EP0000074B1 - Neue Bispidinderivate, Verfahren zu deren Herstellung und Arzneimittel, welche diese enthalten - Google Patents

Neue Bispidinderivate, Verfahren zu deren Herstellung und Arzneimittel, welche diese enthalten Download PDF

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Publication number
EP0000074B1
EP0000074B1 EP78100147A EP78100147A EP0000074B1 EP 0000074 B1 EP0000074 B1 EP 0000074B1 EP 78100147 A EP78100147 A EP 78100147A EP 78100147 A EP78100147 A EP 78100147A EP 0000074 B1 EP0000074 B1 EP 0000074B1
Authority
EP
European Patent Office
Prior art keywords
bispidine
benzyl
denotes
general formula
derivatives
Prior art date
Legal status (The legal status 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 status listed.)
Expired
Application number
EP78100147A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0000074A1 (de
Inventor
Fritz Dr. Binnig
Ludwig Dr. Friedrich
Hans Peter Dr. Hofmann
Horst Dr. Kreiskott
Claus Dr. Mueller
Manfred Dr. Raschack
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of EP0000074A1 publication Critical patent/EP0000074A1/de
Application granted granted Critical
Publication of EP0000074B1 publication Critical patent/EP0000074B1/de
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention also relates to medicaments which contain compounds of the general formula I and their salts with physiologically tolerable acids.
  • physiologically acceptable acids are e.g. in question: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, lactic acid and diamidosulfonic acid.
  • the reaction of the N-monobenzyl bispidine with the compounds II can be carried out, for example, with sodium hydride in dimethylformamide; Sodium hydroxide in water or ethanol; Sodium carbonate in butanol or amyl alcohol; Potassium carbonate in water, methanol, isopropanol, butanol, amyl alcohol, acetone, acetonitrile, toluene, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran; Sodium methylate in methanol; Sodium isopropylate in isopropanol; Potassium tert-butoxide in tert-butanol, tetrahydrofuran or dimethyl sulfoxide; Sodium amide in toluene or xylene etc. be performed.
  • the reaction with sodium hydride in dimethylformamide works best. It is usually carried out at room temperature.
  • the Mannich reaction can be carried out in the usual way.
  • Suitable solvents are e.g. Tetrahydrofuran, chloroform, methylene chloride and particularly good methanol, ethanol and isopropanol. Glacial acetic acid and hydrochloric acid are preferred as acid acids for the reaction.
  • the formaldehyde can also be used as paraformaldehyde in the reaction. It is convenient to carry out the reaction at elevated temperatures, e.g. at the boiling points of the solvents used. The reduction of the keto compounds obtained in this way works best according to Kishner Wolff.
  • the new compounds and their salts have good antiarrhythmic activity and low toxicity.
  • the substances were administered orally to rats (strain: Sprague Dawley, weight: 200 to 250 g) 45 minutes before the start of thiobutabarbital anesthesia (100 mg / kg ip).
  • Akonitin which was infused 60 minutes after substance administration, was used as the arrhythmia-producing substance (dosage rate 0.005 mg / kg per minute).
  • arrhythmias occur after an average of 3.32 minutes, the onset of which can be delayed by antiarrhythmia depending on the dose.
  • the ED 50% is the dose that increases the infusion time by 50% until arrhythmias occur.
  • RW is the relative effect based on quinidine ⁇ 1.00.
  • the maximum effect is that which is achieved when the maximum tolerated dose is applied.
  • A% indicates the percentage by which the duration of the aconitine infusion can be extended.
  • the dose at Toxic effect indicates the amount (mg / kg) at which the first toxic symptoms such as cyanosis or ECG changes occur.
  • Q is the quotient of the toxic dose and the ED 50% .
  • the new compounds and their salts have calcium antagonistic, antiphologistic and antiplatelet properties. They are well absorbed and should be administered orally and parenterally.
  • the daily dose is about 1 to 20 mg / kg for oral administration and about 0.05 to 1.0 mg / kg for intravenous or intramuscular administration.
  • For application e.g. Tablets, coated tablets and solutions.
  • 165 ml of glacial acetic acid are mixed with 165 ml of methanol and, while stirring and cooling with ice, 65 g (0.33 mol) of 2,2-diphenylethylamine, 62.4 g (0.33 mol) of N-benzylpiperidone-4 and 24.6 in succession g (0.82 mol) of paraformaldehyde were added and the mixture was then refluxed for 3 hours with stirring.
  • the glacial acetic acid and the methanol are largely removed in vacuo at 50 ° C., the residue is taken up in 1,000 ml of methylene chloride and, with stirring and ice cooling, 20% sodium hydroxide solution is added until the reaction is strongly alkaline.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP78100147A 1977-06-13 1978-06-13 Neue Bispidinderivate, Verfahren zu deren Herstellung und Arzneimittel, welche diese enthalten Expired EP0000074B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772726571 DE2726571A1 (de) 1977-06-13 1977-06-13 Neue bispidinderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten
DE2726571 1977-06-13

Publications (2)

Publication Number Publication Date
EP0000074A1 EP0000074A1 (de) 1978-12-20
EP0000074B1 true EP0000074B1 (de) 1980-08-06

Family

ID=6011402

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100147A Expired EP0000074B1 (de) 1977-06-13 1978-06-13 Neue Bispidinderivate, Verfahren zu deren Herstellung und Arzneimittel, welche diese enthalten

Country Status (7)

Country Link
US (1) US4183935A (fi)
EP (1) EP0000074B1 (fi)
JP (1) JPS5412398A (fi)
AT (1) AT363937B (fi)
CA (1) CA1105023A (fi)
DE (2) DE2726571A1 (fi)
FI (1) FI63403C (fi)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3226921A1 (de) * 1981-07-20 1983-02-10 Richter Gedeon Vegyészeti Gyár R.T., 1103 Budapest Neue bicyclische verbindungen und verfahren zu ihrer herstellung

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5669785U (fi) * 1979-11-01 1981-06-09
JPS5719791A (en) * 1980-07-11 1982-02-02 Tokyo Shibaura Electric Co L.e.d. driving circuit
DE3112055A1 (de) * 1981-03-27 1982-10-07 Basf Ag, 6700 Ludwigshafen Bispidinderivate, ihre herstellung und diese enthaltende arzneimittel
DE3234697A1 (de) * 1982-09-18 1984-03-22 Kali-Chemie Pharma Gmbh, 3000 Hannover Neue diazabicyclo-(3,3,1)-nonane
WO1989000158A1 (en) * 1987-07-02 1989-01-12 Pfizer Inc. Bridged-diazabicycloalkyl quinolone carboxylic acids and esters
DE3722134A1 (de) * 1987-07-04 1989-01-19 Kali Chemie Pharma Gmbh 3-sulfonyl-3,7-diazabicyclo(3,3,1)nonan- verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
PT88381B (pt) * 1987-09-09 1995-07-06 Kali Chemie Pharma Gmbh Processo para a preparacao de novos compostos 3,7-diazabiciclo{3,3,1} nonano, e de composicoes farmaceuticas que contem estes compostos
DE3732094A1 (de) * 1987-09-24 1989-04-06 Basf Ag Bispidinderivate als klasse iii-antiarrhythmika
DE4019080A1 (de) * 1990-06-15 1991-12-19 Kali Chemie Pharma Gmbh Neue 3,7-diazabicycolo (3,3,1)nonan-verbindungen enthaltende arzneimittel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2428792A1 (de) * 1974-06-14 1976-01-02 Knoll Ag Neue antiarrhythmika

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3226921A1 (de) * 1981-07-20 1983-02-10 Richter Gedeon Vegyészeti Gyár R.T., 1103 Budapest Neue bicyclische verbindungen und verfahren zu ihrer herstellung

Also Published As

Publication number Publication date
CA1105023A (en) 1981-07-14
FI63403C (fi) 1983-06-10
FI63403B (fi) 1983-02-28
FI781872A (fi) 1978-12-14
AT363937B (de) 1981-09-10
DE2860111D1 (en) 1980-11-27
EP0000074A1 (de) 1978-12-20
JPS5412398A (en) 1979-01-30
ATA426578A (de) 1981-02-15
US4183935A (en) 1980-01-15
DE2726571A1 (de) 1978-12-21

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