82571-53-7

Basic information

• Product Name: Ozagrel
• Synonyms: (E)-4-(1-Imidazoylmethyl)cinnamic acid;2-Propenoic acid, 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-, (2E)-;(E)-3-[4-(1H-Imidazol-1-ylmethyl)phenyl]propenoic acid;(E)-3-[p-(1H-Imidazol-1-ylmethyl)phenyl]acrylic acid;Ozagrel API;Ozagrel(OKY-046);(2E)-3-[4-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid;(E)-3-[4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid
• CAS NO: 82571-53-7
• Molecular Formula: C₁₃H₁₂N₂O₂
• Molecular Weight: 228.25
• EINECS: 242-903-4
• Product Categories: Inhibitors;Cardiovascular Series;Cardiovascular;Pharmaceutical material and intermeidates
• Mol File: 82571-53-7.mol

Chemical Properties

• Melting Point: 223-224°
• Boiling Point: 468 °C at 760 mmHg
• Flash Point: 236.8 °C
• Appearance: white powder
• Density: 1.17 g/cm³
• Vapor Pressure: 1.47E-09mmHg at 25°C
• Refractive Index: 1.593
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 4.43±0.10(Predicted)
• CAS DataBase Reference: Ozagrel(CAS DataBase Reference)
• NIST Chemistry Reference: Ozagrel(82571-53-7)
• EPA Substance Registry System: Ozagrel(82571-53-7)

Safety Data

• Hazardous Substances Data: 82571-53-7(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Applications:
Ozagrel is used as an antithrombotic agent for improving cerebral vasospasm after cobweb inferior vena hemorrhage surgery and symptoms of cerebral ischemia associated with cerebral vasospasm. It is also used for managing dyskinesia associated with the acute phase of cerebral thrombosis.
Used in Neurological Applications:
Ozagrel is used as a thromboxane A2 inhibitor for the prevention of ischemic stroke injury and maintaining a strong effect on vascular contraction and vascular endothelial cell dysfunction.
Other indications for ozagrel sodium currently under study include angina pectoris, bronchial asthma, and pulmonary thromboembolism. In patients with angina pectoris, ozagrel sodium reportedly decreases the frequency of anginal attacks and increases exercise tolerance.

Platelet aggregation inhibitor

Ozagrel and clopidogrel, cilostazol, aspirin enteric-coated tablets are commonly used in China at present as platelet aggregation inhibitor, Ozagrel is an anti-thrombosis drug which belongs to a thromboxane alkyl cyclooxygenase (TXA2) inhibitors, originally it was successfully developed by Japan Ono pharmaceutical Co., Ltd. and Kissei pharmaceutical Co., Ltd. ,it was approved for marketing in Japan in 1988. At present, domestic manufacturers include the Liaoning dandong, medical and pharmaceutical industry, Shandong Elohim Pharmaceutical Co., Changchun fine distinctions Pharmaceutical, Dalian Metro big pharmaceutical companies, pharmaceutical Shenyang Jishi, Hainan bikai Pharmaceutical, Changchun Haobang Pharmaceutical and Shandong HuaLu pharmaceutical. Modern medicine has proved that platelets play an important role in the process of atherosclerosis and thrombosis, the effective regulation of platelet can play a multiplier effect on blood vessel lumen stenosis, emboli and diseases caused by occlusion of blood circulatory system . At present, the platelet aggregation inhibitor drugs used clinically are mainly cyclooxygenase (TXA2) inhibitors, phosphodiesterase (PDE) inhibitors, adenosine diphosphate (ADP) receptor antagonists, platelet fibrinogen antagonists drugs. Ozagrel sodium salt has a strong antithrombotic effect, which is the world's first listing inhibitor of the potent thromboxane synthase feature ,it has the inhibiting effect on the platelet aggregation induced by different inducers (such as collagen, arachidonic acid, epinephrine, ADP, 5-HT, etc.) ,it can inhibit TXA2 synthase, while it can promot the generation of PGI2, it has effect on anti-platelet aggregation and relieving the vasospasm, it can inhibit the cerebral thrombosis and cerebral vasospasm. It is Mainly applied to the improvement of subarachnoid hemorrhage after cerebral vasospasm and cerebral ischemic symptoms. It can reduce cerebral infarction fibrin, and factor I,it can reduce blood viscosity and inhibit platelet aggregation.in the cerebral embolism model tests caused by the injection of arachidonic acid , after taking the product ,the occurrence of cerebral thrombosis is suppressed , animal mortality is decreased, while not only the cerebral movement disorders of acute phase is improved , but also the circulatory disorders of the acute phase of cerebral ischemia are improved,and the energy metabolism of cerebral ischemia is improved. Common agents are ozagrel injection, each 20mg.it is diluted by physiological saline or glucose injection then intravenous infusion, every day 80mg. when it is combined with other anti-platelet drugs, the dose of this product should be reduced. There may be bleeding tendency; occasional allergy, liver dysfunction, blood pressure drops, the outdoor contraction, headache, injection site pain, abdominal distension and other adverse reactions. Hemorrhage patients (intracerebral hemorrhage, intraventricular hemorrhage, gastrointestinal bleeding, subcutaneous bleeding, etc.), pregnant women or potentially pregnant women and children should use with caution. And it has a synergistic effect with drugs having inhibition of platelet function ,when they are used together, there must be appropriate reduction. Avoid mixing injection with calcium solution (Green solution, etc.) in order to avoid opacification. The above information is edited by the lookchem of Tian Ye.

production method

Use dehydrated methyl benzaldehyde as materials,after condensation with acetic anhydride aldol ,form 3-tolyl acrylate, become into a 3--tolyl acrylate ethyl after esterification , use benzoyl peroxide as an initiator, with N-bromosuccinimide (NBS) ,make the methyl on the ring become into bromomethyl, and after the hydrolysis reaction with imidazole, ozagrel sodium is obtained , melting point 308 ℃ (decomposition).

InChI:InChI=1/C13H12N2O2/c16-13(17)6-5-11-1-3-12(4-2-11)9-15-8-7-14-10-15/h1-8,10H,9H2,(H,16,17)/b6-5+

Upstream product

• 78712-80-8 ethyl (E)-3-[4-(imidazol-1-ylmethyl)phenyl]acrylate 
• 97585-04-1 ethyl (E)-3-(4-methylphenyl)acrylate 
• 78712-43-3 4-(1-imidazolylmethyl)cinnamic acid hydrochloride 
• 78712-67-1 ethyl (E)-4-(bromomethyl)cinnamate 
• 143945-86-2 cis-ozagrel 

Relevant articles and documents

Synthesis method of ozagrel sodium

The invention discloses a synthesis method of ozagrel sodium, and belongs to the technical field of medicines. The synthesis method comprises the following steps: (1), taking 4-bromobenzyl bromide asa starting material, and reacting with imidazole under an alkaline condition to generate a 1-(4-bromobenzyl)-1H-imidazole intermediate 1; (2), enabling 1-(4-bromobenzyl)-1H-imidazole to react with acrylate under the catalysis of palladium acetate to generate an ozagrel ester intermediate 2; and (3), carrying out alkaline hydrolysis on ozagrel ester to obtain an ozagrel sodium product. The synthesis method disclosed by the invention has the advantages of easily available raw materials, low price cost, few steps, small pollution and the like, and is suitable for industrial production.

Preparation method of Ozagrel sodium

The invention discloses a preparation method of Ozagrel sodium. The method comprises the following steps: performing a bromination reaction on ethyl 4-methylcinnamate and N-bromo-succinimide by takingacetonitrile as a solvent under the triggering of azodiisobutyronitrile, so as to obtain ethyl 4-bromomethylcinnamate; performing a condensation cyclization reaction on the ethyl 4-bromomethylcinnamate and imidazole by taking sodium hydroxide as an acid-binding agent and taking tetrahydrofuran as a solvent, so as to obtain imidazole ethyl 4-methylcinnamate; performing alkali hydrolysis on the imidazole ethyl 4-methylcinnamate, so as to obtain the Ozagrel sodium. According to the preparation method, the condensation cyclization reaction is performed by taking the sodium hydroxide as the acid-binding agent and taking the tetrahydrofuran as the solvent, so that the finally obtained product does not contain toxic components, the yield and the purity of the product can be effectively improved,and the content of genotoxic impurities (the ethyl 4-bromomethylcinnamate and ethyl 4-dibromomethylcinnamate) in the product is zero.

Preparation method of ozagrel

The invention provides a preparation method of ozagrel, which is characterized by comprising the following steps of: adding ozagrel hydrochloride monohydrate into purified water, heating to dissolve the ozagrel hydrochloride monohydrate, adding alkali liquor, carrying out cooling and crystallization after stirring, and carrying out extraction filtration to obtain an ozagrel crude product; carrying out recrystallization on the ozagrel crude product in mixed solution of methyl alcohol and water to obtain an ozagrel finished product. The preparation method is simple and efficient to operate and easy to control, and purity of the obtained ozagrel accords with the requirements of the Japanese pharmacopoeia.

Prominent inclusion effect of dimethyl-β-cyclodextrin on photoisomerization of the thromboxane synthetase inhibitor (E)-4-(1- imidazoylmethyl)cinnamic acid

The direct photoisomerization of (E)-4-(1-imidazoylmethyl)-cinnamic acid (IMC), a thromboxane synthetase inhibitor, to its (Z)-isomer at pH 2.0 was decelerated by β-cyclodextrin (β-CyD) and heptakis(2,6-di-O-methyl)-β- cyclodextrin (DM-β-CyD). The photostationary composition [(Z)-isomer:IMC ratio] was shifted in favor of IMC. These effects were much greater with DM- β-CyD than with the parent β-CyD. The quantum yield of the photoisomerization was significantly decreased by complex formation with β- CyDs, whereas the extinction coefficient of the guest was only slightly decreased. This situation was in sharp contrast to those observed in less polar solvents and suggests that the suppressing mechanism with β-CyD is different from that with less polar solvent systems. Spectroscopic studies (ultraviolet, circular dichroism, and nuclear magnetic resonance) indicated that IMC is tightly included in an axial mode in the cavity of DM-β-CyD and that the rotation of the photoreactive site is sterically hindered. The results suggest that the suppressing effect of β-CyDs on the photoisomerization of IMC results mainly from a steric origin.

Highly selective inhibitors of thromboxane synthetase. 1. Imidazole derivatives

The structure-activity relationships of imidazole derivatives as inhibitors of thromboxane (TX) synthetase were investigated. Introduction of various substituents (e.g., one or two methyl groups, a halogen atom, a methylidene group, unsaturated bonds, or a phenylene group) into the α position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum for the inhibitory potency on TX synthetase in the region of 8.5-9.0 A. Among the tested imidazole derivatives, 1-(7-carboxy-7-methyl-2-octynyl)imidazole, 4-[3-(1-imidazolyl)-propyl]benzoic acid, and (E)-4-(1-imidazolylmethyl)cinnamic acid and its α-methyl analogue showed the highest potency with an IC50 in the range of 10-8 to 10-9 M. Inhibition by these derivatives was highly selective for the TX synthetase, since other enzymes such as fatty acid cyclo-oxygenase and prostacyclin synthetase were not affected.

Imidazole derivative

Novel imidazole derivatives of the general formula (I): STR1 wherein Y is a carboxyl group, an alkoxycarbonyl group, a cyano group, a hydroxymethyl group, an aminomethyl group, a formyl group or a carbamoyl group, and A and B, which may be the same or different, each is a straight- or branched-chain alkylene or alkenylene group, and n and m, which may be the same or different, each is zero or 1, with the proviso that when A is methylene group or n is zero, m is 1; and pharmaceutically acceptable salts thereof. These compounds have a strong inhibitory effect on thromboxane synthetase from rabbit platelet microsomes, and are useful as therapeutically active agents for the treatment of inflammation, hypertension, thrombus, cerebral apoplexy and asthma.