Chemistry:BMY-14802

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BMY-14802, also known as BMS-181100, is a drug with antipsychotic effects which acts as both a sigma receptor antagonist and a 5-HT1A receptor agonist.[1][2][3][4] It also has affinity for the 5-HT2 and D4 receptors.[5] The drug reached phase III clinical trials for the treatment of psychosis but was never marketed.[6]

Synthesis

Patent (Ex1/2/5/6/7):[7]

The reaction of 4-chloro-4'-fluorobutyrophenone [3874-54-2] (1) with ethylene glycol gives the ketal, 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane [3308-94-9] (2). The reaction of 2-chloro-5-fluoro-4-methylthiopyrimidine [87789-51-3] (3) with N-carboethoxypiperazine [120-43-4] (4) gives ethyl-4-(5-fluoro-4-methylthio-2-pyrimidinyl)-1-piperazine carboxylate, PC10470079 (5). Catalytic hydrogenation removes the thiomethyl group giving ethyl-4-(5-fluoro-2-pyrimidinyl)-1-piperazine carboxylate [87789-52-4] (6). Acid hydrolysis of the carbamate protecting group gives a secondary amine and hence 5-fluoro-2-(piperazin-1-yl)pyrimidine [87789-49-9] (7). Alkylation of 2 with 7 and subsequent hydrolysis of the ketal protecting group afforded 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)butan-1-one [133982-66-8] (8). Lastly, reduction of the benzoyl ketone with sodium borohydride gave the alcohol, completing the synthesis of BMY-14802 (9).

See also

References

  1. ↑ "A role for sigma binding in the antipsychotic profile of BMY 14802?". NIDA Research Monograph 133: 125–157. 1993. PMID 8232511. 
  2. ↑ "Discriminative stimulus characteristics of BMY 14802 in the pigeon". The Journal of Pharmacology and Experimental Therapeutics 284 (1): 1–9. January 1998. PMID 9435153. 
  3. ↑ "Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice". Psychopharmacology 203 (4): 781–792. May 2009. doi:10.1007/s00213-008-1425-z. PMID 19052726. 
  4. ↑ "The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism". Psychopharmacology 204 (4): 743–754. July 2009. doi:10.1007/s00213-009-1505-8. PMID 19283364. 
  5. ↑ "Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic Perspectives". Therapeutic Targets: Modulation, Inhibition, and Activation. John Wiley & Sons. 20 April 2012. pp. 248–. ISBN 978-1-118-18552-0. https://books.google.com/books?id=3XJ8PXFCXq4C&pg=PA248. 
  6. ↑ "BMS 181100". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800000679. 
  7. ↑ Joseph P. Yevich & Walter G. Lobeck, Jr., U.S. Patent 4,605,655 (1986 to Bristol Myers Co).



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