(R)-2-Azido-4-methylpentanoic acid cyclohexylamine salt

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Activated protein C concentrate, Ad-CD154, Adeno-Interferon gamma, alemtuzumab, APC-8024, 9-aminocamptothecin, aprepitant, l-arginine hydrochloride, aripiprazole, arsenic trioxide, asimadoline; O6-Benzylguanine, bevacizumab, Bi-20, binodenoson, biphasic insulin aspart, bivatuzumab, 186Re-bivatuzumab, BMS-181176, bosentan, botulinum toxin type B, BQ-123, bryostatin 1; Carboxy- amidotriazole, caspofungin acetate, CB-1954, CC-4047, CDP-860, cerivastatin sodium, clevidipine, CTL-102; 3,4-DAP, darbepoetin alfa, decitabine, desloratadine, DHA-paclitaxel, duloxetine hydrochloride; Efalizumab, EGF vaccine, eletriptan, eniluracil, ENMD-0997, eplerenone, eplivanserin, erlosamide, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, eszopiclone, everolimus, exatecan mesilate, exenatide, ezetimibe; Fondaparinux sodium, FR-901228, FTY-720; Gefitinib, gemtuzumab ozogamicin, gepirone hydrochloride; Hexyl insulin M2, human insulin; Imatinib mesylate, insulin detemir, insulin glargine, iodine (I131) tositumomab, ISV-205, ivabradine hydrochloride, ixabepilone; Levetiracetam, levocetirizine, linezolid, liposomal NDDP, lonafarnib, lopinavir, LY-156735; Mafosfamide cyclohexylamine salt, magnesium sulfate, maxacalcitol, meclinertant, melagatran, melatonin, MENT, mepolizumab, micafungin sodium, midostaurin, motexafin gadolinium; Nesiritide, NS-1209, NSC-601316, NSC-683864; Osanetant; Palonosetron hydrochloride, parecoxib sodium, pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegylated OB protein, pemetrexed disodium, perillyl alcohol, picoplatin, pimecrolimus, pixantrone maleate, plevitrexed, polyglutamate paclitaxel, posurdex, pramlintide acetate, prasterone, pregabalin; Rasburicase, rimonabant hydrochloride, rostaporfin, rosuvastatin calcium; SDZ-SID-791, sibrotuzumab, sorafenib, SU-11248; Tadalafil, targinine, tegaserod maleate, telithromycin, TheraCIM, tigecycline, tiotropium bromide, tipifarnib, tirapazamine, treprostinil sodium; Valdecoxib, Valganciclovir hydrochloride, Vardenafil hydrochloride hydrate; Ximelagatran; Zofenopril calcium, Zoledronic acid monohydrate.

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)-tetrah ydr o-2H-1,3, 2-oxaza-phosphorine-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 degrees 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 degrees 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.(ABSTRACT TRUNCATED AT 250 WORDS)