EP0142543A1 - Azidirino derivatives of tetrameric cyclophosphazenes - Google Patents

Azidirino derivatives of tetrameric cyclophosphazenes

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Publication number
EP0142543A1
EP0142543A1 EP84902089A EP84902089A EP0142543A1 EP 0142543 A1 EP0142543 A1 EP 0142543A1 EP 84902089 A EP84902089 A EP 84902089A EP 84902089 A EP84902089 A EP 84902089A EP 0142543 A1 EP0142543 A1 EP 0142543A1
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EP
European Patent Office
Prior art keywords
aziridino
compound
formula
tetrameric
derivative
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Withdrawn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
EP84902089A
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German (de)
French (fr)
Inventor
Johan Christoph Van De Grampel
Adriaan Albert Van Der Huizen
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.)
Rijksuniversiteit Groningen
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Rijksuniversiteit Groningen
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 Rijksuniversiteit Groningen filed Critical Rijksuniversiteit Groningen
Publication of EP0142543A1 publication Critical patent/EP0142543A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/65812—Cyclic phosphazenes [P=N-]n, n>=3
    • C07F9/65817—Cyclic phosphazenes [P=N-]n, n>=3 n = 4

Definitions

  • the invention relates to an aziridino derivative of a tetrameric cyclochlorophosphazene compound.
  • the (NPCL 2 ) -tetramer having the formula N 4 P 4 Cl 8 and the compound N 4 P 4 Az 8 derived therefrom, in which Az is aziridino, are known from the article by V.A. Chernov, V.B. Lytkina, S.I. Sergievskaya, A.A. Kropacheva, V.A. Parshina and L.E. Sventsitskaya, Farmakol. Toksikol. (Moscow) 22, 365 (1959). Of the compound N 4 P 4 Az 8 it is indicated that it has an anti-tumor activity with respect to S-45 sarcoma in rats. Moreover, Inorg. Chem.
  • N 4 P 4 Az 8 can be prepared by complete aminolysis of the tetrameric N 4 P 4 Cl 8 by means of aziridine or a homologue thereof in an aromatic hydrocarbon as reaction medium and triethylamine as acid acceptor. It is an object of the invention to provide an aziridino derivative of a tetrameric cyclochlorophosphazene compound which may serve as starting-material in the synthesis of tetrameric cyclophosphazene compounds to be derived therefrom and containing one or more aziridino groups by substitution of the chlorine atoms by a properly selected substituent, of which latter compounds it may be expected that they also have an anti-tumor activity.
  • the ratio of mono-aziri- dino to polyaziridino substitution is, e.g. in the case of starting from (NPCL 2 ) 4 ,the ratio in the reaction product of mono-aziridino to di-aziridino substitution, to be varied by affecting the molar ratio of the reaction components and, if required, the reaction time.
  • a suitable solvent in which the process according to the invention can be carried out is dry diethyl ether but also benzene, pentane, hexane and THF (tetrahydrofuran) are suitable for having reactions carried out therein.
  • the aziridino derivative of the tetrameric cyclochlorophosphazene compounds according to the invention are suitable starting materials for preparing compounds therefrom, the chlorine atoms being replaced by properly selected other substituents.
  • the chlorine atoms being replaced by properly selected other substituents.
  • it may be expected that such compounds have an anti-tumor activity.
  • R is an electron donating group of low sensitivity to hydrolysis.
  • the invention will be illustrated by the example given herein below.
  • NPCL 2 (Otsuka Chem.) was recrystaliized from hexane before use.
  • Aziridine was distilled from KOH pills under dry nitrogen just before use.
  • Solvents were purified and dried in the conventional manner. Reactions were carried out under a dry nitrogen atmosphere.
  • 31 P and 1 H NMR spectra were measured with a Nicolet 283A FT spectrometer equipped with an NTCFT1180 data system, in 10 mm tubes at 25°C.
  • the deuterium resonance of the solvent (CDCl 3 ) was used as "field-frequency lock”.
  • HPLC separations were carried out by using two Waters 6000A liquid pumps (each having a capacity of 20 cm 3 /min.) and a Waters R401 refractometer. Lichrosorb Si 60/10 served as column material.
  • fraction 5 consisted of 2 components which were once again separated afterwards with the same eluent (Fig. 3) .
  • N 4 P 4 AzCl 7 gave a ring frequency at 1316 (broad) or 1279 cm -1 (sharp); the "aziridino" band lay at 965 cm -1 (sharp).
  • the IR spectra of the isomeric compounds N 4 P 4 Az 2 Cl 6 were clearly distinguishable. Ring frequencies varied from 1310-1334 cm -1 (broad) or from 1275-1279 cm -1 (sharp). Aziridino bands were visible from 963 to 976 cm -1 (sharp) .
  • Precipitated (polymeric) salts are removed by filtration and, after washing thoroughly with solvent, the combined filtrates containing, the P-N ring compounds are evaporated in vacuo. If acetonitrile or THF is used as solvent, the complete reaction mixture is evaporated in vacuo. Extraction with diethyl ether or benzene yields solutions of the salt-free crude products.
  • mice alive 250 (2 mice alive) (tests conducted with mice taken in groups of 5).

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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)
  • Cephalosporin Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Dérivé aziridino d'un composé cyclochlorophosphazène tétramère de formule N4P4Cl8-nAzn, où Az représente un aziridino et n vaut 1, 2, 3, 4, 5, 6 ou 7; procédé pour lier un tel dérivé aziridino par aminolyse dans une solution de réaction d'un composé de formule N4P4Cl8-nAzn, où n vaut 0, 1, 2, 3, 4, 5, ou 6, et récupération du dérivé aziridino obtenu par "chromatographie liquide à rendement élevé", ainsi qu'un dérivé aziridino - basé sur le dérivé aziridino résultant - d'un composé cyclophosphazène substitué tétramère possédant une activité anti-tumorale et de formule N4P4R8-nAzn, où n vaut 1, 2, 3, 4, 5, 6, ou 7 et R représente les mêmes substituants ou des substituants différents.Aziridino derivative of a tetrameric cyclochlorophosphazene compound of formula N4P4Cl8-nAzn, where Az represents an aziridino and n is 1, 2, 3, 4, 5, 6 or 7; process for linking such an aziridino derivative by aminolysis in a reaction solution of a compound of formula N4P4Cl8-nAzn, where n is 0, 1, 2, 3, 4, 5, or 6, and recovery of the aziridino derivative obtained by " high performance liquid chromatography ", as well as an aziridino derivative - based on the resulting aziridino derivative - of a tetramer substituted cyclophosphazene compound having anti-tumor activity and of formula N4P4R8-nAzn, where n is 1, 2, 3, 4, 5, 6, or 7 and R represents the same or different substituents.

Description

AZIDIRINO DERIVATES OF TETRAMERIC CYCLOPHOSPHAZENES
The invention relates to an aziridino derivative of a tetrameric cyclochlorophosphazene compound.
The (NPCL2 ) -tetramer having the formula N4 P4Cl8 and the compound N4P4Az8 derived therefrom, in which Az is aziridino, are known from the article by V.A. Chernov, V.B. Lytkina, S.I. Sergievskaya, A.A. Kropacheva, V.A. Parshina and L.E. Sventsitskaya, Farmakol. Toksikol. (Moscow) 22, 365 (1959). Of the compound N4P4Az8 it is indicated that it has an anti-tumor activity with respect to S-45 sarcoma in rats. Moreover, Inorg. Chem. 3 (1964) 757-761 discloses that the compound N4P4Az8 can be prepared by complete aminolysis of the tetrameric N4P4Cl8 by means of aziridine or a homologue thereof in an aromatic hydrocarbon as reaction medium and triethylamine as acid acceptor. It is an object of the invention to provide an aziridino derivative of a tetrameric cyclochlorophosphazene compound which may serve as starting-material in the synthesis of tetrameric cyclophosphazene compounds to be derived therefrom and containing one or more aziridino groups by substitution of the chlorine atoms by a properly selected substituent, of which latter compounds it may be expected that they also have an anti-tumor activity. For this purpose the invention provides a compound of the type defined in the opening paragraph, characterized by the formula N4 P4Cl8-nAzn, in which n = 1,2,3,4,5,6 or 7.
Although the preparation of the compounds according to the invention proceeds rather easily with good precautions, the isolation of different, mostly isomeric products is not easy. E.g. the reaction of (NPCL2) 4 with aziridine gives at a molar ratio of 1:3.5, mainly the 6 products N4P4Cl7AZ gem-N4P4Cl6Az2 1,3-cis-N4P4Cl6Az2
1,5-cis-N4P4Cl6,Az2
1,3-trans-N4P4Cl6Az2
1,5-trans-N4P4Cl6Az2,in addition to a number of products N4P4Cl5Az3 A schematic representation of the structural formulae of these compounds, in which the ring-N-atoms and the Cl-atoms have been omitted, is given by formulae 1-6 of the sheet of formulae.
In accordance with what has been stated in the preceding paragraph the invention therefore also relates to a process for preparing an aziridino derivative according to the invention by aminolysis in a reaction solution of a cyclopolychlorophosphazene compound and working up of the reaction mixture,which process is characterized in that in a compound having the formula N4P4Cl8-n Azn, in which n = 0,1,2,3,4,5 or
6, 1-7 chlorine atoms are substituted by an aziridino group and that the resulting aziridino derivative are recovered from the product obtained after working up of the reaction mixture by means of HPLC ("high performance liquid chromatography"). In the process according to the invention the selection of column material and eluent depends, within the scope of application of the HPLC technique, on the reaction mixture to be analyzed.
As will be elucidated hereinafter, the ratio of mono-aziri- dino to polyaziridino substitution is, e.g. in the case of starting from (NPCL2)4 ,the ratio in the reaction product of mono-aziridino to di-aziridino substitution, to be varied by affecting the molar ratio of the reaction components and, if required, the reaction time.
A suitable solvent in which the process according to the invention can be carried out is dry diethyl ether but also benzene, pentane, hexane and THF (tetrahydrofuran) are suitable for having reactions carried out therein.
The aziridino derivative of the tetrameric cyclochlorophosphazene compounds according to the invention are suitable starting materials for preparing compounds therefrom, the chlorine atoms being replaced by properly selected other substituents. In view of the teaching from later published Dutch patent application no. 83.00573 it may be expected that such compounds have an anti-tumor activity.
Consequently, the invention also relates to an aziridino derivative of a tetrameric substituted cyclophosphazene compound having an antitumor activity, characterized by the formula N4P4R8-nAzn, in which n = 1,2,3,4,5,6 or 7 and R represents the same or different substituents.
Preferably, R is an electron donating group of low sensitivity to hydrolysis. The invention will be illustrated by the example given herein below. Example I
Preparation of N4P4AznCl8-n (n=l,2).
(NPCL2)4 (Otsuka Chem.) was recrystaliized from hexane before use. Aziridine was distilled from KOH pills under dry nitrogen just before use. Solvents were purified and dried in the conventional manner. Reactions were carried out under a dry nitrogen atmosphere. 31P and 1H NMR spectra were measured with a Nicolet 283A FT spectrometer equipped with an NTCFT1180 data system, in 10 mm tubes at 25°C. The deuterium resonance of the solvent (CDCl3) was used as "field-frequency lock". HPLC separations were carried out by using two Waters 6000A liquid pumps (each having a capacity of 20 cm3/min.) and a Waters R401 refractometer. Lichrosorb Si 60/10 served as column material.
A. Reaction of (NPCL2)4 with aziridine in the molar ratio of 1:2.5. A solution of 1.4 cm3 of aziridine (27.1 mmol) in 150 cm3 of dry diethyl etherwas added dropwise to a solution of 5.0 g of (NPCL2)4 (10,8 mmol) in 300 cm of dry diethyl ether for 30-45 min., while vigorously stirring and cooling to - 20°C. After the reaction mixture was warmed up slowly to room temperature and after a reaction time of 18 hours filtration of the polyaeric amino-HCL salt and evaporation of the filtrate gave 5.1 g of a white waxy oil which turned out to be slightly sensitive to hydrolysis (Product A) .
B. Reaction of (NPCL2)4 with aziridine inthe molar ratio of 1:3.5.
A solution of 3.9 cm3 of aziridine (77.8 mmol) in 100 cm3 of dry diethyl ether was added dropwise to a solution of 10.0 g (NPCL2)4
(21.6 mmol) in 400 cm3 of dry diethylether for 30-45 min., while vigorously stirring and cooling to - 0°C. the reaction mixture was warmed up slowly to room temperature and stirred further until a total reaction time of 7 hours. The working up procedure as set forth below A. gave 10.5 g of a turbid oil sensitive to hydrolysis (Product B
C. Analysis of the products. Analysis of 31P NMR and mass spectra as well as HPLC diagrams
(Fig. 1 and Fig. 2) showed that products A and B had the same composition in principle. A especially contained N4P4AzCl7while B, in addition to this component, especially contained N4P4Az2Cl6 (namely 5 isomers). The ratio of mono/disubstitution was to be affected by varying the molar ratio and the reaction time. It turned out that a reaction mixture such as product B was also to be obtained starting from N4P4AzCl7, in a 1:2 reaction with aziridine in dry diethyl ether.
D. Separation methods
It turned out that both product A and product B could be separate with HPLC by using a 25% diethyl ether/75% hexane eluent. Product A give N4P4AzCl7as the largest fraction (Fig 1, fraction 1). In total, 2.56 g were obtained (yield 50%). Recrystalization from pentane gave 1.9 g of analytically pure material; melting point 68.5-70.0°C.
Under corresponding conditions product B gave seven fractions (Fig. 2) : Fraction no. : (1) N4P4AzCl7 1.54 g
(2) N4P4Az2Cl6 2.12 g
(3) " 1,26 g different isomers
(4) " 0,65 g
(5) N4P4Az2Cl6 1.63 g Fraction no. : (6) N4P4Az3Cl5 different isomers
(7) N4P4Az3Cl5
Total 8.15 g = 77.8% on product B.
It turned out that fraction 5 consisted of 2 components which were once again separated afterwards with the same eluent (Fig. 3) .
Yield.
Fraction no.: 5I : N4P4Az2Cl6 0.20 g 5II : N4P4Az2Cl6
Total = 75%, calculated on fraction 5
(1.63 g). E. Characterization
Mass spectra
The mass spectra of both N4P4AzCl7 and N4P4Az2Cl6 showed different chlorine isotope peaks in addition to parent peaks of respectively M+ = 467 (for 35Cl) and M+= 474 (for 35Cl). The spectra of the different isomeric forms of N4P4Az2Cl6were not distinguishable.
Infrared spectra N4P4AzCl7gave a ring frequency at 1316 (broad) or 1279 cm-1 (sharp); the "aziridino" band lay at 965 cm-1 (sharp). The IR spectra of the isomeric compounds N4P4Az2Cl6 were clearly distinguishable. Ring frequencies varied from 1310-1334 cm-1 (broad) or from 1275-1279 cm-1 (sharp). Aziridino bands were visible from 963 to 976 cm-1 (sharp) . NMR spectra
31 P "chemical shifts" in ppm relative to H3PO4 85%; 1H "chemical shifts" in ppm with TMS as reference.
Example II
Preparation of a number of aziridino derivative having the formula N4P4R8-nAzn.
In de preparation of the abovementioned aziridino derivative the resulting reaction mixture was worked up according to procedure (a) mentioned herein below:
Procedure (a)
Most reactions afforded considerable amounts of hydrochloride salts, either precipitated or in solution. The use of aziridine as a hydrochloride scavenger resulted in the aziridino chloride salt which is rather unstable andsubsequently polymerized.
Precipitated (polymeric) salts are removed by filtration and, after washing thoroughly with solvent, the combined filtrates containing, the P-N ring compounds are evaporated in vacuo. If acetonitrile or THF is used as solvent, the complete reaction mixture is evaporated in vacuo. Extraction with diethyl ether or benzene yields solutions of the salt-free crude products.
All crude products are purified by recrystallization from an appropriate solvent. Mixtures are separated by HPLC and the resulting fractions are subsequently recrystallized.
Preparation of N4P4AzAm7 and N4P4Az2Am6 (Am = NHme, NMe2, wherein me = methyl: compounds nos. 11-22): the compounds having formulae 1-5II of the sheet of formulae were used as starting compounds. N4P4Az(NHMe) 7 and N4P4Az2 (NHMe) 6
To a stirred solution of 0,5 g (ca. 1 mmol) of the ring compounds in 15 cm3 of chloroform, cooled at 0°C, were slowly added 15cm3 of a
1 M solution of methylamine in benzene. After warming up to room temperature and a reaction time of 18 h application of procedure (a) afforded the crude products. There was obtained a white solid when the compound having formula 2 of the sheet of formulae was used as starting compound. In all other cases the products consisted of resinous oils. All compounds were reerystalilized several times from mixtures of diethyl ether and aiethylene chloride. When the compound having formula 5II of the sheet of formulae was used as starting material, a contaminated oil was obtained. Mass and NMR spectra indicated the presence of the completely aminol zed product. Further data are listed in Table I given herein below.
N4P4Az(MMe2)7 and N4P4Az2 (HMe2)6
To a stirred solution of 0.5 g (ca. 1 mmol) of the ring com- pound in 25 cm3 diethyl ether, cooled at 0°C, was added dropwise
15 cm3 of a 3 M dimethylamine solution in diethyl ether. After warming up to room temperature and a reaction time of 18 h, the working up by using procedure (a) yielded 0.57 g of an oily material. This was dissolved in 25 cm3 of diethyl ether -and refluxed overnight after adding 10 cm3 of a 3 M dimethylamine solution in diethyl ether. Subsequently,procedure (a) was once again used, yielding 0.54 g of a white solid (if the starting material is the compound having formula 1 or formula 2 of the sheet of formulae) or a viscous oil (if the starting material is the compound having formula 3 or formula 5II of the sheet of formulae). The solid was easily crystallized from hexane, whereas the oil required several recrystallizations from small amounts of hexane at -70°C. The product obtained by starting from the compound having formula 2 of the sheet of formulae remained an oil of unsatisfactory purity. Mass and NMR spectra were in agreement with the completely aminoIyzed compound no. 22. Further data are listed in table II given herei below.
1 Characterization data
TABLE III
31P NMR dataa of the compounds nos. 6 - 22
a- "Chemical Shifts" relative to 85 % H3PO4
TABLE IV
Elemental analysis dataa of compounds Nos. 6 - 22
a - the calculated values are mentioned in brackets
In vitro" physiological activity
Compounds nos. 12 and 18 are now measured "in vivo": LD50 - values are compound no. 12 : 165 mg/kg; 18 : 200 mg/kg (mice) . Testing compound no. 12 for L 1210 leukemia in mice gives the following picture.
Doses: 100 mg/kg T/C (= "Treated /Control") %
≥ 300
(3 mice out of 5 alive)
120 mgAg T/C
225 140 mg/kg T/C
225 (one mouse alive) 160 mg/kg T/C
250 (2 mice alive) (tests conducted with mice taken in groups of 5).

Claims

1. An aziridinoderivative of a tetrameric cyclochlorophosphazene compound, characterized by the formula N4 P4Cl8-n Azn, in which n =
1,2,3,4,5,6 or 7.
2. A process for preparing an aziridino derivative according to claim 1 , by aminolysis in a reaction solution of a cyclopoly- chlorophosphazene compound and working up the reaction mixture, characterized in that in a compound having the formula N4 P4Cl8-n Azn, in which n - 0,1,2,3,4,5 or 6, 1-7 chlorine atoms 44 8-n n are substituted by an aziridino group and from the product obtained after working up of the reaction mixture the resulting aziridino derivatives are recovered by means of HPLC ("high performance liquid chromatography").
3. A process according to claim 2, characterized in that the number of chlorine atoms to be substituted is varied by selection of the molar ratio of N4 P4Cl8-n Azn to aziridine, optionally in combination with the reaction time.
4. An aziridino derivativeof a tetrameric substituted cyclophosphazene compound having an anti-tumor activity, characterized by the formula N4 P4 R8-n Azn, in which n = 1,2,3,4,5,6 or 7 and R represents the same or different substituents.
5. An aziridino derivative according to claim 4, characterized in that R is an electron donating group of low sensitivity to hydrolysis.
6. An aziridino derivativeaccording to claim 5, characterized by the formula N4P4Az2(NHMe)6.
EP84902089A 1983-05-06 1984-05-07 Azidirino derivatives of tetrameric cyclophosphazenes Withdrawn EP0142543A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL8301626 1983-05-06
NL8301626A NL8301626A (en) 1983-05-06 1983-05-06 AZIRIDINE DERIVATIVE OF A TETRAMIC CYCLOCHLOROPHOSPHOSPHENE COMPOUND, PROCESS FOR THE PREPARATION THEREOF, AND A AZIRIDINE DERIVATIVE DERIVED BY SUBSTITUTION OF THE CHLOROUS ATOMS OF THE TETRAMERIC CHLOROPHOSPHAZENE.

Publications (1)

Publication Number Publication Date
EP0142543A1 true EP0142543A1 (en) 1985-05-29

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EP84902089A Withdrawn EP0142543A1 (en) 1983-05-06 1984-05-07 Azidirino derivatives of tetrameric cyclophosphazenes

Country Status (6)

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EP (1) EP0142543A1 (en)
JP (1) JPS60501257A (en)
AU (1) AU560606B2 (en)
DK (1) DK7485A (en)
NL (1) NL8301626A (en)
WO (1) WO1984004523A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19947440A1 (en) * 1999-09-24 2001-04-05 Analyticon Discovery Gmbh 1-Aziridino-1-hydroxyiminomethyl derivatives, process for their preparation and medicaments containing these compounds
CN110954628B (en) * 2019-12-19 2022-05-03 山东泰星新材料股份有限公司 High performance liquid detection method of hexaphenoxycyclotriphosphazene

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Publication number Priority date Publication date Assignee Title
FR1493736A (en) * 1966-07-22 1967-09-01 Soc Etu Chimiques Ind Et Agri New derivatives of phosphonitrile chloride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8404523A1 *

Also Published As

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AU2867984A (en) 1984-12-04
WO1984004523A1 (en) 1984-11-22
AU560606B2 (en) 1987-04-09
DK7485D0 (en) 1985-01-07
JPS60501257A (en) 1985-08-08
NL8301626A (en) 1984-12-03
DK7485A (en) 1985-01-07

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