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WO1997031638A1 - UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE - Google Patents

UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
myocardial
ptca
acid
treatment
pharmacologically acceptable
Prior art date
Application number
PCT/EP1997/000861
Other languages
German (de)
English (en)
Inventor
Luigia Ventura Gregorini
Norbert Kolassa
Karl Sanders
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU17943/97A priority Critical patent/AU1794397A/en
Publication of WO1997031638A1 publication Critical patent/WO1997031638A1/fr

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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
    • A61K31/395—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
    • 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
    • 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
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes du récepteur α1-adrénergique et de leurs sels pharmacologiquement tolérables dans la production de médicaments pour la prévention et le traitement d'états pathologiques liés au dysfonctionnement contractile myocardique provoqué par l'ischémie.
PCT/EP1997/000861 1996-02-28 1997-02-22 UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE WO1997031638A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17943/97A AU1794397A (en) 1996-02-28 1997-02-22 Use of alpha1-adrenoceptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19607487.8 1996-02-28
DE1996107487 DE19607487C2 (de) 1996-02-28 1996-02-28 Verwendung von alpha1-Adrenoceptor-Antagonisten

Publications (1)

Publication Number Publication Date
WO1997031638A1 true WO1997031638A1 (fr) 1997-09-04

Family

ID=7786662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000861 WO1997031638A1 (fr) 1996-02-28 1997-02-22 UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE

Country Status (3)

Country Link
AU (1) AU1794397A (fr)
DE (1) DE19607487C2 (fr)
WO (1) WO1997031638A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8586617B2 (en) 2006-10-19 2013-11-19 Hoffmann-La Roche Inc. Aminomethyl-4-imidazoles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2626176A1 (fr) * 1988-01-25 1989-07-28 Baligadoo Soorianarain Preparations medicamenteuses cardioprotectrices comprenant l'amiodarone un derive nitre, et facultativement un beta-bloqueur
WO1991011185A1 (fr) * 1990-02-01 1991-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2626176A1 (fr) * 1988-01-25 1989-07-28 Baligadoo Soorianarain Preparations medicamenteuses cardioprotectrices comprenant l'amiodarone un derive nitre, et facultativement un beta-bloqueur
WO1991011185A1 (fr) * 1990-02-01 1991-08-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8586617B2 (en) 2006-10-19 2013-11-19 Hoffmann-La Roche Inc. Aminomethyl-4-imidazoles

Also Published As

Publication number Publication date
AU1794397A (en) 1997-09-16
DE19607487C2 (de) 1998-09-10
DE19607487A1 (de) 1997-09-04

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