Chemistry:Umespirone

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Short description: Anxiolytic and antipsychotic drug
Umespirone
Umespirone skeletal.svg
Clinical data
Routes of
administration		By mouth
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
Elimination half-lifeUnknown but effects last much longer than other azapirones, up to 23 hours after a single dose in human clinical studies.[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC28H40N4O5
Molar mass512.651 g·mol−1
3D model (JSmol)

Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties.[2][3][4][5] It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM).[2][6][7] Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.[1][5][6]

Synthesis

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Synthesis:[8] Patent:[9]

The condensation between ethyl cyanoacetate (1) and acetone gives ethylisopropylidenecyanoacetate [759-58-0] (2). This product is reacted with N-butylcyanoacetamide [39581-21-0] (3) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide, CID:10681941 (4). The glutarimide is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone, https://pubchem.ncbi.nlm.nih.gov/compound/10825633 CID:10825633 (5).

The reaction between 1-(o-anisyl)piperazine [35386-24-4] (6) and 1,4-dibromobutane [110-52-1] (7) gives the Quat salt CID:15895413(8).

Convergent synthesis (in the presence of potassium carbonate) affords Umespirone (KC-9172) (9).

See also

References

  1. ↑ 1.0 1.1 "Single dose human pharmacology of umespirone". European Journal of Clinical Pharmacology 46 (5): 461–8. 1994. doi:10.1007/bf00191912. PMID 7957544. 
  2. ↑ 2.0 2.1 "The effects of umespirone as a potential anxiolytic and antipsychotic agent". Pharmacology Biochemistry and Behavior 40 (1): 89–96. September 1991. doi:10.1016/0091-3057(91)90326-W. PMID 1685786. 
  3. ↑ "KC 9172 (free base of KC 7218)--an antipsychotic/anxiolytic compound. I. Antipsychotic and anxiolytic activity in comparison with chlorpromazine, clozapine, diazepam and buspirone". Pharmacopsychiatry 21 (6): 396–8. November 1988. doi:10.1055/s-2007-1017024. PMID 2907649. 
  4. ↑ "KC 9172 (free base of KC 7218)--an antipsychotic/anxiolytic compound. II. Discrimination from typical neuroleptics and benzodiazepine-like minor tranquilizers". Pharmacopsychiatry 21 (6): 399–401. November 1988. doi:10.1055/s-2007-1017025. PMID 2907650. 
  5. ↑ 5.0 5.1 "Antagonism of AP-5-induced sniffing stereotypy links umespirone to atypical antipsychotics". Life Sciences 48 (6): 499–505. 1991. doi:10.1016/0024-3205(91)90464-M. PMID 1671523. 
  6. ↑ 6.0 6.1 "Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat". European Journal of Pharmacology 222 (1): 69–74. November 1992. doi:10.1016/0014-2999(92)90464-F. PMID 1361441. 
  7. ↑ "Binding of umespirone to the sigma receptor: evidence for multiple affinity states". Neuropharmacology 29 (2): 181–4. February 1990. doi:10.1016/0028-3908(90)90058-Y. PMID 1970425. 
  8. ↑ Kr鋒ling, H.; Krijzer, F. Drugs Fut 1991,16(5),437.
  9. ↑ DE3529872 idem Uwe Schoen, Wolfgang Kehrbach, Werner Benson, Andreas Fuchs, Michael Ruhland, U.S. Patent 4,771,044 (1988 to Kali-Chemie Pharma Gmbh).




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