Pimobendan

Pimobendan is a selective inhibitor of PDE3 with IC50 of 0.32 μM.Target: PDE3Pimobendan exhibits selective inhibition of PDE III isolated from guinea pig cardiac muscle with IC50 of 0.32 uM compared to the inhibition of PDE I and PDE II (IC50s >30 μM). In human atrial cells, 100 μM pimobendan significantly increases the L-type calcium current (ICa(L)) (evoked by depolarization to +10 mV from a holding potential of -40 mV) by 250.4% with the half-maximal stimulation (EC50) of 1.13 μM. In

Pimobendan is a pyridazinone and a member of benzimidazoles. It has a role as a cardiotonic drug, a vasodilator agent and an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor.

Method 1: Under stirring, propionyl chloride was slowly added dropwise to the solution of carbon disulfide, anhydrous aluminum trichloride and acetanilide, and refluxed. Cool to room temperature, and slowly pour the lower reaction liquid into crushed ice. The solid was collected by filtration and recrystallized from ethanol to obtain compound (I) in a yield of 51.3%. Dimethylamine hydrochloride and 36% formaldehyde solution react at room temperature. Add acetic anhydride and stir until the reaction solution is clear. Then, compound (I) was added and reacted at 100°C. The low-boiling substance was distilled off under reduced pressure at 60-65°C, acetone was added, and then refluxed. Acetone was distilled off, dissolved in water, and washed 3 times with dichloromethane. Add dichloromethane to the water layer, and use 2.5mol/L, sodium hydroxide to neutralize to Ph=10 under cooling. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed twice with saturated brine, dried and concentrated. Then react with methyl iodide in acetone at room temperature. Filtration and drying yielded compound (II) with a yield of 71.3%. Compound (II) was dissolved in aqueous methanol, then an aqueous solution of potassium cyanide was added, and stirred at room temperature. The solid was collected by filtration, washed with a large amount of water until there was no CN-ion, dried, and recrystallized from ethanol to obtain compound (III), with a yield of 76.6%. The compound (III) was added to the mixed acid under stirring and -5 to 0°C to react. Pour into crushed ice and add ethyl acetate. The solid was collected by filtration, washed with water until neutral, and dried to obtain compound (IV) with a yield of 62.8%. Compound (IV) and 6mol/L hydrochloric acid were refluxed. Cool to room temperature, filter and dry to obtain compound (V), yield 77.3%. Compound (V), 95% ethanol and hydrazine hydrate, stirred and refluxed. Cool to room temperature, filter and dry to obtain compound (VI), yield 92.3%. Compound (VI), p-methoxybenzoyl chloride and anhydrous pyridine, react at 40～50℃. Pour into cold water, collect the solid by filtration, dry, then stir and reflux with acetone, cool to room temperature, filter, and dry to obtain compound (VII), yield 51.4%. Compound (VII), 10% palladium-carbon and 95% ethanol were stirred under shaking at a hydrogen pressure of 0.49 MPa. After filtration, the mixture of compound (VIII) and palladium-carbon can be directly used in the next reaction. The product recovered from the mother liquor is recrystallized from acetone-dimethylformamide to obtain compound (VIII). The mixture of the compound (VIII) and palladium-carbon is refluxed in the acid. Cool to room temperature and filter. The filtrate was added with ice water and neutralized with 25% sodium hydroxide. The solid was collected by filtration, dried and chromatographed on a silica gel G column to obtain pimobendan, melting point 175~178°C, yield 68.7% [based on compound (VII)]. Ethanol saturated with hydrogen chloride was added dropwise to pimobendan and stirred. The solid was collected by filtration and dried to obtain pimobendan hydrochloride with a yield of 79.4% and a melting point of >300°C. Method 2: Acetanilide, propionyl chloride and aluminum trichloride are reacted in carbon disulfide to obtain compound (I) with a yield of 76%. Compound (I), glacial acetic acid and bromine are reacted, and the crude product is subjected to silica gel G column chromatography to obtain compound (II) in a yield of 74%. Under stirring in an ice bath, diethyl malonate was slowly added dropwise to sodium hydride in tetrahydrofuran to react. The reaction solution was added to a solution of compound (II) in tetrahydrofuran, and stirred at room temperature. Acidify with 2mol/L hydrochloric acid to Ph=1, add ether. The organic layer was separated, and the aqueous layer was extracted 3 times with ether. The organic layers were combined, washed with saturated sodium bicarbonate and aqueous sodium chloride until neutral, and dried. The ether was distilled off and chromatographed on a silica gel G column to obtain compound (III) with a yield of 89.4%. Compound (III) was nitrated by mixed acid, and the crude product was chromatographed on silica gel G column to obtain compound (IV) in 89% yield. Compound (II) was first nitrified by mixed acid, and then reacted with diethyl malonate to obtain compound (IV) in the same way, with a two-step yield of 68.8%. Compound (IV) is dissolved in ethanol, 5% sodium hydroxide is added, 70-80°C: stirred. Acidify with 3mol/L hydrochloric acid to Ph=1, 70-80℃ and stir again. Cool to room temperature and add ethyl acetate. The organic layer was separated, and the aqueous layer was extracted 3 times with ethyl acetate. Combine the organic layers and dry. The solvent was distilled off and chromatographed on a silica gel G column to obtain compound (V) with a yield of 85%. Compound (V) is dissolved in diphenyl ether and stirred at 160-170°C until no carbon dioxide bubbles are released. After cooling, the solid was collected by filtration, washed with a small amount of petroleum ether, and dried to obtain compound (VI) with a yield of 82%. Compound (VI), absolute ethanol and 85% hydrazine hydrate were refluxed to obtain compound (VII) in 92% yield. Compound (Ⅶ) was dissolved in absolute ethanol, reduced with 85% hydrazine hydrate at 70～80℃ in the presence of 5% palladium-carbon, and then subjected to silica gel G column chromatography to obtain compound (Ⅷ), yield 88% . In sodium metabisulfite, water and methanol, compound (Ⅷ) and p-methoxybenzaldehyde are condensed at 25～60℃. The crude product is chromatographed on silica gel G to obtain pimobendan, yield 92%, melting point 240～241℃ (Decomposition) (the melting point is very different from the melting point of pimobendan in method 1). Pimobendan is then reacted with hydrochloric acid-ethanol saturated solution to obtain pimobendan hydrochloride with a yield of 80% and a melting point of >310°C (decomposition).

Pimobendan is a selective inhibitor of PDE3 with IC50 of 0.32 μM

Molecular Weight:334.4
XLogP3:2.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:334.14297583
Monoisotopic Mass:334.14297583
Topological Polar Surface Area:79.4
Heavy Atom Count:25
Complexity:530
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes