Cinepazide or cinepazide maleate (Kelinao or Anjieli in ChinaDrugs.co

Page accessed Aug 3, 201520 Oct 201
Sihuan Pharm – China's leading player in cardio-cerebral vascular drug – IPO Report
) is a

vasodilator Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

used in China for the treatment of cardiovascular and

cerebrovascular diseases Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The ...

, and peripheral vascular diseases. It appears to work by potentiating A2

adenosine receptors The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a ...

History

Cinepazide was discovered by scientists at Laboratoires Delalande (now part of Sanofi) in 1969 in an effort to explore useful substituted cinnamoyl- piperazine compounds. The drug, in the form of a pill taken orally, was launched by Delalande in 1976 under the tradename Vasodistal, for treatment of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

, balance disorders, cerebrovascular disease, and vascular complications of diabetes.Johnson Sun for Guotai Junan International. Sept 28, 2011
Company Report: Sihuan Pharmaceuticals
/ref>Reactions Weekly 305(1):1. June 199
Cinepazide-related agranulocytosis
/ref> In 1988 the drug was withdrawn from the market in Spain due to risk of

agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...

; other countries where the drug was available added warnings to the label. It was withdrawn from the market in France in 1992.Sidney M. Wolfe, M.D. for the Public Citizen's Health Research Group. February 2, 1995
Differences in the Number of Drug Safety Withdrawals: United States, United Kingdom, Germany and France 1970-1992
/ref> The drug had also been marketed in Japan by Daiichi Pharmeceutical Company under the brand name "Brindel" for dementia, but was withdrawn in 1999, following a review by the Japanese regulatory authorities of dementia drugs after a drug, calcium hopantenate, that had been considered the standard of care and against which cinepazide and other dementia drugs had been compared, had failed to demonstrate efficacy in a re-evaluation. In 2002 Sihuan Pharmaceutical brought an injectable form of the drug to market in China; Sihuan had acquired the drug from a military hospital in China that had developed the formulation.Su Zhang for Standard Chartered Bank (HK) Limited. June 27, 201
China health care: Pharma sector comes of age
/ref> In 2010 it was the highest selling drug in China, with about 1 billion RMB in sales in the 3rd quarter, outselling Plavix in China.Lefei Sun, Jinsong Du, and Iris Wang for Credit Suisse. October 6, 201
China Pharma Sector
/ref> This made Sihuan Pharm the largest company in China in the cardio-cerebral vascular drug market in 2010. In 2014 it was the tenth highest-selling drug in China.

Synthesis

Amide formation between

chloroacetyl chloride Chloroacetyl chloride is a chlorinated acyl chloride. It is a bifunctional compound, making it a useful building block chemical. Production Industrially, it is produced by the carbonylation of methylene chloride, oxidation of vinylidene chlorid ...

(1) and

pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...

(2) gives 1-(chloroacetyl)pyrrolidine 0266-00-6(3). Displacement of the remaining halogen by piperazine gives 1-(pyrrolidinocarbonylmethyl)piperazine 9890-45-4(4). A second Schotten-Baumann reaction this time with 3,4,5-trimethoxycinnamoyl chloride 521-61-3(5) completed the synthesis of cinepazide (6).

References

{{Peripheral vasodilators Carboxamides Cinnamate esters Pyrogallol ethers Piperazines Pyrrolidines