FR2706463A1 - New substituted aziridinospirodiazaalkylcyclotriphosphazene derivatives, their process of preparation and their use as medicaments - Google Patents

Abstract

New substituted aziridinospirodiazaalkylcyclotriphosphazene derivatives corresponding to the general formula I: The invention also relates to the application of these compounds in therapeutics and to the processes of preparation.

Description

The present invention, carried out at the Pierre Fabre Research Center, was

for object of

  new chemical compounds, their preparation and their application in therapeutics.

  The compounds of the invention have the general formula 1: ## STR2 ## Ar-R N-, op O> N

N HN

1

  in which: Ar represents either a phenyl radical necessarily substituted with one () or more R substituents, a naphthyl radical which may or may not be substituted by one or more substituents R, or a pyridyl radical, which may or may not be substituted by one or more R.sub.R substituents; is a linear or branched C1-C6 alkyl group, a halogen atom, a hydroxy group, a nitro group, a sulfamoyl group, a linear or branched C1-C16 alkoxy group, a -NR1R2 group or a -O group - (CH2) n-NRIR2. R1 and R2, independently of each other, represent a hydrogen atom or a linear or branched C1-C4 alkyl group or, taken together, a chain

C3 to C5 alkyl.

  n can take the values 2, 3, 4 or 5.

  The compounds of general formula 1 can be synthesized in two stages according to the following reaction scheme starting from the diamines 3 suitably substituted, prepared

  according to conventional methods described in the literature.

  Synthetic scheme of the compounds of general formula I ClCl ClCl

N - ',, N, NP

  C! P., P-CI. . N..CH, * R CF-P, See above. _aratonr 'eahooyltpopaèeè adaie3 4-fetu ot Ci N N c "N')

  o Ar and R are defined as above.

  The reaction between hexachlorocyclotriphosphazene (and diamine 3 is carried out either: in a monophasic medium at a temperature of between -10 ° C. and the reflux temperature of the reaction medium, in a solvent such as tetrahydrofuran (THF) or toluene , acetonitrile or ethyl ether

  presence of an organic base such as a tertiary amine.

  in biphasic medium comprising an aqueous solution of a mineral base such as sodium hydroxide, potassium hydroxide or a sodium or potassium carbonate and an organic solvent such as ethyl ether, toluene or. methylene chloride and at a temperature between 0 C and the reflux temperature

of the reaction medium.

  This gives, after extraction of the reaction medium and purification, the compound of general formula 4 which, by reaction with an excess of aziridine () and optionally an organic base such as triethylamine at a temperature of between -10 ° C. and 50 C and

  in a solvent such as THF, gives the compound of general formula 1.

  Elemental analyzes and IR and NMR spectra of proton and phosphorus confirm

  the structure of the compounds obtained according to the invention.

  The following examples illustrate the invention without, however, limiting its scope.

EXAMPLES

Example I

s

  7 - [(4-sulfamoylphenyl) methyl-2,2,4,4-tetrachloro-2,2,4,4-tetrahydroI, 3,5,7,11-

  pentaaza-2,4,6,5-triphosphaspiro- [5,5] -undeca-1,3,5-triene: 4eq (Ar = Phenyl, R = 4-

SO2NH2).

  In a 250 ml flask, 5.5 g (0.0158 mol) of hexachlorocyclotriphosphazene (2), 70 ml of THF and 12 ml (0.0864 mol) of triethylamine are introduced. With stirring and at 20 ° C,

  introduced in three times and in 15 minutes, 3.5 g (0.0144 mol) of N (4-sulphamoylbenzyl) -1,3-

  propanediamine (3: Ar = Phenyl, R = 4-SO2NH2). Stirring is maintained for 5 h and then the reaction medium is filtered. The solution is evaporated and the crystalline residue is chromatographed by passage through a silica column (70 g) eluting with a mixture of cyclohexane and ethyl acetate (50% / 50%). The product thus purified is

  triturated in 30 ml of diisopropyl ether and then filtered, rinsed and dried under vacuum at 30 ° C.

  3.7 g of compound is thus obtained in the form of white crystals.

Yield: 50%.

PF: 180 C.

  1H NMR (CDCl3): 1.67 (quint, 2H, C-CH2-C); 2.9 to 3.1 (m, 4H, N-CH 2 -C); 3.98 (d, 2H, N-CH 2 -Ar, JP = 10.33Hz); 5.52 (broad, 1H, NH); 7.36 (s, 2H, NH 2); 7.55 (d, 2H, CH

  arorm, JM = 8.28Hz); 7.81 (d, 2H, CH arom, JF = 8.28 Hz).

  Analysis% Calc C: 23.18 H: 2.92 N: 16.22 CI: 27.37 elemental:% Tr. C: 23.48 H: 2.90 N: 15.85 Cl: 27.59

  7 - [(4-sulfamoylphenyl) methyl-2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-

  1,3,5,7,11-pentaaz24,6S-triphosphaspiro- [5,5] -undeca-1,3,5triene: the (Ar = Phen

nyl, R-4-SO2NH2).

  In a 125 ml jacketed reactor, 3 g (0.00579 mol) of compound 4, 50 ml of THF and 4.85 ml (0.0347 mol) of triethylamine are introduced. The reaction medium is maintained at -10 ° C. by circulation of brine in the jacket. Under stirring, a solution composed of 3 rnl (0.0588 mol) of aziridine and 10 ml of THF is introduced into the reactor in minutes. Stirring is maintained at -10 ° C. and then at room temperature for 24 hours. The reaction medium is filtered, the solution is evaporated and the crystalline residue is chromatographed by passage through a silica column (12 g), eluting with a mixture consisting of chloroform and methanol in the proportions: 97 / o% / 3%. The product as well

  purified was recrystallized from 45mi of TiF, filtered, rinsed and dried under vacuum at 30 ° C.

  2.15 g of compound la are thus obtained in the form of white crystals containing one mole

of water and 0.1 moles of THF.

Yield: 65%.

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PF: 132 C.

  1H NMR (DMSOd6): 1.49 (broad, 2H, C-CH 2 -C); 1.76 to 1.95 (m, 16H, N (CH 2) 2); 2.6 to 3, I (m, 4H, N-CH 2 -C); 3.88 (d, 2H, N-CH 2 -Ar, JPH = 7.63Hz); 4.05 (s, 1H, Nil); 7.31 (s,

  2H-, NH 2); 7.55 (d, 2H, CH armin, JHH = 8.24 Hz); 7.78 (d, 2-H, CH arom, JHH = 8.24 Hz).

  Analysis% Calc C: 38.74 H: 5.98 N: 24.55 Elemental:% Tr. C: 39.09 H: 5.95 N: 24.29 Water Determination: 3.3%

Example 2

  7- [(3,4,5-triMethoxyphenyl) methyl-2,2,4,4-tetrachloro-2,2,4,4-tetrahydro-1,3,5,7,11-

  pentaaza-2,4,6A5-triphosphaspiro [5,5] -undeca-1,3,5-triene: 4_p (Ar = Phenyl, R = 3,4,5-triMethoxy).

  In a 100 ml flask, 1.6 g (0.00629 mol) of N- (3,4,5-trimethoxybenzyl) are introduced.

  1,3-propanediamine (3: Ar = phenyl, R = 3,4,5-triMethoxy), 25 ml of ethyl ether and 7 ml (0.0157 mole) of aqueous sodium hydroxide solution. The temperature of the reaction medium is brought to 0 ° C. and then 2.4 g (0.00692 mol) of hexachloro cyclotriphosphazene (W. The stirring is maintained at 0 ° C. for 30 minutes and then at 20 ° C. for 2 hours. The two phases are separated, the aqueous phase is extracted with 20 ml of ethyl ether The two combined organic phases are washed with 20 ml of water and then with 20 ml of brine.On drying on magnesium sulphate, the ethyl ether is evaporated and the crystalline residue is triturated in After filtration, rinsing and drying under vacuum at 30 ° C., 30 ml of hexane are obtained.

  2.3 g of compound 40 as white crystals.

Yield: 70%.

PF 117 C

  1H NMR (CDCl3): 1.79 (quint, 2, C-CH2-C); 2.3 (broad, 1H, Nil); 3 to 3, 13 (m, 2H, N-

  CH2-C); 3.24 to 3.37 (m, 2H, N-CH 2 -C); 3.84 (s, 3, 4-CH 3 O); 3.88 (s, 6H, 3 and 5 CH 3 O);

  3.9 (cd, 2H, N-CH2-arom); 6.62 (s, 2H, arom).

  Analysis% Calc C: 29.51 H: 3.81 N: 13.23 Cl: 26, 80 elemental:% Tr. C: 28.94 H: 4.03 N: 12.68 Cl: 26.25 [(3,4,5-TriMethoxyphenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) 2,2,4,4-tetrahydro-1,3,7,11-pentaaza-2 , 4,6-S-triphosphaspiro [5,5] undeca-1,3,5-triene: 1D (Ar = Phenyl,

R = 3,4,5-triMethoxy).

  In a 125 ml jacketed reactor is charged with 2.2 g (0.00415 mol) of THF compound ml and 3.47 ml (0.0249 mol) of triethylamine. The reaction medium is maintained at -10 ° C. by circulation of brine in the jacket. With stirring, a solution consisting of 2.13 ml (0.0412 mol) of aziridine and 10 ml of THF is introduced into the reactor in minutes. The stirring is maintained lh at -10 C and then 24h at room temperature. The reaction medium is filtered, the solution is evaporated and the crystalline residue is chromatographed by passage through a silica column (12 g) eluting with a mixture of chloroform of methanol and ammonia in the proportions: 97.5% / 2, 25% / 0.25%. The product thus purified is stirred for 1 h in 50 ml of a mixture of diisopropyl ether and ethyl acetate (80% / 20%) before being filtered, rinsed with 15 ml of

  same mixture and dried under vacuum at 30 C.

  1.2 g of compound 1u are thus obtained in the form of white crystals.

Yield: 52%.

PF: 164 C.

  1H NMR (CDCl3): 1.59 (quint, 2H, C-CH2-C); 1.95 to 2.15 (m, 16H, N (CH 2) 2); 2.32 (t,

  1H, N); 2.85 to 2.99 (sex, 2H, N-CH 2 -C); 3.05 to 3.25 (m, 2H, N-CH 2 -C); 3, 82 (s, 3H, 4-

  MeO); 3.85 (s, 6H, 3 and 5 MeO); 3.88 (d, 2H, N-CH2-arom, JPH = 7.1Hz); 6.62 (s, 2H, arom). Analysis% Calc C: 45.40 H: 6.53 N: 22.69 Element:% Tr.C: 45.76 H: 6.53 N: 22.95

Example 3

  7- [1-naphthylmethyl] -2,2,4,4-tetrachloro-2,2,4,4-tetrahydro-2,4-1,3,5,7,11pentnaza,

  655-triphosphaspiro- [5.5] -undeca-1,3,5-triene: 4u (Ar = Naphtyl, R = Ht).

  In a 250 ml flask, 6 g (0.0209 mol) of N- (1-naphthylmethyl) -1,3-propanediamine dihydrochloride (3: Ar = Naphtyl, R = H), 100 ml of ethyl ether and

  ml (0.125 mole) of aqueous sodium hydroxide solution. The temperature of the reaction medium is brought to 5 ° C. and then 8 g (0.0209 mol) of hexachlorobenzene are introduced.

  cyclotriphosphazene (1). Stirring is maintained 15 minutes at 5 C and 4 hours at 20 C. The two phases are separated, the aqueous phase is extracted with 50 ml of ethyl ether. The two organic phases combined are washed with 50 ml of water and then with 50 ml of brine. After drying over magnesium sulphate, the ethyl ether is evaporated and the oily residue is

  crystallized by trituration in a mixture consisting of 60 ml of hexane and 5 ml of diisopropyl ether. After filtration, rinsing with 20 ml of hexane and drying under vacuum at 30 ° C., 8.07 g of compound 4u are obtained in the form of white crystals. Yield: 79 / o. Mp 118 C.35 1H NMR (CDCl3): 1.66 (quint, 2H, C-CH2-C); 1.8 (broad, 1H, NH); 3.00 (sex, 2H, N-

  CH2-C); 3.29 (sex, 2H, N-CH 2 -C); 4.40 (d, 2H, N-CH 2-arom); 7.39-7.63 (m, 4H, arom); 7.80 to 7.90 (m, 2H, arom); 8.36 (d, 1H, arom).

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  Analysis% Calc C: 34.38 H: 3.30 N: 14.32 Cl: 29.00 elemental:% Tr. C: 34.80 H: 3.35 N: 14.04 Cl: 28.69

  7- [1-Naphthylmethyl] 2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1, 3,5,7,1-penta

  aza-2,4,6,5-triphosphaspiro [5,5] -undeca-1,3,5-triene: (Ar = Naphtyl, R = t). In a 125 ml jacketed reactor, 3 g (0, 00613 mol) of compound 4u, 45 ml of THIF and 5.12 ml (0.0368 mol) of triethylamine were introduced. The reaction medium is maintained at -10 ° C. by circulation of brine in the jacket. Under stirring, a solution composed of 3.17 ml (0.0613 mol) of aziridine and 10 ml of THF is introduced into the reactor in minutes. The stirring is maintained at 10 ° C. and then 48 hours at room temperature. The reaction medium is filtered, the solution is evaporated and the oily residue is chromatographed by passage through a silica column (25 g) eluting with a mixture of chloroform of methanol and ammonia in the proportions: 97.5% / 2.25% / 0.25%. The product thus purified crystallizes after evaporation and is stirred for 1 h in 40 ml of a mixture of diisopropyl ether and ethyl acetate (80% / 20%) before

  to be filtered, rinsed with 15 ml of the same mixture and dried under vacuum at 30 ° C.

  1.5 g of compound are thus obtained in the form of white crystals.

Yield: 47%.

PF: 171 C.

  1 H NMR (CDCl 3): 1.49 (broad, 2H, C-CH 2 -C); 2.06 to 2.20 (m, 16H, N (CH 2) 2); 2.40 (t, 1 H NH); 2.94 (sex, 2H, N-CH 2 -C); 3.22 (m, 2H, N-CH 2 -C); 4.40 (d, 2, N-CH 2-arom);

  7.35 to 7.58 (min, 4H, arom); 7.73 to 7.87 (nl, 2-H, arom); 8.58 (d, 1H, arom).

  Analysis% Calc C: 51.26 H: 6.26 N: 24.45 elemental:% Tr. C: 50.86 H: 6.51 N: 24.07

Example 4

  7- [4-Pyridylmethyl] -2,2,4,4-tetrachloro-2,2,4,4-tetrahydro-1,3,5,7,1pentaaza-2,4,6,5

  -triphosphaspiro- [5.5] -undeca-1,3,5-triene: 4v (Ar = 4-Pyridyl, R = H).

  In a 250 ml flask, 4.9 g (0.0296 mol) of N- (4-pyridylmethyl) -1,3-

  propanediamine (Ar = 4-Pyridyl, R = H), 50ml of ethyl ether and 89ml (0.089 mol) of aqueous sodium hydroxide solution. The temperature of the reaction medium is brought to 5 ° C. and then 13.3 g (0.0384 mol) of hexachlorocyclotriphosphazene () are introduced. The stirring is maintained for 15 minutes at 50 ° C. and then for 2 hours at 20 ° C. 300 ml of ethyl acetate are then added to the mixture.

  the reaction medium is stirred at room temperature for 30 minutes, the two phases are separated and the aqueous phase is extracted twice with 30 ml of ethyl acetate. The three combined organic phases are washed with 50nl of water and then with 50ml of brine. After drying over magnesium sulphate, the solution is evaporated and the oily residue is crystallized by trituration in a mixture consisting of 40 ml of hexane and 15 ml of diisopropyl ether.

  After filtration, rinsing with 20 ml of hexane and drying under vacuum at 30 ° C., 7.9 g of

  4v compound in the form of white crystals.

Yield: 61%.

PF: 192 C.

  1H NMR (CDCl3): 1.82 (quint, 2H, C-CH2-C); 2.99 (broad, 1H, NH); 3.02 to 3.15 (m, 2H, N-CH 2 -C); 3.24 to 3.41 (m, 2H, N-CH 2 -C); 4.02 (d, 2H, N-CH 2 arom); 7.41 (d, 2H, arom);

8.60 (d, 2R, arom).

  Analysis% Calc C: 24.57 H: 2.98 N: 19.10 Cl: 32.23 elemental:% Tr. C: 24.96 H: 2.96 N: 18.75 Cl: 31.91

  7- [4-Pyridylmethyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,11-penta

  aza-2,4,6X5-triphosphaspiro [5,5] -undeca-1,3,5-triene: 1v (Ar = 4Pyridyl, R = H11).

  In a 125 ml jacketed reactor, 3 g (0.00682 mol) of compound 4 v, 45 ml of THF and 5.70 ml (0.0409 mol) of triethylamine are introduced. The reaction medium is maintained at -10 ° C. by circulation of brine in the jacket. With stirring, a solution composed of 3.52 ml (0.0681 mol) of aziridine and 10 ml of THF is introduced into the reactor over 10 minutes. Stirring is maintained lh at -10 C and 48h at room temperature. The reaction medium is filtered, the solution is evaporated and the crystalline residue is chromatographed by passage through a silica column (25 g), eluting with a mixture of chloroform of methanol and ammonia in the proportions: 97.5% /

  2.25% / 0.25%. The product thus purified is recrystallized from 35 ml of ethyl acetate, filtered, rinsed and then dried under vacuum at 30 ° C.

  1.33 g of lv compound are thus obtained in the form of white crystals. Yield: 42%. Mp: 172 C.25 1H NMR (CDCl3): 1.62 (quint, 2H, C-CH2-C); 1.99 to 2.12 (m, 16K, N (CH 2) 2); 2.36 (t,

  1H, Nil); 2.90 to 3.02 (m, 2H, N-CH 2 -C); 3.16 to 3.26 (m, 2H, N-CH 2 -C); 3.98 (d, 2H, N-CH2-arom); 7.36 (d, 2H, arom); 8.53 (d, 2H, arom).

  Analysis% Calc C: 43.78 H: 6.27 N: 30.03 elemental:% Tr. C: 44.04 H: 6.22 N: 29.60 Table I below summarizes the main synthesized products which illustrate the invention

  without limiting its scope.

Table 1

  Compound n Ar R PF (C) Phenyl 2-Me 135 lb Phenyl 3-Me 136 lc Phenyl 4-Me 127 ild Phenyl 4-C (Me) 3 143 Phenyl 2-Cl 139 if Phenyl 3-Cl 151 lg Phenyl 4-CI 124 lh Phenyl 4-F 158 l Phenyl 4-Br 128 lj Phenyl 4-OH 103 lk Phenyl 4-OMe 110 and Phenyl-O (CH2) 3 Me 144 lm Phenyl-O (CH2) 7Me 100 ln Phenyl 4-O (CH 2) 15Me 86 L Phenyl 3-O (CH 2) 15Me 91 1p Phenyl 3,4,5-triOMe 164 1 Phenyl 4-SO 2 NH 2 132 Phenyl 4-NO 2 169 Is Phenyl 4-NMe 2 135 Phenyl 4- O (CH 2) 4 N (Me) 2 118 1-Naphthyl H 171 1v 4-Pyridyl H 172

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PHARMACOLOGICAL ACTIVITY

TEST IN VITRO

  The compounds of the invention were tested in vitro, at a concentration of 100 μM, on three chemosensitive cancer cell lines: MXT, J82 and T24, and on their respective variant resistant to a mixture of three cytotoxics: an alkylating agent, an intercalator and a

vinca alkaloid (Table 2).

  The development of these lines has been described by O. Pauwels and R. Kiss in Cytometry

12: 388-397 (1991).

  The MTT test performed on these lines was described by C. Etiévant and coil in Anticancer

Research 11: 305-312 (1991).

  The results are expressed by: a PIM: Percentage of Mean Inhibition of cell growth of the three lines put in the presence of the test compound, a esm: standard deviation to the average,

  a S / R: report of PIM Sensitive to PIM Resistant.

Table 2

  Compound n Sensitive lines Resistant lines S / R ______ PIM +/- esm PIM +/- esm if 75.8 +/- 6.9 33.0 +/- 5.0 2.3 i lg 69.1 +/- 7.3 35.8 +/- 6.8 1.9 li 63.9 +/- 9.6 31.0 +/- 6.7 2.1 Lan 97.5 +/- 0.1. - 94.7 +/- 0.4 1 o 97.6 +/- 0.1 93.3 +/- 1.3 1 The results in Table 2 show the cytotoxic activity of some derivatives, taken as

  examples, on chemosensitive cell lines and their respective chemoresistant variant.

TESTS IN I7VO

  The activity of the compounds of the invention has also been tested in vivo on the model of

  P 388 murine leukemia (Table 3) and the MXT mammary adenocarcinoma model (Table 4).

  Model P 388 Model P 388 consists of injecting murine P 388 leukemia cells into the peritoneal cavity of mice and then treating the animals (batch of 10 mice) with a compound in order to determine the survival gain, possibly induced by the molecule, compared to the

  survival of untreated animals (control lot).

  The results obtained for some derivatives of general formula 1, taken as examples, are grouped together in Table 3 and are expressed by the ratio, expressed as a percentage,

  between the median survival time of the batch of treated mice and that of the control lot (T / C).

  The experiment is stopped when T / C is equal to 300 and the surviving animals are counted (Long Survivors: LS.). Activity is considered significant

  when the T / C is greater than 130.

Table 3

Compound No. Posology T / C LS.

  lb 4 x 40mg / kg> 300 6 4 x 80mg / lcg> 300 8 If 4 x 40mg / kg> 300 6 4 x 80mg / kg> 300 8 I4 x 120mg / kg> 300 10 _________ 4 x 160mg / kg> 300 6 lx 4 x 80mgkg> 300 6 4 x 120mg / kg> 300 9 lk4 x 40mg / kg> 300 6 4 x 80mg / kg> 300 8 Table 3 shows the very high activity of the compounds taken as examples on the murine leukemia model P 388.30 Model MXT The model of MXT mammary adenocarcinoma is a solid tumor particularly insensitive to anticancer agents [CS Watson, D.Medina, JH Clark, Cancer Res., 37, 3344 (1977); W.T. Bradner and C.A. Claridge, "Antineoplastic Agents", Wiley-Interscience

  (1984); T. W. Redding and A.V. Schally, Proc. Natl. Acad. Sci. U.S.A., 80, 1459 (1983)].

  In this model, B6D2F1 mice are grafted by the subcutaneous injection of a

  tumor fragment of about 10 mm3 from an MXT tumor. From the 17th day after the graft (J17), the product to be tested is administered, i.p., to a batch of 10 mice.

  Injections take place at: D17, D19, D21, D24, 126 and D28 for the protocol at 6 x 40mg / kg and at

  J17, J19, J21, J24, J26, J28, J3 1, J33 and J35 for the protocol at 9 x 40mg / kg.

  The results obtained for some derivatives of general formula 1 taken as examples,

are grouped together in Table 4.

  The MXT test provides two types of results expressing: a by the effect exerted by the studied molecule on the tumor growth, at the fifth week. This effect is expressed by comparing the tumor surface of the treated animals with that of the animals in the control lot. The result is expressed as a percentage of Tumor Regression (RT.) Followed by the significance

  statistic (S.S.), ** = p <0.01, *** = p <0.001.

  a by the survival gain of the animals treated, induced by the compound, compared to the survival of the animals of the control batch. This effect is expressed as the ratio, expressed as a percentage, between the median lot survival time

  of treated mice and that of the Control (T / C) batch.

  Table 4 Compound No. Posology T / C R T. $ .5 | i lbs 6 x 40mg / kg 129 47 *** _ _ _ 9 x 40mg / kg 142 57 * lc6 x 40rng / kg 125 52 *** 9 x 40mg / kg 125 46 *** _lg 6 x 40mg / kg 133 54 *** __25_9 x 40mg / kg 95 49 *; lr 6x 40mg / kg 131 44 ** 9 x 40mg / kg 131 39 ** Table 4 shows strong tumor regressions, induced by the few compounds

  taken as examples, on the model of mammary adenocarcinoma MXT.

  In view of their pharmacological properties, the compounds of the invention can

  be used in human therapy in the treatment of cancer pathology.

  Pharmaceutical preparations containing these active ingredients can be

  form for oral, intravenous or subcutaneous administration.

Claims (18)

CLAIMS (I) New substituted aziridino spirodiazaalkylcyclotriphosphazenes derivatives corresponding to the general formula 1: ## STR1 ## where R is a substituted or unsubstituted naphthyl radical 21) or more substituents R.sup.1 is a naphthyl radical which may or may not be substituted by one or more substituents R, or a pyridyl radical, which may or may not be substituted by one or more substituents R.R represents a linear or branched C1-C6 alkyl group, a 2.5 atom halogen, hydroxy, nitro, sulfamoyl, linear or branched C1-C16 alkoxy, -NR1R2 or -O- (CH2) n-NRIR2. R1 and R2, independently of each other, represent a hydrogen atom or a linear or branched C1-C4 alkyl group or, taken together, a C3-C5 alkyl chain. n can take the values 2, 3, 4 or 5. (2) 13 Compounds of general formula I according to claim 1, characterized in that they are chosen from:   7 - [(2-Methylphenyl) methyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,1 -   2,4,6A-5-pentaaza-triphosphaspiro [5S] -undecane-1,3,5-triene.   7 - [(3-Methylphenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,11 -   2,4-pentaaza, 6X5-triphosphaspiro [5,5] -undecaned 1,3,5-triene.   7 - [(4-Methylphenyl) methyl] -2,2,4,4-tetrahydro (1-aziridinyl) -2,2,4,4tétrahydro-1,3,5,7,11-   pentaaza7-2,4,6.5-triphosphaspiro- [5,5] -undéca-1,3,5-triene.   7 - [(4- (triethylmethyl) phenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-   1,3,5,7, 1-pentaaqa-2,4,6X5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 - [(2-Chlorophenyl) methyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7, 1 -   2,4,6,5-pentaaza-triphosphaspiro [5,5] -undecaned 1,3,5-triene.   7 - [(3-Chlorophenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,11 -   pentaaza7-2,4,6X5-triphosphaspiro- [5,5] -undecaned 1,3,5-triene.   7 - [(4-Chlorophenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,11 -   pentaaza-2,4,6,5-triphosphaspiro [5,5] undunda-1,3,5-triene.   7 - [(4-Fluorophenyl) methyl] -2,2,4,4-tetrahydro (1-aziridinyl) -2,2,4,4tétrahydro-1,3,5,7,11-   2,4,6,5-pentaaza-triphosphaspiro [5,5] -undecaned 1,3,5-triene.   7 - [(4-Bromophenyl) methyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,1-   pentaazas-2,4,6X5-triphosphaspiro- [5,5] -undéca-1,3,5-triene. 7 - [(4Hydroxyphenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1, 3,5,7,   1-pentaaza-2,4,6X5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 - [(4-Methoxyphenyl) methyl] -2,2,4,4-tetrahydro (1-aziridinyl) -2,2,4,4tétrahydro-1,3,5,7,   1 1-pentaaza-2,4,6,5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 - [(4-Butyloxyphenyl) methyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,   11-pentaaza-2,4,6X5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 - [(4-Octyloxyphenyl) methyl] -2,2,4,4-tetra- (aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,   1 1-Pentaaza-2,4,6X5-triphosphaspiro [5,5] undunda-1,3,5-triene.   7 - [(4-Hexadecyloxyphenyl) methyl] -2,2,4,4-tetra (2-aziridinyl) -2,2,4,4-tetrahydro-1,3,7,11-pentaaza-2,4, 6A 5-triphosphaspiro [5,5] -undecaned 1,3,5-triene. 7 - [(3-Hexadecyloxyphenyl) methyl] -2,2,4,4-tetra (aziridinyl) -2,2,4,4-tetrahydro-1,3,7,11-pentaaza-2,4,635 triphosphaspiro- [5,5] -undéca-1,3,5-triene. 7 - [(3,4,5-tri-methoxyphenyl) methyl] -2,2,4,4-tetra- (aziridinyl) -2,2,4,4-tetrahydro-1,   3,5,7,1-pentaaza-2,4,6,5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 [(4-sulfamoylphenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,   3,5,7,1-pentaaza-2,4,6,5-triphosphaspiro [5,5] -undeca-1,3,5-triene.   7 - [(4-Nitrophenyl) methyl] -2,2,4,4-tetra (1-aziridinyl) -2,2,4,4-tetrahydro-1,3,5,7,11 -   pentaaza-2,4,6X5-triphosphaspiro- [5,5] -undéca-1,3,5-triene. 7 - [(4-dimethylaminophenyl) methyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro-1,   3,5,7,1-penta-2,4,6-triphosphaspiro [5,51-undeca-1,3,5-triene.   7 - [(4- [4- (dimethylamino) butyloxy] phenyl) methyl] -2,2,4,4-tetra- (1aziridinyl) -2,2,4,4-   tetrahydro-1,3,5,7,1-pentaaza-2,4,6,5-triphosphaspiro [5,5] undeca-1,3,5-triene.   7- [1-Naphthylmethyl] -2,2,4,4-tetra- (1-aziridinyl) -2,2,4,4-tetrahydro1,3,5,7,11 -penta   aza-2,4,6X5-triphosphaspiro [5,5] -undecaned 1,3,5-triene.   7- [4-Pyridylmethyl] -2,2,4,4-tetra (1-azidinyl) -2,2,4,4-tetrahydro-1,3,5,7,1-penta   aza-2,4,6X5 triphosphaspiro- [5,5] -undéca-1,3,5-sorted. (3) 15   Process for the preparation of compounds of general formula 1, according to claims 1   and 2, characterized in that a compound of general formula 4 is reacted with aziridine in the presence of a base according to the following scheme: Cl Cl N 'p'. 'p'. r-1-p CH2-Ar-RPI C2rR N 'N / N' N Ci - P.P-- + NHL N Ci - P, p. CI NI! HN <HN 41   o Ar and R are defined as before.   (4) Process for the preparation of compounds according to claim 3, characterized in that the reaction between a compound of general formula 4 and aziridine takes place in a solvent such as tetrahydrofuran in the presence of an excess of aziridine and optionally in the presence of an organic base such as triethylamine,   preferably at a temperature between -10 OC and 50 C.   (5) As novel medicaments useful in human therapy, particularly in the treatment of cancerous pathology, the compounds defined according to one of the claims 1 and 2.   (6) Pharmaceutical composition characterized in that it contains as a principle   active at least one compound according to one of claims 1 and 2, associated with a vehicle pharmaceutical acceptable.