1064206-86-5Relevant articles and documents
SUBSTITUTED 6, 7-DIALKOXY-3-ISOQUINOLINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASE 10 (PDE 10A)
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Paragraph 0379, (2015/06/17)
The invention relates to compounds of the formula or a pharmaceutically acceptable salt thereof, wherein R′, R1 through R7 and Ar are as defined herein. These compounds are useful as inhibitors of phosphodiesterase 10 (PDE10A) which are useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type II diabetes, metabolic syndrome, glucose intolerance, pain and ophthalmic diseases.
Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors
Leese, Mathew P.,Jourdan, Fabrice L.,Major, Meriel R.,Dohle, Wolfgang,Hamel, Ernest,Ferrandis, Eric,Fiore, Ann,Kasprzyk, Philip G.,Potter, Barry V. L.
, p. 85 - 108 (2014/01/17)
A structure-activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxyaryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7-methoxy-2-(3- methoxybenzyl)-6-sulfamoyloxy-1,2,3, 4-tetrahydroisoquinoline (20 c) GI50=2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4- tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis- sulfamate Copyright
COMPOUND
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Page/Page column 190, (2008/12/04)
The present invention provides a compound of Formula (I) or Formula (Il) wherein A is selected from CR10R11, -S(=O)2-, -NR12-,and C=O, wherein R10 and R11 independently selected from H, -OH, hydrocarbyl, -CN, -NO2, and halogens, R12 is selected from H and hydrocarbyl; B is selected from (CR13R14)1-3, C=O, CR15R16C=O, -S(=O)2-, -NR17- and -NR18-C(=O)-, wherein each of R13, R14, R15 and R16 is independently selected from H, -OH, hydrocarbyl, -CN, -NO2, and halogens, R17 and R18 are independently selected from H and hydrocarbyl; R1 is selected from OH, O-hydrocarbyl, O-heterohydrocarbyl, -SO2-hydrocarbyl, -CH=CH2, halogen, -OSO2NR19R20, -C(=O)-NR21R22, -NR23-C(=O)H and -NR35R36; wherein each of R19, R20, R21, R22, R23, R35 and R36 is independently is selected from H and hydrocarbyl; R2 is selected from H, -O-hydrocarbyl, -S-hydrocarbyl, hydrocarbyl, -CN, -NO2, and halogens, R3 is selected from Formula (A), Formula (B), Formula (C), Formula (D) wherein each of R4, R5, R6, R7 and R8 is independently selected from H, -OH, hydrocarbyl, -O-hydrocarbyl, -COOH or an ester thereof, halocarbyl, -O-halocarbyl, acyl, -O-acyl, -NR29-acyl, -O-SO2NR19R20, -NR30R31, -NR32SO2R33, -CN, -NO2, and halogens, R9 is selected from H and hydrocarbyl, and each R29 to R33 is independently selected from H and hydrocarbyl; and wherein two or more of R4, R5, R6, R7, R8 and R9 may together form a ring; wherein when R1 is OH and R3 is of Formula (D), (i) at least one of R4, R5, R6, R7 and R8 is independently selected from halocarbyl, -O-halocarbyl, -O-acyl, -NR29-acyl, -O- SO2NR19R20, -NR30R31, -NR32SO2R33, -CN, and halogens, or (ii) two or more of R4, R5, R6, R7 and R8 together form a ring, or (iii) at least three of R4, R5, R6, R7 and R8 are independently selected from -OH, hydrocarbyl, -O-hydrocarbyl, halocarbyl, -O-halocarbyl, -O-acyl, -NR29-acyl, -O-SO2NR19R20, -NR30R31, -NR32SO2R33, -CN, -NO2, and halogens; wherein h is an optional bond, wherein G is CR24R25, wherein R24 and R25 independently selected from H, -OH, hydrocarbyl, -CN, -NO2, and halogens, or wherein when h is present G is CR24, wherein R24 is selected from H, -OH, hydrocarbyl, -CN, -NO2, and halogens; n is 0, 1 or 2, each D is independently selected from O, NR26 and CR27R28, wherein each R26 is independently selected from H and hydrocarbyl; and each R27 and R28 is independently selected from H, -OH, hydrocarbyl, -CN, -NO2, and halogens.
