Wikipedia

Umespirone

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]

Umespirone
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
  • 3-butyl-7-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetrone
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC28H40N4O5
Molar mass512.651 g·mol−1
3D model (JSmol)
  • O=C1N(C(=O)C2C(=O)N(C(=O)C1C2(C)C)CCCCN4CCN(c3ccccc3OC)CC4)CCCC

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

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References

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  1. ^ a b Holland RL, Wesnes K, Dietrich B (1994). "Single dose human pharmacology of umespirone". European Journal of Clinical Pharmacology. 46 (5): 461–8. doi:10.1007/bf00191912. PMID 7957544. S2CID 12117650.461-8&rft.date=1994&rft_id=https://api.semanticscholar.org/CorpusID:12117650#id-name=S2CID&rft_id=info:pmid/7957544&rft_id=info:doi/10.1007/bf00191912&rft.aulast=Holland&rft.aufirst=RL&rft.au=Wesnes, K&rft.au=Dietrich, B&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  2. ^ a b Barnes NM, Costall B, Domeney AM, et al. (September 1991). "The effects of umespirone as a potential anxiolytic and antipsychotic agent". Pharmacology Biochemistry and Behavior. 40 (1): 89–96. doi:10.1016/0091-3057(91)90326-W. PMID 1685786. S2CID 9762359.89-96&rft.date=1991-09&rft_id=https://api.semanticscholar.org/CorpusID:9762359#id-name=S2CID&rft_id=info:pmid/1685786&rft_id=info:doi/10.1016/0091-3057(91)90326-W&rft.aulast=Barnes&rft.aufirst=NM&rft.au=Costall, B&rft.au=Domeney, AM&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  3. ^ Ruhland M, Krähling H, Fuchs A, Schön U (November 1988). "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. doi:10.1055/s-2007-1017024. PMID 2907649. S2CID 260241523.396-8&rft.date=1988-11&rft_id=https://api.semanticscholar.org/CorpusID:260241523#id-name=S2CID&rft_id=info:pmid/2907649&rft_id=info:doi/10.1055/s-2007-1017024&rft.aulast=Ruhland&rft.aufirst=M&rft.au=Krähling, H&rft.au=Fuchs, A&rft.au=Schön, U&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  4. ^ Krähling H, Fuchs A, Ruhland M, Schön U, Mol F, Tulp M (November 1988). "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. doi:10.1055/s-2007-1017025. PMID 2907650. S2CID 260241655.399-401&rft.date=1988-11&rft_id=https://api.semanticscholar.org/CorpusID:260241655#id-name=S2CID&rft_id=info:pmid/2907650&rft_id=info:doi/10.1055/s-2007-1017025&rft.aulast=Krähling&rft.aufirst=H&rft.au=Fuchs, A&rft.au=Ruhland, M&rft.au=Schön, U&rft.au=Mol, F&rft.au=Tulp, M&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  5. ^ a b Schmidt WJ, Krähling H, Ruhland M (1991). "Antagonism of AP-5-induced sniffing stereotypy links umespirone to atypical antipsychotics". Life Sciences. 48 (6): 499–505. doi:10.1016/0024-3205(91)90464-M. PMID 1671523.499-505&rft.date=1991&rft_id=info:doi/10.1016/0024-3205(91)90464-M&rft_id=info:pmid/1671523&rft.aulast=Schmidt&rft.aufirst=WJ&rft.au=Krähling, H&rft.au=Ruhland, M&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  6. ^ a b Ahlenius S, Wijkström A (November 1992). "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. doi:10.1016/0014-2999(92)90464-F. PMID 1361441.69-74&rft.date=1992-11&rft_id=info:doi/10.1016/0014-2999(92)90464-F&rft_id=info:pmid/1361441&rft.aulast=Ahlenius&rft.aufirst=S&rft.au=Wijkström, A&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  7. ^ Itzhak Y, Ruhland M, Krähling H (February 1990). "Binding of umespirone to the sigma receptor: evidence for multiple affinity states". Neuropharmacology. 29 (2): 181–4. doi:10.1016/0028-3908(90)90058-Y. PMID 1970425. S2CID 54326248.181-4&rft.date=1990-02&rft_id=https://api.semanticscholar.org/CorpusID:54326248#id-name=S2CID&rft_id=info:pmid/1970425&rft_id=info:doi/10.1016/0028-3908(90)90058-Y&rft.aulast=Itzhak&rft.aufirst=Y&rft.au=Ruhland, M&rft.au=Krähling, H&rft_id=https://doi.org/10.1016%2F0028-3908%2890%2990058-Y&rfr_id=info:sid/en.wikipedia.org:Umespirone" class="Z3988">
  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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