tert-Butyl 4-(2,3-diaminophenyl)piperazine-1- carboxylate

tert-Butyl 4-(2,3-diaminophenyl)piperazine-1- carboxylate (4)

1H NMR (400 MHz, CDCl3), δ in ppm = 6.68 (t, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 3.56 (br s, 8H), 2.83 (s, 4H), 1.49 (s, 9H). This is consistent with literature data.1

Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor

 

Richard Fjellaksel,*abc  Marc Boomgaren,c  Rune Sundset,ad  Ira H. Haraldsen,e  Jørn H. Hansenc  and Patrick J. Rissefg 

 Author affiliations

*Corresponding authors

aMedical Imaging Group, Department of Clinical Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
E-mail: richard.fjellaksel@uit.no

bDrug Transport and Delivery Group, Department of Pharmacy, UiT The Arctic University of Norway, 9037 Tromsø, Norway

cOrganic Chemistry Group, Department of Chemistry, UiT The Arctic University of Norway, 9037 Tromsø, Norway

dPET imaging center, division of diagnostics, UNN – University Hospital of North-Norway, 9038 Tromsø, Norway

eDepartment of neuropsychiatry and psychosomatic medicine, Oslo University Hospital, Oslo, Norway

fRealomics SFI, Department of Chemistry, University of Oslo, PO BOX 1033, Oslo 0371, Norway

gNorsk Medisinsk Syklotronsenter AS, Postboks 4950 Nydalen, 0424 Oslo, Norway

Abstract

In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition. Our main purpose was to find a more soluble compound based on the WAY207024 lead with nanomolar potency to inhibit the GnRH receptor. A late stage diversification by the use of click chemistry was, furthermore developed to allow for expansion of the library in future optimisations. All compounds were tested in a functional assay to determine the individual potency of inhibiting stimulation of the receptor by the endogenous agonist GnRH. In conclusion, we found that compound 8ashowed improved solubility compared to WAY207024 and nanomolar affinity to GnRH receptor.

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References 1. Pelletier, J. C.; Chengalvala, M.; Cottom, J.; Feingold, I.; Garrick, L.; Green, D.; Hauze, D.; Huselton, C.; Jetter, J.; Kao, W.; Kopf, G. S.; Lundquist, J. T. t.; Mann, C.; Mehlmann, J.; Rogers, J.; Shanno, L.; Wrobel, J., 2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor. Bioorganic & medicinal chemistry 2008, 16 (13), 6617-40.