444731-52-6

Usage

Uses

Used in Oncology:
Pazopanib is used as an anticancer agent for the treatment of advanced renal cell carcinoma, soft tissue sarcoma, epithelial ovarian cancer, and non-small cell lung cancer. It works by inhibiting angiogenesis, the process of new blood vessel formation that tumors rely on for growth and survival.
Used in Thyroid Cancer Treatment:
Pazopanib (trade name Votrient) has been shown to effectively treat thyroid cancer, reducing tumor volume in half of the patients and demonstrating a higher response rate compared to commonly used drugs. It also provides a more prolonged stability that can be maintained for a considerable period of treatment.
Used in Drug Formulations:
Formulations containing pazopanib have been utilized in the treatment of cancer, particularly in targeting multiple myeloma cells and reducing tumor growth, angiogenesis, and increasing survival in a multiple myeloma mouse xenograft model.
Used in the Pharmaceutical Industry:
Pazopanib is used as a potent and selective multi-targeted receptor tyrosine kinase inhibitor in the development of new drugs for cancer treatment, due to its ability to inhibit various receptors involved in tumor growth and angiogenesis.
Used in Clinical Research:
Pazopanib has been the subject of clinical research at institutions such as the Mayo Clinical Research Center, where its effectiveness in treating various types of cancer has been studied and documented.
Approved by Regulatory Agencies:
The US Food and Drug Administration (FDA) approved pazopanib (trade name Votrient) for the treatment of kidney cancer on October 19, 2009. The European Union conditionally approved it for advanced renal cell cancer and first-line treatment in patients with previously received cytokine therapy on June 15, 2010.

The efficacy of the treatment of advanced renal cell carcinoma

In order to investigate the efficacy of molecule targeting drug tyrosine kinase inhibitor pazopanib which inhibist the angiogenesis in patients with advanced renal cell carcinoma, People's Liberation Army General Hospital, in June 2006 to May 2007, the participation of pazopanib in patients with advanced renal cell carcinoma randomized clinical drug trials of outpatient 14 cases, were divided into pazopanib group (n = 10) and placebo group ( 4 cases), were treated with pazopanib 800mg/d and placebo after 12 weeks of treatment duration, according to the results of CT scan before and after medication , efficacy was determined . The results showed that the reduced average ratios of measurable disease focus of pazopanib and placebo patients were 27.6%,-2.8% (P

Adverse reactions

Diarrhea, hypertension, hair color change, nausea, loss of appetite, vomiting, fatigue, weakness, headache, abdominal pain and so on. Cause serious liver problems, so health care workers should take blood tests to monitor liver function before using the drug in patients and during treatment of patients. Hazardous to the fetus,people during pregnancy are forbid using this drug. Pazopanib can also lead to arrhythmias, during treatment patients should have regular electrocardiogram measuring heart rate, and regular blood tests to monitor electrolytes since an electrolyte imbalance will also play a role in arrhythmia.

Clinical Use

Tyrosine kinase inhibitor: Treatment of metastatic renal cell carcinoma and soft tissue sarcoma

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with clarithromycin, rifampicin and telithromycin. Antifungals: avoid with itraconazole, ketoconazole and voriconazole. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis). Antivirals: avoid with atazanavir, boceprevir, indinavir, ritonavir and saquinavir. Grapefruit juice: avoid concomitant administration. Avoid concomitant use with other inhibitors or inducers of CYP3A4. Dose alterations may be required.

Metabolism

Metabolism primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principle pazopanib metabolites account for only 6% of the exposure in plasma. One of these metabolites inhibits the proliferation of VEGF-stimulated human umbilical vein endothelial cells with a similar potency to that of pazopanib, the others are 10- to 20-fold less active. Therefore, activity of pazopanib is mainly dependent on parent pazopanib exposure. Elimination is mostly via the faeces.

InChI:InChI=1/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25);1H

Upstream product

• 444731-75-3 N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazole-6-amine 
• 6973-09-7 5-amino-2-methylbenzenesulfonamide 
• 635702-64-6 pazopanib hydrochloride 
• 6494-19-5 3-methyl-6-nitro-1H-indazole 
• 444731-73-1 2,3?dimethyl?6?nitro?2H?indazole 
• 444731-72-0 2,3-dimethyl-6-amino-2H-indazole 
• 1376676-65-1 N,2,3-trimethyl-2H-indazole-6-amine 
• 20191-74-6 2-ethyl-5-nitroaniline 
• 444731-74-2 N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine 
• 635702-64-6 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide hydrochloride 

Downstream Products

Relevant academic research and scientific papers

Switching on prodrugs using radiotherapy

Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy. [Figure not available: see fulltext.].

Preparation method and intermediate of Pazopanib

The invention discloses a preparation method and an intermediate of Pazopanib. The preparation method comprises the steps of carrying out two-step condensation reaction on 2,4-dichloro-5-nitropyrimidine so as to obtain a compound of a formula 5 (shown in the description), and carrying out reduction on the compound of the formula 5, so as to obtain Pazopanib. The preparation method has the beneficial effects that the yield of Pazopanib is increased, reaction conditions are mild, column chromatography purification is not required, and the preparation method is applicable to industrial production.

Pyrimidineamines as angiogenesis modulators

Pyrimidine derivatives, which are useful as VEGFR2 inhibitors are described herein. The described invention also includes methods of making such pyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

Design, synthesis and biological evaluation of pazopanib derivatives as antitumor agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR-2, EGFR, AKT1, ALK1, and ABL1. The anti-angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR-2 and ABL1 and higher anti-angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents.

A novel practical synthesis of pazopanib: An anticancer drug

Abstract: This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.

PROCESS FOR THE PREPARATION OF PAZOPANIP HCL AND CRYSTALLINE FORMS OF PAZOPANIB HCL

Various crystalline forms of Pazopanib HCl were prepared. In preferred embodiments the obtained Pazopanib HCl is essentially free from CPMI.

5- (4- (N- (2, 3 -DIMETHYL- 2H- INDAZOL- 6 -YL) -N-METHYLAMINO) PYRIMIDIN- 2 -YLAMINO) -2 -METHYLBENZENESULFONAMIDE

The present invention relates to novel forms of Pazopanib and a process for their preparation.

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Upstream product

• 444731-75-3 N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazole-6-amine 
• 6973-09-7 5-amino-2-methylbenzenesulfonamide 
• 635702-64-6 pazopanib hydrochloride 
• 6494-19-5 3-methyl-6-nitro-1H-indazole 
• 444731-73-1 2,3?dimethyl?6?nitro?2H?indazole 
• 444731-72-0 2,3-dimethyl-6-amino-2H-indazole 
• 1376676-65-1 N,2,3-trimethyl-2H-indazole-6-amine 
• 20191-74-6 2-ethyl-5-nitroaniline 
• 444731-74-2 N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine 
• 635702-64-6 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)-N-methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide hydrochloride 

Relevant academic research and scientific papers

Switching on prodrugs using radiotherapy

Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy. [Figure not available: see fulltext.].

Preparation method and intermediate of Pazopanib

The invention discloses a preparation method and an intermediate of Pazopanib. The preparation method comprises the steps of carrying out two-step condensation reaction on 2,4-dichloro-5-nitropyrimidine so as to obtain a compound of a formula 5 (shown in the description), and carrying out reduction on the compound of the formula 5, so as to obtain Pazopanib. The preparation method has the beneficial effects that the yield of Pazopanib is increased, reaction conditions are mild, column chromatography purification is not required, and the preparation method is applicable to industrial production.

Pyrimidineamines as angiogenesis modulators

Pyrimidine derivatives, which are useful as VEGFR2 inhibitors are described herein. The described invention also includes methods of making such pyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

Design, synthesis and biological evaluation of pazopanib derivatives as antitumor agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR-2, EGFR, AKT1, ALK1, and ABL1. The anti-angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR-2 and ABL1 and higher anti-angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents.

A novel practical synthesis of pazopanib: An anticancer drug

Abstract: This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.

PROCESS FOR THE PREPARATION OF PAZOPANIP HCL AND CRYSTALLINE FORMS OF PAZOPANIB HCL

Various crystalline forms of Pazopanib HCl were prepared. In preferred embodiments the obtained Pazopanib HCl is essentially free from CPMI.

5- (4- (N- (2, 3 -DIMETHYL- 2H- INDAZOL- 6 -YL) -N-METHYLAMINO) PYRIMIDIN- 2 -YLAMINO) -2 -METHYLBENZENESULFONAMIDE

The present invention relates to novel forms of Pazopanib and a process for their preparation.