Despite having potent activity and good solubility showed in

Despite having potent activity and good solubility, showed inhibitory activities against cytochrome P450 (CYP) 2C8, 2C9, and 2C19 with an IC value of less than 10 μM. In general, the specificity of the compound to the target should improve and the off-target risk such as CYP inhibitory activity should decline by increasing the molecule’s three-dimensionality (defined as Fraction of sp (Fsp), for example). Against such a background, we were interested in spirocyclic structures with three-dimensionality higher than a piperidine or a piperazine ring. Spirocyclic structures have attracted attention in drug discovery chemistry in recent years and they can be also found in launched drugs. On the other hand, no GPR119 agonist possessing a spirocyclic structure as the right side moiety has been reported so far. We expected that both novelty and reduction of CYP inhibitory activity could be accomplished simultaneously by introducing a spirocyclic structure at the right side. In our design, a cyclohexane ring with high structural similarity to the piperidine ring was adopted. The spiro center was set at the 4-position of the cyclohexane ring, a position in which the substituent should be able to overlap the carbamate group of the piperidine ring (). As shown in , ketal compound with a spiro[4.5] system was obtained from commercially available spiro ketone as a starting material. Olefination of followed by esterification, hydrogenation of olefin, and reduction of ester with LiAlH gave alcohol , which was coupled with 4-hydroxy-,-dimethylbenzamide via mesylation to yield . Compound was exposed under acidic conditions and the resulting ketone was converted to compound with a spiro[5.5] system via ketalization with 1,3-propanediol. Compounds – were synthesized via ketone which was obtained from alcohol (). For the preparation of –, ketone was converted to alcohols and via introduction of four- or three-carbon units with the corresponding phosphonium ylides, respectively. Treatment of and with Bisindolylmaleimide IV (such as BF·OEt or Amberlyst-15) furnished spiro ethers of spiro[5.5] and spiro[4.5] systems, respectively. The resulting mixtures of and isomers were separated by silica-gel chromatography ( and from , and from ). For the preparation of compound , reaction of with trimethylsulfonium iodide using KO--Bu gave epoxide with high diastereoselectivity (93:7 d.r.). Subsequent reaction with lithiated isobutyric acid afforded spiro lactone . Reduction with LiAlH and subsequent mesylation with pyridine provided spiro ether while maintaining high diastereomeric ratio. For the preparation of compound , alcohol , which was synthesized from diol via one-carbon elongation, was treated with Amberlyst-15 and purified by silica-gel chromatography to yield the desired spiro ether . Benzyl groups of , , , , , and were removed by hydrogenation in the presence of Pd-C. The resulting alcohols were mesylated and coupled with 4-hydroxy-,-dimethylbenzamide to yield the final products –. The synthesis of is shown in . Commercially available ketone was converted to tetrahydropyranyl (THP) ether by Wittig’s reaction followed by reduction of the resultant carboxylic acid and protection with 3,4-dihydro-2-pyran (DHP). Hydrogenation of gave intermediate . Lithiation of followed by reaction with 3-chloro-2-methylpropene gave the desired ester with high diastereoselectivity (92:8 d.r.). Reduction of with LiAlH and subsequent treatment with -toluenesulfonic acid monohydrate furnished spiro ether , which was coupled with 4-hydroxy-,-dimethylbenzamide via mesylation to provide . The stereochemistry of and was determined by X-ray crystallography of the derivatives and that of the other spirocyclic compounds –, and was estimated by H NMR spectra. The results of conversion of the right side of into various spirocyclic structures are shown in . Interestingly, compound having a spiro[5.5] system showed agonistic activity with an EC of 27 nM. For the purpose of reducing lipophilicity, we synthesized a propylene ketal and an ethylene ketal possessing two ether oxygen atoms on the right ring. Compound , possessing a spiro[5.5] system, showed agonistic activity equivalent to that of , and which had a spiro[4.5] system; the agonistic activity was only about three fold less than . Moreover, replacing one of two ketal oxygen atoms of and with a methylene group was tolerated ( and vs , and vs ).