Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists

Synthesis and X-ray Structural Studies of a Substituted 2,3,4,5-Tetrahydro-1H-3-benzazonine and a 1,2,3,5-Tetrahydro-4,3-benzoxazonine

“…For example, some 3-benzazonines with a nine-membered ring show 5-HT2A antagonist activity [5], while the eight-membered ring-containing benzoxazocines display a range of biological properties including analgesic [6] and NK1 (neurokinin receptor) inhibitory activity [7]. Synthetic approaches to these systems often involve rearrangement strategies incorporating a ring expansion [8][9][10][11], although ring formation [12][13][14] and ring cleavage approaches [5,15,16] can also be used.…”

Annulation of Eight- to Ten-Membered Oxaza Rings to the Benzo[b]thiophene System by Intramolecular Nucleophilic Displacement

“…[1] Such compounds are of inherent chemical interest and are also of significance as novel scaffolds for pharmaceutical development, [2][3][4] particularly 8-membered systems. [5][6][7][8][9] As part of some structure-pharmacological activity studies on benzo [b]thiophene-based potentiators of the action of serotonin, we required systems in which amide functionality at the 2-position of the benzo [b]thiophene was incorporated in a semi-flexible ring system, while retaining an electronegative group at the 3-position. Fused medium sized [1,5]-oxaza systems 1 (Scheme 1) were thus considered as synthetic targets.…”

Process Development and Large-Scale Synthesis of NK1 Antagonist

“…In particular, we were interested in the relationship between tachykinin and the activation of the micturition-related refluxes, 3,4) with a view to possible application in the treatment of pollakiuria and urinary incontinence. Recently, the Kyorin Discovery Chemistry group reported the design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5]-oxazocin-5-ones. [5][6][7] Among these, 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5]oxazocin-5-one (1, KRP-103) was identified as an effective NK 1 antagonist, and was promoted for development as a drug candidate for the treatment of pollakiuria and urinary incontinence.…”

“…Recently, the Kyorin Discovery Chemistry group reported the design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5]-oxazocin-5-ones. [5][6][7] Among these, 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b] [1,5]oxazocin-5-one (1, KRP-103) was identified as an effective NK 1 antagonist, and was promoted for development as a drug candidate for the treatment of pollakiuria and urinary incontinence. [5][6][7] As a continuation of this research, a large quantity of 1 was required to support the preclinical and clinical development work.…”

“…Condensation of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (2) 8) with 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3), 9) via acid chloride produced a condensation product (4), which was subjected to nucleophilic intramolecular cyclization to afford pyrimido [4,5-b] [1,5]oxazocine (5). Suzuki coupling reaction of 5 with otolylboronic acid provided the coupled product (6), which was subjected to oxidation to afford a sulfone (7).…”