WO1991011185A1 - Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques - Google Patents

Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques Download PDF

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Publication number
WO1991011185A1
WO1991011185A1 PCT/EP1991/000159 EP9100159W WO9111185A1 WO 1991011185 A1 WO1991011185 A1 WO 1991011185A1 EP 9100159 W EP9100159 W EP 9100159W WO 9111185 A1 WO9111185 A1 WO 9111185A1
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WO
WIPO (PCT)
Prior art keywords
compounds
formula
hydrogen
treatment
acceptable salts
Prior art date
Application number
PCT/EP1991/000159
Other languages
German (de)
English (en)
Inventor
Karl Sanders
Wolf-Rüdiger Ulrich
Wolfgang PRÜSSE
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
Publication of WO1991011185A1 publication Critical patent/WO1991011185A1/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
    • 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 relates to the use of known uracil for the production of new drugs.
  • DE-OS 1942405 discloses piperazinylalkylaminouracils with blood pressure-sending properties.
  • the invention therefore relates to the use of compounds of the formula I.
  • Rl is hydrogen or 1-6C-alkyl
  • R2 is hydrogen or 1-6C-alkyl
  • R3 is hydrogen or 1-6C-alkyl
  • R4 is hydrogen, one or two 1-4C-alkyl radicals, one or two 1-4C-alkoxy radicals or one or two halogen atoms and A 2-4C-alkylene, and their pharmacologically acceptable salts for the preparation of medicaments for the prevention and Treatment of disease states that are based on proliferative processes, especially in vessels.
  • 1-6C-A1kyl stands for straight-chain or branched alkyl radicals with 1 to 6 carbon atoms.
  • hexyl, pentyl, neopentyl, isopentyl, butyl, i-butyl, sec-butyl, tert-butyl, propyl, isopropyl or in particular the ethyl or methyl radical may be mentioned .
  • 1-4C-alkyl radicals are the butyl, i-butyl, sec-butyl, tert-butyl, propyl, isopropyl or in particular the ethyl or methyl radical.
  • 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy and ethoxy radicals are preferred.
  • Halogen atoms are bromine and especially fluorine and chlorine.
  • C-alkylene which can be straight-chain or branched, is for example.
  • tetramethylene 1,2-dimethylethylene, 1,1-dimethylethylene, 2,2-dimethyl ethylene, isopropylidene, 1-methylethylene, ethylene and especially propylene.
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobride, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate , Malate, fumarate, succinate, oxalate, tartrate, sonata, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobride, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosal
  • arteriosclerosis diseases which are based on proliferative processes in vessels are primarily all forms of arteriosclerosis, such as, for example, central arteriosclerosis, coronary arteriosclerosis, arteriosclerosis of the brain vessels, arteriosclerosis of the kidneys, arteriosclerosis of the mesentery or that Arteriosclerosis of the extremity vessels.
  • the compounds of the formula I can be used, for example, to prevent and treat the following diseases and pathological changes: Restenosis after percutaneous translucent angioplasty or coronary bypass surgery, angina pectoris, myocardial infarction, cerebral haemorrhage and softening, vascular shrinking kidney, angina abdominalis, intermittent claudication, etc.
  • the invention therefore furthermore relates to a method for the treatment of mammals, in particular humans, who are suffering from a disease based on proliferative processes in vessels.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically tolerable amount of one or more compounds of the formula I and / or their pharmacologically tolerable salts.
  • the invention relates to the use of compounds of formula I and their salts for the treatment of mammals, in particular humans, who are suffering from ei ⁇ ner 'on prol Ferati en processes in vessels based disease.
  • the pharmacologically active compounds of the formula I and their salts are used either as such or, preferably, in combination with suitable pharmaceutical auxiliaries in the form of tablets, coated tablets , 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%.
  • 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, flavoring agents, preservatives, solubilizers, dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active substances can be administered rectally, parenterally (perlingually, intravenously, percutaneously) or orally.
  • the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments.
  • a preferred embodiment of the invention is the use of compounds of the formula I in which R1 is methyl, R2 is methyl, R3 is hydrogen or methyl, R4 is hydrogen, methyl, methoxy or chlorine and A is propylene, and their pharmaceutically acceptable salts for the preparation of drugs for the prevention and treatment of the disease states mentioned.
  • a particularly preferred embodiment of the invention is the use of 6 - ⁇ [3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino ⁇ -1,3-dimethyluraci1 and of 6 - ⁇ [3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] amino ⁇ -1,3,5-trimethylura ⁇ ci1 and its pharmacologically acceptable salts for the production of medicaments for the prevention and treatment of the disease states mentioned.
  • the compounds of the formula I and their salts are outstandingly suitable for the prevention and treatment of disease states which are based on proliferative processes.
  • the blood pressure-sending action of compounds of the formula I and their salts is known. Since arteriosclerosis is often associated with hypertension, the use of compounds of the formula I and their salts is of particular importance in hypertensives with accompanying arteriosclerosis.
  • test substances were administered orally once a day starting with 2 days before the lesion up to 14 days afterwards (2.5 ml / kg).
  • the substances were suspended in 4% solution of Methocel E15.
  • the carotids were removed at the end of the tests.
  • the amount of DNA after sample preparation was determined fluorometrically from defined 5 mm long pieces of vessel from the central area of the lesion, and on the other hand the neointima or media areas of haematoxylin-eosin stained by measuring with an electronic stylus.
  • test results determined in the test model described are summarized in Table 1 below. The following numbers were assigned to the test substances:
  • compound 1 achieved an inhibition of 27 or 37% with regard to new DNA or intima, in the high dose 46% inhibition.
  • the latter effect corresponds to that which can be achieved in the same model by continuous infusion of heparin (A.W. Clowes and M.M. Clowes, Laboratory Investigation 52, 611-616, 1985).

Abstract

L'objet de l'invention est l'utilisation de composés de la formule (I) dans laquelle R1, R2, R3, R4 et A ont la signification donnée dans la description, et de leurs sels acceptables sur le plan pharmacologique pour la fabrication de médications destinées à la prévention et au traitement d'états pathologiques basés sur des processus prolifératifs.
PCT/EP1991/000159 1990-02-01 1991-01-29 Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques WO1991011185A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH32190 1990-02-01
CH321/90-5 1990-02-01

Publications (1)

Publication Number Publication Date
WO1991011185A1 true WO1991011185A1 (fr) 1991-08-08

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Application Number Title Priority Date Filing Date
PCT/EP1991/000159 WO1991011185A1 (fr) 1990-02-01 1991-01-29 Utilisation d'urapidile et derives pour le traitement de maladies arteriosclerotiques

Country Status (4)

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EP (1) EP0513058A1 (fr)
JP (1) JPH05504136A (fr)
AU (1) AU7078691A (fr)
WO (1) WO1991011185A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031638A1 (fr) * 1996-02-28 1997-09-04 Byk Gulden Lomberg Chemische Fabrik Gmbh UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1942405A1 (de) 1969-08-20 1971-09-16 Byk Gulden Lomberg Chem Fab Arylsubstituierte Piperazinylalkylaminouracile bzw. -uracilaether

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1942405A1 (de) 1969-08-20 1971-09-16 Byk Gulden Lomberg Chem Fab Arylsubstituierte Piperazinylalkylaminouracile bzw. -uracilaether
DE1942405B2 (de) * 1969-08-20 1973-10-31 Byk-Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Arylsubstituierte Piperazinyl propylenaminouracile

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Anästh. Intensivther. Notfallmed., Band 24, 1989, Georg Thieme Verlag, (Stuttgart, DE), S. Hussein et al.: "Zur postoperativen Hochdruckbehabdlung mit Urapidil bei Patienten mit Hirnggefässaneurysmen", Seiten 373-376 *
Arzneimittel Forschung, Band 31 (I), Nr. 5, 1981, A. Barankay et al.: "Treatment of hypertension in coronary bypass surgery", Seiten 849-851 *
Laboratory Investigation, Band 57, Nr. 6, 1985, The United States-Canadian Division of the International Academy of Pathology, (US), A.W. Clowes et al.: "Kinetics of Cellular proliferation after arterial injury", Seiten 611-616 *
The American Journal of Cardiology, Band 64, 15. August 1989, E. Bielen et al.: "Urapidil-induced hemodynamic chages in humans", Seiten 16D-21D *
The Rapiewoche, Band 33, 1983, Verlag G. Braun, (Karlsruhe, DE), B.E. Strauer: "Der hypertensive Notfall", Seiten 1700-1712 *
Wiad. Lek, Band 38, Nr. 16, 1985, W. Ruminski et al.: "Ebrantil effect on certain haemodynamic parameters in hypertensive patients during acute myocardial infarction", Seiten 1121-1125 *
Zeitschrift für Kardiologie, Band 78, Nr. 11, 1989, Th. Möllhoff et al.: "Der Einfluss von Urapidil und Natriumnitroprussid auf den intrapulmonalen Rechts-links-Shunt und die arteruekke Oxygenation bei der Behanglung der Hypertonie nach koronarchirurgischen Eingriffen", Seiten 732-737 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031638A1 (fr) * 1996-02-28 1997-09-04 Byk Gulden Lomberg Chemische Fabrik Gmbh UTILISATION D'ANTAGONISTES DU RECEPTEUR α1-ADRENERGIQUE

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Publication number Publication date
JPH05504136A (ja) 1993-07-01
AU7078691A (en) 1991-08-21
EP0513058A1 (fr) 1992-11-19

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