- Decoration of an α-Resorcylate Nucleus as Part of the Manufacture of a Glucokinase Activator
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The need to define a set of processes for the manufacture of a glucokinase activator called for an evaluation of different strategies to differentiate the hydroxyls of an α-resorcylic acid derivative. While direct functionalization proved possible, it did not allow access to crystalline intermediates that offered control over the rejection of process impurities. The strategy taken forward involved the installation of a benzoyl protecting group using careful control of pH in order to achieve useful levels of selectivity. This allowed the remaining α-resorcylate hydroxyl to be functionalized using a Mitsunobu reaction, with liquid-liquid partitioning being used to separate downstream intermediates of interest away from the redox byproducts of this reaction. Downstream challenges that were overcome in order to deliver a commercially viable means of manufacturing the API included developing an amidation reaction with a poorly reactive aminopyrazine coupling partner.
- Hopes, Phillip,Langer, Thomas,Millard, Kirsty,Steven, Alan
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p. 996 - 1006
(2018/07/25)
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- BENZAMIDE COMPOUNDS AS GLUCOKINASE ACTIVATORS AND THEIR PHARMACEUTICAL APPLICATION
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Benzamide compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof useful as Glucokinase activators or modulators are disclosed. The disclosure further relates to
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- Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life
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The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new sc
- Pike, Kurt G.,Allen, Joanne V.,Caulkett, Peter W.R.,Clarke, David S.,Donald, Craig S.,Fenwick, Mark L.,Johnson, Keith M.,Johnstone, Craig,McKerrecher, Darren,Rayner, John W.,Walker, Rolf P.,Wilson, Ingrid
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scheme or table
p. 3467 - 3470
(2011/06/24)
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- N- ( PYRAZOLE- 3 -YL) -BENZAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS
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Novel heterocyclic compounds of the formula (I) in which R1, R2, R3, R4, R5, R6, R7, Alk and D have the meanings indicate in Claim 1, are activators of glucokinase and can be used for the prevention and/or treatment of Diabetes Typ 1 and 2, obesity, neuropathy and/or nephropathy.
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Page/Page column 43
(2009/05/30)
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- 1, 3 - DIHYDROXY SUBSTITUTED PHENYLAMIDE GLUCOKINASE ACTIVATORS
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Compounds are provided which are glucokinase activators and thus are useful in treating diabetes and related diseases and have the structure wherein in the ring represents one or two double bonds; R1 is alkyl, aryl, arylalkyl, heteroaryl, or he
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- NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R4 is —(CH2)n-Z-(CH2)m—PO(OR7)(OR8), —(CH2)nZ-(CH2)m—PO(OR7)Rg, —(CH2)n-Z-(CH2)m—OPO(OR7)Rg, —(CH2)nZ—(CH2)m—OPO(R9)(R10), or —(CH2)nZ—(CH2)m—PO(R9)(R10);R5 and R6 are independently selected from H, alkyl and halogen;Y is R7(CH2)s or is absent; andX, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
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Page/Page column 57
(2008/06/13)
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- HETEROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Compounds of formula (I) wherein R1, R2, R3, and HET-1 are as described in the specification, and their salts, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. P
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Page/Page column 44-45
(2008/06/13)
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- 2 -HETEROCYCLYLOXYBENZOYL AMINO HETEROCYCLYL COMPOUNDS AS MODULATORS OF GLUCOKINASE FOR THE TREATMENT OF TYPE 2 DIABETES
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Compounds of formula (I) wherein R1, HET-1 and HET-2 are as described in the specification, and their salts, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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Page/Page column 57-58
(2010/11/25)
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- HETEROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Compounds of formula (I), wherein R1, R4, HET-1 and HET-2 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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- 2-PHENYL SUBSTITUTED IMIDAZOL [4 , 5B] PYRIDINE/ PYRAZINE AND PURINE DERIVATIVES AS GLUCOKINASE MODULATORS
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Compounds of Formula (I), wherein R1- R10, A and X1 to X3 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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- HETROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Compounds of Formula (I) wherein: R1 is hydroxymethyl; R2 is selected from -C(O)NR4R5, SO2NR4R5, S(O)pR4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R4 is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R5 is hydrogen or (1-4C)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.
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- BENZOYL AMINO PYRIDYL CARBOXYLIC ACID DERIVATIVES USEFUL AS GLUCOKINASE (GLK) ACTIVATORS
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A compound of Formula (I): Formula (I) wherein: R1 is selected from hydrogen and C1-4alkyl; R2 is selected from: R4-C(R5aR5b)- , R4=C(R6)- and R7aC(R7b
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Page/Page column 26
(2008/06/13)
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- BENZOYL AMINO PYRIDIL CARBOXYLIC ACID DERIVATIVES AS GLUOKINASE ACTIVATORS
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Compounds of Formula (I) wherein: R1-X- is selected from: methyl, methoxymethyl and Formula (X); R2 is selected from hydrogen, methyl, chloro and fluoro; n is 1 or 2; or a salt, pro-drug or solvate thereof, are described. Their use a
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Page/Page column 25-26
(2008/06/13)
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- PYRIDINE CARBOXYLIC ACID DERIVATIVES AS GLUCOKINASE MODULATORS
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A compound of Formula (I): wherein: A is phenyl or a 5- or 6-membered heteroaryl ring, optionally substituted; R1 and R2 are selected from hydrogen and methyl; with the proviso that at least one of R1 and R2 is
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Page/Page column 37
(2010/02/11)
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- BENZOYL AMINO PYRIDYL CARBOXYLIC ACID DERIVATIVES USEFUL AS GLUCOKINASE (GLK) ACTIVATORS
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Compounds of Formula: (I); wherein: R1 is selected from: fluoro, chloro, C1-3alkyl and C1-3alkoxy; R2-X- is selected from: methyl, methoxymethyl and Formula: (X); n is 0,1 or 2; or a salt, pro-drug or solvate thereof are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.
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Page/Page column 26-27
(2010/02/12)
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