3543-75-7 Usage
Description
Bendamustine hydrochloride is a nitrogen mustard and purine analog that functions as a DNA-damaging agent. It was initially developed in the early 1860s by Ozegowski and his colleagues, with the aim of connecting an alkylated chloremethine to a purine and amino acids. Bendamustine hydrochloride is characterized by its water solubility compared to chlorambucil and has been widely applied in the treatment of various blood malignancies and solid tumors.
Uses
1. Used in Anticancer Applications:
Bendamustine hydrochloride is used as an anticancer drug for the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, multiple myeloma, and breast cancer, among other solid tumors. It has demonstrated impressive efficacy in reducing recurrence rates and death rates, with minimal adverse reactions and good safety profiles.
2. Used in Drug Development:
Bendamustine hydrochloride is used as a chemotherapy agent for high-throughput screening to test interactions with other compounds, such as BAY87-2243. It is also used as an inhibitor to E3 ubiquitin-protein ligase RNF3 (HOIP) in matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) assays.
3. Used in Clinical Studies:
Bendamustine hydrochloride has been utilized in clinical studies for both monotherapy and combination therapy, with its clinical protocols designated as firstor second-line treatment options for various hematological malignancies by European and American clinical guidelines.
4. Used in Pharmaceutical Industry:
Bendamustine hydrochloride has been marketed under different trade names, such as "Cytostasan" (1971-1992), "Ribomustine" (1993), "Ribomustin" (2003, Germany), and "Treanda" (2008, United States). It is used as an alkylating agent recently approved by the FDA for the treatment of chronic lymphocytic leukemia.
5. Used in Research and Development:
Bendamustine hydrochloride is used in research to monitor spliced and unspliced gene expression in chronic lymphocytic leukemia (CLL) samples, contributing to the understanding of the disease's molecular mechanisms and the development of targeted therapies.
Indications
In March 2008, the US Food and Drug Authority (briefly called FDA) first approved bendamustine hydrochloride for the treatment of chronic lymphocytic leukemia (CLL). In October of the same year, FDA had approved for the second indication of the drug: the indolent B-cell non-Hodgkin's lymphoma (NHL) patients who have their symptoms still be in progress during the treatment with either rituximab or rituximab-containing regimen or within 6 months of the treatment.
The dose and medication
The lyophilized powder of bendamustine is white to off-white. Its specification is 100mg/tube. This storage temperature of this medicine should not exceed 30 ℃ and should be protected from light and should be temporarily prepared before use.
Preparation process: Every 100 mg of the drug must be first dissolved in 20ml of sterile water (for injection), fully shake until completely dissolve it into a clear, colorless or pale yellow solution with dissolution time generally being not more than 5 minutes and the final dissolving concentration being 5mg/ml. Within 30 minutes after the dissolution, extract certain amount of bendamustine solution according to the necessity, transfer it to a 500ml Sodium Chloride Injection (0.9%) or glucose-sodium chloride injection (2.5%/0.45%), and make sure the final concentration of benzene bendamustine in injection be between 0.2~0.6mg/ml. The prepared injection can be kept refrigerated for 24 hours at 2~8 ℃, or stored for 3 hours at room temperature and natural light.
Upon the treatment of chronic lymphocytic leukemia, take 28-day as one treatment cycle. It normally takes six treatment cycles. Drugs should be administered at the first day and the second day of each cycle of treatment; the recommended dose is 100mg/m2. The drug is administered through intravenous infusion with each administration time being no less than 30 minutes.
Upon treatment of indolent B-cell non-Hodgkin's lymphoma, take 21-day as one treatment cycle. It normally takes eight treatment cycles. The drugs should be administered at the first day and the second day of each cycle of treatment with the recommended dose being 120 mg/m2 and each administration time being no less than 60 minutes.
Pharmacological effects
The exact mechanism of action of bendamustine hydrochloride is not yet clear. But it is already known that the drug is a carry a chloremethine derivative carrying a purine-like benzimidazole ring with dual mechanisms of action of both alkylating agents and purine analogs (anti-metabolite). Bendamustine hydrochloride can cause cell death through several different pathways and is effective in treating both division cells as well as stationary phase cells.
The above information is edited by the lookchem of Dai Xiongfeng.
Pharmacokinetics
The plasma protein binding rate of bendamustine hydrochloride should be 94% to 96%. Data has shown that this drug is generally not mutually substitutable with other protein bound drugs. The mean steady-state volume of distribution of bendamustine hydrochloride is approximately 25L. Its whole blood/plasma concentration ratio is 0.84 to 0.86. Bendamustine hydrochloride is mainly metabolized through hydrolysis while forming low-cytotoxic metabolites. The drug can be converted to two active metabolites, M3 and M4 via CYP1A2 metabolic pathway. But the plasma concentrations of both the two metabolites only correspond to 1/10 and 1/100, respectively of the parent compound, and therefore, it can be speculated that the cytotoxic effect of bendamustine mainly orginiates from itself instead of its metabolites.
Contraindications
Patients who are allergic to Bendamustine hydrochloride and mannitol should be disabled for using it.
Drug Interactions
When used in combination with the CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin), it may increase blood concentrations of bendamustine while causing the decrease of the concentration of its metabolites M3 and M4.
When used in combination with CYP1A2 inducers (such as omeprazole, smoking, etc.), it may reduce the blood concentration of bendamustine while increasing the concentration of it metabolites M3 and M4.
Adverse reactions and side effects
Common adverse reactions include nausea, vomiting, diarrhea, fatigue, weakness, skin rashes, itching, some kinds of infection symptoms and body signs (such as persistent sore throat, fever and chills), easy for bruising/bleeding and ulcers in the mouth; in some serious adverse reactions, there may be bone marrow suppression and tumor lysis syndrome.
It may cause mild or severe allergic reaction. During the process of administration or the early phase of post-administration, there may be some allergic symptoms such as rash, facial swelling, and difficulty in breathing.
It may negatively affect the fetus, so women who are during treatment and within three months after treatment should take appropriate contraceptive measures as well as stop breast-feeding.
Biological Activity
Cytostatic agent that displays activity in non-Hodgkin's lymphomas. Exhibits bifunctionality; combines DNA alkylating properties with those of purine analogs.
Biochem/physiol Actions
Bendamustine is a therapeutic agent employed in treating lymphomas and chronic lymphocytic leukemia. It may be useful in central nervous system (CNS) malignancies treatment regimen due to its penetration capacity into brain tissue. Bendamustine is a promising candidate for non-Hodgkin lymphoma and Hodgkin lymphoma therapies.
Clinical Use
Alkylating agent:
CLL, NHL and multiple myeloma
Metabolism
A major route of clearance of bendamustine is
the hydrolysis to monohydroxy- and dihydroxybendamustine. Formation of N-desmethyl-bendamustine
and gamma-hydroxy-bendamustine by hepatic
metabolism involves cytochrome P450 (CYP) 1A2
isoenzyme. Another major route of bendamustine
metabolism involves conjugation with glutathione.
Excreted in the urine and faeces as unchanged drug and
metabolites.
references
[1]. leoni lm, bailey b, reifert j, bendall hh, zeller rw, corbeil j, elliott g, niemeyer cc. bendamustine (treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. clin cancer res. 2008 jan 1;14(1):309-17. [2]. gaul l, mandl-weber s, baumann p, emmerich b, schmidmaier r. bendamustine induces g2 cell cycle arrest and apoptosis in myeloma cells: the role of atm-chk2-cdc25a and atm-p53-p21-pathways. j cancer res clin oncol. 2008 feb;134(2):245-53. [3]. roué g, lópez-guerra m, milpied p, pérez-galán p, villamor n, montserrat e, campo e, colomer d. bendamustine is effective in p53-deficient b-cell neoplasms and requires oxidative stress and caspase-independent signaling. clin cancer res. 2008 nov 1;14(21):6907-15. [4]. cai b, wang s, huang j, lee ck, gao c, liu b. cladribine and bendamustine exhibit inhibitory activity in dexamethasone-sensitive and -resistant multiple myeloma cells. am j transl res. 2013;5(1):36-46.
Check Digit Verification of cas no
The CAS Registry Mumber 3543-75-7 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 3,5,4 and 3 respectively; the second part has 2 digits, 7 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 3543-75:
(6*3)+(5*5)+(4*4)+(3*3)+(2*7)+(1*5)=87
87 % 10 = 7
So 3543-75-7 is a valid CAS Registry Number.
InChI:InChI=1/C16H21Cl2N3O2.ClH/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23;/h5-6,11H,2-4,7-10H2,1H3,(H,22,23);1H
3543-75-7Relevant articles and documents
Bendamustine hydrochloride preparation method suitable for industrial production
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Paragraph 0041; 0046-0050; 0053-0055; 0058-0060; 0065-0068, (2021/04/10)
The invention provides a synthetic method of bendamustine hydrochloride. According to the synthetic method, residual thionyl chloride in a chlorination reaction is removed by using a proper solvent, and water is added for crystallization after part of reaction liquid is evaporated after a hydrolysis reaction is finished, so that the generation of impurities can be obviously reduced, the product purity is improved, and the product color is improved. By adopting the method disclosed by the invention, the pure white bendamustine hydrochloride product with the purity of 99.6% or above and the single impurity content of 0.3% or below can be prepared on a laboratory scale and a production scale without refining steps and decoloration operation, the purity of the product after re-crystallization and refining can reach 99.8% or below, the single impurity content is 0.1% or below, the quality requirements of national chemical bulk drugs are met, and qualified bulk drugs can be provided for research and production of bendamustine hydrochloride for injection. The method is mild in reaction condition, safe, simple and convenient to operate and suitable for industrial large-scale production.
Solid Forms Of Bendamustine Hydrochlorid
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Paragraph 0135; 0136; 0137; 0138; 0139; 0140; 0141, (2017/01/12)
Solid forms of bendamustine hydrochloride are described. The invention relates to a composition containing bendamustine, a pharmaceutical composition containing the bendamustine, methods for their repeat preparation, and pharmaceutical uses thereof.
Process for preparation of Bendamustine
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, (2014/02/15)
The present invention relates to a method for preparation of alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7) from 2-fluoro-5-nitroaniline, comprising the steps of: a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride, conversion of compound (1) to methylammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoate (2) using methylamine; conversion of compound (2) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and condensation of compound (3) to 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4), b) esterification of the product (4) of step a) to alkyl 4-(1-methyl-5-nitro1H-benzimidazol-2-yl)butanoate (5), c) reduction of the product of step b) to alkyl 4-(5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (6), and d) conversion of the product of step c) to alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7).
