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Two anticancer agents, Onrigin (laromustine), formerly cloretazine (VNP40101M), and Triapine, a ribunucloetide reductase inhibitor similar tohydroxyurea, were in human clinical trials. Onrigin (laromustine), a novel alkylating agent, was evaluated in a Phase 2 trial in elderly de novo poor-riskacute myeloid leukemia (AML). In addition, several trials of Onrigin (laromustine) were conducted in elderly patients with AML and myelodysplastic syndrome (MDS) in combination with cytarabine and in patients with brain tumors in combination with temozolomide. After Onrigin was rejected by the Food and Drug Administration for an AML indication in 2009 due to an unfavorable risk-benefit profile, the company went defunct.
Generic name: laromustine
Company: Vion Pharmaceuticals, Inc.
Treatment for: Acute Myeloid Leukemia
Onrigin (laromustine), formerly known as Cloretazine (VNP40101M), is a novel alkylating agent in development for remission induction treatment for patients sixty years of age or older with de novo poor-risk acute myeloid leukemia (AML).
VNP40101M, an anti-neoplasia agent, demonstrates potent anti-tumor activity through alkylation or cross-linking of deoxyribonucleic acid. The compound is classified as a sulfonylhydrazine prodrug, and the proposed mechanism of action suggests formation of a chloroethylating species with a relative specificity for O6-guanine alkylation. An additional decomposition product, methyl isocyanate, may inhibit various DNA repair enzymes (See, Penketh, et al. Biochem Pharmacol 2000, 59(3): 283-291).
A three-step process with a total yield less than 10% has been previously reported published in the following patents and journal articles: U.S. Pat. No. 5,637,619 (Jun. 10, 1997 for VNP40101M); U.S. Pat. No. 4,684,747 (Aug. 4, 1987 for intermediate VNP4090CE); WO97/02029 (Jan. 23, 1997); Journal of Medicinal Chemistry, 1990, 33(8): 2259-2264; Journal of Medicinal Chemistry, 1996, 39(3): 796-801, as illustrated in FIG. 1. 2-Hydroxyethylhydrazine (HEH) was used a starting material and reacted with methanesulfonyl chloride to obtain 1,2-bis(methylsulfonyl)-1-[2-(methylsulfonyloxy)ethyl]hydrazine (BMH) at −20° C. for 18 hours, using pyridine as base. The crude intermediate BMH was treated with lithium chloride in acetone under reflux for 3 days to afford 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (VNP4090CE). After purification by flash column chromatography, an approximately 20% yield was reached for the two steps. VNP4090CE was condensed with methyl isocyanate at room temperature using triethylamine (TEA) as a base. After crystallization from ethanol, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylcarbamoyl)hydrazine (VNP40101M) with an approximately 42% yield. The total yield of this process was less than 10%. It is noted that the process used methyl isocyanate, which is extremely dangerous for manufacturing in scaleup kilogram amounts
Onrigin (3; referred to in this patent as VNP40101M) is an alkylating agent under investigation for treating high-grade brain tumors.An existing process for preparing3gives a poor overall yield of 10%, and it uses methyl isocyanate (MeNCO), a toxic compound not favored by the pharmaceutical industry.
Inventors X. Lin and I. King report three syntheses of 3; the first is shown in Figure 1. This route proceeds through intermediate 2, which is obtained by treating compound 1with COCl2 in the presence of i-Pr2NEt. The intermediate is not isolated but treated with MeNH2 and additional i-Pr2NEt. The reaction is monitored by TLC and HPLC–UV. After workup and crystallization, 3 is isolated in 94% yield and 97% purity.
A second route to onrigin (Figure 2) starts from methanesulfonate 4, which is converted directly to 3 by the reaction with acyl chloride 5 in the presence of Et3N. After workup and crystallization, 3 is isolated in 67% yield and 97% purity. Another synthesis from 4proceeds through ester intermediate 7, formed by treating 4 with ester 6. Compound 7is isolated in 63% yield and then treated with MeNH2 in the presence of AlCl3 to give 3, isolated in 68% yield and 97% purity after crystallization.
The preparation of 4 and its conversion to 1 are outlined in Figure 3. The reaction of hydroxy hydrazine 8 with MsCl gives 4 in 58% isolated yield. The purity is not reported, but the inventors state that the 1H NMR spectrum is “clean”. Chloro compound 1 is prepared from 4 in a reaction with LiCl that requires 24 h. The product is isolated in 88% yield; again, the NMR spectrum is "clean” and identical to reported spectra.
Some of the experiments are carried out on the 500-g scale, suggesting the process’s advanced stage of development. Although the process avoids the dangers of using MeNCO, it does use extremely hazardous COCl2, which is only safe to use when it is generated onsite. (Nanotherapeutics Inc. [Alachua, FL]. US Patent 8,026,395, Sept. 27, 2011; )http://www.google.nl/patents/US8026395
Laromustine is a sulfonyl hydrazine prodrug with antineoplastic activity. Laromustine releases the DNA chloroethylating agent 90CE after entering the blood stream; 90CE chloroethylates alkylates the 06 position of guanine, resulting in DNA crosslinking, strand breaks, chromosomal aberrations, and disruption of DNA synthesis. Intracellular metabolism of this agent also releases methyl isocyanate which inhibits 06-alkyl-guanine transferase, an enzyme involved with DNA repair. Check for active clinical trialsor closed clinical trials using this agent. (NCI Thesaurus).