DE1132145B - Process for the preparation of an anticoagulant 4-oxycoumarin derivative - Google Patents

Process for the preparation of an anticoagulant 4-oxycoumarin derivative

Info

Publication number
DE1132145B
DE1132145B DE1958S0056765 DES0056765A DE1132145B DE 1132145 B DE1132145 B DE 1132145B DE 1958S0056765 DE1958S0056765 DE 1958S0056765 DE S0056765 A DES0056765 A DE S0056765A DE 1132145 B DE1132145 B DE 1132145B
Authority
DE
Germany
Prior art keywords
oxycoumarin
anticoagulant
derivative
preparation
bis
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.)
Pending
Application number
DE1958S0056765
Other languages
German (de)
Inventor
Rn Dr Karel Fucik
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.)
SPOFA SPOJENE FARMACEUTICKE ZD
Original Assignee
SPOFA SPOJENE FARMACEUTICKE ZD
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 SPOFA SPOJENE FARMACEUTICKE ZD filed Critical SPOFA SPOJENE FARMACEUTICKE ZD
Publication of DE1132145B publication Critical patent/DE1132145B/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
    • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
    • C07D311/48—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring with two such benzopyran radicals linked together by a carbon chain

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

DEUTSCHESGERMAN

PATENTAMTPATENT OFFICE

S56765IVb/12qS56765IVb / 12q

ANMELDETAG: 30. J A N U A R 1958REGISTRATION DATE: JANUARY 30, 1958

BEKANNTMACHUNG DER ANMELDUNG UNDAUSGABEDER AUSLEGESCHRIFT: 28. JUNI 1962NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL: JUNE 28, 1962

Es ist bekannt, daß die Alkoxyderivate des 3,3'-Methylen-bis-4-oxycumarins eine blutgerinnungshemmende Wirkung besitzen, so daß diese Substanzen für die Behandlung und gegebenenfalls auch für die Prophylaxe von Thrombose wertvolle Verbindungen darstellen.It is known that the alkoxy derivatives of 3,3'-methylene-bis-4-oxycoumarins Have an anti-coagulant effect, so that these substances for the treatment and possibly also for the Thrombosis prophylaxis are valuable compounds.

Die bisher bekannten Alkoxyderivate aus der Reihe des 3,3'-Methylen-bis-4-oxycumarins besitzen zwischen dem Kohlenstoffatom der Methylenbrücke und dem Sauerstoffatom höchstens noch ein einziges weiters Kohlenstoffatom.The previously known alkoxy derivatives from the series of 3,3'-methylene-bis-4-oxycoumarins have between the carbon atom of the methylene bridge and the oxygen atom there is at most a single one further carbon atom.

Es wurde nun gefunden, daß das l,l-Bis-[4'-oxycumarinyl-(3')]-3-äthoxypropan der FormelIt has now been found that the l, l-bis [4'-oxycumarinyl- (3 ')] -3-ethoxypropane the formula

C. rin—O —■C. rin -O- ■

OH CH2 OHOH CH 2 OH

-CH-CH

=o oJ.= o oJ.

O' Verfahren zur Herstellung O ' method of manufacture

eines blutgerinnungshemmendenan anti-coagulant

4-Oxycumarmderivates4-oxycumarm derivatives

Anmelder:Applicant:

Spofa Spojene farmaceuticke zävody närodni podnik, PragSpofa Spojene farmaceuticke zävody närodni podnik, Prague

Vertreter: Dipl.-Ing. A. Spreer, Patentanwalt, Göttingen, Groner Str. 37Representative: Dipl.-Ing. A. Spreer, patent attorney, Göttingen, Groner Str. 37

Beanspruchte Priorität:Claimed priority:

Tschechoslowakei vom 4. Februar 1957Czechoslovakia from February 4, 1957

(Nr. 654 und Nr. 655)(No. 654 and No. 655)

RN Dr. Karel Fucik, Modfany (Tschechoslowakei), ist als Erfinder genannt wordenRN Dr. Karel Fucik, Modfany (Czechoslovakia), has been named as the inventor

den bekannten Substanzen aus der Reihe der Dicumarine mit Anticoagulationswirkung überlegen ist. Die blutgerinnungshemmende Wirkung der erfindungsgemäß hergestellten Verbindung ist merklich stärker als diejenige der bekannten Dicumarine, wobei diese Wirkung mit einer geringeren Dosis an Anticoagulans erreicht wird als bei den bekannten Verbindungen. Ein weiterer klinischer Vorzug des 1,1-Bis-[4'-oxycumarinyl-(3')]-3-äthoxypropans besteht darin, daß trotz der stärkeren therapeutischen Wirkung keine größere Kumulation im Körper stattfindet als bei den bekannten Anticoagulantien. Außerdem ist es nach der Verabreichung schneller wirksam als die bekannten Dicumarine mit blutgerinnungshemmender Wirkung, wobei es als besonders vorteilhaft anzusehenis superior to the known substances from the series of dicumarins with an anticoagulant effect. The anticoagulant effect of the compound prepared according to the invention is noticeable stronger than that of the known dicoumarins, this effect with a lower dose of anticoagulant is achieved than with the known connections. Another clinical benefit of 1,1-bis- [4'-oxycumarinyl- (3 ')] -3-ethoxypropane consists in the fact that, despite the stronger therapeutic effect, there is no greater accumulation in the body than with the known anticoagulants. Also, it is more effective than that after administration known dicoumarins with anticoagulant effect, whereby it is to be regarded as particularly advantageous

ist, daß das Verfahrensprodukt bereits nach 12 Stunden eine bedeutende Verlängerung der Quickschen Zeit aufweist und daß diese Wirkung bereits nach 48 Stunden abklingt.is that the process product already after 12 hours a significant extension of Quick's Has time and that this effect already subsides after 48 hours.

Die überlegene antikoagulierende Wirkung des Verfahrensproduktes wurde in Vergleichsversuchen gegenüber bekannten Verbindungen mittels des Quickschen Testes ermittelt. Die hierbei durch perorale Verabreichung der zu prüfenden Substanzen an fünf Kaninchen erhaltenen Durchschnittswerte der Gerinnungszeit nach Quick sind aus der folgenden Tabelle ersichtlich.The superior anticoagulant effect of the process product was demonstrated in comparative tests determined compared to known compounds by means of Quick's test. The here through oral administration of the substances to be tested to five rabbits obtained average values of The following table shows the Quick clotting times.

Geprüfte VerbindungTested connection Dosis
mg/kgdose
mg / kg 00 Gerinnu
12Gerinnu
12th ngszeit na(
24ngszeit na (
24 :h Stunden
36: h hours
36 der Verabreichung
48 I 60of administration
48 I 60 18,1
29,818.1
29.8 8484 1,1 -Bis- [4'-oxycumarinyl-(3 ')]-
3-äthoxypropan1,1 -Bis- [4'-oxycumarinyl- (3 ')] -
3-ethoxypropane 2,0
20,02.0
20.0 17,8
16,917.8
16.9 33,8
30,733.8
30.7 50,1
49,250.1
49.2 53,1
69,853.1
69.8 23,7
54,523.7
54.5 17,4
27,517.4
27.5 18,2
24,518.2
24.5 /3-[4-Oxycumarinyl-(3)-]-äthylme-
thylsulfid (bekannt)/ 3- [4-oxycumarinyl- (3) -] - ethylme-
methyl sulfide (known) 2,0
20,02.0
20.0 18,6
20,018.6
20.0 29,8
30,029.8
30.0 40,2
45,440.2
45.4 37,0
59,637.0
59.6 23,8
44,123.8
44.1 17,9
25,817.9
25.8 17,4
19,917.4
19.9 3,3'-Methoxyäthyliden-bis-(4-oxy-
cumarin) (bekannt)3,3'-methoxyethylidene-bis- (4-oxy-
coumarin) (known) 2,0
20,02.0
20.0 19,5
18,619.5
18.6 25,0
31,225.0
31.2 40,2
53,440.2
53.4 40,3
58,640.3
58.6 24,8
45,224.8
45.2 30,130.1 17,6
19,817.6
19.8 3,3'-Methylen-bis-4-oxycumarin
(bekannt) (Dicumarol)3,3'-methylene-bis-4-oxycoumarin
(known) (dicumarol) 2,52.5 17,217.2 27,327.3 41,041.0 42,842.8 33,733.7 18,018.0 27,227.2 3,3'-Bis-4-oxycumarinylessigsäure-
äthylester (bekannt)3,3'-bis-4-oxycoumarinyl acetic acid
ethyl ester (known) 25,025.0 18,418.4 33,933.9 40,040.0 29,829.8 20,220.2 17,417.4

209 617/403209 617/403

Das l,l-Bis-[4'-oxycumarinyl-(3')]-3-äthoxypropan wird erfindungsgemäß erhalten durch Umsetzung von 4-Oxycumarin mit Äthoxy-propionaldehyddialkylacetalen der allgemeinen FormelThe l, l-bis [4'-oxycumarinyl- (3 ')] - 3-ethoxypropane is obtained according to the invention by reacting 4-oxycoumarin with ethoxy-propionaldehyde dialkyl acetals the general formula

OROR

C2Hs — O — CH2 — CH2 — CH ^C 2 Hs - O - CH 2 - CH 2 - CH ^

OROR

in der R einen Methyl- oder einen Äthylrest bedeutet. Die Kondensation wird vorzugsweise in Gegenwart von verdünnten, niedermolekularen Alkoholen, z. B. Methanol, durchgeführt.in which R denotes a methyl or an ethyl radical. The condensation is preferably carried out in the presence of dilute, low molecular weight alcohols, e.g. B. methanol performed.

Beispielexample

32,4 g 4-Oxycumarin werden in 200 ecm einer 50°/0igen wäßrigen Methanollösung bei Siedetemperatur aufgelöst. In diese Lösung läßt man 17,5 g Äthoxypropionaldehyddiäthylacetal zutropfen und kocht das Gemisch weitere 2 Stunden unter Rückfluß. Während der Umsetzung scheidet, sich das Reaktionsprodukt aus. Nach beendeter Reaktion läßt man das Gemisch abkühlen, saugt das Verfahrensprodukt ab und kristallisiert es aus Äthanol oder Essigsäure um. Das erhaltene l,l-Bis-[4'-Oxycumarinyl-(3')]-3-äthoxypropan stellt eine farblose, kristalline, bitter schmeckende Substanz vom F. 1620C dar. Die Ausbeute beträgt 75 % der Theorie.32.4 g of 4-Oxycumarin in 200 cc of a 50 ° / 0 aqueous solution of methanol at boiling temperature dissolved. 17.5 g of ethoxypropionaldehyde diethyl acetal are added dropwise to this solution and the mixture is refluxed for a further 2 hours. The reaction product separates out during the reaction. When the reaction has ended, the mixture is allowed to cool, the process product is filtered off with suction and recrystallized from ethanol or acetic acid. The obtained l, [4'-Oxycumarinyl- (3 ')] l-bis - 3-äthoxypropan is a colorless, crystalline, bitter tasting substance, melting at 162 0 C represents The yield is 75% of theory..

Claims (1)

PATENTANSPRUCH:PATENT CLAIM: Verfahren zur Herstellung eines blutgerinnungshemmenden 4-Oxycumarinderivates durch Umsetzung von 4-Oxycumarin mit Dialkylacetalen, dadurch gekennzeichnet, daß man als Dialkylacetale Verbindungen der allgemeinen FormelProcess for the preparation of a 4-oxycoumarin derivative which inhibits blood coagulation by reacting 4-oxycoumarin with dialkyl acetals, characterized in that the dialkyl acetals are compounds of the general formula OROR C2H5 — O — CH2 — CH2 — CH^C 2 H 5 - O - CH 2 - CH 2 - CH ^ OROR in der R einen Methyl- oder einen Äthylrest bedeutet, verwendet.in which R denotes a methyl or an ethyl radical, is used. In Betracht gezogene Druckschriften:
Deutsche Auslegeschrift N 7892 IVb/12q (bekanntgemacht am 13. 12. 1956);Considered publications:
German Auslegeschrift N 7892 IVb / 12q (published on December 13, 1956); Patentschrift Nr. 12 546 des Amtes für Erfindungsund Patentwesen in der sowjetischen Besatzungszone Deutschlands.Patent specification No. 12 546 of the Office for Invention and Patents in the Soviet Zone of Occupation Germany. © 209 617/403 6.62© 209 617/403 6.62
DE1958S0056765 1957-02-04 1958-01-30 Process for the preparation of an anticoagulant 4-oxycoumarin derivative Pending DE1132145B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CS65557 1957-02-04
CS65457 1957-02-04

Publications (1)

Publication Number Publication Date
DE1132145B true DE1132145B (en) 1962-06-28

Family

ID=25745319

Family Applications (1)

Application Number Title Priority Date Filing Date
DE1958S0056765 Pending DE1132145B (en) 1957-02-04 1958-01-30 Process for the preparation of an anticoagulant 4-oxycoumarin derivative

Country Status (5)

Country Link
BE (1) BE564246A (en)
CH (1) CH365734A (en)
DE (1) DE1132145B (en)
FR (1) FR1201496A (en)
GB (1) GB830098A (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE12546C (en) * G. MÜLLER in Schweinfurt Innovations in cement roof interlocking tiles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE12546C (en) * G. MÜLLER in Schweinfurt Innovations in cement roof interlocking tiles

Also Published As

Publication number Publication date
CH365734A (en) 1962-11-30
GB830098A (en) 1960-03-09
FR1201496A (en) 1959-12-30
BE564246A (en) 1958-02-15

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