Argatroban CAS 74863-84-6
Introduction：Basic information about Argatroban CAS 74863-84-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Argatroban Basic information
| Product Name: | Argatroban |
| Synonyms: | Argatroban (Mixture of Diastereomers);Argatroban（mixture of isomers）;Argipidine;MQP;(2R,4R)-4-Methyl-1-[N-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid;ARG025;MQPA;(2R，4R)-1-[5-[(Aminoiminomethyl)amino]-1-oxo-2-[[(1，2，3，4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid |
| CAS: | 74863-84-6 |
| MF: | C23H36N6O5S |
| MW: | 508.64 |
| EINECS: | 638-764-8 |
| Product Categories: | Amines;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Heterocycles;Sulfur & Selenium Compounds;74863-84-6 |
| Mol File: | 74863-84-6.mol |
Argatroban Chemical Properties
| Melting point | 188-1890C |
| Boiling point | 777.2±70.0 °C(Predicted) |
| density | 1.47±0.1 g/cm3(Predicted) |
| storage temp. | Keep in dark place,Sealed in dry,2-8°C |
| solubility | Soluble in DMSO (up to 50 mg/ml). |
| pka | 10.44±0.40(Predicted) |
| form | White to off-white powder. |
| color | White |
| Stability: | Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month. |
| InChIKey | KXNPVXPOPUZYGB-IOVMHBDKSA-N |
| SMILES | N1(C(=O)[C@@H](NS(C2C3=C(C=CC=2)CC(C)CN3)(=O)=O)CCCNC(N)=N)CC[C@@H](C)C[C@@H]1C(O)=O |
| CAS DataBase Reference | 74863-84-6(CAS DataBase Reference) |
Safety Information
| Hazardous Substances Data | 74863-84-6(Hazardous Substances Data) |
| Description | Argatroban is a new synthetic antithrombotic agent useful in maintenanceanticoagulation themischemic stroke and disseminated intravascular coagulation. In patients on hemodialysis, argatroban is su enor to heparin,generating a more stable antithrombin effect. Other potential uses include progressing ischemic stroke and disseminated intravascular coagulation. |
| Description | Argatroban is a reversible inhibitor of thrombin (IC50s = 0.01 and 0.09 μM for the free and clot-bound forms, respectively). It is selective for thrombin over factor Xa, trypsin, plasmin, and tissue plasminogen activator (Kis = 0.0045, 53, 0.19, 25.7, and 87.7 μM, respectively). It inhibits thrombin-induced platelet aggregation in washed isolated guinea pig platelets with an IC50 value of 0.077 μM. Argatroban (3.2 mg/kg, s.c.) decreases thrombus formation in a guinea pig model of iron chloride-induced arterial thrombosis. Formulations containing argatroban have been used in the prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia. |
| Chemical Properties | White to Off-White Crystalline Solid |
| Originator | Mitsubishi Kasei; Daiichi (Japan) |
| Uses | anticoagulant;direct thrombine inhibitor |
| Uses | (2S,4S)-1-(2R)-Argatroban is an isomeric impurity of Argatroban (74863-84-6 #CAS), which is a synthetic thrombin inhibitor. Antithrombotic. |
| Definition | ChEBI: (2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid is a peptide. |
| Manufacturing Process | To a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-argininein 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamineand 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C.After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2-piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. Atthe end of this period, the reaction mixture was warmed to roomtemperature. The solvent was evaporated and the residue taken up in 400 mlof ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5%sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml ofwater. The ethyl acetate solution was dried over anhydrous sodium sulfate.The solution was evaporated to give 31.5 g (75 %) of ethyl 1-[NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the formof a syrup. To a stirred solution of 30 g of ethyl 1-[NG-nitro-N2-(tert-butoxycarbonyl)-Larginyl]-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate was added80 ml of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution wasadded 200 ml of dry ethyl ether to precipitate a viscous oily product. This wasfiltered and washed with dry ethyl ether to give ethyl 1-[NG-nitro-L-arginyl]-4-methyl-2-piperidinecarboxylate hydrochloride as an amorphous solid. To a stirred solution of ethyl 1-(NG-nitro-L-arginyl)-4-methyl-2-piperidinecarboxylate hydrochloride in 200 ml of chloroform were added inturn 18.5 g of triethylamine, and 14.7 g of 3-methyl-8-quinolinesulfonylchloride at 5°C, and stirring was continued for 3 hours at room temperature.At the end of this period, the solution was washed twice with 50 ml of water.The chloroform solution was dried over anhydrous sodium sulfate. Uponevaporation of the solvent, the residue was chromatographed on 50 g of silicagel packed in chloroform, washed with chloroform and eluted with 3%methanol-chloroform. The fraction eluted from 3% methanol-chloroform wasevaporated to give 32.1 g (91%) of ethyl 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form ofan amorphous solid. A solution of 30 g the above product in 100 ml of ethanol and 100 ml of 1 Nsodium hydroxide solution was stirred for 24 hrs at room temperature. At theend of this period, the solution was neutralized with 1 N hydrochloric acid andthen concentrated to 70 ml. The solution was adjusted to pH=11 with 1 Nsodium hydroxide solution, washed three times with 100 ml of ethyl acetate,acidified with 1 N hydrochloric acid and then extracted three times with 100ml of chloroform. The combined chloroform solution was dried over anhydroussodium sulfate and evaporated to give 28.0 g (97%) of 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid asan amorphous solid. IR (KBr): 3,300, 1,720, 1,630 cm-1. To a solution of 3.00 g of 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-Larginyl]-4-methyl-2-piperidinecarboxylic acid in 50 ml of ethanol was added0.5 g of palladium black and then the mixture was shaken under 10 kg/cm2H2 pressure at 100°C for 8 hrs. At the end of this period, the ethanol solutionwas filtered to remove the catalyst and evaporated to give 2.50 g (90%) of 1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,400, 1,620,1,460, 1,380 cm-1. |
| Brand name | Novastan (MitsubishiChemical Corporation, Japan);Slonnon. |
| Therapeutic Function | Anticoagulant |
| Pharmacokinetics | Argatroban is administered subcutaneously because of the low lipophilicity of the drug. The drug isbound to plasma protein and is metabolized via CYP3A4/5 to the aromatized metabolite and the twohydroxylated metabolites. The M-1 metabolite retains 20 to 30% of the antithromboticactivity. Coadministration of argatroban with inhibitors of CYP3A4 does not appear to produceclinically significant effects. Argatroban is eliminated via biliary secretion into the feces. |
| Clinical Use | Argatroban has been approved for the prophylaxis and treatment of thrombosis in patients with HIT(79). Argatroban is a peptidomimetic that binds selectively to the catalytic site of thrombin as aunivalent competitive DTI. Argatroban is available as a mixture of 21-R and 21-Sdiastereomers (64:36), with the S-isomer approximately twice as potent as the R-isomer. Thedrug is a reversible inhibitor of both free thrombin as well as clot-bound thrombin. |
| Drug interactions | Potentially hazardous interactions with other drugs Analgesics: increased risk of haemorrhage with IV diclofenac and ketorolac - avoid. Antiplatelets and anticoagulants: increased risk of bleeding complications. Heparin: avoid concomitant administration. Urokinase: may increase the risk of bleeding. Thrombolytics: may increase risk of bleeding complications; enhance effect of argatroban. |
| Metabolism | The metabolism of argatroban has not yet been fully characterised. The metabolites identified (M-1, M-2, and M-3) are formed by hydroxylation and aromatisation of the 3-methyltetrahydroquinoline ring in the liver. The main metabolite (M1) exerts 40-fold weaker antithrombin effect than argatroban. Metabolites M-1, M-2 and M-3 were detected in the urine, and M-1 was detected in plasma and faeces. Argatroban is excreted mainly in the faeces, presumably through biliary secretion. Following intravenous infusion of [14C]-argatroban 21.8±5.8% of the dose was excreted in urine and 65.4±7.1% in the faeces. |
| storage | Store at +4°C |
| References | [1] RYOJI KIKUMOTO. Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid[J]. Biochemistry Biochemistry, 1984, 23 1: 85-90. DOI:10.1021/bi00296a014 [2] I K JANG. Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition.[J]. Circulation, 1990, 81 1: 219-225. DOI:10.1161/01.cir.81.1.219 [3] TAKASHI SUGAWARA. Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats.[J]. Stroke, 2009, 40 4: 1530-1532. DOI:10.1161/strokeaha.108.531699 [4] ERIKA B SCHULZE. The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms.[J]. Breast Cancer Research and Treatment, 2008, 112 2: 243-254. DOI:10.1007/s10549-007-9865-4 |
Argatroban Preparation Products And Raw materials
| Raw materials | 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester-->4-METHYL-PYRIDINE-2-CARBOXYLIC ACID-->L(+)-Arginine-->3-Methyl-8-quinolinesulphonyl chloride-->Chloroformate-->Phenylacetic acid isobutyl ester-->Isobutyl chloroformate-->Palladium-->Triethylamine |
