WO1984004523A1 - Azidirino derivatives of tetrameric cyclophosphazenes - Google Patents
Azidirino derivatives of tetrameric cyclophosphazenes Download PDFInfo
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- WO1984004523A1 WO1984004523A1 PCT/NL1984/000013 NL8400013W WO8404523A1 WO 1984004523 A1 WO1984004523 A1 WO 1984004523A1 NL 8400013 W NL8400013 W NL 8400013W WO 8404523 A1 WO8404523 A1 WO 8404523A1
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- aziridino
- compound
- formula
- tetrameric
- derivative
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- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- 238000007098 aminolysis reaction Methods 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims description 27
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000035945 sensitivity Effects 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 229960004132 diethyl ether Drugs 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- IFYDWYVPVAMGRO-UHFFFAOYSA-N n-[3-(dimethylamino)propyl]tetradecanamide Chemical compound CCCCCCCCCCCCCC(=O)NCCCN(C)C IFYDWYVPVAMGRO-UHFFFAOYSA-N 0.000 description 2
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- PEJQKHLWXHKKGS-UHFFFAOYSA-N 2,2,4,4,6,6,8,8-octachloro-1,3,5,7-tetraza-2$l^{5},4$l^{5},6$l^{5},8$l^{5}-tetraphosphacycloocta-1,3,5,7-tetraene Chemical compound ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1 PEJQKHLWXHKKGS-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
An aziridino derivative of a tetrameric cyclochlorophosphazene compound having the formula N4P4Cl8-nAzn, in which Az represents aziridino and n = 1, 2, 3, 4, 5, 6 or 7; a process for bonding such an aziridino derivative by aminolysis in a reaction solution of a compound having the formula N4P4Cl8-nAzn, in which n = 0, 1, 2, 3, 4, 5, or 6, and recovering the resulting aziridino derivative by means of "high performance liquid chromatography" as well as an aziridino derivative - based on the resulting aziridino derivative - of a tetrameric substituted cyclophosphazene compound having an anti-tumor acitivity and having the formula N4P4R8-nAzn, in which n = 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
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK7485A DK7485D0 (en) | 1983-05-06 | 1985-01-07 | AZIRIDINO DERIVATIVES OF TETRAMER CYCLOPHOSPHAZENES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
|---|---|
| WO1984004523A1 true WO1984004523A1 (en) | 1984-11-22 |
Family
ID=19841823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/NL1984/000013 WO1984004523A1 (en) | 1983-05-06 | 1984-05-07 | Azidirino derivatives of tetrameric cyclophosphazenes |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0142543A1 (en) |
| JP (1) | JPS60501257A (en) |
| AU (1) | AU560606B2 (en) |
| DK (1) | DK7485D0 (en) |
| NL (1) | NL8301626A (en) |
| WO (1) | WO1984004523A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001021585A3 (en) * | 1999-09-24 | 2001-10-11 | Analyticon Discovery Gmbh | Bis(1-aziridino-1-hydroxyiminomethyl)-derivatives, method for the production thereof and use thereof as anti-tumoral agents |
| CN110954628A (en) * | 2019-12-19 | 2020-04-03 | 山东泰星新材料股份有限公司 | High performance liquid detection method of hexaphenoxycyclotriphosphazene |
Citations (1)
| 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 |
-
1983
- 1983-05-06 NL NL8301626A patent/NL8301626A/en not_active Application Discontinuation
-
1984
- 1984-05-07 WO PCT/NL1984/000013 patent/WO1984004523A1/en not_active Application Discontinuation
- 1984-05-07 JP JP59501896A patent/JPS60501257A/en active Pending
- 1984-05-07 EP EP84902089A patent/EP0142543A1/en not_active Withdrawn
- 1984-05-07 AU AU28679/84A patent/AU560606B2/en not_active Expired - Fee Related
-
1985
- 1985-01-07 DK DK7485A patent/DK7485D0/en not_active Application Discontinuation
Patent Citations (1)
| 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 (3)
| Title |
|---|
| CHEMICAL ABSTRACTS, Volume 54, No. 8, 25 April 1960 (Columbus, Ohio, US) V.A. CHERNOV et al.: "Antitumor Activity of some Phosphonitrile Trimer and Tetramer Derivatives", see column 7900-i, 7901a,b,c, Farmakol. i. Toksikol. 22, 365-7 (1959) cited in the application * |
| European Journal of Cancer, Volume 15, Pergamon Press Ltd., 1979 (Oxford, GB) J.F. LABARRE et al.: "Antitumor Activity of some Cyclophosphazenes", see pages 637-643 * |
| Inorganic Chemistry, Volume 3, No. 5, 28 April 1964 (Easton, Pennsylvania, US) R. RATZ et al.: "Syntheses and Reactions of 2,2,4,4,6,6 -Hexakis (1-Aziridinyl) - Cyclotriphosphaza-1,3,5-Triene and Related Compounds", see pages 757-761 cited in the application * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001021585A3 (en) * | 1999-09-24 | 2001-10-11 | Analyticon Discovery Gmbh | Bis(1-aziridino-1-hydroxyiminomethyl)-derivatives, method for the production thereof and use thereof as anti-tumoral agents |
| CZ303316B6 (en) * | 1999-09-24 | 2012-08-01 | 1-Aziridino-1-hydroxyiminomethyl derivatives, process of their preparation and medicaments containing these compounds | |
| CN110954628A (en) * | 2019-12-19 | 2020-04-03 | 山东泰星新材料股份有限公司 | High performance liquid detection method of hexaphenoxycyclotriphosphazene |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| NL8301626A (en) | 1984-12-03 |
| EP0142543A1 (en) | 1985-05-29 |
| DK7485A (en) | 1985-01-07 |
| AU2867984A (en) | 1984-12-04 |
| AU560606B2 (en) | 1987-04-09 |
| JPS60501257A (en) | 1985-08-08 |
| DK7485D0 (en) | 1985-01-07 |
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