KML-010

KML-010
Identifiers
	IUPAC name 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-methyl-1,3,8-triazaspiro[4.5]decan-4-one;
CAS Number	217635-62-6 ;
PubChem CID	10404584;
ChemSpider	8580022 ;
UNII	V68MR69LDZ;
CompTox Dashboard (EPA)	DTXSID001028491 ;
Chemical and physical data
Formula	C18H24FN3O2
Molar mass	333.407 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C1NCN(C)C1(CC2)CCN2CCCC(=O)c(cc3)ccc3F;
	InChI InChI=1S/C18H24FN3O2/c1-21-13-20-17(24)18(21)8-11-22(12-9-18)10-2-3-16(23)14-4-6-15(19)7-5-14/h4-7H,2-3,8-13H2,1H3,(H,20,24); Key:GRADLHIYNHRBCW-UHFFFAOYSA-N;
	(verify)

KML-010 is a drug derived from spiperone. It functions as a highly selective 5-HT_2A receptor antagonist, with negligible affinity for the 5-HT_1A or 5-HT_2C receptors, and over 400-fold lower affinity for the D₂ receptor in comparison to spiperone.^[1]

Synthesis

The Strecker condensation between N-Benzyl-4-piperidone [3612-20-2] (1), KCN and MeNH2.HCl produces amino nitrile, 1-Benzyl-4-(methylamino)piperidine-4-carbonitrile [953-79-7] (2). Partial hydrolysis of nitrile with H2SO4 furnishes amide, 1-benzyl-4-(methylamino)piperidine-4-carboxamide [1024-11-9] (3). Condensation of the amino amide with triethyl orthoformate gives rise to the spiro imidazolinone, 8-Benzyl-1-methyl-1,3,8-triazaspiro[4.5]decan-4-one, CID:10539225 (4). Catalytic hydrogenation of the imidazoline double bond of and simultaneous N-benzyl group hydrogenolysis gives rise to 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one [701897-99-6][219563-51-6] (5). Alkylation with 4-chloro-4'-fluorobutyrophenone [3874-54-2] (6) completed the synthesis of KML-010 (7).

References

^ Glennon RA, Metwally K, Dukat M, Ismaiel AM, De los Angeles J, Herndon J, Teitler M, Khorana N (June 2002). "Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists". Current Topics in Medicinal Chemistry. 2 (6): 539–58. doi:10.2174/1568026023393787. PMID 12052193.
^ Metwally, Kamel A.; Dukat, Malgorzata; Egan, Christina T.; Smith, Carol; DuPre, Ann; Gauthier, Colleen B.; Herrick-Davis, Katharine; Teitler, Milt; Glennon, Richard A. (1998). "Spiperone: Influence of Spiro Ring Substituents on 5-HT2ASerotonin Receptor Binding". Journal of Medicinal Chemistry. 41 (25): 5084–5093. doi:10.1021/jm980452a.
^ Janssen Paul Adriaan Jan, U.S. patent 3,155,669 (1964 to Research Laboratorium C Janssen NV).

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[pmid12052193-1] Glennon RA, Metwally K, Dukat M, Ismaiel AM, De los Angeles J, Herndon J, Teitler M, Khorana N (June 2002). "Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists". Current Topics in Medicinal Chemistry. 2 (6): 539–58. doi:10.2174/1568026023393787. PMID 12052193.

[2] Metwally, Kamel A.; Dukat, Malgorzata; Egan, Christina T.; Smith, Carol; DuPre, Ann; Gauthier, Colleen B.; Herrick-Davis, Katharine; Teitler, Milt; Glennon, Richard A. (1998). "Spiperone: Influence of Spiro Ring Substituents on 5-HT2ASerotonin Receptor Binding". Journal of Medicinal Chemistry. 41 (25): 5084–5093. doi:10.1021/jm980452a.

[3] Janssen Paul Adriaan Jan, U.S. patent 3,155,669 (1964 to Research Laboratorium C Janssen NV).

[1]

[2]

[3]

Synthesis

See also

References