WO1997031638A1 - USE OF α1-ADRENOCEPTOR ANTAGONISTS - Google Patents
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- WO1997031638A1 WO1997031638A1 PCT/EP1997/000861 EP9700861W WO9731638A1 WO 1997031638 A1 WO1997031638 A1 WO 1997031638A1 EP 9700861 W EP9700861 W EP 9700861W WO 9731638 A1 WO9731638 A1 WO 9731638A1
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- 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
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Definitions
- the present invention relates to the new use of known ⁇ * l adrenoceptor antagonists for the production of medicaments for the treatment of disease states which are based on myocardial, contractile dysfunction due to ischemia and are referred to as stunned myocardium.
- Myocardial ischemia can have different consequences depending on the extent of the low perfusion. Persistent, severe ischemia leads to irreversible loss of myocardial tissue (infarction). If the perfusion loss is less severe, the myocytes are retained, but their contractile function is weakened. This condition can e.g. after a myocardial infarction, can be chronically manifested as a so-called hibemating myocardium (Rahimtoola, S.H .: The hibernating myocardium. Am Heart J 1989, 117: 211-221).
- contractile dysfunction can occur temporarily after episodes of myocardial ischemia, although the tissue is already completely reperfused.
- This condition was first described experimentally in dogs (Heyndrickx GR et al .: Regional myocardial function and electrophysiological alterations after brief coronary occlusion in conscious dogs. J Clin Invest 1975, 56: 978-985; Braunwald E, Kloner RA: The stunned myocardium : prolonged postischemic ventricular dysfunction. Circulation 1982, 66: 1146-1149), later also in humans (Bolli R: Myocardial " stunning” in man. Circulation 1992, 86: 1671-1691).
- myocardial stunning occurs after percutaneous transluminal coronary angioplasty (PTCA) or after coronary bypass surgery (Kloner, RA et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 ( Suppl.): 397-402; Royster, RL: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2): 19-25).
- inotropic agents have been used for therapeutic intervention in postoperative contractile dysfunction (Kloner, RA et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 (Suppl.): 397-402; Royster, RL: Myocardial dysfunction following cardiopulmonary bypass: recovery pattems, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2): 19-25).
- inotropics it should be noted that these increase the myocardial oxygen requirement and that their use can have negative consequences if regional ischemia persists.
- ⁇ 1-adrenoceptor antagonists are disclosed, for example, in documents DE 28 47 623, DE 24 08 804, DE 28 15 926 and DE 1942 405.
- the international patent application WO 91/11185 describes the use of the ⁇ x1 adrenoceptor antagonist urapidil and structurally closely related compounds for the antiproliferative treatment of arteriosclerotic diseases such as restenosis after PTCA, myocardial infarction or coronary bypass surgery.
- the invention therefore relates to the use of ⁇ 1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the production of medicaments for the prevention and treatment of disease states which are based on myocardial contractile dysfunction due to ischemia and are referred to as stunned myocardium.
- all acid addition salts or all salts with bases can be considered as salts.
- Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as, for example, 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, sulfosalic acid , Maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a single or polybasic Acid is involved and, depending on which salt is desired, be used in an equimolar or a ratio deviating therefrom.
- acids such as, for example, hydrochloric acid, hydrobromic acid
- salts with bases can also be used.
- examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meluminum or guanidinium salts, and here too the Salt production, the bases are used in an equimolar or a quantity ratio deviating therefrom.
- the compounds to be used are chiral compounds.
- the invention therefore encompasses the use of the pure enantiomers as well as their mixtures in any mixing ratio, including the racemates.
- ⁇ 1-adrenoceptor antagonists can be used, for example, for the treatment and prevention of the following diseases and pathological changes: postoperative heart failure after percutaneous transluminal coronary angioplasty (PTCA), after coronary artery bypass surgery, or after other heart surgery, such as open heart surgery with cardioplegia and heart transplants.
- PTCA percutaneous transluminal coronary angioplasty
- the ⁇ 1-adrenoceptor antagonists are particularly suitable for the treatment or prevention of postoperative myocardial stunning in high-risk patients.
- a high-risk patient for example, patients with acute myocardial infarction, with poor preoperative left ventricular function or with unstable angina pectoris.
- the ⁇ 1-adrenoceptor antagonists are also advantageously suitable for the prevention or treatment of the stunned myocardium in patients with a global weakness of contractility of the heart or a delayed spontaneous recovery of the stunned myocardium.
- the invention therefore furthermore relates to a method for the treatment of mammals, in particular humans, who are suffering from a disease state which is based on myocardial contractile dysfunction as a result of ischemia and which is referred to as stunned myocardium, or because of this are in a pathologically altered state are located.
- the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the ⁇ 1-adrenoceptor antagonists and / or their pharmacologically acceptable salts.
- the invention relates to the use of ⁇ 1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the treatment of mammals, in particular humans, who are suffering from a disease state based on myocardial contractile dysfunction as a result of ischemia, which is referred to as stunned myocardium, or on Because of this, you are in a pathologically changed state.
- auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
- active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, colorants or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
- the active ingredients can be administered rectally, parenterally (perlingually, intravenously, percutaneously) or orally.
- parenterally perlingually, intravenously, percutaneously
- similar or generally lower doses in particular when the active compounds are administered intravenously can be used.
- the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments.
- a particularly preferred embodiment of the invention is the use of 6 - ⁇ [3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino ⁇ -1,3-dimethyluracil and / or its pharmacologically acceptable salts for the preparation of medicines for the prevention and treatment of the named disease states.
- ⁇ 1-adrenoceptor antagonists and / or their salts are outstandingly suitable for the prevention and treatment of disease states which are based on myocardial contractile dysfunction as a result of ischemia, which the person skilled in the art calls stunned myocardium.
- PTCA percutaneous transluminal coronary angioplasty
- the myocardial wall movement was recorded continuously using transesophagial echocardiography (TEE).
- TEE transesophagial echocardiography
- the diastolic wall thickness and the systolic wall thickness were evaluated at the following times:
- the wall movement of the myocardium was analyzed both in the supply area of the stenosed coronary vessels (PTCA region) and in wall segments outside this supply area (NO-PTCA region).
- Table 1 shows the results (for 8 patients) in the PTCA region for time points A, B, C and D, which were obtained with intravenous administration of urapidil (600 ⁇ g / kg).
- Table 2 shows the results of applying urapidil to contractility in the NO-PTCA region.
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Abstract
The invention concerns the use of α1-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
Verwendung von α1-Adrenoceptor-AntagonistenUse of α1 adrenoceptor antagonists
Anwendungsgebiet der ErfindungField of application of the invention
Die vorliegende Erfindung betrifft die neue Verwendung von bekannten α*l-Adrenoceptor-Antagonisten zur Herstellung von Arzneimitteln zur Behandlung von Krankheitszuständen, die auf myokardialer, kontraktiler Dysfunktion infolge Ischämie beruhen und als stunned myocardium bezeichnet werden.The present invention relates to the new use of known α * l adrenoceptor antagonists for the production of medicaments for the treatment of disease states which are based on myocardial, contractile dysfunction due to ischemia and are referred to as stunned myocardium.
Stand der TechnikState of the art
Myokardiale Ischämie kann je nach Ausmaß der Minderperfusion unterschiedliche Konsequenzen haben. Bei andauernder, schwerer Ischämie kommt es zu irreversiblem Untergang von Myokardge- webe (Infarkt). Bei weniger starker Perfusionseinbuße bleiben die Myozyten erhalten, jedoch ist ihre kontraktile Funktion abgeschwächt. Dieser Zustand kann, z.B. nach einem Myokardinfarkt, als soge¬ nanntes hibemating myocardium chronisch manifestiert sein (Rahimtoola, S.H.: The hibernating myo¬ cardium. Am Heart J 1989, 117:211-221).Myocardial ischemia can have different consequences depending on the extent of the low perfusion. Persistent, severe ischemia leads to irreversible loss of myocardial tissue (infarction). If the perfusion loss is less severe, the myocytes are retained, but their contractile function is weakened. This condition can e.g. after a myocardial infarction, can be chronically manifested as a so-called hibemating myocardium (Rahimtoola, S.H .: The hibernating myocardium. Am Heart J 1989, 117: 211-221).
Andererseits kann sich eine kontraktile Dysfunktion nach Episoden myokardialer Ischämie vorüberge¬ hend einstellen, obwohl das Gewebe bereits wieder vollständig reperfundiert ist. In diesem Falle spricht man vom stunned myocardium. Dieser Zustand ließ sich zunächst experimentell in Hunden beschreiben (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, Kloner R.A.: The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 1982, 66:1146-1149), später auch am Menschen (Bolli R: Myocardial "Stunning" in man. Circulation 1992, 86:1671-1691).On the other hand, contractile dysfunction can occur temporarily after episodes of myocardial ischemia, although the tissue is already completely reperfused. In this case one speaks of the stunned myocardium. This condition was first described experimentally in dogs (Heyndrickx GR et al .: Regional myocardial function and electrophysiological alterations after brief coronary occlusion in conscious dogs. J Clin Invest 1975, 56: 978-985; Braunwald E, Kloner RA: The stunned myocardium : prolonged postischemic ventricular dysfunction. Circulation 1982, 66: 1146-1149), later also in humans (Bolli R: Myocardial "Stunning" in man. Circulation 1992, 86: 1671-1691).
So tritt myocardial stunning beispielsweise nach der perkutanen transluminalen koronaren Angio- plastie (PTCA) oder nach der koronaren Bypass-Operation auf (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 Vase Anesth 1993, 7(Suppl.2):19-25).For example, myocardial stunning occurs after percutaneous transluminal coronary angioplasty (PTCA) or after coronary bypass surgery (Kloner, RA et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 ( Suppl.): 397-402; Royster, RL: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2): 19-25).
Zur therapeutischen Intervention bei postoperativer kontraktiler Dysfunktion werden bislang nahezu ausschließlich Inotropika eingesetzt (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 pattems, predictors of inotropic need, theore- tical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl.2):19-25). Es gilt jedoch beim Einsatz von Inotropika zu beachten, daß diese den myokardialen Sauerstoffbedarf steigern, und daß ihr Einsatz bei fortbestehender regionaler Ischämie negative Konsequenzen haben kann. So sind Inotropika, die taehykard wirken, auf jeden Fall zu vermeiden (Royster R.L.: Myocardial dysfunktion following cardiopulmonary bypass: recovery patterns, predictors of inotorpic need, theore- tical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2): 19-25; Ferrari, R., Visioli, O.: Stunning: damaging or protective to the myocardium? Cardiovasc Drugs Ther 1991 , 5: 939-946). Experimentell wurde auch der vorteilhafte Einsatz von α1-Adrenoceptor-Agonisten beschrieben, während für den α1-Adrenoceptor-Antagonist Prazosin ungünstige Effekte bekannt sind (Kitakaze M. et al.: Benficial effects of α1-adrenoceptor activity on myocardial stunning in dogs. Circulation Res 1991 , 68:1322-1339).Up to now, almost exclusively inotropic agents have been used for therapeutic intervention in postoperative contractile dysfunction (Kloner, RA et al .: Clinical evidence for stunned myocardium after coronary artery bypass surgery. J Card Surg 1994, 9 (Suppl.): 397-402; Royster, RL: Myocardial dysfunction following cardiopulmonary bypass: recovery pattems, predictors of inotropic need, theoretical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2): 19-25). However, when using inotropics, it should be noted that these increase the myocardial oxygen requirement and that their use can have negative consequences if regional ischemia persists. Inotropics that act taehykard must be avoided in any case (Royster RL: Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotorpic need, theoretical concepts of inotropic administration. J Cardiothoracic Vase Anesth 1993, 7 (Suppl. 2 ): 19-25; Ferrari, R., Visioli, O .: Stunning: damaging or protective to the myocardium? Cardiovasc Drugs Ther 1991, 5: 939-946). The advantageous use of α1-adrenoceptor agonists has also been described experimentally, while unfavorable 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).
α1-Adrenoceptor-Antagonisten sind beispielsweise offenbart in den Dokumenten DE 28 47 623, DE 24 08 804, DE 28 15 926 und DE 1942 405.α1-adrenoceptor antagonists are disclosed, for example, in documents DE 28 47 623, DE 24 08 804, DE 28 15 926 and DE 1942 405.
In der internationalen Patentanmeldung WO 91/11185 wird die Verwendung des <x1-Adrenoceptor-An- tagonisten Urapidil und strukturell nahe verwandter Verbindungen zur antiproliferativen Behandlung von arteriosklerotischen Erkrankungen wie Restenosen nach PTCA, Myocardinfarkt oder koronarer Bypass-Operation beschrieben.The international patent application WO 91/11185 describes the use of the <x1 adrenoceptor antagonist urapidil and structurally closely related compounds for the antiproliferative treatment of arteriosclerotic diseases such as restenosis after PTCA, myocardial infarction or coronary bypass surgery.
Beschreibung der ErfindungDescription of the invention
Es wurde nun überraschenderweise gefunden, daß durch Verabreichung von α1-Adrenoceptor-Anta- gonisten Krankhe'rtszustände, die auf myokardialer kontraktiler Dysfunktion infolge Ischämie beruhen und als stunned myocardium bezeichnet werden, verbessert werden können.It has now surprisingly been found that gonisten by administering α1-adrenoceptor antago- Disease rtszustände based on myocardial contractile dysfunction due to ischemia and are known as stunned myocardium, can be improved '.
Gegenstand der Erfindung ist daher die Verwendung von α1-Adrenoceptor-Antagonisten und/oder ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Verhütung und Behandlung von Krankheitszuständen, die auf myokardialer kontraktiler Dysfunktion infolge Ischämie beruhen und als stunned myocardium bezeichnet werden.The invention therefore relates to the use of α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the production of medicaments for the prevention and treatment of disease states which are based on myocardial contractile dysfunction due to ischemia and are referred to as stunned myocardium.
Als beispielhafte erfindungsgemäße α1-Adrenoceptor-Antagonisten seien genanntExamples 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)piperazin (INN: Do- xazosin), (RS)-1-[4-(2-Methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2-propanol (INN: Naftopidil),
(RS)-1-(4-Carbazolyloxy)-3-[2-(2-methoxyphenoxy)-ethylamino]-2-propanol (INN: Carvedilol) und ins¬ besondere 6-{[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]amino}-1 ,3-dimethyluracil (INN: Urapidil) und die in DE-OS 19 42 405 offenbarten strukturell nahe verwandten Verbindungen, sowie ihre phar¬ makologisch verträglichen Salze.(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-propanol (INN: naftopidil), (RS) -1- (4-carbazolyloxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol (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.
Als Salze kommen - je nach α1-Adrenoceptor-Antagonisten - alle Säureadditionssalze oder alle Salze mit Basen in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren und Basen. Als solche eignen sich einerseits wasserlösliche und wasserunlösliche Säureadditionssalze mit Säuren wie bei¬ spielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Salpetersäure, Schwefelsäure, Essig¬ säure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybeπzoyl)-benzoesäure, Buttersäure, Sulfosalicylsäure, Maleinsäure, Laurinsäure, Äpfelsäure, Fumarsäure, Bernsteinsäure, Oxalsäure, Weinsäure, Embonsäure, Stearinsäure, Toluolsulfonsäure, Methansulfonsäure oder 3-Hydroxy- 2-naphthoesäure, wobei die Säuren bei der Salzherstellung - je nachdem, ob es sich um eine ein- oder mehrbasige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimolaren oder ei¬ nem davon abweichenden Mengenverhältnis eingesetzt werden.Depending on the α1-adrenoceptor antagonist, all acid addition salts or all salts with bases can be considered as salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases commonly used in galenics. Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as, for example, 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, sulfosalic acid , Maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a single or polybasic Acid is involved and, depending on which salt is desired, be used in an equimolar or a ratio deviating therefrom.
Andererseits kommen auch Salze mit Basen in Betracht. Als Beispiele für Salze mit Basen seien Al¬ kali- (Lithium-, Natrium-, Kalium-) oder Calcium-, Aluminium-, Magnesium-, Titan-, Ammonium-, Me- glumin- oder Guanidiniumsalze erwähnt, wobei auch hier bei der Salzherstellung die Basen im äqui¬ molaren oder einem davon abweichenden Mengenverhältnis eingesetzt werden.On the other hand, salts with bases can also be used. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meluminum or guanidinium salts, and here too the Salt production, the bases are used in an equimolar or a quantity ratio deviating therefrom.
Bei den zu verwendenden Verbindungen handelt es sich teilweise - je nach Struktur des αl-Adreno¬ ceptor-Antagonisten- um chirale Verbindungen. Die Erfindung umfaßt daher sowohl die Verwendung der reinen Enantiomeren als auch ihrer Gemische in jedem Mischungsverhältnis, einschließlich der Razemate.Depending on the structure of the α1-adreno¬ ceptor antagonist, some of the compounds to be used are chiral compounds. The invention therefore encompasses the use of the pure enantiomers as well as their mixtures in any mixing ratio, including the racemates.
Als Krankheitszustände, bei denen die als stunned myocardium bezeichneten Zustände myokardialer Dysfunktion auftreten, seien in erster Linie alle transienten ischämischen Insulte am Herzen genannt. Dementsprechend können α1-Adrenoceptor-Antagonisten beispielsweise zur Behandlung und Verhü¬ tung folgender Krankheiten und krankhafter Veränderungen angewandt werden: die postoperative Herzschwäche nach perkutaner transluminaler koronarer Angioplastie (PTCA), nach koronarer Bypa- ss-Operation, oder nach anderen operativen Eingriffen am Herzen, wie Operationen am offenen Her¬ zen mit Kardioplegie und Herztransplantationen.All transient ischemic insults on the heart should be mentioned as diseases in which the states of myocardial dysfunction known as stunned myocardium occur. Accordingly, α1-adrenoceptor antagonists can be used, for example, for the treatment and prevention of the following diseases and pathological changes: postoperative heart failure after percutaneous transluminal coronary angioplasty (PTCA), after coronary artery bypass surgery, or after other heart surgery, such as open heart surgery with cardioplegia and heart transplants.
Insbesondere eignen sich die α1-Adrenoceptor-Antagonisten dabei zur Behandlung oder Verhütung des postoperativen myocardial stunning bei Hoch-Risiko-Patienten. Als Hoch-Risiko-Patienten seien
beispielsweise Patienten mit akutem Myokardinfarkt, mit schlechter preoperativer linksventrikulärer Funktion oder mit unstabiler Angina pectoris genannt.The α1-adrenoceptor antagonists are particularly suitable for the treatment or prevention of postoperative myocardial stunning in high-risk patients. As a high-risk patient for example, patients with acute myocardial infarction, with poor preoperative left ventricular function or with unstable angina pectoris.
Die α1-Adrenoceptor-Antagonisten eignen sich auch vorteilhafterweise zur Verhütung oder Behand¬ lung des stunned myocardium bei Patienten mit einer globalen Kontraktilitätsschwäche des Herzens oder einer verzögerten spontanen Erholung des stunned myocardium.The α1-adrenoceptor antagonists are also advantageously suitable for the prevention or treatment of the stunned myocardium in patients with a global weakness of contractility of the heart or a delayed spontaneous recovery of the stunned myocardium.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behandlung von Säugern, insbe¬ sondere Menschen, die an einem auf myokardialer kontraktiler Dysfunktion infolge Ischämie beruhen¬ dem Krankheitszustand der als stunned myocardium bezeichnet wird erkrankt sind oder sich auf Grund dessen in einem krankhaft veränderten Zustand befinden. Das Verfahren ist dadurch gekenn¬ zeichnet, daß man dem erkrankten Individuum eine therapeutisch wirksame und pharmakologisch verträgliche Menge einer oder mehrerer der α1-Adrenoceptor-Antagonisten und/oder ihrer pharmako¬ logisch verträglichen Salze verabreicht.The invention therefore furthermore relates to a method for the treatment of mammals, in particular humans, who are suffering from a disease state which is based on myocardial contractile dysfunction as a result of ischemia and which is referred to as stunned myocardium, or because of this are in a pathologically altered state are located. The method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts.
Weiterhin betrifft die Erfindung die Verwendung von α1-Adrenoceptor-Antagonisten und/oder ihren pharmakologisch verträglichen Salzen zur Behandlung von Säugern, insbesondere Menschen, die an einem auf myokardialer kontraktiler Dysfunktion infolge Ischämie beruhendem Krankheitszustand der als stunned myocardium bezeichnet wird erkrankt sind, oder sich auf Grund dessen in einem krankhaft veränderten Zustand befinden.Furthermore, the invention relates to the use of α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the treatment of mammals, in particular humans, who are suffering from a disease state based on myocardial contractile dysfunction as a result of ischemia, which is referred to as stunned myocardium, or on Because of this, you are in a pathologically changed state.
Bei der erfindungsgemäßen Verwendung der α1-Adrenoceptor-Antagonisten zur Herstellung der vor¬ stehend genannten Arzneimittel werden die pharmakologisch wirksamen zu verwendenden Verbin¬ dungen und ihre Salze (= Wirkstoffe) entweder als solche, oder vorzugsweise in Kombination mit ge¬ eigneten pharmazeutischen Hilfsstoffen in Form von Tabletten, Dragees, Kapseln, Suppositorien, Pflastern (zur transdermalen Arzneiapplikation), Emulsionen, Suspensionen, Aerosolen, Sprays, Sal¬ ben, Cremes, Gelen oder Lösungen eingesetzt, wobei der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 95% beträgt.When the α1-adrenoceptor antagonists are used according to the invention for the production of the medicaments mentioned above, the pharmacologically active compounds to be used and their salts (= active substances) are in the form either or preferably in combination with suitable pharmaceutical auxiliaries tablets, dragees, capsules, suppositories, plasters (for transdermal drug application), emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, the active ingredient content advantageously being between 0.1 and 95%.
Welche Hilfsstoffe für die gewünschten Arzneimittelformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Ta- blettenhilfsstoffen und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Dispergiermit¬ tel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler, Farbstoffe oder insbesondere Permeationspromotoren und Komplexbildner (z.B. Cyclodextrine) ver¬ wendet werden.The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, colorants or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
Die Wirkstoffe können rektal, parenteral (perlingual, intravenös, percutan) oder oral appliziert werden.
Im allgemeinen hat es sich in der Humanmedizin als vorteilhaft erwiesen, den oder die Wirkstoffe bei oraler Gabe in einer Tagesdosis von etwa 0,5 bis 3 mg/kg Körpergewicht, gewunschtenfalls in Form mehrerer, vorzugsweise 1 bis 4 Einzelgaben zur Erzielung des gewünschten Ergebnisses zu verab¬ reichen. Bei einer parenteralen Behandlung können ähnliche bzw. (insbesondere bei der intravenösen Verabreichung der Wirkstoffe) in der Regel niedrigere Dosierungen zur Anwendung kommen.The active ingredients can be administered rectally, parenterally (perlingually, intravenously, percutaneously) or orally. In general, it has proven to be advantageous in human medicine to add the active ingredient (s) when given orally in a daily dose of about 0.5 to 3 mg / kg body weight, if desired in the form of several, preferably 1 to 4, single doses to achieve the desired result administer. In the case of parenteral treatment, similar or generally lower doses (in particular when the active compounds are administered intravenously) can be used.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.The determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.
Sollen die α1-Adrenoceptor-Antagonisten und/oder ihre pharmakologisch verträglichen Salze zur Be¬ handlung der genannten Krankheiten eingesetzt werden, so können die pharmazeutischen Zuberei¬ tungen auch einen oder mehrere andere pharmakologisch aktive Bestandteile anderer Arzneimittel¬ gruppen enthalten.If the α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts are to be used for the treatment of the diseases mentioned, the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments.
Eine besonders bevorzugte Ausgestaltung der Erfindung ist die Verwendung von 6-{[3-[4-(2-Methoxy- phenyl)-1-piperazinyl]propyl]amino}-1,3-dimethyluracil und/oder seinen pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Verhütung und Behandlung der genannten Krank- heitszustände.A particularly preferred embodiment of the invention is the use of 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino} -1,3-dimethyluracil and / or its pharmacologically acceptable salts for the preparation of medicines for the prevention and treatment of the named disease states.
Hervorzuheben ist dabei die Verwendung von 6-{[3-[4-(2-Methoxyphenyl)-1-piperazinylpropyl]amino}- 1 ,3-dimethyluracil und/oder seinen pharmakologisch verträglichen Salzen zur Herstellung von Arz¬ neimitteln zur Verhütung und Behandlung der postoperativen Herzschwäche nach perkutaner trans- luminaler Angioplastie (PTCA) oder nach koronarer Bypass-Operation.The use of 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinylpropyl] amino} - 1, 3-dimethyluracil and / or its pharmacologically acceptable salts for the production of medicaments for the prevention and treatment should be emphasized Postoperative cardiac insufficiency after percutaneous transluminal angioplasty (PTCA) or after coronary artery bypass surgery.
Gewerbliche AnwendbarkeitIndustrial applicability
Aufgrund ihrer überraschenden Eigenschaften eignen sich α1-Adrenoceptor-Antagonisten und/oder ihre Salze auf hervorragende Weise zur Verhütung und zur Behandlung von Krankheitszuständen, die auf einer myokardialen kontraktilen Dysfunktion infolge Ischämie beruhen, die der Fachmann als stunned myocardium bezeichnet.Because of their surprising properties, α1-adrenoceptor antagonists and / or their salts are outstandingly suitable for the prevention and treatment of disease states which are based on myocardial contractile dysfunction as a result of ischemia, which the person skilled in the art calls stunned myocardium.
Klinische UntersuchungenClinical examinations
Die Wirkung der α1-Adrenoceptor-Antagonisten auf das myocardial stunning, das nach einer perkuta¬ nen transluminalen coronaren Angioplastie (PTCA) auftritt, wurde durch Untersuchung an Patienten, die einer PTCA unterzogen wurden (Stenosierungsgrad ≥ 75%), folgendermaßen geprüft:
Ab 72 Stunden vor PTCA erhielten die Patienten eine standardisierte antianginöse Therapie mit Calci- um-Antagonisten und Nitraten, jedoch keine Betabiocker. Im Verlaufe der PTCA wurden allen Patien¬ ten Stents in den dilatierten Gefäßsegmenten implantiert, um die reaktive Vasokonstriktion zu verhin¬ dern. Bei allen Patienten trat trotz der Vorbehandlung mit einem Caiciumantagonisten (180-360 mg/d Diltiazem) und von oralen bzw. topischen Nitraten sowie der intraoperativen Verabreichung von 1 mg i.e. Linsidomine und wiederholter Injektionen von 3 mg Isosorbiddinitrat postoperativ der Zustand des myocardial stunning auf. Sobald die als myocardial stunning bezeichnete kontraktile Dysfunktion nach PTCA auftrat wurden die α1-Adrenoceptor-Antagonisten, und/oder ihre pharmakologisch aktiven Sal¬ ze zusätzlich verabreicht.The effect of the α1-adrenoceptor antagonists on the myocardial stunning that occurs after percutaneous transluminal coronary angioplasty (PTCA) was examined as follows by examination in patients who had undergone PTCA (degree of stenosis ≥ 75%): From 72 hours before PTCA, the patients received standardized antianginal therapy with calcium antagonists and nitrates, but no beta blockers. In the course of the PTCA, all patient stents were implanted in the dilated vascular segments in order 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 ie linsidomine and repeated injections of 3 mg isosorbide dinitrate, the condition of 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.
Die myocardiale Wandbewegung wurde dabei mittels transösophagialer Echocardiographie (TEE) kontinuierlich erfaßt. Die durch TEE erhaltenen Konturbilder wurden verwendet, um die linksventriku- läre Wandstärke (= Wandbewegung der kurzen Achse) mittels HP 2500-Tomtec zu ermitteln. Die diastolische Wandstärke sowie die systolische Wandstärke wurde zu folgenden Zeitpunkten ausgewer¬ tet:The myocardial wall movement was recorded continuously using transesophagial echocardiography (TEE). The contour images obtained from TEE were used to determine the left ventricular wall thickness (= wall movement of the short axis) using the HP 2500-Tomtec. The diastolic wall thickness and the systolic wall thickness were evaluated at the following times:
A unter basalen Bedingungen,A under basal conditions,
B bei PTCA und Stent-Implantation,B for PTCA and stent implantation,
C zum Zeitpunkt des Auftretens der kontraktilen Dysfunktion bis zu 15 min nach PTCA sowieC at the time of contractile dysfunction up to 15 min after PTCA as well
D nach Verabreichung der αl-Adrenoceptor-Antagonisten 16 min nach PTCA.D after administration of the αl adrenoceptor antagonists 16 min after PTCA.
Analysiert wurde die Wandbewegung des Myokards sowohl im Versorgungsgebiet der stenosierten Koronargefäße (PTCA-Region), als auch in Wandsegmenten außerhalb dieses Versorgungsgebietes (NO-PTCA-Region).The wall movement of the myocardium was analyzed both in the supply area of the stenosed coronary vessels (PTCA region) and in wall segments outside this supply area (NO-PTCA region).
Tabelle 1 zeigt die Ergebnisse (für 8 Patienten) in der PTCA-Region für die Zeitpunkte A, B, C und D, die bei intravenöser Gabe von Urapidil (600 μg/kg) erhalten wurden.
Table 1 shows the results (for 8 patients) in the PTCA region for time points A, B, C and D, which were obtained with intravenous administration of urapidil (600 μg / kg).
Tabelle 1: Effekt auf das myocardial stunning nach PTCA: PTCA-RegionTable 1: Effect on myocardial stunning according to PTCA: PTCA region
Zeitpunkt Wandstärke Änderung vs.C Wandstärke Änderung vs.C systol. diastol.Time of wall thickness change vs.C wall thickness change vs.C systol. diastolic.
(cm, x + SEM, n=8) (cm, x + SEM, n=8)(cm, x + SEM, n = 8) (cm, x + SEM, n = 8)
A 1.075 + 0.083 0.838 + 0.043A 1,075 + 0.083 0.838 + 0.043
B 1.343 + 0.083 0.888 + 0.046B 1,343 + 0.083 0.888 + 0.046
C 0.921 + 0.083 (= 100 %) 0.813 + 0.050 (= 100 %)C 0.921 + 0.083 (= 100%) 0.813 + 0.050 (= 100%)
D 1.519 + 0.088 +49 7+8.1 % * 1.005 + 0.042 +28.2+13% *D 1,519 + 0.088 +49 7 + 8.1% * 1.005 + 0.042 + 28.2 + 13% *
* p < 0.05* p <0.05
Die PTCA und Stent-Implantation führte zunächst zu der erwarteten Verbesserung der Kontraktilität (Zeitpunkt B). Nach 15 min war jedoch eine Verschlechterung der Wandbewegung festzustellen, sogar unter die Ausgangswerte vor Operation (= Zustand des myocardial stunning, Zeitpunkt C).The PTCA and stent implantation initially led to the expected improvement in contractility (time B). After 15 minutes, however, the wall movement deteriorated, even below the initial values before surgery (= state of myocardial stunning, time C).
Die intravenöse Injektion von Urapidil (600 μg/kg) führte nun zu einer völligen Aufhebung des myo¬ cardial stunning und zu einer Wiederherstellung der Verbesserung der Wandbewegung, wie sie unmit¬ telbar nach PTCA erhalten wurde (Zeitpunkt D). Die diastolische Wandstärke veränderte sich jeweils in gleicher Weise wie die systolische Wandstärke, wenn auch die Effekte weniger ausgeprägt waren.The intravenous injection of urapidil (600 μg / kg) now led to a complete abolition of myocardial stunning and a restoration of the improvement in wall movement, as was obtained directly after PTCA (time D). The diastolic wall thickness changed in the same way as the systolic wall thickness, although the effects were less pronounced.
Tabelle 2 gibt die Ergebnisse der Anwendung von Urapidil auf die Kontraktilität in der NO-PTCA-Region wieder.Table 2 shows the results of applying urapidil to contractility in the NO-PTCA region.
Tabelle 2: Effekt auf das myocardial stunning nach PTCA: NO-PTCA-RegionTable 2: Effect on myocardial stunning according to PTCA: NO-PTCA region
Zeitpunkt Wandstärke Änderung vs.C Wandstärke Änderung vs.C systol. diastol.Time of wall thickness change vs.C wall thickness change vs.C systol. diastolic.
(cm, x + SEM, n=8) (cm, x + SEM, n=8)(cm, x + SEM, n = 8) (cm, x + SEM, n = 8)
A 1.316 + 0.061 0.895 + 0.037A 1,316 + 0.061 0.895 + 0.037
B 1.565 + 0.113 0.969 + 0.061B 1,565 + 0.113 0.969 + 0.061
C 1.140 + 0.099 (= 100 %) 0.820 + 0.055 (= 100 %)C 1,140 + 0.099 (= 100%) 0.820 + 0.055 (= 100%)
D 1.621 + 0.098 +44.9+6.5% * 1.015 + 0.036 +27.6+6.4%*D 1,621 + 0.098 + 44.9 + 6.5% * 1,015 + 0.036 + 27.6 + 6.4% *
p < 0.05
Unerwarteterweise kam es auch in diesem Myokardsegment mit normaler Gefäßversorgung und Per- fusion zu einem, bezogen auf den Zeitpunkt der PTCA verzögerten myocardial stunning. Urapidil war wiederum in der Lage, dieses myocardial stunning aufzuheben.p <0.05 Unexpectedly, myocardial stunning was delayed in this myocardial segment with normal vascular supply and perfusion, delayed in relation to the time of the PTCA. Urapidil was again able to remove this myocardial stunning.
9 andere Patienten erhielten ebenfalls die standardisierte antianginöse Therapie mit einem Caiciu¬ mantagonisten und Nitraten, jedoch zum Zeitpunkt D anstelle des α1-Adreπoceptor-Antagonisten le¬ diglich eine Injekton von Kochsalzlösung. Diese Patienten dienten als Kontrollen. Bei diesen Patienten bestand das myocardial stunning über 30 Minuten nach PTCA und Stent-Implantation unverändert fort.
9 other patients also received the standardized antianginal therapy with a calcium antagonist and nitrates, but at time D only an injection of saline solution instead of the α1 adrenoceptor antagonist. These patients served as controls. In these patients myocardial stunning continued unchanged for 30 minutes after PTCA and stent implantation.
Claims
1. Verwendung von α1-Adrenoceptor-Antagonisten und/oder ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Verhütung und Behandlung von Krankheitszuständen, die auf myokardialer kontraktiler Dysfunktion infolge Ischämie beruhen und als stunned myocardium bezeichnet werden.1. Use of α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the production of medicaments for the prevention and treatment of disease states which are based on myocardial contractile dysfunction due to ischemia and are referred to as stunned myocardium.
2. Verwendung gemäß Anspruch 1 von 6-{[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]amino)-1r3-di- methyluracil und/oder seinen pharmakologisch verträglichen Salzen.2. Use according to claim 1 of 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino) -1 r 3-dimethyluracil and / or its pharmacologically acceptable salts.
3. Verwendung von α1-Adrenoceptor-Antagonisten und/oder ihren pharmakologisch verträglichen Salzen zur Behandlung von Säugern, insbesondere Menschen, die an einem auf myokardialer kon¬ traktiler Dysfunktion infolge Ischämie beruhenden Krankheitszustand der als stunned myocardium bezeichnet wird erkrankt sind.3. Use of α1-adrenoceptor antagonists and / or their pharmacologically acceptable salts for the treatment of mammals, in particular humans, who are suffering from a disease state based on myocardial contractile dysfunction due to ischemia, which is referred to as stunned myocardium.
4. Verwendung von 6-{[3-[4-(2-Methoxyphenyl)-1-piperazinylpropyl]amino}-1,3-dimethyluracil und/oder seinen pharmakologisch verträglichen Salzen zur Behandlung der postoperativen Herzschwäche nach perkutaner transluminaler Angioplastie (PTCA) oder nach koronarer Bypass-Operation. 4. Use of 6 - {[3- [4- (2-methoxyphenyl) -1-piperazinylpropyl] amino} -1,3-dimethyluracil and / or its pharmacologically acceptable salts for the treatment of postoperative heart failure after percutaneous transluminal angioplasty (PTCA) or after coronary artery bypass surgery.
Priority Applications (1)
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DE1996107487 DE19607487C2 (en) | 1996-02-28 | 1996-02-28 | Use of alpha1 adrenoceptor antagonists |
DE19607487.8 | 1996-02-28 |
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Cited By (1)
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US8586617B2 (en) | 2006-10-19 | 2013-11-19 | Hoffmann-La Roche Inc. | Aminomethyl-4-imidazoles |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2626176A1 (en) * | 1988-01-25 | 1989-07-28 | Baligadoo Soorianarain | Cardioprotective medicinal preparations comprising amiodarone, a nitro derivative and optionally a beta-blocker |
WO1991011185A1 (en) * | 1990-02-01 | 1991-08-08 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Use of urapidile and derivatives for treating arteriosclerotic diseases |
-
1996
- 1996-02-28 DE DE1996107487 patent/DE19607487C2/en not_active Expired - Fee Related
-
1997
- 1997-02-22 WO PCT/EP1997/000861 patent/WO1997031638A1/en active Application Filing
- 1997-02-22 AU AU17943/97A patent/AU1794397A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2626176A1 (en) * | 1988-01-25 | 1989-07-28 | Baligadoo Soorianarain | Cardioprotective medicinal preparations comprising amiodarone, a nitro derivative and optionally a beta-blocker |
WO1991011185A1 (en) * | 1990-02-01 | 1991-08-08 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Use of urapidile and derivatives for treating arteriosclerotic diseases |
Non-Patent Citations (2)
Title |
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MOLLHOFF, T. ET AL.: "Der Einfluss von Urapidil und Natriumnitroprussid auf den intrapulmonalen Rechts-links-Shunt und die arterielle Oxygenation bei der Behandlung der Hypertonie nach koronarchirurgischen Eingriffen", ZEITSCHRIFT FÜR KARDIOLOGIE, vol. 78, no. 11, November 1989 (1989-11-01), pages 732 - 737, XP000654121 * |
RYNNING, S. E. ET AL.: "Endogenous adenosine attenuates myocardial stunning by antiadrenergic effects exerted during ischemia and not during reperfusion", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, vol. 25, no. 3, March 1995 (1995-03-01), pages 432 - 439, XP000654179 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US8586617B2 (en) | 2006-10-19 | 2013-11-19 | Hoffmann-La Roche Inc. | Aminomethyl-4-imidazoles |
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DE19607487C2 (en) | 1998-09-10 |
DE19607487A1 (en) | 1997-09-04 |
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