DE2919275A1 - NEW 5-IMINO-4-HYDROXYMETHYL-3-ISOXAZOLIDONE WITH ANTITUMOR EFFECT - Google Patents

NEW 5-IMINO-4-HYDROXYMETHYL-3-ISOXAZOLIDONE WITH ANTITUMOR EFFECT

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Publication number
DE2919275A1
DE2919275A1 DE19792919275 DE2919275A DE2919275A1 DE 2919275 A1 DE2919275 A1 DE 2919275A1 DE 19792919275 DE19792919275 DE 19792919275 DE 2919275 A DE2919275 A DE 2919275A DE 2919275 A1 DE2919275 A1 DE 2919275A1
Authority
DE
Germany
Prior art keywords
imino
isoxazolidone
hydroxymethyl
new
antitumor effect
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.)
Withdrawn
Application number
DE19792919275
Other languages
German (de)
Inventor
Giorgio Palamidessi
Franco Zarini
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.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
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 Farmitalia Carlo Erba SRL filed Critical Farmitalia Carlo Erba SRL
Publication of DE2919275A1 publication Critical patent/DE2919275A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C07D261/14—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Die Erfindung betrifft ein Verfahren zur Herstellung von neuen 5-Imino-4—hydroxymethyl-3-isoxazolidonen der allgemeinen FormelThe invention relates to a process for the preparation of new 5-imino-4-hydroxymethyl-3-isoxazolidones the general formula

CH9OHCH 9 OH

(I)(I)

in der R ein niederer Alkylrest mit 1 bis 6 C-Atomenin which R is a lower alkyl radical with 1 to 6 carbon atoms

1
oder ein Aralkylrest und R ein Wasserstoffatom, ein niederer Alkylrest oder ein Aralkylrest ist, durch Hydroxymethylierung der entsprechenden 5-Amino-3— isoxazolidone»1
or an aralkyl radical and R is a hydrogen atom, a lower alkyl radical or an aralkyl radical, by hydroxymethylation of the corresponding 5-amino-3-isoxazolidones »

Die als Ausgangsprodukte verwendeten 5-Amino-3-isoxazolidone werden durch reduzierende Alkylierung von Diäthylcyanacetat mit entsprechenden Aldenyaen üna 'anschließende Isoxazazoiidon-Cyclisierung mit Hilfe von unsubstituiertem Hydroxylamin und substituierten ii-Alkyl- und N-Aralkylhydroxylaminen nach Verfahren, die aus der Literatur (JOC 26 (1961) 4917 und JACS 34 (1912) 925) bekannt sind, hergestellt. Die Hydroxymethylierung dieser Verbindungen erfolgt durch Aldolkondensation unter Verwendung von Formaldehyd auf die in Beispiel 1 beschriebene Weise. Das Ziel der Herstellung dieser Verbindung war die Gewinnung eines v/irksamen antibakteriellen Mittels. Einige dieser neuen Produkte zeigten überraschenderweise eine unvorhergesehene und vorteilhafte tumorhemmende Wirkung. Hiervon erwies sich dieThe 5-amino-3-isoxazolidones used as starting materials are subsequent by reducing alkylation of diethyl cyanoacetate with corresponding Aldenyaen üna ' Isoxazazoiidon cyclization with the help of unsubstituted hydroxylamine and substituted ii-alkyl and N-aralkylhydroxylamines by processes derived from Literature (JOC 26 (1961) 4917 and JACS 34 (1912) 925) are known. The hydroxymethylation of these compounds is carried out by aldol condensation using formaldehyde to that in Example 1 described way. The aim in making this compound was to obtain a potent antibacterial Means. Some of these new products surprisingly showed an unforeseen and beneficial one anti-tumor effect. From this the

909847/0783909847/0783

Verbindung der Formel I, worin R für CpH^ und R für Wasserstoff steht, als besonders wirksam.Compound of formula I wherein R is CpH ^ and R is Hydrogen stands out as being particularly effective.

Beispiel 1 dl^-Äthyl^-hydroxymethyl-S-imino-isoxazolidin-S-onexample 1 dl ^ -Ethyl ^ -hydroxymethyl-S-imino-isoxazolidin-S-one

1,36 ml Formalin (4Q%ig) wurden zu einer Lösung von 2,15 g 4-Äthyl-5-imino-isoxazolidin-3-on in 20 ml Äthanol gegeben. Das Gemisch wurde über Nacht bei Raumtemperatur stehen gelassen. Durch Einengen der Lösung bei 18,6 mbar auf ein kleines Volumen schieden sich 2 g eines kristallinen Produkts vom Schmelzpunkt 148-1520C ab (Ausbeute 76%). Nach Umkristallisation aus Äthanol schmolz das Produkt bei 154-155°C.1.36 ml of formalin (4Q%) were added to a solution of 2.15 g of 4-ethyl-5-imino-isoxazolidin-3-one in 20 ml of ethanol. The mixture was left to stand at room temperature overnight. Concentration of the solution at 18.6 mbar to a small volume separated out 2 g of a crystalline product of melting point 148-152 0 C. (yield 76%). After recrystallization from ethanol, the product melted at 154-155 ° C.

P.M.R. (DMSO-dg): 0,97 5 (t, CH3), 2,05 5 (q, CH2-C(H3)), 4,775 (d, CH2-O(H)), 6,15 5 (t, OH), 7,12 5 (breites s, N-H).PMR (DMSO-dg): 0.97 5 (t, CH 3 ), 2.05 5 (q, CH 2 -C (H 3 )), 4.775 (d, CH 2 -O (H)), 6, 15 5 (t, OH), 7.12 5 (broad s, NH).

I.R. (KBr): 3600 -2100 cm"1 (NH und OH)? 1635 cm"1 (C = 0).IR (KBr): 3600-2100 cm " 1 (NH and OH) - 1635 cm" 1 (C = 0).

Tumorhemmende Wirkung von d,l-4-Äthyl-4-hydroximethyl-5-iminoisoxazolidin-3-on Tumor-inhibiting effect of d, l-4-ethyl-4-hydroximethyl- 5-iminoisoxazolidin-3-one

Als Tumorsystem wurde lymphozytische Leukämie P388 und L1210 verwendet, die intraperitoneal am Tag 0 in einer Menge von 10 Zellen in 0,2 ml eingeimpft wurden. Die chronische Behandlung (Tag 1 bis 9 und 1,5 und 9, wie in der folgenden Tabelle angegeben) wurde angewendet.Lymphocytic leukemia P388 and L1210 were used as the tumor system; Amount of 10 cells in 0.2 ml were inoculated. Chronic treatment (day 1 to 9 and 1.5 and 9, like given in the following table) was applied.

909847/0783909847/0783

TabelleTabel Versuch
Nr.attempt
No. Dosis
mg/kg,
i.p.dose
mg / kg,
ip TC %TC% Verbindunglink Behandlungtreatment 1
21
2 200
100
50
100
50
25200
100
50
100
50
25th 140
130
110
121
96
lOS140
130
110
121
96
Come on d,1-4-Hydroxy-
methy1-5-imine
isoxazölidin-3
on
(NSC 272136)d, 1-4-hydroxy
methy1-5-imine
isoxazolidine-3
on
(NSC 272136) )-
i
Tage 1 bis 9
(P 388) I) -
i
Days 1 to 9
(P 388) I. 33 400
200
100
50400
200
100
50 140
140
127
US140
140
127
US 44th 300
200
100300
200
100 131
131
127131
131
127 Tage 1 bis 9
(P 388) IIDays 1 to 9
(P 388) II 55 400
200
100400
200
100 157
146
115157
146
115 Tage 1,5 und 9
(P 388) III:
IDays 1,5 and 9
(P 388) III:
I. 66th 400
200
100400
200
100 119
111
107119
111
107 Tage 1,5 und 9'
(P 388) IV JDays 1,5 and 9 '
(P 388) IV J. 77th 600
400
200600
400
200 103
115
103 103
115
103 Tage 1,5 und 9
(L 1210) VDays 1,5 and 9
(L 1210) V.

909847/0783909847/0783

Claims (2)

Patentansprüche I)/ Verbindungen der allgemeinen Formel Claims I) / compounds of the general formula in der R ein niederer Alkylrest mit 1 bis 6 C-Atomen oder ein Aralkylrest und R1 Wasserstoff, ein niederer Alkylrest mit 1 bis 4 C-Atomen oder ein Arylalkylrest ist»in which R is a lower alkyl radical with 1 to 6 carbon atoms or an aralkyl radical and R 1 is hydrogen, a lower alkyl radical with 1 to 4 carbon atoms or an arylalkyl radical » 2) Verfahren zur Herstellung von Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man entsprechend substituierte 5-Amino-3-isoxazolidone 20 Stunden bei Raumtemperatur in äthanolischer Lösung mit einer konzentrierten wässrigen Formaldehydlösung (40%ig Gew./ Vol.) umsetzt and die hierbei gebildeten entsprechenden Hydroxymethylderivate isoliert und reinigt.2) Process for the preparation of compounds according to claim 1, characterized in that one correspondingly substituted 5-amino-3-isoxazolidone for 20 hours at room temperature in an ethanolic solution with a concentrated aqueous formaldehyde solution (40% w / v) and the corresponding Hydroxymethyl derivatives isolated and purified. 909847/0783909847/0783
DE19792919275 1978-05-15 1979-05-12 NEW 5-IMINO-4-HYDROXYMETHYL-3-ISOXAZOLIDONE WITH ANTITUMOR EFFECT Withdrawn DE2919275A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT23389/78A IT1098214B (en) 1978-05-15 1978-05-15 5-IMINO-4-IDROSSIMETIL-3-ISOSSAZOLI GIFTS FOR ANTI-TUMOR ACTIVITY

Publications (1)

Publication Number Publication Date
DE2919275A1 true DE2919275A1 (en) 1979-11-22

Family

ID=11206641

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19792919275 Withdrawn DE2919275A1 (en) 1978-05-15 1979-05-12 NEW 5-IMINO-4-HYDROXYMETHYL-3-ISOXAZOLIDONE WITH ANTITUMOR EFFECT

Country Status (5)

Country Link
JP (1) JPS54148780A (en)
BE (1) BE876248A (en)
DE (1) DE2919275A1 (en)
GB (1) GB2020650B (en)
IT (1) IT1098214B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04122588U (en) * 1991-04-19 1992-11-04 株式会社野沢製作所 work trolley

Also Published As

Publication number Publication date
IT7823389A0 (en) 1978-05-15
GB2020650B (en) 1982-07-28
GB2020650A (en) 1979-11-21
IT1098214B (en) 1985-09-07
BE876248A (en) 1979-11-14
JPS54148780A (en) 1979-11-21

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