DE19607487A1 - Use of alpha1 adrenoceptor antagonists - Google Patents

Abstract

The invention concerns the use of alpha 1-adrenoceptor antagonists and their pharmacologically tolerable salts in the production of drugs for the prevention and treatment of conditions related to myocardial contractile dysfunction caused by ischaemia.

Description

Field of application of the invention

The present invention relates to the new use of known ones α1-adrenoceptor antagonists for the manufacture of medicinal products act of disease states related to myocardial contractile dys function due to ischemia.

State of the art

Myocardial ischemia can differ depending on the extent of the reduced perfusion have consequences. Persistent, severe ischemia occurs irreversible loss of myocardial tissue (infarction). With less strong The myocytes remain at a loss of perfusion, but their contrast is tile function weakened. This condition can e.g. B. after a myocardium infarct, chronically manifested as a so-called hibernating myocardium (Rahimtoola, S.H. The hibernating myocardium. Am Heart J 1989, 117: 211-221; Montalescot, G. et al .: Myocardial viability in patients with Q wave myocardial infarction and no residual ischemia. Circulation 1992, 86: 47-55), as well as for unstable and stable angina (Rahimtoola, S.H .: The hibernating myocardium. Am Heart J 1989, 117: 211-221; Bonow R.O. et al .: Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Circulation 1991, 83: 26-37), or with chronic heart failure license (Akins C.W. et al .: Selection of angina-free patients with severe left ventricular dysfunction for myocardial revascularization. Am J Cardiol 1980, 46: 695-700; Louie, H.W. et al .: Ischemic cardiomyopathy criteria for coronary revascular ization and cardiac transplantation. Circulation 1991, 84, Suppl. III: III-290-III-295).

On the other hand, contractile dysfunction after episodes of myo temporarily stop cardiac ischemia, although the tissue already is fully reperfused again. In this case one speaks of stunned myocardium. This state was initially experimentally  Describe dogs (Heyndrickx G.R. et al .: Regional myocardial function and electrophysiological alterations after brief coronary occlusion in conscious dogs. J Clin Invest 1975, 56: 978-985; Braunwald E, cloner R.A .: The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 1982, 66: 1146-1149), later also on humans (Bolli R: Myo cardial "stunning" in man. Circulation 1992, 86: 1671-1691).

For example, myocardial stunning occurs after percutaneous translucency minimal coronary angioplasty (PTCA) or coronary bypass surgery (Kloner, R.A. et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 (Suppl.): 397-402; Royster, R.L .: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vasc Anesth 1993, 7 (Suppl. 2): 19-25).

For therapeutic intervention in postoperative contractile dys up to now, inotropics have been used almost exclusively (Kloner, R.A. et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 (Suppl.): 397-402; Royster, R.L .: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vasc Anesth 1993, 7 (Suppl. 2): 19-25). However, when using inotropics, it should be noted that these are the increase myocardial oxygen demand, and that their use continues at best regional ischemia may have negative consequences. So are Avoid inotropics that have a tachycardia (Royster R.L .: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotorpic need, theoretical concepts of inotropic administration. J Cardiothoracic Vasc Anesth 1993, 7 (Suppl. 2): 19-25; Ferrari, R., Visioli, O .: Stunning: damaging or protective to the myo cardium? Cardiovasc Drugs Ther 1991, 5: 939-946). It was also experimental the beneficial use of α1 adrenoceptor agonists is described while Adverse effects are known for the α1 adrenoceptor antagonist prazosin (Kitakaze M. et al .: Benficial effects of α1-adrenoceptor activity on myocardial stunning in dogs. Circulation Res 1991, 68: 1322-1339).  

For example, α1 adrenoceptor antagonists are disclosed in the documents ten DE 28 47 623, DE 24 08 804, DE 28 15 926 and DE 19 42 405.

In international patent application WO 91/11185 the use of the α1 adrenoceptor antagonists urapidil and structurally closely related ver bindings for the antiproliferative treatment of arteriosclerotic Er diseases such as restenosis after PTCA, myocardial infarction or coronary artery Bypass surgery described.

Description of the invention

It has now surprisingly been found that by administering α1-adrenoceptor antagonists disease states that are due to myocardial contractile dysfunction due to ischemia can be improved can.

The invention therefore relates to the use of α1-adrenoceptor-An tagonists and / or their pharmacologically acceptable salts for Manufacture of medicines for the prevention and treatment of the sick conditions resulting from myocardial contractile dysfunction Ischemia based.

Examples of α1 adrenoceptor antagonists according to the invention are mentioned
(RS) -1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (1,4-benzodioxan-2-yl-carbonyl) piperazine (INN: doxazosin),
(RS) -1- [4- (2-methoxyphenyl) -1-piperazinyl] -3- (1-naphthyloxy) -2-propa-nol (INN: naftopidil),
(RS) -1- (4-carbazolyloxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propa-nol (INN: Carvedilol),
and in particular 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino} - 1,3-dimethyluracil (INN: urapidil) and the structurally closely related compounds disclosed in DE-OS 19 42 405 ,
as well as their pharmacologically acceptable salts.

Depending on the α1-adrenoceptor antagonist, all acid addities come as salts on salts or all salts with bases into consideration. They are particularly worth mentioning pharmacologically acceptable salts of ver applied inorganic and organic acids and bases. Suitable as such water-soluble and water-insoluble acid addition salts Acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, Nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, Benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicyl acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, Oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methane sulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a single or polybasic acid and depending on which salt is desired - in the equimolar or a different quantity ratio can be used.

On the other hand, salts with bases can also be used. As examples of Salts with bases are alkali (lithium, sodium, potassium) or calcium, Aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts mentioned, the bases in the equimolar also here in the salt production or a quantity ratio deviating therefrom.

The connections to be used are partly - depending on Structure of the α1 adrenoceptor antagonist - around chiral compounds. The The invention therefore includes both the use of the pure enantiomers also their mixtures in any mixing ratio, including the Razemate.

As disease states in which the stunned myocardium or hiber nating myocardium designated states of myocardial dysfunction occur be primarily all acute and chronic ischemic insults Called hearts. Accordingly, α1 adrenoceptor antagonists can for example to treat and prevent the following diseases and sick changes are used: the stable and unstable angina pectoris, Prinzmetal's angina, acute myocardial infarction, chronic  left ventricular heart failure, for example after myocardial infarction and generally ischemic cardiomyopathy, the chronic heart sufficiency, as well as postoperative cardiac insufficiency after percutaneous trans luminal coronary angioplasty (PTCA), after coronary bypass surgery, or after other heart operations, such as operations on the heart open heart with cardioplegia and heart transplants.

The α1 adrenoceptor antagonists are particularly suitable for this Treatment or prevention of postoperative myocardial stunning in High-risk patients. For example, as a high-risk patient Patients with acute myocardial infarction, with poor preoperative links called ventricular function or with unstable angina.

The α1 adrenoceptor antagonists are also advantageously suitable for Prevention or treatment of stunned myocardium in patients with global weakness of the heart or a delayed spon Tan recovery of the stunned myocardium.

Another object of the invention is therefore a method for treatment lung of mammals, especially humans who are on myocardial Ischemia-based disease or because of it are in a pathologically altered state. The procedure is thereby characterized in that the diseased individual has a therapeutic effect same and pharmacologically acceptable amount of one or more of the α1 adrenoceptor antagonists and / or their pharmacologically acceptable Salts administered.

The invention further relates to the use of α1-adrenoceptor anta gonists and their salts for the treatment of mammals, especially men suffer from a disease based on myocardial ischemia are, or morbidly due to myocardial ischemia changed state.

When using the α1-adrenoceptor antagonists for Production of the above-mentioned pharmaceuticals are the pharmaco logically active compounds to be used and their salts (= active substances) either as such, or preferably in combination with suitable ones  pharmaceutical excipients in the form of tablets, coated tablets, capsules, Suppositories, plasters (for transdermal drug application), emulsions, Suspensions, aerosols, sprays, ointments, creams, joints or solutions used, the active ingredient content advantageously between 0.1 and Is 95%.

Which excipients are suitable for the desired pharmaceutical formulations are familiar to a person skilled in the art on the basis of his specialist knowledge. In addition to ransom agents, gel formers, suppository bases, tablet excipients and other active ingredient carriers can, for example, antioxidants, dispersants agents, emulsifiers, defoamers, flavoring agents, preservatives medium, solubilizer, dyes or in particular permeation promo tors and complexing agents (e.g. cyclodextrins) can be used.

The active ingredients can be rectal, parenteral (perlingual, intravenous, percutaneous) or administered orally.

In general, it has proven advantageous in human medicine the active ingredient (s) when given orally in a daily dose of about 0.5 up to 3 mg / kg body weight, if desired in the form of several, preferably 1 to 4 individual doses to achieve the desired result pass. With parenteral treatment, similar or (esp especially with intravenous administration of the active ingredients) usually lower doses are used.

The determination of the optimal dosage and appli required in each case The type of cation of the active ingredients can be determined by any specialist on the basis of his or her subject knowingly done easily.

Are the α1 adrenoceptor antagonists and / or their pharmacological tolerated salts used to treat the diseases mentioned are, the pharmaceutical preparations can also one or several other pharmacologically active ingredients in other medicinal products groups included.

A particularly preferred embodiment of the invention is the use of 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino} -1,3-dimethyl  uracil and its pharmacologically acceptable salts for the production of Medicines for the prevention and treatment of the disease mentioned conditions.

Industrial applicability

Due to their surprising properties, α1-adrenoceptor-An are suitable tagonists and their salts in excellent ways to prevent and Treatment of disease based on an ischemic myo cardiac contractile dysfunction are based, which the expert calls stunned myocardium and referred to as hibernating myocardium.

Clinical examinations

The effect of the α1-adrenoceptor antagonists on the myocardial stunning that occurs after percutaneous transluminal coronary angioplasty (PTCA) was tested by examining patients who had undergone PTCA (75% stenosis) as follows:
From 72 hours before PTCA, the patients received standardized anti-anginal therapy with calcium antagonists and nitrates, but no beta blockers. In the course of the PTCA, all patients were implanted with stents in the dilated vascular segments to prevent reactive vasoconstriction. Despite the pretreatment with a calcium antagonist (180-360 mg / d diltiazem) and oral or topical nitrates as well as the intraoperative administration of 1 mg ic Linsidomine and repeated injections of 3 mg isosorbide dinitrate, the condition of the myocardial stunning occurred in all patients. As soon as the contractile dysfunction referred to as myocardial stunning occurred after PTCA, the α1-adrenoceptor antagonists and / or their pharmacologically active salts were additionally administered.

The myocardial wall movement was determined by means of transesophagial Echocardiography (TEE) continuously recorded. The ones obtained by TEE Contour images were used to measure left ventricular wall thickness (= Wall movement of the short axis) using HP 2500-Tomtec. The  diastolic wall thickness and systolic wall thickness became as follows Time points evaluated:

• A under basal conditions,
• B for PTCA and stent implantation,
• C at the time of contractile dysfunction up to 15 min according to PTCA as well
• D after administration of the α1 adrenoceptor antagonists 16 min after PTCA.

The wall movement of the myocardium was analyzed both in the supply area of the stenosed coronary vessels (PTCA region), as well as in wall segments outside this coverage area (NO-PTCA region).

Table 1 shows the results (for 8 patients) in the PTCA region for the Time points A, B, C and D, when intravenous administration of urapidil (600 µg / kg) were obtained.

Table 1

Effect on myocardial stunning according to PTCA: PTCA region

The PTCA and stent implantation initially led to the expected ver improvement of contractility (time B). After 15 minutes there was one Worsening wall movement noted, even below the exit values before surgery (= state of myocardial stunning, time C).

The intravenous injection of urapidil (600 µg / kg) now led to one complete abolition of myocardial stunning and restoration the improvement of wall movement as received immediately after PTCA was (time D). The diastolic wall thickness changed in each case same way as the systolic wall thickness, albeit the effects were less pronounced.

Table 2 gives the results of using Urapidil on the contra tility in the NO-PTCA region again.

Table 2

Effect on myocardial stunning according to PTCA: NO-PTCA region

Unexpectedly, it also occurred in this myocardial segment with a normal vessel Care and perfusion all in one, based on the time of the PTCA  delayed myocardial stunning. Urapidil was in turn able to do this cancel myocardial stunning.

9 other patients also received the standardized antianginal Therapy with a calcium antagonist and nitrates, however at time D instead of the α1 adrenoceptor antagonist, only an injection by Koch saline solution. These patients served as controls. In these patients passed myocardial stunning over 30 minutes after PTCA and stent implan tation continues unchanged.

Claims (5)

1. Use of α1-adrenoceptor antagonists and their pharmacological compatible salts for the manufacture of medicines for contraception and treatment of disease states based on myocardial contractile Dysfunction is due to ischemia. 2. Use according to claim 1 of 6 - {[3- [4- (2-methoxyphenyl) -1-piperaz inyl] propyl] amino} -1,3-dimethyluracil and its pharmacological tolerable salts. 3. Use of α1-adrenoceptor antagonists and their salts for loading act of mammals, especially humans, on one on myocardial contractile dysfunction due to ischemic disease are ill. 4. Use according to claim 1, characterized in that it is in the based on myocardial contractile dysfunction due to ischemia Disease states is a stunned myocardium. 5. Use according to claim 1, characterized in that it is in the based on myocardial contractile dysfunction due to ischemia Disease states is a hibernating myocardium.