ISSN:
1573-0646
Keywords:
4-hydroxy-cyclophosphamide
;
cis- and trans-4-sulfoethylthio-cyclophosphamide
;
synthesis
;
stereochemistry
;
hydrolytic behavior
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary The primary metabolite of cyclophosphamide (CP, 1), i.e. 4-hydroxy-CP 2, has high pharmacological activity, but it is a very unstable compound. Chemical approaches to the stabilization involved in the substitution of the hydroxy group at the C 4-position, especially by a sulfoalkylthio-moiety. Within this new class of compounds ASTA Z 7557 (2-(bis-(2-chloroethyl))-amino-cis-4-((2-sulfoethyl)-thio)-tetrahydro-2H-1,3,2-oxazaphosphorine-r-2-oxide cyclohexylamine salt, i.e. cis-4-sulfoethylthio-CP, cis-13) was chosen for further evaluation. Cis-13 was synthesized by condensation of compound 2 and 2-mercapto-ethanesulfonic acid cyclohexylamine salt 14 in aqueous acetone yielding the cis-isomer with high stereoselectivity. It is a white crystalline powder, m.p. 126–134°C, stable at room temperature, with a solubility of 16% in water. The stereochemistry was confirmed by NMR-data and X-ray diffraction. In 0.07 M phosphate buffer at pH 7 and 37°C cis-13 isomerizes to the epimer trans-13, equilibrating at a cis-trans-ratio of 59 to 41 within less than 5 minutes. Simultaneously a rapid initial hydrolysis occurs to 2 and 14 followed by a time period with lower degradation due to the decomposition of 2. The rate of release of 2 increases with decreasing concentration and especially by addition of an oxidant. It could be retarded by addition of the corresponding thiol mesna, sodium 2-mercapto-ethanesulfonate 15, or of another thiol. In the presence of 3-mercapto-propane sulfonate 13 yielded 4-(3-sulfopropyl)thio-CP17. With changing pH values from 2 to 9, the lowest hydrolytic speed was observed at pH 4.0 to 4.3. For clinical use cis-13 is prepared as a lyophilisate containing additional sodium citrate buffer to guarantee this optimal pH value.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00232342
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