Description
Ozagrel HCl (78712-43-3) is a potent and selective inhibitor of thromboxane A2 (TXA2) synthetase (IC50 = 4 nM). It does not inhibit prostacyclin (PGI2) synthase, cyclooxygenase, or PGE2 isomerase (IC50 > 1 mM)[1]. Ozagrel HCl inhibits platelet aggregation in vitro[2] and arachidonate-induced arterial contraction in vivo. It protects against arachidonate-induced sudden death in rabbits[3] and alleviates liver injury induced by acetaminophen overdose in mice[4].
History
Ozagrel hydrochloride was initially developed jointly by Ono Pharmaceutical Co., Ltd. and Kissei Pharmaceutical Co., Ltd. in Japan. Approved for marketing in Japan in 1988, it became the world's first commercially available potent thromboxane A2 (TXA2) synthase inhibitor. This medication is primarily indicated for the treatment of patients with ischaemic cerebrovascular disease, as it exhibits dual effects of inhibiting platelet aggregation and dilating blood vessels, thereby effectively preventing thrombus formation.
Uses
Ozagrel Hydrochloride is a selective thromboxane A2 synthase inhibitor, which alleviates liver injury induced by acetaminophen overdose in mice.
Definition
ChEBI: Ozagrel hydrochloride is an organic molecular entity.
Synthesis
The main synthetic methods of ozagrel hydrochloride are as follows: 1) take p-toluylaldehyde as raw material, get methyl or ethyl p-toluyl cinnamate by Claisen condensation or by Knoevenagl reaction and then esterification, get alkyl p-bromomethyl cinnamate by bromination, get alkyl p-bromomethyl cinnamate by N-alkylation with imidazole or N-acyl imidazole under the action of strong alkaline and finally hydrolyze it to get ozagrel hydrochloride under alkaline heating condition or hydrolysis to get ozagrel hydrochloride by bromination first and then N-alkylation of p-toluylaldehyde. hydrolysis under alkaline heating conditions to obtain ozagrel hydrochloride, or p-methylbenzaldehyde is first brominated and then N-alkylated, and finally undergoes a Knoevenagl reaction to obtain ozagrel hydrochloride. The acid-binding agents used in this method, sodium hydride, 1-substituted imidazole, N-bromosuccinimide (NBS), are expensive, and there is also the possibility of using corrosive and toxic bromine, carbon tetrachloride, unfriendly to the environment, unsuitable for industrial production; p-carboxymethylbenzaldehyde as a raw material, through a multistep reaction to produce ozagrel hydrochloride, which has a long synthetic route, and needs to be separated by column chromatography, the operation of which is cumbersome and not suitable for industrial production of ozagrel hydrochloride. This method has a long synthetic route and requires column chromatographic separation, which is cumbersome and not suitable for the industrial production of ozagrel hydrochloride. (iii) Ozagrel hydrochloride was obtained by condensation, hydrolysis and acidification of mimosine and methyl 4-bromomethylcinnamate as raw materials under the condition of sodium hydride and N,N-dimethylformamide as solvent. In this synthetic route, the raw material methyl 4-bromomethylcinnamate is more expensive, and if prepared, it has to be re-esterified with p-methylcinnamic acid brominated with NBS, which is the more expensive brominated reagent. The use of sodium hydride and DMF both add to the cost, and sodium hydride is dangerous, and DMF is difficult to remove as a high boiling solvent.
References
[1] SEIJI HIRAKU . Pharmacological Studies on the TXA2 Synthetase Inhibitor (E)-3-[p(1H-lmidazol-1-Ylmethyl)Phenyl]-2-Propenoic Acid (OKY-046)[J]. Japanese journal of pharmacology, 1986, 41 3: Pages 393-401. DOI:
10.1254/jjp.41.393[2] JUN NAITO . Effects of thromboxane synthetase inhibitors on aggregation of rabbit platelets[J]. European journal of pharmacology, 1983, 91 1: Pages 41-48. DOI:
10.1016/0014-2999(83)90359-x[3] LEE C. EDMONDS Allan M L. Protective actions of a new thromboxane synthetase inhibitor in arachidonate induced sudden death[J]. Life sciences, 1984, 35 17: Pages 1763-1768. DOI:
10.1016/0024-3205(84)90273-x[4] YOSHIRO TOMISHIMA. Ozagrel hydrochloride, a selective thromboxane A₂ synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice.[J]. BMC Gastroenterology, 2013, 13: 21. DOI:
10.1186/1471-230x-13-21
