DE2714486A1 - VINCAMINE DERIVATIVE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS MANUFACTURED FROM THEM - Google Patents

VINCAMINE DERIVATIVE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS MANUFACTURED FROM THEM

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Publication number
DE2714486A1
DE2714486A1 DE19772714486 DE2714486A DE2714486A1 DE 2714486 A1 DE2714486 A1 DE 2714486A1 DE 19772714486 DE19772714486 DE 19772714486 DE 2714486 A DE2714486 A DE 2714486A DE 2714486 A1 DE2714486 A1 DE 2714486A1
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DE
Germany
Prior art keywords
vincamine
medicinal products
manufacturing
products manufactured
formula
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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.)
Ceased
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DE19772714486
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German (de)
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Ferrer Internacional SA
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Ferrer Internacional SA
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Publication of DE2714486A1 publication Critical patent/DE2714486A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

PATENTANWÄLTEPATENT LAWYERS PROF. DR. DR. J. REITSTÖTTERPROF. DR. DR. J. REITSTÖTTER DR.-ING. WOLFRAM BUNTEDR.-ING. WOLFRAM BUNTE DR. WERNER KLNZEBACHDR. WERNER KLNZEBACH

271U86271U86

D-BOOO MÜNCHEN AO. BAUERaTRABSC 22 · FERNRUF (Οββ) 37 ββ 83 · TEUEX B21B20B IBAII O POSTANSCHRIFT: D-BOOO MÜNCHEN «3. POSTFACH 7BOD-BOOO MUNICH AO. BAUERaTRABSC 22 · FERNRUF (Οββ) 37 ββ 83 · TEUEX B21B20B IBAII O POSTAL ADDRESS: D-BOOO MUNICH «3. POST BOX 7BO

München, 31. März 1977 M/18Munich, March 31, 1977 M / 18

FERRER INTERNACIONAL S.A. Gran Via Carlos III No.94 Barceiona-14 / Spanien FERRER INTERNACIONAL SA Gran Via Carlos III No.94 Barceiona-14 / Spain

Vincaminderivat, Verfahren zur Herstellung und daraus hergestellte ArzneimittelVincamine derivative, method of manufacture and medicinal products made therefrom

Die Erfindung betrifft ein neues Vincaminderivat, nämlich Vincamin-5-bromnicotinat der Formel I:The invention relates to a new vincamine derivative, viz Vincamine 5-bromonicotinate of the formula I:

H3COOCH 3 COOC

OH C2H5OH C 2 H 5

COO^COO ^

709840/ 1040709840/1040

m/18 116 -jt- 27H486m / 18 116 -jt- 27H486

Vincamin ist das Hauptalkaioid des auch in Europa heimischen Immergrüns Vincajminor. Die reine Substanz £91^26^2^3' MG = 354,43 bildet bei der Kristallisation aus Aceton oder Methanol gelbliche Kristalle vom Schmelzpunkt 232 bis 233°. Die Total synthese des Vincamins ist von Pfäff1i et al. in HeIv. Chim. Acta 58 (1975) 1131-1145 beschrieben worden.Vincamine is the main alkaioid, which is also native to Europe Periwinkle Vincajminor. The pure substance £ 91 ^ 26 ^ 2 ^ 3 ' MW = 354.43 forms on crystallization from acetone or Methanol yellowish crystals with a melting point of 232 to 233 °. The total synthesis of vincamine is from Pfäff1i et al. in HeIv. Chim. Acta 58 (1975) 1131-1145.

Der Erfindung liegt die Aufgabe zugrunde, ein Vincaminderivat zu schaffen, das eine geringere Toxizität und größere therapeutische Wirksamkeit besitzt als die natürliche Base.The invention is based on the object of a vincamine derivative to create that has a lower toxicity and greater therapeutic effectiveness than the natural base.

Gelöst wird diese Aufgabe durch den in den Patentansprüchen gekennzeichneten Gegenstand.This object is achieved by the subject matter characterized in the patent claims.

überraschenderweise fand man, daß durch die Salzbildung mit einer ganz bestimmten Säure, nämlich der 5-Brom-nicotinsäure ein Produkt entsteht, das eine vincaminartige Hypotensorwirkung besitzt, wesentlich weniger toxisch ist als das natürliche Vincamin und besser verträglich als das letztere ist.Surprisingly, it was found that with the salt formation A very specific acid, namely 5-bromo-nicotinic acid, produces a product that has a vincamin-like hypotensor effect possesses, is significantly less toxic than the natural vincamine and better tolerated than the latter is.

Das erfindungsgemäße Vincamin-5-bromnicotinat wird durch direkte Umsetzung zwischen 5-Brom-nicotinsäure und Vincamin in einem nicht polaren Medium, vorzugsweise in Toluol, hergestellt. Man erhält auf diese Weise eine weiße, kristalline Festsubstanz hoher Reinheit mit einem Schmelzpunkt von 179,2 bis 180,50C.The vincamine 5-bromonicotinate according to the invention is produced by direct reaction between 5-bromo-nicotinic acid and vincamine in a non-polar medium, preferably in toluene. Is obtained in this manner, a white, crystalline solid of high purity with a melting point of 179.2 to 180.5 0 C.

Die erfindungsgemäße Verbindung stellt einen wirksamen Arzneimittelwirkstoff zur Behandlung von zerebral-vaskulären Erkrankungen dar.. Er fördert auf diese Weise die SauerstoffVersorgung und den ZeI1 Stoffwechsel. Durch Vermischen mit einem oder mehreren pharmazeutisch verträglichen Trägern und/oder pharmazeutischen Formulierungsmitteln und/oder üblichenThe compound of the present invention is an effective drug ingredient for the treatment of cerebral-vascular diseases. In this way it promotes the oxygen supply and the cell metabolism. By mixing with one or more pharmaceutically acceptable carriers and / or pharmaceutical formulation agents and / or customary

709840/1040709840/1040

M/18 116M / 18 116

-Jf--Jf-

27U48627U486

Arzneimittel zusätzen, erhält man aus der erfindungsgemäßen Verbindung oral, intramuskulär und intravenös verabreichbare Arzneimittel, die in Tagesdosen im Bereich von 15 bis 100 mg verabreicht werden.Add drugs, is obtained from the invention Compound that can be administered orally, intramuscularly and intravenously Medicines in daily doses ranging from 15 to 100 mg administered.

Die nachstehende Tabelle I zeigt die Entwicklung des Blutdruckes mit der Zeit nach Verabreichung der natürlichen Vincaminbase und der erfindungsgemäßen Verbindung im Vergleich zu dem ersten Druckwert nach intravenöser Verabreichung an Ratten, die zuvor mit Äthylurethan anästhesiert worden waren. Verabreicht wurden 2 mg/kg/Tier Vincaminbase und bezüglich Vincamin eine gleich große Dosis Vincamin-5-bromnicotinat. Man arbeitete nach der Methode von Szporny und Görög ("Arch. Int.Pharmacodyn.", J_38, 451-61, 1962: The effect of Vincamine on the blood pressure of the rat).Table I below shows the development of blood pressure with time after administration of the natural Vincamine base and the compound according to the invention in comparison to the first pressure value after intravenous administration to rats previously anesthetized with ethyl urethane was. 2 mg / kg / animal vincamine base and, with regard to vincamine, an equal dose of vincamine-5-bromonicotinate were administered. The method of Szporny and Görög was used ("Arch. Int.Pharmacodyn.", J_38, 451-61, 1962: The effect of Vincamine on the blood pressure of the rat).

TABELLE ITABLE I.

MinutenMinutes 00 55 1515th 3030th 6060 9090 Verbindunglink 76,44
81,51776.44
81.517 114,043
IW, 511114.043
IW, 511 98,863
101,42198.863
101.421 93,711
94,99993.711
94.999 97,111
88,82797.111
88.827 102,529
92,563102.529
92.563 Vincaminbase
Vineamin-5-brom-
nicotinatVincamine base
Vineamine-5-bromo-
nicotinate

Die akuten Toxizitäten von Vincaminbase und Vincamin-5-bromnicotinat wurden bei intraperitonealer Anwendung an Swiss-Mäusen beiderlei Geschlechts nach der akkumulativen Methode von Reed-Müench bestimmt. Die Ergebnisse sind in der nachfol-The acute toxicities of vincamine base and vincamine-5-bromonicotinate were administered intraperitoneally to Swiss mice of both sexes using the accumulative method determined by Reed-Müench. The results are in the following

709840/ 1040709840/1040

M/18 116M / 18 116

-A--A-

27U48627U486

genden Tabelle II zusammengefaßt:summarized in Table II:

TABELLE IITABLE II

Verbindunglink LD50 (mg/kg)LD 50 (mg / kg) LD0 (mg/kg)LD 0 (mg / kg) Vincaminbase
Vincamin-5-brom-
nicotinatVincamine base
Vincamine-5-bromo-
nicotinate 189,8
842,8189.8
842.8 152,8
509,9152.8
509.9

Die Herstellung der erfindungsgemäßen Verbindung kann z.B. auf folgende Weise erfolgen:The preparation of the compound according to the invention can e.g. be done in the following ways:

Beispielexample

Aus 3,54 g Vincamin (10 mMol) in 200 ml trockenem Toluol stellt man eine Suspension her, die unter magnetischem Rühren auf 50 bis 6O0C erhitzt wird. Dann gibt man 2,02 g 5-Bromnicotinsäure hinzu. Die so erhaltene Mischung wird 2 Stunden lang am Rückfluß gehalten, man erhält dabei eine Lösung. Aus der heiß filtrierten Lösung scheiden sich weiße Kristalle ab, die eine große Menge Toluol enthalten. Man filtriert sie ab und trocknet sie im Vakuum bei 800C. Auf diese Weise erhält man 5,1 g Vincamin-5-bromnicotinat mit einem Schmelzpunkt von 179,2 bis 180,50C. Die Elementaranalyse stimmt mit der erwarteten Struktur überein und zeigt, daß die Substanz sehr rein ist. Titration mit n-Tetrabutylammoniumhydroxyd in Dimethylformamid zeigt ein einziges Säureäquivalent. Bei der Titration benutzt man entweder einFrom 3.54 g vincamine (10 mmol) in 200 ml of dry toluene provides a suspension forth, which is heated with magnetic stirring at 50 to 6O 0 C. Then 2.02 g of 5-bromonicotinic acid are added. The mixture thus obtained is refluxed for 2 hours, a solution is obtained. White crystals containing a large amount of toluene separate from the hot-filtered solution. It is filtered off and dried in vacuo at 80 0 C. In this way, one obtains 5.1 g of vincamine 5-bromonicotinate having a melting point of 179.2 to 180.5 0 C. Elemental analysis is consistent with the expected structure and shows that the substance is very pure. Titration with n-tetrabutylammonium hydroxide in dimethylformamide shows a single acid equivalent. Either a is used for the titration

709840/1040709840/1040

M/18 116M / 18 116

27U48627U486

Potentiometer (Glass-Calomel) oder einen sichtbaren Indikator (0,3 % Thymol blau in Methanol).Potentiometer (Glass-Calomel) or a visible indicator (0.3 % thymol blue in methanol).

709840/1040709840/1040

Claims (4)

M/18 116 -S-27H486 PatentansprücheM / 18 116 -S-27H486 claims 1. Vincamin-S-bromnicotinat der Formel I:1. Vincamine S-bromonicotinate of the formula I: Br,Br, COO0 COO 0 (D(D H3COOC ■ 'H 3 COOC ■ ' OH C2H5OH C 2 H 5 2. Verfahren zur Herstellung der Verbindung nach Anspruch 1, dadurch gekennzeichnet, daß 5-Bromnicotinsäure der Formel2. Process for the preparation of the compound according to claim 1, characterized in that 5-bromonicotinic acid of the formula II: !II:! Br. ^ „ COOHBr. ^ "COOH (Π)(Π) mit Vincamin der Formel III:with vincamine of formula III: CHo-O-C
■j ■■CHo-OC
■ j ■■ (III)(III) 709840/1040709840/1040 ORIGINAL INSPECTEDORIGINAL INSPECTED h/18 116 -s- 27K486h / 18 116 -s- 27K486 in einem nicht polaren Medium umgesetzt wird.is implemented in a non-polar medium. 3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß die Umsetzung in Toluol durchgeführt wird.3. The method according to claim 2, characterized in that the reaction is carried out in toluene. 4. Arzneimittel mit einem üblichen pharmazeutisch verträglichen Arzneimittelträger und/oder üblichen Arzneimittelzusätzen, dadurch gekennzeichnet, daß es die Verbindung nach Anspruch 1 als Wirkstoff enthält.4. Medicinal products with a standard pharmaceutically acceptable carrier and / or standard pharmaceutical additives, characterized in that it contains the compound according to claim 1 as an active ingredient. 709340/10709340/10
DE19772714486 1976-03-31 1977-03-31 VINCAMINE DERIVATIVE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS MANUFACTURED FROM THEM Ceased DE2714486A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ES446755A ES446755A1 (en) 1976-03-31 1976-03-31 Vincamine salt and a process for its production

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DE2714486A1 true DE2714486A1 (en) 1977-10-06

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JP (1) JPS52143215A (en)
AT (1) AT352302B (en)
BE (1) BE853136A (en)
CH (1) CH601322A5 (en)
DE (1) DE2714486A1 (en)
ES (1) ES446755A1 (en)
FR (1) FR2346008A1 (en)
GB (1) GB1545012A (en)
NL (1) NL7703550A (en)
YU (1) YU39617B (en)
ZA (1) ZA771977B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58147394U (en) * 1982-03-27 1983-10-04 オンキヨー株式会社 speaker
JPS6395390U (en) * 1986-12-09 1988-06-20

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2274283A1 (en) * 1974-06-12 1976-01-09 Castaigne Sa Vincamine 2-(para hydroxy benzoyl) benzoate - vasodilator and cerebral oxygenator-from salts of vincamine and the substd benzoic acid

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES430059A1 (en) * 1974-09-14 1976-10-16 Roger Lab Process for preparing vincamine nicotinate salt

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2274283A1 (en) * 1974-06-12 1976-01-09 Castaigne Sa Vincamine 2-(para hydroxy benzoyl) benzoate - vasodilator and cerebral oxygenator-from salts of vincamine and the substd benzoic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chem.Abstr., 85, 1976, 154 154v *

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NL7703550A (en) 1977-10-04
CH601322A5 (en) 1978-07-14
ES446755A1 (en) 1977-06-01
BE853136A (en) 1977-07-18
ZA771977B (en) 1978-03-29
JPS5751395B2 (en) 1982-11-01
ATA221577A (en) 1979-02-15
GB1545012A (en) 1979-05-02
AT352302B (en) 1979-09-10
YU39617B (en) 1985-03-20
FR2346008B1 (en) 1985-02-15
YU84577A (en) 1982-08-31
JPS52143215A (en) 1977-11-29
FR2346008A1 (en) 1977-10-28

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