Reference_01_08_2014_165529

By Kusakabe, Ken-Ichi; Yoshida, Hiroshi; Nozu, Kohei; Hashizume, Hiroshi; Tadano, Genta; Sato, Jun; Tamura, Yuusuke; Mitsuoka, Yasunori

From U.S. Pat. Appl. Publ. (2012), US 20120059162 A1 20120308, Language: English, Database: CAPLUS

Title compds. I [A = (un)substituted (non)arom. hydrocarbon or heterocyclic ring; L = single bond, C(O)NH, NHC(O), S(O), etc.; X, Y, V, and W = the combination of (-N=, =CR1-, =N-, CR7=), (-CR1=, =N-, =N-, -CR7=), (-N=, =N-, =N-, - CR7=), or (-N=, =CR1-, -O-, -N=); Z = NH2, NH-alkyl, OH, etc.; R1 = H, halo, OH, CN, NO2, etc.; R6 = H, halo, OH, (un)substituted alkyl, aryl, etc.; R7 = H, halo, CN, (un)substituted alkyl, etc.; R8 = H, halo, OH, (un)substituted alkoxy, etc.], and their pharmaceutically acceptable salts, are prepd. and disclosed as TTK inhibitors. Thus, e.g., II was prepd. by a multistep procedure (prepn. given). Select I were evaluated in TTK and A549 assays, e.g., II demonstrated an IC50 value of 0.0347 μM and >1.0 to ≤10 μM, resp.

58. Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

By Rueeger, Heinrich; Lueoend, Rainer; Rogel, Olivier; Rondeau, Jean-Michel; Mobitz, Henrik; Machauer, Rainer; Jacobson, Laura; Staufenbiel, Matthias; Desrayaud, Sandrine; Neumann, Ulf

From Journal of Medicinal Chemistry (2012), 55(7), 3364-3386. Language: English, Database: CAPLUS, DOI:10.1021/jm300069y

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of primeand nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by mol. modeling studies and by x-ray anal. of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compds. to a physicochem. property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, highly potent compds. were obtained, such as I, with enzymic and cellular IC50 values of 2 and 50 nM, resp., and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant redn. of brain Aβ levels.

~10 Citings

Copyright © 2014 American Chemical Society (ACS). All Rights Reserved.

59. Solution-phase synthesis and evaluation of tetraproline chiral stationary phases

By Dai, Zhi; Ye, Guozhong; Pittman, Charles U.; Li, Tingyu

From Chirality (2012), 24(4), 329-338. Language: English, Database: CAPLUS, DOI:10.1002/chir.22001

Fmoc-Pro-Pro-Pro-Pro-OH and Fmoc-Pro-Pro-Pro-Pro-NMe(CH2)3CO2H were prepd. on multigramm scale by a soln.- phase synthetic route; the two peptides were attached to (methylamino)propylated silica gel, deprotected, and acylated with pivaloyl chloride to provide silica gel-bound Me3CCO-Pro-Pro-Pro-Pro-N(Me)CH2CH2CH2R (R = silica) and Me3CCO-Pro-Pro-Pro-Pro-NMe(CH2)3CONHCH2CH2CH2R (R = silica) as chiral stationary phases for the sepn. of a variety of org. analytes. The resoln. of analytes with the two chiral stationary phases prepd. from tetraproline peptides were compared to the resoln. of analytes by tetraproline synthesized on (methylamino)propylated silica gel; all three silica-bound tetraproline peptides had similar chromatog. performance for resolving the 53 model analytes tested. This suggests that the soln.-phase synthesis of oligoprolines, which allows for the specific benefits of good batch reproducibility, selector homogeneity, and possibly low cost, is a feasible alternative to the solid-phase synthesis of oligoproline CSPs. © 2012 Wiley Periodicals, Inc.

~4 Citings

Copyright © 2014 American Chemical Society (ACS). All Rights Reserved.

61. Preparation of pyrimidin-4(3H)-one derivatives as delta-5-desaturase inhibitors

By Matsunaga, Nobuyuki; Igawa, Hideyuki; Suzuki, Hideo; Okamoto, Rei; Furukawa, Hideki; Murayama, Kyoko From PCT Int. Appl. (2012), WO 2012011592 A1 20120126, Language: Japanese, Database: CAPLUS

The title compds. [I; ring a = (un)substituted 6-membered arom. ring; X1 = a bond, O; R1 = 3- to 11-membered cyclic groupsubstituted C1-6 alkyl, each (un)substituted 3- to 11-membered heterocyclyl or C3-11 cycloalkyl; R2 = H, halo-(un)substituted C1- 6 alkyl; R3 = X2-R5, each (un)substituted C1-6 alkyl, C3-11 cycloalkyl, or 3- to 11-membered nonarom. heterocyclyl; X2 = O, S, SO2, NR6; R6 = each (un)substituted C1-6 alkyl or 3- to 11-membered cyclic group; R4 = each (un)substituted C1-6 alkyl or 3- to 11-membered cyclic group; R6 = H, (un)substituted C1-6 alkyl] or salts thereof are prepd. These compds. such as 6- (pyridin-4-yl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)- one, 6-(1H-pyrazol-4-yl)-3-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidin-4(3H)-one, 6-(furan-3-yl)-3-[4- (2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one, 6-(pyridazin- 4-yl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one, 6- (2-oxo-1,2-dihydropyridin-4-yl)-3-[6-(2,2,2- trifluoroethoxy)pyridin-3-yl]pyrimidin-4(3H)-one, and 1-[4-(2,2,2- trifluoroethoxy)phenyl]-4,4'-bipyrimidin-6(1H)-one derivs. have δ-desaturase-inhibiting activity and are useful in the prevention/treatment of conditions such as arteriosclerosis, diabetes, and obesity, and have excellent efficacy. Thus, a soln. of 3 g (2Z)-3-amino-3-[1-(4-methoxybenzyl)-1H-pyrazol-4- yl]prop-2-enoic acid Et ester and 1-Isothiocyanato-4-(2,2,2- trifluoroethoxy)benzene in 50 mL DMF was treated with NaH (60% oil dispersion, 876 mg) at 0°, stirred at 0° for 2 h, and treated with 1 N aq. HCl soln. to give, after workup and silica gel chromatog., 2.2 g 6-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]- 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3- dihydropyrimidin-4(1H)-one (II). A mixt. of 2.2 g II, 0.558 mL iodoethane, 0.934 g K2CO3, and 40 mL THF was stirred at 70° for 2 h, and treated with 1 N aq. HCl soln. to give, after workup and silica gel chromatog., 2.15 g 2-(ethylsulfanyl)-6-[1-(4- methoxybenzyl)-1H-pyrazol-4-yl]-3-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (III). A soln. of 2.15 g III in 15 mL CF3CO2H was stirred at 70° overnight, treated with toluene, concd. under reduce pressure, and treated with diisopropyl ether for solidification to give 1.76 g 2- (ethylsulfanyl)-6-(1H-pyrazol-4-yl)-3-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (IV). IV in vitro inhibited the activity of δ-5-desaturase by 101% at 10 μM in rat liver microsome and by 103% at 1 μM in HepG2 cells. A tablet formulation contg. IV was described.

Copyright © 2014 American Chemical Society (ACS). All Rights Reserved.

63. Kinetic Resolution of Secondary Alcohols Using Amidine-Based Catalysts

By Li, Ximin; Jiang, Hui; Uffman, Eric W.; Guo, Lei; Zhang, Yuhua; Yang, Xing; Birman, Vladimir B. From Journal of Organic Chemistry (2012), 77(4), 1722-1737. Language: English, Database: CAPLUS, DOI:10.1021/jo202220x

Kinetic resoln. of racemic alcs. has been traditionally achieved via enzymic enantioselective esterification and ester hydrolysis. However, there has long been considerable interest in devising nonenzymic alternative methods for this transformation. Amidine-based catalysts (ABCs), a new class of enantioselective acyl transfer catalysts developed in our group, have demonstrated, inter alia, high efficacy in the kinetic resoln. of benzylic, allylic, and propargylic secondary alcs. and 2- substituted cycloalkanols, and thus provide a viable alternative to enzymes. Both review material and new data are presented.

~21 Citings

Copyright © 2014 American Chemical Society (ACS). All Rights Reserved.

64. Preparation of 2,8-diazaspiro[4,5]decan-1-one derivatives as inhibitors of hormone sensitive lipase

By Ackermann, Jean; Conte, Aurelia; Hunziker, Daniel; Neidhart, Werner; Nettekoven, Matthias; Schulz-Gasch, Tanja; Wertheimer, Stanley

From PCT Int. Appl. (2012), WO 2012007367 A1 20120119, Language: English, Database: CAPLUS

The title compds. I [R1 = alkyl, cycloalkyl, alkyl-cycloalkyl, etc.; R2 = Ph, pyridinyl, pyrazinyl, etc.; R3 = H, alkyl, cycloalkyl, etc.; A = (CH2)n, CO, or SO2, wherein n= 0, 1 or 2; or pharmaceutically acceptable salts thereof] were prepd. For example, to a soln. of 1-benzyl-3-piperidone-4-carboxylic acid benzyl ester (4.7 g) in DMF (50 ML, 0°) was added potassium tert-butoxide (4.23 g) and stirred [room temp., 30 min], and then a soln. of 1-bromo-2-methoxy-ethane (3.4 ML) in DMF (10 ML) was added followed by the addn. of NaI (1.35 g) and stirred [80°, 2 h → 50°, overnight] to give II (2.17 g). To a soln. of II (774 mg) in MeOH (5 ML, 0°) was added NaBH4 (110 mg) and stirred [room temp., 4 h] to provide III (610 mg). To a soln. of III (618 mg) and 4-(trifluoro-methoxy)aniline (516 μL) in toluene (5 ML) under an argon atm. at room temp., was added dimethylaluminium chloride (0.9M in heptane, 4.27 ML) and the mixt. was refluxed for 4 h afforded IV (620 mg). The title compds. I had IC50 values between 0.0001 μM and 1000 μM in the HSL enzyme inhibition assay. Compds. I were claimed useful for treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity. Pharmaceutical formulations comprising I were disclosed.