Introduction：Basic information about Mitiglinide calcium CAS 145525-41-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Mitiglinide calcium Basic informationDescription References
| Product Name: | Mitiglinide calcium |
| Synonyms: | calcium 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate;(as,3ar,7as)-octahydro-gamma-oxo-alpha-(phenylmethyl)-2h-isoindole-2-butanoic acid calcium salt dihydrate;MITIGLINIDE CALCIUM HYDRATE;MITIGLINIDECALCIUM(FORR&DONLY);Monocalcium bis[(2S)-2-benzyl-3-(cis-hexahydro isoindolin -2-carbonyl)propionate]dihydrate;(alphaS,3aR,7aS)-Octahydro-γ-oxo-α-(phenylmethyl)-2H-isoindole-2-butanoic Acid Calcium Salt;calcium 4-(1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl)-4-oxo-2-(phenylmethyl)butanoate;(2S)-Mitiglinide-d5 Calcium Salt |
| CAS: | 145525-41-3 |
| MF: | (C19H24NO3)2.Ca |
| MW: | 668.88 |
| EINECS: | 692-046-9 |
| Product Categories: | Inhibitors;API;White crystal posder;Pharmaceutical material and intermeidates |
| Mol File: | 145525-41-3.mol |
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Mitiglinide calcium Chemical Properties
| Melting point | 146-148°C |
| density | 1.175 |
| storage temp. | Inert atmosphere,Room Temperature |
| solubility | DMSO: ≥10mg/mL at warmed to 60°C |
| form | powder |
| color | white to beige |
| Optical Rotation | [α]/D +5 to +9° (c=1, MeOH) |
| CAS DataBase Reference | 145525-41-3(CAS DataBase Reference) |
Safety Information
| Hazard Codes | Xi |
| Risk Statements | 36/37/38 |
| Safety Statements | 36 |
| WGK Germany | 3 |
| HS Code | 2933.99.7500 |
Mitiglinide calcium Usage And Synthesis
| Description | Mitiglinide is the calcium salt form of Mitiglinide, which is a drug for the treatment of type II diabetes. It belongs to the meglitinide class blood glucose-lowering drug. Its mechanism of action is through stimulating the insulin secretion through closing the ATP-sensitive potassium channels in the pancreatic beta-cells. This process leads to depolarization, further stimulating the influx of calcium through the voltage-gated calcium channels. The high intracellular calcium level results in the exocytosis of insulin granules, alleviating the symptoms of type II diabetes. |
| References | https://www.drugbank.ca/drugs/DB01252
https://en.wikipedia.org/wiki/Mitiglinide |
| Description | Mitiglinide is a non-sulfonylurea hypoglycemic agent that has been developed andlaunched in Japan for the treatment of type-2 diabetes. Similar to the sulfonylureainsulinotropic drugs, mitiglinide adopts a U-shaped configuration in which the baseof the U contains an amide linkage, and each branch of the U incorporates ahydrophobic side chain. This similarity in conformation suggests that mitiglinidealso binds to the sulfonylurea receptor to cause the direct closing of ATP-sensitivepotassium channels in pancreatic β-cells; the result is stimulation of insulin secretion.In contrast to typical sulfonylurea agents that frequently cause hypoglycemiadue to slowly reversed insulinotropic activity, mitiglinide’s short duration of actionshould be advantageous in preventing this adverse effect. It also enjoys a rapidonset of insulin release. Mitiglinide can be prepared by several closely relatedmethods, which involve either classical resolution of racemic intermediates, or enantioselectivemethods, such as, chiral enolate alkylation, and asymmetric hydrogenationwith a rhodium or ruthenium-based chiral diphosphine complex. A highlyefficient preparative method for mitiglinide involves the diasteroselective alkylationof a chiral acylsultam intermediate that is obtained by the reaction of 3-phenylpropionylchloride with (-)-camphorsultam. The chiral enolate of the acylsultam isderived by using sodium hexamethyldisilazane as the base, and is subsequently alkylatedwith tert-butyl bromoacetate to achieve ＞93% diastereomeric purity of theproduct. Following cleavage of the tert-butyl ester with trifluoroacetic acid, the resultantacid is coupled with (3aR,7aS)octahydro-1H-isoindole, and the camphorsultamchiral auxiliary is removed by saponification to produce the parent acid ofmitiglinide in high yield. In vitro, mitiglinide has about a 1000-fold greater affinity forthe Kir6.2/SUR1 form of potassium-ATP channels expressed in β-cells (IC50=4nM)than for the Kir6.2/SUR2A or Kir6.2/SUR2B channel types found in cardiac andsmooth muscle. In fact, it is significantly less potent in blocking potassium-ATPchannels than the prototype sulfonylurea glyburide (IC50=42μM vs. 0.13 μM, respectively);thus, it possesses a more favorable cardiac safety profile. Phase III clinicaldata demonstrated that mitiglinide significantly improved indices of blood glucosecontrol (postprandial glucose and fasting plasma glucose levels) in a double blind,comparative study. It was also confirmed that the incidence of hypoglycemia, a frequentadverse effect, remained as low as placebo. In another placebo-controlledstudy involving twenty-two patients with type-2 diabetes, mitiglinide 5mg t.i.d.treatment significantly suppressed postprandial plasma glucose elevations (181 vs.261mg/dL with placebo), and the daily change in blood glucose level was reducedwith no subjective symptoms. No episodes of hypoglycemia or abnormal clinicallaboratory parameters were noted. Regarding the pharmacokinetics, a single oraldose (unspecified) of mitiglinide reached its peak plasma concentration ofabout 0.5 μg/mL at 30 minutes post dose and then steadily declined to about0.04 μg/mL at 4 h. |
| Originator | Kissei (Japan) |
| Uses | Mitiglinide Calcium is a blood glucose-lowering drugs, stimulating insulin secretion by closing the ATP-sensitive K+ channels in pancreatic beta-cells |
| Definition | ChEBI: Kad 1229 is a polymer. |
| Brand name | Glufast |
| Synthesis | A number of publications andpatents have disclosed the syntheses of mitiglinide.One of the syntheses describing the preparation ofmitiglinide using bis-activated esters to obtain a selectivemono amide is described in Scheme 8. The synthesis startswith racemic 2-benzylsuccinic acid (51) which was resolved into its enantiomer using chiral amine salt formation andcrystallization. Out of several amines used, (R)-1-phenylethylamine gave the best results for the chiralresolution (99.5% ee, 19.5%). Acid 52 was treated withthionyl chloride and triethylamine followed by Nhydroxysuccinamideto give doubly activated ester 53(97%). Treatment of this double ester 53 withtetrahydroisoindoline (54) gave selectively mono amideto di-amide in 99:1 ratio. Hydrolysis of the activated ester in55 with water gave desired product 56 in 99% yield.Subsequent conversion in two steps to the half calcium saltprovided mitiglinide calcium hydrate (VIII) in 91% yield. |
| Mode of action | Mitiglinide is another non-sulfonylurea insulin secretagogue. Insulin secretion is physiologically stimulated by the binding of ATP to a cytosolic nucleotide binding site of the membrane bound ATP-sensitive K+ channel which leads to closure of the K+ channel. The inhibition of K+ permeability depolarizes the plasma membrane, subsequently the voltage-dependent Ca2+ channel opens to promote the Ca2+ influx which finally results in insulin secretion. The insulin secretagogues stimulate insulin secretion by closure of this ATP-sensitive K+ channel of pancreatic -cells. KATP-channel consists of two subunits, a functional ion channel pore and a regulatory protein. The binding of the secretagogues is suggested to occur to the separate regulator protein containing the binding sites for sulfonylureas (sulfonylurea receptor 1, SUR1) but also other compounds. |
Mitiglinide calcium Preparation Products And Raw materials
