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Page 41

~2 Citings

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

53. Preparation of triazine-oxadiazoles for the treatment of chronic pain

By Barker, Oliver; Bentley, Jonathan; Bock, Mark G.; Cain, Thomas; Chovatia, Praful; Dod, Jennifer Ruth; Eustache, Florence; Gleave, Laura; Hargrave, Jonathan; Heifetz, Alexander; et al

From PCT Int. Appl. (2012), WO 2012035023 A1 20120322, Language: English, Database: CAPLUS

The title compds. I [R1 = H, halo, alkyl, haloalkyl; R2 = H, alkyl, haloalkyl, etc.; or R1 and R2, together with the atoms to which they are attached, form (un)substituted 4-7 membered, satd. or partially satd. heterocyclic ring; R = halo, alkyl, haloalkyl, etc.; R3 = -LY (wherein L = a direct bond, C(O), NH, N(alkyl), etc.; Y = (un)substituted cycloalkyl, aryl, heteroaryl, etc.); R8 = H and R9 = H, alkoxyalkyl, alkyl, etc.; m = 0-1; n = 0-2; with the proviso], useful for treating Nav1.7-mediated disorders such as chronic pain, were prepd. thus, reacting 4-amino-N-hydroxy-6- (methyl-phenyl-amino)-[1,3,5]triazine-2-carboxamidine with 2- furoyl chloride, afforded 50% II which showed IC50 of 2426 nM when tested for their potential to block Nav1.7 channels. pharmaceutical compns. comprising compd. I, alone or in combination with other therapeutic agent, were disclosed.

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54. Terpenoid analogues and uses thereof for treating neurological conditions

By Reed, Mark A.; Weaver, Donald; Sun, Shengguo; McLellan, Alexander; Lu, Erhu

From PCT Int. Appl. (2012), WO 2012034232 A1 20120322, Language: English, Database: CAPLUS

The present application provides a terpene analog I [Y is an (un)substituted C1-20-alkylene, C(:O), SO, SO2, or absent; X is H, OR1, N(R2)2, (un)substituted C1-20-alkyl or (un)substituted heterocycle (e.g., heteroaryl), wherein when Y is absent X is not H; R1 is H, (un)substituted C1-20-alkyl or (un)substituted CH2-aryl; each R2 is independently H, (un)substituted C1-20- alkyl, aryl, OR1, CN, C(:O)R3; R3 is a (un)substituted C1-20-alkyl or an (un)substituted aryl; and, W is H, (un)substituted C1-20- alkyl or (un)substituted aryl] or II [R4 is OH, alkoxyl, aryloxy, NH2, SO2-aryl, SO2-alkyl, SO-alkyl, SO2NH-aryl, NHSO2-aryl, NH-alkyl, N(alkyl)2, NHCO-aryl; W, R5 and R6 are each independently H, (un)substituted C1-20-alkyl, (un)substituted aryl or (un)substituted alkylaryl] a pharmaceutically acceptable isomer, salt or ester thereof, and methods and uses thereof for treating neurol. conditions such as pain in general and neuropathic pain. These terpene analogs can also be used to treat other elec. disorders in the central and peripheral nervous system. Also provided are methods of synthesizing the terpene analogs of Formula I. Thus, α-phenylgeranylamine (III) was prepd. from geranial via arylation with PhLi in THF; Mitsunobu amination with phthalimide in THf contg. DIAD and PPh3; aminolysis with MeNH2 in EtOH. The effect of III on sodium channels in rat DRG neurons was detd. [IC50 = <0.1 mM]. Thus, N-geranyl-2-hydroxybenzamide (IV) was prepd. from geranylamine via amidation of PhCO2H in THF contg. DPPA and Et3N. The analgesic effect of IV on zebrafish was detd. [EC50 = 134 μM].

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55. Preparation of heteroarylmethyl amides as HDL-raising agents

By Hebeisen, Paul; Zoffmann Jensen, Sannah; Matile, Hugues; Roever, Stephan; Wright, Matthew From PCT Int. Appl. (2012), WO 2012032018 A1 20120315, Language: English, Database: CAPLUS

The present invention relates to compds. I [A1-A3 = N or CH, provided that at least one of A1-A3 = N and at least one of A1- A3 = CH; R1 = alkyl, cycloalkyl, hydroxyalkyl, etc.; R2, R6 = H, halo; R3, R5 = H, alkyl, alkoxy, etc.; R4 = H, alkoxy, halo, etc.; or R4 and R5 together with the carbon atoms they are attached to form (un)substituted 5-6 membered carbocycle or 5-6 membered heterocycle contg. 1-3 heteroatoms; R7, R71 = H, alkyl; R8 = (un)substituted 5-6 membered heteroaryl contg. 1-3 heteroatoms selected from N, O and S], and to pharmaceutically acceptable salts thereof, their manuf., pharmaceutical compns. contg. them and their use as medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, such as particularly dyslipidemia, atherosclerosis and cardiovascular diseases. One-hundred-five compds. I were prepd. and formulated. Thus, reacting 4-(4-chlorophenyl)-5-(2,2,2- trifluoroethoxy)pyridine-2-carboxylic acid with 3-methoxy-5- isoxazolemethanamine hydrochloride afforded 92% II. Compds. I showed values below 50% inhibition in both the CB1 and CB2 receptor assay at a concn. of 10 μM. Compds. I were also tested for ABCA1 protein increasing efficacy and for their ability to stimulate cholesterol efflux (data given).

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56. Preparation of aminoimidazolpyrazinylbenzamide derivatives and analogs for use as TTK inhibitors

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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.

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Page 45

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

57. Preparation of phenylethynylphenylalkylacetamide derivatives and analogs for use as acetyl-CoA carboxylase inhibitors

By Roth, Gerald Juergen; Fleck, Martin; Heine, Niklas; Kley, Joerg; Lehmann-Lintz, Thorsten; Neubauer, Heike; Nosse, Bernd

From PCT Int. Appl. (2012), WO 2012028676 A1 20120308, Language: English, Database: CAPLUS

Title compds. I [M = (un)substituted Ph or monocyclic arom. carbocyclic ring contg. 1 to 3 heteroatoms selected from N, O, or S; Q = H or alkyl; T = alkyl, alkenyl, alkynyl, carbocyclyl, aryl, etc.; X = (un)substituted alkylene; Y = C(O) or SO2; R1 = (un)substituted aryl or heteroaryl; with provisions], and their pharmaceutically acceptable salts, are prepd. and disclosed as acetyl-CoA carboxylase (ACC) inhibitors. Thus, e.g., II was prepd. by reductive amination of 4-bromophenylacetone with ammonia followed by acetylation with acetyl chloride, iodination, and coupling with 1-chloro-4-ethynylbenzene. Select I were evaluated in ACC2 activity (spectrophotometric

384 well) assays, e.g., II demonstrated an IC50 value of 0.53 μM.

~0 Citings

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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

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

60. Preparation of azabenzimidazole derivatives and analogs for use as anaplastic lymphoma kinase inhibitors

By Bode, Christiane M.; Cheng, Alan C.; Choquette, Deborah; Lewis, Richard T.; Potashman, Michele H.; Romero, Karina; Stellwagen, John C.; Whittington, Douglas A.

From PCT Int. Appl. (2012), WO 2012018668 A1 20120209, Language: English, Database: CAPLUS

Title compds. I [W = H, halo, alkyl, etc.; X = N, CH, COH, COCF3, CNO2, CCN, etc.; Y = (un)substituted cycloalkyl or heterocyclyl; Z = aryl, heteroaryl, heterocyclyl, etc.; R3 = H, halo, OH, CF3, alkyl, etc.; with provisions], and their pharmaceutically acceptable salts, are prepd. and disclosed as anaplastic lymphoma kinase inhibitors. Thus, e.g., II was prepd. by a multistep procedure (prepn. given). Select I were evaluated in ALK enzymic inhibition assays, e.g., II demonstrated an IC50 value of <0.05 μM.

~2 Citings

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Page 48

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.

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62. Functional Paracyclophanes: Synthesis of [2.2]Paracyclophanemethyldithiocarbonates Using Thione-Thiol Rearrangement of S,O-Dithiocarbonates (Benzyl Schoenberg Rearrangement) at Mild Conditions

By Frank, Daniel; Nieger, Martin; Friedmann, Christian; Lahann, Joerg; Brase, Stefan

From Israel Journal of Chemistry (2012), 52(1-2), 143-148. Language: English, Database: CAPLUS, DOI:10.1002/ijch.201100079

A pathway to benzylic [2.2]paracyclophane thiol derivs. or related compds. I (R = Ph, R1 = CH2Ph; R = H, R1 = Me; R = H, R1 = CH2Ph) was investigated using the benzyl Schoenberg rearrangement.

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Page 50

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.

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