SHA-68

SHA-68
Clinical data
ATC code	none;
Identifiers
	IUPAC name N-[(4-fluorophenyl)methyl]-3-oxo-1,1-diphenyl-5,6,8,8a-tetrahydro-[1,3]oxazolo[3,4-a]pyrazine-7-carboxamide;
CAS Number	847553-89-3 [EPA];
PubChem CID	11374217;
IUPHAR/BPS	5813;
ChemSpider	9549134;
UNII	8Q99A974BL;
ChEMBL	ChEMBL469695;
CompTox Dashboard (EPA)	DTXSID801028552 ;
Chemical and physical data
Formula	C26H24FN3O3
Molar mass	445.494 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES c4ccccc4C1(c5ccccc5)OC(=O)N3C1CN(CC3)C(=O)NCc(cc2)ccc2F;
	InChI InChI=1S/C26H24FN3O3/c27-22-13-11-19(12-14-22)17-28-24(31)29-15-16-30-23(18-29)26(33-25(30)32,20-7-3-1-4-8-20)21-9-5-2-6-10-21/h1-14,23H,15-18H2,(H,28,31); Key:SFRQIPRTNYHJHP-UHFFFAOYSA-N;
	(verify)

SHA-68 is a drug which acts as a selective, non-peptide antagonist at the neuropeptide S receptor NPSR. In animal studies it reduced motor stereotypes, and blocks the stimulant action of neuropeptide S.^[1]^[2]

Synthesis

The synthesis of SHA-68 was shown in a patent (ref example 1, Ex 1, Ex 2, Ex 16).^[3]

The Grignard reaction between Methyl 2-piperazine carboxylate [2758-98-7] (1) and phenylmagnesium bromide [100-58-3] (2) occurs to give alpha,alpha-Diphenyl-2-piperazinemethanol [17532-20-6] (3). {This compound is called Azapipradrol}. Protection of the sterically more accessible piperazine nitrogen with Boc anhydride occurs to give PC23122074 (4). Treatment with ethyl chloroformate [541-41-3] (5) gives the cyclic urethane and hence, PC68420957 (6). Deprotection of the Boc group in the presence of trifluoroacetic acid gave 1,1-Diphenyltetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [847555-93-5] [847556-28-9] (7). Lastly, treatment with 4-fluorophenyl isocyanate [1195-45-5] (8) gave the substituted urea, thus completing the synthesis of SHA-68 (9).

SAR reveals similarity to RTI-118 & contains the same precursor.

References

^ Fukatsu K, Nakayama Y, Tarui N, Mori M, Matsumoto H, Kurasawa O, Banno H. Bicyclic Piperazine Compound and Use Thereof. PCT Patent WO 2005/021555 A1. Published 26.08.2004
^ Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK (June 2008). "Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor". The Journal of Pharmacology and Experimental Therapeutics. 325 (3): 893–901. doi:10.1124/jpet.107.135103. PMC 2583099. PMID 18337476.
^ Kohji Fukatsu, et al. WO2005021555 (to Takeda Pharmaceutical Co Ltd).

[1] Fukatsu K, Nakayama Y, Tarui N, Mori M, Matsumoto H, Kurasawa O, Banno H. Bicyclic Piperazine Compound and Use Thereof. PCT Patent WO 2005/021555 A1. Published 26.08.2004

[pmid18337476-2] Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK (June 2008). "Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor". The Journal of Pharmacology and Experimental Therapeutics. 325 (3): 893–901. doi:10.1124/jpet.107.135103. PMC 2583099. PMID 18337476.

[3] Kohji Fukatsu, et al. WO2005021555 (to Takeda Pharmaceutical Co Ltd).

[1]

[2]

[3]

Synthesis

See also

References