691880-06-5

Upstream product

• 691880-05-4 3-(2-((trimethylsilyl)oxy)ethyl)-1H-indole 
• 100-59-4 phenylmagnesium chloride 
• 77253-85-1 dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)amine 
• 65619-92-3 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile 
• 4746-97-8 cyclohexanedione monoethylene ketal 
• 65619-20-7 4-dimethylamino-4-phenylcyclohexanone 

Relevant academic research and scientific papers

Discovery of a potent analgesic NOP and opioid receptor agonist: Cebranopadol

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′, 9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H) -pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

Discovery of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as potent NOP and opioid receptor agonists

We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.