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According to the patent, aminocyanoacetamide is synthesized in two steps by the reaction of cyanoacetic acid alkyl ester using sodium nitrite in the presence of glacial acetic acid to form a hydroxyimino intermediate, which is then reduced in the presence of platinum on carbon to yield aminocyanoacetic acid alkyl ester, which is unstable.The alkyl ester intermediate is then in situ reacted with aqueous ammonia to give the desired product.Now also available in an IV form for people who can not swallow capsules or who have insurance that does not cover oral cancer agents. Laboratory studies and clinical trials are investigating whether it might be possible to further increase the anticancer potency of temozolomide by combining it with other pharmacologic agents. Temozolomide, the compound of formula 1 : In this process, 5-amino-1 H-imidazole-4-carboxamide (A) is converted into 5- diazo-1 H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of temozolomide.For example, clinical trials have indicated that the addition of chloroquine might be beneficial for the treatment of glioma patients. However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1 H-imidazole-4-carboxamide (B). Commun., 1994, 1687-1688 provides a low overall yield from 5-amino-1 H- imidazole-4-carboxamide (A): less than 20% (unoptimized – about 17% through 5- diazo-1 H-imidazole-4-carboxamide (B) and about 15% through 5-amino-N Moreover, the unstable 5-diazo-1 H-imidazole-4-carboxamide (B) still has to be isolated in the branch of this process that uses it as an intermediate.Further, cycloaddition reaction requires a very long period of 21 to 28 days, which makes the process unattractive for industrial scale.US patent 5,003,099 discloses a process for preparation of aminocyanoacetamide, a key intermediate for the synthesis of temozolomide.According to said patent, temozolomide is prepared by the reaction of 5-diazoimidazole-4-carboxamide with methyl isocyanate in the presence of N- methylpyrrolid-2-one in dichloromethane at room temperature for three to four weeks.
In the laboratory, this combination indeed showed increased temozolomide activity in tumor cell culture in vitro and in animal models in vivo.-BG and temozolomide were given to patients with temozolomide-resistant anaplastic glioma, there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant glioblastoma multiforme. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Temozolomide of formula I, is an antitumor drag and is chemically known as 3-methyl-8- aminocarbonyl-imidazole[5,l-d]-l,2,3,5-tetrazin-4(3H)-one.After extraction of inteπnediate from the filtrate, the combined yield is only 67 %.The intermediate obtained is only 93 to 94% pure and requires additional purifications, crystallization using ethyl acetate and slurry wash with mixture of methyl tertiary butyl ether and isopropanol.There are also efforts to engineer hematopoietic stem cells expressing the MGMT gene prior to transplanting them into brain tumor patients. Formula I It is indicated for treating patients with malignant glioma such as cancer, breast cancer, refractory anaplastic, astrocytoma, i.e.This would allow for the patients to receive stronger doses of temozolomide, since the patient’s hematopoietic cells would be resistant to the drug. Temozolomide, 3-methyl-8-aminocarbonyl-imidazo[5,1-d]- 1 ,2,3,5-tetrazin- 4(3H)-one, is a known antitumor drug; see for example Stevens et al., J. patient at first relapse who have experienced disease progression in malignant glioma, glioblastoma multiform and anaplastic astrocytoma, on a drug containing a nitrosourea and procarbazine.