176161-24-3

Basic information

• Product Name: BENZIMIDAVIR
• Synonyms: 5,6-DICHLORO-2-(ISOPROPYLAMINO)-1-(BETA-L-RIBOFURANOSYL)-1H-BENZIMIDAZOLE;BENZIMIDAVIR;BENZIMIDAVIR, 5,6-DICHLORO-2-（ISOPROPYLAMINO）-1-(β-L-RIBOFURANOSYL)-LH-BENZIMIDAZOLE;5,6-DICHLORO-2-ISOPROPYLAMINO-1-(-L-RIBOFURANOSYL)-LH-BENZIMIDAZOLE;BENZIMIDAVIR: 5,6-DICHLORO-2-(ISOPROPYLAMINO)-1-(SS-L-RIBOFURANOSYL)-LH-BENZIMIDAZOLE;Maribavir;1263W94;5,6-Dichloro-N-(1-methylethyl)-1-beta-L-ribofuranosyl-1H-benzimidazol-2-amine
• CAS NO: 176161-24-3
• Molecular Formula: C15H19Cl2N3O4
• Molecular Weight: 376.24
• Product Categories: Inhibitors
• Mol File: 176161-24-3.mol

Chemical Properties

• Boiling Point: 611°Cat760mmHg
• Flash Point: 323.3°C
• Appearance: /
• Density: 1.67±0.1 g/cm3 (20 ºC 760 Torr)
• Vapor Pressure: 8.74E-16mmHg at 25°C
• Refractive Index: 1.703
• Storage Temp.: 2-8°C(protect from light)
• PKA: 13.20±0.70(Predicted)
• CAS DataBase Reference: BENZIMIDAVIR(CAS DataBase Reference)
• NIST Chemistry Reference: BENZIMIDAVIR(176161-24-3)
• EPA Substance Registry System: BENZIMIDAVIR(176161-24-3)

Safety Data

• Hazardous Substances Data: 176161-24-3(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
BENZIMIDAVIR is used as an antiviral agent for the treatment of cytomegalovirus infections. It specifically targets the CMV UL97 kinase, inhibiting the virus's ability to replicate and spread within the host.
Used in Transplant Recipients:
BENZIMIDAVIR was in phase III clinical trials for the prevention of CMV infection in transplant recipients at risk. The drug was being developed under the "fast track" status granted by the US Food and Drug Administration, aiming to provide a solution for patients undergoing transplantation procedures who are at a higher risk of developing CMV infections.

Mechanism of action

Maribavir inhibits the CMV UL97 kinase, an enzyme which is required for the normal replication of the virus . In the absence of functioning UL97 kinase, viral replication is severely impaired in vitro, with an abnormal cell culture cytopathic effect characterized by the nuclear aggregation of excess amorphous viral proteins, mainly the tegument protein pp65. Impaired UL97 function appears to cause a defect in viral encapsidation and/or egress of viral particles from the nucleus. In addition, viral DNA synthesis may also be reduced. CMV replication is not completely shut off in the absence of the UL97 kinase; the widely varying maribavir IC50s under different assay conditions suggest that host cells can variably substitute for the normal function of UL97, a factor that may affect the therapeutic potency of maribavir in vivo.

Drug interactions

Since CYP3A4 appears to be the major maribavir-metabolizing enzyme, there are potential drug interactions with CYP3A4 inhibitors, such as azole antifungals, macrolide antibiotics, and HIV protease inhibitors, or CYP3A4 inducers, such as rifampicin or efavirenz. There are insufficient data to assess the clinical significance of this interaction. Phase I clinical trials examined the pharmacokinetics of maribavir in HIV-infected subjects, many of whom were concomitantly using antifungals and protease inhibitors. Overall, the pharmacokinetic data were not significantly different from those of healthy individuals not on these drugs. In healthy adults, oral administration of ketoconazole, a potent CYP3A4 inhibitor, resulted in a 35% decrease in the clearance of maribavir, which is not expected to have adverse consequences because of the low observed toxicity of maribavir. Further studies are required to assess potential impairment of antiviral activity by CYP3A4 inducers. Maribavir may have some inhibitory effect on cytochrome P450 isozymes, CYP2C19 and CYP2D6, as assessed after administration of multiple concurrently administered drug probes, including omeprazole (2C19) and dextromethorphan (2D6).

InChI:InChI=1/C15H19Cl2N3O4/c1-6(2)18-15-19-9-3-7(16)8(17)4-10(9)20(15)14-13(23)12(22)11(5-21)24-14/h3-4,6,11-14,21-23H,5H2,1-2H3,(H,18,19)/t11-,12-,13-,14-/m0/s1

Upstream product

• 75-31-0 isopropylamine 
• 202119-41-3 UMJD₈₅₃ 
• 202119-42-4 1-(α-D-lyxofuranosyl)-2,5,6-trichlorobenzimidazole 
• 219674-93-8 2,5,6-trichloro-1-(2,3,5-tri-O-acetyl-α-L-arabinofuranosyl)benzimidazole 
• 220007-81-8 2,3'-O-anhydro-5,6-dichloro-1-(β-L-lyxofuranosyl)benzimidazole 
• 176161-56-1 5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole 
• 16865-11-5 2,5,6-trichloro-1H-benzo[d]imidazole 
• 226703-35-1 2,5,6-trichloro-1-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)benzimidazole 
• 226703-38-4 2bromo-5,6-dichloro-1-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)benzimidazole 
• 226703-47-5 2-bromo-5,6-dichloro-1-(3,5-di-O-benzoyl-β-L-xylofuranosyl)benzimidazole 
• 226703-42-0 2,5,6-trichloro-1-(3,5-di-O-benzoyl-β-L-xylofuranosyl)benzimidazole 
• 201287-82-3 1,2-di-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyle 
• 142356-40-9 2-bromo-5,6-dichloro-1H-1,3-benzodiazole 
• 56272-01-6 1,2,3,5-tetra-O-acetyl-L-arabinofuranose 

Relevant articles and documents

Design, synthesis and antiviral activity of α-L-arabinofuranosyl derivatives of 2-substituted-5,6-dichlorobenzimidazoles

A number of 2.-s. have been prepared by condensation of 2-bromo-5,6- dichlorobenzimidazole or 2,5,6-trichlorobenzimidazole with tetra-O-acetyl-L- arabinofuranose. 2-Alkylamino derivatives were prepared by a substitution of the 2-chloro group with the appropriate amines. All target compounds were evaluated for activity against HCMV and HSV-1. The 2-chloro and 2-bromo derivatives showed moderate activity against HCMV at non-cytotoxic concentrations.

Crystalline forms of an antiviral benzimidazole compound

The invention relates to crystalline forms of 5,6-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole, pharmaceutical compositions comprising the same, processes for preparing the same, and their use in medical therapy.

Form vi 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)-1h-bezimimidazole

The invention relates to Form VI 5,6-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole, pharmaceutical compositions comprising the same, and their use in medical therapy.

Lyxofuranosyl benzimidazoles as antiviral agents

The present invention pertains to D- and L-lyxofuranosyl benzimidazole compounds. In one embodiment, the present invention pertains to D- and L-lyxofuranosyl benzimidazole compounds selected from the group consisting of compounds having a formula selected from the following: wherein R2, R4, R5, R6, and R7are independently the same or different and independently selected from the group consisting of: —H, —F, —Cl, —Br, —I, —NO2, —N(R8)2, —OR8, —SR12, and —CF3, wherein R8is independently —H or an alkyl group having 1-6 carbon atoms and wherein R12is independently —H or a hydrocarbyl group having 1-10 carbon atoms; and, R9, R10and R11are independently the same or different and are H or a hydroxyl protecting group; anomeric and optical isomers thereof; and, pharmaceutically acceptable salts and prodrug derivatives thereof. The present invention also pertains to antiviral compositions using these compounds, methods of treating a viral infection using these compounds, and the use of these compounds in the preparation of a medicament for use in the treatment of a viral infection.

Crystalline forms of an antiviral benzimidazole compound

The invention relates to Form physical forms of 5,6-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole, pharmaceutical compositions comprising the same, and their use in medical therapy.

L-benzimidazole nucleosides

The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.

Antiviral benzimidazole nucleoside analogues and method for their preparation

The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.

Design, synthesis, and antiviral activity of α-nucleosides: D- and L- isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles

Several 2-substituted α-D- and α-L-lyxofuranosyl and 5- deoxylyxofuranosyl derivatives of 5,6-dichloro-2-(isopropylamino)-1-(β-L- ribofuranosyl)benzimidazole (1263W94) and 2,5,6-trichloro1-(β-D- ribofuranosyl)benzimidazole (TCRB) were synthesized and evaluated for activity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxicity against HFF and KB cells. Condensation of 1,2,3,5-tetra-O- acetyl-L-lyxofuranose (2a) with 2,5,6-trichlorobenzimidazole (1) yielded the α-nucleoside 3a. The 2-bromo derivative and 2-methylamino derivative were prepared by treatment of 3a with HBr followed by deprotection or from methylamine, respectively. Compound 3a was deprotected and the resultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopropylamino derivatives. The 2-alkylthio nucleosides were prepared by condensing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprotection. Alkylation of this adduct gave the 2-methylthio and 2-benzylthio derivatives. Condensation of 5-deoxy-1,2,3-tri-O-acetyl-L-lyxofuranosyl, prepared from L-lyxose, with 1 or 2-bromo-5,6-dichlorobenzimidazole (15), followed by deprotection, gave the 2-chloro or 2-bromo-5'-deoxylyxofuranosyl derivative, respectively. The cyclopropylamino derivative was prepared from the 2-chloro derivative. All D- isomers were prepared in an analogous fashion from D-lyxose. Either compounds were inactive against HSV-1 or weak activity was poorly separated from cytotoxicity. In contrast, the 2-halogen derivatives in both the α-lyxose and 5-deoxy-α-lyxose series were active against the Towne strain of HCMV. The 5-deoxy α-L analogues were the most active, IC50'S = 0.2-0.4 μM, plaque assay; IC90's = 0.2-2 μM, yield reduction assay. All of the 2- isopropylamino or 2-cyclopropylamino derivatives were less active (IC50's = 60-100 μM, plaque assay; IC90's = 17-100 μM, yield reduction assay) and were not cytotoxic. The methylamino, thio, and methylthio derivatives were neither active nor cytotoxic. The benzylthio derivatives were weakly active, but this activity was poorly separated from cytotoxicity. The α-lyxose L- isomers were more active in a plaque assay against the AD169 strain of HCMV compared to the Towne strain, thereby providing additional evidence of antiviral specificity.