DE1050339B - Process for the preparation of cytostatic 1,4-disubstituted piperazines - Google Patents

Process for the preparation of cytostatic 1,4-disubstituted piperazines

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Publication number
DE1050339B
DE1050339B DENDAT1050339D DE1050339DA DE1050339B DE 1050339 B DE1050339 B DE 1050339B DE NDAT1050339 D DENDAT1050339 D DE NDAT1050339D DE 1050339D A DE1050339D A DE 1050339DA DE 1050339 B DE1050339 B DE 1050339B
Authority
DE
Germany
Prior art keywords
cytostatic
cooc
preparation
piperazine
ethyleneimine
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
DENDAT1050339D
Other languages
German (de)
Inventor
Forest Brüssel Henri Morren (Belgien)
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.)
Individual
Original Assignee
Individual
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.)
Publication date
Publication of DE1050339B publication Critical patent/DE1050339B/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms
    • C07D203/20—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms by carbonic acid, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/224—Phosphorus triamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/564—Three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

DEUTSCHESGERMAN

Es sind bereits Verbindungen mit einem organischen Rest R und einer oder mehreren Äthylenimingruppen der allgemeinen FormelThere are already compounds with an organic radical R and one or more ethyleneimine groups general formula

CH,CH,

bekannt.known.

In diesen Verbindungen kann der vom Äthylenimin bekannte cytotoxische Effekt weitgehend erhalten sein, weshalb aus diesem Grund ihre Verwendung zur Verhinderung der Bildung maligner Tumoren vorgeschlagen wurde. Die in diesen Verbindungen enthaltenen Äthylenimingruppen verleihen diesen jedoch zuweilen eine nicht außer acht zu lassende Toxizität.The cytotoxic effect known from ethyleneimine can largely be retained in these compounds, hence their use for preventing malignant tumor formation has been proposed for this reason became. However, the ethyleneimine groups contained in these compounds sometimes do not give them one neglect toxicity.

Es ist auch schon bekannt, daß die von W. Hanby und H. Rydon (Journal of the Chemical Society [London], 1947, S. 513) hergestellten Piperaziniumsalze der allgemeinen FormelIt is also already known that W. Hanby and H. Rydon (Journal of the Chemical Society [London], 1947, p. 513) prepared piperazinium salts of the general formula

R.R.

ClCH2CH2 -y ClCH 2 CH 2 -y

erhe

— CH2 - CH 2

CH0-CH9 CH 0 -CH 9

.Nr.No

,R, R

CH2CH2Cl
XlCH 2 CH 2 Cl
Xl

—n:—N:

C H9 — C HoCH 9 - C Ho

C H9 — C HoCH 9 - C Ho

:n—co—n;: n-co-n;

CHR'CHR '

XH9 XH 9

in der R ein niederer Alkylrest ist, bereits mit Erfolg bei Lymphosarkomen angewendet wurden (vgl. Kaufmann, »Arzneimittelsynthese« [1953], S. 288).in which R is a lower alkyl residue, has already been used with success in lymphosarcoma (cf. Kaufmann, "Drug Synthesis" [1953], p. 288).

Die Erfindung betrifft nun ein Verfahren zur Herstellung von l-Carboxylalkyl-piperazm-4-äthyleniminen der allgemeinen FormelThe invention now relates to a process for the preparation of 1-carboxylalkyl-piperazm-4-ethyleneimines the general formula

in der R -COOCH3, -COOC2H5, -COOC3H7, — CH2COOC2H5 und R' H oder — CH3 bedeutet, durch Umsetzen von Piperazin-l-carboxyalkyl-4-carbonsäurechloriden mit Äthylenimin oder 2-Methyläthylenimin in Gegenwart eines Chlorwasserstoff bindenden Mittels.in which R is -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -CH 2 COOC 2 H 5 and R 'is H or -CH 3 , by reacting piperazine-1-carboxyalkyl-4-carboxylic acid chlorides with ethyleneimine or 2-methylethyleneimine in the presence of a hydrogen chloride binding agent.

Es wurde nun gefunden, daß auf diese Weise Verbindungen hergestellt werden können, die eine beträchtliche cytotoxische Wirkung aufweisen und sich bei Tieren intravenös injizieren lassen, wobei ein genügender Sicherheitsbereich zwischen der therapeutisch wirksamen und der toxischen Dosis besteht. Diese Verbindungen können im Kampf gegen die Entwicklung maligner Tumoren verwendet werden.It has now been found that in this way connections can be made which have a considerable have cytotoxic effects and can be injected intravenously in animals with a sufficient safety margin exists between the therapeutically effective and the toxic dose. These connections can used in the fight against the development of malignant tumors.

Beispiel 1example 1

1 - Carboxym ethyl - 4(1' - carbonyl - äthylenimin) - piperazin 0,5 Mol Piperazin-l-carboxymethyl-4-carbonsäure-1 - carboxymethyl - 4 (1 '- carbonyl - ethyleneimine) - piperazine 0.5 mol of piperazine-1-carboxymethyl-4-carboxylic acid

chlorid (Kp. 1?s = 135° C) werden tropfenweise unterchloride (bp 1? s = 135 ° C) are added drop by drop

Rühren einer Lösung von 0,5 Mol Äthylenimin und 0,5 Verfahren zur HerstellungStirring a solution of 0.5 mol of ethyleneimine and 0.5 method of preparation

von cytostatisch wirkendenof those with a cytostatic effect

1,4-disubstituierten Piperazinen1,4-disubstituted piperazines

Anmelder:
Henri Morren, Forest, Brüssel (Belgien)Applicant:
Henri Morren, Forest, Brussels (Belgium)

Vertreter:Representative:

Dr.-Ing. A. v. Kreisler und Dr.-Ing. K. Schönwald,
Patentanwälte, Köln 1, DeichmannhausDr.-Ing. A. v. Kreisler and Dr.-Ing. K. Schönwald,
Patent attorneys, Cologne 1, Deichmannhaus

Beanspruchte Priorität:
Belgien vom 27. November 1952Claimed priority:
Belgium from November 27, 1952

Henri Morren, Forest, Brüssel (Belgien),
ist als Erfinder genannt wordenHenri Morren, Forest, Brussels (Belgium),
has been named as the inventor

Mol Triäthylamin in 200 cm3 Benzol zugegeben, wobei die Temperatur unter 10° C gehalten wird. Das Triäthylaminchlorhydrat wird abfiltriert, das Lösungsmittel im Vakuum abgedampft und der Rückstand destilliert. Das Kondensationsprodukt mit dem Äthylenimin schmilzt nach dem Umkristallisieren aus einem Benzol-Hexan-Gemisch bei 77 bis 78° C. Ausbeute 90 % der Theorie.Moles of triethylamine in 200 cm 3 of benzene were added, the temperature being kept below 10 ° C. The triethylamine chlorohydrate is filtered off, the solvent is evaporated off in vacuo and the residue is distilled. The condensation product with the ethyleneimine melts after recrystallization from a benzene-hexane mixture at 77 to 78 ° C. Yield 90% of theory.

Beispiel 2Example 2

1 -Carboxymethyl-4(1 '-carbonyl-2'-methyl-äthylenimin)-piperazin 1-Carboxymethyl-4 (1'-carbonyl-2'-methyl-ethyleneimine) -piperazine

Diese Verbindung wird gemäß Beispiel 1 aus Piperazinl-carboxymethyl-4-carbonsäurechlorid und einer Lösung von 2-Methyläthylenimin und Triäthylamin hergestellt. Kp. 0,3 = 146 bis 148° C. Ausbeute 85% der Theorie.This compound is prepared according to Example 1 from piperazinl-carboxymethyl-4-carboxylic acid chloride and a solution of 2-methylethyleneimine and triethylamine. Kp. 0, 3 = 146 to 148 ° C. Yield 85% of theory.

Beispiel 3Example 3

1 - Carboxypropyl- 4(1'- carbonyl- äthylenimin) - piperazin Es wird gemäß Beispiel 1 Piperazin-1-carboxypropyl-4-carbonsäurechlorid (Kp. λ = 142° C) mit einer Lösung von Äthylenimin und Triäthylamin behandelt. Kp. 0>5 = 15O0C. Ausbeute 70% der Theorie.1 - Carboxypropyl- 4 (1'- carbonyl- äthylenimin) - piperazine It is treated according to Example 1 piperazine-1-carboxypropyl-4-carboxylic acid chloride (bp. Λ = 142 ° C) with a solution of ethyleneimine and triethylamine. Kp. 0> 5 = 15O 0 C. Yield 70% of theory.

Beispiel 4Example 4

1-Methylcarboxyäthyl-4(1 '-carbonyl-äthylenimin)-piperazin 1-methylcarboxyethyl-4 (1'-carbonyl-ethylenimine) -piperazine

Diese Verbindung wird gemäß Beispiel 1 aus Piperazinl-methylcarboxyäthyl-4-carbonsäurechlorid und Äthylenimin hergestellt. Das Kondensationsprodukt siedet bei 150° C/l mm. Ausbeute 70% der Theorie.This compound is prepared according to Example 1 from Piperazinl-methylcarboxyethyl-4-carboxylic acid chloride and ethyleneimine produced. The condensation product boils at 150 ° C./1 mm. Yield 70% of theory.

809 749.378809 749.378

Das Piperazin -1 - methylcarboxyäthyl - 4 -carbonsäurechlorid (Kp.? = 141° C; F. = 42° C) wird in an sich bekannter Weise durch Umsetzung von Chloressigsäureäthylester und Piperazin zu Mono-(methylcarboxyäthyl)-piperazin (Kp.16 = 130° C) und Behandlung dieser Verbindung mit überschüssigem Phosgen erhalten. ... -The piperazine -1 - methylcarboxyäthyl - 4 -carbonsäurechlorid (?. Kp = 141 ° C; F. = 42 ° C) is in manner known per se by reaction of ethyl chloroacetate and piperazine mono (methylcarboxyäthyl) -piperazine (Kp sixteenth = 130 ° C) and treatment of this compound with excess phosgene. ... -

Claims (1)

Patentanspruch:Claim: Verfahren zur Herstellung von cytostatisch wirkenden 1,4-d!substituierten Piperazinen der allgemeinen FormelProcess for the production of cytostatic 1,4-d! Substituted piperazines of the general formula CHR'CHR ' R —N<R -N < -co —n:-co —n: in der R -COOCH3, -COOC2H5, -COOC3H7 oder —CH2COOC2H6 und R' Wasserstoff oder —XH3 bedeutet, dadurch gekennzeichnet, daß man Äthylen- bzw. 2-Methyläthylenimin mit einem Säurechlorid der allgemeinen Formelin which R -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 or -CH 2 COOC 2 H 6 and R 'denotes hydrogen or -XH 3 , characterized in that ethylene or 2-methylethyleneimine is used with a Acid chloride of the general formula R —Ν!R -! GH2 : CH2GH2: CH2 CH9 —CH 9 - ;n —co —ei; n -co -ei in der R die angegebene Bedeutung hat, in Gegenwart eines Salzsäure bindenden Mittels umsetzt.in which R has the meaning given, is reacted in the presence of a hydrochloric acid binding agent. In Betracht gezogene Druckschriften:
USA.-Patentschrift Nr. 2 643 255.Considered publications:
U.S. Patent No. 2,643,255.
DENDAT1050339D 1952-11-27 Process for the preparation of cytostatic 1,4-disubstituted piperazines Pending DE1050339B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
BE313878X 1952-11-27

Publications (1)

Publication Number Publication Date
DE1050339B true DE1050339B (en) 1959-02-12

Family

ID=3867602

Family Applications (2)

Application Number Title Priority Date Filing Date
DENDAT1050339D Pending DE1050339B (en) 1952-11-27 Process for the preparation of cytostatic 1,4-disubstituted piperazines
DEM33442A Pending DE1043336B (en) 1952-11-27 1953-11-21 Process for the production of cytostatically acting 1,4-disubstituted piperazines

Family Applications After (1)

Application Number Title Priority Date Filing Date
DEM33442A Pending DE1043336B (en) 1952-11-27 1953-11-21 Process for the production of cytostatically acting 1,4-disubstituted piperazines

Country Status (5)

Country Link
CH (1) CH313878A (en)
DE (2) DE1043336B (en)
FR (1) FR1094046A (en)
GB (1) GB750363A (en)
NL (1) NL87451C (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4886790A (en) * 1982-04-12 1989-12-12 The Research Foundation Of State University Of New York Novel bis(2,2-dimethyl-1-aziridinyl) phosphinic amides for use in the treatment of tumors

Also Published As

Publication number Publication date
GB750363A (en) 1956-06-13
CH313878A (en) 1956-05-15
NL87451C (en) 1900-01-01
FR1094046A (en) 1955-05-11
DE1043336B (en) 1958-11-13

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