85622-93-1 Usage
Anticancer drugs
Temozolomide is the first effective orally-taken imidazole and tetrazine-class anticancer drug which belongs to the second generation of an alkylating agent with antitumor activity without liver metabolic activation after oral administration. It is characterized by easily penetration through the blood-brain barrier, good tolerance and being not superimposed with other drugs toxicity, and having synergistic effect with radiotherapy which is suitable for treating malignant glioma recurrence after conventional treatment such as glioblastoma multiforme tumors or degenerative astrocytoma. It is first-line drug for treatment of metastatic melanoma.
Temozolomide had been first synthesized by Cancer Research UK Group, and then be transferred to the Schering-Plough Company (United States) for development. The drug is different from the existing Antineoplastic drug. It has a novel chemical structure and belongs to a four-imidazole derivative. Temozolomide does not play a direct role. At physiological pH, it is first quickly converted into active compound MTIC [5-(3-methyl-triazene-1-) imidazole-4-carboxamide] via non-enzymatically way. People think that the cytotoxicity of MTIC is mainly due to its DNA alkylation (methylation) effect. Alkylation mainly occurs in the O6 and N7 position of guanine. Basic and clinical studies of temozolomide have confirmed that it is effective in treating some of the most common glioma cells. In 1999, it has been approved for enter into market in EU and the US wherein the permitted indication in United States is mainly for second-line treatment of glioblastoma multiforme and degenerative star gliomas and approved indications of EU is for treating developing or relapsing glioblastoma multiforme which has already been subject to conventional therapy. The efficacy of temozolomide on treating glioblastoma multiforme has received more recognition in Europe.
Pharmacokinetics
This medicine can be completely oral absorbed and has a nearly 100% availability. It can exhibit a broad spectrum of activity in murine tumor model systems and can penetrate through the human blood-brain barrier. The toxic effects of temozolomide cells originate from its role in strong methylation of DNA bases. Under alkaline conditions, temozolomide can quickly be broken for formation of active methyl diazonium ion. Since the brain has a higher basicity than the surrounding tissue, so that the activation of this drug can relatively concentrate and occur at the tumor site. It has a strong anti-tumor effect with certain selectivity with its side-effect profile being alleviated, small bone marrow toxicity and improved patient tolerance.
Toxicological effects
Genetic Toxicity: Temozolomide has in vitro mutagenesis effect on bacteria (Ames test), and can cause the collapse of mammalian cell chromosomes (human peripheral blood lymphocytes clear test).
Reproductive toxicity: There currently have been no reproductive toxicity performed for temozolomide, but the toxicity study of repeated medication test of rat and dog have shown that when the administered doses of 50mg/m2 and 125mg/m2, for rat and dog, respectively (calculated by body surface area, equivalent to approximately 1/4 and 5/8 of maximum recommended dosage, respectively), this product is toxic to animal testicles exhibited as syncytial cells (i.e. immature sperm) occurs and testicular atrophy.
Carcinogenicity: There have been no conventional carcinogenicity studies about temozolomide yet. Giving 125 mg/m2 of temozolomide to rats in a cycle of 5 consecutive days per 28 days to (according to calculation of body surface area, it is comparable to the maximum recommended daily amount for human) for three cycles can produce breast cancer for both male and female rats. According to calculation of 25, 50, 125mg/m2 (according to the calculation of body surface area, it is roughly equivalent to 1/8 to 1/2 of the maximum recommended dosage) after administration of 6 cycles, the animals in all the dose group got breast cancer: at high-dose group, fibrosarcoma occurs in the heart, eyes, seminal vesicles, salivary glands, abdomen, uterus and prostate tissue. It is also appeared in seminal vesicle cancer, heart, nerve sheath tumors, optic nerve cancer, and Bernhard's adenocarcinoma. Moreover, adenoid tumor also occurs in other visible tissues such as animal skin, lung, pituitary, and thyroid.
The treatment of recurrent glioblastoma multiforme tumor
The treatment of Temozolomide for recurrent glioblastoma multiforme trials have confirmed upon clinical assays to be safe and effective. A randomized controlled trial in phase II have showed that 225 cases of glioblastoma multiforme patients suffering the first reoccurrence of pleomorphic glioblastoma who have been treated by temozolomide or procarbazine (every 56 days once every 28 d, oral administration of 125~150 mg/m2 per day) for 6 months, respectively, the temozolomide group of patients have got no disease deterioration with survival and overall survival rate being 21% and 60%, respectively. This was significantly higher than that in procarbazine group (8% and 44%). The average survival time and overall survival time for patients in the temozolomide group with no disease progression was 2.9 and 7.3 months, respectively, which were significantly higher than that in procarbazine group that was 1.9 and 5.8 months, respectively. The Experimental have also evaluated the health-related quality of life in both the first 3 months and 6 months after the starting of the treatment, the results also have confirmed that temozolomide group had more patients with quality of life being improved or remaining stable.
The main side effect for temozolomide is transient and non-retention bone marrow suppression which is both predictable and easy to handle with a trials incidence of 24%. Temozolomide is also prone to cause moderate nausea and vomiting in patients, however these adverse reactions can be prevented with conventional antiemetic therapy. The efficacy of temozolomide for treating recurrent glioblastoma multiforme efficacy and its property of adverse reaction were significantly better than the existing standard drug procarbazine.
Clinical evaluation
Temozolomide is effective in treating newly diagnosed glioblastoma multiforme cell tumor. A small II trial results has shown that 33 cases of such patients who had been subject to temozolomide (200mg/m2) treatment where 17 patients had achieved complete or partial remission, and other four patients were in stable condition. The average time from the disease remission to disease progression for 17 patients was seven months, and was two months for the treatment of non-responders with their average survival time being 12 months and 6 months. But the effect of temozolomide in treating newly diagnosed degenerative astrocytomas remains unclear.
Temozolomide is of high efficacy on glioma cells, especially has a significant effect on the most common pleomorphic glioblastoma. No matter in tumor response rates, or in patient survival and tolerability it all has a good effect. More importantly, the quality of patients’ life is significantly better than the existing standard drug procarbazine, moving a big step toward the treatment of tumors using this kind of drug. The first-line position of Temozolomide in treatment of progressive metastatic melanoma has been affirmed in clinical assays. Applications for applying it widely in Europe and the United States are being conducted. A recent randomized controlled trial results in III phase have shown about the 305 cases of these patients who subjected to temozolomide (200 mg/m2) and dacarbazine (every 21 days once a 5d, 250 mg/m2 per day) treatment, temozolomide group of patients had a overall survival and treatment response rates of 7.9 months and 13.5%, respectively, which was better than that of 5.7 months and 12.1% as observed in dacarbazine group. Patients in Temozolomide group had a better tolerance than dacarbazine group with its life-qualify evaluation (reflected by reduced physiological function) also significantly better than dacarbazine group (the rate of decline was 18% and 42% after three months of treatment, respectively). Melanoma skin tumors are rare skin cancer, even though it accounts for only about 4% of all skin cancers, but the mortality rate accounted for about 79% of all skin cancer. The current standard drug for treating it is still dacarbazine. Temozolomide has exhibited high clinical efficacy towards glial cells and melanoma, and thus is worthy of attention.
The above information is edited by the lookchem of Dai Xiongfeng.
Patent No
DE 3237255; US 5260921
Production methods
Amino-4-carboxamido-imidazole is first subject to nitrite diazotization, and has reaction with methyl isocyanate in dichloromethane for cyclization to obtain ammonium temozolomide.
Originator
CRC Technology (UK)
Manufacturing Process
Reaction of 1H-imidazole-4-carboxilic acid amide with nitrous acid leads to the
diazonium salt (5-diazenyl-1-H-imidazole-4-carboxilic acid amide).
Condensation of the diazonium salt with methylisocyanate leads to initial
formation of unstable urea which cyclizes under the reaction condition to give
3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide
(temozolomide).
Therapeutic Function
Antineoplastic
Biological Activity
DNA methylating, chemotherapeutic agent. Displays antitumor activity against a board spectrum of tumors, including leukemias, lymphomas and solid tumors (IC 50 = 5.0 μ M for cytotoxicity against mouse TLX5 lymphoma cells).
Biochem/physiol Actions
Temozolomide is a DNA methylating agent and drug resistance-modifying agent; anti-tumor and anti-angiogenic. Temozolomide induces G2/M arrest and apoptosis through adduction of a methyl group to O6 position of guanine in genomic DNA and functional inactivation of DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) in base excision repair (BER) pathway.
Clinical Use
This imidazolotetrazine derivative is administered orally in capsule form for the treatment of glioblastoma multiforme or in patients with anaplastic astrocytoma who have not responded to procarbazine or the nitrosoureas.
Metabolism
Oral absorption is rapid and complete. The CYP450 enzymes are not extensively involved in temozolomide metabolism, and less than 6% of the drug is excreted unchanged in the urine. Women clear the drug less effectively than men and have a higher incidence of severe neutropenia and thrombocytopenia in the initial therapy cycle. Food decreases temozolomide absorption, and myelosuppression is the most significant adverse effect.
References
1) Kurzen et al. (2003), Inhibition of angiogenesis by non-toxic doses of temozolomide; Anticancer Drugs, 14 515
2) Gunther et al. (2003), Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids; Br. J. Cancer, 88 463
3) Danson et al. (2001), Temozolomide: a novel oral alkylating agent; Curr. Opin. Expert Rev. Anticancer Ther., 10 13
4) Natsumeda et al. (2011), Induction of autophagy in temozolomide treated malignant gliomas; Neuropathology, 31 486
Check Digit Verification of cas no
The CAS Registry Mumber 85622-93-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,5,6,2 and 2 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 85622-93:
(7*8)+(6*5)+(5*6)+(4*2)+(3*2)+(2*9)+(1*3)=151
151 % 10 = 1
So 85622-93-1 is a valid CAS Registry Number.
InChI:InChI=1/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13)
85622-93-1Relevant articles and documents
Alternative syntheses of the antitumour drug temozolomide avoiding the use of methyl isocyanate
Wang,Stevens,Thomson
, p. 1687 - 1688 (1994)
Ethyl (8-carbamoyl-3,4-dihydro-4-oxoimidazo[5,1-d] -1,2,3,5-tetrazin-3-yl)acetate 5 can be prepared by two routes starting from 5-aminoimidazole-4-carboxamide 2; hydrolysis of 5 to the corresponding carboxylic acid 6 followed by Barton radical decarboxylation gives the antitumour imidazotetrazinone temozolomide 1.
Identification and physicochemical characteristics of temozolomide process-related impurities
Laszcz, Marta,Kubiszewski, Marek,Jedynak, Lukasz,Kaczmarska, Monika,Kaczmarek, Lukasz,Luniewski, Wojciech,Gabarski, Krzysztof,Witkowska, Anna,Kuziak, Krzysztof,Malinska, Maura
, p. 15344 - 15356 (2013)
In this article the crystal structures of the starting material TZ-5 and the key intermediate TZ-6 of temozolomide (TZ-7), an anticancer therapeutic agent, are presented, together with their spectroscopic and thermal characteristics. Both compounds crystallize in the triclinic P-1 space group. X-ray crystallography studies proved that the compound TZ-6 exists as a monohydrate. A complete structural assignment was obtained for the signals in the 1H-, 13C- and 15N-nuclear magnetic resonance spectra and the structures were confirmed by Fourier-Transform infrared and Raman spectroscopy. The article describes the importance of the high purity of TZ-6 during the small-scale plant production of TZ-7 in a desired polymorphic form III with the purity higher than 99.50%, according to an HPLC method.
Preparation method of temozolomide
-
Paragraph 0101-0104, (2021/10/13)
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of temozolomide, which comprises the following steps: reacting a nitrosoimidazole compound with methylhydrazine to generate an azo compound IV, further hydrolyzing the compound IV to obtain an intermediate V, and further performing nucleophilic substitution on the compound V and p-nitrophenyl chloroformate to obtain a new intermediate VII; and carrying out intermediate VIIcyclization to obtain temozolomide. According to the method, the use of methyl isocyanate with high toxicity and the process of instable diazo compound intermediates are avoided, the synthesized intermediates do not generate dimerization impurities, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, the method is economical and environmentally friendly, the yield is high, and the method is suitable for industrial production.
Temozolomide intermediate compound VII
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Paragraph 0092-00100, (2021/10/13)
The invention belongs to the field of pharmaceutical and chemical engineering, and particularly relates to a novel intermediate VII VII used for synthesizing temozolomide by using an imidazole azo intermediate compound as a raw material, and a novel method for synthesizing temozolomide by using the intermediate. The method is economical, environment-friendly, high in yield and suitable for industrial production.
Temozolomide intermediate compound IV
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Paragraph 0026; 0090-0098, (2021/10/13)
The invention belongs to the field of pharmaceutical chemical engineering, and particularly relates to a IV novel method for synthesizing temozolomide by reacting a nitroimidazole type substrate with methylhydrazine, and the method IV avoids the use of dangerous chemical reagents, and the synthesized intermediate does not generate new impurities. The method is economical, environment-friendly, high in yield and suitable for industrial production.
Preparation method of temozolomide
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Paragraph 0070; 0071; 0079-0080; 0089-0090; 0091; 0099-0100, (2020/06/20)
The invention discloses a preparation method of temozolomide, which comprises the following steps: carrying out formylation reaction on N-methylurea and a formylation reagent to obtain N-methyl-N'-formyl urea, and carrying out cyclization reaction on the N-methyl-N'-formyl urea and 2-amino-2-ethyl cyanoacetate in an acid and solvent system to obtain 1-(methylaminoformyl)-5-aminoimidazole-4-ethyl formate; with temozolomide as a raw material, performing diazotization and cyclization synergistic reaction to obtain 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-ethyl formate, and performing amidation reaction with an amidation reagent solution under the condition to obtain temozolomide. According to the method, ideal yield and purity can be obtained under mild reaction conditions, side reactions are reduced, post-treatment is simple, adopted reagent raw materials are cheaper and easier to obtain, and the method is safe, environmentally friendly and suitable for industrial large-scale production.
ORAL SUSPENSION OF TEMOZOLOMIDE
-
, (2020/07/07)
The present invention concerns a pharmaceutical composition, advantageously a liquid suspension, comprising: a. temozolomide or a salt thereof;b. at least one agent controlling the solid state of temozolomide in suspension;c. a pharmaceutically acceptable liquid vehicle, advantageously water;d. optionally at least one acid in a quantity so that the pH of the composition is below 5; or a powder blend for reconstituting said suspension.
PROCESS FOR PREPARING HIGHLY PURE TEMOZOLOMIDE
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Page/Page column 17, (2020/10/18)
The present invention provides a commercially viable process for preparation of highly pure Temozolomide (VI), which is useful in the treatment of cancer. The invention also provides an economically viable process for an intermediate compound of formula III useful in the process for preparing Temozolomide.
Synthesis and growth-inhibitory activities of imidazo?5,1-d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position
Cousin, David,Hummersone, Marc G.,Bradshaw, Tracey D.,Zhang, Jihong,Moody, Christopher J.,Foreiter, Magdalena B.,Summers, Helen S.,Lewis, William,Wheelhouse, Richard T.,Stevens, Malcolm F.G.
, p. 545 - 553 (2018/03/28)
A series of 3-(benzyl-substituted)-imidazo?5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values >50 μM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT- isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.
PROCESS FOR PREPARING TEMOZOLOMIDE AND AN INTERMEDIARY
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Paragraph 057, (2018/07/29)
The present invention relates to an efficient and industrially advantageous process for preparing temozolomide and the carbamoyl-AICA intermediate through the use of N-methyl carbamoylimidazole in a good overall yield and high purity.
