Azelnidipine

Base Information

• Chemical Name: Azelnidipine
• CAS No.: 123524-52-7
• Molecular Formula: C33H34N4O6
• Molecular Weight: 582.656
• Hs Code.: 2933990090
• European Community (EC) Number: 634-143-0
• UNII: PV23P19YUG
• DSSTox Substance ID: DTXSID3020120
• Wikipedia: Azelnidipine
• Wikidata: Q4832365
• NCI Thesaurus Code: C73023
• Pharos Ligand ID: TDZ18N7WPMVW
• Metabolomics Workbench ID: 152262
• ChEMBL ID: CHEMBL1275868
• Mol file: 123524-52-7.mol

Synonyms:3-(1-diphenylmethylazetidin-3-yl)-5-isopropyl-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate;azelnidipine;CS 905;CS-905

Chemical Property of Azelnidipine

Chemical Property:

• Appearance/Colour: light yellowish powder
• Vapor Pressure: 5.74E-20mmHg at 25°C
• Melting Point: 120-126 ºC
• Refractive Index: 1.658
• Boiling Point: 709.3 ºC at 760 mmHg
• PKA: 7.89(at 25℃)
• Flash Point: 382.8 ºC
• PSA: 139.71000
• Density: 1.33 g/cm³
• LogP: 6.18470
• Storage Temp.: Room temp
• Solubility.: DMSO: >10mg/mL
• XLogP3: 6
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 9
• Rotatable Bond Count: 10
• Exact Mass: 582.24783482
• Heavy Atom Count: 43
• Complexity: 1080

Purity/Quality:

99% ^*data from raw suppliers

Azelnidipine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn
• Hazard Codes: Xn
• Statements: 22-41
• Safety Statements: 26-39

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC1=C(C(C(=C(N1)N)C(=O)OC2CN(C2)C(C3=CC=CC=C3)C4=CC=CC=C4)C5=CC(=CC=C5)[N+](=O)[O-])C(=O)OC(C)C
• Recent ClinicalTrials: Stratification of Blood Pressure Control Against Progress of Cerebral Small Vessel Diseases in Poststroke Patients
• Recent NIPH Clinical Trials: Effects of high dose angiotensin II receptor blocker or combination of angiotensin II and calcium channel blocker on ambultory blood pressure in patients with hypertension and type 2 diabetes (randomized controlled clinical trial)
• Description: Azelnidipine, a member of the 1,4-dihydropyridine class of L-type calcium channel blockers with a slow onset profile, was marketed in Japan for the treatment of hypertension. Azelnidipine is synthesized via the condensation of iso-propyl 2-(3- nitrobenzylidene)acetoacetate with (1-diphenylmethylazetidin-3-yl)-3,3-diamino acrylate. The diamino acrylate intermediate is prepared from the cyanoacetic ester by sequential treatment with HCl and ammonia. In receptor binding studies using porcine heart membrane fractions, azelnidipine exhibits an IC50 of 3.1 nM and an apparent Ki of 2.1 nM. Its tight binding and slow onset are correlated with its high lipophilicity. A slow onset is also noted in vitro in a rat aortic strip contraction assay, and this effect continues after removal of the drug from the bath solution. In the conscious spontaneously hypertensive rat (SHR) model of hypertension, it was more potent that nicardipine and also had a more gradual onset and long-lasting effect. This effect was noted both when dosed orally or intravenously. When SHR dosed at 1 or 3 mpk/day for 15 weeks, a sustained reduction in systolic blood pressure was noted (19 and 43 mmHg reduction, respectively). Cardiac output was increased and total peripheral resistance was decreased in each group. Clinical studies of patients with mild-to-moderate hypertension have shown that long-term treatment with azelnidipine provided a sustained decrease in blood pressure (mean reduction systolic /diastolic: 27.8/16.6 mmHg). It similarly controlled blood pressure, as did amlodipine at 24 h. It possesses a gradual onset of activity with plasma levels increasing before the antihypotensive effect is attained. After plasma levels drop, the pharmacodynamic effect is sustained. In clinical studies, azelnidipine did not show reflex tachycardia, a common side effect of this class. Most common side effects were facial flushing and headache, similar to other dihydropyridines. Azelnidipine is dosed orally once daily (8–16 mg), is rapidly absorbed in a dose-dependent fashion, and has a mean terminal half-life of 19.2 h (8 mg dosage p.o. for seven days). Uniquely, it possesses a 2-amino function associated with a longer half-life than related agents wherein this moiety is a methyl. The very highly lipophilic 3-carboxylic ester side-chain is purported to contribute to the gradual onset of activity and prolonged pharmacodynamic effect, unlike other drugs in this class. This compound exhibits a much less pronounced first-pass metabolic effect than nicardipine.
• Uses: Azelnidipine is a dihydropyridine calcium channel blocker with antihypertensice activity. Azelnidipine is used for treating ischemic heart disease and cardiac remodeling after myocardial infarction. S tudies show that Azelnidipine ttreatment can reduce the risk of hyperglycemia induced metabolic disorders

Technology Process of Azelnidipine

There total 7 articles about Azelnidipine 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: 90.01%

3-oxo-2-(3-nitrophenylmethylene)butanoic acid isopropyl ester (39562-25-9) + 1-benzhydrylazetidin-3-yl 3-amino-3-iminopropanoate acetate (170749-59-4) → azelnidipine (123524-52-7,116573-93-4)

Guidance literature:

With sodium amide; In toluene; for 4h; Reflux;

Reference yield: 89.0%

isopropyl 3-aminocrotonate (14205-46-0) + C26H23N3O5 → azelnidipine (123524-52-7,116573-93-4)

Guidance literature:

With sodium methylate; In ethanol; for 6h; Reflux;

Reference yield:

isopropyl acetoacetate (542-08-5) → azelnidipine (123524-52-7,116573-93-4)

Guidance literature:

Multi-step reaction with 2 steps

1: 65 percent / piperidinium acetate / propan-2-ol / 1 h / 45 - 55 °C

2: 74 percent / sodium methoxide / propan-2-ol / 4 h / Heating

With sodium methylate; piperdinium acetate; In isopropyl alcohol;

DOI:10.1248/cpb.43.797

upstream raw materials:

3-oxo-2-(3-nitrophenylmethylene)butanoic acid isopropyl ester

1-benzhydrylazetidin-3-yl 3-amino-3-iminopropanoate acetate

isopropyl acetoacetate

isopropyl 3-aminocrotonate

Downstream raw materials:

3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Azelnidipine citrate

(-)-Azelnidipine

Refernces

• 1、 -. "Preparation method of azelnidipine". Paragraph 0017-0018. . Retrieved 2017/03/08.
• 2、 Kobayashi,Inoue,Nishino,Fujihara,Oizumi,Kimura. "Novel 2-amino-1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having N,N-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-positions". . p. 797 - 817. Retrieved 2007/10/02.