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J-113,397

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Chemical compound

Pharmaceutical compound

J-113,397
Clinical data

Other names	J-113,397
Identifiers
IUPAC name 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one
CAS Number	256640-45-6^N 217461-40-0 (racemic)
PubChemCID	5311194
IUPHAR/BPS	1691
ChemSpider	4470714^N
UNII	00M5444DIY
ChEMBL	ChEMBL357076^N
CompTox Dashboard(EPA)	DTXSID801018432
Chemical and physical data
Formula	C₂₄H₃₇N₃O₂
Molar mass	399.579 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C4CCCCCCC4CN(CC1CO)CCC1n3c2ccccc2n(CC)c3=O
InChI InChI=1S/C24H37N3O2/c1-2-26-22-12-8-9-13-23(22)27(24(26)29)21-14-15-25(17-20(21)18-28)16-19-10-6-4-3-5-7-11-19/h8-9,12-13,19-21,28H,2-7,10-11,14-18H2,1H3/t20-,21+/m0/s1^N Key:MBGVUMXBUGIIBQ-LEWJYISDSA-N^N
^NY (what is this?) (verify)

J-113,397 is anopioid drug which was the first compound found to be a highly selective antagonist for thenociceptin receptor, also known as the ORL-1 receptor.^[1]^[2] It is several hundred times selective for the ORL-1 receptor over other opioid receptors,^[3]^[4] and its effects in animals include preventing the development oftolerance tomorphine,^[5] the prevention ofhyperalgesia induced by intracerebroventricular administration ofnociceptin (orphanin FQ),^[6] as well as the stimulation ofdopamine release in thestriatum,^[7] which increases the rewarding effects ofcocaine,^[8] but may have clinical application in the treatment ofParkinson's disease.^[9]^[10]^[11]

Synthesis

[edit]

Patents for treatingarrhythmia:^[12]

Improved synthesis:^[13] Additional patents:^[14]^[15]

Condensation between 1-Benzyl-3-methoxycarbonyl-4-piperidone [57611-47-9] (1) andO-Phenylenediamine (2) givesCID:16726310 (3). Reaction withboc anhydride followed by treatment withtrifluoroacetic acid givesCID:16726358 (4). Reaction withiodoethane in the presence of base alkylates the urea nitrogen givingCID:16726359 (5). Reduction of the enamine by treatment with magnesium metal in methanol solvent occurs to give predominantly the trans isomer,CID:16726360 (6). Catalytic removal of the benzyl group givesCID:16726362 (7). Reductive amination with Cyclooctanecarbaldehyde [6688-11-5] (7) givesCID:16726364 (9). Lastly, reduction of the ester with lithium aluminium hydride completed the synthesis of J-113397 (10).

References

[edit]

^Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, et al. (December 1999). "Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397)".Journal of Medicinal Chemistry.42 (25):5061–3.doi:10.1021/jm990517p.PMID 10602690.
^De Risi C, Piero Pollini G, Trapella C, Peretto I, Ronzoni S, Giardina GA (July 2001). "A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist".Bioorganic & Medicinal Chemistry.9 (7):1871–7.doi:10.1016/s0968-0896(01)00085-2.PMID 11425589.
^Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Iwasawa Y, Ohta H (January 2000). "A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1) antagonist: J-113397".European Journal of Pharmacology.387 (3): R17-8.doi:10.1016/s0014-2999(99)00822-5.PMID 10650183.
^Smith ED, Ariane Vinson N, Zhong D, Berrang BD, Catanzaro JL, Thomas JB, et al. (January 2008)."A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay".Bioorganic & Medicinal Chemistry.16 (2):822–9.doi:10.1016/j.bmc.2007.10.023.PMC 2323199.PMID 17976996.
^Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK (July 2006). "Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance".The Journal of Pharmacology and Experimental Therapeutics.318 (1):262–7.doi:10.1124/jpet.106.103960.PMID 16595734.S2CID 15569763.
^Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, et al. (August 2000). "In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist".European Journal of Pharmacology.402 (1–2):45–53.doi:10.1016/s0014-2999(00)00520-3.PMID 10940356.
^Marti M, Mela F, Veronesi C, Guerrini R, Salvadori S, Federici M, et al. (July 2004)."Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior".The Journal of Neuroscience.24 (30):6659–66.doi:10.1523/JNEUROSCI.0987-04.2004.PMC 6729727.PMID 15282268.
^Marquez P, Nguyen AT, Hamid A, Lutfy K (March 2008)."The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine".Neuropharmacology.54 (3):564–8.doi:10.1016/j.neuropharm.2007.11.003.PMC 2276976.PMID 18082848.
^Marti M, Trapella C, Viaro R, Morari M (February 2007)."The nociceptin/orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway".The Journal of Neuroscience.27 (6):1297–307.doi:10.1523/JNEUROSCI.4346-06.2007.PMC 6673573.PMID 17287504.
^Viaro R, Sanchez-Pernaute R, Marti M, Trapella C, Isacson O, Morari M (June 2008)."Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism".Neurobiology of Disease.30 (3):430–8.doi:10.1016/j.nbd.2008.02.011.PMC 2605654.PMID 18413287.
^Visanji NP, de Bie RM, Johnston TH, McCreary AC, Brotchie JM, Fox SH (October 2008). "The nociceptin/orphanin FQ (NOP) receptor antagonist J-113397 enhances the effects of levodopa in the MPTP-lesioned nonhuman primate model of Parkinson's disease".Movement Disorders.23 (13):1922–5.doi:10.1002/mds.22086.PMID 18759357.S2CID 46116472.
^Guo Zheng, et al.CN 111249279 &CN 111265663 (2020).
^Sulima, A., Folk, J., Jacobson, A., Rice, K. (2 May 2007). "A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist J-113397".Synthesis.2007 (10):1547–1553.doi:10.1055/s-2007-966037.
^Satoshi Ozaki, et al.WO 1998054168 (to MSD KK).
^Hiroshi Kawamoto, et al.WO 2000031061 (to MSD KK).