|Product Name:||Alogliptin benzoate|
|Synonyms:||ALOGLIPTIN BENZOATE;2-[[6-[(3R)-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate;2-[[6-[(3R)-3-aMino-1-piperidinyl]-3,4-dihydro-3-Methyl-2,4-dioxo-1(2H)-pyriMidinyl]Methyl]-Benzonitrile Monobenzoate;SYR 322;Nesina;2-[6-[3(R)-AMinopiperidin-1-yl]-3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyriMidin-1-ylMethyl]benzonitrile benzoate;(R)-2-((6-(3-aMinopiperidin-1-yl)-3-Methyl-2,4-dioxo-3,4-dihydropyriMidin-1(2H)-yl)Methyl)benzonitrile benzoate;2-[6-[3(R)-AMinopiperidin-1-yl]-3-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyriMidin-1-ylMethyl]benzonitrile benzoate Monobenzoate|
|Product Categories:||Final material;Inhibitors|
|Alogliptin benzoate Chemical Properties|
|Alogliptin benzoate Usage And Synthesis|
|Type 2 diabetes drugs||Alogliptin benzoate is a kind of serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by the Takeda Company (Japan). This product can maintain the in vivo level of glucagon-like (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels, stimulating the secretion of insulin, and thus playing a hypoglycemic effect. A randomized, placebo-controlled clinical trial results have showed that compared to placebo, the Alogliptin monotherapy can significantly improve the glycemic control in patients with type 2 diabetes without increasing the incidence of hypoglycemia as well as with a good tolerance. Alogliptin and its pharmaceutical composition are orally effective specific DPP-IV inhibitor following the emergence of sitagliptin and vildagliptin, providing a new and important treatment option for type 2 diabetes patients and have a wide range of application prospects. Alogliptin benzoate is officially marketed at the beginning of 2014, and is the first batch of type 2 diabetes drugs with confirmed cardiovascular safety approve in China, providing more and better choices for the treatment of type 2 diabetes.
|Pharmacological effects||Incretin is the postprandial peptide hormone produced in gastrointestinal tract and can promote the islet β cells to secrete insulin. It includes glucagon-like peptide -1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), secreted by the L cells in the ileum and colon and K cells in the duodenum, respectively. GLP-1 and GIP, as an active hormone, can be released into the blood circulation within a few minutes after food intake and further quickly degraded and inactivated by serine protease DPP-4. The in vivo postprandial incretin levels of patients of type 2 diabetes was significantly reduced, thereby preventing the inactivation of incretin to increase the duration of action for effectively lowering blood sugar. Alogliptin benzoate, as a kind of DPP-4 inhibitors, can increase the in vivo GLP-1 level via selective inhibition of DPP-4 and reduction of the inactivation of GLP-1, and thus reducing blood sugar. When the blood sugar to normal levels, they will not continue to play a hypoglycemic effect, so it can also effectively reduce the risk of hypoglycemia. Additionally, DPP-4 inhibitors can also delay gastric emptying and increase satiety, suppress appetite, and help the patients lose weight. Therefore, these drugs, while effectively reducing the blood sugar, can also reduce the risk of hypoglycemia and weight gain, further overcoming the obstacles for patients to reach standard indicators levels , bringing new hope for the treatment of diabetes.
|Synthetic method||(1) Take 6-chloro-3-methyl uracil as a starting material; it has the alkylation reaction with 2-bromomethyl-benzonitrile under alkaline conditions, and further has substitution reaction with (R) -3- aminopiperidine di-hydrochloride to give (R) -2 - [(6- (3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1 ( 2H)-yl) methyl] benzonitrile (A01), and then obtain the alogliptin benzoate salt through reaction with benzoic acid. This method has a total absorption rate being 56.1% with many advantages such as easy available raw materials, mild reaction condition, high purity product, less kinds of reagent, etc., This method is more suitable for industrial production. |
Figure 1 Synthetic roadmap of alogliptin benzoate with 3-methyl-6-chloro-uracil as the raw material
(2) Take 6-chloro uracil as the starting material; it has alkylation reaction with 2-bromomethyl benzonitrile under the action of sodium hydride and lithium bromide, and further has reaction with methyl iodide under the action of sodium hydride; further has substitution reaction with (R)-3-aminopiperidine di-hydrochloride to get (A01); (A01) has salinization with benzoic acid to obtain alogliptin benzoate. This method has a total absorption rate being up to 27.2%, but requires a lot of sodium hydride and lithium bromide with a high demand on the anhydrous anaerobic reaction conditions; on the other hand, due to the large toxicity of methyl iodide, this is not good for environmental protection and is not suitable for industrial production.
The above information is edited by the chemicalbook of Dai Xiongfeng.
|Detection method - high performance liquid chromatography (HPLC) method||Column: Kromasil C18 (250mm × 4.6 mm, 5μm); mobile phase: 0.05mol/L of KH2PO4 solution (use phosphate to adjust to pH3.0) - acetonitrile (65:35), flow rate: 1.0ml / min; detection wavelength: 224 nm; column temperature: room temperature; injection volume: 20 μl. As a result, the number of theoretical plates for alogliptin benzoate was 14.654, retention time 8.433min, symmetrical peak shape. |
|Pharmacokinetics||Absorption and Distribution: healthy volunteers being subject to a single oral dose of 25 mg of alogliptin benzoic acid get rapid absorption with tmax is 1.0 ~ 2.0 h, Cmax of 110 ~ 193ng ml-1, and AUC0 ~ 24 to 1051 ~ 1605 ng.h.ml-1. Food has no effect on the oral absorption of alogliptin benzoate. For type 2 diabetes patients, oral administration of 25 mg of alogliptin daily for treatment of 12 weeks gives the mean trough plasma concentrations being 25 ng.ml-1. The plasma protein binding rate of alogliptin benzoate is 28% to 38%. |
Metabolism and clearance: alogliptin benzoate is metabolized to active metabolite M-1 through CYP2D6 and metabolized to non-active metabolite M-2 through acetylation reaction is not active metabolite M-2. The plasma and urine concentration of M-1 and M-2 accounted for <2% and <6% of the total alogliptin benzoate concentration, respectively. Owing to that alogliptin benzoate is mainly eliminated through the kidney, patients with renal damage has increased in vivo concentration of alogliptin benzoate. Compared with healthy volunteers, patients with mild to severe renal impairment have their body concentration of alogliptin increased by about 1.7 to 3.8 times. Patients with mild renal impairment do not need to adjust the dose alogliptin, but it is necessary for patients of moderate to severe renal impairment to adjust the dose. Alogliptin is mainly excreted in its prototype form of the drug (60% to 71%) through the urine. The average renal clearance rate of alogliptin in single dose and multiple-dose of oral administration is 8.6 ~ 13.6 L/H-1 and the mean elimination half-life is 12.5 ~ 21.1h. For healthy volunteers, alogliptin in combination with metformin, pioglitazone, glyburide, cimetidine, norethindrone, ethinyl estradiol, cyclosporine, warfarin, and digoxin cause no change in the pharmacokinetic parameters.
|Safety||Alogliptin monotherapy or combination therapy with other antidiabetic drugs for treatment of patients of type 2 diabetes with poor glycemic control can usually give a well tolerance. The drug has a low risk of causing hypoglycaemia, with the incidence in alogliptin treatment and placebo groups being ≤8.3% and ≤10.5%, respectively. There is also no significant difference between the young and elderly patients. The long-term safety of alogliptin treatment remains to be investigated in clinical practice and clinical research.
|Adverse reactions||The most common adverse reactions of alogliptin benzoate are nasopharyngitis, headache and upper respiratory tract infection. Most adverse events were mild to moderate, and have no correlation with the dose.
|Alogliptin benzoate compound medicines||The fixed dose tablet of Alogliptin-metformin hydrochloride and fixed-dose combination tablet alogliptin- pioglitazone, trade names are Kazano and Oseni. A multicenter, randomized, double-blind, placebo-controlled clinical trial results have showed that the combination therapy of alogliptin and metformin can significantly improve glycemic control in patients. The most common adverse reactions of Kazano were upper respiratory tract infection, nasal congestion, runny nose, sore throat, diarrhea, headache, high blood pressure, and back pain and urinary tract infections. The other two randomized, double-blind, placebo-controlled clinical trial results have showed that: compared with the treatment of pioglitazone plus placebo, combination therapy between pioglitazone and alogliptin can significantly improve glycemic control. The most common adverse reactions of Oseni include nasal congestion, runny nose, sore throat, back pain and upper respiratory tract infection.
|Alogliptin benzoate Preparation Products And Raw materials|