Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs

Journal of Medicinal Chemistry

Volumn 43, Issue 6, 2000, Pages 1234-1241

  Hale, Jeffrey J ^a   Mills, Sander G ^a   MacCoss, Malcolm ^a   Dorn, Conrad P ^a   Finke, Paul E ^a   Budhu, Richard J ^a   Reamer, Robert A ^a   Huskey, Su Er W ^a   Luffer Atlas, Debra ^a   Dean, Brian J ^a   McGowan, Erin M ^a   Feeney, William P ^a   Chiu, Shuet Hing Lee ^a   Cascieri, Margaret A ^a   Chicchi, Gary G ^a   Kurtz, Marc M ^a   Sadowski, Sharon ^a   Ber, Elzbieta ^a   Tattersall, F David ^b   Rupniak, Nadia M J ^b   Williams, Angela R ^b   Rycroft, Wayne ^b   Hargreaves, Richard ^b   Metzger, Joseph M ^a   MacIntyre, D Euan ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 [3,5 BIS(TRIFLUOROMETHYL)PHENYL]ETHOXY (4 FLUORO)PHENYL 4 (5 (2 PHOSPHORYL 3 OXO 4H 1,2,4 TRIAZOLO)METHYLMORPHOLINE; NEUROKININ 1 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DOG; DRUG SOLUBILITY; FERRET; GUINEA PIG; HUMAN; HUMAN TISSUE; INFLAMMATION; LIVER CIRCULATION; NONHUMAN; RECEPTOR AFFINITY; VOMITING;

ACETALS; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTIEMETICS; ANTINEOPLASTIC AGENTS; CISPLATIN; DOGS; DRUG EVALUATION, PRECLINICAL; FERRETS; GUINEA PIGS; HUMANS; MORPHOLINES; PRODRUGS; RATS; RECEPTORS, NEUROKININ-1; SOLUBILITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; VOMITING; WATER;

EID: 0034704822     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990617v     Document Type: Article

References (41)

1. Tavorath, R.; Hesketh, P. J. Drug Treament of Chemotherapy-Induced Delayed Emesis. Drugs 1996, 52, 639-648.
2. (a) Roila, F.; The Italian Group for Antiemetic Research. Dexamethazone, Granisetron, or Both for the Prevention of Nauseas and Vomiting During Chemotherapy for Cancer, N. Engl. J. Med. 1995, 332, 1-5.
3. (b) Andrews, P. L. R.; Rapeport, W. G.; Sanger, G. J. Neuropharmacology of Emesis Induced by Anti-Cancer Therapy. Trends Pharmacol Sci. 1988, 9, 334-341.
4. Bountra, C.; Gale, J. D.; Gardner, C. J.; Jordan, C. C.; Kilpatrick, G. J.; Twissel, D. J.; Ward, P. Towards Understanding the Aetiology and Pathophysiology of the Emetic Reflex: Novel Approaches to Antiemetic Drugs. Oncology 1996, 53, 102-109.
5. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. J. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. Structural Optimization Affording 2-GR)-(1-(R)-(3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3- oxo-1,2,4-triazol-5-yl)methyl morpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor Antagonist. J. Med. Chem. 1998, 41, 4607-4614 and references therein.
6. (a) Navari, R., M.; Reinhart, R. R.; Gralla, R. J.; Kris, M. G.; Hesketh, P. J.; Khojasteh, A.; Kindler, H.; Grote, T. H.; Pendrgras, K.; Grunberg, S. M.; Carides, A. D.; Gertz, B. J. for the L-754,030 Antiemetic Trials Group. Reduction of Cisplatin-Induced Emesis by a Selective Neurokinin-1 Receptor Antagonist. N. Engl. J. Med. 1999, 340, 190-195.
7. (b) Hesketh, P. J.; Gralla, R. J.; Webb, R. T.; Ueno, W.; Silberman, S. Randomised Phase II Study of the Neurokinin-1 Antagonist CJ 11,974 for the Control of Cisplatin-Induced Emesis. Proc. Am. Soc. Clin. Oncol. 1998, 17, A19.
8. (c) Gesztesi, Z. S.; Song, D.; White, P. F. Comparison of a New NK-1 Antagonist (CP 122,721) to Ondansetron in the Prevention of Post-Operative Nausea and Vomiting. Anesth. Anal. 1998, 86, A1780.
9. (d) Diemunch, P., Schoeffler, P., Bryssine, B., Muller, L.; Lees, J.; McQuade, B.; Spraggs, C. Anti-Emetic Activity of the NK-1 Antagonist GR 205171 in the Treatment of PONV Following Major Gynaecological Surgery. Anesth. Anal. 1998, 86, S436.
10. (e) Kris, M. G.; Radford, J. E.; Pizzo, B. A.; Inabinet, R.; Hesketh, A.; Hesketh, P. J. Use of an NK-1 Receptor Antagonist to Prevent Delayed Emesis After Cisplatin. J. Natl. Cancer Inst. 1997, 89, 817-818.
11. Hale, J. J.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M. 2-(S)-((3,5-Bis(trifluoromethyl)benzyl)oxy)-3-(S)-phenyl-4-((3-oxo-1,2,4- triazol-5-yl)methyl) morpholine: A Potent, Orally Active, Morpholine-Based Human Neurokinin-1 Receptor Antagonist. J. Med. Chem. 1996, 39, 1760-1762.
12. Newby, D. E.; Sciberras, D. G.; Ferro, C. J.; Mendel, C. M.; Gertz, B. J.; Majumdar, A.; Lowry, R. C., Webb, D. J. Antagonism of Substance P-Induced Forearm Vasodilation by the Neurokinin Type I Receptor Antagonist L-754,030. Presented at the British Pharmacological Society Autumn Meeting, Edinburgh, Scotland, September 1-4, 1997; Abstract XX.
13. (a) Gould, P. L. Salt Selection for Basic Drugs. Int. J. Pharm. 1986, 33, 201-217.
14. (b) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C. Pharmaceutical Salts. J. Pharm. Sci. 1977, 66, 1-19.
15. (a) Fleisher, D.; Bong, R.; Stewart, B. H. Improved Oral Drug Delivery: Solubility Limitations Overcome by the Use of Prodrugs. Adv. Drug Delivery Rev. 1996, 19, 115-130.
16. (b) Balant, L. P.; Doekler, E.; Buri, P. Prodrugs for the Improvement of Drug Adsorption Via Different Routes of Administration. Eur. J. Drug Metab. Pharm. 1990, 15, 143-153.
17. Stella, V. J. A Case for Prodrugs: Fosphenytoin. Adv. Drug Delivery Rev. 1996, 19, 311-330.
18. For other examples, see: (a)Murdock, K. C.; Lee, V. J.; Citarella, R. V.; Durr, F. E.; Nicolau, G.; Kohlbrenner, M. N-Phosphoryl Derivatives of Bisantrene. Antitumor Prodrugs with Enhanced Solubility and Reduced Potential for Toxicity. J. Med. Chem. 1993, 36, 2098-2101.
19. (b) Varia, S. A.; Schuller, S.; Sloan, K. B.; Stella, V. J. Phenytoin Prodrugs III: Water Soluble Prodrugs for Oral and/or Parenteral Use. J. Pharm. Sci. 1984, 73, 1068-1073.
20. (a) Hoffmann, H.; Hammann, I.; Stendel, W. Insecticidal and Acaricidal O-Triazolylthiophosphoric(phosphinic) Acid Esters. Ger. Offen. 2,403,711, 1975.
21. (b) Boehner, B.; Meyer, W.; Dawes, D. Triazolyl Phosphorodithioates. Ger. Offen. 2,352,140, 1974.
22. (a) Watanbe, Y.; Nakahira, H.; Bunya, M.; Ozahi, S. An Efficient Method for Phosphorylation of Inositol Derivatives. Tetrahedron Lett. 1987, 28, 4179-4180.
23. (b) Khorana, H. G.; Todd, A. R. Studies on Phosphorylation. Part XI. The Reaction Between Carbodiimides and Acid Esters of Phosphoric Acid. A New Method for the Preparation of Pyrophosphates. J. Chem. Soc. 1953, 2257-2260.
24. Macher, I. A Convenient Synthesis of 2-Deoxy-2[(R)-3-Hydroxytetradecanamido]-3-0-[(R)-Hydroxydecanoyl]-a-D- Glucopyanose-1-Phosphate. Carbohydrate Res. 1987, 162, 79-84.
25. Watanabe, Y.; Hyodo, N.; Ozaki, S. Dibenzyl Phosphorfluoridate, A New Phosphorylating Agent. Tetrahedron Lett. 1988, 29, 5763-5764.
26. Perich, J. W.; Johns, R. B. Synthesis of Casein-Related Peptides and Phosphopeptides. The Efficient Global 'Phosphite-Triester' Phosphorylation of Protected Serine Derivatives and Peptides by Using Dibenzyl or Di-tert-Butyl N, N.-Diethylphosphoramidite. Aust. J. Chem. 1990, 43, 1623-1632.
27. Ion exchange chromatography was carried out using Amberchrom CG-161, a nonfunctionalized polystyrene/divinylbenzene resin.
28. Difficulties were encountered in obtaining fractions of pure 7 during the preparative reverse-phase HPLC purification of 3 or 4. The observed relative lability of 7 as compared to 3 or 4 also hindered attempts to isolate it in pure form. Subjection of 7 to treatment with NaHMDS both in the presence and absence of TBPP would serve to demonstrate that it is converted to the 3 or 4.
29. 13C NMR Experiments of Peptides. J. Magn. Reson. 1990, 86, 657-662.
30. (b) Davies, D. B.; Christofides, J. C. Secondary Isotope Multiplet NMR Spectroscopy of Partially Labeled Entities. Carbon-13 SIMPLE NMR of Carbohydrates. J. Am. Chem. Soc. 1983, 105, 5099-5105.
31. 13C NMR Signals of Compounds with Exchangeable Hydrogen Atoms Using Two and Three Bond Isotope Effects: Cellobiose. J. Chem. Soc., Chem. Commun. 1983, 324-326. For a general treatment of this phenomenon, see: Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy; VCH Publishers: New York, 1987; pp 109-117.
32. 13C NMR Signals of Compounds with Exchangeable Hydrogen Atoms Using Two and Three Bond Isotope Effects: Cellobiose. J. Chem. Soc., Chem. Commun. 1983, 324-326. For a general treatment of this phenomenon, see: Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy; VCH Publishers: New York, 1987; pp 109-117.
33. Huskey, S.-E. W.; Luffer-Atlas, D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P. Chiu, S.-H. L. Substance P Receptor Antagonist. I. Conversion of Phosphoramidate Prodrug L-758,298 to L-754,030 Following Intravenous Administration in Rats and Dogs. Drug Metab. Dispos. 1999, 27, 1367-1373.
34. Acronym for Resiniferatoxin-Induced SYstemic VAscular Leakage.
35. Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.; Rycroft, W.; Carlson, E. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Seward, E.; Huscroft, I.; Owen, S.; Swain, C. J.; Hill, R. G.; Hargreaves, R. J. In Vitro and In Vivo Predictors of the Anti-Emetic Activity of Tachykinin NK-1 Receptor Antagonists. Eur. J. Pharmacol. 1997, 326, 201-209.
36. Tattersall, F. D.; Rycroft, W.; Cumberbatch, M.; Mason, G.; Tye, S.; Williamson, D. J.; Hale, J. J.; Mills, S. G.; Finke, P. E.; MacCoss, M.; Sadowski, S.; Ber, E.; Cascier, M. A.; Hill, R. G.; MacIntyre, D. E.; Hargreaves, R. J. The Novel NK-1 Receptor Antagonist MK 0869 (L-754,030) and Its Water Soluble Phosphoryl Prodrug, L-758, 298, Inhibit Acute and Delayed Cisplatin-Induced Emesis in Ferrets. Neuropharmacology 1999, in press.
37. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal, A.; Swain, S.; Seward, E.; Frances, B.; Burns, D.; Strader, C. D.; Characterization of the Binding of a Potent, Selective Radioiodinated Antagonist to the Human Neurokinin-1 Receptor. Mol. Pharmacol. 1992, 42, 458-465.
38. 50 values in the 1.0-1.5 nM range.
39. (a) Newby, D. E.; Sciberras, D. G.; Ferro, C. J.; Gertz, B. J.; Sommerville, D.; Majumdar, A.; Lowry, R. C.; Webb, D. J. Substance P-Induced Vasodilation is Mediated by the Neurokinin Type I Receptor But Does Not Contribute to Basal Vascular Tone in Man. Br. J. Clin. Pharmacol. 1999, 48, 336-344.
40. (b) Norman, B.; Panebianco, D.; Block, G. A. A Placebo-Controlled, In-Clinic Study to Explore the Preliminary Safety and Efficacy of Intravenous L-758,298 (A Prodrug of the NK-1 Receptor Antagonist L-754,030) in the Acute Treatment of Migraine. Cephalalgia 1998, 18, P42, 407.
41. Van Belle, S.; Cocquyt, V., De Smet, M.; Decramer, M.; O-Brien, M.; Schellens, J.; Reinhardt, R. R.; Gertz, B. J. Comparison of a Neurokinin-1 Antagonist, L-758,298, to Ondansetron in the Prevention of Cisplatin-Induced Emesis. Presented at the 34th Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998, Abstract No. 198.