the stronger the effect of
• Acetylcholine The maximum dictatorial effect is expressed as the percentage of the effect of the vasoconstrictor phenylephrine that was antagonized at the maximum effective concentration of acetylcholine (1 ⁇ M).
• the endothelial dysfunction induced by cholesterol feeding alone (control) can be recognized by the significantly reduced potency and maximum potency of acetylcholine (*, p ⁇ 0.05).
• PETN significantly (#, p ⁇ 0.05) improves the potency of acetylcholine and thus the endothelial function after cholesterol feeding, while there is a significant deterioration in endothelial function after standard feeding. Overall, this shows the protective effect of PETN on endothelial function in experimentally induced
• PETN pentaerythrityl mononitrate
• a typical tablet has the following composition:
• a tablet containing 20 mg pentaerythrityl trinitrate (PETriN) has the following composition:
• a tablet containing 20 mg pentaerythrityl dinitrate (PEDN) has the following composition:
• a tablet containing 20 mg erythrityl tetranitrate (ETN) has the following composition:
• a tablet containing 20 mg isosorbide mononitrate (ISMN) has the following composition:
• a tablet containing 20 mg isosorbide dinitrate (ISDN) has the following composition:
• a tablet containing 40 mg pentaerythrityl tetranitrate (PETN) and 40 mg propranolohydrochloride has the composition:
• the standard feed contained pentaerythrityl tetranitrate (150 mg / kg) in both cases and an additional 0.75% cholesterol for the cholesterol group.
• the concentration of pentaerythrityl mononitrate was determined quantitatively after working up the plasma samples by means of gas chromatography / mass spectroscopy.

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• 1994
  • 1994-03-30 DE DE4410997A patent/DE4410997A1/de not_active Withdrawn
• 1995
  • 1995-03-28 WO PCT/DE1995/000421 patent/WO1995026725A1/de not_active Application Discontinuation
  • 1995-03-28 JP JP7525343A patent/JPH09510979A/ja active Pending
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