CEP-26401 Irdabisant; Histamine H3 Receptor Antagonists

1005402-19-6

313.3941, C18 H23 N3 O2

Histamine H3 Receptor Antagonists in phase 1

6-[4-[3-[2(R)-Methylpyrrolidin-1-yl]propoxy]phenyl]pyridazin-3(2H)-one

3(2H)-Pyridazinone, 6-[4-[3-[(2R)-2-methyl-1-pyrrolidinyl]propoxy]phenyl]-

6-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyridazin-3(2H)-one

6-[4-[3-[(2R)-2-methyl-1-pyrrolidinyl]propoxy]phenyl]-3(2H)-pyridazinone

irdabisant

Cephalon Inc, innovator

CEP-26401 is a histamine H3 receptor antagonist in phase I clinical development at Cephalon to improve cognition in Alzheimer’s disease patients and for the treatment of schizophrenia. Cephalon was acquired by Teva in October 2011.

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H₃ receptor (H₃R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H₃R was demonstrated in radioligand binding displacement assays in rat brain membranes (K_i = 2.7 ± 0.3 nM) and recombinant rat and human H₃R-expressing systems (K_i = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively).

CEP-26401 displayed potent antagonist and inverse agonist activities in [³⁵S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H₃R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC₅₀ = 0.1 ± 0.003 mg/kg), and antagonism of the H₃R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED₅₀ = 0.06 mg/kg).

CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H₃R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders.

CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics

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By Carmen Drahl • Posted in http://cenblog.org/the-haystack/2011/03/drug-candidate-structures-revealed-at-acsanaheim/    

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WO 2008013838 or  http://www.google.com/patents/EP2502918A1?cl=en

Example 11

Step 1.

• [0174]
• A mixture of 1-(4-hydroxyphenyl)ethanone (20.4 g, 150 mmol), K₂CO₃ (62.1 g, 3.0 eq.), and 3-bromo-1-chloropropane (29.6 mL, 2.0 eq.) in CH₃COCH₃ (200 mL) was heated to 65 °C overnight. The mixture was filtered, washed with acetone, and concentrated to dryness. The crude product was dissolved in 150 mL of CH₂Cl₂, and washed with saturated NaHCO₃, NaCl solution and dried over Na₂SO₄. Concentration to dryness under vaccum afforded product (31.5 g, 99 % yield): MS m/z 213 (M + H).

Step 2.

• A mixture of the product from step 1 1 (4.6 g, 1.0 eq.) and glyoxalic acid monohydrate (4.6g, 1.0 eq.) was stirred in 15 mL of acetic acid at 100 °C for 2 h. The solvent was evaporated and to the residue was added 25 mL of water, and cooled to 0 °C while conc. aqueous NH₄OH was added to pH 8. To this mixture, hydrazine hydrate (4.76 mL, 2 eq.) was added and heated to 100 °C for 1 h. The resulting solid was filtered, washed with water. The crude material was dissolved in CH₂Cl₂/MeOH and purified by column chromatography with CH₂Cl₂ to 10 % MeOH in CH₂Cl₂; Mp 191-3 °C; MS m/z 265 (M + H).

Step 3.

• A mixture of the product from step 2 (5.5 g, 21 mmol), K₂CO₃ (3.5 eq, 10.1g), 100 mg ofNaI, and R-2-methylpyrrolidine hydrochloride (2 eq., 5.1 g) in 250 mL of acetonitrile was heated to 80 °C for 2 days. The reaction mixture was then filtered, washed with CH₂Cl₂ (2 x 50mL), and concentrated. The residue was dissolved in 200 mL of CH₂Cl₂, and washed with saturated NaHCO₃, saturated NaCl, dried with Na₂SO₄ and concentrated. The residue was purified by ISCO graduate chromatography with 100% CH₂Cl₂ to 5%MeOH: 95% CH₂Cl₂:0.5 mL of 2-aminopropane and then to 10%MeOH: 90% CH₂Cl₂:0.5 mL of 2-aminopropane to give the product. The product was dissolved in 15 mL of MeOH and then added 30 mL of 0.5 N HCl in EtOH. Evaporation of the solvent, and crystallization from MeOH: Et₂O afforded the example 11 as the HCl salt (2.65g, 41 %): Mp 240-2 °C; MS m/z 314 (M + H).

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Bioorg Med Chem Lett. 2012 Jun 15;22(12):4198-202. doi: 10.1016/j.bmcl.2012.04.001. http://www.sciencedirect.com/science/article/pii/S0960894X12004404

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Bioorganic and Medicinal Chemistry Letters, 2014 ,  vol. 24,   5  p. 1303 – 1306

http://www.sciencedirect.com/science/article/pii/S0960894X14000912

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Journal of Medicinal Chemistry, 2011 ,  vol. 54,   13  p. 4781 – 4792

http://pubs.acs.org/doi/full/10.1021/jm200401v