NL8301626A - 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. - Google Patents

Description

* I, i VO 4821

Title: Aziridinoden vessel of a tetrameric cyclochlorophosphazene compound, process for its preparation, and an aziridino derivative derived by substitution of the chlorine atoms of the tetrameric chlorophosphazene compound.

The invention relates to an aziridine derivative of a tetrameric cyclochlorophosphazene compound.

The (NPClgJ tetramer of the formula N ^ Clg and the compound N ^ Azg to be derived from it, in which Az represents aziridino, are known from the article by VA Chernov, VB Lytkina, SI Sergievskaya, AA Kropacheva, VA Parshina and LE Sventsitskaya, Farmakol, Toksikol (Moscow) 22, 365 (1959) The compound Nz Azg has been reported to have anti-tumor activity with respect to S-45 sarcoma in rats.

10 From Inora. Chem. 3 (1964) 757-761, it is also known that the compound N 2 AZg can be prepared by complete aminolysis of the tetrameric N 2 Clg using aziridine or a homologue thereof in an aromatic hydrocarbon as the reaction medium and triethylamine as the acid acceptor.

The object of the invention is to derive an aziridino derivative of a tetrameric cyclochlorophosphazene compound which can serve as a starting material in the synthesis thereof, one or more aziridino groups containing tetrameric cyclophosphazenes compounds by replacing the chlorine atoms with a suitably selected substituent, the latter of which The said compounds can be expected to have anti-tumor activity as well.

According to the invention there is provided for this purpose a compound of the type mentioned in the opening paragraph, characterized by the formula Wg-1g-n Azn in which n = 1,2,3,4,5,6 or 7.

Although the preparation of the compounds according to the invention is relatively simple under good precautions, the isolation of various, usually isomeric, products is not simple.

For example, the reaction of (NPC1 with aziridine at a molar ratio of 1: 3.5 mainly produces the 6 products 8301626 -2-4% n4p4ci7az gem-N4P4Cl6Az2 1,3-cis-N4P4ClgAz2 1,5-cis-N4P4Cl6Az2 5,3-trans- N4P4ClgAz2 1.5-trans-N4P4ClgAz2, in addition to some products N ^ ClgAz ^.

A schematic representation of the structural formulas of these compounds, with the Rinq N atoms and Cl atoms omitted, are represented by formulas 1-6 of the formula sheet.

In accordance with the above 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 the reaction mixture, which process is characterized in that in a compound of the formula N4P4C1g_nAzn, in which n = 0, 1,2,3,4,5 or 6-1-7 chlorine atoms are substituted by an aziridino group and the aziridine derivatives formed from the product obtained after working up the reaction mixture are recovered by means of HPLC ("high performance liquid chromatography"). In the method according to the invention, in the context of the application of the HPLC technique, the choice of column and eluent depends on the reaction mixture to be analyzed.

As will be explained later, the ratio mono-aziri-dino / polyaziridino substitution, for example in case of (NPC12) 4, the ratio in the reaction product of mono-aziridino / di-aziridino substitution, is vary by influencing the molar ratio of the reaction components and possibly 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 carrying out the reactions.

The aziridino derivatives of the tetrameric cyclochlorophosphazene compounds of the invention are suitable starting materials for preparing compounds therefrom, the chlorine atoms being replaced by suitably selected other substituents. Such compounds may be 830 1 62 6 * 1 * -3- The disclosed in the non-prepublished Dutch Patent Application No. 83.00573 are expected to have anti-tumor activity.

The invention therefore also relates to an aziridino-5 derivative of a tetrameric substituted cyclophosphazene compound with anti-tumor activity, characterized by the formula N4P4Rs-n ^ zn where n = 1,2,3,4,5,6 or 7 and R whether or not equal substituents.

Preferably R is a low hydrolysis sensitive electron donating group.

The invention is further elucidated by means of the example below.

Example

Preparation of N ^ P4AznClg-n (n = 1.2).

(NPClg ^ (Otsuka Chem.) Was recrystallized from hexane before use. Aziridine was distilled from KOH pills under dry nitrogen just before use. Solvents were normally purified and dried. Reactions were carried out under a dry nitrogen atmosphere P and H NMR spectra were recorded with a Nico! 20 283A FT spectrometer equipped with an NTCFT-1180 data system, in 10 irni tubes at 25 ° C. The deuterium resonance of the solvent (CDCl2) was used as Field-frequency lock, HPLC separations were performed using two Waters 6000A liquid pumps (capacity 20cm? min each) and a Waters R401 refractometer. Lichrosorb Si 60/10 acted as 25 column material.

A, Reaction of (NPC3] ^ with aziridine in the molar ratio 1: 2.5 3

To a solution of 5.0 g (NPC ^ 1 ^ (10> 8 mmol) in 3 g0 cm dry diethyl ether was stirred with good stirring and cooling to -20 ° C for ^ 30-45 min, a solution of 1.4 cra Aziridine (27.1 mmol) dripped in 150 ml dry diethyl ether After slowly warming to room temperature and a reaction time of 18 hours, filtration of the polemere amino HCl salt and evaporation of the filtrate gave 5.1 g of a white waxy oil. , which was found to be slightly hydrolysis-sensitive (Product A), 8 30 1 6 2 Si-4 -4 -B.

3

A solution of 3.9 cm aziridine was added to a solution of 10.0 g (NPC12) 4 (21.6 mmol) in 400 cm dry diethyl ether with good stirring and cooling to 0 ° C for 30-45 min. (77.8 mmol) in 100 ml of dry diethyl ether. The reaction mixture was slowly warmed to room temperature and further stirred to a total reaction time of 7 hours. The work-up procedure as under A provided 10.5 g of a cloudy hydrolysis sensitive oil (Product B).

C. Analysis of the products.

31

Analysis of P NMR and mass spectra as well as HPLC diagrams (fig. 1 and fig. 2) showed that products A and B in principle had the same composition. In A mainly N ^ P ^ AzCl ^ occurred, while B, 15 in addition to this component mainly contained N ^ AZgClg (namely 5 isomers). The mono / disubstitution ratio could be influenced by varying the mole ratio and reaction time. A reaction mixture as product B was also found starting from N 2 AzCly in a 1: 2 reaction with aziridine in dry diethyl ether.

20 D. Separation Methods.

Both product A and product B were found to be separable by HPLC using a 25% diethyl 6 ^ 75 ^ hexane eluent. The largest fraction of product A is N ^ AzCly (fig. 1, fraction 1). A total of 2.56 g was obtained (yield 50¾). Recrystallization from pentane provided 1.9 g of analysis of pure material; m.p. 68.5-70.0 ° C.

Under similar conditions, product B produced seven fractions (fig. 2):

Fraction no .: (1) N ^ P ^ AzCly 1.54 g 30 (2) V4Az2C16 2§12g ^ (3) "1.26 g (4)" 0.65 g V different isomers (5) N4P4Az2C16 1, 63 g) 8301626 m «.« * -5-

Fraction no .: (6) N, P.Az3C1c 0.57 g 7.

(7) N4P, Az3C15, and various types

Total 8.15 g = 77.8¾ on product B.

Fraction 5 appeared to consist of 2 cone elements, which were subsequently separated again with the same eluent (fig. 3).

Yield.

Fraction no .: 5 *: N ^ AzgClg 0.20 g 5Π: N4P4Az2C16 1.02 g

Total 1.22 g = 75%, calculated on fraction 5 (1.63 g).

* ^ E. Characterization.

Mass spectra.

The mass spectra of both N ^ AzCl ^ and N ^ AZgClg in addition to parent gave peaks of reso. H + = 467 (for 38C1) and Nf = 474 (for 38C1) 15 various chlorine isotope peaks can be seen. The spectra of the different isomeric forms of N-AzgClg were indistinguishable.

Infrared spectra.

N ^ AzCly gave a ring frequency at 1316 (wide) resp. 1279 cm "* (sharp); the" aziridino "band lan at 965 cm" * (sharp). The IRstra 20 of the isomeric compounds N2A2gClg were clearly distinguishable. Ring frequencies ranged from 1310-1334 cm "* (wide) and 1275-1279 cm" * (sharp), respectively. Aziridino bands were visible from 963 to S76 cm * * (sharp).

NMR spectra.

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25 fraction (vonSr (H2} (¾ S H (¾ IS0TO)

WzC17 1 AM2X 8'57 '4> 68 ~ 7'17 27'6 30.6 2.35 22 N4P4Az2C16 2 A2X2 8.37 -1.92 27.9 2.32 22 (1.5) N4P4Az2C16 3 A2X2 8 , 71 -2.61 28.4 2.32 22 (1.5) 'VaAz-CI * 4 AA' XX '11.88 -4.67 2.30 22 (1.3) M M4P4Az2Clg 5U AA1XX1 10, 38 -4.85 2.29 22 (1.3) ^ t ^ AZgClg 5 AMgX 18.80 -6.2 (multipTet) 2.26 * 8.8 9öm.

3IP "chemical shifts" in Dom relative to H3PO4 85%; * H "chemical shifts" in ppm with TMS as reference.

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Claims (5)

1. Aziridine nodules of a tetrameric cyclochlorophosphazene compound, characterized by the formula Ν4Ρ4 ^ _ηΑζη where n = 1,2,3,4,5,6 or 7. 2. A process for the preparation of an aziridino derivative according to claim 1, by aminolysis in a reaction solution of a cyclopolychlorophosphazene compound and working up the reaction mixture, characterized in that a compound of the formula N ^ Clg ^ Azn »in which n = 0,1,2,3,4,5 or 6-1-7 chlorine atoms through an aziridino group substituent and the aziridine derivatives formed from the product obtained after working up the reaction mixture are recovered by HPLC (high performance liquid chromatography). 3. 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 N 4 P 2 Cl 2 N az 2 / aziridine, whether or not in combination with the reaction time. Aziridino derivative of a tetrameric substituted cyclo-phosphazene compound with anti-tumor activity, characterized by the formula ^ 4P4R8-nAzn where n = 1 * 2,3,4,5,6 or 7 and R or equal substituents proposes. 20 Aziridino derivative according to claim 4, characterized in that R is a low hydrolysis sensitive electron donating group. 8301626