100286-90-6 Usage
Uses
1. Antineoplastic: Irinotecan hydrochloride is used as an antineoplastic agent for its topoisomerase I inhibitory activity, which helps in the treatment of various cancers.
2. Inhibitor of topoisomerase I: It is used as an inhibitor of topoisomerase I, playing a crucial role in DNA replication and transcription.
Used in Oncology:
Irinotecan hydrochloride is used as a chemotherapeutic agent for the treatment of metastatic colon cancer when used in combination with 5-FU and leucovorin as a first-line treatment. It may also be used as a single agent in colorectal cancer as a second-line therapy when 5-FU therapy has failed.
Used in Cancer Research:
Irinotecan hydrochloride is used in combination with 5-fluorouracil for screening growth inhibitory functionality in MDA-MB-231 breast cancer cells, in chemosensitivity screening of high-grade appendiceal (HGA) and low-grade appendiceal (LGA) organoids, and as a chemotherapeutic agent in cytotoxicity studies in combination with heat shock proteins inhibitors (HSPC1) in HT29 colon cancer cells.
Used in Pharmaceutical Industry:
Irinotecan hydrochloride is used in the form of its trihydrate, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. It is converted via hydrolysis of the carbamate linkage to its active metabolite, SN-38, which is ~1000 times more active.
Chemical Properties:
Irinotecan hydrochloride is a yellow crystalline powder.
Brand Name:
Camptosar (Pharmacia & Upjohn); Topotecan.
Originator
Yakult Honsha (Japan)
Manufacturing Process
7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin was
synthesized by 2 methods.Method 1.7-Ethyl-10-hydroxycamptothecin (500 mg, 1.27 mmol) was suspended in dry
dioxane (400 ml) and dissolved therein by adding triethylamine (2 ml) to the
suspension under warming. This solution was stirred at room temperature
while introducing thereinto phosgene prepared toties quoties by decomposing
phosgene dimer (trichloromethoxychloroformate, 400 ml) in the presence of
an active carbon catalyst. After 0.5 hours, consumption of the starting
materials was confirmed and insoluble 10-chlorocarbonyloxy-7-
ethylcamptothecin was removed by filtration.10-Chlorocarbonyloxy-7-ethylcamptothecin (300 mg, 0.66 mmol) is
suspended in dry dioxane (50 ml). To this suspension is added 4-
piperidinopiperidine (330 mg, 1.96 mmol) as the amine, the reaction followed
by the after-treatment was carried out whereby the 7-ethyl-10-[4-(1-
piperidino)-1-piperidino]carbonyloxycamptothecin title compound (154 mg,
39.8%) was obtained.Method 2.7-Ethyl-10-hydroxycamptothecin (790 mg, 2.01 mmol) and 1-chlorocarbonyl-
4-piperidinopiperidine (910 mg, 3.95 mmol) were dissolved in anhydrous
pyridine (50 ml), and the mixture was stirred for 1 hour at 20°C. The reaction
mixture was evaporated to dryness in vacuo, the residue was dissolved in
CHCl3 (200 ml). The solution was washed successively with a 7% aqueous
solution of NaHCO3 (200 ml), a saturated aqueous solution NaCl, and the
CHCl3 layer was filtered, and evaporated in vacuo. The residual material was
decolorized by passing it through a short silica gel column. 7-Ethyl-10-[4-(1-
piperidino)-1-piperidino]carbonyloxycamptothecin was obtained as a pale
yellow mass, which was recrystallized from ethanol (ca. 60 ml) to give
colorless needles (750 mg, 63.5% in yield).To an ice-cooled suspension in distilled water (15 ml) of 7-ethyl-10-[1-(4-
piperidino)piperidino]carbonyloxycamptothecin (1.00 g, 1.7 mmol) was added
0.1 N HCl (15.3 ml, 1.53 mmol), and the suspension was stirred vigorously
for 5 minutes under cooling in an ice bath and filtered off. 7-Ethyl-10-[4-(1-
piperidino)-1-piperidino]carbonyloxycamptothecin hydrochloride was obtained
in yield 96%.
Therapeutic Function
Antineoplastic
Biological Activity
Inhibitor of DNA topoisomerase I that displays antitumor activity against a range of tumor types.
Biochem/physiol Actions
The anticancer agent, irinotecan, is a prodrug that is converted by tissue carboxylesterase to 7-ethyl-10-hydroxycamptothecin (SN-38), a potent inhibitor of DNA topoisomerase I. Its action is terminated by glucuronidation by UDP glucuronosyl transferase 1A1 (UGT1A1). It proves useful in radiation treatment of tumors by sensitizing tissue to radiation damage.
Clinical Use
In combination with fluorouracil, this prodrug camptothecin analogue is considered to be first-line therapy in the treatment of metastatic colorectal cancer. It also has shown efficacy in small cell and nonsmall cell lung cancers when used in combination with cisplatin.
Side effects
Delayed diarrhea induced by irinotecan is dose-limiting and potentially fatal, and vigorous loperamide therapy should be instituted at the first sign of symptoms. Acute diarrhea is attributed to the drug's ability to inhibit acetylcholinesterase and can be addressed through anticholinergic pretreatment. Pretreatment also helps patients to avoid “cholinergic syndrome,” a collection of annoying side effects that include flushing, sweating, blurred vision, lacrimation, and less commonly, bradycardia. Camptothecins also are myelosuppressive, and neutropenia can be severe, particularly in patients with elevated bilirubin levels. Extensive biotransformation also demands cautious use of irinotecan in patients with hepatic dysfunction.
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: concentration reduced by St John’s
wort - avoid.
Antifungals: increased toxicity with itraconazole -
avoid; concentration reduced by ketoconazole, but
active metabolite of irinotecan increased - avoid.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).
Antivirals: metabolism possibly inhibited by
atazanavir (increased risk of toxicity).
Cytotoxics: concentration of active metabolite of
irinotecan increased by lapatinib, consider reducing
dose of irinotecan; avoid with panitumumab;
concentration possibly increased by sorafenib.
Live vaccines: risk of generalised infections - avoid.
Metabolism
The drug is slowly bioactivated in the liver through hydrolysis of the C10-carbamate ester. The catalyzing enzyme is a saturable carboxylesterase known as irinotecan-converting enzyme. Levels of active metabolite, known as SN-38, are 50- to 100-fold lower than the parent drug, but preferential protein binding of the lactone (95%) permits significant plasma levels of the optimally active SN-38 compared to the hydroxy acid metabolite. SN-38 has a terminal half-life of 11.5 hours (compared to 5.0–9.6 hours for the prodrug parent) and is glucuronidated at the C10 phenol before elimination. CYP3A4 also cleaves the terminal piperidine ring through oxidation at the α-carbons, followed by hydrolysis of the resultant amides, producing inactive metabolites. Excretion of the parent drug and metabolites is renal (14–37%) and, to a lesser extent, biliary.
Check Digit Verification of cas no
The CAS Registry Mumber 100286-90-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,0,2,8 and 6 respectively; the second part has 2 digits, 9 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 100286-90:
(8*1)+(7*0)+(6*0)+(5*2)+(4*8)+(3*6)+(2*9)+(1*0)=86
86 % 10 = 6
So 100286-90-6 is a valid CAS Registry Number.
InChI:InChI=1/C33H38N4O6.ClH/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2;/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3;1H/t33-;/m0./s1
100286-90-6Relevant articles and documents
Scalable synthetic route to 2-amino-5-hydroxypropiophenone: Efficient formal synthesis of irinotecan
Rao, A. V. Rama,Rao, Ramakrishna,Yadav,Khagga, Mukkanti
, p. 1661 - 1667 (2013)
2-Amino-5-hydroxypropiophenone, a key precursor in the total synthesis of irinotecan, has been synthesized. Regioselective nitration and a SNAr displacement are the key steps involved in this strategy, which is high yielding, is economical, and has been performed on a plant scale. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
Preparation method of irinotecan hydrochloride
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Paragraph 0020; 0023; 0026; 0029; 0032, (2020/05/30)
The invention relates to a preparation method of irinotecan hydrochloride. The preparation method comprises the following steps: a) enabling 4-piperidylpiperidine and N, N'-carbonyldiimidazole to react with 7-ethyl-10-hydroxycamptothecine in an aprotic solvent containing a hemp and cotton resin compound to generate an irinotecan monomer, and b) adding water to dissolve the irinotecan monomer, adding a hydrochloric acid solution to adjust the pH value to 2-3, adding acetone of which the volume is 3-5 times that of the water, carrying out crystallizing, filtering and recrystallizing with a mixedsolvent of acetone and water, and carrying out vacuum drying to obtain the irinotecan hydrochloride finished product. Compared with the prior art, according to the invention, in preparatuion of irinotecan hydrochloride, no high-toxicity dangerous reagent is used, the N, N-dimethylformamide with relatively stable commercial easy-to-obtain property is used, a carbonyl group is introduced into N, N'-carbonyldiimidazole, an irinotecan monomer is obtained through a one-step reaction, the harsh condition that N, N'-carbonyldiimidazole needs to be anhydrous is avoided through cooperation with a hempand cotton resin compound, the reaction process is greatly simplified, the production period is shortened, and the preparation method has obvious industrial production advantages.
A preparation method of irinotecan hydrochloride (by machine translation)
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Paragraph 0027; 0033; 0034; 0040; 0041; 0047, (2019/06/27)
The invention relates to a preparation method of irinotecan hydrochloride. Its steps are: parent ring to camptothecin as raw material generated by the reaction with the aldehyde 7 - ethyl camptothecin; hydrogen peroxide oxidation then N - oxide - 7 - ethyl camptothecin; by the illumination rearrangement 7 - ethyl - 10 - hydroxy camptothecin; 4 - piperidyl with dimethyl carbonate reaction to produce 4 - piperidyl carbonic acid methyl ester; 7 - ethyl - 10 - hydroxy camptothecin with 4 - piperidyl carbonic acid methyl ester reaction generating irinotecan monomer; irinotecan monomers with hydrochloric salt to obtain the finished product of the irinotecan hydrochloride. Compared with the prior art, the present invention avoid the use of phosgene in the reaction process, chloroform poisonous substance, in production with safe, convenient, less pollution and the like; in addition, the synthetic method avoids the need of the prior process in the defects of the chromatographic column separation and purification, reduces the production cost of the irinotecan, has great economic benefit. (by machine translation)
Preparation method of irinotecan hydrochloride
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Paragraph 0062; 0066, (2017/07/06)
The invention discloses a preparation method of irinotecan hydrochloride. The preparation method comprises following steps: 1, chemical raw materials of racemic indolizine derivatives are taken as initial raw materials, ring closing reaction and alkali ring-opening reaction are carried out so as to obtain an organic acid intermediate; 2, a chiral amine and the organic acid intermediate are subjected to salt forming resolution so as to obtain a chiral intermediate; 3, the chiral intermediate is subjected to acid ring-opening reaction so as to remove the chiral amine; 4, esterification with a piperidine derivative, and salt forming are carried out so as to obtain the target product irinotecan hydrochloride. The preparation method is used for total synthesis of irinotecan hydrochloride, large scale production is realized, reaction conditions are mild, the preparation method is easy to control, product purity is 98% or higher, and the largest individual impurity content is lower than 0.1%.
A method for preparation of irinotecan of hydrochloric acid
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Paragraph 0045; 0046; 0047; 0048; 0049; 0050; 0051, (2017/01/09)
The present invention provides a method for preparation of irinotecan of hydrochloric acid. The method, through intermediate 7-ethyl -10-hydroxy camptothecin and 4-piperidyl formyl chloride or its salt, in the 4-dimethylamino-pyridine or its salt, or its analogs in the presence of a reaction, after concentration, washing, salt and other steps to a final product. The method of the invention avoid the use of regulating, easy to change pyridine take part in the reaction, reduced side reaction, has improved the purity of the product and the yield, the improvement of color and luster of the product at the same time, easy large-scale production.
PROCESS FOR THE MANUFACTURE OF IRINOTECAN HYDROCHLORIDE BY TOTAL SYNTHESIS
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Page/Page column 9, (2012/03/27)
Disclosed herein is a highly safe and easily scalable process for the production of 7-Ethyl- 10-hydroxycamptothecin and its conversion to Irinotecan hydrochloride by total synthesis.
PROCESS FOR THE PREPARATION OF 7-ETHYL-10-[4- (1-PIPERIDINO)- 1-PIPERIDINO] CARBONYLOXY-CAMPTOTHECIN HYDROCHLORIDE TRIHYDRATE
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Page/Page column 7, (2011/06/26)
The present invention relates to process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin hydrochloride trihydrate and process for the isolation of 1-chlorocarbonyl-4-piperidinopiperidine and novel crystalline form of 1-chlorocarbonyl-4-piperidinopiperidine and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin.
Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate
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Page/Page column 10, (2011/07/30)
The present invention relates to process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin hydrochloride trihydrate and process for the isolation of 1-chlorocarbonyl-4-piperidinopiperidine and novel crystalline form of 1-chlorocarbonyl-4-piperidinopiperidine and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin.
Crystalline irinotecan hydrochloride and methods for the preparation thereof
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Page/Page column 4, (2010/06/15)
Disclosed is a crystalline form of irinotecan hydrochloride (I) and processes for the preparation thereof from crude irinotecan hydrochloride or another polymorphic form of irinotecan. Said crystalline form is particularly suitable for industrial use, bec
CRYSTALLINE IRINOTECAN HYDROCHLORIDE AND METHODS FOR ITS PREPARATION
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Page/Page column 2-3, (2010/08/03)
Disclosed is a crystalline form of irinotecan hydrochloride (I) and processes for the preparation thereof from crude irinotecan hydrochloride or another polymorphic form of irinotecan. Said crystalline form is particularly suitable for industrial use, bec
