Johan C. van de Grampel

NEW DIOXYTETRAETHYLENEOXY MACROCYCLIC CYCLOPHOSPHAZENE DERIVATIVES

Abstract A series of macrocyclic cyclophosphazene containing derivatives of mono-ansa, mono-spiro, spiro-ansa and bis-ansa structure together with polymeric materials have been obtained by the reaction of hexachlorocyclotriphosphazene with tetraethylene glycol in the presence of sodium hydride. Structure determination was based on mass and 31P NMR spectral analysis. The formation of macrocyclic compounds points to a template effect being operative during substitution. The structure of the mono-ansa compound has been confirmed by an X-ray diffraction study. Crystals are triclinic, P 1 , a=7.797(1), b=10.705(1), c=12.336(1), A, α=88.74(1), β=72.404(7), γ=72.15(1)°, Z=2 at 130 K. The refinement converged to R=0.034 for 3434 unique reflections (I ⩾ 2.5σ(I)) and 273 parameters. The basic structure consists of an N3P3 six-membered ring in which two different P atoms are coupled to an O(CH2CH2O)4 chain, forming a 16-membered diphosphaza crown ether.

New designs in inorganic ring systems as anticancer drugs. Antitumor activity of the aziridino (ethyleneimino) derivatives (NPAz2)2NSOX with X = F, Az, Ph

Abstract As a result of a preliminary screening, 3 aziridino (ethylene-imino) derivatives of the thiatriazadiphosphorine ring system with formula (NPAz2)2NSOX (X = F, Az, Ph) were found to exhibit significant antitumor activity. Experiments in vivo were carried out on P388 and L1210 leukemias in female DBA 2 mice and on B16 melanoma in female C57 black mice. Both the toxicity and the antitumor activity are to a large extent determined by the sulphur-bonded group X.

PHASE-II EVALUATION OF TRANS-N3P3AZ2(NHME)4 (AZP) IN NON-SMALL CELL LUNG-CANCER

Trans-N3P3Az2(NHMe)4 (AZP), an aziridinyl substituted cyclophosphazene, was evaluated in a phase II study in non-small cell lung cancer at a dose of .33 mg/m2 i.v. bolus every 3 weeks. There were no tumor responses seen. Cumulative bone marrow toxicity, comparable to other cyclophosphazenes, was noted. AZP is not useful for the treatment of NSCLC.

Bone marrow toxicity of cyclophosphazenes is related to their structure and the treatment schedule

For three aziridinyl-substituted inorganic heterocycles belonging to the cyclophosphazene group, the tendency for cumulative bone marrow toxicity was studied in mice. In a one-day regimen, one of these drugs, gem-N3P3Az4Pyr2 (Az = aziridinyl, Pyr = pyrrolidinyl) (AZX), led to an increased death rate after a repeated injection, the number of bone marrow stem cells (CFUgm) being decreased 5 weeks after the second injection of this drug. In a four-day regimen two drugs, (NPAz2)2 NSOAz (Soaz) and AZX, led to an increased death rate after the second treatment course. In surviving animals leucocyte and thrombocyte counts were significantly lower in the second than in the first course. CFUgm counts were decreased for both drugs. For the third drug, trans-N3P3(Az)2(NHMe)4 (AZP), no evidence of cumulative bone marrow toxicity was demonstrated. It is suggested that whereas cytostatic activity of these compounds seems to be comparable, their tendency to cause cumulative marrow toxicity may vary.

Dalton communications. Preparation, crystal structure and fluxional behaviour of σ-S-bonded palladium and platinum complexes of the Ph4P2N4S2R–(R = Me or But) anions

The reaction of the Ph4P2N4S2R– anions (R = Me or But), generated from 1,5-Ph4P2N4S2 and the appropriate alkyllithium reagent, with cis- or trans-[MCl2(PEt3)2](M = Pd or Pt) produces the complexes [MCl(PEt3)2(Ph4P2N4S2R)](R = Me, M = Pd or Pt; R = But, M = Pt) shown by X-ray crystallography (M = Pd, R = Me) to involve σ-S bonding of the P2N4S2 ring to the metal; variable-temperature 31P NMR spectra of these complexes indicate a significant energy barrier to rotation about the M–S bond of 41–46 kJ mol–1.

PREPARATION, SPECTROSCOPIC AND STRUCTURAL CHARACTERIZATION OF ETA-1-N AND ETA-2-SE,SE' COMPLEXES OF A P2N4SE2 RING

The reaction of 1,5-Ph4P2N4Se2, 1, prepared by the treatment of Ph2PN2(SiMe3)3 with a mixture of SeCl4 and Se2Cl2 in acetonitrile, with [PtCl2(PEt3)]2 gives the adducts [PtCl2(PEt3)]n[η1-N-Ph4P2N4Se2](2, n- 1; 3, n- 2) in which the P2N4Se2 ring is shown by an X-ray structural determination of 3 to contain a transannular Se–Se interaction; the oxidative addition of 1 or 2 to Pt(C2H4)(PPh3)2 produces the corresponding η2-Se,Se′ complexes.

REACTION OF THE LITHIUM ENOLATE OF ACETALDEHYDE, LI(OCH=CH2), WITH CYCLOTHIAPHOSPHAZENES

Reactions of the lithium enolate of acetaldehyde, Li(OCHCH2), with the mixed ring systems [NS(O)Ph]3–n(NPCl2)n(n= 1 or 2) lead to a complete series of vinyloxy derivatives. The vinyloxy group is stable in subsequent substitution reactions using amines as nucleophiles. The compound [NS(O)Ph]NPCl2[NPCl(OCHCH2)] is a useful precursor in polymerization reactions.

Geminal bis[(triphenylphosphoranylidene)amino]cyclotriphosphazenes synthesis: substitution reactions, and nuclear magnetic resonance spectra

Cyclotriphosphazenes bearing an amino ligand are readily converted into the corresponding (triphenylphosphoranylidene)amino (–NPPh3) derivatives by means of an excess of triphenylphosphine–tetrachloromethane in an acetonitrile–triethylamine medium (Appel reaction). Thus prepared, N3P3Cl4(NPPh3)2 reacts with dimethylamine in various solvents according to a geminal substitution pattern; this is an indication of SN1-type reactions, as a result of the strong electron-donating character of the ligands. The ultimate substitution product N3P3(NMe2)4(NPPh3)2, also prepared from N3P3(NMe2)4(NH2)2, is isolated as its HCl or 2HCl adduct, depending on the method of preparation. In both adducts the protons are attached to ring nitrogen atoms, and variable-temperature 1H and 31P n.m.r. measurements show prototropic behaviour at elevated temperatures. Trends within the 31P n.m.r. parameters of the derivatives are discussed in terms of the electron-donating ability of the ligands.

Determination of the antitumor agent SOAz (1,3,3,5,5 Pentakis(Aciridino)-1λ6,2,4,6,3λ5,5λ5 Thia-Triazadiphosphorine-1-Oxide) by a gas chromatographic assay suitable for pharmacokinetic studies in man

SummaryA sensitive method, based on capillary gas chromatography using a thermionic detector, has been developed for the new antitumor agent pentakis(aziridino)-thiatriazadiphosphorine-oxide, (NPAz2)2NSOAz (‘SOAz’), in order to obtain pharmacokinetic data from patients receiving this drug IV in clinical trials. A structural analog of SOAz, (NPAz2)2NSOPh (‘SOPh’), was used as an internal standard.The detection limit of SOAz with this method was 0.01 mg/l for serum and 0.04 mg/l for urine.The coefficient of variation (n=10) was 6,0% at 1.5 mg/l in serum and 1.6% at 75.0 mg/l in urine.Analytical recoveries averaged 89.9% from serum and 86.7% from urine. In two patients treated with subtoxic doses of SOAz (55 mg/m2), serum levels were found ranging from 3.0 to 0.16 mg/l at 10 min and 12 h, respectively, after administration.This assay seems to be useful for determining SOAz in samples from patients receiving subtoxic doses of SOAz.

A propene-substituted cyclotriphosphazene : Synthesis, characterization and polymerization

The elimination reaction of the sulfonium-substituted chlorocyclotriphosphazene N 3 P 3 Cl 4 Pr i (CMe 2 OSO 2 Me) with 1,8-diazabicyclo[5.4.0]undec-7-ene afforded a new olefin-substituted chlorocyclotriphosphazene, N 3 P 3 Cl 4 Pr i (CMe CH 2 ), and an ansa derivative with formula N 3 P 3 Cl 3 Pr i (CMe 2 CHCMeO). The crystal structures of the three compounds were determined. The sequence of N–P bond lengths in the molecules can be explained from the difference in group electronegativity of the phosphorus centres. For N 3 P 3 Cl 4 Pr i (CMe 2 OSO 2 Me) two crystallographic independent molecules are present in the asymmetric unit. In N 3 P 3 Cl 3 Pr i (CMe 2 CHCMeO) the bridge between two phosphorus atoms compresses the inorganic ring, which is reflected in a large deviation of 0.563(2) A of one of the N atoms from the least-squares plane through the remaining ring atoms. This distortion is accompanied by a contraction of the non-bonded P · · · P distances. The propene derivative has been used in radical copolymerization with methyl methacrylate and styrene. A maximum incorporation of 18 mol % was achieved with styrene as comonomer.