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Bendamustine hydrochloride
- Iupac Name：4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydrochloride
- CAS No.: 3543-75-7
- Molecular Weight：394.72
- Modify Date.: 2022-11-29 11:32
- Introduction:
Bendamustine hydrochloride is a DNA cross-linking agent that causes DNA breaks, with alkylating and antimetabolite properties.
Bendamustine is a parenterally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of chronic lymphocytic leukemia and refractory forms of non-Hodgkin lymphoma. Bendamustine therapy is associated with minor transient serum enzyme elevations during treatment and to rare instances of clinically apparent liver injury, with jaundice generally arising as a part of a generalized hypersensitivity syndrome. Bendamustine also has potent immunosuppressive activity and can cause reactivation of chronic hepatitis B that can be severe and even fatal.|Bendamustine Hydrochloride is the hydrochloride salt of bendamustine, a bifunctional mechlorethamine derivative with alkylator and antimetabolite activities. Bendamustine possesses three active moieties: an alkylating group; a benzimidazole ring, which may act as a purine analogue; and a butyric acid side chain. Although its exact mechanism of action is unknown this agent appears to act primarily as an alkylator. Bendamustine metabolites alkylate and crosslink macromolecules, resulting in DNA, RNA and protein synthesis inhibition, and, subsequently, apoptosis. Bendamustine may differ from other alkylators in that it may be more potent in activating p53-dependent stress pathways and inducing apoptosis; it may induce mitotic catastrophe; and it may activate a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Accordingly, this agent may be more efficacious and less susceptible to drug resistance than other alkylators.|A nitrogen mustard compound that functions as an ALKYLATING ANTINEOPLASTIC AGENT and is used in the treatment of CHRONIC LYMPHOCYTIC LEUKEMIA and NON-HODGKIN'S LYMPHOMA.
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1. Names and Identifiers
- 1.1 Name
- Bendamustine hydrochloride
- 1.2 Synonyms
1H-Benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl-, hydrochloride (1:1) 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl-, monohydrochloride 1-methyl-5-bis(2-chloroethyl)amino-2-benzimidazolinebutryric acid hydrochloride 1-methyl-5-bis(2-chloroethyl)amino-2-benzimidazolinebutryricacihydrochlor 4-(5-(Bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoic acid hydrochloride 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoic acid hydrochloride 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoic acid hydrochloride (1:1) 5-(Bis(2-chloroethyl)amino)-1-methyl-1H-benzimidazole-2-butanoic Acid Monohydrochloride acide 4-{5-[bis(2-chloroéthyl)amino]-1-méthyl-1H-benzimidazol-2-yl}butanoïque chlorhydrate BendaMustin HCl BENDAMUSTIN HYDROCHLORIDE Bendamustine (hydrochloride) BENDAMUSTINE HCL Bendamustine Hydrochloride Hydrate Bendamustinhydrochlorid Bendamustinum CYTOSTASAN CytostasanHCl gamma(1-methyl-5-bis(beta-chloraethyl)aminobenzimidazoyl-2)buttersaeurehydro Levact MFCD01658758 Ribomustin Treanda ZIMET-33/93
- 1.3 CAS No.
- 3543-75-7
- 1.4 CID
- 77082
- 1.5 EINECS(EC#)
- 631-540-0
- 1.6 Molecular Formula
- C16H22Cl3N3O2 (isomer)
- 1.7 Inchi
- InChI=1S/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
- 1.8 InChkey
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N
- 1.9 Canonical Smiles
- CN1C2=C(C=C(C=C2)N(CCCl)CCCl)N=C1CCCC(=O)O.Cl
- 1.10 Isomers Smiles
- CN1C2=C(C=C(C=C2)N(CCCl)CCCl)N=C1CCCC(=O)O.Cl
2. Properties
- 2.1 Melting point
- 149-151°C
- 2.1 Boiling point
- 585.2 °C at 760 mmHg
- 2.1 Flash Point
- 585.2 °C at 760 mmHg
- 2.1 Precise Quality
- 393.07800
- 2.1 PSA
- 58.36000
- 2.1 logP
- 4.06660
- 2.1 Solubility
- H2O: >30mg/mL
- 2.2 Appearance
- off-white
- 2.3 Storage
- Desiccate at RT
- 2.4 Chemical Properties
- Pale Brown Crystals
- 2.5 Color/Form
- Powder
- 2.6 Water Solubility
- H2O: >30mg/mL
- 2.7 StorageTemp
- room temp
3. Use and Manufacturing
- 3.1 Methods of Manufacturing
- HBI-ethylbutyrate (molecular weight = 349.42 g/mol) was dissolved in CHCICharge 600 ml lot I dichloromethane in round bottom flask at 25-30° C. and then charge stage E product. Slowly add 24 ml Thionyl chloride drop wise below 30° C. (exothermic reaction). Raise the temperature to 55-60° C. and maintained for 2 hrs. Cooled the reaction mass to 25-30° C. Added 400 ml of dichloromethane. Added 200 ml lot I purified water and separated the layer. Combined the organic layer and wash it with 200 ml saturated sodium bicarbonate solution. Combined the organic layer and wash it with 200 ml saturated sodium chloride solution. Settle and separated the layer. Combined the organic layer and dry it over sodium sulphate. Distill out the reaction mass under vacuum at 40° C. upto one volume. Then added 370 ml N-heptane into the reaction mass and stirred for 2 hrs at room temperature. Filter the reaction mass and washed it with 10 ml N-heptane and suck dried for 1 hr. Taken the insitu mass in round bottom flask and added 40 ml dilute hydrochloric acid into the reaction mass. Slowly heat the reaction mass to 55-60° C. Maintained for 7-8 hrs (checking and confirming the impurity profile). Cool the reaction mass to room temperature and stir for 3-4 hrs. Filter the reaction mass and wash it with 2 ml chilled water. [0174] Again Charge crude Bendamustine Hydrochloride monohydrate isolated in the wet stage in round bottom flask containing 136 ml purified water and 40 ml hydrochloric acid (Preparation of bendamustine hydrochloride. 4-{5-[Bis-(2- chIoroethyl)amino]-1-methyl-1 H-benzimidazol-2-yl}-butyric acid isopropyl ester (3 g) is charged into a round bottom flask and 50percent hydrochloric acid solution (21 mL) is slowly added. The mixture is heated to 35-40°C, maintained for about 90 minutes, and concentrated under vacuum at about 55-58°C, to give a viscous mass. Warm water (12 mL, 55-60°C) is added and the mixture is stirred for about 1 hour. The obtained solid is collected by filtration, , washed with water (3 mL), and dried under vacuum at 45-50°C for 4 hours to give bendamustinehydrochloride. Yield: 2.2 g (75percent).
- 3.2 Usage
- Used as an anticancer drug
4. Safety and Handling
- 4.1 Hazard Codes
- T,Xn
- 4.1 Risk Statements
- 60-61-22-40
- 4.1 Safety Statements
- 36-37
- 4.1 Packing Group
- III
- 4.1 Hazard Class
- 6.1
- 4.1 Hazard Declaration
- H301
- 4.1 RIDADR
- UN 2811 6.1 / PGIII
- 4.1 Caution Statement
- P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, P501
- 4.1 WGK Germany
- 3
- 4.1 RTECS
- DE1590000
- 4.1 Toxicity
- LD50 (monohydrate) in mice, rats (mg/kg): 400-500, 200-300 orally; 80, 40 i.v. (Horn)
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Acute toxicity - Oral, Category 3
Carcinogenicity, Category 2
Reproductive toxicity, Category 1B
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |   |
| Signal word | Danger |
| Hazard statement(s) | H301 Toxic if swallowed H351 Suspected of causing cancer H360 May damage fertility or the unborn child |
| Precautionary statement(s) | |
| Prevention | P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. |
| Response | P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026 P321 Specific treatment (see ... on this label). P330 Rinse mouth. P308+P313 IF exposed or concerned: Get medical advice/ attention. |
| Storage | P405 Store locked up. |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
7. Synthesis Route
3543-75-7Total: 20 Synthesis Route
9. Other Information
- 9.0 Merck
- 14,1034
- 9.1 Product description
- Bendamustine hydrochloride was first successfully developed in the early 1860s by the Ozegowski and his colleagues in the “Microbiology Experiment Association (Jena in Germany)”. The original purpose of developing it is intended to make a kind of alkylated chloremethine (a non-effective alkylating agent) be connected to a purine and amino acids. Compared with the chlorambucil, the main advantage of the newly synthesized compound is its water solubility. It was then widely applied. However, it is not until the end of the Cold War before the drug had been applied in Europe to clinical studies in either a number of single medication or in combination with other drugs for treating various kinds of blood malignancies and non-Hodgkin's lymphoma, multiple myeloma, CLL and breast cancer and some other solid tumors. The efficacy is very impressive. The drug had significantly reduced the recurrence rate and death rate with small adverse reactions and good security. So far, the clinical protocols of both monotherapy and combination therapy of bendamustine hydrochloride has been designated as either first-or second-line treatment option for treating various kinds of hematological malignancies by Europe and America clinical guidelines.
From 1971 to 1992, Bendamustine was sold by the Jena pharmaceutical companies in the trade name of “Cytostasan”. From 1993, the cell growth inhibitor entered into market with the trade name “Ribomustine” mediated by Ribosepharm Company.
In 2003, the bendamustine hydrochloride product developed by German Ribosepharm Company entered into market in Germany with the trade name "Ribomustin".
In 2008, the Bendamustine hydrochloride injection product developed by the United States Cephalon Company entered into market in United States under the trade name “Treanda” which is used for the treatment of the relapsed and refractory B-cell non-Hodgkin’s lymphoma which is failed be to be treated rituximab monotherapy.
- 9.2 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.
- 9.3 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.
- 9.4 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.
- 9.5 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.
- 9.6 Contraindications
- Patients who are allergic to Bendamustine hydrochloride and mannitol should be disabled for using it.
- 9.7 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.
- 9.8 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.
- 9.9 Description
- Bendamustine is a purine analog and DNA alkylating agent.1 It inhibits growth of SKW-3, Reh, CML-T1, BV-173, and HL-60 leukemia cell lines (IC50s = 27.0, 28.6, 15.6, 20.8, and 57.7 μM, respectively) but not MCF-7 and MDA-MB-231 breast cancer cell lines (IC50s = >200 and >200 μM, respectively).2 It kills B cell-chronic lymphocytic leukemia (B-CLL) cells derived from na?ve and bendamustine-pretreated patients (LD50s = 6.8-8.3 and 3.8-4.9 mg/ml, respectively).3 Bendamustine (50 mg/kg) inhibits tumor growth by 9% and 96% alone and in combination with ofatumumab, respectively, in a JVM-3 CLL mouse xenograft model.4 It activates the DNA-damage stress response, the base excision DNA repair pathway, and apoptosis, as well as inhibits mitotic checkpoints and induces mitotic catastrophe.1 Formulations containing bendamustine have been used to treat CLL and non-Hodgkin lymphoma.
- 9.10 Chemical Properties
- Pale Brown Crystals
- 9.11 Uses
- Used as an anticancer drug
- 9.12 Uses
- Bendamustine HCL is a DNA-damaging agent with IC50 of 50 μM.
- 9.13 Uses
- alkylating agent recently approved by the FDA for treatment of Chronic Lymphocytic Leukemia
- 9.14 Uses
-
Bendamustine hydrochloride hydrate has been used as:
- a chemotherapy agent for chronic lymphocytic leukemia (CLL) samples to monitor spliced and unspliced gene expression
- an inhibitor to E3 ubiquitin-protein ligase RNF3 (HOIP) in?matrix-assisted laser desorption ionization time-of-flight mass spectrometry?(MALDI-TOF) assay
- a cytotoxic chemotherapeutic drug in high-throughput screening to test interaction with BAY87-2243
- 9.15 Storage Conditions
- HBI-ethylbutyrate (molecular weight = 349.42 g/mol) was dissolved in CHCICharge 600 ml lot I dichloromethane in round bottom flask at 25-30° C. and then charge stage E product. Slowly add 24 ml Thionyl chloride drop wise below 30° C. (exothermic reaction). Raise the temperature to 55-60° C. and maintained for 2 hrs. Cooled the reaction mass to 25-30° C. Added 400 ml of dichloromethane. Added 200 ml lot I purified water and separated the layer. Combined the organic layer and wash it with 200 ml saturated sodium bicarbonate solution. Combined the organic layer and wash it with 200 ml saturated sodium chloride solution. Settle and separated the layer. Combined the organic layer and dry it over sodium sulphate. Distill out the reaction mass under vacuum at 40° C. upto one volume. Then added 370 ml N-heptane into the reaction mass and stirred for 2 hrs at room temperature. Filter the reaction mass and washed it with 10 ml N-heptane and suck dried for 1 hr. Taken the insitu mass in round bottom flask and added 40 ml dilute hydrochloric acid into the reaction mass. Slowly heat the reaction mass to 55-60° C. Maintained for 7-8 hrs (checking and confirming the impurity profile). Cool the reaction mass to room temperature and stir for 3-4 hrs. Filter the reaction mass and wash it with 2 ml chilled water. [0174] Again Charge crude Bendamustine Hydrochloride monohydrate isolated in the wet stage in round bottom flask containing 136 ml purified water and 40 ml hydrochloric acid (Preparation of bendamustine hydrochloride. 4-{5-[Bis-(2- chIoroethyl)amino]-1-methyl-1 H-benzimidazol-2-yl}-butyric acid isopropyl ester (3 g) is charged into a round bottom flask and 50percent hydrochloric acid solution (21 mL) is slowly added. The mixture is heated to 35-40°C, maintained for about 90 minutes, and concentrated under vacuum at about 55-58°C, to give a viscous mass. Warm water (12 mL, 55-60°C) is added and the mixture is stirred for about 1 hour. The obtained solid is collected by filtration, , washed with water (3 mL), and dried under vacuum at 45-50°C for 4 hours to give bendamustinehydrochloride. Yield: 2.2 g (75percent).
- 9.16 Livertox Summary
- Bendamustine is a parenterally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of chronic lymphocytic leukemia and refractory forms of non-Hodgkin lymphoma. Bendamustine therapy is associated with minor transient serum enzyme elevations during treatment and to rare instances of clinically apparent liver injury, with jaundice generally arising as a part of a generalized hypersensitivity syndrome. Bendamustine also has potent immunosuppressive activity and can cause reactivation of chronic hepatitis B that can be severe and even fatal.
- 9.17 Drug Classes
- Antineoplastic Agents, Alkylating Agents
- 9.18 Mesh
- A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)
- 9.19 Use Classification
- Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
10. Computational chemical data
- Molecular Weight: 394.72g/mol
- Molecular Formula: C16H22Cl3N3O2
- Compound Is Canonicalized: True
- XLogP3-AA: null
- Exact Mass: 393.077760
- Monoisotopic Mass: 393.077760
- Complexity: 380
- Rotatable Bond Count: 9
- Hydrogen Bond Donor Count: 2
- Hydrogen Bond Acceptor Count: 4
- Topological Polar Surface Area: 58.4
- Heavy Atom Count: 24
- Defined Atom Stereocenter Count: 0
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 2
- CACTVS Substructure Key Fingerprint: AAADceB7MAAGAAAAAAAAAAAAAAAAAWAAAAAwAAAAAAAAAFgB8AAAHgIACAAACAvBl0Qz2LcMEgCoASbybACCgC0hEqAJ2CE4dJiIaLLA2dHUZAhsgALIyCeYEQIAAACAAAQAACAAAQAACAAAQAAAAAAAAA==
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