EP0000074A1 - Nouveaux dérivés de la bispidine, leur procédé de préparation et médicaments les contenant - Google Patents

Nouveaux dérivés de la bispidine, leur procédé de préparation et médicaments les contenant Download PDF

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Publication number
EP0000074A1
EP0000074A1 EP78100147A EP78100147A EP0000074A1 EP 0000074 A1 EP0000074 A1 EP 0000074A1 EP 78100147 A EP78100147 A EP 78100147A EP 78100147 A EP78100147 A EP 78100147A EP 0000074 A1 EP0000074 A1 EP 0000074A1
Authority
EP
European Patent Office
Prior art keywords
bispidine
benzyl
general formula
compounds
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.)
Granted
Application number
EP78100147A
Other languages
German (de)
English (en)
Other versions
EP0000074B1 (fr
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/fr
Application granted granted Critical
Publication of EP0000074B1 publication Critical patent/EP0000074B1/fr
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-monobenzylbispidine 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.
  • Suitable acids for the reaction are preferably glacial acetic acid and hydrochloric acid.
  • 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 a good antiarrhythmic effect and a 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 application, was used as the arrhythmia-producing substance (dosage speed 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 the occurrence of arrhythmias.
  • 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. ⁇ % indicates by how much the duration of the aconitine infusion can be extended. RMW is the relative maximum effectiveness, based on quinidine ⁇ 1.00.
  • the dose for the 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. Tablets, coated tablets and solutions are suitable for application.
  • 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 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 stripped off 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP78100147A 1977-06-13 1978-06-13 Nouveaux dérivés de la bispidine, leur procédé de préparation et médicaments les contenant Expired EP0000074B1 (fr)

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 true EP0000074A1 (fr) 1978-12-20
EP0000074B1 EP0000074B1 (fr) 1980-08-06

Family

ID=6011402

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100147A Expired EP0000074B1 (fr) 1977-06-13 1978-06-13 Nouveaux dérivés de la bispidine, leur procédé de préparation et médicaments les contenant

Country Status (7)

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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103833A2 (fr) * 1982-09-18 1984-03-28 Kali-Chemie Pharma GmbH Diazabicyclo(3.3.1)nonanes
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
EP0306871A2 (fr) * 1987-09-09 1989-03-15 Kali-Chemie Pharma GmbH Composés de 3,7-diazabicyclo [3,3,1] nonane, procédé pour leur préparation et médicaments les contenant
EP0461574A2 (fr) * 1990-06-15 1991-12-18 Kali-Chemie Pharma GmbH Médicaments contenant des 3,7-diazabicyclo(3,3,1)nonanes

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5669785U (fr) * 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
HU184960B (en) * 1981-07-20 1984-11-28 Richter Gedeon Vegyeszet Process for preparing new derivatives of 3,7-diazabicyclo/3.3.1/ nonane
WO1989000158A1 (fr) * 1987-07-02 1989-01-12 Pfizer Inc. Acides et esters carboxyliques de quinolone de diazabicycloalkyle shunte
DE3732094A1 (de) * 1987-09-24 1989-04-06 Basf Ag Bispidinderivate als klasse iii-antiarrhythmika

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Keine Entgegenhaltungen. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103833A2 (fr) * 1982-09-18 1984-03-28 Kali-Chemie Pharma GmbH Diazabicyclo(3.3.1)nonanes
EP0103833A3 (en) * 1982-09-18 1984-11-28 Kali-Chemie Pharma Gmbh Diazabicyclo(3.3.1)nonanes
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
EP0301245A2 (fr) * 1987-07-04 1989-02-01 Kali-Chemie Pharma GmbH Composés de 3-sulfonyl-3,7-diazabicyclo-(3,3,1)nonane, leurs procédés de préparation et médicaments contenant ces composés
EP0301245A3 (en) * 1987-07-04 1989-05-24 Kali-Chemie Pharma Gmbh 3-sulfonyl-3,7-diazabicyclo-(3,3,1)nonane compounds, processes for their preparation, and medicaments containing these compounds
US4906640A (en) * 1987-07-04 1990-03-06 Kali-Chemie Pharma Gmbh 3-sulfonyl-3,7-diazabicyclo[3,3,1]nonane compounds and medicaments containing said compounds
EP0306871A2 (fr) * 1987-09-09 1989-03-15 Kali-Chemie Pharma GmbH Composés de 3,7-diazabicyclo [3,3,1] nonane, procédé pour leur préparation et médicaments les contenant
EP0306871A3 (en) * 1987-09-09 1990-08-01 Kali-Chemie Pharma Gmbh 3,7-diazabicyclo û3,3,1¨ nonane compounds, process for their preparation and medicaments containing them
EP0461574A2 (fr) * 1990-06-15 1991-12-18 Kali-Chemie Pharma GmbH Médicaments contenant des 3,7-diazabicyclo(3,3,1)nonanes
EP0461574A3 (en) * 1990-06-15 1992-03-25 Kali-Chemie Pharma Gmbh Medicines containing 3,7-diazabicyclo(3,3,1)nonanes

Also Published As

Publication number Publication date
FI63403C (fi) 1983-06-10
EP0000074B1 (fr) 1980-08-06
DE2726571A1 (de) 1978-12-21
FI63403B (fi) 1983-02-28
FI781872A (fi) 1978-12-14
AT363937B (de) 1981-09-10
DE2860111D1 (en) 1980-11-27
CA1105023A (fr) 1981-07-14
US4183935A (en) 1980-01-15
JPS5412398A (en) 1979-01-30
ATA426578A (de) 1981-02-15

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