BMY-14802

BMY-14802

Clinical data
Other names	BMS-181100; MJ-14802
ATC code	None
Identifiers
IUPAC name 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]butan-1-ol
CAS Number	105565-56-8  N
PubChem CID	108046
IUPHAR/BPS	8
ChemSpider	97151  N
UNII	A5NB5G07JO
ChEMBL	ChEMBL60859  N
CompTox Dashboard (EPA)	DTXSID70909596
Chemical and physical data
Formula	C18H22F2N4O
Molar mass	348.398 g·mol−1
3D model (JSmol)	Interactive image
SMILES c1cc(F)ccc1C(O)CCCN2CCN(CC2)c3ncc(F)cn3
InChI InChI=1S/C18H22F2N4O/c19-15-5-3-14(4-6-15)17(25)2-1-7-23-8-10-24(11-9-23)18-21-12-16(20)13-22-18/h3-6,12-13,17,25H,1-2,7-11H2 N Key:ZXUYYZPJUGQHLQ-UHFFFAOYSA-N N
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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-HT_1A 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

• Enciprazine
• Ensaculin
• Mafoprazine
• Azaperone
• Fluanisone

References

1. Taylor DP, Eison MS, Moon SL, Schlemmer RF, Shukla UA, VanderMaelen CP, et al. (1993). "A role for sigma binding in the antipsychotic profile of BMY 14802?". NIDA Research Monograph. 133: 125–157. PMID   8232511.
2. Vanecek SA, Essman WD, Taylor DP, Woods JH (January 1998). "Discriminative stimulus characteristics of BMY 14802 in the pigeon". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 1–9. PMID   9435153.
3. Kitanaka J, Kitanaka N, Tatsuta T, Hall FS, Uhl GR, Tanaka K, et al. (May 2009). "Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice". Psychopharmacology. 203 (4): 781–792. doi:10.1007/s00213-008-1425-z. PMC   3157915 . PMID   19052726.
4. Paquette MA, Foley K, Brudney EG, Meshul CK, Johnson SW, Berger SP (July 2009). "The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism". Psychopharmacology. 204 (4): 743–754. doi:10.1007/s00213-009-1505-8. PMC   2845289 . PMID   19283364.
5. Zamanillo D, Portillo-Salido E, Vela JM, Romero L (20 April 2012). "Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic Perspectives". In Botana LM, Loza M (eds.). Therapeutic Targets: Modulation, Inhibition, and Activation. John Wiley & Sons. pp. 248–. ISBN   978-1-118-18552-0.
6. "BMS 181100". AdisInsight. Springer Nature Switzerland AG.
7. Joseph P. Yevich & Walter G. Lobeck, Jr., U.S. patent 4,605,655 (1986 to Bristol Myers Co).