BAY 73-4506(Regorafenib)
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
CAS: 755037-03-7
Molecular Formula: C21H15ClF4N4O3
BAY 73-4506(Regorafenib) - Names and Identifiers
BAY 73-4506(Regorafenib) - Physico-chemical Properties
| Molecular Formula | C21H15ClF4N4O3 |
| Molar Mass | 482.82 |
| Density | 1.491±0.06 g/cm3(Predicted) |
| Melting Point | 206.0 to 210.0 °C |
| Boling Point | 513.4±50.0 °C(Predicted) |
| Flash Point | 264.3 °C |
| Solubility | DMSO ≥95mg/mL;Water <1 mg/mL;Ethanol <1 mg/mL |
| Appearance | White powder. |
| Color | Pale Pink to Light Pink |
| pKa | 12.04±0.70(Predicted) |
| Storage Condition | Refrigerator |
| Use | This product is for scientific research only and shall not be used for other purposes. |
BAY 73-4506(Regorafenib) - Risk and Safety
| HS Code | 29242990 |
BAY 73-4506(Regorafenib) - Introduction
Regorafenib (BAY 73-4506) is a multi-target inhibitor. The IC50 for VEGFR1,VEGFR2,VEGFR3,PDGFRβ,Kit,RET and Raf-1 are 13 nM,4.2 nM and 46 nM respectively
Last Update：2022-10-16 17:28:26
BAY 73-4506(Regorafenib) - Reference Information
| anticancer drugs | colorectal cancer (CRC) is one of the most common gastrointestinal tumors. Approximately 1.25 million people worldwide are diagnosed with CRC each year, with more than 600,000 deaths, ranking third and fourth Incidence Rate and Case Fatality Rate, respectively. In China, 220,000 new cases and 110,000 deaths occur each year, ranking fifth Incidence Rate and Case Fatality Rate. More than 30% of CRC patients have distant metastasis at the time of diagnosis, A considerable part of the patients have been unable to cure through surgery. Surgery is the main treatment principle of colorectal cancer. After early surgical resection with traditional Chinese medicine long-term conditioning, without radiotherapy and chemotherapy. In order to improve the survival rate, reduce the recurrence rate and improve the quality of life, traditional Chinese medicine must be supplemented with radiotherapy, chemotherapy and molecular targeted therapy after operation. The basic drugs of the standard chemotherapy regimen include fluorouracil and its derivatives oxaliplatin and irinotecan, but cytotoxic drugs often produce more serious side effects, and CRC has strong resistance to chemotherapy, the effect of conventional chemotherapy is often unsatisfactory. The emergence of molecular targeted drugs provides a new choice for the treatment of advanced colorectal cancer. These include cetuximab panitumumab and bevacizumab, which target the epidermal growth factor receptor (EGFR), in K-Ras of patients with wild-type mCRC, regorafenib, which targets vascular endothelial growth factor (VEGF), is an oral multi-kinase inhibitor, targeting the maintenance of tumorigenesis, tumor angiogenesis and tumor microenvironment signaling by inhibiting multiple protein kinases. regorafenib,BAY73-4506; Trade name Stivarga Is a small molecule multi-kinase inhibitor, the molecular structure is similar to sorafenib, the difference is only in the middle of the benzene ring on the fluorine atom. It is a new molecular targeted drug developed by Bayer company. It was approved by the US Food and Drug Administration (FDA) on September 27, 2012 for the treatment of metastatic colorectal cancer (mCRC), FDA approval for the treatment of patients with advanced GIST who are inoperable and otherwise ineffective. As a novel oral multi-target protein kinase inhibitor, it can block tumor cell proliferation, inhibit tumor angiogenesis and regulate tumor microenvironment. The "CORRECT" study confirmed that it is a TKI with therapeutic activity in patients with metastatic colorectal cancer, S. FDA approved in September 2012 for the treatment of mCRC patients who have failed multiple lines of standard treatment regimens. In China, a multi-center Phase III clinical trial is underway for the treatment of mCRC in China. Figure 1 structural formula |
| pharmacological action | , sorafenib-based synthesis of the more potent Oral TKIs, is a new type of oral small molecule tyrosine kinase inhibitors, can inhibit multiple tyrosine kinase targets, angiogenesis is mainly inhibited by inhibiting the activity of VEGF receptor (VEGFR)1, VEGFR2, VEGFR3 tyrosine kinase receptor TIE-2 and platelet-derived growth factor receptor. (2016-07-22) |
| Clinical Study | 1. Phase I clinical study: foreign scholars have carried out a number of phase I clinical studies to evaluate the safety of regafenib to determine its maximum tolerated dose (MTD), and roughly evaluate its efficacy in refractory solid tumors. In 2011, Schultheis and others first reported the results of a Phase Ib clinical study of this product in the treatment of mCRC at the ASCO Annual Meeting, which included 45 patients with advanced mCRC, the treatment plan is FOLFOX6 or FOLFIRI regimen as first-line or second-line treatment, to explore its safety, pharmacokinetics and efficacy. The administration regimen of this product is 160mg oral d4 ~ d10,d18 ~ d24, and the results show that this product has no obvious effect on the metabolism of these chemotherapeutic drugs. In the FOLFOX6 and FOLFIRI groups, there were 4 cases of partial remission (PR),15 cases and 11 cases of stable disease (SD). In 2013, Schultheis and others reported the final results of Phase B clinical study of this product in the treatment of mCRC, the median treatment time was 108 days (2 to 345 days), of which 17 cases discontinued treatment due to adverse reactions or death, 11 cases of disease progression, 11 cases of treatment, in the end of the study, only 6 patients adhered to the use of the drug until the end of the study (2 of them gave up chemotherapy), and 44 patients had drug-related adverse reactions during the treatment, among them, 32 cases had Grade 3 or more adverse reactions, mainly bone marrow suppression in 17 cases (38%), Hand Foot Syndrome in 4 cases (9%) and hypophosphatemia in 4 cases (9%). 33 cases of disease control (Efficacy Evaluation of PR and SD), the median progression-free survival (PFS) was 126 days (42~281 days), the results of the study showed that the drug had no significant effect on the metabolism of fluorouracil oxaliplatin and other chemotherapy drugs, and had good resistance to chemotherapy. Sexual intercourse. In 2012, Mross and others announced the results of Phase I clinical study of this product in the treatment of solid tumors. The study group recommended that the dose of regafenib should be 160mg oral d1 ~ d21,28 days for 1 cycle, this study suggests that the safety of this product can be accepted, and it is preliminarily proved to have anti-solid tumor effect. In 2012, Strumberg et al published the results of another phase -2 clinical study on the treatment of mCRC with regafenib, the safety and anti-tumor activity of the single agent of the mCRC were proved, which laid the foundation for the Phase II/III clinical study. 4/2013 S unakawa et al announced the results of a Phase I clinical study of regafenib in the treatment of solid tumors in Japan, this study evaluated the safety pharmacokinetic characteristics and anti-tumor activity of this product in Japanese patients. The toxicity of this study showed that there was no serious adverse reaction to the regimen, which could be used in Japanese patients. The results of a number of phase I clinical studies have shown that the drug toxicity is tolerable and may have anti-mCRC activity. The results published by Japanese scholar Sunakawa and others preliminarily confirmed the drug tolerability and anti-tumor activity of this product in Asian mCRC patients. The above research results show encouraging research prospects. 2. Phase III clinical study: based on the phase I clinical study of the treatment of mCRC with the treatment of mCRC, in order to obtain more sufficient and strong evidence for the application of mCRC, A large international multi-center Phase III clinical study was initiated in 2010. In COR-RECT, Grothey et al. published the results of this international, multicenter, double-blind clinical trial (trial) of mCRC patients with disease progression after standard chemotherapy, A total of 760 mCRC patients were screened at 16 national centers in North America, Europe, Asia and Australia, patients were randomly assigned in a 2: 1 ratio to the placebo group and the regaffinil group; All patients were pathologically diagnosed as colorectal adenocarcinoma, the patient also presented with disease progression when receiving local standard treatment or within 3 months after the end of treatment, the main efficacy evaluation index of this study is overall survival (OS), and the supportive efficacy observation indexes include PFS and tumor objective response rate (RR), the final results showed a significant improvement in median OS and PFS in the regerafenib group: the hazard ratio (HR) for OS in the regerafenib group versus the placebo group was 0.77, with a median OS of 6.4 months and 5.0 months, respectively; the HR for PFS was 0.49, and the median PFS was 1.9 months and 1.7 months, respectively. In addition, the study found that the OS was prolonged in patients with either K-Ras gene wild type or mutant type, although the RR comparison between the two groups was not statistically significant, and no patients achieved CR, but the rate of disease control (DCR) was 41% in the regaffinil group and 15% in the placebo group. After the interim analysis, the double-blind limit was removed from the clinical study, and patients in the placebo group could be transferred to the treatment group for which the toxicity was small and well tolerated compared to traditional cytotoxic drugs, however, the drug still has common adverse reactions similar to other molecularly targeted drugs. In the correction trial, the incidence of treatment-related adverse reactions (mainly Fatigue and hand-foot syndrome) was 93%, grade 3-4 treatment-related adverse events occurred in 61% patients (270) in the placebo group and in 54% patients (17%), fatigue, 48 cases (9.6%), Diarrhea 36 cases (7%), hypertension 36 cases (7%), skin rash or peeling 29 cases (6%), A total of 110 patients died, of which 11 died of serious adverse reactions caused by treatment, 8 of which 2 died Pneumonia and 2 died of gastrointestinal bleeding, 4 cases died of intestinal obstruction, pulmonary hemorrhage, epilepsy and sudden death respectively. In addition, 333 (67%) of the patients in the regafenib group and 57 (23%) of the placebo group had to adjust their doses due to serious adverse events, however, most of the patients were still able to continue the treatment after dose adjustment. The results of this study suggest that, for patients with mCRC who are resistant to standard treatment, the only small molecule multi-kinase inhibitor that has been shown to prolong their survival, and its safety is consistent with the results of previous clinical studies, no serious adverse reactions. Therefore, it is possible that the treatment of rilafenib may be another treatment option for refractory mCRC after multi-line therapy. |
| synthesis | Method 1: 2-picolinic acid as raw material, after chlorination, amidation of 4-chloro-2-pyridinecarboxamide hydrochloride, 4-amino-3-fluorophenol, 4-chloro-3-trifluoromethylphenyl isocyanate one-pot method to obtain regofenib, the specific reaction process is as follows: Method 2: 4-chloro-2-pyridinecarboxamide is obtained from 2-piperidinecarboxylic acid by chlorination, methanolysis and amidation, nucleophilic substitution with 4-amino-3-fluorophenol affords 4-(4-amino-3-trifluoromethyl)-n-methylpyridine-2-carboxamide, then it is condensed with 4-chloro-3-trifluoromethylphenyl isocyanate to obtain regerfenide. The specific reaction process is as follows: |
| pharmacokinetics | during the 24h dosing interval, multiple plasma concentration peaks were observed, which are highly bound to the human plasma protein (99.5%). And uridine diphosphate glucuronosyltransferase (UGT1A9) metabolism, the main metabolite of ranafenib in human plasma determined at steady state is N-oxide (M-2) and N-oxide and N-demethylate (M-5), both with similar in vitro pharmacological activity and high protein binding rates at steady-state concentrations of M-2 and M-5 (99.8% and 99.95%, respectively) the geometric mean elimination half-life of plasma after a single oral dose of M-2 mg was 28H (14-58H) and 25H (14-32H), respectively. M-5 has a longer mean elimination half-life of 51H (32-70h) within 12 days after administration of a 120mg dose of radiolabeled oral solution, approximately 71% of the radiolabeled dose was excreted in feces (47% of parent compound, 24% of metabolite). About 19% were excreted in urine (17% were glucuronides). |
| indication | unresectable, advanced or recurrent colorectal cancer, gastrointestinal stromal tumor aggravated by tumor chemotherapy. |
| specification | 40mg (calculated as regaffenib hydrate). |
| usage and dosage | under normal circumstances, adults are given 160mg once daily for three weeks, then rest for a week, this as a cycle. |
| adverse reactions | , including hand-foot syndrome Fatigue Diarrhea hypertensive rash or peeling, etc., but by adjusting the drug dose, most patients can still tolerate.|
| use in pregnant and lactating women | administration in pregnant and lactating women is prohibited. |
| Use in Children | the safety of low birth weight infants, neonates, infants or children has not been established. |
| medication for elderly patients | the physical function of the elderly is decreased, and the patient's condition should be observed while taking it. |
| Main reference materials | [1] Wang Xiao, a Democratic editor. Practical Integrative Oncology. Beijing: Chinese Medicine Press. 2014 [2] Wang Qing et al. Molecular targeted therapy for colorectal cancer. Shanghai Medical University. 2015,36(21):21-27. [3] Wang Weilin et al. Advances in anti-angiogenic targeted therapy for advanced colorectal cancer. Medical Review. 2015,21(13):2366-2368. [4] Li xueshong et al. Advances in molecular targeted therapy for hepatocellular carcinoma. Chinese Journal of Practical Surgery. 2014,34(8):786-789. [5] Liu Zheng exercise, etc. Progress in the treatment of metastatic and recurrent colorectal cancer with regafenib. Journal of Clinical Oncology. 2014,19(2):176-179. [6] Wang Decai et al. One-pot synthesis of regorafenib. Application No. 201510098300.2. Application date 2015-03-05. [7] Sun Song et al. A method for preparing regorafenib. Application No. 201510862570.6. Application date 2015-11-30. [8] regorafenib. http://zy.yaozh.com/data/medical/00061354.pdf. [9] Liu Changyan et al. Research progress of anticancer drugs blocking MAPK signaling pathway. Journal of Pharmaceutical Sciences of PLA. 2015, 31(6):548-551. |
Last Update：2024-04-09 21:21:28
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