- MACROCYCLIC AZOLOPYRIDINE DERIVATIVES AS EED AND PRC2 MODULATORS
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The invention relates to modulators of Embryonic Ectoderm Development (EED) and/or Polycomb Repressive Complex 2 (PRC2) useful in the treatment of disorders and diseases associated with EEC and PRC2, being macrocyclic azolopyridine derivatives and compositions thereof of Formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, or tautomer thereof, wherein X1, X2, X3, A1, A2, Y, R1, R2, R3, and R4 are as described herein.
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Paragraph 1138
(2020/10/09)
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- 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity
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The benzimidazole sulfoxide class of antisecretory H+/K+-ATPase inhibitors need to possess high stability under neutral physiological conditions yet rearrange rapidly at low pH to the active sulfenamide 2. Since the initial reaction involves internal nucleophilic attack by the pyridine nitrogen, control of the pyridine pK(a) is critical. In this paper we show that by utilizing the powerful electron-donating effect of a 4-amino substituent on the pyridine, moderated by the electron-withdrawing effect of a 3- or 5-halogen substituent, a combination of high potency (as inhibitors of histamine-stimulated gastric acid secretion) and good stability under physiological conditions can be obtained. Furthermore, the role of the steric interaction between the 3/5-substituents and the 4-substituent in modifying the electron-donating ability of the 4-amino group is exemplified, and additional factors affecting stability are identified. One compound, in particular, 2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)- benzimidazole (3a, SK and F 95601), was chosen for further development and evaluation in man.
- Ife,Dyke,Keeling,Meenan,Meeson,Parsons,Price,Theobald,Underwood
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p. 1970 - 1977
(2007/10/02)
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- Benzimidazoles
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Compounds of structure (I) and pharmaceutically acceptable salts thereof, in which R5 and R6 are the same or different and are each hydrogen, C1-6alkyl or C3-6cycloalkyl or together with the nitrogen atom to which they are attached form an acetidino, pyrrolidino, piperidino, piperazino, N-C1-4alkylpiperazino or morpholino group and one of R7 and R8 is halogen, and the other is hydrogen, halogen or C1-6alkyl; processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric acid secretion.
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