Levosimendan

Base Information

• Chemical Name: Levosimendan
• CAS No.: 141505-33-1
• Molecular Formula: C14H12N6O
• Molecular Weight: 280.289
• European Community (EC) Number: 663-528-6
• NSC Number: 759644
• UNII: C6T4514L4E
• DSSTox Substance ID: DTXSID9046445
• Nikkaji Number: J550.713H
• Wikipedia: Levosimendan
• NCI Thesaurus Code: C174653
• Pharos Ligand ID: 6TKB6AKSH8LV
• Metabolomics Workbench ID: 43189
• ChEMBL ID: CHEMBL2051955
• Mol file: 141505-33-1.mol

Synonyms:((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propanedinitrile;dextrosimendan;Levosimendan;OR 1259;OR 1855;OR-1259;OR-1855;Simadax;simendan

Chemical Property of Levosimendan

Chemical Property:

• Appearance/Colour: yellow crystalline powder
• Melting Point: 216-219°C (dec.)
• Refractive Index: 1.673
• PKA: 6.3(at 25℃)
• PSA: 113.43000
• Density: 1.33 g/cm³
• LogP: 1.19916
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO: ≥20mg/mL
• XLogP3: 2.3
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 3
• Exact Mass: 280.10725903
• Heavy Atom Count: 21
• Complexity: 549

Purity/Quality:

99% ^*data from raw suppliers

Levosimendan ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn
• Hazard Codes: Xn
• Statements: 20/21/22
• Safety Statements: 36/37

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N
• Isomeric SMILES: C[C@@H]1CC(=O)NN=C1C2=CC=C(C=C2)NN=C(C#N)C#N
• Recent ClinicalTrials: Levosimendan Versus Placebo Before Tricuspid Valve Surgery in Patients With Right Ventricular Dysfunction
• Recent EU Clinical Trials: A Randomized, Double-Blind, Placebo-Controlled Multicenter Study of Levosimendan Therapy in low ejection fraction Takotsubo Syndrome (LevoTako Trial)
• Description: Levosimendan was introduced in Sweden as an i.v. infusion for the treatment of acute heart failure or refractory symptoms of chronic heart failure in cases where conventional treatment (e.g., diuretic or ACE inhibitor) is not sufficient. Levosimendan is the (R)- enantiomer of simendan that belongs to the same class as pimobendan (Boehringer Ingelheim). Levosimendan is an innovative myofilament calcium sensitizer that increases myocardial contractility by selectively binding to the N-terminus of troponin C and by stabilizing the Ca2+-bound conformation of this contractile protein. It also activates ventricular and arterial adenostne triphosphate-regulated potassium channels which causes vasodilatation in vascular smooth muscle and protects myocardium against infarction. Its low phosphodiesterase III inhibiting activity is probably not responsible for its positive inotropic, lusitropic and dilating effects. Unlike other cardiotonic drugs, levosimendan is able to produce positive inotropic effects without prolonging myocardial relaxation or increasing the incidence of malignant arrythmias. It was clinically shown to have a lower risk of mortality in patients with heart failure when compared to placebo and dobutamine. Since it has a larger potential, levosimendan is currently under further clinical evaluation as a chronic treatment for congestive heart failure. Levosimendan is a calcium sensitizer that can cause increased cardiac contractility by binding troponin C (EC50 = 9 nM), promotes vasodilation by activating ATP-sensitive potassium channels on vascular smooth muscle cells (EC50 = 0.28 μM), and performs a cardioprotective function by prompting the opening of mitochondrial potassium channels in cardiomyocytes. It also has been reported to inhibit phosphodiesterases 3 and 4 in left ventricular cardiac tissue with IC50 values of 2.5 nM and 25 μM, respectively.
• Uses: Levosimendan has been used for screening its anti-human immunodeficiency virus type 1 (HIV-1) property. It has also been used for screening its cytotoxic effects in TP53 mutant and wild-type lung adenocarcinoma cell lines Bioactive enantiomer of racemate, Simendan. Positive inotropic agent with vasodilating activity. Cardiotonic anesthetic Levosimendan is a positive inotropic agent that acts by sensitising troponin C to Ca2+, prolonging actin-myosin cross-bridge formation and therefore increasing contractility. This is an energy-independent process and therefore does not increase myocardial oxygen demand. Levosimendan also causes vasodilatation by opening ATP-sensitive K+ channels in vascular smooth muscle, reducing pre- and afterload and improving myocardial oxygen supply. It may have a role in the management of acute heart failure and postresuscitation myocardial dysfunction.

Technology Process of Levosimendan

There total 5 articles about Levosimendan which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield:

OR-1855 (36725-28-7,101328-84-1,101328-85-2,107295-33-0) + malononitrile (109-77-3) → levosimendan (141505-33-1,144238-75-5)

Guidance literature:

OR-1855; With hydrogenchloride; sodium nitrite; In water; for 0.166667h;

malononitrile; In water; at 20 ℃; for 1h;

With sodium acetate; In water; pH=6;

Reference yield:

(5S)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (101328-84-1) → levosimendan (141505-33-1,144238-75-5)

Guidance literature:

Multi-step reaction with 3 steps

1.1: sodium hydroxide / 90 °C

2.1: ethanol; water / 15 - 65 °C

3.1: hydrogenchloride; sodium nitrite / water / 0.17 h

3.2: 1 h / 20 °C

3.3: pH 6

With hydrogenchloride; sodium hydroxide; sodium nitrite; In ethanol; water;

Reference yield:

6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (36725-28-7) → levosimendan (141505-33-1,144238-75-5)

Guidance literature:

Multi-step reaction with 3 steps

1.1: ethanol; water / 1.5 h / 15 - 65 °C

2.1: ammonia / water / 0.5 h / 25 - 30 °C / pH 8 - 9

3.1: hydrogenchloride; sodium nitrite / water / 0.17 h

3.2: 1 h / 20 °C

3.3: pH 6

With hydrogenchloride; ammonia; sodium nitrite; In ethanol; water;

upstream raw materials:

(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]-propanedinitrile

(5S)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one

6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone

OR-1855

Refernces

• 1、 Soini, Helena,Stefansson, Morgan,Rlekkola, Marja-Lllsa,Novotny, Mllos V.. "Maltooligosaccharides as chiral selectors for the separation of pharmaceuticals by capillary electrophoresis". . p. 3477 - 3484. Retrieved 2007/10/02.