Cinepazide

Cinepazide or cinepazide maleate[1] (Kelinao or Anjieli in China[2][3]) is a vasodilator used in China for the treatment of cardiovascular and cerebrovascular diseases, and peripheral vascular diseases.[4] It appears to work by potentiating A2 adenosine receptors.[5]

Cinepazide
Clinical data
ATC code
Identifiers
IUPAC name
  • (2E)-1-{4-[2-Oxo-2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.739
Chemical and physical data
FormulaC22H31N3O5
Molar mass417.49864 g·mol−1
3D model (JSmol)
SMILES
  • O=C(N1CCCC1)CN3CCN(C(=O)\C=C\c2cc(OC)c(OC)c(OC)c2)CC3
InChI
  • InChI=1S/C22H31N3O5/c1-28-18-14-17(15-19(29-2)22(18)30-3)6-7-20(26)25-12-10-23(11-13-25)16-21(27)24-8-4-5-9-24/h6-7,14-15H,4-5,8-13,16H2,1-3H3/b7-6+ N
  • Key:RCUDFXMNPQNBDU-VOTSOKGWSA-N N
 NY (what is this?)  (verify)

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.[6][7] 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failure, balance disorders, cerebrovascular disease, and vascular complications of diabetes.[6][8] In 1988 the drug was withdrawn from the market in Spain due to risk of agranulocytosis; other countries where the drug was available added warnings to the label.[9][10] It was withdrawn from the market in France in 1992.[11] The drug had also been marketed in Japan by Daiichi Pharmeceutical Company under the brand name "Brindel"[2] for dementia, but was withdrawn in 1999, following a review by the Japanese regulatory authorities of dementia drugs after a drug, calcium hopantenate, that had been considered the standard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.[12]

In 2002 Sihuan Pharmaceutical brought an injectable form of the drug to market in China;[13] Sihuan had acquired the drug from a military hospital in China that had developed the formulation.[14] 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.[13][3] This made Sihuan Pharm the largest company in China in the cardio-cerebral vascular drug market in 2010.[3] In 2014 it was the tenth highest-selling drug in China.[14]

Synthesis

Thieme Synthesis:[15][16] Background patent:[17] Sino:[18]

Amide formation between chloroacetyl chloride (1) and pyrrolidine (2) gives 1-(chloroacetyl)pyrrolidine [20266-00-6] (3). Displacement of the remaining halogen by piperazine gives 1-(pyrrolidinocarbonylmethyl)piperazine [39890-45-4] (4). A second Schotten-Baumann reaction this time with 3,4,5-trimethoxycinnamoyl chloride [4521-61-3] (5) completed the synthesis of cinepazide (6).

References

  1. "Anjieli, Kelinao, cinepazide maleate - Product Profile - BioCentury". www.biocentury.com. Retrieved 2015-08-04.
  2. Drugs.com Drugs.com International listings for cinepazide Page accessed Aug 3, 2015
  3. 20 Oct 2010 Sihuan Pharm – China's leading player in cardio-cerebral vascular drug – IPO Report Archived 2015-09-23 at the Wayback Machine
  4. Sihuan Pharmaceutical Kelinao/Anjieli official site Page accessed Aug 3, 2015
  5. Ruffolo RR, Hieble JP, Brooks DP, Feuerstein GZ, Nichols AJ (1991). "Drug receptors and control of the cardiovascular system: recent advances". Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progrès des Recherches Pharmaceutiques. 36: 117–360. doi:10.1007/978-3-0348-7136-5_4. ISBN 978-3-0348-7138-9. PMID 1876708.
  6. Johnson Sun for Guotai Junan International. Sept 28, 2011. Company Report: Sihuan Pharmaceuticals
  7. Cameron BD, Chasseaud LF, Hawkins DR, Taylor T (July 1976). "The metabolic fate of the coronary vasodilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine (cinepazide) in the rat, dog and man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 6 (7): 441–55. doi:10.3109/00498257609151657. PMID 997590.
  8. Reactions Weekly 305(1):1. June 1990 Cinepazide-related agranulocytosis
  9. Laporte JR, Capellà D, Juan J (1990). "Agranulocytosis induced by cinepazide". European Journal of Clinical Pharmacology. 38 (4): 387–8. doi:10.1007/bf00315580. PMID 2344862. S2CID 19427552.
  10. Department of Economic and Social Affairs of the United Nations Secretariat Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments Twelfth Issue: Pharmaceuticals United Nations – New York, 2005
  11. 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
  12. Takeda M, Tanaka T, Okochi M (August 2011). "New drugs for Alzheimer's disease in Japan". Psychiatry and Clinical Neurosciences. 65 (5): 399–404. doi:10.1111/j.1440-1819.2011.02253.x. PMID 21851448. S2CID 21519637.
  13. Lefei Sun, Jinsong Du, and Iris Wang for Credit Suisse. October 6, 2011 China Pharma Sector
  14. Su Zhang for Standard Chartered Bank (HK) Limited. June 27, 2014 China health care: Pharma sector comes of age
  15. C. Fauran and M. Turin, Chim. Ther., 4, 290 (1969).
  16. Ohtaka, H., Yoshida, K., Suzuki, K., Shimohara, K., Tajima, S., Ito, K. (1988). "Benzylpiperazine derivatives. VIII. Syntheses, antiulcer and cytoprotective activities of 1-(aminocarbonylalkyl)-4-benzylpiperazine derivatives and related compounds". Chemical and Pharmaceutical Bulletin. 36 (10): 3948–3954. doi:10.1248/cpb.36.3948.
  17. Yasuo Itho, et al. U.S. Patent 4,478,838 (1984 to Abbott Japan Co Ltd).
  18. Liu Da, et al. CN 112028856 (2020 to Kamp Pharmaceuticals Co Ltd).
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