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Pharmaceutisch Weekblad

, Volume 2, Issue 1, pp 547–556 | Cite as

Photochemical decomposition of 1,4-benzodiazepines

Quantitative analyses of decomposed solutions of chlordiazepoxide and diazepam
  • P. J. G. Cornelissen
  • G. M. J. Beijersbergen van Henegouwen
Original Articles

Abstract

By labelling chlordiazepoxide and diazepam with14C it was possible to follow quantitatively the photochemical decomposition of these compounds. It was found for chlordiazepoxide that the wavelength of light does not determine the character, but only the concentrations of the products formed.

On irradiation of chlordiazepoxide, dissolved in methanol or methanol-water (pH=7.4), an oxaziridine is formed, which is subsequently converted into a quinoxaline and a benzoxadiazocine derivative. However, by irradiation in the presence of glutathione, the rate of decomposition is increased and the scheme is completely changed. Instead of the quinoxaline and the benzoxadiazocine derivative, the reduced form of chlordiazepoxide and a conjugate are formed. It was established that the oxaziridine, the first photoproduct of chlordiazepoxide, reacts spontaneously with glutathione at room temperature without light.

On irradiation of diazepam, dissolved in methanolwater (pH=7.4), with light of 300 nm a benzophenone derivative is the only decomposition product, while with light of 254 nm also a quinazoline derivative is formed as a minor product. With methanol as solvent (λ=254 nm) the concentration of the products formed is strongly influenced, quinazoline derivatives become the main products and the benzophenone derivative a minor product.

Keywords

Public Health Methanol Internal Medicine Glutathione Diazepam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bell, S. C., C. Gochman andS. J. Childress (1962b) Some analogs of chlordiazepoxide,J. Med. Pharm. Chem. 5, 63–69.Google Scholar
  2. Bell, S. C., T. S. Sulkowski, C. Gochman andS. J. Childress (1962a) 1,3-Dihydro-2H-1,4-benzodiazepine-2-ones and Their 4-Oxides,J. Org. Chem. 27, 562–566.Google Scholar
  3. Bellamy, F., andJ. Streith (1976) The Photochemistry of Aromatic N-oxides. A Critical Review,Heterocycles 4, 1391–1447.Google Scholar
  4. Beuersbergen van Henegouwen, G. M. J. (1977) Relevantie van fotochemie binnen de farmacie,Pharm. Weekblad 112, 1101–1106.Google Scholar
  5. Black, D. St. C., andK. G. Watson (1973) Nitrones and Oxaziridines VI. Deoxygenation of oxaziridines by sulphur-containing nucleophiles,Australian J. Chem. 26, 2159–2176.Google Scholar
  6. Cornelissen, P. J. G., G. M. J. Beijersbergen van Henegouwen andK. W. Gerritsma (1978) Photochemical Decom-position of 1,4-Benzodiazepines. Diazepam,Intern. J. Pharmac. 1, 173–181.Google Scholar
  7. Cornelissen, P. J. G., G. M. J. Beijersbergen van Henegouwen andK. W. Gerritsma (1979) Photochemical Decomposition of 1,4-Benzodiazepines. Chlordiazepoxide,Intern. J. Pharmac. 3, 205–220.Google Scholar
  8. Cornelissen, P. J. G., andG. M. J. Beijersbergen van Hene-Gouwen (1979) Photochemical Decomposition of 1,4-Benzodiazepines. Nitrazepam,Photochem. Photobiol. 30, 337–342.Google Scholar
  9. Field, G. F., andL. H. Sternbach (1968) Quinazolines and 1,4-Benzodiazepines XLII: Photochemistry of some N-oxides,J. Org. Chem. 33, 4438–4440.Google Scholar
  10. Fitzpatrick, T. B., M. A. Pathak, L. C. Harber, M. Seiji andA. Kukita (1974) Sunlight and Man (Ed.T. B. Fitzpatrick) Ch. 1, University of Tokyo Press, Tokyo.Google Scholar
  11. Han, W. W., G. J. Yakatan andD. D. Maness (1976) Kinetics and Mechanisms of Hydrolysis of 1,4-Benzodiazepines I: Chlordiazepoxide and Demoxepam,J. Pharm. Sci. 65, 1198–1204.Google Scholar
  12. Han, W. W., G. J. Yakatan andD. D. Maness (1977) Kinetics and Mechanisms of Hydrolysis of 1,4-Benzodiazepines II: Oxazepam and Diazepam,J. Pharm. Sci. 66, 573–577.Google Scholar
  13. Henderson, J. S., andI. H. Jenks (1979) Sun, Light and Human Health,Photochem. Photobiol. 29, 1–5.Google Scholar
  14. Kaneko, C., M. Yamamor, A. Yamamoto andR. Hayashi (1978) Irradiation of aromatic amine oxides in dichloromethane in presence of triphenylphosphine: A facile deoxygenation procedure of aromatic amine N-oxides,Tetrahedron Letters 31, 2799–2802.Google Scholar
  15. Kosower, E. M. (1976) in ‘Glutathione: Metabolism and Function’ (Edited byArias, I. M., andW. B. Jakoby) Ch. 1, Raven Press, New York.Google Scholar
  16. Ljunggren, B., andH. Möller (1978) Drug Phototoxicity in Mice,Acta Dermato-Venereol. 58, 125–130.Google Scholar
  17. Magnus, I. A. (1976)Dermatological Photobiology, Black-well, London.Google Scholar
  18. Maulding, H. V., J. P. Nazareno, J. E. Pearson andA. F. Michaelis (1975) Practical Kinetics III: Benzodiazepine Hydrolysis,J. Pharm. Sci. 64, 278–284.Google Scholar
  19. Mayer, W., S. Erbe andR. Voigt (1972) Beiträge zur Analytik und Stabilität einiger pharmazeutisch interessanter 1,4-Benzodiazepine,Pharmazie 27, 32–42.Google Scholar
  20. Mayer, W., S. Erbe, G. Wolf andR. Voigt (1974) Beiträge zur Analytik und Stabilität einiger pharmazeutisch interessanter 1,4-Benzodiazepine,Pharmazie 29, 700–707.Google Scholar
  21. Metzler, M., andH. -G. Neumann (1977) Epoxidation of the Stilbene Double Bond, a Major Pathway in Aminostilbene Metabolism,Xenobiotica 7, 117–132.Google Scholar
  22. Ning, R. Y., andP. B. Madan (1976) Heterocyclic compounds, Ger. Offen 2, 540, 586 (Cl. CO7FD), 25 March 1976; US Appl. 504, 924, 11 Sep. 1974; 54 pp.Google Scholar
  23. Oelschläger, H., andH. Hoffmann (1967) Ringverengung bei der elektrochemischen Reduktion eines 1,4-Benzodiazepin-Derivates,Arch. Pharm. 300, 817–822.Google Scholar
  24. Rannug, U., A. Sundvall andC. Ramel (1978) The Mutagenic Effect of 1,2-Dichloroethane on Salmonella Typhimurium 1. Activation through conjugation with Gluathione in Vitro,Chem.-Biol. Interactions 20, 1–16.Google Scholar
  25. Seutter-Berlage, F., L. P. C. Delbressine, F. L. M. Smeets andH. C. J. Ketelaars (1978) Identification of Three Sulphur-containing Urinary Metabolites of Styrene in the Rat,Xenobiotica 8, 413–418.Google Scholar
  26. Spence, G. G., E. C. Taylor andO. Buchardt (1970) The Photochemical Reactions of Azoxy Compounds, Nitrones and Aromatic Amine N-Oxides,Chem. Rev. 70, 231–265.Google Scholar
  27. Splitter, J. S., andM. Calvin (1965) Oxaziridines 1. The Irradiation Products of Several Nitrones,J. Org. Chem. 30, 3427–3436.Google Scholar
  28. Sternbach, L. H., S. Kaiser andE. Reeder (1960) Quinazo-line-3-Oxide Structure of Compounds Previously Described in the Literature as 3, 1, 4-Benzoxadiazepines,J. Am. Chem. Soc. 82, 475–480.Google Scholar
  29. Sternbach, L. H., E. Reeder, O. Keller andW. Metlesics (1961) Quinazolines and 1,4-Benzodiazepines III: Substituted 2-amino-5-phenyl-3H-1,4-benzodiazepine 4-oxides,J. Org. Chem. 26, 4488–4497.Google Scholar
  30. Widmer, O., K. Zurcher andA. Krebs (1976) Hautnebenwirkungen interner Arzneimittel IV. C. Medikamentöse Lichtempfindlichkeit (Photosensibilität),Dermatologica 152, 216–253.Google Scholar

Copyright information

© Bohn, Scheltema & Holkema 1980

Authors and Affiliations

  • P. J. G. Cornelissen
    • 1
  • G. M. J. Beijersbergen van Henegouwen
    • 1
  1. 1.Department of Pharmacochemistry, Subfaculty of PharmacyState University of Leiden, Gorlaeus LaboratoriesLeidenThe Netherlands

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